Pharmacology for Therapists

Course Description: This course utilizes the text: Orthopedic Clinical Advisor by Derrick Sueki, PT, DPT, GCPT, OCS and Jacklyn Brechter, PhD, PT. This course will help you access the information you need to confidently handle the pharmacology that accompanies a therapy diagnosis. This course covers: ACE inhibitors, Alpha-Agonists, Alpha-Blockers, Alternative Medications, Angiotensin II Receptor Blockers, Antiarrhythmics, Antiasthmatic, Antibacterial, Anticholinergics, Anticonvulsants, Antidepressants, Antiemetics, Antifungal, Antihelminthics, Antihistimines, Antilipidemics, Antineoplastics, Antiprotozoals, Antipsychotics, Antivirals, Anxiolytics, Beta-Agonists, Beta-Blockers, Calcium Channel Blockers, Cholinergic Agonists, CNS Dopaminergic Agonists, Corticosteroids, Diuretics, Drugs and Blood Clotting, Drugs and Bone Formation, Drugs and Substance Abuse, Drugs and the Thyroid Gland, Female Hormones, Gastrointestinal Drugs, Hemopoietic Drugs, Hypoglycemic Drugs I, Hypoglycemic Drugs II, Immunomodulators, Local Anesthetics, Male Hormones, Miscellaneous Vasodilators, Nonnarcotic Analgesics, Nonsteroidal Antiinflammatory Drugs, Opioid or Narcotic Analgesics, Over-The-Counter Drugs, Sedatives and Hypnotics, and Skeletal Muscle Relaxants.

Each drug section will cover: Common Drugs Mechanism of Action Indications Examples of Common Dosages Administration Contraindications Common Adverse Reactions Drug Interactions Implications for Therapists

Methods of Instruction: Online course available via internet

Target Audience: Physical Therapists, Physical Therapist Assistants, Occupational Therapists, Occupational Therapist Assistants and Athletic Trainers

Educational Level: Intermediate

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Prerequisites: None Course Goals and Objectives: At the completion of this course, participants should be able to: 1. Identify drug names and therapeutic considerations of drug actions 2. Recognize the classification of drugs 3. Identify common types of ACE Inhibitors 4. Recognize implications for therapists of Alpha-Blockers 5. Recognize common drug contraindications for Antiarrhythmic Drugs 6. Recognize drug interactions for Antiasmatic Drugs 7. Identify the indications for using Antidepressant Drugs 8. Recognize implications for therapists of Antineoplastic Drugs 9. Differentiate between indications for Calcium Channel Blockers 10. Recognize contraindications for CNS Dopaminergic Agonists 11. Identify the mechanisms of action for Diuretics 12. Identify the implications for therapists of Thyroid Drugs 13. Identify the implications for therapists of Hypoglycemic Drugs 14. Recognize common adverse reactions of Vasodilators 15. Identify the implications for therapists of Skeletal Muscle Relaxants

Criteria for Obtaining Continuing Education Credits: A score of 70% or greater on the written post-test

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DIRECTIONS FOR COMPLETING

THE COURSE:

1. This course is offered in conjunction with and with written permission of Elsevier Science Publishing.

2. Review the goals and objectives for the module. 3. Review the course material. 4. We strongly suggest printing out a hard copy of the test. Mark your

answers as you go along and then transfer them to the actual test. A printable test can be found when clicking on “View/Take Test” in your “My Account”.

5. After reading the course material, when you are ready to take the test, go back to your “My Account” and click on “View/Take Test”.

6. A grade of 70% or higher on the test is considered passing. If you have not scored 70% or higher, this indicates that the material was not fully comprehended. To obtain your completion certificate, please re-read the material and take the test again.

7. After passing the test, you will be required to fill out a short survey. After the survey, your certificate of completion will immediately appear. We suggest that you save a copy of your certificate to your computer and print a hard copy for your records.

8. You have up to one year to complete this course from the date of purchase.

9. If we can help in any way, please don’t hesitate to contact us utilizing our live chat, via email at info@advantageceus.com or by phone at 405-974-0164.

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Pharmacology

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873Introduction to Pharmacology Pharmacology

AUTHOR: WOLFGANG VOGEL

INTRODUCTION TO PHARMACOLOGY

DRUG A drug is a chemical substance that medi-cal professionals are allowed to use to treat, diagnose, prevent, or cure diseases and medical conditions. This permis-sion is granted by the Food and Drug Administration (FDA ) after the drug com-pany has demonstrated that the drug is effective and relatively safe, using animal studies and human clinical trials.

Alternative medications, such as herbal preparations, are treated like “food,” and thus the manufacturer is only required to state content but not amounts and does not have to prove scientifically or clinically efficacy or toxicity. Manufacturers often make unsub-stantiated claims, and varying amounts and fraud are encountered with these “drugs.”

DRUG NAME A drug has three names, as follows: • Chemical name (e.g., 7-chloro-1,

3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one).

• Generic or scientific name (e.g., diazepam): Only one name per drug and often written in parentheses after the brand name.

• Brand name (e.g., Valium): Different brand names can be used for the same drug.

BRAND NAME VERSUS GENERIC DRUG A brand name drug is the original drug manufactured by a company while the pat-ent is in force and also after the patent has expired. A generic drug is manufactured by other companies after the patent has expired. A generic drug is a copy of a brand name drug in composition, dosage, safety, strength, administration, performance, and intended use. A generic drug contains the same active ingredient and must show the same bioavailability as a brand name drug but looks different. Unless a physician spe-cifically prescribes or recommends one or the other, they are interchangeable.

THERAPEUTIC CONSIDERATIONS OF DRUG ACTION Therapeutic effects are the intended beneficial actions. Adverse effects are unwanted actions and must be evaluated as to the possibility and more importantly, probability. Adverse effects can have the following characteristics:

• Range from mild to severe • Reversible to irreversible • Avoidable (caused by mistake) or

unavoidable • Often reduced or reversed when

recognized early

Adverse reactions can be classified as the following

• Side effects, which are associated with a specific drug, are seen in all individ-uals at different degrees and are often predictable.

• Idiosyncratic reactions, which are caused by a biochemical peculiarity of an individual that becomes appar-ent only after drug exposure, are seen only in few patients, do not involve the immune system, and are unpredictable.

• Allergic reactions, which are caused by an immunological peculiarity of an individual that becomes only apparent after drug exposure, are seen in only a few patients and are unpredictable.

PLACEBO A placebo is an inert substance that can cause “beneficial” and “adverse” reactions. Drugs can also, in addition to their real effects, produce “placebo” effects based on a health professional’s attitudes and a patient’s expectations.

TREATMENT OUTCOME Treatment outcome can never be pre-dicted with certainty for individual patients and depends on the following: • Drug: Physical and chemical properties

(structure) are exactly known; this not a variable factor.

• Patient: Most patients respond similarly to drugs, but differences in genetic back-grounds (family history), environment (polluted air), habits (smoking, physi-cal fitness), and compliance can cause unpredictable drug responses; this is a variable factor.

• Health professional: Most health pro-fessionals are well trained, but differ-ences exist in knowledge (“relevant and irrelevant facts”), experience, atti-tude (placebo), and instructions (writ-ten) provided; this is a variable factor.

DRUG USE The use of a particular drug is based on benefit versus risk: The benefits of the use of a drug MUST outweighs the risks to the patient.

Some abbreviations found on drug pre-scriptions are as follows:

d dayq everyq4h every 4 hoursqd every day, take one

dose a dayqod every other daybid twice a daytid three times a dayqid four times a daytiw three times a weekhs at bed timepc after mealsad lib, prn use when or as needed

IMPLICATIONS FOR THE PHYSICAL THERAPIST • Patients today are often afraid to take

medications because of widely publi-cized adverse reactions. Advise patients that drugs are given only when the ben-efit outweighs the risk and should be taken as recommended. Many adverse reactions are only listed as possibilities for legal reasons and their actual occur-rence is often doubtful. Tell patients that taking a drug is like driving a car: There is a definite benefit involved, but there is always the possibility of an accident.

• Advise patients that many adverse reac-tions are minor and often disappear if the drug is discontinued early on. Patients should not “look” for adverse reactions but should be aware of such reactions when they occur and then should con-tact the physician immediately.

• Inform patients that humans are individ-uals and that therapeutic and adverse reactions can vary from individual to individual. If no therapeutic effect is experienced or an adverse reaction manifests, patients should contact the physician.

• Inform patients that generic drugs look different from brand name drugs but contain exactly the same active ingre-dients and are as effective as the brand name drug, with very few exceptions as indicated by the physician.

PHARMACODYNAMICS

INTRODUCTION Pharmacodynamics describes the inter-action between a drug and a special part of a cell called a receptor. This interaction produces a biochemical and/or physiolog-ical effect and is referred to as the phar-macological response. This response can be a therapeutic or an adverse reaction.

RECEPTOR A receptor is usually a small area (specific chemical configuration, active site) of a macromolecule on or in a cell (in rare cases, the area can be extracellular such as on blood constituents). This macromole-cule is mostly a protein . When stimulated, specific biochemical and/or physiological responses occur.

Receptors are constantly synthesized by the nucleus, transported to their respective sites, and later on degraded. Receptors determine specificity (which drug is going to be bound to which recep-tor, the drug is the “key” and the receptor the “lock”) and affinity (how strong a drug is going to be bound to the receptor).

Most receptors are membrane recep-tors and are usually located on a protein that “snakes” through a cell membrane:

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874 Pharmacodynamics Pharmacology

Other receptors can be located on an enzyme or on deoxyribonucleic acid (DNA) molecules. Receptors are usually classified according to endogenous stimu-lating agents (e.g., neurotransmitters, hor-mones) and are then further subdivided into subtypes based on drug action (adds therapeutic specificity):

Endogenous acetylcholine → all cholinergic receptors

Exogenous compounds affect the follow-ing cholinergic receptors differently:

Muscarine → only some cholinergic receptors : Classified as muscarinic

receptors

( M → M1 , M2 , M3 , . . . )

Nicotine → other cholinergic receptors : Classified as nicotinic

receptors

( N → Nn , Nm , . . . )

Receptors are coupled directly or via second messenger systems (signal trans-duction) to an effector unit (e.g., ion chan-nels) to produce the following response:

Drug → receptor → opens channel → starts flow of electrolytes ( e .g . , origination of nerve impulse )

Drug → receptor → G - protein ( family , + , − ) → enzymes ( adenylyl

cyclase , guanylyl cyclase , phospholipase I , other ) → second messengers ( cyclic adenosine monophosphate or c - AMP , cyclic guanosine monophosphate or c - GMP , inositol triphosphate or IP3 , diacetylglycerol or DAG ) → muscle activation or channel opening ( e .g . ,

cardiac muscle contraction ) .

A cell can carry many different receptor types, each consisting of thousands of indi-vidual receptors. The same receptor type can occur on cells of different tissues.

DRUG

A drug possesses a specific structure, including molecular size, functional groups, lipophilic or hydrophilic proper-ties, and others, that determine its find-ing of and binding to a specific receptor (specificity and affinity or “lock and key”)

and its response (e.g., contraction of a skeletal muscle).

CLASSIFICATION OF DRUGS

Agonists, which show affinity and intrin-sic activity, cause a response and can be further divided into full agonists (which cause the maximum biological response) and partial agonists (which cause less than the maximum biological response and can be antagonists at high endoge-nous ligand activity).

Antagonists, which show only affin-ity, do not cause a response directly but block action of endogenous compounds and reduce their responses. They can be further divided into competitive, revers-ible antagonists and their effects can be overcome by increased amounts of endogenous or agonistic compounds (surmountable effects) and noncompeti-tive, irreversible antagonists that bind covalently to receptors and their effects can not be or only partially be overcome (insurmountable effects).

Most drugs are specific for and bind to only one particular receptor type. Some drugs can bind to more than one recep-tor type causing multiple pharmacological effects.

DRUG-RECEPTOR INTERACTION The interaction of a ligand (drug [D] or endogenous chemical) with a receptor (R) produces the physiological/pharma-cological response (e.g., increase in heart rate ). The binding forces involve Van der Waals forces (weak) and ionic, hydrogen, and/or covalent bonds (the latter results in irreversible, prolonged binding).

D + R → D - R complex + response → D + R

Most D-R complexes are very short-lived, and the drug is quickly removed from receptor (e.g., by destruction, dif-fusion from receptor or tissue uptake). If covalent bonding occurs, actions are prolonged.

D-R binding depends on drug con-centration (law of mass action, see equa-tion below) and the maximal response depends on the number of receptors stimulated by the ligand. The response is usually graded (stepwise increases in response) and shows ceiling effect (no further increases).

A theoretical example is as follows: Only a fraction of available receptors (e.g., 10 out of 100, in reality there are thousands) will be activated. Only 20 drug molecules are shown (in reality there are millions):

1D + 1R → 1D -- R + EFFECT = 0 → 1D + 1R below threshold

5D + 5R → 5D -- R + EFFECT = 5 → 5D + 5R increment

10D + 10R → 10D -- R + EFFECT = 10 → 10D + 10R increment

20D + 10R → 10D -- R + EFFECT = 10 → 20D + 10R ceiling

Initial drug response depends on drug dose (to reach threshold values where first response is detected and graded increases of this response), and the final maximal drug response depends on num-ber of receptors present and stimulated.

For all drug effects, there is a therapeu-tic threshold (beneficial effects occur) and as the dose increases, a toxic thresh-old (overdose) is reached—the difference in doses is the margin of safety of a drug.

Clinically, drugs can be compared by their efficacy and potency: Efficacy is the maximal effect of a drug, whereas potency is the dose that produces a specific effect. A drug can show a high potency (causes effect at a low dose) but low efficacy (response is mild).

The dose-frequency response curve among individuals is bell-shaped. It depicts the response of groups of patients who respond to a particular drug dose.

A theoretical example is as follows: 102 patients with headache are tested with a

xxxxxx xXXx xxxx xxxxx x x x x x x

x x x x x x xx x x x x x x

xxxx xxxx xxxx xxxxxxxxxx

Membrane

x � Amino acidXX � Amino acids representing receptor

EFFECT Ceilingx x x x x x x

Graded,saturableresponse

of oneaction

xx

xx

xx

xDOSE

EFFECTx x x x

xx

xxx

xx

Log DOSE (sigmoid)

E max(max response)

1/2 E max(ED 50)

(50% of effective dose)

Toxic threshold

Therapeutic threshold

EFFECTx x x x

xx

xx

xx

xLog DOSE

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Classification of Drugs Pharmacology

drug and the number of patients obtain-ing relief from a particular dose in milli-grams of the drug is plotted against drug concentrations.

Distribution (a bell-shaped curve) rep-resents normal variability within a popula-tion; most individuals fall within a narrow dose range (normal distribution, minor individual variations).Very few (x) indi-viduals fall outside, representing major biological differences.

FACTORS INFLUENCING DRUG PHARMACODYNAMIC DRUG RESPONSES • Specificity and number of receptors are

genetically determined and vary from patient to patient and so do their drug responses.

• Chronic stimulation of receptors by agonists causes downregulation (decrease in number/affinity of recep-tors or reduced activity) and chronic blockade of receptors by antagonists causes upregulation (increase in num-ber/affinity of receptors or increased activity). These processes play a role in some drug responses (e.g., antidepres-sant drugs) and the development of tol-erance and physical dependence.

• Diseases can cause receptor abnormali-ties (usually decreases) that result in idiosyncratic drug responses (e.g., myas-thenia gravis in which the immune system destroys the receptors on skeletal muscles and causes muscle fatigue and weakness).

• Receptors develop during the early days, months, and years of life (neonatal phar-macology) and decline during older age (geriatric pharmacology). This results in fewer numbers of receptors (includ-ing enzymes involved in biotransforma-tion). In general, starting dose in “young”

and “old” patients is usually one-half to one-third of a normal adult dose.

• Drugs can compete for the same recep-tor and an antagonist can reduce the effects of an agonist (drug interaction).

SUMMARY

The pharmacological responses, whether therapeutic and adverse, arise from the interaction of the drug (molecular weight, chemical and physical properties, or spe-cific functional groups) and endogenous receptors (small active areas usually located on a macromolecule; structure and number determined by genetics but also affected by age, diseases, and certain drugs). This binding follows the “lock” and “key” principle. One tissue may contain many different receptor types, and a spe-cific type might occur on different tissues.

The structure of the receptor deter-mines the specific pharmacological response (therapeutic or adverse) of the drug and the number of receptors deter-mines its maximal effect.

IMPLICATIONS FOR THE PHYSICAL THERAPIST

Be aware that younger and older individ-uals may respond somewhat differently to medications. Young individuals and geriatric patients must be watched more carefully because they often show more adverse reactions.

Geriatric patients often receive mul-tiple medications that are sometimes prescribed by different physicians and obtained at different pharmacies. Patients should make a list of all medications and show this to every physician. Also, patients should obtain all medications from the same pharmacy so the pharma-cist can prevent potentially dangerous drug interactions.

Patient should be informed that thera-peutic and adverse reactions can never be predicted with certainty because individ-uals will have different genetic and envi-ronmental backgrounds. It is mostly the patient who must monitor therapeutic progress and spot adverse reactions, but this can be helped by health professionals who can observe patients closely.

PHARMACOKINETICS

INTRODUCTION Pharmacokinetics describes the effects of the body on the drug or its “jour-ney” into, through, and out of the body. Pharmacokinetics determines to a large extent the best formulation of a drug, the dose to be used, the route of administra-tion, onset and duration of action of a drug,

the distribution in the body, dosing sche-dule by repeated applications, and some unexpected drug reactions.

STRUCTURE OF DRUG The chemical structure of the drug (small or large molecular weight or hydrophilic or lipophilic properties) and the composi-tion of the tablet (quick or slow release of the drug) are major factors in the kinetics of a drug. Most drugs are manufactured to deliver the dose gradually into the body (e.g., a tablet can be broken in half), but some drugs are manufactured as slow-release drugs where the dose is delivered over a longer period of time (these prepa-rations cannot be broken in half).

DRUG ADMINISTRATION Drugs can be administered via the ali-mentary routes (oral, sublingual, or rec-tal administration), parenteral routes (intravenous [IV], intramuscular [IM], or subcutaneous [SC] administration), or topically (eyes, skin, or lungs via inhala-tion). Transdermal means administration into the blood stream via a patch on the skin.

IV injections and inhalation produce the fastest onset, whereas oral administra-tion is most convenient but delays onset of action.

DRUG DISTRIBUTION After oral administration, the tablets must be dissolved in the stomach and intestines and are then absorbed into the blood stream. After IM or SC injection, absorp-tion occurs from the site of injection into the blood stream. After IV injection, the drug is injected directly into the blood stream. From the blood, drugs reach all tissues in the body, except certain drugs that will not cross the blood-brain barrier. This initiates therapeutic responses in the target organs; adverse reactions usually occur in tissues other than the intended site(s). Some tissues, such as adipose tis-sues, trap certain drugs without showing a response (site of loss) but can release the drug slowly (e.g., weeks) even after the drug has been stopped.

Distribution for most drugs occurs by diffusion following Fick’s law: Drug mol-ecules move along a concentration gradi-ent (from high to low) until equilibrium is reached. Some drugs are distributed by other mechanisms such as active trans-port processes.

In the blood, some drugs can be highly bound to plasma proteins, which can slow down distribution into individual tissues but can also prolong its action even after the drug has been stopped.

ELIMINATION Drugs must eventually be eliminated from the body to prevent accumulation.

NUMBER RESPONDING TO ONE DOSE

DOSE (mg)

100

50

00 50 100 150 200 250 500 1000

(X) (X)X

X

XX

X

Numberresponding Drug (mg)

15

20502051

575

125150175225

1000

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876 Pharmacokinetics Pharmacology

The action of the drug is terminated by the body by two major processes: Removal or excretion mostly through the kidneys and chemical inactivation or biotransfor-mation (metabolism) in the liver.

Excretion in the kidney starts with glomerular filtration (GF) in which most drug molecules are filtered into the nephron. Here, lipophilic drug molecules are reabsorbed into the blood (generally, the kidney can not excrete lipophilic mol-ecules) and hydrophilic drug molecules are excreted into the urine. In addition, there are special secretory processes for some drugs. Thus the health of the kidney can influence how fast a drug can leave the body (or the duration of action). Renal diseases necessitate a reduction in dose to avoid overdose reactions.

Biotransformation or drug metab-olism is the inactivation or chemical alteration of a drug mostly by the liver. The main purpose is to convert lipophilic drugs (which the kidney cannot excrete) into hydrophilic compounds (which the kidney can excrete). These products are called metabolites, and they can be devoid of therapeutic action (inactive metabolites) or can still maintain the ther-apeutic action (active metabolites), which in the latter case would prolong duration of the drug action. A drug can have many (sometimes tens) of metabolites.

Drug → active metabolite → inactive metabolite ( final excretion of

drug → inactive metabolite and / or metabolites by kidney )

These chemical reactions are per-formed by enzymes referred to as p450 enzymes or mixed function oxidases. They are divided into phase I reactions (oxidation, reduction, and hydrolysis reac-tions) and phase II reactions (conjugation to hydrophilic endogenous compounds). Some drugs are so quickly metabolized when passing through the liver for the first time that they must be given at very high oral doses or must be injected (first-pass effect). Some drugs can induce drug metabolizing enzymes and accel-erate their own metabolism or slowly shorten the duration of action—this is referred to as tolerance and necessitates an increase in dose over time. Hepatic dis-eases with decreased biotransformation

capacity often demand a reduction in dose to avoid overdose reactions.

Elimination is the combined action of excretion and metabolism. Most drugs are eliminated following first-order kinet-ics (constant fraction or % is eliminated). This determines the half-life ( t 1 ⁄ 2 ) of a drug, which is the time it takes for the drug levels in the blood to fall to one-half. (Few drugs follow zero-order kinetics in which a constant amount is eliminated per unit time.)

A theoretical example of first order ( µ g/mL [drug blood levels]) is as follows:

Time (hr)Dose A (10 mg)

Dose B (40 mg)

0 100 400

1 50 200

2 25 100

3 12.5 50

4 6.2 25

5 3.1 12.5

6 — 6.2

7 — 3.1

Different drugs can have different half-lives (example shows 1 hr half-life); an increase in dose increases blood and tis-sue levels but prolongs time of action rel-atively little; after 4 to 5 half-lives, about 95% of the drug has disappeared from the blood (and the body).

Chronic drug administrations must be performed in proper time intervals, which are the half-life time of the particular drug (if half-life is 6 hours, drug is to be taken every 6 hours). Chronic drug therapy is often started with regular doses (delay in onset of therapeutic action by about 4 to 5 half-lives) or a high dose (loading dose) followed by maintenance doses at half-time intervals (quick onset of action).

SUMMARY

Dosage considerations are based on a careful observation of the patient. Genetic makeup, health status, and compliance can markedly influence the efficacy and toxic-ity of a drug. For example, higher than rec-ommended doses are necessary in obese individuals (large volume of distribution) or fast metabolizers (drug too quickly inactivated). Lower doses should be given to small individuals, slow metabolizers, individuals with impaired kidney function or hepatic problems (including alcohol abuse), or young or geriatric individuals (elimination process not fully developed or already declining). Drugs can compete with each other for drug metabolizing enzymes and slow down their inactiva-tion, leading to overdose drug levels in the body (drug interactions). Diet can inter-fere with the absorption of some but not all drugs (e.g., tetracyclines should not be taken with antacids or foods). Failure to obey dosing schedules by the patient can lead to too low or too high drug lev-els with decreased efficacy or increased toxicity.

IMPLICATIONS FOR THE PHYSICAL THERAPIST • Inform patients to take medications

exactly as prescribed, because too low or missed doses can decrease the ben-eficial effects of a drug or too much of

Hydrophilic compounds

Lipophilic compounds Blood

Hydrophilic comp

Lipophilic comp

Urine (GF)

NEPHRON (schematic)

Some organic acids, bases (active transport)

Passive diffusion (back into blood)

Overview

Elimination(Liver: metabolism)

Blood(Free, bound)

DISTRIBUTION TO TISSUES

Elimination(Kidney: excretion)

Topical(e.g., eye)

IV administration(injection: large dose, quick;infusion: small dose over time)

Gases,vaporsLUNG

OralGI-TRACT(mouth,

stomach, intestines)

(RECEPTORS = Therapeutic and adverse reactions, sites of loss with no effects)

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ACE Inhibitors ACE Inhibitors

a drug can increase its adverse reac-tions. The patient should make a list and record the times when the drug should be taken.

• Inform patients that it is very important if a drug should be taken with meals or before or after a meal, because this can significantly affect the therapeutic response and adverse reactions.

• Inform patients that the drug should be taken as long as directed by a physician even if he or she feels better (e.g., in the case of antibiotics, remaining bacteria that do not cause clinical signs must still be eliminated.

• If a dose has been missed, inform the patient (unless otherwise instructed by the physician) to take the next dose if it is less than half the time before the next dose. For most drugs, the follow-ing is recommended: If a drug should be taken every 6 hours and the last dose was taken at 8 AM, then next doses should be taken at 2 PM and the next at 8 PM . If the 2 PM dose was missed, it can still be taken at 4 PM but not at 6 PM ; in this case, it is better to skip the dose.

• Tell patients that they can split tablets, because sometimes the higher dose is as expensive as the lower dose. By splitting, the patient can obtain double the lower doses for the same amount of money. Also, warn the patient that they should NOT split slow-release or extended-release tablets.

• Inform patients that topically prescribed drugs (e.g., ointments) are effective and penetrate into the designated area but can also diffuse into and throughout the entire body. Thus excessive amounts should be avoided because they can cause unnecessary adverse reactions.

ACE INHIBITORS COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Benazepril LotensinCaptopril CapotenEnalapril VasotecFosinopril MonoprilLisinopril Prinivil, ZestrilMoexipril UnivascPerindopril AceonQuinapril AccuprilRamipril AltaceTrandolapril Mavik

MECHANISM OF ACTION Peripheral blood pressure is regulated by many mechanisms one of which is the angiotensin system. The enzyme renin is released from the kidney, which converts angiotensinogen into angio-tensin I. Then, angiotensin-converting enzyme (ACE) converts angiotensin I to

angiotensin II. Angiotensin II acts on angio-tensin receptors in the blood vessels, causing vasoconstriction and increased blood pressure. In addition, angiotensin increases aldosterone secretion, which leads to salt and water retention, adding to the increased blood pressure.

ACE inhibitors inhibit ACE and reduce the formation of angiotensin II, which causes less stimulation of angiotensin rece-ptors, blood vessel dilation, and a fall in blood pressure. In addition, ACE inhibitors reduce aldosterone secretion, resulting in more water and salt excretion, lower blood volume, and decreased pressure.

INDICATIONS • Hypertension: Vasoconstriction or

increased peripheral resistance is a major cause of increased blood pres-sure. Hypertension untreated is linked to myocardial infarctions (MIs) and strokes. ACE inhibitors reduce formation of the vasoconstrictor angiotensin II and reduce blood pressure and can reduce the risk of secondary MIs and strokes.

• Congestive heart failure (CHF): When the heart cannot pump enough blood to other organs of the body, the result of this increased action is an enlarged but inefficient heart and the patient becomes quickly fatigued and short of breath (pulmonary edema) during even the slightest exertion. ACE inhibitors cause vasodilation and reduce afterload and peripheral resistance, which helps the heart to eject blood more easily and efficiently.

• Diabetic nephropathy: ACE inhibitors decrease the progression of diabetic nephropathy possibly by dilating renal blood vessels and increasing blood flow to the kidney (captopril).

• Migraine headaches (lisinopril) by an uncertain mechanism.

• All of these drugs inhibit ACE, but their indications and dosages vary among patients and the diseases to be treated. African-American patients with hyper-tension seem to respond less to some of these drugs.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Benazepril 5-40 mg 1-2 times daily by

mouth (PO)Captopril 12.5-150 mg 3 times daily

POEnalapril 2.5-40 mg 1-2 times daily

POFosinopril 10-80 mg once daily PO

for a maximum of 80 mg/day

Lisinopril 10-40 mg once daily POMoexipril 7.5-30 mg once daily PO

Perindopril 4-16 mg 1-2 times daily PO

Quinapril 10-80 mg once daily PORamipril 2.5-20 mg/day in 1-2 divided

doses POTrandolapril 1-4 mg once daily PO

ADMINISTRATION ACE inhibitors are given IV and PO. They vary in onset between 20 to 60 minutes and have a duration of action of 6 to 24 hours.

CONTRAINDICATIONS ACE inhibitors are contraindicated in cases of hypersensitivity with some cross-sensitivity among the drugs. These drugs should be used with caution in cases of renal or hepatic impairments. Mixing some ACE inhibitors with nonsteroidal antiinflammatory drugs (NSAIDs) can cause kidney failure.

COMMON ADVERSE REACTIONS Adverse reactions include headache, dizziness, hypotension, cough, taste disturbances, and rarely, agranulocytosis, neutropenia, or angioedema.

DRUG INTERACTIONS Hypotensive effects are enhanced by other antihypertensive drugs. Hyperkalemia may occur with potassium-sparing diuretics. Antacids may decrease absorp-tion and effectiveness of ACE inhibi-tors. Sympathomimetic over-the-counter (OTC) cold medications can antagonize the blood-pressure lowering effects of ACE inhibitors. ACE inhibitors can enhance the hypoglycemic action of hypoglycemics.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Advise the patient to change positions

and get up slowly because orthostatic hypotension may occur mostly in the beginning of therapy and in geriatric individuals. This can be aggravated if patient sweats heavily in a warm envi-ronment during strenuous exercise.

• If the patient complains about a sore throat, notify the physician or have the patient notify the physician, because this could be an early warning sign of agranulocytosis. If you notice or patient complains about swollen ankles or welts, notify the physician or have the patient contact the phy-sician because this could indicate an angioedema.

• Be careful when using a heated thera-peutic pool because warm water can aggravate the vasodilatory effects of peripheral vascular dilators and lead to a marked decrease in blood pressure.

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a -AGONISTS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Direct-acting α

1 -agonists

Epinephrine (has also beta activity)

Adrenaline, Ana-Guard, Primatene Mist, other

Midodrine ProAmatinePhenylephrine Neo-Synephrine

(OTC)Direct-acting α

2 -agonists (see

Miscellaneous Vasodilators)Clonidine Catapres, Duraclon

Direct- and indirect-acting α –agonists (have also beta activity)EphedrinePseudoephe-

drine

GenericSudafed, Drixoral,

Decofed, other (OTC)

MECHANISM OF ACTION α

1 -Receptors are usually but not exclu-

sively found opposite postganglionic sympathetic fibers, which release nore-pinephrine,which activates these recep-tors. Activation of these receptors constricts blood vessels (with increased peripheral resistance and increased blood pressure), closes the sphincter muscle and the neck of the bladder (preventing uri-nary outflow), and constricts the capsule/muscles of the prostate. α

1 -Agonists stimu-

late these receptors directly or indirectly. α

2 -Receptors are mostly found in the

brain where their stimulation in the vaso-motor center reduces sympathetic out-flow, which decreases heart rate and contractility and relaxes blood vessels. These effects reduce blood pressure.

Direct- and indirect-acting drugs stim-ulate α

1 - and/or α

2 -receptors. They stim-

ulate directly but also cause stimulation indirectly by increasing synaptic levels of norepinephrine by facilitating its release.

INDICATIONS α -Agonists are indicated in the following: • Nasal congestion: Viral or allergic

causes produce vasodilatation and leakage of water into adjacent tissue. α

1 -Agonists and indirect-acting drugs

constrict blood vessels, stop leakage, and open airways; common nasal sprays contain naphazoline, xylometazoline, phenylephrine, or oxymetazoline.

• Allergic conditions, in which part of the problem is vasodilation. α

1 -Agonists and

indirect-acting drugs constrict blood vessels. Ocular drugs that counteract congestion and redness are naphazo-line, oxymetazoline, tetrahydrozoline, and phenylephrine. In case of an ana-phylactic reaction, epinephrine SC is necessary.

• Shock caused by fluid loss, bleeding, or other causes. Drugs increase blood pressure by vasoconstriction and car-diac stimulation, in the case of indirect-acting drugs. Ephedrine is also used in cases of mild hypotension.

• Bronchoconstriction: Constriction of bronchi interferes with airflow. Indirect-acting drugs and epinephrine are used as sprays or orally to open airways.

• Ocular eye examinations: Phenyle-phrine causes mydriasis, allowing bet-ter examination of the posterior parts of the eye or for minor ocular irritation to constrict dilated blood vessels (e.g., oxymetazoline).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Epinephrine 1-2 puffs or 0.1 to

0.5 mg SCMidodrine 2.5-10 mg 2 to

3 times daily POPseudoephedrine 60 mg q6h (not to

exceed 240 mg/day) PO

Ephedrine 25 mg 4 times a day PO

ADMINISTRATION α -Agonists can be given SC, IM, IV, PO, inhalation, and topical in the eye.

CONTRAINDICATIONS α -Agonists are contraindicated or should be used with caution in hypertension, arrhythmias, and benign prostatic hyper-plasia (leading to urinary hesitancy, retention).

COMMON ADVERSE REACTIONS Adverse reactions include nervousness, restlessness, tremor, hypertension, angina, bradycardia (caused by increased blood pressure), and arrhythmias. Indirect-acting drugs may cause central nervous system (CNS) stimulation and anorexia. Nasal and ocular applications in rapid succession (after 2 to 3 days) can lead to a rebound effect in which congestion becomes worse with each application. For epineph-rine only: Excessive use of inhalers can lead to bronchospasm.

DRUG INTERACTIONS • α -Agonists antagonize the effects of the

α -blockers and antihypertensive drugs. They can precipitate a hypertensive crisis in conjunction with monoamine oxidase (MAO) inhibitors. Antacids that alkalinize the urine can intensify their effects.

• Foods that acidify (cheeses, fish, and meat) or alkalinize (most fruits and

vegetables) the urine can decrease or intensify effects of α -agonists.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Some of these drugs are available OTC

in nasal sprays, cold medications, and ocular solutions. Patients often assume that OTC drugs are safe and can be used without any precautions. Advise patients that OTC medications are drugs and must be used with care and according to instructions.

• If you notice that blood pressure has increased in a patient taking antihy-pertensive medication or if the patient shows increased restlessness, inquire about the use of OTC medications and if an α -agonist is used. Advise the patient to contact the physician.

• If you notice that the patient uses a nasal spray too often, inform the patient that he or she might suffer from a rebound effect and should contact the physician.

• Advise older men with benign prostatic hyperplasia that use of OTC α -agonists can lead to urinary hesitancy or even retention.

α -BLOCKERS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Doxazosin CarduraPhenoxybenzamine DibenzylinePrazosin MinipressTamsulosin FlomaxTerazosin Hytrin

MECHANISM OF ACTION α

1 -Receptors are usually but not exclu-

sively found opposite postganglionic sympathetic fibers, which release norepi-nephrine which activates these receptors. Activation of these receptors constricts blood vessels (with increased peripheral resistance and increased blood pressure), closes the sphincter muscle and neck of the bladder (prevents urinary outflow), and constricts the capsule/muscles of the prostate.

Competitive blockade of these recep-tors by α -antagonists or blockers causes the opposite effects (which can be antag-onized or overcome by use of α -agonists).

INDICATIONS α -Blockers are indicated in the following: • Hypertension: Vasoconstriction or

increased peripheral resistance is a major cause of increased blood pres-sure. α -Blockers block α -receptors and relax blood vessels, decrease peripheral resistance, and lower blood pressure.

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• Benign prostatic hyperplasia: α -Blockers relax the sphincter muscle and bladder neck, leading to more efficient bladder emptying, and relax the capsule/muscles of the prostate, providing improved uri-nary flow.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Doxazosin 1-16 mg once daily

POPhenoxyben-

zamine10-40 mg twice daily

POPrazosin 1-15 mg 2-3 times

daily (not to exceed 40 mg/day) PO

Tamsulosin 0.4-0.8 mg once daily PO

Terazosin 1-5 mg once or twice a day (not to exceed 20 mg/day) PO

ADMINISTRATION α -Blockers are administered PO. Some, such as phentolamine, are only given IV or IM.

CONTRAINDICATIONS Hypersensitivity to α -blockers.

COMMON ADVERSE REACTIONS Common adverse reactions include head-ache, stuffy nose, fatigue, palpitations, and tachycardia (as blood pressure drops, heart rate increases reflexly); marked “first dose” syncope (fainting); and later, less severe orthostatic hypotension. Geriatric patients are at increased risk of experi-encing adverse reactions.

DRUG INTERACTIONS There is an increased risk of hypotension with drugs that also lower blood pres-sure, including alcohol, sildenafil, and others. Some cold medications contain-ing phenylephrine or other α -agonistic compounds can antagonize actions of α -blockers.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Be careful when a patient changes posi-

tions or stands up because of possible orthostatic hypotension (dizziness, fainting), in particular, at the beginning of therapy or in geriatric patients.

• Watch patient when he or she stops after strenuous exercise because risk of a hypotensive episode is increased.

• Advise patients to be careful when using a heated therapeutic pool because

warm water can aggravate the vasodila-tory effects of peripheral vascular dila-tors and lead to a marked decrease in blood pressure.

ALTERNATIVE MEDICATIONS Alternative medications include herbal preparations, vitamins, minerals, and other products (but not prescription drugs and OTC medications) used for other than nutritional reasons.

Prescription drugs and OTC drugs have to be approved by the FDA after compa-nies have performed extensive studies in animals and humans to establish efficacy and toxicity. Drugs are then approved for a specific indication and must state active ingredient(s), inactive ingredients, and exact dose and administration schedule, as well as suggested mode of action and adverse reactions as compiled (e.g., in the Physician’s Desk Reference [PDR]).

Alternative medications are handled like foods by the FDA and must state con-tent but NOT dose, and companies are not required to submit proof of efficacy and toxicity as long as companies do not make a specific health claim but remain vague in their indications (“might be good for your health”). Because of this lack of control, products often contain varying amounts of the specified product and sometimes are subject to fraudulent practices.

Claims for their beneficial effects are often based on cultural aspects (“has been used by the Chinese for centuries”), folk-lore (“this herb is known for a long time to help you to sleep”), and some epidemi-ological correlations (“a survey of a large number of individuals has shown that indi-viduals who consume a lot of a specific mineral will have less breast cancer”—although this is a valid correlation, it does not indicate that this mineral does prevent this cancer). In addition, there is the mis-conception by many people that naturally occurring alternative medications are safe because they are derived from nature—which is wrong because natural products can be quite toxic ( e.g., poison ivy, poi-sonous mushrooms).

At present, a number of controlled clinical trials are conducted with certain alternative medications and in the years to come, more information about the benefits and dangers of alternative med-ications will become more evident. At present, many “hopes” about these medi-cations have been shattered by these clini-cal trials. Thus most information available today is tentative at best and is constantly changing.

VITAMINS Vitamins are a group of unrelated sub-stances essential for many normal bio-

chemical and physiological processes (e.g., catalysts for enzymes) that are obtained from the diet or synthesized (vitamin D) by the body. For nutritional purposes, they are required only in small quantities as estimated by the recommended dietary allowances (RDA) and are present in suf-ficient amounts in a balanced daily diet (meats, carbohydrates, and dairy prod-ucts and lots of fruits and vegetables—plus, many foods are now vitamin/mineral fortified) to prevent vitamin or mineral deficiency diseases. There is no need for supplementation in healthy individuals on a balanced diet to maintain a healthy body and mind except perhaps for some infants, older people, work-related condi-tions, heavily menstruating or pregnant/lactating women, individuals consuming improper diets, certain diseases, and/or some drug therapies.

Recently, higher doses of certain vita-mins have been suggested to prevent or to cure certain diseases such as emphy-sema/asthma/bronchitis, cardiovascular diseases, cancer, aging, mental disorders, the common cold, and other health prob-lems. At present, there is no firm evidence that this is indeed the case. However, very high doses of some vitamins (e.g., vita-mins A, D, and perhaps E) can be quite toxic and/or increase the risk of certain diseases for which they were actually rec-ommended in the first place. Legitimate and documented OTC uses include vita-min preparations that somewhat slow down age-related macular degeneration (vitamins E and C and beta-carotene) and vitamin D to increase calcium absorption. If vitamins are used, preparations that carry the label of the US Pharmacopeia are recommended because this private organization recognized by Congress has established some standards for vita-mins and minerals (strength or amount of active ingredient, purity, disintegration, and dissolution).

MINERALS Minerals are necessary for many bio-chemical processes (e.g., cofactors for enzymes), physiological functions (e.g., hemoglobin), and structural requirements (e.g., teeth, bones). Optimal mineral intake values for humans are still estimates, but a balanced diet seems to provide all nec-essary minerals to healthy individuals. In addition, many foods are supplemented with minerals.

Recently again, higher doses have been suggested even for healthy individuals to prevent or cure health problems. No firm evidence supports the use of min-erals with the exception of calcium and vitamin D to increase bone formation and zinc to slow age-related macular degenera-tion but under the supervision of a health professional.

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880 Alternative Medications Angiotensin II Receptor Blockers

HERBAL PREPARATIONS A variety of herbal medications is avail-able claiming or suggesting many benefits (most of which have not been medically verified or have been proven wrong in the meantime). Also, some of these prepa-rations have been found to cause signifi-cant health problems or even death (e.g., ephedra) or can significantly interfere with prescription drugs either reducing their efficacy or increasing their toxicity.

It has been claimed that echinacea stimulates the immune system (if true, it would be strongly contraindicated in cases of autoimmune diseases), garlic reduces the risk of cardiovascular dis-eases (but bleeding episodes can occur with heparin, warfarin, and aspirin), gin-ger reduces nausea and vomiting (with some evidence), gingko biloba increases memory and cognition and improves cir-culation (bleeding episodes with heparin, warfarin, and aspirin can occur), St. John’s wort improves mood (with some sup-port for mild depression but can interfere with some antiviral drugs and anticancer medications), and valerian treats anxiety and insomnia (it indeed has some calming properties).

BIOCHEMICALS A number of biochemicals are offered for a variety of health problems, most of which have not been documented with rigorous scientific trials. For example, melatonin is a naturally occurring substance in the body that physiologically is involved in sleep and is now marketed as a sleep promoter. Although its use is safe, it does not seem to induce sleep and help jet lag in most except a few individuals. Glucosamine and chondroitin are components needed to build and maintain articular cartilage and synovial fluid, and it has been claimed that their use can help patients with osteoar-thritis. Although most individuals do not seem to get relief, a few individuals indeed seem to benefit. Unfortunately, both com-pounds cause significant gastrointesti-nal (GI) problems like nausea, cramping, and heart burn. Omega-3 polyunsaturated fatty acids might be beneficial to prevent certain cardiovascular risks, but many experts recommend that these biochemi-cals can be obtained from eating fish 2 to 3 times a week.

IMPLICATIONS FOR THE PHYSICAL THERAPIST • It is important to stress to the patient

that the most important aspects of maintaining good health and prevent-ing diseases are a well-balanced diet, an optimistic outlook on life, and daily physical exercise.

• It is important to inform the patient that the benefits of alternative medications, with exceptions as outlined above, are

still unproved, the use of these prepara-tions is not risk–free, and that some of alternative medications can interfere det-rimentally with prescription drugs. They should not be taken without the advice of a physician, and their use must be stated when a medical history is taken.

• It is important to inform the less afflu-ent patient to spend available money on good food rather than alternative medications.

• It is important to warn the patient about advertisements of these products on TV, in newspapers, or websites because they often contain half-truths. When searching the internet, attention should be paid to websites that end in “.edu” or “.gov” because these come from univer-sities and government agencies and can be trusted. Many other websites may or may not have correct information, and their intention is mostly to sell rather than inform.

ANGIOTENSIN II RECEPTOR BLOCKERS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Candesartan AtacandEprosartan TevetenIrbesartan AvaproLosartan CozaarOlmesartan BenicarTelmisartan MicardisValsartan Diovan

MECHANISM OF ACTION Peripheral blood pressure is regulated by many mechanisms including the angio-tensin system. The enzyme renin is released from the kidney and converts angiotensino-gen into angiotensin I. The enzyme ACE converts this to angiotensin II. Angiotensin II acts on angiotensin receptors (AT1) in the blood vessels, causing vasoconstric-tion and increases in blood pressure. In addition, angiotensin II increases aldos-terone secretion, which leads to salt and water retention in the kidney and also an increase in blood pressure.

Angiotensin II receptor blockers block the action of angiotensin II on the blood vessel receptors, causing vasodilation and reducing the secretion of aldosterone, which enhances renal excretion of salts and water. Both actions reduce blood pressure.

INDICATIONS Angiotensin II receptor blockers are indi-cated in the following: • Hypertension: Vasoconstriction or

increased peripheral resistance is a major cause of increased blood pres-sure. Hypertension untreated is linked

to MIs and strokes. These antagonists block the action of the vasoconstrictor angiotensin and also reduce the secre-tion of aldosterone; both of these lower blood pressure and can reduce the risk of secondary MIs and strokes.

• CHF: When the heart cannot pump enough blood to other organs of the body, the result is an enlarged but inef-ficient heart and the patient becomes quickly fatigued and short of breath (pulmonary edema) during even the slightest exertion. These drugs (cande-sartan, valsartan) cause vasodilatation and reduce afterload or peripheral resis-tance, which helps the heart eject blood more easily and efficiently.

• Other uses include diabetic nephropa-thy in type II diabetes, possibly by dilat-ing renal blood vessels and increasing blood flow to the kidney (irbesartan, losartan).

• All drugs block angiotensin II receptors, but their indications and dosages vary among patients and the diseases to be treated. African-American patients with hypertension seem to respond less to some of these drugs.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Candesartan 2-32 mg once or twice

daily POEprosartan 400-800 mg once daily POIrbesartan 150-300 mg once daily POLosartan 25-100 mg once daily POOlmesartan 10-20 mg once daily POTelmisartan 20-80 mg once daily POValsartan 40-320 once or twice daily

PO

ADMINISTRATION Angiotensin II receptor blockers are mostly given PO and often used in combination with other antihypertensive medications.

CONTRAINDICATIONS Angiotensin II receptor blockers are contraindicated or should be used with caution in patients with renal and hepatic impairments and certain cardiac conditions.

COMMON ADVERSE REACTIONS Adverse reactions include dizziness, fatigue, hypotension, angioedema, and in rare cases, renal failure.

DRUG INTERACTIONS • NSAIDs may decrease the effectiveness

of these drugs. They can aggravate potas-sium retention with potassium-sparing diuretics and enhance the effects of other antihypertensive drugs.

• Effects are increased with mistletoe, astragalus, black cohosh, and others.

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IMPLICATIONS FOR PHYSICAL THERAPISTS • Advise the patient to change positions

and get up slowly because orthostatic hypotension may occur in the begin-ning of therapy and in geriatric individu-als. This can be aggravated if the patient sweats heavily in a warm environment during strenuous exercise.

• Be careful when using a heated thera-peutic pool because warm water can aggravate the vasodilatory effects of peripheral vascular dilators and lead to a marked decrease in blood pressure.

ANTIARRHYTHMIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Class IADisopyramide NorpaceProcainamide Procanbid, Promine,

PronestylQuinidine Quinalan, Cardioquin,

Quinora, otherClass IBLidocaine Xylocaine, otherMexiletine MexitilPhenytoin Dilantin, PhenytexTocainide TonocardClass ICFlecainide TambocorPropafenone RythmolClass II or β -Blockers (see β -Blockers)AcebutololEsmololPropranololSotalolClass IIIAmiodarone Cordarone, PaceroneIbutilide CorvertClass IV or Calcium Channel Blockers (see Calcium Channel Blockers)VerapamilMiscellaneous DrugsAdenosineAtropine (see Cholinergic Antagonists)

MECHANISM OF ACTION Conduction/contraction coupling des-cribes the movement of electrical and muscular activity over the heart that ini-tiates sequential atrial and ventricular contractions to eject blood. Normally, the electrical impulses are initiated in the sinoatrial (SA) node and spread throughout the atria via multiple tracks initiating coordinated contraction of the muscles of the atria. Impulses converge on the atrioventricular (AV) node that sits at the juncture of the four chambers of the heart. They traverse the AV node and the bundle of His, enter the right and

left conduction bundles in the right and left ventricles, and are distributed via the Purkinje fibers in a coordinated fashion to the muscles of the right and left ventri-cles, which now contract. Important phar-macological events are the initiation of electrical activity by b receptors in the SA node, the influx of sodium into cardiac cells leading to rapid depolarization, and the efflux of potassium and calcium from the cells causing slow repolarization. This is followed by a refractory period during which the cells of the electrical system reestablish their original electrolyte dis-tribution and are unable to respond to an electrical impulse. Normal conduction starts within certain cells (called pace-maker cells ) that depolarize spontane-ously, initiating conduction. These cells are located mostly in the SA node and are responsible for initiation of normal car-diac rhythm. Lesser normal pacemaker cells are located in various areas of the heart and may become active only under abnormal circumstances.

Drugs can affect some of these events selectively. Class I drugs are essentially sodium channel blockers and reduce cellular sodium influx, the rate of depo-larization, conduction, and membrane excitability. They can have other activi-ties as well, and based on these effects, these drugs are subdivided into Class IA, IB, and IC drugs. Class II drugs or β -blockers block β

1 -receptors in the SA

and AV nodes, thus decreasing the rate of pacemaker activity or automaticity and slowing the rates of the develop-ment and propagation of the electrical impulses. Class III drugs slow the efflux of potassium from the cells, prolonging repolarization and slowing the electri-cal recovery period and thus the rate of conduction. Class IV drugs or calcium channel blockers block calcium chan-nels, prolonging the period of repolariza-tion, decreasing excitability, and slowing the rate of conduction.

INDICATIONS Antiarrhythmic drugs are indicated in the following: • Arrhythmias (or dysrhythmias

because arrhythmia means no rhythm) are caused by the malfunction of pace-maker cells that are unable to maintain normal activity, the emergence of new pacemaker cells competing with the original ones, the interruption of nor-mal conductance over the heart in that conduction cannot reach certain areas (heart blocks), or an upward and circu-lar fashion with reexcitation of cardiac tissue (reentry), or a combination of above causes. Several different types of arrhythmias can range from harmless to life-threatening.

• These abnormalities are specifically influ-enced by different drug classes that try to normalize abnormal conduction patterns by selectively affecting β -receptors or individual electrolyte fluxes (sodium, potassium, or calcium) and to reestablish a normal rhythm. Generally, Class I drugs are used for ventricular dysrhythmias like ventricular ectopy (skipped heart beats) and ventricular tachycardias (as well as quinidine for atrial tachycardias). The frequent deleterious effects of these drugs and the development of Class III drugs have caused a marked diminution of their usage especially the drugs in Class IA. Class II drugs are used for sinus tachy-cardia, atrial fibrillation and flutter, and some ventricular dysrhythmias. Class III drugs are mostly used for ventricular dys-rhythmias but also for atrial fibrillation. Class IV drugs are used in atrial fibril-lation and flutter and supraventricular tachycardia. Miscellaneous drugs, such as adenosine, are used mostly for diag-nostic purposes; atropine is also used for certain bradycardias.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Disopyramide 100-200 mg q6h PO or

200-400 mg q12h for slow-release preparations PO

Procainamide 1 g followed by 50 mg/kg/day q6h PO

Quinidine 200-600 mg q2-3h up to 4 g/day PO

Lidocaine Injections, infusions at various dosages

Mexiletine 200-400 mg followed by 200-400 mg q8h PO

Phenytoin 1 g divided over one day then 500 mg/day for 2 days PO

Tocainide 400-1800 mg/day in divided doses PO

Flecainide 50 mg q6-12h, up to 300 mg/day PO

Propafenone 150 mg q8h up to 900 mg/day PO

Amiodarone 800-1600 mg/day for 1-3 weeks followed by 600-800 mg for 1 month and followed by 400 mg/day PO

Ibutilide IV infusions at different rates

Verapamil 240-320 mg/day in 3-4 divided doses PO

Adenosine IV infusions at different rates

Atropine IV bolus injections at different dosages

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ADMINISTRATION Antiarrhythmic drugs can be given IV (bolus, infusion) and PO. It is important to follow exactly the prescribed dosage pro-tocol, because these drugs can be quite toxic if taken too frequently or at higher than prescribed dosages.

CONTRAINDICATIONS Antiarrhythmic drugs are contraindicated or should be used with care in patients with heart failure, myocardial ischemia, and previous MIs.

COMMON ADVERSE REACTIONS Antiarrhythmic drugs carry a high risk of adverse reactions. Most drugs have the potential to normalize one type of dys-rhythmias while causing another type. They can cause dizziness, confusion, and nausea, which sometimes are indications of the presence of such an adverse dys-rhythmia. Depending on the class, Class I drugs can cause hypotension, bradycardia, edema, syncope (fainting), heart failure, leukopenia, constipation, urinary retention, and rarely, agranulocytosis. In addition, tin-nitus (ringing in the ears) and hearing loss mostly with quinidine; GI bleeding with mexiletine; nephritis (urine discoloration), and Stevens-Johnson syndrome with phe-nytoin and respiratory depression with flecainide. Class II drugs can cause bron-choconstriction and excessive bradycar-dia. Class III drugs are relatively safe except amiodarone, which can cause deposits in the cornea, a toxic epidermal necrolysis, and pulmonary fibrosis (warning signs are dyspnea, cough, and pain). Class IV drugs, or calcium channel blockers, may cause bradycardia and hypotension.

DRUG INTERACTIONS • Antiarrhythmic drugs can interact with

other antidysrhythmic drugs, β -blockers, anticholinergics, and other drugs.

• Toxicity is increased by a large num-ber of herbal products. Alcohol and caf-feine in foods and drinks can aggravate dysrhythmias.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Advise the patient that these are very effec-

tive but also potentially dangerous drugs and that the patient must adhere strictly to the prescribed dosing schedule because deviations can significantly reduce the therapeutic and increase the toxic effects.

• Advise the patient to adhere strictly to office appointments and laboratory tests because early recognition of an adverse reaction can prevent subsequent health problems.

• If you notice peripheral edema or the patient complains about dyspnea, notify

or have patient contact the physician because dosage adjustments or a differ-ent drug might be indicated.

• Have the patient change position slowly, in particular during early ther-apy, because dizziness and orthos-tatic hypotension might occur causing patient to fall.

• If the patient complains about nausea and dizziness, have him or her contact the physician because these could be a warning sign of another dysrhythmia.

• Advise the patient to abstain from caf-feine containing drinks or foods because they can aggravate dysrhythmias.

• If a patient on quinidine complains about tinnitus, have the patient contact the physician because this can lead to hearing problems.

• If the patient complains of a fever fol-lowed by a rash and painful skin areas, have the patient immediately call the physician because this could be warning signs for a toxic epidermal necrolysis, which could be very serious.

• Check pulse rate during more strenu-ous exercises or if the patient gets pre-maturely fatigued and stop exercises if an abnormal rate is felt.

ANTIASTHMATIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) b-Agonists (see b -Agonists) Albuterol Formoterol Bitolterol Levalbuterol Metaproterenol Pirbuterol Terbutaline Anticholinergics (see Anticholinergic Drugs) Ipratropium Tiotropium Adrenergics (see α -Agonists) Epinephrine Corticosteroids (see Corticosteroids) Beclomethasone Betamethasone Budesonide Cortisone Dexamethasone Flunisolide Fluticasone Hydrocortisone Methylprednisolone Prednisone Triamcinolone Leukotriene Antagonists Zafirlukast Accolate Mast Cell Stabilizer (see Antihistamines) Cromolyn Nedocromil

Phosphodiesterase InhibitorsTheophylline Accurbron, Bronkodyl,

Lanophyllin, otherMonoclonal Antibodies (see Antihistamines)Omalizumab Xolair

MECHANISM OF ACTION The diameter of the bronchi and air flow are controlled by the action of a number of receptors, such as muscarinic, histamine (released from mast cells in response to certain allergens), and leukotriene recep-tors (LTC4, LTD4, LTE4, formed from arachidonic acid via lipoxygenase), that constrict the bronchi and β -receptors that dilate the bronchi.

In order to relax the constricted bronchi and to increase air flow, muscarinic recep-tor blockers (see Anticholinergic Drugs), antihistamines (see Antihistamines), or β -agonists (see β -Agonists) are used. In addition, phosphodiesterase inhibitors are employed that prevent the destruc-tion of cyclic adenosine monophosphate (cAMP) by phosphodiesterase, which is a second messenger that relaxes bronchi. Leukotriene antagonists block the action of leukotrienes, preventing the constric-tive effects of these compounds and lead-ing to relaxation of bronchi.

INDICATIONS Antiasthmatic drugs are indicated in the following: • Asthma which is caused by the bron-

choconstriction action of histamine, leukotrienes, and acetylcholine and an inflammation that narrows the inner diameter of the bronchi, reduces air flow, and causes “air hunger” (wheez-ing). Drugs relax the bronchi by block-ing constricting causes (anticholinergic drugs, leukotriene antagonists, and his-tamine antagonists or mast cell sta-bilizers ) or by promoting relaxation ( β -agonists, theophylline), as well as reducing the inflammation (corticoster-oids). Omalizumab is a monoclonal anti-body which binds to IgE and prevents the release of histamine and other asth-matic mediators. In all cases, the inner diameter of the bronchi is increased and a more efficient airflow is established.

• Chronic obstructive pulmonary disease (COPD) and emphysema which are lung diseases in which the lung is damaged by smoking, making it difficult to breathe.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Theophylline 100-800 mg q6h POZafirlukast 20 mg bid POOmalizumab 150-375 mg 2x4 wk

SC

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ADMINISTRATION Antiasthmatic drugs can be given IV, SC, or PO. Onset of action is fastest with inhaled preparations, and adverse reactions are less severe.

CONTRAINDICATIONS Theophylline should not be used in patients with tachydysrhythmias.

COMMON ADVERSE REACTIONS Adverse reactions for leukotriene antagonists include headache, nausea, dyspepsia, and the very rare but poten-tially dangerous Churg-Strauss syndrome. Theophylline can cause restlessness, insomnia, seizures, tachycardia, dysrhyth-mias, and dyspepsia.

DRUG INTERACTIONS • Interleukin antagonists interact with a

small number of drugs such as aspirin and warfarin. Theophylline increases cardiotoxicity of β -blockers.

• Black/green tea, coffee, and ephedra increase some of the adverse reactions of theophylline.

IMPLICATIONS FOR PHYSICAL THERAPISTS • If a patient on zafirlukast complains

about a rash and nodules, have the patient contact or inform the physi-cian immediately because this could be the beginning of the Churg-Strauss syndrome.

• Advise the patient taking theophylline to take the medication exactly as pre-scribed because dosage schedule is very important and deviations can increase risk of adverse effects (margin of safety is very small).

ANTIBACTERIAL DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) PenicillinsAmoxicillin Augmentin (with

clavulanate)Penicillin G Bicillin, MegacillinOthersCephalosporinsCefazolin AncefCefepime MaxipimeCefotaxime ClaforanCephalexin KeflexOthersQuinolonesCiprofloxacin Cipro, ProquinLevofloxacin LevaquinOthersAminoglycosidesGentamicin GaramycinOthers

TetracyclinesTetracycline Tetracyn,

Achromycin, other

OthersMacrolidesAzithromycin Zithromax, ZmaxOthersSulfonamidesSulfisoxazole Gantrisin(Trimethoprim) Primsol, Trimpex,

otherOthersMiscellaneous DrugsBacitracinImipenem Primaxin (with

cilastatin)

MECHANISM OF ACTION Bacteria are unicellular organisms that consist of a cell wall, sometimes a mem-brane, DNA (regular, plasmid) without a nuclear envelope, and protoplasm con-taining metabolites and enzymes. They are classified according to genus and spe-cies (e.g., genus Escherichia and species coli ). Many bacteria are beneficial to the host in that they prevent pathogenic bac-teria from growing or assist in the synthe-sis of certain nutrients. Some bacteria are pathogenic and cause specific diseases (e.g., Treponema pallidum causes syphi-lis) by competing for essential nutrients with host cells, secreting toxic materi-als, and/or causing an excessive immune response that damages the host cells.

Drugs that affect these microorganisms are called antibacterial drugs and are rel-atively specific for bacteria only. They can be divided into antibiotics that are derived from other microorganisms (e.g., molds), semisynthetic antibiotics that are chemi-cally altered antibiotics, and synthetic drugs that are completely synthesized in the laboratory. Drugs are classified and named after their origin (e.g., penicillin from Penicillium notatum ), their action (a drug that affects bacterial cell walls is named a cell wall inhibitor or a drug that kills bacteria is named bactericidal , whereas a drug that prevents multiplica-tion is named a bacteriostatic drug), their structure (drugs whose structure contains the lactam ring necessary for antibacterial action are referred to as lactam drugs), and/or their specificity against bacteria (drugs that affect gram-positive bacteria are named gram-positive drugs, and drugs that affect gram-negative bacteria are named gram-negative drugs; drugs that affect only a few different bacteria are classified as narrow, and drugs that affect many different bacteria are classified as wide-spectrum drugs).

Antibacterial drugs are grouped into classes, each of which consists of many

individual drugs that have similar actions and adverse reactions. Antibacterial drugs do not affect all bacteria but are selective for a specific species or strains. Most anti-bacterial drugs have five major sites of action as follows: • Inhibition of synthesis and/or damage

to the peptidoglycan component of the bacterial cell wall. This biochem-ical is unique and necessary to the microbial cell wall and its disruption kills the microorganism (e.g., penicil-lins, cephalosporins, imipenem, and others).

• Inhibition of synthesis and/or damage to the microbial cytoplasmic membrane (e.g., polymyxins).

• Modification of synthesis and/or metab-olism of microbial nucleic acids by affecting two microbial enzymes, gyrase and topoisomerase, that are necessary for replication and cell division (e.g., quinolones).

• Inhibition or modification of microbial protein synthesis by disrupting micro-bial ribosomal function and impairing protein synthesis (e.g., aminoglycosides, tetracyclines, and macrolides).

• Inhibition or modification of micro-bial cell metabolism by affecting folic acid synthesis/metabolism that has to be synthesized by bacteria and that is necessary for their nucleic acid synthe-sis (e.g., sulfonamides, trimethoprim). (Other modes of action include effects on RNA and other bacterial cellular components sometimes by an unknown mechanism). Resistance to penicillin drug action is

noted, because certain bacteria possessed an enzyme penicillinase or lactamase that can open the antibacterial lactam ring of penicillin and render a drug ineffective. However, other ways of drug resistance are also emerging as a result of mutations and plasmid exchanges (in which plasmid DNA from one is transferred to another bacteria), which create “pumps” that expel the drug from the bacteria, cause thicker walls preventing entry of the drug and/or lose special receptors with which the drugs interact.

Sometimes, certain antibacterial drugs are administered concomitantly with drugs that prevent their rapid renal elim-ination and prolong their action (e.g., cilastatin) or inhibit the bacterial enzyme penicillinase, which now cannot inacti-vate penicillins (e.g., clavulanate).

INDICATION Antibacterial drugs are indicated in the following: • Bacterial infections are treated with

drugs that are specific for a particular bacterial species or strain. Examples are ciprofloxacin and imipenem for Bacillus

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anthracis (anthrax), penicillin G for Clostridium tetani (tetanus), amoxi-cillin or trimethoprim/sulfonamide for E. coli (bacteremia, urinary tract infec-tions), cefotaxime for Haemophilus influenzae (otitis, pneumonia), peni-cillin G for streptococci (endocardi-tis), cefotaxime and ciprofloxacin for Salmonella typhi (typhoid fever) and cephalosporins or aminoglycoside for Klebsiella pneumoniae (pneumonia).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Amoxicillin 750-1750 mg in divided

doses daily POPenicillin G 2.4 million units IMCefazolin 250-2000 mg q6-8h

IM, IVCefepime 0.5-2000 mg q12h

IV, IMCefotaxime 1-2 g q4-12h IM, IVCephalexin 250-1000 mg q6h POCiprofloxacin 100-500 mg q12h daily

POLevofloxacin 250-750 mg daily PO,

IVGentamicin 3-6 mg/kg/day in

divided doses q8h IV infusion or 3 mg/kg/day in divided doses q8h IM

Tetracycline 250-500 mg q6h daily PO

Azithromycin 250-2000 mg daily POSulfisoxazole 2-4 g followed by

1-2 g daily POTrimethoprim 100 mg q12h daily POImipenem 250-1000 mg q6-8h IV

ADMINISTRATION Depending on the drug, antibacterial drugs are administered PO, IV, or IM.

CONTRAINDICATIONS Antibacterial drugs are contraindicated or should be used with caution in patients with renal and/or hepatic problems.

COMMON ADVERSE REACTIONS In general, antibacterial drugs can cause nausea, vomiting, allergic reactions, pseudo-membranous colitis, Stevens-Johnson syn-drome, and superinfections. In addition, penicillins and cephalosporins are rela-tively free of adverse reactions except aller-gic reactions with some cross-sensitivity between classes. Similarly, macrolides show mostly allergic reactions. Aminoglycosides are more toxic and might cause nephro-toxicity and ototoxicity. Tetracyclines cause photosensitivity to ultraviolet (UV) light and should not be given to growing individuals because they stain teeth and interfere with bone calcification. Quinolones can cause visual disturbances, photosensitization, and

inflammations of the tendons. Sulfonamides taken at high doses may cause renal stone formation and necessitate the consumption of large amounts of fluids.

DRUG INTERACTIONS • A large number of interactions exist.

Penicillins can decrease the effects of contraceptives. Tetracyclines can reduce the efficacy of penicillins. Some cephalosporins show increased toxicity with a large number of herbal preparations.

• Generally, acidophilus should not be used with antiinfectives. Antacids and/or dairy products (calcium and other metals) decrease efficacy of tetracy-clines, macrolides, and quinolones.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Advise patients to follow prescrip-

tion schedule strictly and to continue taking drugs even if clinical signs or symptoms have subsided because the schedule is designed to eradicate the microorganism in all places even those in which no clinical problems are manifested.

• If the patient exhibits an unexplained rash, inform the physician or have the patient contact the physician because this could be the beginning of Stevens-Johnson syndrome.

• If the patient has abdominal discom-fort, ask the patient to check stool and if pus or mucus is detected, inform the physician or ask the patient to contact the physician because this could be a pseudomembranous colitis.

• Advise patients and reinforce drug warnings that tetracyclines and qui-nolones must be taken as prescribed because their use with food or antacids can render them ineffective.

• Patients on quinolones complaining about tendon pain, in particular, pain of the Achilles tendon, should not be exer-cised strenuously and should be care-fully evaluated. The physician should be informed because this could indi-cate a tendonitis requiring a change in medication.

• Avoid UV light therapy or cover exposed areas of patients on tetracyclines and quinolones because these drugs cause photosensitization.

• Be aware that health care profes-sionals have been shown to be a pri-mary source of spreading infections including serious and life threaten-ing infections. It is recommended that gloves should be worn and discarded, hands should be washed with soap for at least15–30 seconds or disinfec-tive solutions be used to minimize the spread of infection.

ANTICHOLINERGIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Atropine Generic

BelladonnaDicyclomine BentylHyoscyamine Levsin, Anaspaz,

Donnamar, othersIpratropium Atrovent, othersOxybutynin DitropanScopolamine Transderm-ScopTiotropium SpirivaTolterodine DetrolBenztropine CogentinBiperidin AkinetonTrihexyphenidyl Artane

MECHANISM OF ACTION Muscarinic (M) cholinergic receptors are usually but not exclusively found opposite parasympathetic postganglionic nerve fibers, which release acetylcholine which stimulates these receptors. The acetyl-choline is then quickly inactivated and destroyed by the enzyme acetylcholin-esterase. Activation of these receptors decreases heart rate and contractility, con-stricts bronchial muscles (decreased air flow), constricts the pupil, and increases gut and bladder activity. Anticholinergic drugs block the M receptors, reduce action of acetylcholine, and cause the opposite effects of their stimulation.

INDICATIONS Anticholinergic drugs are indicated in the following: • Arrhythmias, such as sinus bradycar-

dia, in which these drugs increase heart rate and normalize abnormal cardiac rhythm.

• Peptic ulcer and irritable bowel syn-drome, in which these drugs antago-nize excessive M-receptor stimulation and gastric and intestinal activity.

• Urinary bladder hypermotility, includ-ing enuresis, in which these drugs relax the bladder and decrease the need for frequent urination or bed wetting.

• Asthma, in which these drugs reduce secretion and dilate the bronchi with increased air flow.

• Cases of pesticide poisoning, in which these drugs protect the receptors from excessive acetylcholine stimulation caused by inhibition of acetylcholinest-erase by these poisons.

• Ocular applications, in which these drugs dilate the pupil and relax the cili-ary body (topically applied tropicamide, cyclopentolate, and atropine).

• Parkinson’s disease which is a move-ment disorder characterized by a masklike face, shuffling gait, and pill-rolling tremor. The cause is believed to

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be an overactivity of cholinergic and an underactivity of dopaminergic activ-ity in the basal ganglia of the brain. The last three drugs in the Common Drugs list reduce cholinergic overactivity and restore the balance between the two systems, thus improving rigidity and tremor.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Atropine Various schedules,

mostly as given as Belladonna extract 10-100 mg (calculated as 0.5 mg alkaloid) PO

Dicyclomine 10-20 mg 3-4 times daily (up to 160 mg/day) PO

Hyoscyamine 0.125-0.25 mg 3-4 times daily PO or 0.375-0.75 mg q12h as sustained-release preparation PO

Ipratropium 1-4 inhalations 3-4 times daily (not to exceed q4h)

Oxybutynin 5 mg 2-3 times daily PO or 5-10 mg once daily as sustained-release preparation PO

Tiotropium Inhalation of 18 µ g once daily

Benztropine 1 to 2 mg/day in 1-2 divided doses (up to 6 mg/day) PO

Biperidin 2 mg 1-4 times daily (not to exceed 16 mg/day) PO

Trihexyphe-nidyl

1-6 mg/day in divided doses PO

ADMINISTRATION Anticholinergic drugs can be given IV, IM, inhalation, and PO.

CONTRAINDICATIONS Anticholinergic drugs are contraindicated or should be used with caution in patients with cardiovascular problems, seizure dis-orders, benign prostatic hyperplasia, and GI hypomotility.

COMMON ADVERSE REACTIONS Adverse reactions include confusion (more severe in geriatric patients), dry skin and mouth, decreased sweating, blurred vision, constipation, and urinary hesitancy and retention (mainly in geri-atric patients). Anticholinergic drugs may cause contact lens intolerance as a result of dry eye.

DRUG INTERACTIONS • Anticholinergic drugs can slow down

the absorption of a number of other drugs and can antagonize the effects of some antiglaucoma medications.

• Increased anticholinergic effects have been reported with Jimson weed, sco-polia, and angel’s trumpet.

• In addition, there are a number of antihis-tamines, antipsychotics, and antidepres-sants that also show strong anticholinergic effects (see specific sections).

IMPLICATIONS FOR PHYSICAL THERAPISTS • Expect some increases in heart rate as a

result of blockade of cardiac M receptors. • Expect some mental confusion in older

patients taking anticholinergic drugs (or drugs that have anticholinergic properties).

• When exercising a patient on anticholin-ergic medication, keep the environment cool because there is the risk of heat prostration caused by the decreased ability to sweat and lose heat.

ANTICONVULSANT DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) BarbituratesPhenobarbital Luminal, Solfoton,

otherPrimidone MysolineOtherBenzodiazepinesClonazepam KlonopinDiazepam ValiumOtherHydantoinsPhenytoin Dilantin, PhenytexOtherSuccinimidesEthosuximide ZarontinOtherCarboxylic AcidsValproic acid Depakene, Depacon,

otherIminostilbenesCarbamazepine Tegretol, Atretol,

otherOxcarbazepine TrileptalSecond-Generation DrugsGabapentin NeurontinLamotrigine LamictalTiagabine GabitrilOther

MECHANISM OF ACTION Normal neuronal activity without exces-sive swings is controlled in the brain by excitatory and inhibitory processes. Sodium and potassium fluxes, excitatory

neurotransmitter actions such as gluta-mate, and inhibitory neurotransmitter actions such as γ -aminobutyric acid (GABA) are mostly responsible for this delicate balance. Anticonvulsant drugs can relatively selectively interact with these processes and reduce abnormal excessive cerebral neuronal activity. Barbiturates and benzodiazepines stimulate special recep-tors on the GABA complex that cause an increased action of the inhibitory neu-rotransmitter GABA. Hydantoins and imi-nostilbenes seem to primarily reduce sodium fluxes and reduce depolarization, which reduces neuronal firing. Valproic acid seems to predominantly affect potas-sium channels and hyperpolarize neurons and thus reduce neuronal activity. The neu-ronal depressant action of the other drugs is somewhat obscure, although ethosuxim-ide does affect calcium fluxes and gabap-entin-GABA release in an unknown way.

INDICATION Anticonvulsant drugs are indicated in the following: • Epilepsy which is characterized by

seizures, which are episodes of sudden and uncontrolled but transient hyperex-citability of small groups of neurons or “foci.” The cause for that sudden hyper-excitability or spontaneous but delete-rious discharges is poorly understood but defects in the GABA system of the brain, excessive Na+ fluxes and faulty K+ and Ca ++ fluxes have been sug-gested. These anomalies can be genetic in nature or caused by brain trauma, strokes, or drugs. These discharges can produce muscle contractions (convul-sions) or behavioral abnormalities (loss of consciousness). They can be local-ized or spread over the entire brain and can be divided into partial and general-ized seizures. Anticonvulsants basically prevent this unwanted and deleterious hyperexcitability by initiating or reduc-ing it to a nonpathological level. Most drugs increase the action of the inhibi-tory neurotransmitter, GABA, which opens chloride channels, causes a hyperpolarization, and slows neuronal firing. Phenytoins blocks sodium chan-nels, which slows the influx of sodium and prevents or reduces depolarization. Valproic acid affects potassium chan-nels, leading to hyperpolarization and again a reduction in neuronal firing. The mechanism of the other drugs is still somewhat unknown. In addition to these mechanisms, other neuronal effects do certainly play a supporting or even crucial role.

• Other uses for some selective drugs include essential tremors, restless leg syndrome, panic disorders, neuropathic pain, certain dysrhythmias, manic epi-sodes, and trigeminal neuralgia.

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EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Phenobarbital 1-3 mg/kg/day in

divided doses or total dose at bed-time PO

Primidone 100-250 mg 3-4 times daily up to 2 g/day PO

Clonazepam 1.5 mg/day in 3 divided doses up to 20 mg/day PO

Diazepam 2-10 mg 3-4 times daily or 15-30 mg once daily extended-release preparations PO

Phenytoin 1 g as loading dose in 3-4 divided doses and later as maintenance dose 300-600 mg/day PO

Ethosuximide 250-750 daily POValproic acid 10-15 mg/kg/day in

2-3 divided doses not to exceed 60 mg/kg/day PO

Carbamazepine 200 mg 2 times daily up to 800-1600 mg/day PO

Oxcarbazepine 300-600 mg 2 times daily PO

Gabapentin 900-1800 mg/day in 1-3 divided doses PO

Lamotrigine 50-500 mg/day in 2 divided doses PO

Tiagabine 4 mg/day in divided doses up to 56 mg/day PO

ADMINISTRATION Most drugs are given PO, but for certain conditions they have to be injected or infused. Anticonvulsant drugs are often prescribed in combination. Anticonvulsant drugs must be taken at exact dosages and times to be maximally effective.

CONTRAINDICATIONS Anticonvulsant drugs should not be used or must be used with caution in patients with renal and hepatic diseases.

COMMON ADVERSE REACTIONS All drugs will cause to a varying degree gastric discomfort, sedation, drowsi-ness, and ataxia (confusion occurs mostly in geriatric patients). Barbiturates may cause paradoxical excitement in selected individuals. Some drugs, such as barbiturates, oxcarbazine, gabapentin, and lamotrigine, can cause the Stevens-Johnson syndrome. Some drugs, such

as barbiturates and carbamazepine, can cause blood disorders (agranulocytosis, leukopenia, megaloblastic, or aplastic anemia). Phenytoin is associated with gingival hyperplasia, hirsutism, nephritis (colored urine), and hepatitis. Valproic acid may cause hepatitis and pancreati-tis. Carbamazepine may worsen seizures and cause cardiac rhythm disturbances. Ethosuximide may cause movement dis-orders such as dyskinesia and bradyki-nesia. Drugs should not be discontinued abruptly because this can precipitate seizures.

DRUG INTERACTIONS • Sedative effects are enhanced by drugs

that also have sedative properties. Long term use of barbiturates can decrease the effectiveness of corticosteroids and anticoagulants.

• St. John’s wort should be avoided and drug actions can be affected by gingko and ginseng.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Epileptic patients even with drug treat-

ment are vulnerable to intense lights and sounds that can precipitate a seizure. Keep patients in a quiet area without flickering lights and repetitive noise.

• Inform the patient to take the medica-tion exactly as prescribed because only this will assure maximal antiepileptic effects. Tell the patient not to stop the medication abruptly because this can precipitate seizures. Also, if blood tests were ordered, have the patient adhere to such a schedule because early detec-tion of a problem can often prevent or reverse pathological changes.

• If the patient is too sedated for therapy, discuss this with the patient and sched-ule appointments at times when patient feels less sedated.

• If the patient has an unexplained rash, notify or have the patient contact the physician immediately because some drugs can cause a Stevens-Johnson syndrome, which necessitates immedi-ate drug withdrawal.

• If the patient should appear excessively sedated, the patient should contact the physician because a dosage change or other drug might be indicated.

ANTIDEPRESSANT DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) TricyclicsAmitriptyline Elavil, Endep,

otherAmoxapine AsendinClomipramine Anafranil

Desipramine NorpraminDoxepin SinequanImipramine Norfranil, Tofranil,

otherNortriptyline Aventyl, PamelorTrimipramine SurmontilMonoamine Oxidase InhibitorsPhenelzine NardilTranylcypromine ParnateSecond-Generation DrugsBupropion WellbutrinCitalopram CelexaEscitalopram LexaproFluoxetine ProzacFluvoxamine LuvoxMirtazapine RemeronParoxetine PaxilSertraline ZoloftTrazodone DesyrelVenlafaxine Effexor

MECHANISM OF ACTION Mood and its normal fluctuations between a healthy sadness and happiness are con-trolled by many chemical processes (neu-rotransmitters) and special electrical circuits in the limbic and cortical areas of the brain. In this case, the neurotrans-mitters norepinephrine, dopamine, and serotonin seem to play major roles. These neurotransmitters are synthesized in nerve terminals and released so that they can interact with their respective recep-tors. They are transported back into the nerve terminals (reuptake) where part is stored and used again, while another part is metabolized by the enzyme monoam-ine oxidase (MAO) subtypes A and B. In addition, other neurotransmitters will also participate in mood regulation.

All antidepressant drugs interact with these systems by increasing synaptic levels of all neurotransmitters by either inhibit-ing their reuptake systems or by inhibit-ing their metabolism by the enzyme MAO. Elevated levels and continuous stimulation of these receptors cause a downregulation with decreased activity in about 4 weeks. These actions generally will cause a shift to a more elated mood.

INDICATION Antidepressant drugs are indicated in the following: • Depression can be roughly divided

into unipolar and bipolar depression. Unipolar depression is characterized by dysphoria, lack of interest, fatigue, lack of energy, low self-esteem, irratio-nal guilt, and suicidal ideation. Bipolar depression is characterized by swings between depression and mania. Mania is characterized by endless energy, increased activity, excessive euphoria, extreme irritability, racing thoughts and fast talking, needing little sleep, unrealis-tic beliefs in one’s abilities and powers,

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poor judgment, and aggressive behav-ior. It is hypothesized that these disor-ders are caused mostly by a pathological supersensitivity of the presynaptic and postsynaptic receptors of the norepi-nephrine, serotonin, and dopamine sys-tems. Antidepressant drugs now seem to increase synaptic neurotransmitter levels, downregulate these receptors, normalize excessive receptor sensitivity, and improve mood. Receptor downregu-lation may be the major effect because mood improvement usually occurs after 4 weeks of therapy. The tricyclic drugs act by blocking the reuptake of all three neurotransmitters, although slightly dif-ferently. The MAO inhibitors inhibit the enzyme that decreases neurotransmit-ter destruction and increases intran-euronal levels and release. They affect both enzyme types; inhibition of type A seems to be more beneficial. The second- generation drugs are also reuptake inhib-itors but are somewhat more selective in their actions. These drugs include the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine, and sertraline, which mostly affect sero-tonin. Lithium is used mostly to prevent mood swings in bipolar depression, and its action is uncertain but might involve an action on neuronal excitability and the formation and action of certain sec-ond messengers.

• Chronic pain (neuropathic pain, fibro-myalgia, and chronic low back pain) involves some of the previously men-tioned neurotransmitters, in particular serotonin, in its pathogenesis. But the specific action of the drugs in this con-dition is unknown.

• Other conditions such as enuresis (based on anticholinergic properties), migraine, premenstrual disorder, attention deficit hyperactivity disorder(ADHD), obses-sive-compulsive disorders (fluoxetine, sertraline), anxiety disorders (venla-faxine), and smoking cessation (bupro-pion). Mechanisms of action are often poorly understood.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Amitriptyline 75-150 mg/day in

divided doses (not to exceed 300 mg/day) PO

Amoxapine 50-100 mg 2-3 times daily (not to exceed 300 mg/day) PO

Clomipramine 25-250 mg in divided doses daily PO

Desipramine 100-200 mg/day in divided doses up to 300 mg/day PO

Doxepin 25-75 mg/day in divided doses up to 300 mg/day PO

Imipramine 75-100 mg/day up to 300 mg/day in divided doses PO

Nortriptyline 25 mg up to 150 mg/day in divided doses PO

Trimipramine 50-200 mg/day in divided doses PO

Phenelzine 45-60 mg/day in divided doses PO

Tranylcypromine 10-30 mg 2 times daily PO

Bupropion 100-150 mg 2-3 times daily PO

Citalopram 20-40 mg/day once daily PO

Escitalopram 10-20 mg/day once daily PO

Fluoxetine 20 mg 1-2 times daily (not to exceed 80 mg/day) PO

Fluvoxamine 50-100 mg 1-2 times daily (not to exceed 300 mg/day) PO

Mirtazapine 15-45 mg once daily PO

Paroxetine 20-60 mg once daily PO

Sertraline 50-200 mg once daily PO

Trazodone 150-600 mg in divided doses daily PO

Venlafaxine 75-150 mg 2-3 times daily PO

Lithium 300-600 3 times daily PO

ADMINISTRATION Most antidepressant drugs are given PO.

CONTRAINDICATIONS Antidepressant drugs should not be used (or must be used with caution) in patients with strong suicidal tendencies, seizure disorders, cardiac problems, and hepatic and renal diseases.

COMMON ADVERSE REACTIONS Adverse reactions differ among the drug classes, but patients are generally at higher risk of committing suicide at the beginning of therapy with all drugs. Also, long-term therapy will lead to different degrees of physical dependence, causing a withdrawal syndrome (fatigue, head-ache, muscle pain) at abrupt drug therapy cessation. Tricyclics cause sedation, anti-cholinergic effects, orthostatic hypoten-sion, cardiac dysrhythmias, and seizures, although there are differences among

individual drugs. Occurrence of blood dis-orders (agranulocytosis) is rare but can be serious. MAO inhibitors show fewer of these effects, except a tendency for ortho-static hypotension. Second-generation drugs show seizure possibilities but fewer of the other adverse reactions, except maprotiline, mirtazapine, nefazodone, and trazodone, which are similar to the tricy-clics. A few of the latter drugs may cause malignant hyperthermia. Lithium has a very small margin of safety requiring peri-odic blood level tests to avoid serious toxicity. Some adverse reactions include confusion, lethargy, ataxia, increased deep tendon reflexes and a fine tremor, and sei-zures and coma at higher doses.

DRUG INTERACTIONS • Antidepressant drugs can interact with

MAO inhibitors resulting in seizures and hypertension, as well as a large number of other drugs such as benzodiazepines and alcohol, resulting in enhanced sedation.

• Salt intake can affect lithium effects, and salt intake should not be changed dur-ing lithium therapy.

• MAO inhibitors can cause a severe hypertensive crisis with chest pain, headache, and nausea when taken with foods and drinks containing the chemi-cal tyramine.

• Drugs can show increased toxicity with many herbs, including St. John’ wort, chamomile, valerian, and jimsonweed. Increased toxicity of antidepressants occurs with methionine supplements.

IMPLICATIONS FOR PHYSICAL THERAPISTS • If the patient complains about not feel-

ing the beneficial effects of drug ther-apy in the first few weeks, advise the patient that it might sometimes take up to 6 weeks before such beneficial effects set in.

• If a patient should talk about “life is not worth living” in the beginning of ther-apy, notify the physician immediately because there is an increased risk of sui-cide during this time.

• If a patient on long-term therapy plans to discontinue the drug without advice of the physician, warn the patient and contact the physician because the pos-sibility of a serious withdrawal reaction exists.

• If a patient on lithium talks incessantly and becomes easily irritated and even aggressive, notify the physician because this might require a change in dosage.

• Advise the patient to change position or get up slowly because some drugs can cause marked orthostatic hypotension.

• Advise the patient on lithium to follow strictly the physician’s advice in taking

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the drug as prescribed and in having blood levels checked periodically. If the patient exhibits tremors, lethargy, hyperreflexia, and ataxia, notify the physician immediately because this may require dosage adjustments.

• Ask older patients if they have trouble voiding and if they have regular bowel movements, because some drugs with anticholinergic properties can cause urinary hesitancy and significant con-stipation. Advise these patients to increase water and bulk food intake to prevent constipation and its possible complications.

ANTIEMETIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Serotonin 3 AntagonistsDolasetron AnzemetOndansetron ZofranOtherHistamine AntagonistsDimenhydrinate Dramamine, Gravol,

other (OTC)Meclizine Antivert, Antrizine,

other (OTC)OtherPhenothiazinesChlorpromazine ThorazineProchlorperazine Compazine, otherPromethazine PhenadozOtherCholinergic AntagonistsScopolamine ScopolamineOtherMiscellaneous DrugsMetoclopramide Reglan, otherOther

MECHANISM OF ACTION Nausea and vomiting are complex pro-cesses involving dopamine, serotonin, acetylcholine, and histamine receptors in the stomach, as well as in two major CNS centers such as the chemoreceptor trig-ger zone and vomiting center. In addition, vestibular nuclei (motion sickness) influ-ence these centers. Nausea is an uneasy feeling and often the antecedent to vomit-ing, which occurs when abdominal mus-cles abruptly contract and expel the food from the stomach.

Serotonin antagonists block the stimu-latory action of serotonin on type 3 recep-tors in the stomach, intestines, and brain, reducing nausea and vomiting. Histamine antagonists block the action of histamine on H1 receptors in the periphery and pre-sumably with their cholinergic- blocking activity inhibit central activity in the ves-tibular system, as well as the chemore-ceptor trigger zone and vomiting center. The phenothiazines seem to exert their

action mostly via blockade of dopamine, histamine, and acetylcholine receptors. Metoclopramide seems to block dop-amine receptors in the chemoreceptor trigger zone and to increase gastric emp-tying time.

INDICATION Antiemetic drugs are indicated in the following: • For the prevention of and therapy for

nausea and vomiting; given before, during, and/or after surgery, cancer chemotherapy, or radiation therapy.

• Motion sickness (histamine antago-nists, scopolamine); mostly given 1 hour before exposure.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Dolasetron 100 mg once PO or

1.8 mg/kg once IV

Ondansetron 8 mg to be repeated when needed PO or 0.15 mg/kg to be repeated if needed IV

Dimenhydrinate 50-100 mg q4h POMeclizine 25-100 mg daily in

divided doses POChlorpromazine 10-25 mg q4-6h

PO or 25-50 mg q3h IM

Prochlorperazine 5-10 mg 3-4 times PO

Promethazine 12.5-25 mg q4-6h PO, IM, IV, or rectally

Scopolamine 1.5 mg transdermal (patch)

Metoclopramide 1-2 mg /kg can be repeated IV

ADMINISTRATION Depending on the drug, antiemetic drugs can be given PO, IV, IM, or rectally. Scopolamine is administered in a patch behind the ear.

CONTRAINDICATIONS Antiemetic drugs are contraindicated or should be used with caution in older patients (see sections on Antipsychotic and Anticholinergic Drugs).

COMMON ADVERSE REACTIONS Most antiemetic drugs cause sedation and drowsiness. Serotonin antagonists can cause musculoskeletal pain, dysrhyth-mias, and rarely, bronchospasm. Histamine antagonists cause sedation, confusion in geriatric individuals, dry mouth and eyes, and constipation. The phenothiazines can cause a number of adverse effects

(see Antipsychotic Drugs). Scopolamine causes anticholinergic effects (see Anticholinergic Drugs). Metoclopramide can cause seizures and suicidal ideation.

DRUG INTERACTIONS Serotonin antagonists show few inter-actions. Histamine antagonists show enhanced anticholinergic activity with all drugs that also have these effects. Phenothiazines show a series of interac-tions (see Antipsychotic Drugs).

IMPLICATIONS FOR PHYSICAL THERAPISTS • Observe patients for signs of dizziness

and drowsiness, in particular older indi-viduals, and be close by to prevent falls. In the case of phenothiazines, be aware of orthostatic hypotension.

ANTIFUNGAL DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Amphotericin B Fungizone, Abelcet,

otherAzole DrugsClotrimazole Mycelex, Lotrimin,

other (OTC)Itraconazole SporanoxMiconazole Monistat, otherOtherMiscellaneous DrugsGriseofulvin Grifulvin, otherNystatin Nilstat, Nystex, otherTolnaftate Tinactin, Aftate, otherOther

MECHANISM OF ACTION Fungi are single or multicellular organ-isms with a cell membrane and cell wall. The wall protects them from the environ-ment, and the membrane keeps in essen-tial nutrients necessary for metabolism inside the fungus. The fungal membrane contains phospholipids and ergosterol (while the human membrane contains cholesterol). They live mostly on plants, dirt, and water and are mostly pathogenic to plants. Human fungal infections or mycoses are rare except in patients with immunocompromise such as those with acquired immunodeficiency syndrome (AIDS) or those taking steroids, anticancer drugs, immune system suppressing drugs, and certain antibiotics; the latter can kill nonpathogenic bacteria that prevent fun-gal growth.

Antifungal drugs act on some of the fun-gal peculiarities. Amphotericin B binds to ergosterol and forms with it a channel through which necessary nutrients escape, leading to the death of the fungus. Azole

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drugs inhibit the enzyme that synthe-sizes ergosterol. This reduces formation of a firm membrane that is now leaky and leads to the loss of nutrients and death of the fungus. Nystatin acts similarly to ampho-tericin B, griseofulvin binds to spe cific fungal mitotic spindles during division and interferes with replication, and tolnaf-tate acts by an unknown mechanism.

Antifungal drugs are fungus specific and must often be taken for long periods of time and exactly as prescribed to be fully effective. Drug resistance is not a major problem with fungi at this time.

INDICATION Antifungal drugs are indicated in the following: • Topical and systemic fungal infections

affecting the skin, vagina, nails, lungs, and other parts of the body. Some exam-ples are systemic aspergillosis, candidi-asis, cryptococcosis, and histoplasmosis, which are treated with amphotericin B as a primary drug and sometimes with itraconazole as a secondary medica-tion; tinea infections (“ringworm”) with tolnaftate or clotrimazole; vulvovaginal candidiasis with clotrimazole; infections of the scalp, skin, and toes with griseof-ulvin, and oropharyngeal candidiasis with nystatin.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Amphotericin B 0.25-0.5 mg/kg IVClotrimazole Topical preparationsItraconazole 200-400 mg daily POMiconazole Topical preparationsGriseofulvin 500-1000 mg daily

PONystatin Topical preparations

and 500,000-1,000,000 U 3 times daily PO

Tolnaftate Topical preparations

ADMINISTRATION Amphotericin B is usually given by slow infusion with test doses preceding the actual therapeutic amounts. The other drugs are mostly given topically or orally.

CONTRAINDICATIONS Antifungal drugs are contraindicated or should be used with caution in patients with renal and hepatic disorders.

COMMON ADVERSE REACTIONS Amphotericin is quite toxic and can cause seizures, renal toxicity, blood dis-orders, and allergic reactions. The other drugs show few adverse reactions when given topically. Oral administrations carry a higher risk with nausea, vomiting, and

abdominal discomfort. Itraconazole can cause muscle pain and hepatotoxicity.

DRUG INTERACTIONS • Depending on the drug, the azole drugs

can interfere with the biotransforma-tion of other drugs and can increase each other’s toxicity.

• Gossypol increases itraconazole nephro-toxicity.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Advise the patient who uses OTC anti-

fungal preparations to contact a phy-sician because successful therapy of a fungal infection requires the expertise of a physician.

• Observe the patient who takes antifun-gal drugs, which can be hepatotoxic, for skin and eye color and notify the physician or have the patient contact the physician if yellowing of the skin or eyes is seen; this yellowing could be drug-induced liver toxicity.

• If you notice redness between the toes of a patient, notify the physician or have the patient contact the physician because this could be a tinea infection (athlete’s foot). If the patient is a stu-dent or a person using a locker room, you should also contact those facilities and have locker rooms disinfected.

ANTIHELMINTHIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Albendazole AlbenzaMebendazole VermoxPraziquantel BiltricidePyrantel Antiminth, Ascarel,

otherOther

MECHANISM OF ACTION Helminths, or worms, are multicellular organisms. They have different life cycles and often enter the body through their eggs located in dirty water or contami-nated food. They live in the intestines but also in other parts of the body, including the heart, muscles, and eyes. They can cause mild-to-severe clinical problems partly caused by competing for dietary needs by the human cells or by an inflam-matory response of the body.

INDICATION Antihelminthic drugs are indicated in the following: • Tape worm infections are treated with

praziquantal and albendazole, which paralyze or deprive the worms of glu-cose and nutrients.

• Fluke infections are treated with prazi-quantel, which paralyzes the flukes.

• Trichinosis and other infections are treated with albendazole or mebenda-zole, which deprive the worms of glu-cose and other nutrients.

• Drugs usually affect only adults but not eggs, which can infect other individuals during therapy.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Albendazole 400 mg 2 times daily

POMebendazole 100 mg 1-2 times a day

for 3 days POPraziquantel 20 mg/kg 3 times a

day POPyrantel 11 mg/kg once or for

3 days PO

ADMINISTRATION Depending on the antihelminthic drug, they are given mostly PO.

CONTRAINDICATIONS Antihelminthic drugs are contraindicated or should be used with caution in patients with hepatic diseases.

COMMON ADVERSE REACTIONS In general, antihelminthic drugs may cause nausea, headache, abdominal discomfort, and diarrhea (in addition to the use of a laxative which is often prescribed to help expel intestinal worms). Albendazole and mebendazole can be hepatotoxic.

DRUG INTERACTIONS Few serious interactions have been observed, except some drugs, including cimetidine (OTC), increase albendazole tissue concentrations.

IMPLICATIONS FOR PHYSICAL THERAPISTS • If a patient with a worm infection is

treated, wear gloves and wash hand thoroughly after therapy, because eggs can spread easily. If the patient uses the toilet, have the toilet cleaned with disin-fectant soap.

• If you notice a yellow skin color or yel-lowing of the eyes, notify the physician or have the patient contact the physi-cian because some drugs can cause liver problems.

ANTIHISTAMINIC DRUGS

DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) AntihistaminesCetirizine ZyrtecDesloratadine ClarinexDimenhydrinate Dramamine (OTC)

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Diphenhydramine Allermed, Benadryl, other (OTC)

Fexofenadine AllegraLoratadine Alavert, Claritin,

other (OTC)OtherMast-Cell StabilizerCromolyn NasalCrom, otherNedocromil TiladeCorticosteroids (see Corticosteroids)

MECHANISM OF ACTION Allergic reactions are unwanted, inflam-matory immune system responses based on a “peculiarity” of an individual’s immune system toward a specific chem-ical or substance and are manifested as redness, swelling, hives, runny nose and watery eyes (vasodilatation), and itching (activation of special nerves). In some cases, it can precipitate a potentially fatal anaphylactic reaction. The causes are sub-stances called antigens or allergens that are considered by the immune system of such individuals as “dangerous,” initiating the immune response or allergic reaction. The amount of allergens causing such reactions can be extremely small (part of a peanut or a whiff of shrimp). Different allergens cause the same clinical picture, which is in contrast to adverse reactions that are drug specific. There are four types of allergic reactions, but types I and IV are most important. Allergy type I is caused by combination of an allergen with anti-bodies type immunoglobulin (IGE) on mast cells releasing histamine. Onset is quick and occurs within minutes. Type IV involves the action of T cells and shows a similar clinical picture as type I, but the onset is delayed by 24 to 48 hours.

The typical antihistamines prevent his-tamine binding and replace already bound histamine on histamine 1 (H1) receptors and reduce or prevent vasodilation and activation of special nerves. Mast-cell sta-bilizers only stabilize mast cells and pre-vent histamine release with a delayed onset of action, but they do not act on already released histamine. Steroids (see Corticosteroid Drugs) cause blood ves-sel constriction and permeability reduc-tion by enhancing the sensitivity of α -receptors in blood vessels to circulating epinephrine. (see α -Agonists).

INDICATIONS Antihistaminic drugs are indicated in the following: • Type I allergy is caused by histamine

and its vasodilating and nerve-irritating action. Typical antihistaminics, mast-cell stabilizers, or steroids are used to antag-onize these effects. Massive histamine release precipitates an anaphylactic reaction (bronchoconstriction, marked fall in blood pressure), which responds

to epinephrine, causing vasoconstric-tion and bronchial relaxation.

• Type IV allergy is caused by T-cell actions and only steroids are effective. The cause of this allergy (e.g., cosmet-ics) is often difficult to identify because of delayed onset of action.

• Other uses such as motion sickness and nausea (dimenhydrinate, diphen-hydramine), Parkinson’s disease and nonproductive cough .

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Cetirizine 5-10 mg/day PODesloratadine 5 mg/day PODimenhydrinate 50-100 mg q4-6h PODiphenhydramine 25-50 mg q4-6h POFexofenadine 60-180 mg/day POLoratadine 10 mg/day POCromolyn 1 spray into each

nostril, not to exceed 6 sprays

Nedocromil 2 inhalations 2-4 times a day

ADMINISTRATION Antihistaminic drugs are administered PO, except for inhalations of mast-cell stabilizers.

CONTRAINDICATIONS Few contraindications exist except hyper-sensitivity to drugs.

ADVERSE REACTIONS All antihistamines cause some sedation and drowsiness, as well as anticholinergic effects (see Anticholinergic Drugs) but mostly with diphenhydramine. Hepatitis may occur with desloratadine, blood dis-orders (hemolytic anemia) have been reported with diphenhydramine and fexofenadine, and dysrhythmias with fex-ofenadine. Mast-cell stabilizers show few adverse reactions except some throat irritation.

DRUG INTERACTIONS • Enhanced sedation and anticholinergic

effects may occur with drugs that also have these effects. Alcohol enhances the sedative actions. Drugs used at higher doses can interfere with a num-ber of other drugs, although given at high doses.

• Sedative and anticholinergic effects are increased by hops, senega, and corkwood.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Antihistaminic drugs can produce some

sedation and confusion (mostly in geri-atric patients) and can interfere with therapy. Appointments should be sched-uled at the end of drug actions.

• Advise individuals who take OTC anti-histaminic drugs that they can inter-fere with urination in cases of benign prostatic hyperplasia in older men and can cause contact lens intolerance. Self-medication is recommended for short periods of time only.

• Advise patients that diphenhydramine is not recommended by physicians to be used as a hypnotic because it does not cause a restful sleep.

ANTILIPIDEMIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) HMG-CoA Reductase InhibitorsAtorvastatin LipitorFluvastatin LescolLovastatin Altocor, MevacorRosuvastatin CrestorSimvastatin ZocorBile Acid SequestrantsCholestyramine LoCholest,

Prevalite, otherColesevelam WelCholColestipol ColestidMiscellaneous DrugsEzetimibe ZetiaFenofibrate Antara, Lofibra,

otherGemfibrozil LopidNiacin Niac, Niaspan,

other (also available OTC)

Also available as nicotinic acid and nicotinamide

MECHANISM OF ACTION Lipids, such as cholesterol and triglycer-ides, are essential chemicals (e.g., choles-terol is part of the cell membranes and triglycerides liberate fatty acids, via the enzyme lipoprotein lipase, which are used as an energy source). Cholesterol is derived from our diet (exogenous source; about 15%). Cholesterol is also synthesized in the liver from precursors by hydroxyl-3-methyl- glutaryl coenzyme A reductase or HMG-CoA (endogenous source; about 85%). Some of the endogenously synthe-sized cholesterol moves into the blood directly, and some is secreted in the bile into our intestines to help absorb fats and later on is absorbed back into the body and enters the blood. In the blood, cholesterol and triglycerides are bound to specific proteins to form lipoproteins, which differ in size and function. Among them are the very low density lipopro-teins (VLDLs), which are later converted to low density lipoproteins (LDLs). Other lipoproteins are the high density proteins (HDLs). Generally, the LDLs deliver and

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deposit cholesterol to blood vessel mem-branes (“bad” cholesterol) and tissues, while the HDLs remove cholesterol from blood vessels (“good” cholesterol). High levels of HDL can partially counteract the “bad” effects of LDL.

Antilipidemic drugs affect various steps in the absorption and metabolism of cho-lesterol. The HMG-CoA reductase inhibi-tors (“statin” drugs) inhibit the enzyme in the liver that synthesizes cholesterol, thereby lowering cholesterol levels. Bile acid sequestrants bind to cholesterol in the intestines, prevent its absorption into the blood, and excrete it with the feces. Ezetimibe prevents the absorption of cho-lesterol in the small intestines and also excretes it with the feces. Fenofibrate increases lipolysis by activating lipopro-tein lipase, which decreases triglycerides levels and changes the size of the LDLs to render them less effective because it pro-motes their rapid breakdown. Gemfibrozil decreases triglyceride levels and inter-feres with the synthesis of VLDLs, which also reduces LDL levels. Niacin or vitamin B3 reduces the release of fatty acids from fat, decreases LDLs, and perhaps most sig-nificantly, seems to increase HDLs.

Recently, it was shown that the “statin” drugs are also antiinflammatory, provid-ing additional benefits to individuals with high C reactive protein levels and high risk of cardiovascular accidents.

INDICATION Antilipidemic drugs are indicated in the following: • Dyslipidemias (genetic basis, diet,

diseases such as diabetes, or drugs) are characterized by increased levels of cholesterol and/or triglycerides in the blood. If levels are permanently ele-vated, pathological changes can occur in blood vessels. Initiated by a chronic inflammatory response in the vessel walls partly caused by the action of white blood cells, LDLs deposit exces-sive amounts cholesterol and trig-lycerides without adequate removal. This leads to hardening of the arteries (arteriosclerosis) and the formation of plaques (atherosclerosis) that narrow and finally block blood vessels. The hardening of blood vessels increases blood pressure and impairs the supply of nutrients and oxygen to tissues, including the heart and brain. Parts of these plaques can break loose and block subsequent smaller vessels. In addition, small blood clots formed elsewhere can get stuck in and block such nar-rowed vessels. These can be the cause of MI and stroke. Although high choles-terol and lipid levels increase the risk of such events, they are only soft indi-cators because some individuals with low cholesterol levels can have strokes

and MIs and some individuals with high levels might not. Drugs used in hyper-cholesterolemia and/or elevated trig-lyceride levels will lower cholesterol and lipid levels by various actions, and thus reduce the risk of arteriosclerosis and the sequela of cardiac and central problems. The HMG-CoA reductase inhibitors are the most effective drugs for lowering cholesterol and can lower cholesterol levels by about 30%.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Atorvastatin 10-80 mg once daily

(not to exceed 80 mg/day) PO

Fluvastatin 20-80 mg once or divided PO

Lovastatin 20-80 mg in single or divided doses PO

Rosuvastatin 5-40 mg daily POSimvastatin 5-40 mg daily (not

to exceed 80 mg/day) PO

Cholestyramine 4 g twice a day up to 24 g/day PO

Colesevelam Three 625 mg tabs twice a day PO

Colestipol 2-8 g twice a day POEzetimibe 10 mg/day POFenofibrate 40-160 mg /day POGemfibrozil 600 mg twice a day

PONiacin 100-500 mg/day in

divided doses

ADMINISTRATION Drugs can be given IV or PO. Some of these drugs can be prescribed in combination.

CONTRAINDICATIONS Antilipidemic drugs should not be used or must be used with caution in individuals with hepatic diseases.

COMMON ADVERSE REACTIONS Common adverse reactions include head-ache, abdominal cramps, dizziness, and heartburn.

In addition, HMG-CoA reductase inhibi-tors can cause lens opacities (eye exami-nations are warranted), liver dysfunction (frequent liver function tests are indi-cated in the beginning of therapy), mus-cle pain with rhabdomyolysis (breakdown of skeletal muscle), hemolytic anemia, and photosensitivity reactions. Bile acid sequestrants can cause constipation; fecal impact; flatulence; decreased absorption of vitamins A, D, and K with increased risk of bleeding; red blood cell forma-tion; and hyperchloremic acidosis (rapid breathing, confusion). Ezetimibe causes

few major adverse reactions. Fenofibrate can cause dysrhythmias. Gemfibrozil can cause leukopenia and anemia. Niacin causes flushing, orthostatic hypotension, and sometimes hepatotoxicity (jaundice, dark urine).

DRUG INTERACTIONS • HMG-CoA reductase inhibitors in the pres-

ence of some antifungal drugs, erythro-mycin, and niacin show an increased risk of rhabdomyolysis. Bile acid sequestrants can interfere with the absorption of many drugs.

• Grapefruit juice may increase toxic-ity, and St. John’s wort and bran may decrease therapeutic response.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Ask the patient who is overweight and

not taking antilipidemic drugs if choles-terol levels have been checked in the past. If not, strongly advise the patient to see a physician because high cholesterol levels can be a silent (no symptoms) killer.

• Warn patient not to self-medicate with OTC niacin because the use of niacin should be monitored by a physician because niacin can cause liver damage. Blood tests are necessary during ther-apy, and early detection of such a prob-lem can prevent liver damage.

• If patient is using an HMG-CoA redu-ctase inhibitor or a statin drug and complains about muscle pain or men-tions a darkening of the urine, contact the physician or have the patient notify the physician immediately because this could be a sign of rhabdomyolysis.

• Tell the patient to see the physician at scheduled intervals in particular in the beginning of therapy because special laboratory tests have to be made to assure that no adverse liver reac-tions manifest themselves with some of the drugs like niacin and HMG-CoA reductase inhibitors. Early detection can prevent permanent damage.

• Advise the patient that in addition to drug therapy a diet low in cholesterol and fats should be followed combined with some daily exercise and a normal body weight.

ANTINEOPLASTIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Alkylating AgentsCarmustine BCNU, GliadelCyclophosphamide Cytoxan, NeosarMechlorethamine Mustargen,

Nitrogen Mustard

Other

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Platinum Containing CompoundsCisplatin PlatinolOtherAntimetabolitesFluorouracil Adrucil, Efudex,

otherMercaptopurine PurinetholMethotrexate Amethopterin,

Folex, otherAntibioticsBleomycin BlenoxaneDactinomycin CosmegenDoxorubicin AdriamycinOtherPlant AlkaloidsEtoposide VePesid,

EtopophosPaclitaxel Taxol, OnxolTopotecan HycamtinVincristine Oncovin, VincasarOtherTyrosine Kinase inhibitorsErlotinib TarcevaOtherBiological Response ModifiersInterferons Roferon, PEG-

INTRON, otherRituximab RituxanOtherOther DrugsHydroxyurea Droxia, HydreaOther

MECHANISM OF ACTION Neoplastic cells roughly divided into tumor (not spreading) and cancer (spread-ing or metastasizing) cells divide faster and do not die (show no apoptosis or controlled cell death). They rapidly form and synthesize new DNA-RNA proteins. However, all cells in a tumor do not pro-liferate at the same time. In addition, they form new blood vessels (angiogenesis) to support this rapid cell growth.

Antineoplastic drugs limit or stop this excessive proliferation by killing these cells or by attenuating their divisions. This interference can occur at specific phases of mitosis (cell cycle specific drugs mostly at S phase in which DNA synthe-sis occurs) or more generally (nonspecific drugs). Alkylating agents bind covalently to two opposite bases and crosslink the two DNA strands together so that they can not separate, which is necessary for cell division. Platinum-containing compounds also crosslink DNA strands and prevent their separation. Antimetabolites are drugs that are structurally similar to some of the endogenous bases necessary for DNA syn-thesis. These drugs are either incorporated into the DNA chain where they produce a nonfunctioning base or DNA sequence or inhibit the enzymes that are forming the endogenous bases from precursors; in both cases, normal DNA synthesis and

proliferation is impaired. Antibiotics only used for neoplastic diseases act in differ-ent and often poorly understood ways. They might be inserted into DNA strands, cause strand splitting, inhibit DNA-related enzymes, form highly toxic radicals, and/or disturb the cell walls of these cells. Plant alkaloids are either antimitotic drugs that bind to and disrupt the function of the microtubules, which are necessary for cell division, or enzyme inhibitors, which inhibit certain enzymes (topoisomerase), causing a break in the DNA strands. Tyrosine kinase inhibitors inhibit a special tyrosine kinase enzyme that participates in the rapid cell division of these neoplas-tic cells. Biological response modifiers are interleukins, interferons, and monoclonal antibodies (ending in -mab), which among other actions stimulate the body’s immune system to fight such abnormal cells. In addition, a number of other drugs are available that act by different often poorly understood mechanisms.

Because all cells will not proliferate at the same time, only a fraction will be killed by a drug at one treatment. Thus multiple drugs with different modes of action and repeated treatments often have to be employed to increase the num-ber of cells being killed (or to increase the “total cell kill”). It is then hoped that the remaining cells will be eliminated by the body’s immune system. Another com-plication is the occurrence of drug resis-tance in which neoplastic cells develop mechanisms that render these drugs inef-fective. Such cells might have “pumps” that remove the drug from the cell, form chemicals to which the drug binds, or develop repair mechanisms that repair drug-induced damage.

INDICATION Antineoplastic drugs are indicated in the following • All types of tumors and cancers . Drugs

interfere selectively with different steps in DNA synthesis, cell division, and growth. The specific drug used depends on the type of neoplasm to be treated. “Cocktails” or 2 to 5 drugs are used simul-taneously to increase “total cell kill.”

• Other uses such as keratoses (fluorou-racil), ulcerative colitis, and psoriatic arthritis (mercaptopurine).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Carmustine 150-200 mg/m 2

single dose every 6 weeks IV

Cyclophosph amide 1-5 mg/kg/day PO or 40-50 mg/kg in divided doses over 2-5 days IV

Mechloretha mine 0.4 mg/kg as single or divided doses over 2-4 days IV

Cisplatin 20-100 mg/m 2 once or for several days every 3–4 weeks IV

Fluorouracil 370-425 mg/m 2 daily for 5 days IV

Mercaptopurine 2.5-5 mg/kg/day PO

Methotrexate 15-30 mg/day for 5 days PO, IM or 40 mg/m 2 IV

Bleomycin 0.25-0.5 units/kg 1-2 times weekly SC, IV, IM or 15 units 2 times weekly IV

Dactinomycin 500 µ g/m 2 /day for 5 days to be repeated IV

Doxorubicin 60-75 mg/m 2 3 times a week IV

Etoposide 50-100 mg/m 2 for 5 days to be repeated every 3-4 weeks IV

Paclitaxel 175 mg/m 2 over 3 hrs every 3 weeks for 4 courses IV

Topotecan 1.5 mg/m 2 /day for 5 days IV

Vincristine 1-2 mg/m 2 /wk IVErlotinib 150 mg daily POInterferons Many different

schedules depending on interferon

Rituximab 375 mg/m 2 once weekly for 4-8 doses IV

Hydroxyurea 80 mg/kg single dose every 3 days PO

ADMINISTRATION Depending on the drug, antineoplastic drugs can be given PO, IV, intracavitary, intrapericardial, or by infusion. Drug com-binations and schedules depend on the type of cancer and the tolerance of the patient.

CONTRAINDICATIONS Antineoplastic drugs are contraindicated or should be used with caution in patients with infections, anemia, or ulcers. Because neoplasm is eventually a fatal disease, therapy usually overrides most possible contraindications.

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COMMON ADVERSE REACTIONS Many adverse reactions are shared by antineoplastic drugs and are caused by interference with DNA synthesis and multiplication of healthy but rapidly dividing cells. Hair formation is inhibited in the hair follicles, resulting in hair loss. Suppression of bone marrow leads to a paucity of erythrocytes with anemia, platelets with bleeding episodes, and leu-kocytes with a decrease in immune activ-ity and an increased risk of infections. The latter adverse reactions can be coun-teracted (see sections on Hemopoietic Drugs and Immunomodulators). Effects on the GI system cause nausea, vomiting, diarrhea, lesions, and ulcers, and antidiar-rheal drugs or antiemetic drugs can pro-vide relief (see Antiemetics Drugs). Also, fatigue is commonly encountered with these drugs. Fortunately, many of these adverse reactions are reversed when drug therapy is stopped. In addition, renal, cardiac, and hepatic toxicities can occur. Different chemotherapeutic drugs will show their own toxicities in addition such as pulmonary fibrosis, seizures, and allergic reactions, including anaphylaxis.

DRUG INTERACTIONS Depending on the drug, many interactions are possible, in particular with drugs that weaken the immune system, affect blood clotting, and may cause anemia. NSAIDs increase GI problems.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Inquire about unusual bleeding episodes

(bruising, gum bleeding) and touch the patient gently because the ability for blood clotting may be seriously impaired. If such hemorrhagic episodes are pres-ent, have patient inform the physician.

• Do not treat the patient if you have an infectious disease because the patient’s immune system is weakened. Also, sep-arate this patient from other patients and inform the patient to avoid public, crowded places because of the increased risk of an infection.

• Assess the patient’s breathing abil-ity because these drugs can affect the lungs. If impairment is noticed, have the patient inform the physician.

• Many cancers involve pain and the use of pain medication. The use of mas-sage, heat, and transcutaneous electrical nerve stimulation (TENS) can provide some pain relief and reduce the use of pain medications.

• The physical therapist can encour-age the patient by assuring him or her that many of the cancers can now be cured or placed into long-lasting remis-sion and that most of the bothersome adverse reactions will disappear after cessation of therapy.

ANTIPROTOZOAL DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Chloroquine AralenMefloquine LariamMetronidazole Flagyl, ProtostatPrimaquine PrimaquinePyrimethamine Daraprim, Fansidar

(with sulfadoxine)Other

MECHANISM OF ACTION Protozoans are one-celled organisms liv-ing mostly in dirty water. They are sub-divided into many subgroups. They have complex and different life cycles and can affect different parts of the body.

Antiprotozoal drugs interfere relatively selectively with the metabolism of the par-asites such as feeding habits in red blood cells (RBCs), DNA synthesis, and/or some other poorly understood mechanisms. Chloroquine and mefloquine bind to the DNA of the certain parasites and inter-fere with transcription and also inhibit the parasitic enzyme heme polymerase, which inactivates free heme that is toxic to the parasite (plasmodium). Some spe-cies have become resistant to the drug. Pyrimethamine is a folate antagonist with a higher affinity for the parasitic than the host folate metabolism. Primaquine act-ing by uncertain mechanisms kills per-haps by impairing DNA function of the exo-RBC forms of the parasite in the liver. Metronidazole is believed to be metabo-lized to a substance that binds to and inhibits parasitic DNA synthesis.

INDICATION Antiprotozoal drugs are indicated in the following: • Malaria is a mosquito-borne disease

that is caused by the plasmodium spe-cies. These parasites enter the human blood stream via a female mosquito bite and later are taken up from the blood by the mosquito to be introduced into other humans. Different species cause different problems, ranging from mild-to-severe forms of the disease. They accumulate in the liver and RBCs where they feed on hemoglobin and multiply. Chloroquine, mefloquine, and other drugs are used. Parasites are becoming more resistant to drug therapy.

• Amoebiasis is caused by an amoeba and results in mild-to-severe diarrhea, and trichomoniasis is a protozoal infec-tion of the vagina (men usually remain asymptomatic). In both cases, metron-idazole is used (which also has anti-bacterial activity), and it is relatively nontoxic.

• Acanthamoeba keratitis (red, painful eyes bothered by light) is caused by acanthamoeba living in dirty water and in nonsterile solutions used for clean-ing contact lenses. Therapy includes use of itraconazole, polymyxin, and/or neo-mycin or polymyxin B (see Antifungal Drugs) for prolonged periods, some-times months.

• Toxoplasma gondii is a protozoal infec-tion transmitted to humans via cat feces or contaminated meat. Drugs of choice are pyrimethamine-sulfadiazine, which interfere with protozoal folic acid metabolism.

• Other protozoal infections are mostly present outside the United States.

• Other uses such as rheumatoid arthri-tis (chloroquine).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Chloroquine 5 mg/kg/wk 1-2 wks

before exposure and for 8 wks after leaving the endemic area PO

Mefloquine 1250 mg once PO, not to be repeated

Metronidazole 250 mg 3 times daily for 7 days PO or 2 g once PO

Primaquine 15 mg daily POPyrimethamine 100 mg followed by

25 mg/day for 4-5 wks PO

ADMINISTRATION Depending on the drug, antiprotozoal drugs can be administered IM and PO.

CONTRAINDICATIONS Antiprotozoal drugs are contraindicated or should be used with caution in blood disorders for antimalarial drugs.

COMMON ADVERSE REACTIONS Most antiprotozoal drugs are tolerated rel-atively well and most adverse reactions are observed after high dose and long-term therapy. Chloroquine can affect the retina and heart, and primaquine might cause hemolytic anemia in susceptible indi-viduals. Metronidazole is associated with bone marrow depression and seizures. Pyrimethamine might cause seizures, agranulocytosis, and respiratory problems.

DRUG INTERACTIONS • Antimalarials show few interactions

with other drugs. • Folic acid supplements may decrease

action of folate inhibitors. Acidophilus should not be taken simultaneously with metronidazole.

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IMPLICATIONS FOR PHYSICAL THERAPISTS • Inquire about the color of the urine

in patients on primaquine because this drug can cause hemolytic anemia. If color changes are noted, inform the physician or have patient contact the physician.

• If a patient on chloroquine therapy mentions visual disturbances, inform the physician or have the patient con-tact the physician because this drug can damage the retina.

• Advise contact lens wearers to use sterile solutions and be careful in cleaning contact lenses because an acanthamoeba infection is very difficult to treat and carries certain health risks that could have been easily prevented.

ANTIPSYCHOTIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) PhenothiazinesChlorpromazine Thorazine, otherFluphenazine Prolixin, ModitenPerphenzine Perphenzine,

TrilafonProchlorperazine Chlorpazine,

Compazine, otherThioridazine MellarilThiothixene Navane (rarely used)Trifluoperazine Stelazine, Suprazine,

otherButyrophenoneHaloperidol HaldolMiscellaneous DrugsAripiprazole AbilifyClozapine ClozarilLoxapine LoxitaneOlanzapine Zydis, ZyprexaPaliperidone InvegaQuetiapine SeroquelRisperidone RisperdalZiprasidone Geodon

MECHANISM OF ACTION Mental activities such as perception of real-ity, cognitive functions, and mood are reg-ulated by the harmonious interaction of a multitude of chemical (neurotransmitters) processes and electrical circuits. Normal functioning of dopamine and dopamine receptors, mostly D2, D3 subtype, in the mesolimbic and mesocortical areas of the brain are of utmost importance. In addition, α -adrenergic, serotonergic, glutaminergic, and cholinergic receptors also play a role.

The typical antipsychotic drugs block mostly D2 receptors, whereas their actions on other receptors like α - and cholinergic receptors are more involved in adverse reactions. Blockade of the dopaminergic receptors may cause their

upregulation, which takes time and may explain the delayed therapeutic effect seen in patients. The atypical antipsy-chotic drugs also block dopaminergic receptors (D2, D3), but less and have a more significant action on inhibiting serotonergic (1A, 2A) receptors.

INDICATION Antipsychotic drugs are indicated in the following: • Schizophrenia is characterized by delu-

sions, hallucinations, thought disorders (positive symptoms), reduced emotions, reduced social contact, reduced speech, and reduced pleasure (negative symp-toms). Studies have shown the brains of schizophrenic patients to show cer-tain abnormalities like enlarged cere-bral ventricles, a decreased number of synaptic connections in the prefrontal cortex, and an increased or decreased functioning of dopamine D2, D3 recep-tors, depending on the area. All drugs affect a number of neurotransmitters, but they all seem to cause a blockade and perhaps upregulation of dopamin-ergic receptors (mostly D2 receptors). The typical antipsychotics also affect other receptors such as blockade of α -receptors with a decrease in blood pressure; cholinergic receptors with dry mouth, blurred vision, and consti-pation (see Anticholinergic Drugs); and dopamine receptors in the basal gan-glia with movement disorders (see CNS Dopaminergic Agonists). They mostly alleviate positive symptoms. The atypi-cal antipsychotic drugs block dopamin-ergic and serotonergic receptors and alleviate some of the positive and neg-ative symptoms. Clinically, about one-third of patients improves markedly, one-third improves somewhat, and one-third does not respond.

• Other uses for individual drugs include depression (see Antidepressant Drugs), dementia in older individuals (thi-oridazine), nausea (see Antiemetic Drugs), Tourette’s syndrome (see Movement Disorders), and mania (see Antidepressant Drugs).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Chlorpromazine 10-50 mg q2h with

a gradual increase up to 2 g/day PO

Fluphenazine 2.5-10 mg in divided doses up to 40 mg/day PO

Perphenazine 8-16 mg in divided doses up to 64 mg/day PO

Prochlorperazine 5-10 mg 3-4 times a day up to 150 mg/day PO

Thioridazine 25-100 mg 3 times a day up to 800 mg/day PO

Thiothixene 2-5 mg2-3 times a day up to 30 mg/day PO

Trifluoperazine 2-5 mg 2 times daily up to about 40 mg/day PO

Haloperidol 0.5-5 mg 2-3 times daily up to 100 mg/day PO

Aripiprazole 10-15 mg/day up to 30 mg/day PO

Clozapine 300-600 mg in divided doses PO

Loxapine 10 mg 2-4 times daily up to 100 mg/day PO

Olanzapine 5-10 mg/day up to 15 mg/day PO

Paliperidone 6 mg/day POQuetiapine 25 mg 2 times daily up

to 300 mg/day PORisperidone 1 mg 2 times a day up

to about 3 mg POZiprasidone 20 mg 2 times daily

up to 80 mg/day PO

ADMINISTRATION Antipsychotic drugs can be given orally or by injection, including depot preparations because psychotic patients often refuse to take the medication as prescribed.

CONTRAINDICATIONS Antipsychotic drugs should not be used or must be used with caution in patients with hepatic disorders, hyper- or hypoten-sion, and cerebral arteriosclerosis.

COMMON ADVERSE REACTIONS Common adverse reactions for most drugs include sedation and dizziness. Typical antipsychotics can cause pseudoparkin-sonism, dystonia, akathisia, irreversible tardive dyskinesia, seizures, malignant hyperthermia, orthostatic hypotension, tachycardia, cardiac arrest, jaundice/ hepatitis, constipation, urinary hesitancy, laryngospasm, respiratory depression, and rarely, agranulocytosis. Some drugs inter-fere with body temperature regulation. Haloperidol has similar adverse reactions but seems to be less anticholinergic but more dopaminergic. Atypical antipsychot-ics have similar adverse reactions but show less respiratory effects and a decreased risk of developing tardive dyskinesia.

DRUG INTERACTIONS • These drugs interact with a large num-

ber of drugs, in particular, drugs with

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sedative, anticholinergic, and antihyper-tensive actions.

• Henbane leaves, nutmeg, and kava increase their toxicities.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Patients often may not be cooperative

or they may be fearful of novel environ-ments and procedures if their paranoia is only partially controlled by drugs.

• Check the patient for movement prob-lems such as pseudoparkinsonism, dys-kinesia, dystonia, akathisia, and tardive dyskinesia, and if detected, inform the physician directly because the patient might not do so.

• Watch for orthostatic hypotension with some of the drugs and have the patient change positions slowly or avoid long standing periods. Watch the patient leaving a warm therapeutic pool to avoid fainting.

• Patients who are on medications with strong anticholinergic actions will show an increase in heart rate; advise the patient to chew gum when a dry mouth becomes a disturbing problem.

• Ask older patients on drugs with strong anticholinergic actions if they have experienced constipation or uri-nary hesitance (mostly men) and if yes, inform the physician to avoid complica-tions of constipation or possible urinary retention.

• Check older patients who have received olanzapine IM for respiratory problems, and notify the physician immediately if such problems are detected to avoid the occurrence of pneumonia.

ANTIVIRAL DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) DNA InhibitorsAcyclovir ZoviraxFamciclovir FamvirFoscarnet FoscavirGanciclovir Cytovene, VitrasertValacyclovir ValtrexOtherNeuraminidase InhibitorsOseltamivir TamifluOtherReverse Transcriptase InhibitorsStavudine ZeritTenofovir VireadZidovudine RetrovirOtherProtease InhibitorsLopinavir Kaletra (with

ritonavir)Ritonavir NorvirOther

Miscellaneous ActionAmantadine Symadine, SymmetrelEnfuvirtide FuzeonInterferonsOther

MECHANISM OF ACTION Viruses consist of single or double strands of DNA or RNA enclosed in a protein coat (capsid). They need the metabolism of a specific host cell to multiply (loss of drug specificity occurs because they partly use the host cell metabolism). The life cycle of a virus generally involves attaching to a host cell, penetrating, uncoating (shed-ding the protein coat), incorporating viral DNA into the host cell DNA, forming indi-vidual virus parts, cutting long proteins to the size needed by the virus (done by spe-cial proteases), assembling new viruses, and leaving the cell. Influenza viruses also need the enzyme neuraminidase to complete their biosynthesis and release. Some RNA viruses must first form DNA, whereas others can synthesize proteins directly. Viruses then affect other cells but can also retreat during drug treatment into tissues in which they hide and can-not be attacked by the immune system. Thus virus infections are difficult to cure (e.g., herpes infections) and some can reemerge after decades of inactivity (e.g., shingles after a chicken pox infection).

Antiviral drugs exploit some of the differences between the host cell and virus. DNA inhibitors are first monophosphory-lated (some by viral enzymes) and then diphosphorylated and triphosphorylated by host cell enzymes; the triphosphory-lated compound is the active antiviral com-pound and competes with endogenous bases for DNA polymerase and is partly incorporated as a “faulty” base terminating viral DNA chain synthesis. Foscarnet works in a similar fashion but does not have to be phosphorylated. Neuraminidase inhib-itors inhibit the enzyme neuraminidase and interfere with the completion of the synthesis and release of influenza viruses. Reverse transcriptase inhibitors affect RNA viruses where RNA is first transcribed into DNA by the enzyme reverse transcriptase whose action is inhibited by these drugs resulting in impairment of DNA synthesis and viral multiplication. Protease inhibi-tors inhibit proteases and prevent the cleavage of the newly formed long protein molecules into smaller protein molecules necessary for viral assembly. Some drugs act by interfering with the attachment/penetration and uncoating (amantadine, enfuvirtide), and others (interferons) pro-tect neighboring cells from being infected Vaccines can prevent many viral infections today.

Antiviral drugs can be given prophylac-tically and therapeutically. Unfortunately,

viruses become more and more resistant to these drugs by losing some of their special enzymes or by altering their DNA expression.

INDICATION Antiviral drugs are indicated in the following: • Herpes infections: Both initial and recur-

rent infections are treated with acyclo-vir or valacyclovir.

• Herpes and zoster infections are treated with famciclovir or valacyclovir.

• Influenza A and B infections are treated with oseltamivir (A and B) or amantadine (A).

• Cytomegalovirus infections are treated with ganciclovir.

• Chronic hepatitis can be treated with interferon α -2b or peg-interferon α -2a.

• AIDS is treated mostly with reverse tran-scriptase inhibitors, protease inhibitors, and enfuvirtide. Antiviral drugs mostly in combination have to be given for long periods. During pregnancy, they can prevent vertical transmission of the virus (mother to fetus).

• Transplants: Drugs, such as ganciclovir, are given to prevent viral infections in the recipient.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Acyclovir 200-800 mg q4h POFamciclovir 500 mg q8h POFoscarnet 60 mg/kg given over

1 hr q8h for 2-3 weeks IV

Ganciclovir 1000 mg 3 times daily PO or 5 mg/kg/dose over 1 hour for 2-3 weeks IV

Valacyclovir 1000 mg 3 times daily PO

Oseltamivir 75 mg 2 times daily POStavudine 40 mg q12h POTenofovir 300 mg once daily POZidovudine 600 mg/day in divided

doses or 1-2 mg/kg q4h IV

Lopinavir 400/100 mg 2 times daily or 800/200 mg once daily (with ritonavir) PO

Ritonavir 300 mg 2 times daily followed by increased doses up to 600 mg 2 times daily PO

Amantadine 200 mg/day or 100 mg 2 times daily PO

Enfuvirtide 90 mg 2 times daily SCInterferons Different schedules

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ADMINISTRATION Depending on the drug, antiviral drugs can be given PO, IV, SC, or topically (on blisters and eyes). Some must be injected into the eye.

CONTRAINDICATIONS Antiviral drugs are contraindicated or should be used with caution in patients with blood, renal, and hepatic disorders.

COMMON ADVERSE REACTIONS Generally, most antiviral drugs can affect the kidneys, liver, and blood. Drugs taken at high doses may precipitate in the kid-neys to form stones that can be prevented by consumption of large quantities of water. Also, neuralgia and myopathies are encountered. Except for the reactions mentioned previously, DNA inhibitors are generally well tolerated except foscarnet which can cause cardiac arrest, acute renal failure, pulmonary embolism, and bron-chospasm. Neuraminidase inhibitors, such as oseltamivir, may cause Stevens-Johnson syndrome. Reverse transcriptase inhibi-tors can cause blood dyscrasias and hepa-totoxicity. Protease inhibitors may shift fat from other body places to the abdo-men and cause insulin resistance, as well increase cardiovascular risks. Amantadine has been associated with mood changes, loss of concentration in elderly individu-als, and orthostatic hypotension, and enfu-virtide can cause neuropathy. Interferons have been associated with neuropsychi-atric disorders, pancreatitis, blood dyscra-sias, and autoimmune disorders.

DRUG INTERACTIONS • DNA inhibitors show few serious interac-

tions. Antiviral drugs taken at high doses will interact with other drugs because of interference with renal excretion or metabolism. Some antiviral drugs inter-act with each other and when they are to be used simultaneously, administra-tion must be spaced. Lopinavir/ritona-vir interacts with sildenafil and related drugs to cause severe hypotension. Ritonavir interacts with a large num-ber of drugs, including St. John’s wort, which decreases its efficacy.

• Use of alcohol will increase toxicity of most drugs.

IMPLICATIONS FOR PHYSICAL THERAPISTS • If a skin rash is noticed, notify the phy-

sician or have the patient contact the physician because some drugs can cause the Stevens-Johnson syndrome.

• If you notice a yellow skin color or yellowing of conjunctiva, have patient contact or personally inform phy-sician because some drugs can be hepatotoxic.

• Emphasize that mothers should follow the physician’s instructions and not breast feed because some drugs can pass through the milk into the child.

• Watch male patients carefully who use lopinavir/ritonavir and drugs for erec-tile dysfunction because they are prone to experience severe hypotensive episodes with syncope.

• If the patient has been instructed to drink large amounts of fluids, have the patient periodically drink water in particular when he/she is sweating to prevent formation of kidney stones.

• Emphasize to the patient that open her-pes blisters will transmit the virus by contact and advise abstinence from or use of condoms during intercourse.

ANXIOLYTIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) BenzodiazepinesAlprazolam XanaxChlordiazepoxide Librium, otherClonazepam KlonopinClorazepate TranxeneDiazepam Valium, otherLorazepam AtivanOxazepam SeraxAzapironesBuspirone BuSparAntidepressants (see Antidepressant Drugs) Doxepin Hydroxyzine Paroxetine Venlafaxine

MECHANISM OF ACTION Normal anxiety is characterized by acceptable tension, apprehension, and nervousness in response to appropriate environmental challenges and is a helpful part of human life. Anxiety is controlled by many chemical processes (neurotrans-mitters) and electrical circuits. In this case, the neurotransmitter GABA in the limbic and hypothalamic areas seems to play a major role. GABA is formed in spe-cial neurons, then released and interacts with GABA receptors (subtypes A, B, C, and more) on adjacent neurons to open chloride channels in their neuronal mem-branes. Influx of negative chloride ions hyperpolarizes these cells and reduces their firings or activity. Thus, depending on the circumstances, the inhibitory GABA system can cause anxiety when indicated by decreasing its action and terminate anxiety when not necessary by increasing its action. In addition, GABA also controls

skeletal muscle activity and increased GABA actions causes muscle relaxation. In addition to GABA, other neurotrans-mitter systems also play a role like the serotonergic system.

Benzodiazepine drugs act on various sites of the GABA-receptor complex in which they all seem to enhance the action of GABA, increase hyperpolarization of overly excited neurons, and reduce their neuronal firing, resulting in a decrease in anxiety. Buspirone does not act on GABA but is a serotonin partial agonist on the serotonergic receptors. Antidepressant anxiolytics act on norepinephrine and/or serotonin (see Antidepressant Drugs).

INDICATION Anxiolytic drugs are mainly indicated in the following: • Anxiety disorders are characterized

by an excessive, irrational fear of every situation, which can be disabling and significantly interfere with daily activ-ities and functioning of the individ-ual. There are five types: Generalized Anxiety Disorder (chronic exaggerated worry, tension, insomnia, and irritabil-ity with no apparent cause), Obsessive-Compulsive Disorder (urgent need to engage in certain rituals such as obsessing over germs or dirt and wash-ing hands over and over again), Panic Disorder (pounding heart, chest pains, lightheadedness or dizziness, nausea, shortness of breath, fear of dying, sweating, and feelings of unreality), Posttraumatic Stress Disorder (persis-tent frightening thoughts and mem-ories of past ordeals), and Phobias (irrational fear of things, animals, or people). In these cases, the existing GABA and/or the serotonergic systems are apparently not able to dampen excessive neuronal excitation to a more normal level. Benzodiazepines increase GABA action, increase hyper-polarization in adjacent cells, reduce their neuronal firing, and dampen excessive neural activity, leading to a relatively quick reduction of anxiety. Buspirone also dampens excessive neuronal activity but through agonis-tic actions on the serotonin receptors, resulting in a delayed (2 to 4 weeks) antianxiety effect. Antidepressant drugs (see Antidepressant Drugs) affect depression, which is often associated with anxiety.

• Other conditions such as premenstrual syndrome , depression , alcohol with-drawal, muscle relaxation, restless leg syndrome, seizure disorders, and cer-tain medical, diagnostic, and surgical procedures.

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EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Alprazolam 0.25-0.5 mg 3 times

a day up to 4 mg/day PO

Chlordiazepoxide 5-25 mg 3-4 times daily PO

Clonazepam 1.5 mg/day in 3 divided dose (not to exceed 20 mg/day) PO

Diazepam 2-10 mg 2-4 times daily PO

Lorazepam 2-6 mg in divided doses up to 10 mg/day PO

Oxazepam 10-30 mg 3-4 times daily up to 120 mg/day PO

Buspirone 5 mg 3 times daily up to 60 mg/day PO

ADMINISTRATION Anxiolytic drugs are given mostly PO but can also be injected IM or IV.

CONTRAINDICATIONS Anxiolytic drugs should not be used or must be used with caution in patients with a history of drug abuse and respira-tory problems.

COMMON ADVERSE REACTIONS Benzodiazepines will cause some seda-tion and psychomotor impairment. Less frequent are electrocardiogram (ECG) changes, tachycardia, and agranulocyto-sis. Depending on the drug, they will all cause some physical dependence after long-term therapy, and a withdrawal syndrome (excitation, rebound anxiety, insomnia) might occur after abrupt cessa-tion of therapy. Alprazolam must be with-drawn very slowly because convulsions may occur. Buspirone is almost devoid of adverse reactions except some dizzi-ness and restlessness. Adverse reactions of the antidepressants are described in Antidepressant Drugs.

DRUG INTERACTIONS • Sedation caused by anxiolytics with sed-

ative properties is increased by drugs that also have sedative actions.

• Sedative effects are increased by a num-ber of herbs, including chamomile, mistletoe, and valerian. St. John’s wort seems to reduce their effectiveness.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Physical therapists can be helpful in

promoting nonpharmacological inter-ventions, such as relaxation techniques,

exercises, or massages, to reduce feelings of anxiety and the use of anxiolytics.

• Patients on higher doses of benzodi-azepines may have to be scheduled at times when the sedative and psychomo-tor impairments are less noticeable and will not interfere with therapy.

• Always watch older patients on benzo-diazepine therapy for motor incoordi-nation, sedation, and impaired gait to avoid falls that could lead to serious fractures.

• Advise patients on buspirone at the start of therapy to be patient because it will take about a month before anxi-olytic effects become apparent.

b -AGONISTS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) β

1 -Agonists

Dobutamine Dobutamine β

2 -Agonists (Relatively Selective)

Albuterol Salbutamol, Ventolin, Volmax, other

Formoterol Foradil, Perforomist

Metaproterenol AlupentPirbuterol MaxairSalmeterol SereventTerbutaline Brethine β

1 - and β

2 -Agonists

Isoproterenol IsoproterenolMixed Acting α -and β -Agonists (see α -Agonists)

MECHANISM OF ACTION β

1 -receptors (mostly in the heart) and β

2 -

receptors (mostly other organs) are usu-ally but not exclusively found opposite postganglionic sympathetic nerve fibers, which release norepinephrine, which stimulates these receptors. Activation of these receptors in the lungs causes bronchial dilation (with increased air flow) and vasodilation in the blood ves-sels, increases in heart rate and contrac-tility (with an increase in systolic blood pressure), reduces gut activity, increases blood glucose levels and fluid inflow in the eye, increases skeletal muscle activ-ity (perhaps through central β -receptors), and increases secretion of rennin from the kidneys. Activation of beta recep-tors on the pregnant uterus reduces its contractions.

These drugs stimulate β -receptors and cause the appropriate physiologi-cal responses as outlined previously. β

2 -agonists are more selective for β

2 -

receptors, although this distinction breaks down at high doses or in certain individuals.

INDICATIONS β -Agonists are indicated in the following: • Asthma, in which bronchoconstric-

tion (caused by allergy, exercise, cold air, other) decreases air flow and makes breathing difficult (wheezing). Selective β

2 -receptor agonists stimulate

β 2 -receptors on bronchi, cause bronchi

to dilate, and allow air to flow through bronchi more easily. β

2 -agonists are some-

times combined with steroids because inflammatory processes are often asso-ciated with bronchial constrictions (see Corticosteroids).

• Chronic obstructive pulmonary disease ( COPD) and emphysema, in which air flow is impaired because of lung dam-age mostly from smoking. Selective β

2 -

receptor agonists stimulate β 2 -receptors

on bronchi, cause bronchi to dilate, and allow air to flow through bronchi more easily.

• Other conditions such as the preven-tion of premature contractions during pregnancy (ritodrine, terbutaline), CHF (dobutamine IV), or severe hypotension (dopamine IV).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Albuterol 2-4 mg 2-4 times daily

PO (not to exceed 8 mg/day) or 4-8 mg twice daily for extended-release preparations PO or 2-4 inhalations q4-6h or 15 min before exercise

Formoterol 1 cap (12 µ g) q12h by inhalation

Metaproterenol 20 mg 3-4 times daily PO

1-2 inhalations q4-6h (not to exceed 12 inhalations)

Salmeterol 1 inhalation (50 µ g)Terbutaline 2.5-5 mg q6-8h PO

(not to exceed 15 mg/day)

ADMINISTRATION β -Agonists can be given IV, PO, or by inha-lation. Administration schedules vary among drugs because of differences in duration of action.

CONTRAINDICATIONS β -Agonists must be used with caution in patients with cardiovascular disease, dia-betes mellitus, and seizure disorders.

COMMON ADVERSE REACTIONS Common adverse reactions include ner-vousness, restlessness, insomnia, tremor,

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chest pain, and increases in heart rate and blood pressure (the latter two less with b

2 agonists) and blood sugar lev-

els. Excessive use of inhalers can lead to tolerance or sometimes paradoxical bronchospasm.

DRUG INTERACTIONS • β -Agonists should not be used with

MAO inhibitors because they may alter potassium and sugar levels.

• Caffeine in coffee or tea, fig wort, and motherwort may enhance CNS effects.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Be aware that exercise and cold air can

aggravate asthma and bronchoconstric-tion. Have the patient use an inhaler 15 to 30 minutes before exercise, depending on the drug, and avoid cold or drafty places.

• After inhalation or oral use, heart rate and blood pressure can be increased. Patients with angina should be exer-cised slowly because β -agonists can increase the risk of angina.

• If patient uses the inhaler too often, have patient notify the physician because excessive use can cause tolerance or paradoxical bronchoconstriction.

• If a patient shows a fine tremor, notify or have patient contact the physi-cian because the dose may have to be adjusted or a different drug may have to be prescribed.

b -BLOCKERS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Acebutolol SectralAtenolol TenorminBisoprolol Zebeta, MonocorCarteolol CartrolCarvedilol CoregLabetalol Normodyne, TrandateMetoprolol Lopressor SR,

Toprol-XLNadolol CorgardPenbutolol LevatolPindolol ViskenPropranolol Inderal, InnoPran XLSotalol Betapace

MECHANISM OF ACTION β

1 -receptors (mostly in the heart) and

β 2 -receptors (most other organs) are usu-

ally but not exclusively found opposite postganglionic sympathetic nerve fibers, which release norepinephrine, thus acti-vating these receptors. Activation of these receptors in the lungs causes bronchial dilation (with increased air flow) and dila-tion in blood vessels, increases in heart

rate and contractility (with an increase in systolic blood pressure), reduces gut activity, increases blood glucose levels and fluid inflow in the eye, increases in skeletal muscle activity (through a central mechanism), and increases secretion of renin in the kidney.

Competitive blockade of these recep-tors by β -antagonists or blockers causes the opposite effects (which can be antagonized by or overcome by use of β -agonists). Most drugs affect β

1 -receptors

and β 2 -receptors, but some are somewhat

more selective for β 1 blockade. In addi-

tion, they reduce renin secretion from the kidney and peripheral sympathetic activ-ity by a central mechanism. Labetalol also blocks α -receptors in blood vessels and reduces vasoconstriction leading to more incidences of orthostatic hypotension. Pindolol is a partial antagonist that can antagonize, as well as stimulate, depend-ing on the activity of the system.

INDICATIONS β -Antagonists or β -blockers are indicated in the following: • Angina pectoris, which is character-

ized by pain usually in response to physical activity or emotional factors. This results when the oxygen demand of the compromised heart exceeds the oxygen supply from damaged coronary blood vessels (e.g., atherosclerosis). β antagonists decrease heart rate and con-tractility, reduce the oxygen need, and decrease or eliminate pain.

• Hypertension, which occurs when blood pressure is increased above nor-mal limits, leading eventually to infarcts and strokes. β -Blockers lower blood pressure by reducing cardiac output (heart rate and contractility), block-ing rennin release (which reduces the formation of the vasoconstrictor angiotensin II), and depressing central outflow of sympathetic stimulation (causing vasodilation).

• Arrhythmias, which are caused by abnormal electrical activity. β -Antagonists reduce overly excited car-diac activity and normalize heart rhythm (certain types only; see Antiarrhythmic Drugs).

• Tremors, migraine, anxiety, drug induced akathisia, aggressive behav-ior, and other conditions in which the mechanism of action is uncertain, but β -antagonists seem to be helpful.

• Open-angle glaucoma, in which intraocular pressure is elevated so that it can damage the retina, leading even-tually to tunnel vision and blindness. Certain β -blockers (timolol, betaxolol, levobunolol) administered topically block the inflow of fluid into the eye and lower intraocular pressure.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Acebutolol 400-800 mg/day once or

twice (up to 1200 mg/day) PO

Atenolol 25-100 mg once daily (up to 200 mg/day) PO

Bisoprolol 5 mg once daily (up to 20 mg/day) PO

Carteolol 2.5-10 mg once daily POCarvedilol 3.125-6.25 mg twice daily

(up to 50 mg daily) POLabetalol 100-400 mg twice daily

(up to 2.4g daily)Metoprolol 25-100 mg/day as a single

or divided dose (up to 450 mg/day) PO

Nadolol 40-80 mg once daily (up to 320 mg/day) PO

Penbutolol 20 mg once daily POPindolol 5 mg twice daily (up to

45-60 mg/day) POPropranolol 40-320 mg/day single or

divided daily POSotalol 80 mg twice daily (up to

320 mg) PO

ADMINISTRATION β -Blockers can be given PO, IV, and in some cases, topically into the eye. Long-term therapy must be stopped slowly or the drug must be tapered to avoid with-drawal syndrome (cardiac problems).

CONTRAINDICATIONS β -Blockers must be used with caution in bradycardia, renal impairment, pulmo-nary disease (e.g., asthma), and diabetes mellitus.

COMMON ADVERSE REACTIONS • Common adverse reactions include

weakness, drowsiness, bradycardia, pulmonary edema, hypotension, impo-tence, cold extremities and masking of hypoglycemic and thyrotoxic episodes (e.g., masking of tachycardia).

• Topical administration causes fewer and milder systemic adverse reactions.

DRUG INTERACTIONS β -Antagonists or β -blockers may alter the effectiveness of insulin or hypoglycemics, antagonize the use of β –agonists, and should not be used with MAO inhibitors.

IMPLICATIONS FOR PHYSICAL THERAPISTS • When exercising a patient, be aware that

heart rate will be affected (reduced) by β -blockers.

• Advise patients to consult a physician if breathing difficulties are experienced

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during exercise because these drugs can cause bronchoconstriction and pulmonary edema.

• Have older patients get up slowly because drugs can (mostly labetalol) cause orthostatic hypotension in partic-ular in the beginning of therapy.

• Use exercise with caution in patients using insulin and β -blockers because the β -blocker may mask the onset signs and symptoms of a hypoglycemic episode.

• Patients on β -blockers are sensitive to a cold environment, in particular, experi-encing cold extremities.

• Warn patient to not suddenly discon-tinue long-term β -blocker use because abrupt cessation can precipitate a seri-ous withdrawal syndrome (including life-threatening arrhythmias).

CALCIUM CHANNEL BLOCKERS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Amlodipine NorvascDiltiazem Cardizem, Cartia XT,

Dilacor XR, otherFelodipine PlendilIsradipine DynaCirc, DynaCirc CRNicardipine Cardene, Cardene SRNifedipine Adalat, Adalat CC,

Procardia, Procardia XL

Nisoldipine SularVerapamil Apo-Verap, Calan,

Isoptin, other

MECHANISM OF ACTION Movement of calcium in muscle cells is necessary for normal muscle contraction. This provides for normal skeletal muscle contractions, cardiac conduction and con-tractibility (cardiac output), and blood vessel wall tension (peripheral resis-tance). The latter regulate blood pressure (peripheral resistance and cardiac out-put [heart rate, stroke volume] determine blood pressure).

Calcium channel blockers inhibit these calcium fluxes by blocking calcium chan-nels. This causes mostly a decreased exci-tation-contraction coupling in the heart (at one phase, the depolarizing current is carried primarily by a relatively slow, inward movement of calcium) with reduced contractility and cardiac output, as well as relaxation of blood vessels with reduced peripheral resistance. Both lower blood pressure.

These drugs differ somewhat in their action on the heart and blood vessels; nifedipine, amlodipine, and nicardipine are strong vasodilators, and verapamil and diltiazem are more effective on the elec-trical conduction system and the heart’s contractile strength.

INDICATIONS Calcium channel blockers are indicated in the following: • Hypertension, in which vasoconstric-

tion or increased peripheral resistance is a major cause of increased blood pres-sure. Drugs block calcium fluxes in car-diac tissue and blood vessel walls and reduce both cardiac contractibility and relax blood vessels. This decreases car-diac output and peripheral resistance and lowers blood pressure.

• Angina pectoris , which is character-ized by pain usually in response to physical activity or emotional factors. This results when the oxygen demand of the compromised heart exceeds the oxygen supply from damaged coro-nary blood vessels (e.g., atherosclero-sis). These drugs reduce contractibility (which reduces cardiac oxygen requirements), dilate coronary arteries to supply more blood and oxygen to the heart, and relax peripheral blood vessels (which decreases periph-eral resistance), making it easier for the heart to eject the blood into the periphery. (A special form is Prinzmetal angina, which is a spastic blood vessel constrictive form.)

• Certain arrhythmias such as supraven-tricular tachycardia or atrial flutter and fibrillations. In these cases, electrical activity is conducted too fast or irregu-larly over the heart so that the cardiac muscle cannot contract completely and efficiently. Drugs reduce excitation-con-traction coupling by slowing calcium movements, normalizing conduction, slowing the heart, and achieving more efficient contractions.

• Congestive heart failure or CHF, in which the heart cannot pump enough blood to other organs of the body, and results in an enlarged heart with the patient becoming quickly fatigued and short of breath (pulmonary edema) dur-ing even the slightest exertion. These drugs cause vasodilation, which helps the heart to eject blood more easily and more efficiently.

• Migraine, with uncertain mechanism, and to prevent neurological damage caused by cerebral blood vessel spasms (nimodipine).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Amlodipine 5-10 mg once daily PODiltiazem 30-120 mg 3-4 times daily

PO or 60-120 mg 2 times daily as sustained-release capsules PO

Felodipine 5-10 mg once a day PO

Isradipine 2.5-10 mg twice daily PO or 5-20 mg once daily as controlled-release tab-lets PO

Nicardipine 20-40 mg 3 times daily PO or 30-60 mg 2 times daily with sustained-release form PO

Nifedipine 10 mg 3 times daily PO (not to exceed 180 mg/day) or 30-120 mg once daily with sustained-release form PO

Nisoldipine 20-60 mg once a day POVerapamil 80-120 mg 3 times daily

PO or 120-240 mg once a day with extended-release preparations PO

ADMINISTRATION Calcium channel blockers are given IV or PO. Dose must be adjusted in frail, geriatric patients and those with hepatic impairment.

CONTRAINDICATIONS Calcium channel blockers are contraindi-cated or to be used cautiously in patients with certain arrhythmias, hypotension, and CHF.

COMMON ADVERSE REACTIONS Calcium channel blockers can cause headache, certain arrhythmias, dizziness, peripheral edema, CHF, cough, joint stiff-ness, muscle cramps, gingival hyperplasia (diltiazem), and rarely, Stevens-Johnson syndrome.

DRUG INTERACTIONS • Hypotensive episodes may occur with

nitrates, antihypertensives and alcohol. Toxicity may be increased with use of H

2 -blockers.

• Grapefruit juice may reduce metabo-lism of some drugs and increase serum levels, leading to overdose signs and symptoms. High fat meals can increase blood levels of nisoldipine.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Have the patient change position and

get up slowly, in particular in the begin-ning of therapy because orthostatic hypotension may occur.

• Be careful when using a heated thera-peutic pool because warm water can aggravate the vasodilatory effects of peripheral vascular dilators and lead to a marked decrease in blood pressure.

• Observe the patient for signs of CHF (peripheral edema, rales/crackles, dyspnea, weight gain, jugular venous distension) and if present notify physician.

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• If you notice joint stiffness and mus-cle cramps, which could be an adverse reaction, notify the physician.

• If you notice peripheral edema, sig-nificant bradycardia or irregular heart beats, or swelling of gums, notify the physician.

• If patient feels feverish and exhibits an unexplained skin rash ask patient to immediately notify the physician because this could be the onset of Stevens-Johnson syndrome and the calcium channel blocker should be stopped as soon as possible.

CHOLINERGIC AGONISTS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Cholinergic Drugs Bethanechol

Pilocarpine

Neostigmine Pyridostigmine Other

Duvoid, Urabeth, Urecholine

Akarpine, Pilocar, other

Prostigmin Mestinon, Regonol

Anti-Alzheimer Drugs Donepezil Galantamine Rivastigmine Tacrine Memantine Other

Aricept Razadyne Exelon Cognex Namenda

MECHANISM OF ACTION Cholinergic M (muscarinic) and Nn (nic-otinic nerve) receptors are usually but not exclusively found opposite parasym-pathetic preganglionic (Nn) and postgan-glionic nerve (M) fibers, which release acetylcholine, which stimulates these receptors. The synaptic acetylcholine is then quickly inactivated and destroyed by the enzyme acetylcholinesterase. Activation of these receptors decreases heart rate and contractility, constricts bronchial muscles (decreased air flow), and increases gut and bladder activity. Cholinergic receptors Nm (nicotinic mus-cle) are found on skeletal muscles oppo-site motoneurons. Stimulation initiates skeletal muscle movements. Furthermore, cholinergic receptors of all classifications and glutaminergic receptors are found in the brain, in which, among other func-tions, they seem to be involved in cogni-tive processes (memory).

Cholinergic agonists can either stimu-late directly these receptors (bethanechol, pilocarpine for M receptors) or inhibit the enzyme acetylcholinesterase, which increases synaptic acetylcholine concen-trations that then indirectly stimulate all of these receptors. Memantine antago-nizes the action of glutamate.

INDICATIONS Cholinergic agonists are indicated in the following: • Postoperative gastrointestinal and uri-

nary atony to stimulate M receptors and restore activity (bethanechol).

• Myasthenia gravis, which manifests itself in rapid fatigability and mus-cle weakness, is an autoimmune dis-ease in which the immune system destroys and reduces the number of Nm receptors on skeletal muscles. Indirect-acting cholinergic agonists can increase synaptic acetylcholine levels, which now can activate the remaining receptors and restore mus-cle activity.

• Dementia of the Alzheimer type, in which it is believed that this condition is caused by a loss of nicotinic recep-tors plus other abnormalities, includ-ing overstimulation of glutaminergic receptors with resulting nerve damage. Indirect-acting cholinergic agonists can increase central synaptic acetylcholine levels, stimulate remaining nicotinic receptors, and slightly improve mem-ory but will not alter the course of the disease. In addition, action of exces-sive detrimental glutamate activity is blocked by memantine, preventing its damaging effects.

• Reversal of the effects of nondepo-larizing neuromuscular blockers by increasing synaptic acetylcholine levels at skeletal muscles that compete with and remove the blockers.

• Open-angle glaucoma, in which a defect in the trabecular outflow sys-tem increases intraocular pressure, lead-ing eventually to retinal damage, tunnel vision, and blindness. Cholinergic drugs (e.g., pilocarpine) applied topically increase outflow and lower the dam-aging effects of increased intraocular pressure.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Bethanechol 25-50 mg three times

daily PODonepezil 5-10 mg once daily (not

to exceed 5 mg in frail, geriatric women) PO

Galantamine 4-12 mg twice daily (up to 24 mg) PO

Memantine 5-10 mg 2 times daily PO

Neostigmine 15 mg q3-4h initially, can be increased to 375 mg/day PO

Pyrido-stigmine

600 mg/day in divided doses up to 1.5 g/day PO

Rivastigmine 1.5 mg twice daily, to be increased to 6 mg twice daily PO

Tacrine 10 mg 4 times daily, can be increased to 160 mg/day PO

ADMINISTRATION Cholinergic agonists are given PO, IM, and IV (or topically in case of glaucoma). After topical administration, observed systemic adverse reactions are milder.

CONTRAINDICATIONS Cholinergic agonists are contraindications in patients with asthma, ulcer, cardiovas-cular disease, and epilepsy.

COMMON ADVERSE REACTIONS Adverse reactions include bronchocon-striction with decreased airflow, head-ache, abdominal cramps, diarrhea (can cause dehydration), salivation, tearing, sweating, and bradycardia with heart block. Memantine might cause some drowsiness.

DRUG INTERACTIONS • Cholinergic agonists can antagonize

the actions of anticholinergic drugs and may increase GI bleeding caused by NSAIDs.

• Jimson weed and scopolia reduce their effectiveness.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Cholinergic agonists can reduce heart

rate, and heart rate should be measured periodically, particularly during and after exercise.

• Cholinergic agonists can cause dizzi-ness, and in particular, older patients must be observed when getting up, standing, or walking.

• If a patient is well-controlled on med-ication for myasthenia gravis and later on shows sudden reoccurrence of symptoms, such as muscle weakness with some tremors, ask about the dos-age taken. Taking too little or too much of the drugs (the latter is referred to as “myasthenic crisis”) can resemble the original condition, and the original dos-age should be used again or physician should be contacted.

CNS DOPAMINERGIC AGONISTS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Amantadine (1) SymmetrelCarbidopa/

levodopa (2)Parcopa, Sinemet,

otherEntacapone (5) Comtan

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Pergolide (3) PermaxPramipexole (3) MirapexRopinirole (3) RequipSelegiline (4) Carbex, Eldepryl,

otherTolcapone (5) TasmarOther

MECHANISM OF ACTION The neurotransmitter dopamine in the brain acts on stimulatory and inhibitory dopaminergic receptors that are involved in many mental processes. Dopamine is synthesized from dihydroxyphenylalanine (L-DOPA) via the enzyme decarboxylase and is destroyed by the enzymes cate-chol- O -methyltransferase (COMT), and monoamine oxidase (MAO B). Dopamine is involved in movement control (among other functions) in the basal ganglia, in which normal movements are controlled by a balance between dopaminergic and cholinergic activity.

Dopaminergic agonists increase dop-aminergic activity and work in various ways in the brain by increasing the release of dopamine (1), or the synthesis of dop-amine through increases in the supply of neuronal DOPA (2), with carbidopa inhib-iting peripheral but not central decarbox-ylase activity, by stimulating dopamine receptors directly (3), or by inhibiting the enzymes MAO B (4), or COMT (5), which destroy dopamine, thus increasing synap-tic dopamine levels.

INDICATIONS Dopaminergic agonists are indicated in the following: • Parkinson’s disease, which is mostly a

movement disorder, among other prob-lems, and is characterized by a mask-like face, shuffling gait, and pill-rolling tremor. The cause is believed to be, among other problems, an overactiv-ity of cholinergic and an underactivity of dopaminergic activity in the basal ganglia of the brain. These drugs stim-ulate dopaminergic receptors directly, increase the synthesis of dopamine, or prevent the destruction of dopamine. This increase in dopaminergic activity restores the balance between the two neurotransmitter systems. One of these drugs (amantadine) is also an antiviral drug used for influenza A infections. See also Anticholinergic drugs.

• Drugs that reduce cholinergic activity have been discussed in Anticholinergic Drugs.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Amantadine 100 mg 1-2 times daily

(up to 400 mg/day) PO

Carbidopa/levodopa

10-25 mg carbidopa/100-250 mg levodopa 3-4 times daily PO or 25 mg/100 mg or 50 mg/200 mg twice daily for extended-release preparations PO

Entacapone 200 mg up to 8 times daily PO

Pergolide 50 µ g-1 mg/day 1-3 times daily (not to exceed 5 mg/day) PO

Pramipexole 1.5-4.5 mg/day in 3 divided doses PO

Ropinirole 0.25-1.5 mg/ day 3 times daily (not to exceed 9 mg/day) PO

Selegiline 2.5-10 mg 1-2 times daily PO

Tolcapone 100-200 mg 3 times daily PO

ADMINISTRATION Dopaminergic agonists are usually given PO. They are often started at low doses and then increased until optimal effective-ness is achieved. Effects may only be seen after 1 to 4 weeks of therapy; chronic administration should not be stopped abruptly because a severe parkinsonian crisis may occur. Some drugs are given concomitantly.

CONTRAINDICATIONS Dopaminergic agonists are contraindi-cated in patients with seizure, cardiac, or psychiatric disorders.

COMMON ADVERSE REACTIONS Adverse reactions include dizziness, seda-tion, drowsiness (with sleep attacks), hal-lucinations, involuntary movements, night mares and hypotension. Malignant neuro-leptic syndrome and rhabdomyolysis have been reported with entacapone. Some drugs (e.g., L-DOPA) can produce the “on-off” syndrome in which therapeutic effects may temporarily disappear (apo-morphine is used to counteract the “off” episodes). After a while, some drugs lose effectiveness; however, effectiveness can sometimes be increased with “drug-free holidays.”

DRUG INTERACTIONS • Dopaminergic agonists should not

be used with MAO inhibitors and can increase risk of hypotension with anti-hypertensives or interact adversely with some antipsychotic drugs.

• Kava and B6 vitamin decrease the effectiveness of carbidopa/levodopa. Selegiline can interact with a large number of prescription and OTC drugs and can cause a hypertensive crisis when consuming tyramine-containing foods.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Reinforce that patients on levodopa

therapy should not take large doses of multivitamins or vitamin B6 because these vitamins can reduce the drug’s effectiveness.

• Patients on levodopa showing the “off” phase during therapy should be rescheduled at times when they expe-rience the “on” phase. Often, taking the medication with a light meal can reduce the “off” phase.

• Be aware that patients on some of these drugs can show involuntary move-ments and dystonias, and these should be reported to the treating physician.

• Some drugs can produce pronounced drowsiness with “sleep” attacks. Reschedule the patient at different times after taking the drug if this is a problem.

• If the patient is taking entacapone and complains about muscle weakness or pain and brown-colored urine, notify the physician immediately because this could be a warning sign of rhabdomyolysis.

• Advise the patient to change positions slowly because some drugs can cause marked orthostatic hypotension, which is particularly dangerous in these patients.

CORTICOSTEROIDS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Short-Acting Drugs Cortisone Hydrocortisone

Cortone Cortef, A-Hydrocort,

other Intermediate-Acting Drugs Methylpredni-

solone

Prednisolone

Prednisone

Triamcinolone

A-methaPred, Depopred, Depoject, other

Articulose, Cortolone, Predate, other

Cordrol, Deltasone, Orasone, other

Amcort, Aristocort, Clinacort, other

Long-Acting Drugs Betamethasone Budesonide Dexamethasone

Celestone Entocort Cortastat, Dalalone,

Decadron, Decameth, other

Other

MECHANISM OF ACTION Glucocorticoids, or steroids, are secreted by the adrenal cortex and include cor-tisol and cortisone. They have multiple metabolic effects on glucose, carbohy-drate, and lipid metabolism, as well as on inflammatory processes. Here, the anti-inflammatory actions are pertinent in that they stabilize lysosomal membranes

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preventing the release of proteolytic enzymes, decrease capillary permeabil-ity inhibiting the migration of inflamma-tory white blood cells into tissues, affect lymph nodes reducing antibody forma-tion, and enhance the effects of circulat-ing catecholamines such as epinephrine causing vasoconstriction and other func-tions. The action of the natural steroids is short acting.

Drugs or steroids are mostly analogs of these natural products that have a longer duration of action, possess more antiin-flammatory activity, with more therapeu-tic action, and affect fewer metabolic processes, with fewer adverse reactions.

INDICATIONS Steroids are indicated in the following: • Inflammations,which are unwanted

or excessive . An inflammation is usu-ally characterized by swelling, red-ness, warmth, and pain and eventual tissue damage if it becomes excessive. The first three signs are initiated by vasodilatation allowing white blood cells to invade the tissue, which helps fight infections or to help heal dam-aged tissues. However, if an inflamma-tion becomes excessive or is unwanted (autoimmune diseases, transplants, allergies, asthma, croup, rheumatoid arthritis, osteoarthritis, ankylosing spon-dylitis, bursitis, or other conditions), it starts to damage healthy tissue. Drugs curtail excessive and reduce or prevent unwanted inflammations, thus protect-ing healthy tissue.

• Adrenocortical insufficiency, in which the adrenal glands do not produce enough glucocorticoids. Steroids are used as replacement therapy and sup-ply glucocorticoid activity to the body.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES)

Betamethasone 0.6-7.2 mg once or in divided doses daily PO

Budesonide 9 mg once daily POCortisone 25-300 mg once

daily PODexamethasone 0.5-9 mg single or

divided doses daily PO

Hydrocortisone 5-30 mg 1 to 4 times daily PO

Methyl-prednisolone

2-160 mg once or in divided doses PO

Prednisolone 5-20 mg 1-4 times daily PO

Prednisone 5-200 mg 1-4 times daily PO

Triamcinolone 4-12 mg 1-4 times daily PO

ADMINISTRATION Steroids can be given IM, IV, rectally, or PO and differ, depending on the route of administration, in onset (1 to 2 hours) and duration (1 to 6 days). Steroids should not be discontinued abruptly because they suppress adrenocorticotropic hormone (ACTH) secretion, which needs time to recover and before recovery can cause a glucocorticoid deficiency syndrome. Some of these drugs plus other steroids are used by inhalation, nasally, topically, and locally in the eye and include flunisolide, flutica-sone, beclomethasone, mometasone, flu-orometholone, loteprednol, medrysone, rimexolone, alclometasone, amcinonide, clobetasol, clocortolone, desonide, desoxi-metasone, diflorasone, and fluocinolone.

CONTRAINDICATIONS Steroids should not be used during chronic infections, and live vaccines should not be administered during chronic therapy with high doses. They should be used with caution in children because they retard growth.

COMMON ADVERSE REACTIONS Adverse reactions include either depres-sion or euphoria, increased risk of infec-tions, restlessness, anorexia, ecchymosis (blood caused discolorations ), petechiae (red spots), hypertension, fluid retention, osteoporosis, muscle wasting, weaken-ing of tendons and ligaments, metabolic changes like hyperglycemia, fat shifts within the body (“buffalo hump,” “moon face”), increased ocular pressure, and cataracts.

Topically applied or inhaled drugs can cause the same but milder effects (except cataract formation and increased ocular pressure after ocular use in some but not all patients).

DRUG INTERACTIONS • Steroids can interact with a large num-

ber of drugs and may require increases in dosages of insulin and oral hypoglyce-mic agents and may enhance the effects of drugs that affect potassium excre-tion. They increase the risk of stomach ulcer with the use of NSAIDs.

• Grapefruit juice can increase the levels of some steroids, leading to overdose effects.

IMPLICATIONS FOR PHYSICAL THERAPISTS • If you have an infection, wear a mask

or do not handle the patient who is on long-term, high-dose steroid therapy because his or her immune system is weakened.

• If you notice signs like “moon face” or “buffalo hump,” notify or have the patient notify the physician because the dosage may need to be adjusted.

• Be aware that older people on long-term, high-dose steroid therapy may suf-fer from osteoporosis and might incur further weakening of bones so exer-cise should be adjusted accordingly. However, gentle exercise can prevent or slow down osteoporosis.

• If you notice personality changes in your patient, notify or have the patient contact the physician because this can be a “steroid psychosis” and drug or dose may need to be adjusted.

• If you notice muscle wasting in a patient, notify or have the patient contact the physician because steroids can interfere with muscle metabolism. However, gen-tle exercises can prevent or slow down this adverse process.

• Treat the joints of the patient who has received a steroid injection in a joint gently because steroids can weaken lig-aments and tendons.

• Measure blood pressure in these patients frequently because drugs can cause hypertension.

DIURETICS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Thiazide and Thiazide-Like DiureticsChlorothiazide DiurilHydrochlorothiazide Esidrix, Hydro-

chlor, Microzide, other

Chlorthalidone Hygroton, Thalitone

Indapamide LozolOtherLoop DiureticsBumetanide BumexFurosemide LasixTorsemide DemadexPotassium-Sparing DiureticsAmiloride MidamorSpironolactone AldactoneTriamterene DyreniumOsmotic DiureticsMannitol Osmitrol,

Resectisol

MECHANISM OF ACTION The kidneys filter blood by glomerular fil-tration and process urine in the nephrons. This regulates in part the water and salt homeostasis of the body. Water excretion is controlled by the concentrations of elec-trolytes and hormones in the nephrons. Electrolytes such as sodium, potassium, and chloride are reabsorbed from the tubular filtrate, which also affects tubu-lar water reabsorption; the more salts are reabsorbed, the more water is reabsorbed or the less water is excreted or the less salts are reabsorbed, the less water is reab-sorbed or more water is excreted into the

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urine (“water follows salts”). Aldosterone from the adrenals retains sodium and water but enhances potassium and hydro-gen excretion or reduces water excretion and vasopressin from the pituitary gland reduces water excretion directly.

Diuretics cause diuresis or increase water excretion by blocking salt reabsorp-tion on various places in the nephron. The thiazides inhibit reabsorption of sodium and potassium (and other electrolytes) in the early portion of the distal tubules, retain both electrolytes and water in the tubule, and increase water excretion. The loop diuretics inhibit sodium, chlo-ride, and potassium reabsorption in the loop of Henle and distal tubule, retain all electrolytes with water in the tubule, and increase water excretion. The potas-sium-sparing diuretics (spironolactone blocks the action of aldosterone) reduce sodium reabsorption and increase sodium and water but not potassium excretion. Osmotic diuretics increase the osmolar-ity of the urine, which keeps water in the tubules and increases water excretion.

INDICATIONS Diuretics are indicated in the following: • Hypertension, in which they increase

water excrtion and reduce blood vol-ume and reduce blood pressure. They possibly also cause some sodium deple-tion in blood vessel walls, resulting in some vasodilatation that also reduces blood pressure.

• Edema, or excessive fluid accumula-tion as a result of CHF or other causes, in which they reduce this fluid accumu-lation by increasing water excretion.

• Various problems including an attack of narrow-angle glaucoma to quickly reduce excessively elevated intraocu-lar pressure or cerebral edema (e.g., IV mannitol).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Chlorothiazide 250-1000 mg/day

as a single or divided doses PO

Hydrochlorothiazide 12.5-100 mg/day in 1 or 2 doses up to 200 mg/day PO

Chlorthalidone 25-100 mg/day once daily PO

Indapamide 1.25-5 mg/day once PO

Bumetanide 0.5-2 mg/day once, with additional doses if needed up to 10 mg/day PO

Furosemide 20-80 mg/day once or twice PO

Torsemide 5-20 mg once daily PO

Amiloride 5-10 mg/day (up to 20 mg) PO

Spironolactone 12.5-400 mg/day as a single dose PO

Triamterene 100 mg twice daily (not to exceed 300 mg/day) PO

Mannitol 50-100 g as a 5%-25% solution IV

ADMINISTRATION Diuretics can be given IV, IM, and PO. Drugs are often used in combination with each other or other drugs. Loop diuret-ics are the strongest diuretics but are also associated with more adverse reactions.

CONTRAINDICATIONS Diuretics should not be given to patients with electrolyte imbalances. Thiazide diuretics may show cross-sensitivity with sulfonamides. Patients with gout can have an increased risk of an attack with thiaz-ides as a result of hyperuricemia.

COMMON ADVERSE REACTIONS Adverse reactions include dehydration (hypotension, tachycardia, and dysp-nea), hypokalemia (palpitations, skeletal muscle weakness or cramping, paralysis, nausea or vomiting, polydipsia, delirium, and depression) with thiazide and loop diuretics and hyperkalemia (confusion, hyperexcitability, muscle weakness, flac-cid paralysis, and arrhythmias) with the potassium-sparing diuretics. In addition, drugs can cause other electrolyte and metabolic imbalances (metabolic alka-losis), drowsiness, dizziness, orthostatic hypotension, increases in blood glucose, and cholesterol levels. Hearing loss (tin-nitus) occurs mostly with loop diuretics after IV administration.

DRUG INTERACTIONS • Potassium-losing diuretics can cause

severe hypokalemia with diuretics, which also cause potassium loss. Potassium loss increases digitalis toxicity and reduces lithium excretion precipitating lithium toxicity. Potassium-sparing diuretics can cause significant hyperkalemia in the presence of drugs like ACE inhibitors, which also retain potassium. Hearing problems caused by loop diuretics are made worse by aminoglycosides.

• Licorice and herbal laxatives (senna) may increase the risk of hypokalemia. Ginkgo may decrease the antihyperten-sive effects.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Advise the patient to change position

slowly, in particular, getting up because drugs decrease blood pressure and carry the risk of orthostatic hypotension.

• Monitor the patient for muscle activ-ity and other unusual signs because some diuretics can cause hypokalemia, whereas others can cause hyperkalemia. If this is observed, notify the physician immediately.

• UV light should be used with caution and other parts of the patient should be covered because some diuretics can cause photosensitivity reactions.

• When exercising the patient in a warm environment, monitor sweating and rec-ommend frequent water supplementa-tion to prevent dehydration.

DRUGS AND BLOOD CLOTTING

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Oral AnticoagulantsWarfarin CoumadinParental Anticoagulants Heparin Other

Fragmin, Lovenox, Arixtra, Innohep

Antiplatelet Drugs Aspirin Clopidogrel Dipyridamole

Plavix Dipiradol

Fibrinolytic or Thrombolytic Drugs Alteplase or TPA Reteplase Streptokinase Urokinase

Activase

Clotting FactorsFactors VIII and IX

MECHANISM OF ACTION Blood clotting is a very complex mecha-nism that basically involves platelet aggre-gation and coagulation. If, for example, a blood vessel is injured, the vessel first con-stricts to reduce blood flow. Then plate-lets are attracted to the wound, become “sticky,” and form a platelet plug at the opening. This process of aggregation involves a number of endogenous fac-tors: Adenosine diphosphate (ADP) and thromboxane A

2 and the expression of a

glycoprotein IIb/IIIa receptor at the site of injury are among the most important ones. Thromboxane is formed (besides prostaglandins) by the action of cyclooxy-genase (COX) from arachidonic acid (see Nonsteroidal Antiinflammatory Drugs). This is followed by coagulation, which involves a large number of endogenous compounds called clotting factors, includ-ing vitamin K, as well as the conversion

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904 Drugs and Blood Clotting Drugs and Blood Clotting

of prothrombin to thrombin, which in turn converts fibrinogen to fibrin and which finally seals the platelet plug tight. After the wound is healed, plasminogen is converted to plasmin, which splits and dissolves the plug. Unfortunately, some-times blood clots can form within ves-sels (thrombi) and the clots can dislodge and travel through the vessel system (as emboli) where they can become stuck in small vessels. Here, they block blood flow and deprive the tissue of oxygen and nutrients. The consequences can be an ischemic heart attack, pulmonary embo-lism, or stroke. These thrombi are formed by either excessive platelet aggregation (arteries) or coagulation (veins) activity usually in the legs where inactivity (sit-ting for long periods of time such as in airplanes) promotes their formation.

Drugs are used to suppress the unwanted formation of thrombi or emboli and in their quick dissolution if they have been already formed before tissue damage can occur. Antiplatelet drugs prevent platelet aggregation by interfering with thrombox-ane formation (aspirin), ADP attachment to platelets (clopidogrel), or uncertain mechanisms such as on phosphodiesterase (dipyridamole). Anticoagulants prevent for-mation of thrombi by interfering with the synthesis of vitamin K–dependent clotting factors (warfarin) or by inhibiting thrombin formation (heparin, which is a natural prod-uct). Fibrinolytic drugs dissolve unwanted blood clots, usually by activating plasmin formation. Clotting factors are used in defi-ciency diseases when blood does not clot normally such as occurs in hemophilia.

INDICATIONS Drugs are indicated in the following: • Pulmonary embolism, when a blood

vessel in the lungs becomes blocked. In most cases, the blockage is caused by one or more blood clots that travel to the lungs from another part of the body. It manifests itself with sudden shortness of breath, chest pain often mimicking a heart attack, cough, tachycardia, wheez-ing, leg swelling, sweating, anxiety, and lightheadedness or fainting. It is mostly mild but can become fatal. Initially, hep-arin is administered IV or under the skin, which prevents existing clots from growing and stops the formation of new clots. Later, warfarin may be prescribed.

• Strokes, which occur mostly when the blood supply to a part of the brain is reduced or stopped by a blood clot (isch-emic stroke) so that within a few min-utes, neurons start to die. Warning signs include trouble with walking, dizziness, loss of balance or coordination, numb-ness, trouble speaking or seeing, and headache, which are persistent. If signs are fleeting, it is called a transient isch-emic attack in which blood flow is only

temporarily interrupted. The signs and symptoms are similar but usually milder and disappear mostly within minutes but should be brought to the attention of a physician. A few strokes are caused by bleeding in the brain (hemorrhagic strokes). Intervention of a stroke must occur quickly to prevent brain damage. It is recommended not to give aspirin at home but to rush the individual to a hos-pital as soon as possible. At the hospital, it will be determined what type of stroke it is and if it is a hemorrhagic stroke, sur-gery may be indicated (administration of aspirin in this case would have increased further bleeding). In the case of an isch-emic stroke, aspirin is given and fol-lowed by fibrinolytic drugs to dissolve the clot. They must be administered within 3 hours, although they might still be effective after this time. Later, drugs that reduce clot formation are indicated to prevent their formation.

• Heart attack or MI can occur when a blood clot blocks a coronary blood ves-sel and prevents blood flow and sup-ply of nutrients and oxygen to cardiac muscle, resulting in damage and death of cardiac tissue. Common signs and symp-toms of a heart attack include pressure and pain in the center of the chest that extends to the shoulder, arm, back, or teeth and jaw; shortness of breath; sweat-ing; fainting; and nausea and vomiting.

• Atrial fibrillation or prosthetic heart valves can give rise to the formation of thrombi, which later can travel and block blood vessels, leading to tissue damage. Drugs like clopidogrel reduce their formation and prevent possible tissue damage.

• D eep vein thrombosis prevention, in which these drugs dissolve or prevent the formation of thrombi and their pos-sible travel through the vascular system.

• Hemophilia is a rare, inherited bleeding disorder in which blood does not clot nor-mally. Bleeding episodes can range from mild to fatal and can be caused by injuries or can be internal. The cause is a lack of certain clotting factors. Hemophilia A is caused by a lack or too little clotting fac-tor VIII, and hemophilia B is caused by low levels of clotting factor IX. Treatment involves replacement therapy by giving or replacing the necessary clotting fac-tor. These factors can be obtained from human blood or be made by recombinant techniques. They are injected.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Warfarin 2.5-10 mg/day PO or IVHeparin Depending on the

preparationAspirin 81 mg once daily PO

Clopidogrel 75 mg once daily PODipyridamole 225-400 mg in 3-4

divided doses daily PO

ADMINISTRATION These drugs can be given IV, SC, or PO. A number of drugs in these categories (fibrinolytic or thrombolytic drugs) are administered in the hospital.

CONTRAINDICATIONS Contraindications or cautious use includes patients at risk of bleeding and pending surgery, in which case these drugs should be stopped about 1 week before.

COMMON ADVERSE REACTIONS Adverse reactions include fatigue, head-ache, increased risk of bleeding by external or internal injuries, and rarely a potentially fatal thrombotic thrombocytic purpura. Orthostatic hypotension can occur with dipyridamole. Discontinuation of long-term therapy with these drugs, such as before surgery, can carry a slightly increased risk of the formation of thrombi.

DRUG INTERACTIONS • These drugs can interact with NSAIDs

by increasing bleeding episodes. • Risk of bleeding is increased with con-

current use of gingko, garlic, ginseng, and other herbal products. Foods high in vitamin K content may antagonize the action of warfarin.

IMPLICATIONS FOR PHYSICAL THERAPISTS • If the patient complains about nose

bleeds, bleeding gums, unusual bruising, or black stools, notify or have patient contact the physician because this might require a dose adjustment.

• Gently hold an older, frail patient taking these medications because firm or tight handling can lead to bruising or bleed-ing episodes.

• Advise the patient not to take NSAIDs that are OTC or to notify the physician before taking these drugs because they can increase the risk of bleeding.

• Patients should use vitamins only on the advice of a physician; in particular, they should avoid vitamin K preparations when on anticoagulant therapy.

• Instruct the patient to strictly adhere to the dosing schedule because doses taken too rapidly or in excess can increase the risk of severe bleeding.

• Advise older patients who do not take these medications not to sit quiet for long periods of time but to tense their legs or to get up and walk periodically, for example, on long airplane flights, to exercise leg muscles, keep blood flow-ing, and prevent thrombi formation. Also, suggest wearing pressure stock-ings on such trips.

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DRUGS AND BONE FORMATION

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Calcium

supplementsMany different

preparations with or with-out vitamin D supplementation

BisphosphonatesAlendronate FosamaxEtidronate DidronelIbandronate BonivaPamidronate ArediaRisedronate ActonelCalcitoninCalcitonin Calcimar,

Salmonine, otherParathyroid HormoneTeriparatide Forteo

MECHANISM OF ACTION Bones consist mainly of calcium and phosphate, provide rigidity to the body, and serve as an internal source of calcium. For this reason, they are not static but continuously remodeled with osteoclasts (OC) digesting old bone and osteoblasts (OB) building new bone. This process is regulated by a number of biochemi-cals. Calcium and phosphate levels in the blood, which are derived from food, must be maintained within limits. Parathyroid hormone (PTH) from the parathyroid gland, can increase bone resorption but also and more importantly can enhance bone formation. Vitamin D synthesized in the body by UV light increases intestinal calcium and phosphate absorption and assures the necessary supply of these min-erals. Minor roles are played by calcitonin and estrogens, which stimulate bone for-mation, and glucocorticoids, which can break down bone.

Bone formation can be increased by supplying calcium that might be miss-ing in the diet or is not fully absorbed. Calcium in supplements is mostly com-bined with carbonate, citrate, phosphate, lactate, and gluconate. Vitamin D sup-plementation alone or in combination with calcium supplements will increase calcium absorption. Bisphosphonates, which seem to be incorporated into bone, reduce OC activity and seem to promote a more adequate and efficient mineraliza-tion. Calcitonin will also increase bone formation.

INDICATION These drugs are indicated in the following: • Osteoporosis, which is characterized by

excessive porousness of the bone that is caused by enlargement of the canals or formation of cavities. This can lead

to bone fractures. Osteoporosis occurs during aging (genetic differences among individuals) or caused by exogenous factors such as chronic steroid use. All drugs slow down the progression of the disease by promoting new and stronger bone formation. Drugs also counteract steroid-induced osteoporosis.

• Hypoparathyroidism, which leads to impaired bone breakdown and hypocal-cemia. Administration of calcium and vitamin D supply the needed calcium for the body or injections of PTH are used.

• Rickets, which is a vitamin D deficiency in children (no longer in the United States but in other parts of the world) and causes abnormal bone formation. Calcium and vitamin D supply the needed calcium for the body.

• Other conditions include certain can-cers, osteomalacia, and Paget disease .

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Calcium SupplementsAlendronate 10 mg once daily or

70 mg once weekly PO

Etidronate 5-10 mg/kg/day once daily PO

Ibandronate 2.5 mg once daily or 150 mg once a month PO

Pamidronate 30-90 mg in single or divided doses IV

Risedronate 5 mg once daily or 35 mg once weekly PO

Calcitonin 200 IU/day by nasal spray

Teriparatide 20 µ g/day SC

ADMINISTRATION Bisphosphonates must be taken PO with water on an empty stomach in the morn-ing while sitting or standing for at least 30 to 60 minutes (to prevent reflux into the esophagus, which can cause severe irri-tations). The PTH preparation is injected. Calcitonin is inhaled.

CONTRAINDICATIONS Bisphosphonates should not be used by patients with renal and GI disorders.

COMMON ADVERSE REACTIONS Bisphosphonates are generally well toler-ated except for some GI distress; in partic-ular, if NSAIDs are being used. Calcitonin can cause some allergic reactions. The PTH preparation may cause pain at the site of the injection, some weakness, and although still uncertain, may increase the risk of bone cancer.

DRUG INTERACTIONS Bisphosphonates should not be taken with caffeine drinks or mineral water.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Encourage the patient to eat a balanced

diet and to walk at least an hour a day in daylight and to do weight-bearing exercises to strengthen bones and to avoid possible fractures. Furthermore, the patient at risk should stop smoking, lose weight if overweight and avoid excessive alcohol consumption.

• Advise patient to follow the administra-tion schedule for the bisphosphonates exactly as prescribed since otherwise significant adverse reactions can occur.

DRUGS AND SUBSTANCES OF ABUSE

Only a small list of legally and illegally abused drugs and substances is given with a definition of physical dependence and addiction.

ALCOHOL • Alcohol or ethanol is metabolized

mostly by 2 enzymes at the rate of about 100 mg/kg/hr or roughly 10 mL/hr/person (about one glass of wine or beer per hour in the average person) and is also partially exhaled by the lungs (breathalyzer test). It is evenly distrib-uted throughout the body, and a blood test can predict tissue levels.

• Alcohol is a CNS depressant and seems to affect inhibitory pathways, first result-ing in the loss of inhibitions and aggres-sive behavior. This is followed by general CNS depression with impaired sensory function and muscular coordination, changes in mood, personality, behavior, and mental activity. Intoxicated persons often are not aware of these impair-ments, and alcohol causes the feeling of increased performance, although there actually is a decrease!

• Small amounts of alcohol, such as 1 to 2 drinks or glasses of wine (in particu-lar red wine), seem to be beneficial for maintaining good health, whereas large amounts of alcohol consumed over long periods lead to alcoholism, with significant health risks that are often exacerbated by poor diets and vitamin deficiencies (such as thiamine). Adverse reactions include damage to the liver (cirrhosis), stomach (ulcer), heart, and brain (the Korsakoff-Wernicke syn-drome with memory loss and psychotic behavior), and infants who are born with fetal alcohol syndrome (facial/mental abnormalities).

• Alcoholism is treated with limited suc-cess with various drugs and behavioral modification techniques.

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• Alcohol can enhance the sedative and gastric damaging effects of many drugs (e.g., NSAIDs).

TOBACCO • Tobacco smoke contains hundreds of

chemicals that the smoker inhales; nico-tine, tar, and carbon monoxide (CO) are the most toxic ones.

• Nicotine will stimulate the nicotinic receptors in the brain, causing the rewarding feeling, and in the body, in which excessive smoking can lead to hypertension, tachycardia, gastric prob-lems, and cardiovascular pathology.

• Tar is the product of incomplete combus-tion of organic material and causes inflam-mation of the lungs (smoker’s cough, bronchitis, or emphysema) and cancer of throat, lungs, and bladder. If a heavy smoker stops smoking, his or her chances of dying from cancer will slowly diminish.

• CO is also formed by incomplete com-bustion of tobacco and will bind to hemoglobin, replacing oxygen and lead-ing to a reduction in the oxygen supply to all tissues.

• Cessation of smoking is attempted with nicotine gum or a patch, drugs, and behavioral modification.

MARIHUANA • Marihuana/hashish smoke contains

hundreds of chemicals; tetrahydrocan-nabinol (THC) is the active and reward-ing compound.

• Effects of THC include relaxation, dis-turbed sensory perception (interferes with driving a car), stimulation of appe-tite, and antiemetic effects (allowed in certain states for cancer patients to com-bat drug-induced nausea or vomiting).

• Chronic, heavy use may include the toxic effects of inhaled CO and tar (see Tobacco). The theory that marihuana is a stepping stone to other drugs has been largely abandoned.

• THC, as drug (dronabinol), is available to reduce nausea and vomiting during cancer chemotherapy.

HEROIN • Heroin is converted in the body to

morphine, which produces both CNS and peripheral effects (see Opioid or Narcotic Analgesics). Users prefer her-oin because it provides a quicker and more rewarding effect than morphine because it crosses more quickly into the brain. High doses cause respiratory depression and death.

• Methadone is used to treat heroin abuse and to prevent the withdrawal syndrome.

COCAINE AND AMPHETAMINES • Both drugs are sympathomimetic (see

α -Agonists and β -Agonists) and stimulate

adrenergic receptors. In the brain, they cause their rewarding effects mostly through the action of dopamine activity; in the body, alpha and β stimulation pre-vails with tachycardia and hypertension.

• They will counteract the therapeutic effects of α -blockers and β -blockers.

DEPENDENCE AND ADDICTION • Physical dependence is an altered phys-

iological state caused by the repeated administration of a drug or substance, which later on demands continued use to prevent the “withdrawal or absti-nence syndrome.” The occurrence of the withdrawal syndrome indicates exis-tence of physical dependence. Physical dependence can occur with the use of some but not all illegal and prescription drugs. Physical dependence carries cer-tain health risks but withdrawal can be dangerous or even life-threatening. The degree of physical dependence depends on the drug, dose, and time used.

• Withdrawal occurs only after abrupt cessation of a drug or substance in a physically dependent individual. Signs and symptoms are usually opposite to original drug effects (morphine use causes miosis or constipation and with-drawal from morphine causes mydria-sis or diarrhea). Most drugs that cause physical dependence (illegal as well as legal) should be discontinued slowly after long-term, high-dose therapy; no withdrawal symptom will become apparent.

• Addiction is a behavioral pattern of compulsive drug or substance use char-acterized by the overwhelming involve-ment with the drug, the securing of its supply, and a high tendency to relapse after its cessation. Also, addiction can be described as an “uncontrollable drug-using behavior” resulting in loss of “nor-mal” functioning and harm to the user and society. Controlled use of drugs is not considered addiction (e.g., social consumption of alcohol or other drugs). Genetic and environmental factors seem to determine addiction to a large extent (some individuals can avoid or handle drugs or substances “socially” regardless of availability, whereas others cannot).

“STREET” DRUG TOXICITY • Illegally obtained drugs or substances

carry additional health risks that can be more severe and even fatal because of illegal manufacturing techniques and unscrupulous selling practices.

• The user can never be sure if the sub-stance bought from street sellers is indeed the right drug (often a more dangerous drug is sold than actually offered), if it is the right dose (often a too-high dose is sold, e.g., most her-oin-related deaths), and in addition if

it contain dangerous impurities (often contains chemicals much more toxic than the drug sold such as rat poi-sons, which resulted in some deaths). Furthermore, improper use carries sig-nificant health risks such as shared nee-dles that can spread hepatitis and AIDS.

IMPLICATIONS FOR PHYSICAL THERAPISTS • The physical therapist must be aware

that some legal and illegal drugs can cause physical dependence and it is important for the patients not to stop these drugs abruptly but to discontinue them slowly to avoid serious withdrawal reactions.

• The physical therapist must also be aware of the fact that addiction is not only asso-ciated with illegal drugs but also with excessive long-term alcohol and tobacco use or excessive use of nasal sprays, androgenic steroids, or laxatives.

• The physical therapist can be helpful in advising the individual about the dangers of using or abusing certain substances and to encourage them to stop. This is particularly true when smoking or alco-hol is detected on the breath during ther-apy sessions early during the day.

• The physical therapist can warn the ille-gal drug user, if known, or younger indi-viduals who express thoughts about buying drugs on the street that he or she may experience serious ill effects and even death not only from the substances bought but also from unsanitary and unprofessional manufacturing techniques and unscrupulous selling practices.

DRUGS AND THE THYROID GLAND

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) HypothyroidismLiothyronine

(T3)Cytomel, Triostat,

otherLevothyroxine

(T4)Synthroid, Levo-T,

otherHyperthyroidismPropylthiouracil PropylthiouracilOther

MECHANISM OF ACTION The thyroid gland is located at the neck around the trachea and synthesizes and secretes the thyroid hormones. Their formation is stimulated by the thyroid-stimulating hormone (TSH). Organic pre-cursors and iodide are converted in the gland via the action of two oxidases in a process called organification of iodine to thyroglobulin. This protein is metabolized

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to thyroxine (T4) and triiodothyronine (T3), both of which are released into the body. T4 is now converted largely to T3, which is the most active form. They stimu-late carbohydrate, fat, and protein metabo-lism, as well as regulate body heat and are involved in bone formation.

Drugs like T4 or T3 can replenish or replace low or missing endogenous levels of both hormones. Propylthiouracil and related drugs will inhibit the organifica-tion and synthesis of both T3 and T4 and reduce excessively high levels of both hor-mones. High doses of iodide will inhibit its uptake into the gland. In addition, sur-gery and radioactive iodine are being used to either remove or to destroy part of an overactive gland.

INDICATION Drugs are indicated in the following: • Hypothyroidism, or a lack of sufficient

hormone secretion, can be caused by an autoimmune disease but can also result from the surgical removal of a cancerous gland. It manifests itself as physical and mental fatigue, weight gain, dry and rough skin, and muscle cramps and aches. Drug therapy consists of replacement therapy with the hormones. Both thyroxine and liothyronine have a somewhat delayed onset of action, and levothyroxine is pre-ferred for long-term therapy. Drugs have a narrow margin of safety, and it is often difficult to find the right dose and main-tain the patient on it.

• Hyperthyroidism, or a surplus of the hormone, which can also be caused by an autoimmune disease in which anti-bodies stimulate the gland to produce too much hormone. It manifests itself in palpitations and tachycardia, heat intol-erance, insomnia, weight loss, warm and moist skin, and muscle weakness. Propylthiouracil and related drugs, sur-gery, or radioactive destruction of the gland are indicated.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Liothyronine 25-75 µ g /day POLevothyroxine 50-200 µ g/day POPropylthiouracil 100-300 mg 3 times

daily PO

ADMINISTRATION Hormones and drugs are used PO.

CONTRAINDICATIONS Hormones are contraindicated or should be used with caution in patients with adrenal insufficiency and MIs; propyl-thiouracil is contraindicated in patients with hepatic diseases and bone marrow depression.

COMMON ADVERSE REACTIONS Generally, adverse reactions of hormone replacement therapy often result from an overdose resembling hyperthyroid-ism with angina in compromised patients. Propylthiouracil may cause hepatic and renal problems, as well as agranulocytosis and bleeding episodes and hypothyroidism if doses are too high.

DRUG INTERACTIONS • Thyroid hormones increase the effects

of anticoagulants and decrease effec-tiveness of insulin and oral hypoglyce-mics. Propylthiouracil interacts with iodide and lithium.

• Efficacy of thyroid hormones is decreased by soy, bugleweed, and carnitine. Also, foods high in iodine should be avoided.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Observe patients on hormone replace-

ment therapy carefully and check for signs and symptoms of hyperthyroidism or hypothyroidism. If present, notify or have the patient notify the physician because this might indicate a dose adjustment.

• Weight loss is often a physiological response to the medications. Patients may take it upon themselves to utilize the medication for weight loss purposes. Weight loss, nervousness and excitabil-ity can be signs of medication misuse. If misuse is suspected, the patient’s physician should be notified and the patient should be educated regarding the potential hazards to their health.

• Patients on propylthiouracil should be watched for yellowing skin and eyes indicating jaundice, bleeding episodes, and an unexplained sore throat indicat-ing agranulocytosis. If this occurs, notify or have patient notify the physician about these observations.

FEMALE HORMONES

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) EstrogensEstradiol Estrace, Vivelle, otherEthinyl Estradiol EstinylOtherProgestinsProgesterone Gesterol, PrometriumNorgestrel OvretteOtherContraceptives: Ethinyl EstradiolPlus desogestrel Desogen, Mircette,

otherEthynodiol Demulen, ZoviaLevonorgestrel Levlen, Nordette,

otherNorethindrone Loestrin, Brevicon,

other

Norgestimate Ortho-Cyclen, otherNorgestrel OvralContraceptives: MestranolPlus norethin-

droneGenora, Norinyl, other

Norethindrone MicronorNorgestrel OvretteOtherPostcoital DrugsMifepristone MifeprexOtherEstrogen-Receptor ModulatorsRaloxifene EvistaTamoxifen NolvadexOther

MECHANISM OF ACTION Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are released from the pituitary gland. FSH and LH stim-ulate the maturation of follicles in the ova-ries. The ruptured follicle will develop into the corpus luteum and will secrete estrogens and progesterone. Estrogens are a group of hormones, and progestins con-tain several active compounds of which progesterone is the most important. Both cause proliferation and thickening of the endometrium in the uterus. If the egg is fertilized, it will be implanted in the uterus and develop into an embryo and fetus later. The high levels of estrogens and progesterone will, in a negative feed-back, prevent the secretion of FSH and LH. In addition, progesterone causes the vaginal environment to become “hostile” to sperm so that no sperm can reach the ovaries. No new ovulation or conception will occur. If the egg is not fertilized, the corpus luteum stops secretion and the endometrium sloughs off and is expelled (menstruation). Thereafter FSH and LH are secreted and the cycle starts over again.

Drugs (except the estrogen-receptor modulators) are the natural hormones or their analogues which can now act like the endogenous hormones and correct deficiency states. They can also interfere with the natural processes and reduce FSH and LH release and cause an environ-ment “hostile” to sperm to prevent ovula-tion and conception (contraceptives) or to prevent implantation and to expel a fertil-ized egg from the uterus (postcoital pills). Estrogen antagonists can block estrogen receptors on breasts, which in a subset of women have been found to promote cancer when stimulated by estrogen.

INDICATION Drugs are indicated in the following: • Estrogen replacement therapy, in which

an estrogen deficiency causes postmeno-pausal problems (hot flashes, osteoporo-sis, arteriosclerosis, or vaginal dystrophy). Exogenous estrogen will now assume

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the role of the deficient endogenous hormones and reduce these bothersome problems. This practice is now reserved for severe cases only because this ther-apy has been linked to a higher inci-dence of cardiovascular morbidity.

• Amenorrhea and dysfunctional uter-ine bleeding caused by an abnormal hormone balance. Estrogens and/or progestins administered can restore the normal balance.

• Contraception, when no pregnancy is desired. The combination pill, estrogen plus progesterone, delivers high levels of both hormones into the body, sup-pressing FSH and LH secretion from the pituitary and preventing ovulation (“pseudopregnancy”). In addition, pro-gesterone causes a vaginal environment “hostile” to sperm, preventing sperm from traveling further. This pill is almost 99% to 100% effective. The progester-one-only pill works by the creation of the environment “hostile” to sperm and also by somewhat reducing FSH and LH secretion. Its effectiveness is about 98%.

• Postcoital intervention, when no con-ception was intended after unprotected sex. High doses of estrogens and/or progesterone are given (within 3 to 5 days) and probably act by inhibiting implantation of the fertilized egg (e.g., plan B, which is a high dose of levonorg-estrel and is available without a pre-scription for individuals 18 years and older). Similarly, mifepristone (taken within 50 days) blocks the progester-one receptors in the uterus, prevents the endometrium supporting action of progesterone and leads to endometrial shedding and expulsion of the embryo (sometimes helped by administration of a prostaglandin analog, misoprostol, which stimulates uterine contractions and helps in this ejection process).

• Breast cancer, which in some women is promoted by estrogen-receptor activity. Estrogen-receptor blockers or modulators will block these receptors and reduce estrogen’s effects on cancer promotion.

• Other uses include treatment of endo-metriosis, prostate cancer, and endo-metrial cancer .

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Estradiol 1-2 mg/day POEthinyl

Estradiol0.02 mg or 0.05 mg

daily PO

Contraceptives Many different combinations and dosages

Mifepristone 200-600 mg PO (fol-lowed by 400 mcg misoprostol PO)

Raloxifene 60 mg once daily POTamoxifen 10-20 mg 2 times

daily PO

ADMINISTRATION • Depending on the drug, they can be

given orally, IM, SC, by spray, patch, implant, or vaginal ring. The contracep-tive combination pill is either given for 3 weeks with 1 week placebo (1-month cycle) or for 84 days with 1 week pla-cebo (3-month cycle).

• It is important to take contraceptives as directed because breakthrough bleed-ing and reduced protection can occur. General guidelines will vary among drugs and are as follows: if one dose is missed and remembered the same day, then the missed dose should be taken immediately. If it is remembered the next day, 2 tablets are taken on that day and then back to 1 tablet per day. If 2 doses are missed, 2 tablets are taken for 2 days, then back to 1 tablet per day. If 3 or more tablets are missed, consult physician, pharmacist, or nurse.

CONTRAINDICATIONS These drugs should not be used in patients with thromboembolic disorders.

COMMON ADVERSE REACTIONS Estrogen replacement therapy has been associated with a higher risk of MI, stroke, pulmonary embolism, and thromboembo-lism and can increase the risk of endome-trial and breast cancer, although the latter is restricted to a subset of women. Both hormones can cause sodium and water retention with weight gain and swelling of the feet. Estrogens in susceptible individu-als may cause depression. Contraceptives carry the same risks. Combination pills increase the risk of blood clot forma-tion, which is intensified by smoking. Tamoxifen has been associated with uter-ine malignancies.

DRUG INTERACTIONS • These drugs can interact with a number

of other drugs. Estrogens are contrain-dicated with tamoxifen, raloxifene, and steroids.

• Saw palmetto decreases their effective-ness.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Patients on estrogens and in particular

on combination contraceptives should be advised to stop smoking if they do. Explain the increased risk of cardiovas-cular accidents with this habit.

• If a patient complains about unexplain-able pain in the legs, notify or have patient notify the physician imme-diately because this could indicate a deep vein thrombosis that needs quick

attention to prevent health-threatening problems.

• Check blood pressure periodically because salt retention in susceptible individuals can cause hypertension.

• If you notice that a patient on estro-gens is fatigued and depressed, have the patient notify the physician because estrogens can cause depression.

• Inform the patient that it is impor-tant to take contraceptives as directed because missed doses reduce or negate protection.

• Inform the patient that contraceptives protect against pregnancy but not vene-real diseases. Only condoms do this.

• Inform the patient that postcoital inter-vention procedures are emergency pro-cedures only and should not be used routinely.

GASTROINTESTINAL DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Antacids (H

2 -Blockers)

Cimetidine Famotidine Nizatidine Ranitidine

Tagamet Pepcid Axid Zantac

Proton Pump Inhibitors Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole

Nexium Prevacid Prilosec Protonix AcipHex

Antidiarrheal Drug Kaolin, Pectin Bismuth Diphenoxylate Loperamide Other

Kapectolin Pepto-Bismol Lomotil, Lonox, other Imodium, other

Laxatives Psyllium Bisacodyl Senna Docusate Other

Metamucil Dulcolax, Deficol,

Correctol Senokot, other Colace, Sulfolax,

other

MECHANISM OF ACTION The main digestive processes occur in the mouth, stomach, and intestines. In the stomach, hydrochloric acid (HCl) and digestive enzymes are released into the lumen. Acid secretion is stimulated by the action of acetylcholine, histamine acting on H

2 -receptors and the enzyme

H + ,K + ATPase, also called a proton pump, which moves H + into the lumen. In addi-tion, a high pH (alkaline conditions) and spicy and irritating foods can cause acid formation. The digestive processes con-tinue in the intestines. Motility of the stom-ach and intestines (peristalsis) in moving food and feces is increased by stimulation

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of cholinergic receptors and stretching the intestinal wall and decreased by stim-ulation of opioid receptors.

GI drugs affect these processes in vari-ous ways. Antacids consist of a base, such as carbonate, silicate, or hydroxide, which is combined with aluminum, calcium, or magnesium. The antacids combine with the acid and remove H + . The H

2 -blockers

block the action of histamine on H 2 -

receptors and the proton pump inhibi-tors inhibit the pump, which in both cases leads to a reduction in H + secretion. Antidiarrheal drugs, such as the absor-bents (kaolin, pectin, and bismuth), absorb substances that might increase peristalsis, and loperamide and diphenoxylate relax intestinal muscles by stimulating opioid receptors. The laxatives increase the bulk in the intestines promoting the stretch reflex (psyllium), soften the stool (docu-sate), or irritate the intestines (bisacodyl, senna), resulting in increased peristalsis and easier defecation.

INDICATION GI drugs are indicated in the following: • Dyspepsia, gastritis, and peptic ulcer,

in which excessive acid production (among others such as bacteria) irritates and finally erodes the mucosa, causing an ulcer. GI drugs reduce acid formation and promote healing of inflammations and ulcers.

• Gastric esophageal reflux disease (GERD), in which acid enters the esophagus, causing inflammation, pain, spasm and eventually cancer. GI drugs reduce acid production so that less or no acid will enter the esophagus.

• Constipation, in which peristalsis is decreased, can lead to fecal impacts. GI drugs increase peristalsis and promote fecal transport and evacuation.

• Diarrhea, in which excessive motility leads to frequent evacuations, can result in marked water and electrolyte losses. GI drugs slow peristalsis and reduce or prevent fluid and electrolyte loss.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Cimetidine 300-1600 mg/day in

divided doses POFamotidine 20-40 mg/day once

daily PONizatidine 150 mg 1-2 times daily

PORanitidine 150 mg 1-2 times daily

POEsomeprazole 20-40 mg/day once

daily POLansoprazole 15-30 mg/day once

daily POOmeprazole 20-40 mg/day once

daily PO

Pantoprazole 40 mg/day once daily PO

Rabeprazole 20 mg/day once daily PO

Kaolin, Pectin 60-120 mL after loose bowel movement PO

Bismuth 525-1050 mg several times as needed PO

Diphenoxylate 5 mg 3 times daily (combined with atropine) PO

Loperamide 4 mg followed by 2 mg up to 16 mg/day PO

Psyllium 1-2 tsp in 8 oz water 2-3 times daily PO

Bisacodyl 10-30 mg 1-2 times daily PO

Docusate 50-300 once daily POSenna 1-8 tabs /day PO

ADMINISTRATION Most drugs are given PO with some also available rectally.

CONTRAINDICATIONS GI drugs should not be used or must be used with caution in patients with a num-ber of problems, depending on the drug employed.

COMMON ADVERSE REACTIONS Adverse reactions differ among drugs. A rebound phenomenon (increased H + secretion) can occur after long-term use of acid reducers. Large doses of antacids cause constipation (aluminum) or diar-rhea (magnesium). H

2 -blockers can cause

some dizziness and rarely blood disorders. Proton pump inhibitors show few adverse reactions, except some rarely cause blood disorders and Stevens-Johnson syndrome. Loperamide and diphenoxylate may cause nausea, drowsiness, and dizziness. Irritating laxatives may cause nausea and intestinal cramps. Long-term use can lead to laxative dependence, in which physio-logical functions of the intestines start to decline.

DRUG INTERACTIONS Interactions with other drugs depend on the individual drug. Antacids reduce avail-ability of some antibiotics from the intes-tines. Altering the pH of the stomach can affect solubility and absorption of certain medications; instructions of individual drugs should be observed.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Instruct the patient that OTC prepara-

tions of these preparations should only be taken exactly as indicated on pack-ages and for a short period of time. If no

relief is obtained, a physician must be consulted because there could be more serious underlying problems.

• Inform the patient that proper eating habits with the consumption of bulk can reduce constipation problems.

• Advise patients against long-term use of laxatives, unless prescribed by a physi-cian, because this could lead to laxative dependence. Tell patients that individu-als differ in their bowel movements and that a bowel movement need not occur every day.

• Instruct patient who takes OTC cimeti-dine to do so not for more than 2 weeks and to consult physician if further use is needed.

HEMOPOIETIC DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Iron preparations Feosol, Feostat,

Feratab, Ferrlecit, other

Epoetin Epogen, ProcritNandrolone Deca-Durabolin,

KabolinCyanocobalamin Cobex, Cobolin-M,

Nascobal, Vibal, other

Hydroxoco-balamin

Alphamin, Vibal LA, other

Folic acid Apo-Folic, Folate, Folvite, other

MECHANISM OF ACTION RBCs, or erythrocytes, contain hemoglobin (consisting of the iron-containing red pig-ment heme plus the protein globin) that transports oxygen to and carbon dioxide away from tissue cells. Erythrocytes derive from hemopoietic stem cells in the bone marrow. They are formed under the influ-ence of erythropoietin, which is secreted from the kidneys. Among the many chemi-cals necessary for the synthesis of hemoglo-bin are folic acid and B12; the latter needs a special intrinsic factor secreted by the stomach to be absorbed from the GI tract.

Iron preparations supply the iron. Epoetin stimulates erythrocyte formation from stem cells and nandrolone stimulates erythropoietin synthesis. Cyanocobalamin or B12 and folic acid promote the synthe-sis of hemoglobin.

INDICATIONS Hemopoietic drugs are indicated in the following • Iron-deficiency anemia (extensive

blood loss, severe menstruation, kidney problems requiring hemodialysis), in which iron preparations (usually ferrous salts) are used. Iron is available in

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different combinations with an onset of action of about 4 days and peak effects at 1 to 2 weeks.

• Folic acid deficiency anemia, in which supplementation with folic acid is used.

• B12 or pernicious anemia (mostly caused by a lack of intrinsic factor). Pernicious anemia also damages the nervous system. It is treated with cyano-cobalamin and hydroxocobalamin.

• Anemias caused by chemotherapy or renal failure are treated with epoetin and/or nandrolone.

COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Ferrous

prepara tions120-240 mg/day in 2-4

divided doses PO.Iron polysac-

charide50-100 mg/day twice

daily as tablets or 150-300 mg/day as capsules PO

Epoetin 50-100 units/ kg 3 times weekly SC or IV

Nandrolone 50-100 mg every week IM

Folic acid 1 mg/day initially then 0.5 mg daily PO

Cyanoco-balamin

1000 µ g daily PO or 500 µ g weekly by nasal spray or 30-100 µ g/day IM

ADMINISTRATION Hemopoietic drugs can be given orally, IM, SC, IV, or nasal spray. Onset of action is delayed and varies among medications and routes of administration.

CONTRAINDICATIONS Iron preparation should be used with extreme caution in patients with GI prob-lems (ulcer).

COMMON ADVERSE REACTIONS Iron preparations can cause GI prob-lems (epigastric pain, constipation) and color stool black (masking GI bleeding). Overdosing leads to iron toxicity (bluish lips, drowsiness, weakness, or seizures). Epoetin can cause hypertension, and nan-drolone can cause allergic reactions. Folic acid and B12 are relatively safe.

DRUG INTERACTIONS • Iron preparations chelate with tetra-

cyclines, quinolones, and reduce their absorption.

• Vitamin C increases, and food decreases iron absorption.

IMPLICATIONS FOR PHYSICAL THERAPISTS • If the patient is easily exhausted and

appears bluish and anemic, advise the

patient to see a physician and warn against self-medications because dif-ferent types of anemia exist and each needs special therapies. Brittle, concave nails with ridges often indicate an iron-deficiency anemia.

• Warn the patient who uses iron or folic acid without medical advice to treat an anemic condition to consult a physician because a B12-deficient anemia may respond somewhat to these prepara-tions, whereas nerve damage will con-tinue unchecked.

• If the patient is using iron preparations and has black stools but also severe epi-gastric pain, advise the patient to see a physician because this could indicate internal bleeding. Also, advise the patient not to overdose with iron because this can lead to iron toxicity.

• Advise the pregnant patient, if not already recommended by the physician, to supplement with folic acid even in the absence of an anemic condition to reduce the risk of fetal abnormalities (spina bifida).

HYPOGLYCEMIC DRUGS I

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Insulin lispro/prota-

mine insulinHumalog Mix

75/25NPH/regular insulin

mixturesHumulin 50/50,

70/30, Novolin 70/30

Short-acting insulin Humulin R, Novolin R

Intermediate-Acting InsulinsIsophane insulin Humulin N, Iletin

II NPHLente (zinc) insulin Humulin L,

Novolin ge Lente

Long-Acting InsulinsUltralente (zinc)

insulinHumulin U

Ultralente, Novolin U

Insulin glargine LantusRapid-Acting InsulinsInsulin aspart NovoLogInsulin lispro HumalogInsulin glulisine Apidra

MECHANISM OF ACTION Glucose is necessary for many metabolic and physiological processes, including energy supply to skeletal muscles. Glucose metabolism is mostly regulated by the hormones insulin and glucagon, both synthesized and released from the pan-creas. Insulin, a polypeptide, is released when blood glucose levels rise and it low-ers blood glucose levels by promoting glycogenesis in the liver (glucose is con-verted to glycogen) and activating special

receptors, insulin receptors, which pro-mote uptake of glucose into skeletal mus-cles and other cells, such as liver and fat cells. Insulin release from the pancreas is facilitated by the action of special short-lived peptides and related endogenous compounds. If blood glucose falls, insu-lin release is decreased and glucagon is released, which works the other way in increasing blood glucose levels. In addi-tion, insulin affects protein and fat metab-olism and inhibits fatty acid oxidation and ketone body formation, which could cause a ketoacidosis.

Insulin administration is used as a replacement therapy when endogenous insulin is insufficient or missing. It low-ers blood glucose by promoting glucose uptake into skeletal muscles and other tis-sues. It prevents fatty acid oxidation and the formation of acidic ketone bodies.

INDICATIONS Hypoglycemic drugs are indicated in the following: • Diabetes mellitus is caused by a defi-

ciency or lack of insulin and mani-fests itself as polydipsia and polyuria with highly increased blood glucose levels (spilling into the urine, which now “tastes” sweet, causing its name). Untreated it leads to ocular, renal, and cardiovascular health consequences, as well as ketoacidosis. It can be divided into two types. Type I can be caused by an autoimmune or viral disease where the gland does not produce insulin. Type II has usually an adult onset often caused by genetic factors, as well as obesity. In this case, the cause is either an insufficient release of insulin from the pancreas or unresponsive insulin receptors on tissues. In type I, insulin is injected (because oral preparations would be destroyed in the stomach) to replace the missing endogenous hormone. In type II, treatment starts with carbohydrate restrictions, exer-cise, and weight loss, and if unsuccess-ful, is followed by oral hypoglycemics (see Hypoglycemic Drugs II) and only if necessary by insulin.

• Diabetic ketoacidosis, in which organic acids and ketone bodies are formed from fat because of poor glucose control, which can be life threatening. Short-acting insu-lins plus other drugs and measures are used to correct this problem.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES)

Insulin lispro/protamine insulin

0.5-1 unit/kg/day SC

NPH/regular insulin mixtures

0.5-1 unit/kg/day SC

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Short-acting insulin 0.5-1 unit/kg/hr SCIntermediate-acting

insulins0.5-1 unit/kg/day

SCLong-acting insulins 0.5-1 unit/kg/day

SCRapid-acting insulins 0.5-1 unit/kg/day

SC(all preparations once or repeated)

ADMINISTRATION Insulin has to be injected SC (IV for ketoac-idosis) or given by pump or nasally. It now comes mostly from human recombinant DNA sources. Preparations are manufac-tured to have different onsets and dura-tions of action to suit the characteristics of the disease of the patient. Onset of action ranges from 15 to 60 minutes and duration of action from 2 to 24 hours. Some prepa-rations are used in the morning and oth-ers before meals. Stress, exercise, trauma, drugs, infections, or changes in diet may change the glucose response to insulin and may require dosages adjustments.

CONTRAINDICATIONS There are no major contraindications except that nasal preparations should not be used in patients with lung problems such as asthma or emphysema.

COMMON ADVERSE REACTIONS The most common adverse reactions are hypersensitivity reactions, which can range from rashes and itching to an anaphylactic reaction. Hyperglycemia and hypoglyce-mia (sweating, weakness, dizziness, tremor, and tachycardia to unconsciousness) can result from too much or too little insulin. Insulin can cause local lipoatrophy or lipo-hypertrophy, which can be minimized by changing injection sites. Poorly controlled glucose levels can lead to ketoacidosis (fatigue, flushed skin, nausea, vomiting, and dyspnea), which can be life-threatening.

DRUG INTERACTIONS • Glucose-lowering effects may be reduced

by a large number of drugs, including cor-ticosteroids, certain antipsychotic and antiviral drugs, and diuretics. Glucose-lowering effects may be enhanced by ACE inhibitors and salicylates. β -Blockers may mask the onset of a hypoglycemic reaction (e.g., tachycardia).

• Glucosamine, chromium, and coenzyme Q-10 enhance blood glucose levels, low-ering the effects of insulins.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Make sure that the patient wears an

identification tag indicating that he or she is a diabetic and what type and dose of insulin is being used. Also, make sure that the patient carries some sugar, a glu-cose preparation, or sweetened orange

juice to counteract a possible hypogly-cemic reaction.

• Do not recommend glucosamine to a diabetic patients to treat joint problems unless this has been cleared with a phy-sician because glucosamine can cause hypoglycemic episodes in unadjusted insulin dosages.

• Be aware of the occurrence of hypogly-cemia, as well as hyperglycemia (unusual thirst, drowsiness, fruit-like breath, and flushed). Treat the first with sugar (arti-ficial sweeteners do not work) and the other by asking the patient to adminis-ter the needed insulin.

• Do not massage the site of injection because this could cause an unwanted increase in insulin absorption and a hypoglycemic reaction.

• Exercise a diabetic patient carefully, in particular at the beginning of insu-lin therapy because exercise can reduce blood glucose levels. Also, sug-gest having insulin injected into the abdomen instead of skeletal muscle. Check glucose levels during and after exercise.

• If you feel that the patient’s blood glu-cose levels are fluctuating ask if he or she has changed dietary habits or is using an OTC drug because these can cause poor glucose control.

HYPOGLYCEMIC DRUGS II

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Glucosidase inhibitorsAcarbose PrecoseMiglitol GlysetBiguanidesMetformin Fortamet, Glucophage,

RiometMeglitinidesNateglinide StarlixRepaglinide GlucoNorm, PrandinSulfonylureasGlimepiride AmarylGlipizide GlucotrolGlyburide DiaBeta, Glynase,

MicronaseThiazolidinedionesPioglitazone ActosRosiglitazone AvandiaHormonesPramlintide SymlinInsulin-release facilitatorsExenatide ByettaSitagliptin Januvia

MECHANISM OF ACTION Glucose is necessary for many metabolic and physiological processes, including energy supply to skeletal muscles. Glucose

metabolism is mostly regulated by the hormones insulin and glucagon, both syn-thesized and released from the pancreas. Insulin, a polypeptide, is released when blood glucose levels rise and it lowers blood glucose levels by promoting glyco-genesis in the liver (glucose is converted to glycogen) and activating special receptors, insulin receptors, which promote uptake of glucose into skeletal muscles and other cells such as liver and fat cells. Insulin release from the pancreas is facilitated by the action of special short-lived peptides and related endogenous compounds. If blood glucose falls, insulin release is decreased and glucagon is released, which works the other way in increasing blood glucose levels. In addition, insulin affects protein and fat metabolism and inhib-its fatty acid oxidation and ketone body formation, which could cause a ketoaci-dosis. Drugs work by different mecha-nisms to lower elevated blood glucose. Glucosidase inhibitors lower postprandial blood glucose by inhibiting α -glucosidase in the GI tract, which is involved in the breakdown of carbohydrates to sugar and reduces and slows sugar absorption. Biguanides decrease hepatic glucose pro-duction, somewhat reduce intestinal glu-cose absorption, and increase insulin receptor sensitivity. Meglitinides close pancreatic potassium channels and open calcium channels, which causes insulin release. Sulfonylureas also affect potas-sium channels, release insulin from the pancreas, may increase insulin recep-tor sensitivity, and decrease hepatic glu-cose formation. Thiazolidinediones act as agonists on cellular insulin receptors and improve glucose uptake into tis-sues. Pramlintide slows gastric emptying, decreases glucagon secretion, and curbs appetite to reduce postprandial hyperg-lycemia. Insulin-release facilitators mimic the action of endogenous compounds that facilitate insulin release.

INDICATIONS Hypoglycemic drugs are indicated in the following: • Diabetes mellitus, is caused by a defi-

ciency or lack of insulin and mani-fests itself as polydipsia and polyuria with highly increased blood glucose levels (spilling into the urine, which now “tastes” sweet, causing its name). Untreated it leads to ocular, renal, and cardiovascular health consequences, as well as ketoacidosis. It can be divided into two types. Type I can be caused by an autoimmune or viral disease, in which the gland does not produce insu-lin. Type II has usually an adult onset often caused by genetic factors, as well as obesity. In this case, there is either an insufficient release of insulin from the pancreas or unresponsive insulin

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receptors on tissues. Drugs used in the treatment of type II diabetes mellitus vary among patients. Treatment starts usually with carbohydrate restrictions, exercise, and weight loss. Drugs act by slowing carbohydrate metabolism and absorption, blocking gluconeogenesis in the liver, increasing release of insulin from the pancreas, and/or increasing tis-sue receptor sensitivities that enhances glucose uptake. If drugs do not provide adequate glucose control, insulin has to be used (see Hypoglycemic Drugs I).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Acarbose 50-100 mg 3 times daily

POMiglitol 25-100 mg 3 times daily

POMetformin 500 mg 2 times daily up

to 2000 mg/day PO or 500-1000 mg once daily up to 2500 mg as extended-release tablets PO

Nateglinide 120 mg 3 times daily PORepaglinide 0.5-4 mg 3 times daily

not to exceed 16 mg/day PO

Glimepiride 1-2 mg once daily to be increased to 8 mg/day PO

Glipizide 2.5-40 mg/day POGlyburide 1.25-20 mg once daily

PO or 1.5-12 mg 2 times daily as micron-ized preparation PO

Pioglitazone 15-45 mg once a day PORosiglitazone 4-8 mg once or 2-4 mg

twice a day POSitagliptin 25-200 mg once daily POPramlintide 60-120 µ g once daily SC

ADMINISTRATION Hypoglycemic drugs are given PO and SC (using a pen). Some orally administered drugs may take time to become fully effective. Hypoglycemic drugs may be used in combinations with each other or with insulin.

CONTRAINDICATIONS Hypoglycemic drugs should not be used or used with caution in patients with hepatic failure.

COMMON ADVERSE REACTIONS Hypoglycemic drugs can cause hypoglyce-mia (sweating, weakness, dizziness, tremor, and tachycardia to unconsciousness), but this occurs least with glucosidase inhibi-tors, thiazolidinediones, and biguanides. Drugs can cause nausea and GI prob-lems. Glucosidase inhibitors also cause

flatulence. Biguanides can cause lactic acidosis (chills, dizziness, hypotension, muscle pain, bradycardia, and dyspnea), which can be serious. Sulfonylureas cause photosensitization and rarely agranulocy-tosis and aplastic anemia. Rosiglitazone may increase the risk of cardiovascular problems like CHF (early warning signs are dyspnea, rules/crackles, and periph-eral edema) or cardiac infarct.

DRUG INTERACTIONS • β -Blockers add to drug effects and can

mask onset of a hypoglycemic episode (e.g., tachycardia). Drugs interact with some diuretics like thiazide and loop diuretics, corticosteroids, and calcium channel blockers, which increase blood glucose levels. Risk of lactic acidosis with metformin is increased by a num-ber of drugs, including alcohol, mor-phine, calcium channel blockers, and ranitidine. Cross-sensitivity with sulfon-amides can occur mostly with the sulfo-nylureas. Antifungal agents may interfere with glucose control of meglitinides.

• Glucosamine, chromium, and coenzyme Q-10 may interfere with blood sugar control by hypoglycemic drugs.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Make sure that the patient wears an iden-

tification tag or other visible marker indi-cating that he or she is a diabetic. Also, make sure, depending on the drug, that the patient carries some sugar, a glucose preparation, or sweetened orange juice to counteract a hypoglycemic reaction.

• Do not recommend glucosamine to dia-betic patients to treat joint problems unless this has been cleared with a phy-sician because glucosamine can cause hypoglycemic episodes in unadjusted hypoglycemic drug dosages.

• Be aware of the occurrence of hypogly-cemia, as well as hyperglycemia (unusual thirst, drowsiness, fruit-like breath, and flushed). Treat the first with sugar (arti-ficial sweeteners do not work) and the other by asking the patient to adminis-ter the needed drug dose.

• If you feel that patient’s blood glucose levels are fluctuating, ask if he or she has changed dietary habits or is using an OTC drug because these can cause poor glucose control.

• Do exercise a diabetic patient, carefully in particular at the beginning of drug therapy, because exercise can reduce blood glucose levels. Check glucose lev-els during and after exercise.

• If your patient usually on metformin complains about chills, dizziness, hypotension, muscle pain, bradycardia, and dyspnea, notify the physician imme-diately because these could be warning signs of a ketoacidosis.

IMMUNOMODULATORS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) DNA InhibitorsAzathioprine Azasan, ImuranCyclophosphamide CytoxanMethotrexate Trexall,

RheumatrexT-Cell InactivatorsCyclosporine Neoral,

Sandimmune, other

Sirolimus RapamuneTacrolimus Prograf, ProtopicGold CompoundsAuranofin RidauraOtherNSAIDs (see Nonsteroidal Antiinflammatory Drugs)Corticosteroids (see Corticosteroids)Miscellaneous DrugsChloroquine AralenEtanercept EnbrelOtherImmunostimulatorsImmune globulins Gamma globu-

lin, Iveegam, Carimune, other

Filgrastim NeupogenSargramostim LeukineOther

MECHANISM OF ACTION The immune system consists of the innate and the adaptive parts. The first involves certain leukocytes, is present since birth and is relatively unspecific. The second forms later in life, is more specific and involves B cells that form various antibod-ies and T cells, which are more directly involved in immune responses. In addi-tion, lymphokines or cytokines, inter-leukins, and tumor necrosis factor are involved and amplify the actions of this adaptive system.

Immunomodulators now inhibit or stimulate the actions of the immune system. Most drugs are inhibitory. They interfere with DNA synthesis (see Antineoplastic Drugs), like azathioprine, cyclophosphamide, and methotrexate, reducing proliferation of immune cells or they reduce the activity of T and/or B cells like cyclosporine, tacrolimus, and siroli-mus. They inhibit the formation of the inflammatory prostaglandins like NSAIDs and corticosteroids. Gold compounds like auranofin and aurothioglucose reduce T cell activity by an uncertain mecha-nism. Chloroquine is thought to damage immune cells by changing their pH, and etanercept blocks the action of the tumor necrosis factor.

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Few drugs are available to stimulate the immune system. Filgrastim and sargra-mostim stimulate the formation of white blood cells in bone marrow, which may be decreased during anticancer therapy. Immunoglobulins provide exogenous antibodies to the body.

INDICATION Immunomodulators are indicated in the following: • Transplantation of tissues and organs,

in which the immune system tries to destroy foreign cells as it is supposed to do but which in these cases is unwanted. Immunomodulators like T-cell inactiva-tors reduce the activity of T-cells which are mostly involved in the rejection of transplants.

• Autoimmune diseases, such as rheu-matoid arthritis, systemic lupus ery-thematosus, polymyositis, myasthenia gravis, and others, in which an exag-gerated immune response damages healthy tissue and causes health prob-lems. Immunomodulators reduce this response and prevent further damage.

• White blood cell deficiency during che-motherapy is treated with filgrastim or sargramostim, to stimulate white blood cell formation.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Azathioprine 1-3 mg/kg/day PO

or 3-5 mg/kg IVCyclophosphamide 1-2.5 mg/kg/day

POMethotrexate 7.5 mg/wk up to

20 mg/wk POCyclosporine 2.5-10 mg/kg/day

once or divided doses PO

Sirolimus 2 mg/day up to 5 mg/day PO

Tacrolimus 0.03-0.05 mg/kg/day IV then 0.15 mg/kg 2 times daily PO

Auranofin 6 mg once or 3 mg 2 times daily up to 9 mg/day PO

Chloroquine 250 mg/day POEtanercept 50 mg /week SCFilgrastim 5-10 µ g/kg/day

once IV SC Infusion

Sargramostim 250-500 µ g/m 2 /day IV Infusion

Immunoglobulins Various schedules

ADMINISTRATION Most drugs are given PO but can be injected or used topically. Often, drugs are administered in combination. In some cases, the response is delayed by weeks or months.

CONTRAINDICATIONS Immunomodulators should not be used or must be used with caution in patients with immune system and blood problems.

COMMON ADVERSE REACTIONS Adverse reactions of all immune suppres-sants are an increased risk of infections. Other adverse reactions differ among the groups (see Antineoplastic Drugs, Nonsteroidal Antiinflammatory Drugs, and Corticosteroids). T cell inactivators can cause hepatic and renal damage, blood disorders, lung problems, seizures, and confusion. Gold compounds cause some GI distress but also some blood dis-orders like leukopenia. Chloroquine is usually well tolerated but may cause some retinal damage. Etanercept is more toxic and can cause serious infections and cer-tain malignancies.

DRUG INTERACTIONS • Immunomodulators, depending on the

class, can interact with a large number of other drugs.

• Ginseng and St. John’s wort can decrease effectiveness of T-cell inactiva-tors, and grapefruit juice can affect their bioavailability.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Inform the patient about the differ-

ence between rheumatoid arthritis and osteoarthritis (the latter is somewhat of a misnomer because no inflammation is the causative process). Explain that NSAIDs can be used in both conditions, whereas acetaminophen, which lacks antiinflammatory properties, should only be used in osteoarthritis.

• Inform the patient that foods rich in meat and proteins have been shown to aggravate and foods high in fish oils to ameliorate the signs of rheuma-toid arthritis. Stress the importance of weight loss in overweight individuals because excessive weight worsens the problem.

• Wear a mask or do not treat the patient if you have an infection (flu, respiratory infection, or other infection) because immune suppressants increase the risk of an infection in these patients.

• Emphasize that muscle and bone strengthening exercise can be helpful in preventing further deterioration, in particular, if corticosteroids are used.

• Observe the patient if skin rashes or unexplained joint pain may be experi-enced by the patient because this could signal a more serious condition and might necessitate a change in drug.

LOCAL ANESTHETICS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Benzocaine Anbesol, Lanacane,

other (OTC)Bupivacaine Marcaine,

SensorcaineDibucaine NupercainalLevobupivacaine ChirocaineLidocaine Xylocaine,

Dilocaine, otherProcaine NovocainRopivacaine NaropinTetracaine Pontocaine

MECHANISM OF ACTION Pain impulses starting at a particular site (involving prostaglandins, see Nonnarcotic Analgesics) are then transmitted via nerve impulses to the spinal cord and brain where pain is finally experienced. Nerve impulses conducting the pain signals are initiated by an influx of sodium into and then an efflux of potassium out of the nerve (action potential).

Local anesthetics attach to sodium channels and do not allow the influx of sodium into the nerve. No action poten-tial can occur, and pain nerve impulses stop at this site and do not reach the brain where no pain can be perceived and experienced. Action is only transient. (If these drugs do not solve a major pain problem, phenol or alcohol injections, which are not local anesthetics, can be given that actually damage nerves and whose effects might last for months or years).

INDICATION Local anesthetics are indicated in the following: • Surgery, in which blockade of pain

impulses allows for analgesia during the procedure.

• Hypertonic muscles (cerebrovascular accidents, head trauma) or minor sur-face inflammation/irritation (abra-sions, burns). Local anesthetics reduce or abolish pain sensation and decrease excessive feedback on efferent motor pathways.

• Therapy of painful subcutaneous struc-tures (bursae, tendons) or low back pain . Local anesthetics are applied topi-cally with iontophoresis or phonopho-resis or by patch. Again, pain sensation and muscle relaxation are achieved by blockade of nerve impulses.

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• Muscle spasms, in which a “vicious” cycle keeps muscle contracted. Local anesthetics injected into the affected area break this cycle by interfering with nerve impulses and relax the muscle.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Benzocaine Various preparationsBupivacaine 25-100 mg as a 0.5%

solution epiduralDibucaine Various preparationsLevobupivacaine 50-150 mg as a 0.5%

solution epiduralLidocaine 300 mg IM or

50-100 mg IVProcaine 50-100 mg for spinal

anesthesiaRopivacaine 12-16 mg epiduralTetracaine Various routes and

dosages

ADMINISTRATION Local anesthetics are used topically, like benzocaine, dibucaine, and tetracaine, either alone or assisted by iontophoresis or phonophoresis or by injection or infil-tration. Some drugs are applied as patches. In some cases, α -agonists are added to injectable preparations to cause vasocon-striction, which allows smaller amounts of the local anesthetic to remain longer at the injection site and not to be trans-ported into other body parts.

CONTRAINDICATIONS Local anesthetics should not be used or must be used with caution in patients with cardiac and hepatic diseases; this applies mostly to injections.

COMMON ADVERSE REACTIONS Adverse reactions differ among drugs. In general, no major toxicities are expected by topical application unless very large doses are used. In the case of injections, car-diotoxicity (bradycardia, dysrhythmias, or hypotension) and CNS effects (tinnitus, agitation, restlessness, confusion, tremors, twitching, dizziness, fainting, and seizures) can be expected. Repeated injections into the same place can cause muscle pain and necrosis.

DRUG INTERACTIONS Interactions occur mostly after injections with other drugs.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Local anesthetics allow the physical

therapist to do manipulations and reha-bilitation techniques without inflicting unnecessary pain.

• Patients with infiltration therapy might experience hypotension, sensory impairment, and motor deficits. Patients must be watched carefully when walk-ing and when getting up to avoid falls. As a precaution, these functions should be tested before therapy.

• Patients with infiltration therapy may have abolished or decreased pain per-ception, and thermal and electrical stimuli must be applied with care. As a precaution, sensory functions should be tested before therapy.

• Watch out for tinnitus, agitation, trem-ors, and confusion in patients with epidural therapy because this could indicate an overdose reaction requiring dosage adjustments.

MALE HORMONES

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Androgens Testosterone

Nandrolone Other

Andronate, Dura-test, other

Hybolin, Kabolin

Antiandrogens Finasteride Dutasteride Other

Proscar Avodart

MECHANISM OF ACTION LH and FSH are released from the pituitary gland and stimulate the synthesis of the androgen testosterone in the testes. This hormone and its more active metabolite dihydrotestosterone are responsible for the development of the male sex charac-teristics, including sex organs (including development and growth of the prostate gland) and increased bone and muscle mass.

Male hormones, which are the natural hormones or analogs, can now stimulate this development by acting like testoster-one or as antiandrogens that can inhibit the conversion of testosterone to its more active metabolite dihydrotestosterone and reduce its stimulatory action.

INDICATION Male hormones are indicated in the following: • Replacement therapy, in which there is a

deficiency, such as after removal of testes, hypogonadism, and other forms of testos-terone underfunctioning. Testosterone or its analogs are administered to fulfill the function of a deficiency or lack of the endogenous hormone.

• Beni g n prostatic hyperplasia, in which the prostate is enlarged and inter-feres with normal bladder emptying.

Antiandrogens lower dihydrotestos-terone levels and actually shrink an enlarged prostate, reducing urinary problems.

• Other uses include certain anemias (see Hemopoietic Drugs).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Testosterone 25-50 mg 2-3 times a

week or 100 mg/month IM

Nandrolone 100-200 mg/week IMFinasteride 5 mg/day PODutasteride 0.5 mg/day PO

ADMINISTRATION Depending on the drug, male hormones are given PO, IM or by patch.

CONTRAINDICATIONS Male hormones should not be used or must be used with caution in patients with renal, cardiac, and/or hepatic disease.

COMMON ADVERSE REACTIONS • Adverse reactions differ, but androgens

may affect blood glucose levels and may cause jaundice. Antiandrogens decrease libido and sexual performance.

• In case of abuse of very high doses of androgens over long periods of time by athletes who try to increase bone and muscle mass, as well as perfor-mance (although it is still uncertain in how much these androgens actually contribute to increased muscle mass and performance), number and inten-sity of adverse reactions increase mark-edly. Abuse has been associated with liver problems, cardiomyopathy and other heart diseases, dysrhythmias, and bone damage all of which can markedly decrease life expectancy.

DRUG INTERACTIONS Male hormones can interact with a num-ber of drugs.

IMPLICATIONS FOR PHYSICAL THERAPISTS If an athletic person with well-developed muscles is seen, inquire carefully about illegal use of androgens. Inform this indi-vidual that these substances may not do what he or she expects them to do but can significantly increase the risk of adverse reactions, which can shorten life expec-tancy and cause an early death. Athletes often trust physical therapists more than other health professionals.

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MISCELLANEOUS VASODILATORS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Peripherally Acting Vasodilator Hydralazine Other

Apresoline

Centrally Acting Vasodilators Clonidine Other

Catapres

Vasodilators for Erectile Dysfunction Sildenafil Vardenafil Tadalafil Other

Viagra Levitra Cialis

Antianginals Isosorbide

Nitroglycerin

Dilatrate, Isordil, other Nitrocot, Nitro-Time,

Nitrogard, other

MECHANISM OF ACTION Vasodilation can be achieved by various mechanisms. In this case, one mechanism is the stimulation of muscarinic receptors in blood vessels that form nitric oxide (NO) and that activates guanylyl cyclase to synthesize the second messenger cyclic guanosine monophosphate (cGMP). This relaxes blood vessels and decreases blood pressure but is quickly broken down by the enzyme phosphodiesterase (PDE). Another mechanism is located in the brain where stimulation of α

2 -receptors

decreases central sympathetic outflow to blood vessels, leading to vasodilatation and a fall in blood pressure.

Antianginals form NO, which stimu-lates guanylyl cyclase, promotes cGMP formation, and causes vasodilatation. This increases coronary blood flow and oxy-gen supply and dilates systemic blood vessels, which reduces cardiac after load. Hydralazine seems to inhibit PDE, which prevents the destruction of cGMP and keeps its levels increased longer, dilating blood vessels and causing a fall in blood pressure. Vasodilators for erectile dysfunc-tion also inhibit PDE, but this inhibition is more localized in the cavernosal smooth muscles of the penis (special PDE5). Here, they allow blood accumulation initiating and maintaining an erection. However, this effect needs sexual stimulation to be fully effective. Centrally acting vasodilators stimulate α

2 -receptors in the brain and

decrease sympathetic outflow, peripheral resistance, and cardiac output. This results in a fall in blood pressure. Clonidine also seems to have analgesic actions.

INDICATIONS Vasodilators are indicated in the following • Hypertension, in which increased car-

diac output and/or peripheral resistance

increases blood pressure. Hypertension untreated is linked to MIs and strokes. Vasodilators, such as hydralazine and clonidine, dilate blood vessels and reduce blood pressure and can reduce the risk of secondary MIs and strokes.

• Angina, in which insufficient blood flow (e.g., atherosclerosis) does not supply enough oxygen to cardiac muscle. If heart rate and contractil-ity increase (usually under emotional or physical stress), the oxygen need markedly exceeds the oxygen supply and anginal pain occurs. Antianginals dilate coronary blood vessels, which increases cardiac blood flow and oxy-gen supply to the heart and dilate peripheral blood vessels to ease car-diac blood ejection.

• Erectile dysfunction is an inability to initiate and/or maintain an erection. An erection begins with sensory or mental sexual stimulation allowing the muscles of the corpora cavernosa to relax and the penis to fill with blood. This relax-ation is initiated and maintained by cGMP. Vasodilators increase and main-tain levels of cGMP longer by blocking its destruction by the special PDE5.

• Opioid withdrawal and pain manage-ment in the cancer patient not respond-ing to opioids may involve the use of clonidine.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Hydralazine 10-50 mg 4 times daily (not

to exceed 320 mg/day) PO

Clonidine 0.1-0.6 mg 2 times daily PO

Sildenafil 25-100 mg taken 30-60 minutes before sexual activity PO

Vardenafil 5-20 mg taken 60 minutes before sexual activ-ity PO

Tadalafil 5-20 mg 15 minutes before sexual activity PO

Isosorbide 2.5-10 mg every 5-10 min for 3 doses SL or 5-40 mg q6h (dinitrate) PO

Nitroglycerin 0.3-0.6 mg every 5 min for 15 min SL or 1 mg q5h buccal 2.5-9 mg q8h for extended-release capsules or 0.1-0.6 mg/hour by patch

ADMINISTRATION Vasodilators are given PO or by injec-tions usually only in hospitals. Clonidine can be given by transdermal or epidural

administration. Antianginals can be given sublingual. Vasodilators for erectile dys-function have a similar onset (between 30 to 60 minutes) but last between 4 to 36 hours (tadalafil is longest lasting). Antianginals have a very quick (minutes) onset of action and are used to prevent or abort an attack of angina.

CONTRAINDICATIONS Vasodilators are contraindicated in cases of hypersensitivity. Drugs should be used with caution in cases of renal or hepatic impair-ments. Vasodilators for erectile dysfunction should not be used in individuals with car-diovascular disease or 6 month after MI.

COMMON ADVERSE REACTIONS Peripheral vasodilators can cause tachy-cardia, hypotension, sodium retention (edema), and a lupus syndrome. Central vasodilators can cause drowsiness, dry mouth, and bradycardia and should not be discontinued abruptly. Vasodilators for erectile dysfunction can cause headache, nasal decongestion, vision loss (rare), GI problems, flushing, cardiovascular collapse, and priapism (erection lasting longer than 4 hours). Antianginals may cause hypoten-sion, tachycardia, dizziness, and headaches.

DRUG INTERACTIONS Peripheral vasodilators can increase the antihypertensive effects of other antihy-pertensives and alcohol. Central vasodila-tors increase sedative effects of drugs with similar actions. Vasodilators for erectile dysfunction should not be used or used with caution with antihypertensive drugs, alcohol, nitrates, or α -antagonists because of the possibility of a severe hypotensive episode. Antianginals should be used with caution with β -blockers and should not be used with vasodilators used for erec-tile dysfunction.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Advise patient to change positions

and get up slowly because orthostatic hypotension may occur mostly in the beginning of therapy and in geriatric individuals.

• If patient complains about unexplained joint pain, notify the physician or have patient contact the physician because this could be a lupus-like syndrome.

• If you notice peripheral edema such as swollen ankles, notify or have patient contact the physician because this could be caused by excessive sodium retention.

• Be aware that central vasodilators may cause drowsiness, which can interfere with your therapeutic routine. This should slowly diminish during drug therapy.

• If the patient has an attack of angina and responds to nitroglycerin, have him

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or her get up slowly because orthostatic hypotension might occur. If the patient does not respond to 3 doses of nitro-glycerin, call 911 because this could sig-nal a MI.

NONNARCOTIC ANALGESICS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Acetaminophen Tylenol, Abenol, Aceta,

Dapacin, Dynafed, other (OTC)

Diclofenac Cataflam, Voltaren, Solaraze

Etodolac LodineIbuprofen Motrin, Advil, Nuprin,

Actiprofen, Genpril (OTC)

Ketoprofen Actron, Orudis, Oruvail, Rhodis, Apo-Keto

Ketorolac ToradolMeloxicam MobicNaproxen Aleve, Anaprox,

Naprosyn, Synflex, Naprelan, other (OTC)

Salicylates (acetyl-)

Aspirin, Acuprin, Arthrisin, other (OTC)

(Aspirin is acetyl-salicylic acid to be metabolized to active metabolite salicylic acid.)

Salicylates, Tricosal, Anaflex, Arthropan, other

Other See Nonsteroidal Antiinflammatory Drugs

MECHANISM OF ACTION Pain impulses originate through the com-bined action of bradykinin and prosta-glandins and are then transmitted via nerve impulses to the CNS. Prostaglandins are a group of biochemicals or local hor-mones, which are synthesized by the enzyme cyclooxygenase (COX) that occurs as COX-1 (always present in tis-sues) and COX-2 (induced during trauma). They are involved in the initiation and maintenance of pain, inflammation, and fever (see Nonsteroidal Antiinflammatory Drugs). They also protect the stomach lin-ing from the action of gastric acid, cause vasodilatation in certain vascular beds, contract smooth muscles such as the uterus, induce with other chemicals plate-let aggregation, and somehow maintain proper renal blood flow.

Nonnarcotic analgesics are thought to inhibit these two forms of COX and reduce pain by inhibiting the synthesis of the pain-initiating biochemical prostaglandins.

INDICATIONS Nonnarcotic analgesics are indicated in the following: • Mild-to-moderate pain caused by

trauma, headaches, tooth aches, mus-cle soreness and aches, dysmenorrhea, osteoarthritis, and inflammatory dis-orders, including rheumatoid arthritis, bursitis, and others. Drugs reduce pros-taglandin formation and reduce pain. They show similar analgesic actions with some exceptions. Ketorolac has been found to be particularly effective in postoperative pain. Drugs are most effective if taken early on at the onset of pain. Some patients may not respond to one but will respond better to another drug. Usually, higher doses than those recommended do not provide for more pain relief. Dosage for analgesic effects is usually lower than that used for inflammatory conditions.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDE LINES, MANY DIFFERENT DOSAGE SCHEDULES) Acetaminophen 650-1000 mg q4-6h

(existing maximal dose of 4 g per day to be reduced in the future) PO

Aspirin 325-500 q4h (not to exceed 4 g) PO

Diclofenac 100 mg initially and/or 25-50 mg q6h PO

Etodolac 200-400 mg q6h (not to exceed 1200 mg) PO

Ibuprofen 200-400 mg q5h (not to exceed 1200 mg) PO

Ketoprofen 25-50 mg q6h (not to exceed 75 mg) PO

Ketorolac 20 mg followed by 10 mg q5h (not to exceed 20 doses/days and not more than 5 days) PO

Meloxicam 7.5 mg once a day PONaproxen 250-400 mg and

250 mg q6h (not to exceed 1.5 g). Slow-release preparation 375-500 2 times a day PO

ADMINISTRATION Nonnarcotic analgesics are used mostly orally. They are best taken with a large glass of water or food while remaining in an upright position for about 30 minutes. Onset of action is usually 15 to 30 minutes. Duration of action varies among drugs but is generally between 4 to 8 hours (slow-release preparations can increase

duration). Advise patient that self-admin-istration with acetaminophen over longer periods with high doses can cause serious liver damage (in some cases even death) and that the existing daily dose of 4 g/day will be reduced and the newly established dose should not be exceeded.

CONTRAINDICATIONS Contraindications to the use of these drugs include hypersensitivity, GI prob-lems (gastritis, ulcer), and renal and hepatic disorders.

COMMON ADVERSE REACTIONS All nonnarcotic analgesics can cause abdominal pain, dyspepsia, and GI bleed-ing (tarry stools are indicative of internal bleeding). Some nonnarcotic analgesics can be photosensitizing. Hypersensitivity reactions are rare and occur more fre-quently if the patients are sensitive to aspirin and have asthma and nasal pol-yps (except acetaminophen). Drugs can be liver toxic and show renal toxicity but mostly in individuals with already compro-mised hepatic and renal functions. They can slightly increase the risk of cardiovas-cular events again mostly during chronic use and in individuals with cardiovascular problems. Chronic use has been shown to cause renal problems. Acetaminophen causes fewer GI problems but is more liver toxic and can affect blood glucose moni-toring. Ketoprofen has a higher incidence of headache and dizziness. Aspirin should not be used in children with viral infec-tions because it can cause the potentially fatal Reye syndrome (acetaminophen is the drug of choice in these cases).

DRUG INTERACTIONS There is an increased risk of GI problems (gastritis, ulcer) enhanced by concur-rent use of spicy foods, alcohol, and some herbal products such as arnica, garlic, and ginseng. Use of acetaminophen and alco-hol (more than 2 glasses of wine or beer) has been associated with increased liver toxicity.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Patients often report only prescrip-

tion drugs when asked about drug use. Because some analgesics are also obtained without a prescription, the question should also include use of OTC drugs (and vitamins/herbal medica-tions). Advise patient that OTC drugs are drugs and must be used with caution.

• Analgesics may mask pain during mobil-ity movements. This can lead to damage by exceeding movement limitations or by providing the impression of better mobility than actually exists.

• Extensive UV radiation should be avoided or other body parts should be

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covered because some drugs can cause photosensitivity reactions.

• Some patients may experience drowsi-ness and might exhibit slight incoordi-nation but this is very rare with these drugs.

• Advise the patient to use acetamino-phen for low back pain because a recent study suggests that this drug seems to be most effective and to carry the least side effects.

• Advise the patients that OTC analge-sics should not be taken longer than 2 weeks without consulting a physician because these drugs can mask a serious underlying health problem.

NONSTEROIDAL ANTIINFLAMMATORY DRUGS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Diclofenac Cataflam, Voltaren, Sola-

raze,Etodolac LodineIbuprofen Motrin, Advil, Nuprin,

Actiprofen, Genpril (OTC available)

Indomethacin Indocin, Indocron, otherKetoprofen Actron, Orudis, Oruvail,

Rhodis, Apo-KetoKetorolac ToradolMeloxicam MobicNabumetone RelafenNaproxen Aleve, Anaprox,

Naprosyn, Synflex, Naprelan, other (OTC available)

Oxaprozin DayproPiroxicam FeldeneSulindac ClinorilSalicylates

(acetyl-)Aspirin, Acuprin, Arth-

risin, other (OTC available)

(Composed of acetyl-salicylic acid to be metabolized to active metabolite salicylic acid.)

Salicylates, Tricosal, Anaf lex, Arthropan, other

Tolmetin TolectinCelecoxib Celebrex (See Nonnar-

cotic Analgesics and Corticosteroids)

MECHANISM OF ACTION Prostaglandins are a group of biochemi-cals or local hormones, which are synthe-sized from phospholipids via arachidonic acid by the enzyme COX that occurs as COX-1 (always present in tissues) and COX-2 (induced during trauma). They are mostly involved in the initiation and maintenance of pain, inflammation, and

fever. In the case of an inflammation, they cause vasodilatation, which allows water and white blood cells to migrate from the blood to the tissues (this causes warmth, redness, and swelling). If inflammations are contained, they are beneficial in fight-ing infections and repair tissue damage. Prostaglandins also protect the stom-ach lining from the action of gastric acid (mostly via COX-1), cause vasodilatation in certain vascular beds, contract smooth muscles like the uterus, induce with other chemicals platelet aggregation, and some-how maintain renal blood flow.

NSAIDs inhibit COX-1 and -2 and reduce or prevent prostaglandin synthe-sis and reduce inflammatory processes. Because gastric protection is achieved by prostaglandins synthesized by COX-1, drugs lower this protective mechanism (except celecoxib, which is less inhibi-tory on COX-1 and less damaging to the stomach). Drugs often work best when taken at the beginning of an inflamma-tory process. Indomethacin is one of the strongest antiinflammatory drugs but also carries the more severe adverse reactions.

INDICATIONS NSAIDs are indicated in the following: • General inflammations, which are char-

acterized by swelling, redness, warmth and pain, and eventually tissue damage if they become unwanted or excessive such as occurs in certain autoimmune diseases, transplants, allergies, asthma, croup, rheumatoid arthritis, ankylosing spondylitis, or bursitis. NSAIDs curtail excessive and reduce unwanted inflam-mations to protect healthy tissue.

• Dysmenorrhea, in which excessive prostaglandin formation stimulates the uterus, causing painful contractions. NSAIDs reduce prostaglandin levels and excessive contractions and cramps.

• Fever, which is initiated by a central action of prostaglandins in the brain area that regulates body temperature. NSAIDs reduce prostaglandin formation and lower fever.

• Ocular inflammations after eye sur-gery (e.g., topical administration of bromfenac, diclofenac, flurbiprofen, ketorolac, nepafenac, or suprofen), in which NSAIDs reduce prostaglandin synthesis and prevent or reduce inflam-matory processes.

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES)

Aspirin 325-500 mg q4h (not to exceed 4 g) PO

Celecoxib 100-200 mg once or twice a day PO

Etodolac 300 mg 2-3 times daily PO or 400-1200 mg once daily as extended-release preparation PO

Ibuprofen 400-800 mg 3-4 times daily (not to exceed 3600 mg/day) PO

Indo-methacin

25-50 mg 2-4 times daily PO or 75 mg once daily with extended-release preparations PO

Ketoprofen 150-300 mg/day in 3-4 divided dose PO or 100-200 mg once daily with extended-release preparations PO

Ketorolac 20 mg followed by 10 mg q5h (not to exceed 40 mg/day) PO

Meloxicam 7.5-15 mg once a day PONaproxen 250-500 mg 2-3 times

a day (not to exceed 1.5 g) or 375-500 mg twice a day with the slow-release prepara-tion PO

Nabumetone 1000-2000 mg once or twice a day PO

Oxaprozin 1200-1800 mg once daily PO

Piroxicam 10-20 mg once or twice a day PO

Sulindac 150-200 mg twice a day PO

Tolmetin 400-1800 mg/day in 3 divided dose (not to exceed 2000 mg/day) PO

ADMINISTRATION NSAIDs can be given IV, PO or topically into the eye. They are best taken with meals or a large glass of water and sit-ting up or standing for 30 minutes after ingestion.

CONTRAINDICATIONS Contraindications include hypersensitiv-ity to a drug that often manifests itself as hypersensitivity to the entire group and GI problems (gastritis, ulcers). NSAIDs should be used cautiously in cases of severe hepatic, renal and cardiovascular diseases.

COMMON ADVERSE REACTIONS Adverse reactions include dizziness, drowsiness, abdominal distress, dyspepsia, gastritis, ulcer, photosensitivity and after long term use nephritis. Rarely, they can cause Stevens-Johnson syndrome, hepa-titis, or exfoliate dermatitis. Celecoxib is a COX II inhibitor and somewhat gentler on the stomach but can increase the risk of cardiovascular accidents. Patients with

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nasal polyps, asthma, and aspirin-induced allergy are at high risk to develop hyper-sensitivity reactions towards other drugs in this group.

DRUG INTERACTIONS • NSAIDs can interact with a large num-

ber of drugs such as enhancing the effects of warfarin and related drugs in increasing bleeding times or decreas-ing the effects of antihypertensives and insulin. Alcohol increases adverse effects on the stomach.

• Arnica, dong quai, garlic, ginseng, and ginkgo increase the risk of bleeding. Spicy foods aggravate stomach problems.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Patients often report only prescription

drugs when asked about drugs used. Because some NSAIDs are also obtained without a prescription, the question should also include use of prescription, as well as OTC drugs (and vitamins/mineral/herbal medications).

• Advise the patient that antiinflamma-tory OTC drugs are drugs and must be used with caution and the patient must adhere to the warning statements on the container.

• NSAIDs may mask pain during mobility movements and can give the impression of better mobility than actually exists and may cause damage by exceeding movement limitations.

• Extensive UV radiation should be avoided or other body parts should be covered because some drugs cause photosensitization.

• Some patients may experience drowsi-ness and may exhibit slight incoordi-nation, but this is very rare with these drugs.

• If the patient complains about stom-ach problems, tell the patient to take medication with lots of water sitting up or standing for at least 30 minutes or with a meal. The patient should also watch the stool and if black (occult bleeding), he or she should stop the drug and notify the physician immediately.

• If the patient complains about an upper respiratory infection, cough, muscle aching, and a rash with blisters, ask the patient to contact the physician imme-diately because this could be a Stevens-Johnson syndrome.

• If you notice dry, itchy, red areas on hands and other parts of the body, have the patient notify the physician immedi-ately because this could be an exfoliate dermatitis.

• Explain to patient that acetaminophen is not antiinflammatory and should not be used if an antiinflammatory drug has been prescribed.

OPIOID OR NARCOTIC ANALGESICS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Buprenorphine Buprenex, SubutexButorphanol StadolCodeine PaveralFentanyl Actiq, Sublimaze,

Duragesic (transdermal)

Hydrocodone Hycodan, Robidone In combination with

acetaminophen: Anexsia, Bancap, Dolacet, other

In combination with aspirin: Alor, Azdone, other

In combination with ibuprofen: Vicoprofen

Hydromorphone Dilaudid, HydrostatMeperidine Demerol, PethidineMethadone Dolophine,

MethadoseMorphine Astramorph, Avinza,

Epimorph, Roxanol, other

Nalbuphine NubainOxycodone Endocodone,

OxyContin, Percolone, Roxicodone

Oxymorphone NumorphanPentazocine Talwin

In combination with acetamino-phen: Talacen

In combination with aspi-rin: Talwin compound

Propoxyphene Darvon In combination

with aspirin: Darvon-N c ASA

In combination with aspirin and caffeine: Darvon 32 or 65

In combination with acetamino-phen: Darvocet

MECHANISM OF ACTION Pain impulses originating from the affected site (see Nonnarcotic Analgesics) are transmitted via nerve impulses (see Local Anesthetics) to the CNS where pain is finally experienced. Opioid receptors ( µ , κ , and δ receptors) in the CNS that are physiologically activated by endogenous compounds, such as enkephalins, endor-phins, and dynorphins, can prevent pain

impulses from reaching their final desti-nation and suppress or alter pain percep-tion. Some of these receptors also occur in other brain areas (respiratory cen-ter, cough center, and centers associated with nausea/vomiting) and the periphery (intestines).

Opioids are full or partial agonists and are thought to stimulate these recep-tors in the CNS and cause analgesia. (Action of these drugs can be reversed by opioid antagonists like naloxone and naltrexone.)

INDICATIONS Opioids are indicated in the following: • Moderate–to-severe pain of all kinds,

which is often measured on a subjective scale of 0 to 10. Opioids cause analgesia and pain is reduced, felt less discomfort-ing, or is completely gone. Opioids work best for analgesia if given at the onset of pain. Best results are obtained when the patient controls the proper use of anal-gesics (patient-controlled analgesia in hospitals) because only he or she feels the pain.

• Therapy of opioid dependence and withdrawal (buprenorphine, metha-done), cough (codeine, hydrocodone, hydromorphone), diarrhea (codeine), and before, during, and after surgery (fentanyl, meperidine, nalbuphine). Drugs act on opioid receptors and reduce withdrawal, discomfort, cough, diarrhea, and pain.

COMMON DOSAGES Butorphanol 1-2 mg q3-4h IM,

IV; 1 mg as nasal spray q3-4h

Buprenorphine 0.3 mg q4-6h IM, IVMorphine 10-30 mg q3-4h PO;

4-15 mg q3-4h IMPentazocine 50-100 mg q3-4h PO

(up to 600 mg/day); 30 mg q3-4h IM, IV

Plus acetaminophen: 25 mg and 650 mg

Plus aspirin: 12.5 mg and 325 mg)

Codeine 15-60 mg q3-6h PO; 15-60 mg q4-6h IM, IV

Plus acetaminophen: 30-60 mg and 300 mg

Plus aspirin: 60 mg and 325 mg)

Fentanyl 200 µ g dissolved in mouth (higher doses available up to 1600 µ g); 0.5-1 µ g/kg to be repeated every 60 min IV

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Hydrocodone 2.5-10 mg q3-6h PO Plus acetaminophen:

5 mg and 500 mg Plus aspirin: 5 mg

and 500 mg Plus ibuprofen:

7.5 mg and 200 mg

Hydromorphone 4-8 mg q3-4h PO; 1.5 mg q3-4h IM, IV, SC

Meperidine 50-150 mg q3-4h PO, IM, IV (short-term use only)

Methadone 20 mg q7h PO; 10 mg q7h IM, SC

Nalbuphine 10 mg q3-6h (total dose 160 mg) IV, IM

Oxycodone 5-10 mg q3-4h POOxymorphone 0.5 mg q3-6h IV;

1-1.5 mg q3-6h SC, IM

Propoxyphene 65 mg q4h (not to exceed 390 mg) PO

Plus aspirin: 100 mg and 325 mg

Plus aspirin and caffeine: 32 or 65 mg, 389 mg, 30 mg

Plus acetamino-phen: 50, 65, or 100 mg, 325, 500, or 650 mg

(See Nonnarcotic Analgesic Drugs)

ADMINISTRATION Drugs can be given PO, rectally, IM, IV, by infusion pump (often controlled by patient), or patch (fentanyl). Onset of action after oral use is about 30 minutes and duration of action varies but can be increased with sustained-release tablets. Injections provide relief in minutes.

CONTRAINDICATIONS Contraindications to the use of these drugs include hypersensitivity, head trauma, and increased intracranial pressure.

COMMON ADVERSE REACTIONS Opioids cause sedation, drowsiness, inco-ordination and some respiratory depres-sion (in particular in geriatric patients). Most patients suffer from constipation (which might require the use of laxatives). Some individuals experience nausea and vomiting, which can be avoided by assum-ing a supine position, and hypotension, which is more marked when assuming quickly an upright position. Miosis inter-feres with vision in dim or dark condi-tions. Chronic use of these drugs can lead to physical dependence and tolerance

(except miosis and constipation do not show tolerance). In case of tolerance, change to another drug is often benefi-cial. Some drugs are prone to be abused, including the substance “heroin,” which is converted to morphine in the body.

DRUG INTERACTIONS Opioids should not be used in patients receiving MAO inhibitors for depression. There is an increased risk of sedation and CNS depression with drugs, which also cause CNS depression, as well as alcohol, valerian, chamomile, or kava.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Analgesics may make movement exer-

cises easier by reducing pain. They also may mask pain during mobility move-ments and can cause damage by exceed-ing movement limitations. Drugs might feign and give the impression of better mobility than actually exists.

• If manipulations under opioid analgesia must be made which otherwise can be painful, arrange therapy at the peak of drug effects usually 2 hours after use of the drug.

• Assess alertness of patient because he or she can be more or less sedated, drowsy, and uncoordinated, and cer-tain tasks requiring attention and quick reflexes should be modified or omitted.

• Ask the patient to change position, in particular from a lying to a stand-ing position, slowly to avoid orthos-tatic hypotension, which can cause the patient to become dizzy, faint, and fall.

• Respiratory depression must be consid-ered when using exercise because this can reduce breathing and can lead to hypoxia.

• If the patient has to lie on the back for longer periods and breathes very shallow, ask the patient every 30 min-utes to take a few deep breaths to expand the lungs to reduce risk of lung collapse.

• During withdrawal from chronic use of one of these drugs, diffuse muscle dis-comfort might occur that can be allevi-ated with heat or massages.

OVER-THE-COUNTER DRUGS

INTRODUCTION OTC drugs are nonprescription medica-tions that are made available based on three criteria: (1) the consumer must be able to easily understand the medical con-dition to be treated and monitor its prog-ress, (2) the drug must have a favorable adverse reaction profile, and (3) drug use must be simple and easy.

Although these drugs are efficacious and have a low adverse reaction profile, they can nevertheless show these adverse reactions, mask serious medical problems, can be used for the wrong reasons, can be used wrongly even for the right reason, and can interact with prescription drugs.

The user must read the label carefully to avoid medical problems. For instance, the consumer must be aware of the medical condition, how much and how long to use the medication, of other medical conditions that might preclude using this drug, and of prescription drugs that might interact with the medication. OTC drugs must always be mentioned to a physician. The consumer must be aware that some ingredients are not obvious such as the additions of etha-nol or caffeine, which can cause their own effects. Also, OTC drugs should not be used when pregnant or breast feeding (unless advised by a physician) because some drugs can reach the fetus or infant through the placenta or milk.

The consumer should not give adult drugs to infants or small children unless it is stated on the label that it is permit-ted. Recently, many of these infant and children preparations had to be removed from the market because they were found not to be necessary and sometimes even harmful to infants.

The consumer must be observant when treating a problem. If two tablets are rec-ommended but a person is small or old, then it is advisable to start with 1 tablet and should only be increased if there is no relief. Similarly, an obese person might need three tablets instead of the recom-mended two.

Major adverse reactions to watch out for include the following:

• Analgesics: GI discomfort, rebound headaches, bleeding, can interact with antiinflammatory drugs and anticoagulants

• Acetaminophen: Liver damage with moderate-to-high doses of ethanol, although it is analgesic and antipyretic, it is not antiinflammatory

• Antihistamines: Drowsiness, urinary hesitancy/retention (elderly), contact lens intolerance, enhanced sedation with alcohol (have been misused in date-rape cases)

• Decongestants: Increased blood pres-sure, counteract antihypertensive medications, rebound effect with pro-longed use of nasal preparations

• H 2 -blockers: Dysrhythmias, constipa-

tion, agranulocytosis • Pump inhibitors: Liver and renal prob-

lems, neutropenia • Vaginal creams: Headache, missed

menstrual periods, fever • Emergency: Nausea, vomiting, stom-

ach pain, dizziness, headache, diar-rhea, contraceptives

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920 Sedatives and Hypnotics Sedatives and Hypnotics

IMPLICATIONS FOR PHYSICAL THERAPISTS • The physical therapist can play an

important role in advising patients on the use of OTC drugs or in suggesting the use of such drugs because many patients may not read the entire label or may not understand their uses or contents.

• Patients must be advised that OTC drugs are drugs that can produce serious adverse reactions if used improperly and that a physician must be contacted if this occurs.

• All OTC medications must be men-tioned in a medical history to avoid det-rimental interactions with prescription drugs.

• Advise patient about the difference between antiinflammatory drugs and acetaminophen, which is not antiinflammatory.

• Advise patient that use of acetamino-phen with even moderate doses of alco-hol can damage the liver.

• Advise the patient that topical drugs (e.g. ointments) will be absorbed into the body and that use of excessive amounts can cause serious systemic effects.

• Physical therapists can warn and help individuals with rebound headaches (no relief and even worse headaches in spite of drug use) where continued and excessive use of analgesics for head-aches can cause such a problem and suggest instead relaxation techniques, massages, or gentle exercises.

SEDATIVES AND HYPNOTICS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Hypnotic Benzodiazepines Flurazepam Temazepam Triazolam

Dalmane Restoril, Razepam Halcion

Miscellaneous Hypnotics Zaleplon Zolpidem Eszopiclone Other

Sonata Ambien Lunesta

Barbiturates Secobarbital Pentobarbital Other

Seconal Nembutal

OTC ProductMelatonin OTC

MECHANISM OF ACTION Alertness is governed by many chemical processes (neurotransmitters) and electri-cal circuits in the brain. In this case, the neurotransmitter GABA in the limbic, thal-amic, and/or hypothalamic areas seems to

play a major role. GABA is formed in neu-rons, released, and interacts with GABA receptors (subtypes A, B, C and more) to open chloride channels in membranes of adjacent neurons. Influx of negative chlo-ride ions hyperpolarizes these neurons and reduces their firings or activity. Thus normal GABA action causes alertness, whereas increased GABA action reduces alertness, increases sedation, and eventu-ally leads to sleep or hypnosis. GABA also affects centers that control skeletal mus-cle activity and its increased actions cause muscle relaxation. In addition, melatonin found in the pineal gland of the brain is physiologically involved in sleep.

Hypnotic drugs act on various sites of the GABA receptor complex where they all seem to enhance the action of GABA, increase hyperpolarization, and reduce fir-ing of adjacent neurons, resulting first in sedation and then in hypnosis. It has been suggested that melatonin taken orally may be beneficial for a few individuals in pro-moting sleep.

INDICATION Sedatives and hypnotics are mainly indi-cated in the following: • Insomnia, which is a sleep disorder

characterized by a persistent difficulty to fall asleep or to stay asleep. It is usu-ally followed by tiredness and functional impairment the next day. This disor-der can be assumed to be caused by an underfunctioning of the GABA system, which does not reduce neuronal activity sufficiently. Sedative and hypnotic drugs (dose–dependent) enhance GABA activ-ity, leading first to sedation and finally hypnosis. Generally, barbiturates are more sleep inducing, and the others are more sleep promoting. Drugs that are quickly absorbed and have a short dura-tion of action are helpful in the initiation of sleep (e.g., triazolam), and drugs with a slow absorption and long duration of action keep individuals asleep longer (e.g., flurazepam). Hypnotic effects of melatonin are still uncertain, with some studies showing a slight benefit while other studies do not.

• Other conditions such as epilepsy (see Anticonvulsant Drugs), movement dis-orders (see Skeletal Muscle Relaxants), or anxiety (see Anxiolytic Drugs).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Flurazepam 15-30 mg once POTemazepam 7.5-30 mg POTriazolam 0.125-0.5 mg POZaleplon 10-20 mg POZolpidem 10 mg (for 10 days only)

PO

Eszopiclone 2-3 mg POPentobarbital 100-200 mg POSecobarbital 100-200 mg POMelatonin 0.5-50 mg PO

ADMINISTRATION Sedatives and hypnotics are taken at bed time orally. Barbiturates are sometimes injected or given rectally.

CONTRAINDICATIONS Sedatives and hypnotics should not be used or must be used with caution in patients with renal and hepatic diseases.

COMMON ADVERSE REACTIONS Common adverse reactions are residual effects that might cause individuals to be drowsy or have decreased motor func-tion and muscular coordination the next day. This occurs mostly in older individ-uals. All drugs, to varying degrees, cause tolerance and physical dependence so that long-term treatment should not be discontinued abruptly. The withdrawal syndrome might manifest itself in irrita-tion, excitation, and insomnia (and rarely convulsions). High doses can cause some respiratory depression. Other adverse reactions are usually mild. Some indi-viduals might experience anterograde amnesia (forgetting events that took place before the drug was consumed). Zolpidem might cause “sleep walking and eating.”

DRUG INTERACTIONS • Action of sedatives and hypnotics is

enhanced, in particular residual effects, in the presence of other drugs with sed-ative effects, including alcohol.

• Sedative effects are increased by a num-ber of herbs, including chamomile, mistletoe, and valerian. St. John’s wort seems to reduce their effectiveness.

IMPLICATIONS FOR PHYSICAL THERAPISTS • If patient using these drugs appears

drowsy and uncoordinated at the morn-ing sessions, schedule this patient in the afternoon when most after-effects should have disappeared. Warn them not to drive if they feel drowsy.

• Warn the patient not to discontinue drugs abruptly after long-term use by themselves but to first consult the phy-sician because they might experience a withdrawal syndrome.

• Tell the patient not to drink or eat products containing caffeine because they can decrease drug effectiveness or might even be a cause of the sleep problem.

• If a patient on zolpidem notices weight gain without having changed eating

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Skeletal Muscle Relaxants Skeletal Muscle Relaxants

habits, ask the patient to notify the phy-sician because the patient might be “sleep eating.”

• The physical therapist can also suggest relaxation techniques, exercises, or mas-sages to reduce sleep problems and the need for sleep medications.

SKELETAL MUSCLE RELAXANTS

COMMON DRUGS (SELECTION OF SOME OF THE MOST COMMONLY USED DRUGS) Centrally Acting Drugs Baclofen Carisoprodol Chlorzoxazone Cyclobenzaprine Diazepam Gabapentin Metaxalone Methocarbamol Orphenadrine Tizanidine

Lioresal Soma, Vanadom Paraflex, Parafon,

other Flexeril, other Valium, other Neurontin Skelaxin Carbacot,

Robaxin, other Antiflex, Norflex Zanaflex

Direct-Acting Drugs Dantrolene Dichlorofluoromethane

Dantrium

Neuromuscular Blocking Drug Botulinus toxin A Botulinus toxin B

Botox Myobloc

MECHANISM OF ACTION Skeletal muscle movements are initiated and regulated by a balance between excit-atory and inhibitory chemical processes (neurotransmitters) and electrical circuits (monosynaptic and polysynaptic connec-tions) in the cerebral cortex, cerebellum, spinal cord, and finally at the neuromuscu-lar junction and the muscles per se. Among the inhibitory neurotransmitters is GABA and among the excitatory neurotransmit-ters is glutamate in the CNS. Acetylcholine is released at the neuromuscular junction and calcium fluxes are necessary for final muscle contractions.

Centrally acting skeletal muscle relax-ants can enhance the action of the inhib-itory GABA system with drugs such as diazepam (see Anxiolytic Drugs), baclofen, and gabapentin (see Anticonvulsant Drugs) and reduce muscle tone. Tizanidine, an α 2-receptor agonist, increases pre-synaptic inhibition of motoneurons, and the other drugs seem to act in the spinal cord by suppressing polysynaptic reflex activity with uncertain mechanisms. The remaining drugs act on the periph-ery. Dantrolene acts by blocking calcium release from the sarcoplasmic reticulum in skeletal muscles, which is necessary for contractions. Dichlorofluoromethane cools the muscle and reduces metabolic and physical activity. These drugs reduce

muscle tone to varying degrees. In con-trast, neuromuscular-blocking drugs, such as botulinus toxin, will prevent acetylcho-line release at the neuromuscular junction and paralyze the muscles. Effects are irre-versible and motoneuron terminals must be newly formed before acetylcholine release can start again, which might take up to 3 months.

INDICATION Skeletal muscle relaxants are indicated in the following: • Spasticity, which is characterized by

excessive skeletal muscle excitation and contraction (exaggerated muscle stretch reflex). It is caused by central pathol-ogy such as occurs in multiple sclerosis, cerebral palsy, injury, or stroke. It occurs when supraspinal control is lost. Drugs frequently used are baclofen, diazepam, gabapentin, tizanidine, and dantrolene.

• Spasm which is characterized by increased muscle tension caused by muscle injury or inflammation. It is caused by a vicious cycle when mus-cular injury or inflammation induces increased afferent nociceptive input. Drugs frequently used are carisoprodol, methocarbamol, cyclobenzaprine, and chlorzoxazone.

• Malignant hyperthermia (dantroline), tetanus, seizures, neuralgia, and cos-metic purposes (botulinus toxin).

EXAMPLES OF COMMON DOSAGES (GENERAL GUIDELINES, MANY DIFFERENT DOSAGE SCHEDULES) Baclofen 5-20 mg 3 times daily

up to 80 mg/day POCarisoprodol 350 mg 3 times daily

POChlorzoxazone 250-750 mg 3-4 times

daily POCyclobenzaprine 5 mg 3 times daily up

to 30 mg/day PODiazepam 2-10 mg 3-4 times

daily or 15-30 mg extended-release preparations PO

Gabapentin 900-1800 mg/day in 3 divided doses PO

Metaxalone 800 mg 3-4 times daily PO

Methocarbamol 1-1.5 g 3-4 times daily PO

Orphenadrine 100 mg 2 times daily PO

Tizanidine 8 mg 3-4 times daily PO

Dantrolene 25-100 mg 2-4 times daily PO

Dichlorofluoro-methane

Spray

Botulinus toxin A 200-300 units IM, SCBotulinus toxin B 2500-5000 units IM, SC

ADMINISTRATION Most drugs are given PO but can be injected or delivered by pumps (intrath-ecal baclofen). Drugs might be started at a low dose that will then be gradually increased. Botulinus toxin is only injected IM or SC. Dichlorofluoromethane is applied topically as spray.

CONTRAINDICATIONS Skeletal muscle relaxants should not be used or must be used with caution in patients with hepatic diseases. Baclofen and dantrolene should not be or be used with caution in patients who use spastic-ity to partially maintain balance.

COMMON ADVERSE REACTIONS All skeletal muscle relaxants will cause sedation, drowsiness, and muscle weak-ness, as well as GI distress to a varying degree. Older individuals may experi-ence periods of confusion. Some drugs might cause physical dependence and should not be discontinued abruptly. Drugs such as baclofen, carisoprodol, or methocarbamol, can precipitate seizures in patients but mostly in those with a seizure history. Chlorzoxazone has been associated with hepatitis, GI bleeding, and anemia.

DRUG INTERACTIONS • Sedation is increased with all drugs that

also possess sedative properties such as antihistamines, alcohol, antidepressants, and opioids.

• Increased sedation will occur with chamomile and valerian.

IMPLICATIONS FOR PHYSICAL THERAPISTS • Drugs are extremely helpful in rehabili-

tation because they allow the therapist a more effective therapy.

• Patients starting drug therapy who have used extensor spasticity to maintain bal-ance must be watched carefully while walking because loss of this spasticity might compromise their balance and they might fall.

• Observe all patients carefully when walking or getting up because drowsi-ness and muscle weakness can cause falls.

• Physical therapists can best evaluate the effectiveness of treatment with these drugs and should share his or her evalu-ation with the physician to ensure that the best drug and dosage are used for the fullest benefit of the patient.

• Dichlorofluoromethane spray should be applied from the muscle origin to insertion while the muscle is pas-sively stretched. Never overcool the area. After warming, the spray can be reapplied.

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922 Skeletal Muscle Relaxants Skeletal Muscle Relaxants

GLOSSARY

Agranulocytosis is a deficiency of gran-ulocytes, a subspecies of white blood cells. It manifests itself in immune system impairment, starting with a slight fever and a sore throat possibly with ulcerations. Akathisia is the inability to sit still. Allergic reactions are immune responses (either histamine- or T-cell mediated) to exogenous allergens and manifest them-selves as hives, redness, and itching (most severe form is anaphylaxis). Anaphylaxis is a severe allergic reaction (caused by excessive histamine release), which manifests itself as trouble breath-ing caused by bronchoconstriction and fainting from severe hypotension. It can be fatal. Churg-Strauss syndrome is a systemic vasculitis first manifested by rashes and nodules under the skin, later on damaging internal organs. Exfoliate dermatitis is a severe skin dis-ease characterized by redness, scaling, and shedding of the skin. Epidermal necrolysis is a detachment of the top layer of skin. It manifests itself with fever followed by a rash, redness, blisters, pain, and the peeling of the skin from the underlying dermis. It can be fatal. Dystonia is a disordered tonicity of muscles causing twitching and twisting motions. Dyskinesia describes involuntary movements. Hepatitis and jaundice are liver diseases showing flu-like symptoms, muscle and joint pains, fever, nausea, dark urine, and yellowing of the eyes and skin.

Lupus syndrome is a chronic, inflam-matory autoimmune disorder with joint pain and arthritis. Frequently affected joints are the fingers, hands, wrists, and knees. Malignant hyperthermia is character-ized by highly elevated body temperature, muscle rigidity, and is life-threatening. It is caused by drug-induced excessive cal-cium fluxes in skeletal muscles. Orthostatic hypotension, also called pos-tural hypotension, is a form of low blood pressure that occurs when a person stands up from sitting or lying down. Orthostatic hypotension lasts for only seconds or a minute but can cause dizziness and faint-ing with falls. It occurs more often in older individuals and can be induced by α -blockers and related drugs, which pre-vent vascular constriction or lower blood pressure. Effects can be minimized if a person gets up slowly and holds on firm to something fixed. Photosensitivity is a relatively general term used to describe any cutaneous reac-tions to light that could be allergic or toxic. Drug-induced photosensitivity is mostly of the toxic type, may occur after first exposure to a drug, and is typically manifested by a delayed erythema (red-ness) and edema (swelling) followed by hyperpigmentation and desquamation (shedding of skin). Pseudomembranous colitis manifests itself with nausea, abdominal cramps and pain, fever (which may be higher than 101 ° F), urge to have a bowel movement (fecal urgency), and pus or mucus in the stool. Signs and symptoms of a disease or drug action are defined as follows: a sign is an objective finding of a disease or drug

effect (e.g., loss of a reflex or tachycardia) and a symptom is a subjective finding of a disease or drug effect (e.g., pain or fatigue experienced by the individual). Stevens-Johnson syndrome is a poten-tially fatal skin disease starting with a nonspecific upper respiratory infection, cough, aching, headaches, feverishness followed by a red rash across the face and the trunk of the body, spreading later to other parts such as the mouth and skin. Finally, the top layer of the skin or epider-mis starts to peel off. Superinfection is an infection that occurs during antibacterial drug therapy. It is caused by the sudden growth of a dif-ferent type of bacteria than the type originally diagnosed and treated. This is a common cause of treatment failure because the new type of bacteria is often resistant to the first-line antibiotic. It can be caused when benign bacteria, which ordinarily keep other pathogenic bacte-ria from growing in the body, are killed by the drug. Death of the benign bacte-ria allows these pathogens to grow and to cause a sore throat, fever, fatigue, and diar-rhea. It occurs usually 1 to 2 weeks after drug therapy was started. Tardive dyskinesia is an uncontrolled rhythmic movement often in oral areas such as the “lip smacking” syndrome, which occurs usually after long-term therapy with antipsychotic drugs. It is irreversible. Thrombotic thrombocytic purpura is a very rare but life-threatening disease in which microthrombi block small ves-sels in tissues and organs, causing bizarre behavior, hemolytic anemia (dark urine), and jaundice (yellowing of eyes and skin).

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