basic and essential pharmacology

LECTURE NOTES

ON

PHARMACOLOGY OF ESSENTIAL DRUGS.

(for community health workers).

Lecture Notes on Pharmacology of Essential Drugs. – IORJIIM, W.M ( B.pharm) 1

INTRODUCTORY PHARMACOLOGY.

DEFINITION.

Pharmacology can be defined as the study of substances that interact with living

systems through chemical processes, especially by binding to regulatory molecules and

activating or inhibiting normal body processes. These substances may be chemicals

administered to achieve a beneficial therapeutic effect on some process within the patient

or for their toxic effects on regulatory processes in parasites infecting the patient. Or

Pharmacology is the study of drugs.

A drug on the other hand is defined as any chemical substance of plant, animal or

chemical origin used in the diagnosis, prophylaxis and treatment of diseases in man and

other animals.

SOURCES OF DRUGS.

The range of raw materials used in the manufacture of medicinal products is

extremely large. Principally, pharmaceutical raw materials are derived from three

sources namely Animal, Plant and Mineral Sources.

Plants Based Raw Materials.

Plant based drugs are obtained in the form of extract and may further be processed into

different form of the drugs as tablets, capsules, tinctures, etc.

Drugs source use

Quinine Cinchona bark, antimalaria

Atropine Atropa belladonna Iritis, Uveitis, Mydriatic

Organophosphate Poisoning

Reserpine Rawolfia serpentine antihypertensive

Artesunate Atemisia annua antimalaria


Animal Based Raw Materials.

Animal based drugs may be obtained from organs or glands of animals or they may be

obtained from microorganisms.

e.g Drug (animals) source use

Adrenaline Adrenal cortex hypersensitivity reaction.

Thyroxin Thyroid gland thyrotoxicosis

Insulin Pancretic cells Diabetes mellitus

Vasopressin Hypothalamus Diabetes insipidus.

Testosterone Testis hormonal replacement.

e.g Drug (microbes) source use

Penicillines Penicillium notatum antibiotics

Vancomycin Septococcus orientalis antibiotics

Bacitracin Bacillus subtilis antibiotics

Chloramphenicol Sreptomyces venezuelae ‘’

Tetracyclines Streptomyces aureofaciens ‘’

Mineral Based Raw Materials.

Mineral based drugs may be obtained from single mineral element or a combination of

two or more such mineral elements through a process or method known as chemical

synthesis. Examples include. Acetylsalicylic acid which entails the bringing together

of salicylic Acid and Acetic anhydride in a chemical reaction. Other drugs produced

synthetically include: Paracetamol, chloroquine phosphate, Normal Saline, etc.

Genetic Pharmacy ( or Recombinant DNA technique)

The gene responsible for the production of a complex protein is isolated from human

cells and inserted into other vector (carrier ) cells ( e.g E. coli or yeast) which divide

rapidly and are manipulated to produce the required protein in large quantities. This

method is used for Insulin and Erythropoeitein production.


NAMING OF DRUGS.

A drug commonly has three names viz: chemical name, Generic name and Trade name.

Generic name of a drug refers to a name assigned to a drug by the World Health

organization ( WHO) and is independent of that of the manufacturer. A generic name is

also known as non-proprietary name. eg. Paraceamol and Cprofloxacin. Trade name of

drug is the name given to a drug by its manufacrurer. A Trade name is also known as

brand name or proprietary name. A trade name distinguishes a given drug name by a

company from same drug made by another company e.g Panadol is a trade name given to

paracetamol by Glaxosmithkline while the same paracetamol made by Dana

Pharmaceuticals is known as Danamol. Chemical name of drug is the name given to a

drug by virtue of its chemical composition. E.g Paracetamol is called N-acetyl-para-

Aminophenol.

CLASSIFICATION OF DRUGS.

Drugs can be classified into many groups using several systems. Some of the systems of

classifying drugs include:

1. Classification drugs base of dosage forms.

In actual pharmacy practice, pure drugs are rarely administered alone. They are

combined with inactive (or inert) materials to produce a pharmaceutical dosage form.

The term “dosage form” refers to the physical form in which the drug product is made

available for administration to the patient. Some of the common dosage forms used

in pharmacy practice today includes:

1. SOLID DOSAGE FORMS.

Tablets. Capsules.

2. LIQUID DOSAGE FORMS.

Solutions, Syrups, Elixirs, Tinctures, Suspensions, Emulsions,Enemas.

Enemas are liquid medications introduce into the rectum for local effect: - cleansing the

bowel prior to surgery or as stool softeners. e.g soap enemas.

3. SEMI-SOLID OR TOPICAL DOSAGE FORMS.

Ointments, Pastes; Creams, Powders, Gels and Jellies.


2. Classification of Drugs According to Pharmacological Actions.

Drugs may also be classified according to the known action in the human system. eg.

Anti- convulsants. These are drugs used in the treatment of acute fits or convulsions.

Examples include Diazepam, paraldehyde and phenobarbitone sodium.

Antehelmintics: these are a group of drugs that are effective against worm infestations.

Eg. Albendazole, Mebendazole, Levamisole etc

Anti-malaria. Drugs used in the treatment of malaria infection. Eg. Artesunate,

chloroquine etc

Antibacterial drugs. These are drugs that are used in the treatment of bacterial infections.

Examples include Ciprofloxacin, Metronidazole, Streptomycin, Tetracycline, etc.

3. Classification Based on Organ or System of Body the Drug works.

Drugs may similarly be classified based on the organ or system the drug is known to

elicit their pharmacological or therapeutic action.

Cardiovascular system drugs: These include all the drugs that are used in the treatment of

cardiovascular system disorders eg.

Anti-hypertensives ( Propranolol, Atenolol, Nifedipine, Lisinopril,

etc),

Cardiac glycosides eg. Digoxin,

Antiarrhythmic agents ( drugs in the treatment of cardiac

arrythmias) eg. Propranolol, Quinidine, Amiaodarone, Acebutolol

etc.

Endocrine System Drugs. These are drugs used in the treatment of endocrine system

disorders. eg.


Antidiabeties ( drugs used in the treatment of diabetes mellitus) e.g

Insulin, Metformin (Glucophage), Glibenclaminde ( Daonil), etc.

Antithyroid drugs (drugs in the treatment of thyrotoxicosis) e.g

Carbimazole, Methimazole, Iodine etc.

Central Nervous System (CNS) Drugs: These include drugs used in the management of

CNS disorders e.g

Antispychotics (Chlopromazine, Haloperidol),

Antiepiletics ( Diazepam, Penytoin, Carbamazipine etc),

Antiparkinson drugs ( Levodopa, Tolcapone, etc)

Gastrointestinal drugs: These are drugs with action on the gastrointestinal tract.

Examples include:

Antiulcer drugs (Cimetidine, Omeprazole, Ransoprazole, Gascol

etc),

Antispasmodic drugs ( drugs that reduces the contraction of GIT

smooth muscles eg Hyoscin-N-Butylbromiden (Buscopan),

Propantheline etc,

Laxatives eg. Bisacodyl ( Ducolax), Antiemetics eg. Metocloramide

( Plasil).

Dermatological drugs. These include topical preparations for skin infections e.g topical

antifungal agents ( e.g Clotrimazole cream, Tioconazole cream etc) , topical antibacterial

agents ( Ampicillin ointment etc)

BASIC PHARMACOLOGICAL CONCEPTS.

Pharmacology is the study of drugs. The two main areas of pharmacology are

pharmacokinetics and pharmacodynamics.

Pharmacokinetics

Pharmacokinetics is the study of the activity of a drug within the body over a period of

time is known as pharmacokinetics. It is the actions/effects of the body on the drug.


Pharmacokinetic processes govern the absorption, distribution, and elimination of drugs

and are of great practical importance in the choice and administration of a particular drug

for a particular patient.

Drug Absorption.

This is the process whereby a drug enters the circulatory system. That is , the chemical

constituents of the drug are absorbed into the blood stream. The absorption of a drug

molecule depends on its physiochemical properties. To gain access to the site of action,

drug molecule must cross one or more barriers- the GIT mucosa, and the membranes that

separate the various aqueous compartments of the body. Drug molecules cross cell

membranes and become absorbed in the following ways.

* Diffusion through lipids.

Many drugs are highly soluble in lipids and therefore penetrate cell membranes

freely, by diffusion. Lipid solubility is one of the most important pharmacokinetic

characteristic of a drugs, which determine it site of action.

* Diffusion through aqueous ( i.e water) channels.

In most parts of the body there are gaps between the endothelia cells of the

capillaries, which are large enough to permit small drugs molecules to cross by aqueous

diffusion, but too small to allow protein.

* Carrier mediated transport.

Many cell membranes posses highly specific transport mechanism (i.e a protein

molecule incorporated in the cell membrane) which binds the drug molecule and ships it to

other side of the membrane in the manner of a ferry. The carrier mediated drug transport

plays an important role in the transfer of drugs at the renal tubules, GIT and blood brain

barrier sites.

* Endocytosis and Exocytosis.

A few substances are so large that they can enter cells only by endocytosis, the process by

which the substance is engulfed by the cell membrane and carried into the cell by pinching

off of the newly formed vesicle inside the membrane. The substance can then be released

inside the cytosol by breakdown of the vesicle membrane. This process is responsible for


the transport of iron and vitamin B12, each complexed with appropriate binding proteins,

across the wall of the gut into the blood. The reverse process (exocytosis) is responsible

for the secretion of many substances from cells. For example, many neurotransmitters

are stored in membrane-bound vesicles in nerve endings to protect them from metabolic

destruction in the cytoplasm. Appropriate activation of the nerve ending causes fusion of

the storage vesicle with the cell membrane and expulsion of its contents into the

extracellular space.

Drug Distribution.

This is the process by which a drug moves from the blood stream into other body

fluids and tissues and ultimately to its sites of action. Blood flow is the most important

rate limiting factor for distribution of a drug.. Many drugs are poorly soluble in plasma

and are bound to plasma proteins. It is important to know that the free (unbound) fraction

of drugs produces the desired pharmacological action or therapeutic effect.

Drug metabolism. ( Biotransformation)

This is the process in the body by which drugs are converted to other biochemical

compounds, and then excreted through metabolic path ways. The liver is the man site of

metabolism for most lipid soluble drugs,. These lipid soluble drugs are change in the liver

to more water soluble forms ready for excretion via the kidney or skin. A substance into

which a drug is converted by metabolism is called metabolite of the drug. Drugs that must

be converted to their metabolite before their actions are produced are called produrugs e.g

an antiparkinson drug Levodopa to dopamine. Many factors can alter metabolism e.g

disease states, age and genetic predisposition all affect the way the body metabolizes

drugs.

Drug Elimination.

The removal of a drug or its metabolites from the body occurs primarily in the kidney

( through urine) and the liver ( through feces). Other routes of excretion include skin ( via

perspiration), saliva, and breast milk. The rate of drug metabolism, it half life and

subsequent elimination is useful in predicting its duration of action and frequency of

dosing e.g twice a day with elimination half life of about 12 hours.


Half life. The elimination half life of a drug is the time taken for the circulating

concentration of the drug to fall by half. For most of the drugs, the rate of decline in the

plasma concentration is constant and directly proportional to the amount present.

PHARMACODYNAMIC.

Pharmacodynamcis is the study of pharmacological properties of a drug and its

mechanism of action. It is the actions/effects of the drug on the body. Drug effects are the

results of physiochemical reactions between the drug and functionally important

molecules in the body. They interact with the body’s natural physiological control

systems that include receptors, enzymes, etc. some of the known mechanisms of drugs

actions are:

Drug Receptors.

The term receptor is used to mean any clearly defined cellular protein to which a drug

binds to initiate its effect. The drug is thought to fit onto a receptor rather as a key fits a

lock. It may then either stimulate the receptor and producer ifs effect similar to that of a

naturally occurring (endogenous) substances and it is called an agonist or it may occupy

the receptor without producing any effect and block the effect of an endogenous agonist

and is called antagonist. A few drugs have been show to be partial agonists (antagonists

at low concentrations and agonist at high concentrations) e.g pindolol

Enzyme inhibition

Interaction between drug and enzyme is in many respects similar to that between

drug and receptor. Many important drugs owe their action due to inhibition of the enzyme

activity, because they structurally resemble a natural substrate and hence compete with it

for the enzyme. Examples of enzyme inhibition include Angiotensin Converting Enzyme

Inhibitors (ACE Inhibitors) ( Lisinopril Captopril etc), Cyco-oxygenase inhibitors

( NSAIDs -Aspirin, Diclofenac), Xanthine oxidase Inhibitor e.g Allopurinol (zyloric) in

the treatment of Gout arthritis.

Chemical Interaction.

Drugs extra-cellulary react according to simple chemical equation know as neutralization

reactions. e.g ( acid + base Salt + water) as in the use of antacids to


neutralize HCl in the treatment of peptic ulcers. For example, the HCl in the stomach can

be neutralized by Aluminum hydroxide ( an antacid) as follows.

Al (OH)3 (base) + 3HCl (acid) AlCl3 (salt) + 3H2O (water)

Other reactions are: acidifying and alkalinizaing agents, oxidizing agents and chelating

agents.

Action on cell membranes

General and local anaesthetics appear to act on the lipid, protein or water constituents of

nerve cell membranes and interfere with the movement of ions and thus, prevent nerve or

muscle function.

Cytotoxic Effect.

Here, a drug kills bacteria or malignant cells without undue change to the patient’s cells.

e.g cancer drugs

ROUTES OF DRUG ADMINISTRATION.

This is the ways drugs are administered in a patient. There are various routes of drugs

administration viz: Enteral route, Parenteral route, and Topical route

Enteral Route. This refers to the administration of drugs through the gastro-intestinal

tract. The different ways this is done include.

(b) Per Oral Route. This refers to administration of drugs through the mouth.

Examples of dosage forms suitable for oral route include: Tablets,

Capsules, Syrups, Suspensions, etc.

Advantages.

it is economical i.e cheap to use,

Easy to use as the patient can administer the drug by him/herself.

In case of accidental overdose, the drug may (where appropriate) be easily

removed via gastric larvage.

It is the safest i.e has low incidences of fatal side effects.

Disadvantages.

Onset of action is slow therefore unsuitable for emergency cases.

Drugs are subjected to first pass effect.

Lecture Notes on Pharmacology of Essential Drugs. – IORJIIM, W.M ( B.pharm)10

Not convenient for unconscious patients

Bitter taste may discourage drug use.

Absorption is affect by food.

Not convenient for treatment of nausea and vomiting.

The route requires patient’s cooperation.

(c) Sublingual/ Buccal Route: this refers to administration of drugs under the

tongue ( i.e sublingual) or between the cheek and gum (i.e buccal cavity).

The drug is place under the tongue or at the cheek and it slowly dissolves.

An example of sublingual drug is Nitroglycerin tables. The major

advantages of this route are:

- Onset of action is fast because the drug bypasses first pass effect. i.e the

medication enters the blood stream directly from the richly vascularized mucous

membrane of the mouth and produces its effect more quickly than drugs that

are swallowed. Other advantages and disadvantages are similar to oral route

Parenteral Route.

Administration of drugs by injection is referred to as the parenteral route

( meaning outside of the intestines). . Here, drugs are given by injection or by

infusion directly into the blood circulation. There are different ways of

administering drugs through the parental route. Drugs may be injected into:

a muscle - intramuscular ( IM)

a vein- intravenous ( IV)

the skin- intradermal

the tissue beneath the skin- subcutaneous ( SC)

the spinal column- intraspinal or intrathecal.

Advantages

Quickest onset of action therefore most useful in emergencies.

Parenteral route provide a way of administering drugs that are inactivated by

GIT secretions eg. Insulin


Some drugs are inactivated by first-pass metabolism, so they are injected

directly into the tissues of the body.

Convenient for treatment of nausea and vomiting.

Disadvantages.

Injection can be painful.

There is a risk of infection at the site of puncture

Has highest incidence of side effect.

In case of accidental overdose, drug cannot be withdrawn.

It is expensive in that the patients pays for syringes/needles besides the real

cost of drugs.

Ideally, patients require the services of trained personnel to administer their

drugs.

Topical routes.

Topical medications are applied to the surface of the skin or mucous

membranes. The desired effect can be local or systemic. Other topical routes

are: inhalation, ophthalmic ( the eye) , otic ( the ear) , nasal( the nose) , rectal,

and vaginal.

Rectal Route: this refers to administration of drugs through the anal cavity or

anus. Examples Anusol Suppositories.

Advantages.

Drugs bypasses first pass effect.

Onset of action if fast.

Convenient for unconscious patients and children.

Cheap.

Easy to use by patients or relatives.

Convenient for treatment of nausea and vomiting.

Disadvantages.

Route may be embarrassing to patient.

Presence of fecal matter affect drug absorption.


Drugs may irritate anal mucosal.

The inhalation route delivers medications to the respiratory system. These

medications are intended for one or more of the following purposes: to alter the condition

of the mucous membranes, to alter the character of the secretions in the respiratory

system, to treat diseases and infections of the respiratory tract, or to produce general

anaesthesia.

Medications can be administered via the ophthalmic route by instillation

( administration of medication drop by drop) of a cream, ointment, or drops of a liquid

preparation into the conjunctival sack of the eye.

Drugs administered by the otic route, into the ear, are used locally to treat

inflammation or infection of the external ear canal or to remove excess cerumen ( wax) or

foreign objects from the canal.

Medications given by the vaginal route can be used to treat a local infection caused

by either bacteria or fungi or for systemic effect.

BASIC PRINCIPLES OF DRUG ADMINSTRATION.

a. Dosage of a drug.

The dose of a drug is the quantitative amount administered or taken by a patient for the

intended medicinal effect. The dose may be expressed as:

1. A single dose = the amount taken at one time.

2. A daily dose = the amount taken in 24 hours.

3. A total dose = the amount taken during the time-course of therapy.

A daily dose may be subdivided and taken in divided doses; 2 or more times per day

depending on the characteristics of the drug and the illness.

4. The schedule of the dosing e.g 4 times per day x 10 days is called dosing

regiment.

Dosages are an important aspect of drug use because accurate choice of dosages of drugs

determines the final outcome of a disease being treated. There are number of factors that

influence choice of dosages of drugs. They include:

b. Age. The age of a patient is an important consideration in the choice of dose of a drug.

This factor is particularly important for children who need smaller doses of drugs.


c. Genetic make-up- patients respond or ract to drugs differently in accordance with how

their genes are made. E.g chloroquine ( an antimalaria drug) produces severe itching in

some people whereas it is well tolerated by others.

Acquired Tolerance- by acquired tolerance is meant tolerance developed from continued

use of a drug. In such patients, large doses of a drug which could have caused harmful

effect in normal patients, are taken without any harmful effect. Drug that can product

tolerance on continued use include drugs of abuse and addiction such as Pentazocine ( i.e

Soseqon or Fortwin) , diazepam (valium) etc.

d. Route of Administration

The rate and degree of absorption of a drug and finally the rapidity with witch its effect is

felt or exerted depends on the method of administration. Generally, drugs administered by

injection or parenteral route act faster than those given via oral route. This explains why

parenteral doses are usually smaller than the oral doses.

e. Rate of Elimination of the drug.

The rate at which a drug is eliminated from the body determines the dose of such a drug.

As mentioned before, the elimination of drugs depends largely on the functional status of

the kidneys and the liver. In a condition where any of these organs is diseased, the

function of excreting or eliminating drugs have to be reduced. Therefore doses of drugs

that are eliminated by these organs should be reduced.

f. Drug interactions.

Two drugs given at the same time may react together either negatively or positively. In a

positive way the effect of one may be enhanced by the other or in a negative way, the

other may reduce the effect of one. These effects are therefore employed when two drugs

are to be given together. In a case where the negative interaction is known, the drug

whose effect is diminished has to be removed. To avoid harmful drug interactions,

polypharmacy which is the concurrent use of multiple medications, should be avoided.

There are two principal types of interactions between drugs – pharmacokinetic

interactions resulting from alterations in delivery of drugs to their sites of actions and

pharmacodynamic interactions which modify the responsiveness of the target organ or

system.


* Pharmacokinetic interactions that reduce drug delivery include:

Impaired absorption eg. Antacids form insoluble complexes with

Tetracyclines preventing the absorption of the later.

Enzyme induction. Many drugs increase the synthesis of microsomal enzyme

protein that metabolizes drugs there by reducing drug effect. Eg.

Barbiturates ( phenobarbitone), Griseofulvin, are enzyme inducers therefore

when taken concomitantly with drugs whose metabolism is significantly

affect by enzyme induction ( e.g contraceptives corticosteroids) may have

their effect diminished.

* Pharmacokinetic interactions causing increased drug delivery are:

Enzyme inhibition. Many drugs have the potential for interfering with the

metabolism of other drugs, usually by competing for binding sites on the

appropriate enzymes. Inhibition of the metabolism of the affected drug

results in higher plasma concentration with risk of toxicity. e.g co-

trimoxazole and Cimetidine are enzyme inhibitors and my increase the

levels of warfarin ( an anticoagulant) resulting to excessive bleeding.

Affecting renal excretion: Drugs are eliminated through the kidney both by

glomerular filtration and by active tubular secretion. Competition occurs

between those which share the same active transport mechanism\ in the

proximal tubule. Example, Probenicid delays the excretion of many drugs

including Penicillins, some Cephalosporins, indomethacin and Dapsone,

which may result to increased concentration and prolonged action of these

drugs. Similarly, thiazide diuretics ( e.g hydrochlothiazide) delay the renal

excretion of lithium ( use in mania) , which may result in serious lithium

toxicity.

Pharmacodynamic interactions.

These are interactions between drugs which have similar or antagonistic

pharmacological effects or side effects. They may be due to competition at

receptor sites or occur between drugs acting on the same physiological system.

Synergism: Synergism occurs if two drugs with the same effect, when given

together produce an effect that is greater in magnitude than the sum of the


effect when the drugs are given individually. For example, the effect of a

drug depressing the CNS (say Benzodiazepines) will be enhanced by another

CNS depressant ( say alcohol). synergism of drugs with similar actions

may be beneficial also as with antibacterial components of Co-trimoxazole

(trimethoprim-sulphamethoxazole) and antimalaria effect of Fansidar

(sulphadoxine- pyrimethamine)

Antagonism: When one drug decreases or inhibits the action of another drug

antagonism occurs. E.g Naloxone (narcotic antagonist) decreases the effect

of narcotics analgesics like morphine. Another classic example of

antagonism is the suppression of the bactericidal activity of penicillin (which

acts on divining bacteria) by Tetracycline, a bacteriostatic agent , which

reduces bacterial division. This explains why bactericidal antibacterials are

not given concurrently with bacteriostatic antibacterials.

PHARMACOLOGY OF ESSENTIAL DRUGS

CHEMOTHERAPY

Chemotherapy was formerly thought to be the use of synthetic chemicals to

destroy infective organisms. However; it now include the use of antibiotics which

are substances produced by some microorganisms which kill/inhibit the growth of

other microorganisms. Chemotherapeutic agents are supposed to be toxic to the

parasite and harmless to the host; hence it is referred to as selective toxicity. This


selective toxicity depends on the existence of biochemical differences between

the parasite and the host cells.

Parasitic cells include bacteria, protozoa, helminthes (or worms), viruses

also (but they are not actually cell since they do not have their own synthesis). A

virus depends on the host cell and therefore is not selective toxicity in this case.

Cancer cell belongs to another category. These are host cells, which have

become malignant, i.e they are no longer being controlled by the regulatory

devices that control the normal cells of the host. Although the cancer cells can be

considered as foreign or parasitic, they also constitute a difficult problem for

selective toxicity.

The ability of one microorganism to interfere with the growth of another is

called antibiosis and is due to specific diffusible metabolic products termed

antibiotics. Since the introduction of penicillin in 1940, research has produced a

wide range of antibiotics. In addition, a variety of other chemotherapeutic agents

such as metronidazole, trimethoprim, ciprofloxacin and isonazid followed the

demonstration of the therapeutic effect of sulphonamide in 1935. A general term

for all of these substances is antimicrobial agents. Those that kill microorganisms

are said to be bactericidal in action while agents that inhibits their growth are

said to be bacteriostatic in action .

MISUSE OF ANITMICROBIAL AGENTS AND CAUSES OF FAILURE IN

THERAPY WITH CHEMOTHERAPEUTIC AGENTS.

Factors that contributes to the failure of treatment with chemotherapeutic

agents include:

Treatment of infection which do not respond to antibiotics eg

1. The treatment of viral infection with antibiotics.

2. Treatment of fever of undetermined origin with antipyretics can lead to

masking of infection.

3. Improper dosage; this can be of three types

4. The use of sub-optimal doses.

5. The use of excessive doses


6. Correct doses for too short a period i.e Improper duration of use can lead

to resistance.

7. The use of wrong antibiotics for a particular condition can also lead to masking

of the infection.

PROBLEMS OF CHEMOTHERAPY

Development of Resistance. One of the most important problem of antimicrobial

therapy is the development resistance. This is a situation where the

microorganism become resistance to the drug even though the drug maybe

present in adequate doses. To minimize /stop the development of resistance,

antibiotics should be used when they are absolutely needed and for a sufficient

length of time and in adequate doses.

Super-infection. Another problem of antibiotic therapy is development of super-

infection. In this case, the antimicrobial agent may kill/ suppress part of the

normal bacterial flora. This allows the remaining bacterial to proliferate to

pathogenic levels thereby causing secondary infection. For example the broad-

spectrum antibiotic Tetracycline when used (for a long time) for GIT infection can

eliminate most of microbes except the fungus Candida. This then proliferates

excessively to cause intestinal candidiasis. Super- infection is common with the

broad-spectrum antibiotics.

FACTORS WHICH DETRMINE THE CHOICE OF ANTIBIOTICS.

1. The choice of antibiotics can follow form clinical diagnosis. This can be done

when the causative organism is always the same and is always sensitive to the

same antibiotic e.g in the treatment of Malaria, Tuberculosis, Syphilis etc.

2. It can also be based of sensitivity test where possible. This should be done

when the causative organism cannot be detected by clinical diagnosis e.g in

Bronchopneumonia, Meningitis and Urinary Tract Infections. ( UTIs)

3. Toxicity or adverse effect. The least toxic antibiotic should be used.

Site of infection. Some drugs penetrate body fluids better then others


4. The patient’s clinical status. A patient with renal failure should not be given

antibiotics that are excreted mainly unchanged via urine eg. Aminoglycosides:

Gentamicin etc.

ANTIBIOTIC POLICES.

Many hospitals/clinics limits the antibiotics that may be used to achieve

reasonable economy consistent with adequate cover and to reduce the

development of resistant organisms. A policy may indicate a range of drugs for

general use and permit other drugs only on the advice of physician responsible for

the control of infectious diseases.

PRECAUTION BEFORE INITIATING CHEMOTHERAPY

Before starting therapy with antibiotics, the following should be considered.

1. Viral infections should not be treated with antibiotics.

2. Samples should be taken for culture and sensitivity testing.

3. Knowledge of prevalent organisms and their current sensitivity is of great help

in choosing an antibiotic before bacteriological conformation and sensitivity

testing is available.

4. Doses of antibiotics. The dose of antibiotic will vary according to a number of

factors including.

Age, Weight, Renal function and, Severity of infection.

NB: The prescribing of the so-called “standard” dose in serious infections may

result in failure of treatment or even death of the patient, therefore it is important

to manage all cases at the PHC level by CHO or CHEW in line with the provision

of Standing Orders only and refer accordingly to avoid trial and error type of

patient’s management.

ANTI BACTERALS USED IN CHEMOTHERAPY

THE - LACTAM ANTIBIOTICS


These are Penicillins and Cephalosporins. Resistance is common due to bacterial

enzymes called -lactamase (penicillinase and cephalosporinase), which can

destroy and inactivate the antibiotics.

The Penicillins

The penicillins constitute one of the most important groups of antibiotics with

unique advantage they are drugs of choice for large number of infectious

diseases.

MECHANISM OF ACTION (MAO): They are bactericidal and act by inhibiting

bacterial cell wall synthesis.

Penicillins distribute well into the body tissues and fluids and are excreted

in the urine. Examples of penicillins include:

A: PARENTERAL PENICILLINS

Benzyl Penicillin (penicillin G, crystalline Penicillin etc)

Pharmacology

Penicillin G exerts a bactericidal action against penicillin-sensitive microorganisms

during the sate of active multiplication. This action is affected (reduced) by the

activities of penicillinase ( the enzyme that destroys penicillins) producing

bacterials which include many strains of staphylococci. It acts through inhibition of

biosynthesis of cell wall.

Indications.

Pen G is indicated in the treatment of infections caused by susceptible gram-

positive and gram-negative organisms, including wound infections, abscesses,

boils, acute tonsillitis, otitis media, pneumococcal pneumonia, gonorrhoea,

syphilis.

NB: Penicilins are the drug of choice for the treatment of bacterial infection in

pregnancy.

Side effects.


Allergic manifestations are common with all penicillins and may be severe. This is

more frequent and severe when given parenterally ( i.e by injection) than by oral

route.

Haemolytic anaemia

Convulsions

Dose:- consults the standing orders (or other reference books eg. Emdex).

Benzathin penicillin ( Penadur L-A, Reterpen )

Benzathin penicillin is hydrolysed to penicillin G (benzyl penicillin). It is very poorly

soluble and thus is slowly released from the intramuscular infection site. The

combination of hydrolysis and slow absorption results in low serum levels, much

lower but much more prolonged than other parenteral penicillins. As a result, in

many indications, injections at intervals of 1-2 weeks are sufficient so that the

frequency of administration and the resultant local trauma can be reduced.

Indications

Treatment of infections due to penicillin G sensitive microorganisms

It is used as a single agent in the treatment of acute tonsillitis, wound infections,

bite wounds, Syphilis and other treponemal infections.

Precautions

Patients should be alerted to the potential occurrence of allergic reactions and

instructed to report them. Patients should be watched for 30 minutes after drug

administration and adrenalin (epinephrine) should be kept ready so that if allergic

reaction occurs the drug should be withdrawn and the usual treatment with

epinephrine, antihistamine and corticosteriods be instituted.

Contraindications

Hypersensitivity reaction to any penicillin or related drugs eg. Cepalosporins.

Procaine penicillin

Same as benzathin penicillin except that procaine penicillin is shorter acting and

therefore is administered daily.


B: ORAL PENICILLINS

Penicillins are also active via oral route. Some examples of oral penicillins

include.

Ampicillin (aminobenzyl penicillin)

Indication

Infections sensitive to penicillins . it is contra-indicated in hypersensitive patients.

Important points to consider

1. Ask patient about allergy to penicillins

2. Obtain specimen for culture and sensitivity

3. Give orally on an empty stomach (i.e one hour prior to or 2 hours after food.)

4. Administers round the clock 6 hourly( in equal intervals to promote less

variation in serum level)

Dose: give according to standing orders.

The cephalosporin

Cephalosporin inhibits bacterial cell wall synthesis in a manner similar to that of

peniciin.

Classification.

Cephalosporins may be classified by their chemical structure, clinical

pharmacology, resistance to -lactamase, or antimicrobial spectrum, the well

accepted system of classification by generations is very useful.

1st Generation cephalosporins. E.g Cephalothin, Cephalexin, Cefazolin,

Cepharodine, Cepaprin.

2ND Generation cephalosporins. E.g Cefaclor, Cefuroxime, and Cefoxtin.

3rd Generation cephalosporins. e.g Cefperazone, Moxalactine, Ceftazidine,

Cefotaximine, Ceftriazone.

4th Generation cephalosporins. e.g. Cefepine.

Clinical uses:


a. septicemia especially, wen he causative organism is not known or other

antibiotics are contraindicated.

b. Menigities caused by menigococci or pneumococci or H. influenzae.

c. Peritonitis and biliary tract infections.

d. Typhoid fever

e. Pneumonia of unkown aetiology.

f. Acute pyelonephrities or prostates and resistant urinary tract infections.

g. Other infections simiilar to penicillins.

In areas where there are no facilities for estimating the blood levels of

antibiotics, cephalosporins are usually preferred due to their lower toxicity.

Cephalosporins are also safe in pregnancy.

Side effects.

Usual doses of cephalosporins are not toxic. Excesses parenteral doses can lead

to drowsiness and mental disturbances. Skin rashes may occur due to

sensitization to the cephalosporins nucleus as in penicillins.

AMINOGLYCOSIDES.

This group of antibiotics includes gentamycin, kanamycin, Tobramycin, amikacin,

Neomycin, Streptomycin etc. they have a number of common properties.

a. They are bacteriocidal

b. They are not orally absorbed

c. They have potential toxicity and nephrotoxicity, especially in elderly and

patients with renal failure.

Antibacterial spectrum.

Aminoglycosides are effective against a wide range of Gram-positive and Gram-

negative organisms.

MOA: Aminoglycosides inhibit protein biosynthesis.

Therapeutic uses.

Gnetamycin is the drug of choice and used in:

a. peritonitis and biliary tract cephalosporin resistant infections.


b. Endocarditis ( inflammation of cardiac muscles)

c. Meningitis cause by listeria ( in combination with amoxicillin)

d. Acute pyelonephritis or prostatitis

e. Septicemia community or hospital acquired

f. Prulent conductivities ( as gentamycin eye drops)

Adverse effects.

Aminoglycosides may cause vestibular and auditory damage and nephrotoxicity.

These class of antibiotics are contra-indicated in pregnancy. Co-adminstration

with Frusemide increases the risk of ototoxicity.

TETRACYCLINES

Tetracyclines are bacteriostatic agents which for practical purpose, have identical

range of activity examples include doxycycline, tetracycline, oxytetracycline, etc.

Mechanism of Action. Tetracyclines are broad spectrum antibiotics that inhibit

protein synthesis. They are bacteriostatic for many gram-positive and gram-

negative bacteria.

Indications

Tetracyclines are used in chlamydia (lymphogranuloma venerum and non-

gonococcal urethritis). They are also employed systemically in acne vulgaris and

rosaea. Doxycycline is also used in the treatment of plasmodiasis. They are used

in combination regimens to treat gastric and duodenal ulcer disease cased by

Helicobacter pylori.

Dose

The oral adult dose is 250 –500mg 6 hourly before meals because the absorption

of most Tetracyclines is reduced by chelating with heavy metals (eg calcium) or

milk. Doxycycline is an exception and also has the advantage that it is given once

daily 200mg first day and 100mg thereafter or twice a day i.e 100mg 12 hourly.

Side effects


Tetracyclines are generally safe antibiotics with few side effects. The commonest

is diarrhoea which usually stops when the antibiotic is discontinued. Tetracyclines

chelates with calcium and are deposited in developing bone and teeth causing a

brown discolouration. They should not therefore be given to children or pregnant

women with the exception of doxycycline and minocycline. The tetracyclines can

exacerbate renal failure and should not be given to patients with impaired renal

function.

MACROLIDES

These are Erythromycin, clarithromycin, Azithromycin (zithromax) etc

Erythromycin has similar though not identical spectrum of activity with penicillins

and is commonly used to treat infections caused by gram-positive organisms in

penicillin allergic patients.

Mechanism of action

Erythromycin and other macrolides inhibit protein synthesis in bacterial.

Indications

It is effective in whooping cough ( as well as other coughs) campylobacter

enteritis. It is effective in many acute respiratory infections and other infections

where it is found to be sensitive.

Dose

Erythromycin is prescribed in doses of 250mg-500mg by mouth six (6) hourly.

There is a preparation for intravenous injection.

Side effects

Diarrhoea, vomiting and abdominal pian are principal side effects. Cholestatic

jaundice may rarely develop if the course of treatment exceeds ten days.

CHLORAMPHENICOL

Chloramphenicol is a potent broad-spectrum antibiotic similar to tetracyclines with

the important addition of salmonella and paratyphoid organisms. The daily oral


dose for an adult is 1g-3g given every six hours. The preparation for parenteral

administration is also available.

Mechanism of Action.

Chloramphenicol act as inhibitor of protein synthesis.

Indication

Chloramphenicol is a drug of choice in meningitis due to H. Influenzae. It is used

in typhoid fever and other infections where it is found to be sensitive.

Chloramphenicol eye drop and ointment are useful for purulent conjunctivitis.

Side effects

Chloramphenicol is known to cause bone marrow depression. It should never be

given to premature infants or to the newborn because of the risk of the

development of the frequently fatal “grey baby syndrome”. This is a state of acute

circulatory failure caused by the very high blood levels of chloramphenicol due to

its inadequate metabolism in the liver at this age.

Ciprofloxacin is the most important of the 4-quinolones. It has THE 4-

QUINOLONES

a relatively broad spectrum with particularly high activity against aerobic gram-

negative bacilli including salmonellae, shigellae, campylobacter and

pseudomonas spices. It is also active against chlamydia but not against anaerobic

bacterial. Although many gram-positive organisms are sensitive to ciprofloxacin

the activity is only moderate especially against pneumococi.

Mechanism of Action. Quinolones block baterial DNA synthesis.( they are

commonly called DNA gyrase inhibitors.)

Dose: The oral dose is 250mg –750 mg 12 hourly and for intravenous infusion

200 mg 12 hourly.

Indication


Ciprofloxacin has a wade range of indications including gastrointestinal, urinary

tract and lower respiratory tract infections (not phneumococcal), septicaemia and

gonorrhoea.

Other 4-quinolones include Norfloxacin (norbactin), ofloxacin (tarivid),

Sparfloxacin, Levofloxacin (levoxin), etc.

Side effects

The adverse effects encountered with the 4 qunolones include

Nausea, vomiting, diarrhoea, rashes insomnia, dizziness, headache and

convulsions (especially when combined with NSAIDs).Quinolones may damage

growing cartilage and case an arthorpathy. Thus , they are not routinely

recommended for use in patients under 12years of age and pregnant women.

However, the arthoropathy is reversible

METRONIDAZOLE

This is an imidazole compound. It has high activity against anaerobic bacteria and

interstinal protozoa but none against aerobic bacteria.

Mechanism of Action.

Within anaerobic bacteria and sensitive protozoal cell, metronidazole is reduced

by ferredoxin. The reduction products appear to be esponsible for killing the

organisms by reacting with various intracellular molecules. In amobiasis,

metronidazole kills Entamoeba histolytica trophozoites but not cysts. In

dracunculiasis, its action apparently is anti-inflammatory.

Indications

Metronidazole is effective against infection due to Trichomonas vaginalis, Giardia

lamblia and Entamoeba histolytica and is widely used for treatment and

prophylaxis of infections caused by anaerobic bacteria, notably B. fragilis,

clostridium tetani and clostridium difficile.

Side effects


Side effects of metronidazole are usually limited to headache and nausea but it

should not be given to women during the first trimester of pregnancy. Alcohol

should be avoided during therapy with metronidazole, which has a similar action

to disulfiram.

CO-TRIMOXAZOLE

This is the combination of Trimethoprim 80mg + Sulphamethoxazole 400mg,

which act by inhibiting enzymes at two successive stages in the synthesis of para-

aminobenzoic acid to folic acid and DNA.

Mechanism of Action. It inhibit the synthesis of DNA.

Uses

Co-trimoxazole is used in the treatment of exacerbation of chronic bronchitis and

urinary tract infections. It is also effective in the treatment of invasive salmonella

infections. Double-dose co-trimexazole is used to treat pneumonia caused by

pneumocystis carinii commonly prevalence among HIV/AIDS patients.

Dose

Usually 2 tabs (960mg) 12 hourly but 1440mg (3 tablets) 8 hourly Or 920mg (4

tablets) 12 hourly can be used in pneumocystis carinii common in AIDS patients.

Side effects

Rash, ( commonly called Seven-Johshon’s syndrome), jaundice, headache,

vomiting and diarrhea.

CHEMOTHERAPEUTIC AGENTS IN TUBERCULOSIS

MYCOBACTERIAL INFECTION: A BRIEF REVIEW


Tuberculosis (TB) is a bacterial infection. The causative organism, mycobacterium

tuberculosis, thrives best in organs with high oxygen tension e.g lungs. The

infection is transmitted by inhalation of infected droplets or by acquired ingestion

of milk from infected cattle. The bacterial can enter the body by several routes

viz: lungs, and gastrointestinal tract or by direct cutaneous inoculation

(vaccination, accident at autopsy)

CLINICAL FEATURES

In most clinical cases of TB, the disease is present in the form of post-

primary pulmonary TB. The disease is often bilateral, starting in one lung and

commonly spread via the bronchi to the other. The clinical findings of TB can be

divided into:

Systemic symptoms

Symptoms due to the systemic effects of the disease include fever, loss of weight,

tachycardia (increase heart rate) loss of appetite, anaemia, malaise and sweating

especially during sleep.

Specific symptoms

Cough, Hemoptysis (blood in sputum) and Dyspnea (difficulty in breathing)

PHARMACOLOGY OF ANTI-TB DURGS.

Chemotherapy is the most important measure taken in the treatment of all forms

of tuberculosis and is therefore given to every person with the active disease.

Drug therapy has transform TB from a disabling and often fatal disease into one in

which almost 100% cure is obtainable. Chemotherapy was formerly protracted but

a better understanding of the pharmacology of TB drugs has allowed the

development of effective short course regimen.

PRINCIPLES OF ANTI-TB THERAPY

A large number of actively multiplying bacilli must be killed: Isoniazide

achieves this.


Treat persisters, i.e semidormant bacilli that metabolize slowly or

intermittently: Rifampicin and Pyrazinamide are the most efficacious.

Prevent the emergence of drug resistance by multiple therapies to

suppress drug-resistance mutants that exist in all large bacteria

populations.

Combined formulations are used to ensure that poor compliance

does not result in monotherapy with consequent drug resistance.

SPECIFIC ANTI-TB DRUGS

Many drugs are available, whose use is primarily limited to the treatment of

tuberculosi. ANTI-TB Drusg are classified into:

First line drugs: these include Isoniazid ( INH), Pyrazinamide (PZA), Rifampicin,

Streptomycin and Ethambutol

Second line drugs: these include Ethionamide, cycloserine, ofloxacin, etc.

ISONIAZID (INAH, INH, Isonicontinic Acid Hydrazide)

MOA: INH prevents the synthesis of mycolic acid, an important constituent of

mycobacterium cell wall. It is bacteriocidal against actively multiplying bacilli but it

is bacteriostatic against non-multiplying bacilli. It has little or no activity against

other bacteria.

Dose: In adult the usual adult dose is 5mg/kg

Indication: Treatment of TB in combination with other drugs.

Side effects: INH is generally well tolerated. The most sever side effect is liver

damage. INH causes an increase in metabolism and in urinary excretion of

pyridoxine (vitamin B6). The principal result of vitamin B6 deficiency is Peripheral

Neuropathy characterized by numbness and tingling of the feet, Neuropathy is

more frequent in a person that metabolizes INH slowly, malnourished people, the

elderly, those with pre-existing liver disease, Alcoholism, diabetes and HIV

infection. Such patients should receive pyridoxine (10mg- 50my) daily by mouth,


which prevent neuropathy and does not interact with therapeutic effect; some

prefer simply to give pyridoxine to all patients. Other side effects are

Mental disturbances, incoordination, nausea and vomiting

Patients advice

INH should be taken on an empty stomach. If taken with food to reduce GIT

irritation, oral absorption and bioavailability may be impaired.

RIFAMPICIN

Rifampicin has bactericidal activity against the tubercle bacillus, comparable that

of INH. Rifampicin is a semi-synthetic from the group of Rifamycine antibiotics.

MECHANISM OF ACTION:

Rifampicin act by inhibiting RNA synthesis, bacterial being sensitive to this effects

at much lower concentration than mammalian cells. It is particularly effective

against mycobacterium that lie semi dormant within cells.

INDICATION

Rifampicin has wide range of antimicrobial activity. Its uses include: Anti TB, Anti

leprosy, Chemoprophylaxis of meningicoccal meningities, Staphylococcal

endocarditis and osteomylitis.

Dose: 10mg/kg daily (usual adult dose = 600mg daily)

Side effect: severe GIT disturbances including nausea, vomiting a diarrhoea.

Headache, rashes, urine, tears, saliva and sputum colorued orange red. Hepatitis

sometimes reported in some selected individuals taking the drug.

Patients advice

Do not stop taking drug except on medical advice

This medicine may colour urine (or other body fluids) or stool.

Take half to one hour before food or on an empty stomach


Observe for signs of liver damage eg fever, loss of appetite, fatigue, jaundice,

dark urine, liver enlargement etc.

PYRAZINAMIDE (PZA) pyrazinoic acid Amide.

Pyrazinamide is the synthetic pyrazine analogue of nicotinamide. It is included in

the first choice combination regimen because of its particular ability to kill

“persisters”; i.e mycobacteria that are semi dormant , often within cells.

Indication

TB in combination with other drugs.

Mechanism of action

The action of Pyrazinamide is dependent on the activity of intrabacterial enzyme,

pyrazinamidase, which converts pyrazinamide to the active pyrazinoic Acid. This

enzyme is most effective in an acidic environment such as the interior of cells.

This explains why pyrazinamide is very effective in killing the semi-dormant

bacterial.

DOSE: 25mg/Kg

Side effects: The most common and serious unwanted effect of PZA is injury to

the liver with jaundice, and often preceded by nausea and vomiting. This is not a

problem again with the modern short course schedules. Hyperuricaemia with

acute episodes of gout may occur. The use of NSAIDs is sufficient to reduce

pains.

Patients instruction

Observe for signs of liver damage and report it to the health worker

Take drugs on an empty stomach.

ETHAMBUTOL


Ethambutol is a synthetic anti-TB drug. It is bacteriostatic therefore must be used

only in combination with other anti-TB drugs to delay or prevent the emergence of

resistance bacilli.

MOA: Its mode of action is unknown.

Indication: TB in combination with other drugs.

Dose: 15mg/Kg daily

Side effects

In recommended oral doses (15mg/Kg /day). Ethambutol is re3latively nontoxic.

The main problem is opitc neuritis (unilateral or bilateral) with a reduction I visual

acuity and loss of ability to perceiver the colour green. Regular ophthalmological

tests should be performed during ethambutol therapy.

Contraindication:

Optic neuritis, Children under 5 years, (these cannot report symptomatic visual

disturbances)and in Severe renal impairment

Patient’s advice.

Patient to observe visual disturbance and report immediately.

Other instructions as applied to other anti-TB

STREPTOMYCIN

Streptomycin is an aminoglycoside antibiotic obtained from streptomyces griseus.

Mode of action:

The aminoglycosides (streptomycin, gentamicine etc) are bactericidal. They act

inside the cell by inhibiting bacterial protein synthesis.

Aminoglycosides are water-soluble and do not readily cross cell membranes. Poor

absorption form the intestine necessitates their administration IV or IM for

systemic use.


Indications

Treatment of TB in combination with other drugs.

Dose: 15mg/Kg/day

Streptomycin is one of the very few drugs that is not only used against

mycobacterium but is also active against other bacteria.

Side effects

1 Ototoxicity due to damage on eight (8) cranial nerve which result in the

progressive destruction of vestibular and auditory cells. The effect is seen as

hearing loss , vertigo and tinnitus which may be permanent if not discontinued.

Neuromuscular blockade: streptomycin causes acute muscular paralysis and

apnea due to inhibition of prejuctional Acetylcholine release. The drug may

aggravate myasthenia gravis or cause a transient myasthenia syndrome in patient

whose neuromuscular transmission is normal. The most effective treatment of this

problem is administration of calcium salt e.g. calcium gluconate

THIOCETAZOLE

This drug is tuberculostatic and is used with Isoniczid (as in Diateben®) to inhibit

the emergence of resistance to the later .

Dose= 2.5 mg/Kg/day orally only.

Side effects.

Thiocetazone causes the following

Nausea, vomiting, diarrhoea, conjunctivitis, rashes, acute hepatic failure and may

increase the ototoxic effect of streptomycin.

Indications: TB and Leprosy.

ANTIFUNGAL DRUGS.

Fungal infections are generally divided into superficial infections affecting

skin, nails hair mucus membranes and systemic infections involving deeper


tissues and orgsna. The increasing use of broad spectrum antibiotics and

immunosuppressant ( e.g glucocorticoids) drugs is one of the reasons for the

increased incidence of fungal diseases. The patients with AIDS are potential

candidates for fungal infections.

Most of antifungal drugs act by inhibiting the synthesis of ergosterol, an

essential components of fungal cell remembrance or by binding to the wall of the

fungus, disrupting its integrity.

Topical antifungal.

Nystatin. An antibiotic is fungistatic at low concentrations and fungiscidal at

high concentrations. It is not absorbed appreciably from the gut, skn or mucus

membranes. It is not used parenterally.

Uses.

Nystatin is used in candida infections of the skin, mucuous membranes and

intestinal tract. Thrush ( oral candidiasis) and vaginitis are treated by topical

application, whereas intestinal candidiasis is treated by oral administration.

Side effects.

Occasional nausea, vomiting and diarrhea occur with high oral doss of nysatin.

Rash and rarely Stenvens-Johnson syndrome have reported.

Clotrimazole and Miconazole are most effective if applied locally as pessareis in

the treatment of vaginal canddiasis. They are also effective in ringworm and other

fungal skin infections.

SYSTEMIC ANTIFUNGALS.

These are antifungal agents internally for their antifungal effect. They produces

appreciable absorption from the gut and some may be administered parenterally.

Griseofulvin-, a fungistatic antibiotic, is effective for widespread or intractable

dematophyte (i.e skin) infections but has been superseded by newer antifungal

agent particularly for nail infections. It is ineffective in candidiasis.

Griseofulvin is well absorbed from the gut, has a particular affinity for

keratin and is eliminated unchanged in the feces. Because of its affinity for

keratin, it is useful in the treatment of ringworm infections of the kin, hair and nails.


Side effect.

Griseofulvin is usually well tolerated. GIT upset and rashes may occur. It is

contraindicate in severe liver disease and pregnancy.

TERBINAFINE is given orally and is the drug of choice for fungal nail and

ringworm infections. Side effect include GIT upset and rashes. Serious skin

reactions and rarely liver toxicity have also been reported

KETOCONAZOLE is largely used in severe candidiasis and other systemic fungal

infections. It is well absorbed and given orally. The most important side effect is

jaundice, when the drug must be stopped. Others include nauseas, drowsiness

and rarely adrenal suppression.

FLUCONAZOLE can be administered orally or by intravenous infusion.

Penetration of the drug into the CSF and other body fluid is very good. It is

effective in candidiasis and all other forms of fungi infections.

Side effects.

Fluconazole does not cause serious side effects, particularly liver damage. GIT

distress and rashes are mot common side effects.

CARDIOVASCUALR SYSTEM DRUGS.

Cardiovascular system comprises of the heart and blood vessels. The

cardiovascular system drugs are therefore drugs in the treatment of disease

conditions affecting the heart and or blood vessels. Some of these conditions

include. Hypertension, heart failure, angina pectoris, cardiac arrhythmias,

myocardial infarction etc.

ANTIHYPERTENSIVE DURGS

Hypertension is the persistence increase in blood pressure above acceptable

range measured over a long period of time.


There are two approaches aimed at the reduction of blood pressure.

a. Non- pharmacological therapy

b. Pharmacological therapy

NON-PHARMACOLOGICAL THERAPY OF HYPERTENSION

The non-pharmacological approach to the reduction of blood pressure is generally

advisable as the initial approach to treatment of patient with diastolic blood

pressure in the range of 90-95mmHg. Further, these approaches will augment the

effectiveness of pharmacological therapy in patients with higher levels of blood

pressure. All drugs have side effects. If minor alterations of normal activity or diets

can reduce blood pressure to a satisfactory level, the complications of drug

therapy can be avoided. In addition, non-pharmacological methods to lover blood

pressure allow the patient to participate actively in management o his or her

disease. Some of these non-pharmacological approaches to BP reduction include

1. REDUCTION OF BODY WEIGHT

Obesity and hypertension are closely associated and the degree of obesity is

positively correlated with the incidence of hypertension. Obese hypertensives may

lower their BP by loosing weight regardless of a change in salt consumption.

2. SODIUM RESTRCTION ( SALT RESTRICTION)

Sever restriction of salt will lower the blood pressure in most hospitalized

hypertensives patients; this treatment method was advocated prior to the

development of effective antihypertensive drugs. However, severe salt restriction

is not practical forma a standpoint of compliance. Several studies have shown that

moderate restriction of salt intake to approximately 5g per day (2g Na+) will on

average, lower blood pressure by 12mmHg systole and 6mmHg diastolic . The

higher the initial blood pressure, the greater the response. In addition, subject


over 40 years of age are more responsive to hypertensive effect of moderate

restriction of salt.

3. ALCOHOL RESTRICTION

Consumption of alcohol can raise blood pressure but it is unclear how much

alcohol must be consumed to observe this effect. Heavy consumption of alcohol

increases the risk of cerebrovascular accidents (stroke)

4. PHYSICAL EXCERCISE

Increase physical activity lowers rates of cardiovascular disease in men. Lack of

physical activity is associated with a higher incidence of hypertension.

5 RELAXATION THERAPY

The fact that long term stressful stimuli can cause sustained hypertension in

animals has given credence to the possibility that relaxation therapy will lower

blood pressure in some hypertensive patients. A few studies have generated

positive results but in general relaxation therapy has consistent and modest

effects on blood pressure.

6. REDUCTION OF FATTY FOODS. (HIGH CHOLESTEROL)

Cholesterol is a fat-like material carried by the blood to every cell in the body. It is

important in maintaining the integrity of the cell walls and forms part of some

hormones in the body. Our body makes all the cholesterol it requires. Problems

begin when the body makes extra cholesterol for the foods we eat especially fatty

foods. High cholesterol s a factor that increases your chance of getting heart

diseases. This is because, when there is too much cholesterol in the blood, some

of it may begin to stick to the wall of the blood vessels. Over time, the blood

vessels may clog and slow down the flow of blood or stop the flow entirely.

PHARMACOLOGY OF ANTI-HYPERTENSIVE AGENTS.

-Diuretics


-Beta

Generic name: Methyldopa

Trade names: Aldomet, Dopamed, Dopatab etc.

Methyldopa is a centrally acting antihypertensive agent. It is a prodrug that exerts

its antihypertensive action via an active metabolite. Methyldopa metabolises to

alpha-methyldopamine , which then is converted to alpha-methylepinephrine.

Mechanism of action

Alpha-methylnorephinephrine acts in the brain as alpha 2 receptor agonist to

inhibit or attenuate the output of vasoconstrictor adrenergic signals to the

peripheral sympathetic nervous system. Because the site of action is mainly in the

brain stem where it is metabolized to its active form, methyldopa is commonly

referred to as centrally acting antihypertensive agent.

Indications

1 It is an effective antihypertensive agent.

2. It is the preferred drug for treatment of hypertension during pregnancy bases

on its effectiveness and safety for both mother and foetus.

Dose. The usual initial dose of mehtyldopa is 250mg twice daily. Administration of

a single daily dose of methyldopa at bed time minimizes sedative effect, but

administration twice daily may be required for some patients.

Patient’s instructions.

Administer drug before food.

Dry mouth can be relieved with chewing gum or ice chips

Teach patient not to discontinue medication abruptly as this may cause headache,

raise BP, tremors nausea, vomiting

Change position slowly as this may cause postural (orthostatic hypotension)

Adverse effects


Transient sedation, Dry mouth, Reduction in libido ( this may be worrisome

in men, Hyperprolactinemia causing gynaecomastia and galactorrhea and

Haemolytic anaemia.

NB: the management of Hypertension by a community health worker must base

on the provision in the standing orders.

CONGESTIVE HEART FAILURE

In CHF, the contractibility of the cardiac muscle decrease and the heart is

not able to empty itself completely, resulting in a low cardiac output. The pressure

in the venous system, filling the heart rises and the neck veins become distended

and the hearth dilates. Low cardiac output leads to inadequate bloods supply to

various organs in the body. This is particularly important in the kidney as poor

renal blood flow activates the angiotensin/renin system, causing the kidney to

retain salt and water with resultant oedema of dependent parts and lungs.

Angiotensin causes vasoconstriction and increase in peripheral resistance with

increases the work of an already failing heart.

Drugs used in CHF mainly belong to three groups.

(a) Cardiac Glycosides. These drugs increase the force of myocardial

contraction thereby raising the cardiac output. This is called positive

inotropism (positive inotropic effect) i.e increase in the contraction of the

cardiac muscles. eg Digoxin and digitoxin which are the two principal

glycosides obtained from there dried leaves of the foxglove Digitalis

purpurea.

Side effects. Undue slowing of the heart. ( i.e decrease pulse rate),

nausea, vomiting, visual disturbances, headache etc.

(b) ACE Inhibitors. These drugs inhibit the overactive angiotensin/rennin

mechanism, thereby cause a reduction in the retention of salt and water

and more importantly by dilating arterioles lower the resistance to blood

flow from the heart . eg. Lisinopril, Captopril, enalapril.


Side effects. ACE inhibitors may cause dry cough, abdominal pain, renal

failure and abnormal foetal growth. ACE inhibitors are contraindicated in

pregnancy.

(c) Diuretics. These drugs causes the kidney to excrete excess salt and

water thereby relieve the oedema. E.g Furosemide, Hydrochlorthiazide

etc.

Side effects. These include biochemical disorder such as hypokalaemia,

hypomagnesaemia, hyperuricaemia, gout, hyperlipidaemia and

hyperglycaemia.

CNS DRUGS.

The Central Nervous System comprises of the brain and the spinal cord. The

CNS drugs are the drugs that produces their effect via the actions on the CNS.

Examples of CNS drugs include:

ANTIPSYCHOTIC DRUGS

Antipsychotics are the drugs that quiten disturbed patients with psychotic

disorders irrespective of psychopathology.

Psychosis can be divided into schizophrenia and affective disorders. Facets

of schizophrenia indicates that it is a complex set of entities rather than a single

disorder. In actual clinical settings, schizophrenia of the undifferentiated type is

most often seen. Schizophrenia syndrome share similar symptoms that can be

alleviated with the use of antipsychotic agents.

Schizophrenia has a profound effect on the total personal it, mod ,

behaviour and thinking. The symptoms include inappropriate behaviour,

delusions, hallucination, loose associations, social withdrawal, disorder of affect,

bizarre thinking, confusion, mental blocking, personal neglect and excitement.

ETIOLOGY

The etiology is unknown but the current understanding of schizophrenia

suggests that it has metabolic, genetic and psychosocial components. However;

it is currently believe that amines (Dopamine and norepinephrine in particular) are


involved in the schizophrenic process and that an imbalance between the two is

associated with the disease.

BASIC PHARMACOLOGY OF ANTIPSYCHOTIC DURGS

Several classes of drugs are effective in the symptomatic treatment of psychiatric

disorders. Antipsychotic drugs share many pharmacological effects and

therapeutic applications. They are classified into the following classes:

-Phenothiazines eg Chlorpromazine (largactil), Fluphenazine (Modecate) etc

-Butyrophenones eg. Haloperidol (Haldol, Serenace)

Thioxantines eg Flupenthixol (depixol) etc

Chlorpromazine (CPZ) is commonly taken as prototype for The older

antipsychotics.

CHLORPROMAZINE (CPZ, Largactil etc)

Chlorpromazine is a Phenothiazine antipsychotic agent. It brings about its action

by inhibiting (or blocking) dopamine receptors. It is therefore commonly referred to

as dompamine receptor antagonist. This is the mechanism by which all

antipsychotics produces their therapeutic effects.

INDICATION

CPZ is a representative antipsychotic agent used in the management of

schizophrenia and other psychotic disorders. It is also used as an antiemetic and

intractable hiccup.

SIDE EFFECTS

CPZ causes extrapyramidal symptoms, and on prolonged administration,

occasionally tardive dyskinesia occurs. Components of extrapyramidal symptoms

include

Acute dystonia = spasms of muscles of tongue, face, neck and back.

Akathisia = motor restlessness. It is a strong felling of distress or discomfort.

Parkinsonism = slowing of movement, rigidity and tremor at rest especially the

upper extremities.


Tardive dyskinesia- this is a late appearing neurological syndrome characterized

by painless, involuntary movement of the face, eyelids (blinks and spasms) mouth

(grimaces), tongue, extremities (especially the upper extremities). These

movements all disappear in sleep

Other side effects include: Nightmares, depression convulsions, nasal

congestions, dry mouth, blurred vision

Dosage forms available: tablets, oral solutions, injectables, suppositories, syrup

and suspensions.

NB: Owing to the risk of contact sensitization, Health workers should avoid direct

contact with CPZ. Tablets should not be crushed and solutions should be handled

with care.

HYPNOTICS AND SEDATIVES

A sedative drug decreases activity, moderate excitement and calms the

recipient while a Hypnotic drug produces drowsiness and facilitate the onset and

maintenance of a state of sleep that resembles natural sleep form which that

recipient (i.e the patient ) can be aroused easily.

Hypnotics-Sedatives depresses the CNS in a dose dependent fashion i.e a

drug may be a sedative at small dose; at higher doses; the drug may produce

hypnosis in e same individual. The commonly use sedative hypnotics are

Benzodiazepines and

Barbiturates.

BENZODIAZEPINES

Examples of benzodiazepine include Diazepam (valium), chlordiazepoxide

(Librium) , Bromazepam ( Lexotan) etc.

PHARMACOLOGY OF BENZODIAZEPINES

All effects of Benzodiazepines result from their activity on the CNS. The

most prominent of these effects are:


Sedation, Hypnosis, Decreased anxiety, Muscle relaxation and

Anticonvulsants activities

All Benzodiazepines share similar pharmacological profile as their doses

increases, sedation increases to hypnosis. They do not cause true anesthesia,

since awareness usually persists and relaxation sufficient to allow surgery cannot

be achieved.

MECHANISM OF ACTION

Benzodiazepines act directly on Gama Aminobutyric Acid (GABA) receptors. They

directly activate GABA receptors which leads to proofed CNS depression. GABA

is an inhibitory neurotransmitter in the CNS.

INDICATIONS

Diazepam (valium) is used in

Anxiety disorders, Status epilepticus, Skeletal muscle relaxant

Anesthetic premeditation (to improve muscle relaxation and alley fear of surgical

procedures) and Management of alcohol withdrawal.

Side effects

Benzodiazepines share many common side effects and these include:

Light headaches, Motor incoordination, Confusion, Weakness, Blurred vision,

Nausea and vomiting, Rebound insomnia upon discontinuance.

BARBITUREATES

Examples of barbiturates include Phenobarbitone, Thiopental etc.

The barbiturates enjoy a long period of extensive use as sedative –hypnotic

drugs; however; except for a few specialized uses, they have been largely

replaced by the much safer benzodiazepines.


MECHANISM OF ACTION

The barbiturates reversibly depresses the activity of all excitable tissues.

Enhancement of inhibition occurs primarily at synapses where neurotrasmission is

mediated by GABA. Barbiturates also inhibits glutamate induced action potentials.

Glutamic acid is an excitatory neurotransmitter in the CNS.

INDICATIONS

The uses of barbiturates has reduced drastically due to their low therapeutic

index. They are commonly use as

Sedative in insomnia

Anticonvulsants such that occurs in Tetanus, Eclampsia, Status epilepticus,

Cerebral hemorrhage and Poisoning with convulsant drugs.

Anesthetic agents. (intravenous)

Benzodiazepines are however superior for these uses due to their high

therapeutic index and low incidences of drug interactions.

Side effect

Drowsiness, Distortion of mood, Impaired judgment, Vertigo

Nausea and vomiting.

Drug interaction

Barbiturates taken concomitantly with alcohol causes severe CNS depression.

Barbiturates inhibit the metabolism of other drugs eg vitamin D and K.

NB:

The Benzodiazepines and Barbiturates have been termed “minor tranquilizers”. This term is misleading because not only do they differ markedly from psychotic drugs ( the so called “major tranquillizers”) but their use is by no means minor. Antipsychotic in low doses are also sometimes used in severe anxiety for their sedative action but long term use is discouraged in view of a risk of Tardive dyskinesia.


ANALGESICS

REVIEW OF PAIN MANAGEMENT

Pain is the activation of electrical activity in afferent neurons with sensory endings

in puerperal tissues that have a higher firing threshold than those of temperature

or touch. These neurons are activated by stimulation sufficient to cause tissue

damage. Pain is primarily a protective signal to warn of damage or the presence

of disease. It is also part of the normal healing process. This process involves

inflammation, in which protective cells move into the injured area and release

chemical mediators that causes fluids and plasma proteins to leak into the

surrounding tissue. The result is repair and healing, but also stimulation of pain

nerve endings.

Pain is classified as acute, chronic nonmalignant chronic malignant.

Acute. This type of pain is associated with trauma or surgery. Acute pain is

usually easier to manage by identifying and treating the cause, and it

disappears when the body heals.

Chronic Nonmalignant. This type of pain may have a diagnosed or an

undiagnosed cause, such as a nonmalignant disease. The pain last for

more than three months and may respond poorly to treatment. Chronic

nonmalignant pain may have signs and symptoms of depression in patients


with a high tolerance of pain. The neurotransmitters involved in pain

transmission are the same as those involved with depression

(norepinephrine, dopamine, and serotonin). In this syndrome, pain lasts

longer than three months, may or may not have an identifiable physical or

chemical basis, creates an overwhelming lifestyle burden for the patient,

and does not respond to medication.

Chronic malignant. This type of pain accompanies malignant disease ( eg.

Cancer pain) and often increases in severity as the disease progresses.

Acute and chronic pain differs in one important way. Whereas acute pan

has a beginning and an end and warns of a problem, chronic pain does not

cease when an illness or injury is cured or healed.

Total pain has physical, psychological, social and spiritual components.

Adequate sleep, mood elevation, diversion, sympathy, and understanding all

can raise an individual’s pain threshold. Alternatively, fatigue, anxiety, fear,

anger, sadness, depression, and isolation can lower the pain threshold.

Analgesics.

Analgesics are drugs that relieve pain without loss of consciousness. They are

usually classified into narcotics and non-narcotics analgesics. The narcotics

analgesics are also called opioid analgesic a name coined after the opium poppy,

papaver somniferum from which they are derived. Conversely, the non-narcotics

are also called non-opiates.

OPIATES ANALGESICS

These drugs act on pain perception within the central nervous system. At

the PHC level, the naturally occurring opiate in the standing order is Codeine

phosphate. Other examples relating to codeine are morphine, Heroine and

cocaine. A synthetic opiate in the standing order is pethidine. Other examples

relating to pethidine include Pentazocine (sosegon, Fortwin) Tramadol (Tramal)

Opiates work because they are agonists of opioid receptors sites having

their main effects on the CNS, GI tract, and, to a lesser extent, peripheral tissues.

The body (especially the brain) products three distinct types of natural opiods-


endorphins, enkephalins, and dynorphins – in response to pain stimuli. As pain

increases, the levels of these chemicals also increase. When opioid receptors

are activated, nerve transmission to CNS centres for pain processing is

decreased, so the sensation of pan is diminished. Narcotics bind to the same

receptors as these natural substances, causing activation ( agonist effect).

Narcotics have the following effect.

Analgesia i.e they reduce pain

Sedation i.e they allay anxiety and cause drowsiness.

Euphoria and dysphoria i.e they induce feelings of well-being or feelings of

disquiet, restlessness, or malaise, respectively. All narcotics have the potential to

induce tolerance and dependence.

Narcotics also reduce the cough reflex and respiratory drive; increase mental

clouding; and can cause nausea, vomiting, and constipation.

Persistent pain should be treated in a stepwise fashion: first

acetaminophen, then Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and then

the opiods. A simple scheme for analgesic selection is known as the analgesic

ladder, which is illustrated below.

The WHO analgesic ladder for pain relief.

Pain persisting or increasing

Pain persisting or increasing.

Pain

Pharmacology of Narcotic analgesic


e.g morphine, oxycodone, fentanyl Adjuvant.

e.g Codeine, Pentazocin.

e.g aspirin, acetaminophen or an NSAID

Non-opioidAdjuvant

Opioid for moderate to sever pain Non-opiod, Adjuvant

Opioid for moderate to sever pain Non-Opioid, Adjuvant

Opioid (or narcotic) analgesic provide relieve of pain, but the underlying disease

remains. The health worker should weigh the benefit of the relief against any

potential risk to the patient, which may be quite different in an acute compared

with a chronic disease.

CODEINE

Codeine is an opioid analgesic. Its use has been restricted as a prescription only

drug due to its highly addictive property. When taken codeine is converted to

morphine in the body . it is available both as oral and parenteral formulation

respectively.

Indications

Codeine is indicated in mild to moderate pain.

It is also used as an antitussive (cough suppressant) examples of cough

preparations containing codeine include Benylin and Phensydyl linctus.

Side effect

Severe constipation, Nausea and vomiting, Drowsiness and urinary retention.

MEPERIDINE

(PETHIDINE, Demerol)

meperidine produces a pattern of effect similar but not identical to tat described

for codeine. Meperidine is a synthetic opioid. It is less potent and short acting

analgesic. It has no effect on cough centers. It is less depressant to respiratory

center and does not cause constipation.

Indication

Meperidine is indicated in moderate to sever pain. It is not suitable for severe

continuing pain. It is used for analgesic in Labour and in neonate is associated

with less respiratory depression, (probably because its action is weaker). Other

uses of opioids are: Treatment of diarrhoeas and Anaesthesia


NON-OPIOIDS ANALGESICS

These include paracetamol, and other general class known as Non-Steroidal Anti-

inflammatory Drugs (NSAIDs). NSAIDs are very useful in the control of painful

inflammatory conditions in general

NSAIDs: Pharmacological properties.

These drugs, besides analgesia, have

Antipyretic property and Anti-inflammatory property.

They do not affect temperature when it is elevated by factors like exercise and

ambient temperature. The prototype of NSAIDs is Acetylsalicylic Acid (ASA,

Aspirin)

Mechanism of actions.

All NSAIDs acts by inhibiting the enzyme cyclo-ogygenase thereby preventing the

conversion of arachidonic acid to prostaglandins as shown in the schematic pain

pathway below.

Pain pathway in tissue injury

Tissue injury

Arachidonic acid

(-) NSAIDs

Cyclo-oxygenase

Inflammation.

* Oedema Prostaglandins

* Pain

* Fever

ASPRIN


This is the oldest and cheapest NSAID typically taken as the prototype. Its

pharmacological action include:

Antipyretic action.

Aspirin is rapidly effective in febrile patients. It has no effect on normal body

temperature. The antipyretic effect is believed to be due to inhibition of

prostaglandin synthesis.

Anti-inflammatory action.

The anti-inflammatory activity is responsible for the use of aspirin in

musculoskeletal disorders such as rheumatoid arthritis.

Analgesic action

Aspirin is effective against pain of low intensity through peripheral and central

mechanism. It inhibits the synthesis of prostagaladins peripherally in inflamed

tissues and centrally in close proximity to the antipyretic region in the

hypothalamus.

Respiration

Aspirin stimulates respiration directly and indirectly. High doses results in

medullary stimulation leading to hyperventilation and respiratory alkalosis. Toxic

doses can depress the medulla resulting in metabolic acidosis.

Gastrointestinal tract

Aspirin can cause dyspepsia, nausea and vomiting by irritating the gastric mucosa

and stimulating chemoreceptor Triger Zone (CTZ) in the central nervous system

(CNS). It may lead to a dose dependent gastric ulcer and bleeding .

Liver


Hepatotoxicity associated with encephalopathy (Reye’s syndrome) can occur in

children. Therefore, it is contraindicated in children below 12 years of age.

Blood

Aspirin , by inhibiting cyclo-oxygenase irreversibly inhibits thromboxane ( the

prostaglandin produced by platelets) which is responsible for platelet

aggregation . The net result is inhibition of platelet “stickiness”.

Therapeutic uses

Analgesia. ASA in low doses ( 300-600mg) is effective in conditions such as

headache, musculoskeletal pain, dysmenorrheoea etc.

Anti-inflammatory agent: High doses (3.6-4.2g a day) are required to achieve a

clinical anti-inflammatory effect in rheumatoid arthritis and acute rheumatic fever.

However; other NSAIDS may be better tolerated and preferred over ASA for

inflammatory conditions. Eg Diclofenac, Ibuprofen etc

Antiplatelet: Aspirin in low doses (75-100mg daily) inhibits platelet aggregation

and has important therapeutic benefit in angina pectoris, myocardial infarction,

and heart failure.

Side effect

In large doses when given over a prolonged period, aspiring causes dyspepsis,

( nausea, vomiting and epigastric pains) dizziness, tinnitus (ringing in the ear) and

deafness. Hepatotoxicity and hypersensitity may also occur.

Aspirin is contraindicated for fever myalgia and malaise in children aged

under 12 years as it may precipitate hepatotoxicity associated with

encephalopathy (Reye’s syndrome)

Other NSAIDs

Examples of other non-sterioidal anti-inflammatory drugs include:

Ibuprofen ( Brustane-N), Diclofenac (cataflam, voltaren etc,) Piroxicam (Feldene),

Tenoxicam, Celecoxib (celebrex) etc.


PARACETAMOL

Paracetamol is a widely used minor analgesic and antipyretic. It has

practically no anti-inflammatory action. It is believed to act as analgesic by raising

the threshold to pain perception in the CNS.

Unlike Aspirin, paracetamol has no effect on other body systems. It is less

irritant to stomach and for this reason, it is generally preferred to aspirin as an

analgesic for many type of pains.

Paracetamol is the drug of choice for mild pain and fever in children as it

does not cause Reye’s syndrome seen with aspirin.

RESPIRATORY SYSTEM DRUGS.

The pulmonary disease include asthma, chronic obstructive pulmonary disease

(COPD). COPD is irreversible. Asthma, a reversible syndrome, obstructs

inspiration, whereas Emphesema, and chronic bronchitis obstruct expiration.

Related diseases, also obstructive include pneumonia, respiratory distress

syndrome, tuberculosis, and histoplamosis. In addition, the lungs are frequently

attacked by less severe upper respiratory tract infections including the common

cold.

DRUGS USED IN THE MANAGEMENT OF ASTHMA

Asthma is a chronic disease characterized by inflammation of the airways and

reversible bronchoconstriction resulting in wheezing, coughing, shortness of

breath, and exercise intolerance. The prevalence of asthma is increasing,

particularly in young people.

PATHOPHYSIOLOGY


In 1997, the National Heart, Lung, and Blood institute release an updated set of

guidelines for the diagnosis and management of asthma. In their treatment

guidelines, asthma is described as a chronic inflammatory disorder in which mast

cells, eosinophils, T-lymphocytes, and other cellular elements contribute to

ongoing inflammation. These inflammatory cells secrete mediators that affect

airway function either directly or thorough neural mechanisms.

Inflammatory mediators can cause airway injury through increased smooth

muscle responsiveness, mucus hypersecretion, altered vascular permeability,

aberrations in control of autonomic neurons, and alterations in mucociliary

function. Theses mediators also cause proliferation of epithelia cells and

myofibroblasts that deposit collagen beneath basement membrane. This can

cause subendothelial thickening, leading to possibly irreversible airway changes.

Asthma is also associated with an exaggerated bronchoconstrictor response to

various stimuli, which is mediated through the beta2 receptors on the airway. This

hyperresponsiveness is correlated with airway inflammation which ma be

controlled with anti-inflammatory therapy but not completely eradicated by it.

Changes in the airway associated with the activation of inflammatory mediators

include acute bronchoconstriction, airway edema, and chronic mucus plug

formation, and airway “remodeling” (i.e irreversible thickening of the basement

membrane). These changes lead to bronchial obstruction, resulting in limited

airflow. Thus, inflammation contributes to airway hperresponsiveness, respiratory

symptoms, limited airflow, and a chronic disease process.

DIAGNOSIS

To make a diagnosis of asthma, a physical examination is performed as well as

an evaluation of patient’s medical and family history. Findings may include a

history of cough, recurrent wheezing, difficulty breathing, tightness of the chest,

and exercise intolerance. Symptoms often worsen at night. Patients often

complain of sleep disturbance with asthma symptoms, and frequently wake in the


morning with a feeling of chest tightness or wheezing worsening of symptoms

usually occurs in the presence of viral infection, dust mites, animal dander,

feathers, mold, smoke, pollen, chemicals or dust in the air, or during weather

changes, exercise, menstrual cycles or stressful emotions. While all of these

factors support the diagnosis of asthma, pulmonary function testing (Spirometry)

is also required to demonstrate reversibility of airway obstruction.

CLASSIFICATION OF ASTHMA

Asthma severity is classified into one of the following four categories:

Mild intermittent

Symptoms occur less or up to two times per week

Exacerbations are brief, ranging from a from hours to a few days.

Nighttime symptoms occur less than two times perk month

Mild Persistent

Symptoms occur more than two times per week

Exacerbations can affect patient’s activity.

Nighttime symptoms occur more than two times perk month

Moderate Persistent

Symptoms occur daily

Exacerbations affects patient’s activity.

Nighttime symptoms more than one time a week

Severe Persistent

Symptoms are continuous

Physical activity is constricted

Exacerbations occurs frequently

Nighttime symptoms occur frequently

Management

The principal goals of asthma management are:


To prevent the occurrence of symptoms that are chronic or troublesome ( such as

coughing or breathlessness after exercise) in the night or in the morning.

To maintain near normal pulmonary function;

To sustain normal levels of physical activity, including exercise;

To prevent the recurrence of asthma exacerbations;

To provide optimal pharmactherapy with minimal adverse effects

To provide asthma care that meets the needs and expectations and their families.

Care of these patients by health workers well versed in the underlying

pathophysiology of asthma as well as current available comprehensive

pharmacotherapeutic agents can achieve these goals.

Asthma therapies are sometimes divided into two categories

A: Short-term relievers and

B: Long-term controllers.

SHORT-TERM RELIEVERS

Short-term relief is most effectively achieved with broncodilators, agents that

increase airway caliber by relaxing airway smooth muscle and of these the beta2

adrenoceptor stimulants (eg Salbutamol) are the most widely used. Theophylline,

a methylxanthine drug is also used for reversal of airway constriction.

LONG-TERM CONTROLLERS

The long-term control is moat often achieved with anti-inflammatory agents such

as corticosteriod (eg methylprednesolone etc). The distinction between “short-

term relievers” and long-term controllers” has become blurred.

Salbutamol (Ventolin)

This is a beta2 adrenoceptor agonist these group of drugs have several

pharmacological actions that are important in the treatment of asthma – i.e they

relax airway smooth muscle and inhibit release of some bronchoconstricting


substances from mast cells. The beta2 adrenoceptor agonist drugs are the most

widely used sympatomimetcis for the management of asthma at the present time.

Indications

Salbutamol is indicated in Asthma and other conditions associated with reversible

airway obstructions. Uncomplicated premature labour because stimulation of

uterine smooth muscles via beta2 results to uterine relaxation.

Mechanism of action

Salbutamol acts by stimulating beta2 (2) in bronchial airway smooth muscle

resulting to the dilation of the airways.

Side effects.

Salbutamol causes fine tremors (usually hands), headache, palpitations, slight

pain on intramuscular injection, hypokalaemia after high doses.

Dose: adult by moth 4mg (elderly and sensitive patients initially 2mg) 6-8 hourly.

Maximum single dose 8mg (but unlikely to provide much extra benefit).

Children

Under 2 years 100mcg/kg 6 hourly

2-6 years 1-2mg 6 hourly

6-12 years 2mg 6 hourly

By parenteral route

250-500mcg PRN

By aerosol inhalations

1-2 puffs 6-8 hourly.

An important method of administering asthama medications is by a metered dose

inhaler ( MDI). The following are the steps involved in using an MDI


1. Remove cap and shake inhaler

2. Breathe out all the way

3. Place mouthpiece between lips

4. press down on inhaler, hold for a few seconds, then breathe in slowly

5. Hold breath and count to 10

6. Breathe out slowly.

Always clean the mouthpiece after each use and rinse the mouth if a

corticosteroid is used.

METHYLXANTHINE DRUGS

The three important methylxanthines are theophylline, theobromine and caffeine.

Their major source is of course beverages (tea, coca and coffee respectively). Of

the xanthines, theophyline is most effective bronchodilator and it has been shown

repeatedly both to relieve airflow obstruction in acute asthma and to reduce

severity of symptoms in chronic asthma.

Mechanism of action

The methylxanthine inhibits the enzyme phosphodiesterase. Since

phosphodiesterase hydrolyzes cyclic Adenosine Monophosphate (cAMP) this

inhibition results in higher concentrations of intracellular cAMP. cAMP is a potent

smooth muscle relaxant. Theophylline also has an anti-inflammatory property,

which makes it very popular in the management of asthma.

AMINOPHYLLINE

This is a stable mixture or combination of theophylline and ethylenediamine,

which is 20 times more soluble than theophylline alone. The ethylenediamine

confers greater solubility in water. Aminophylline must be given by very slow

intravenous injection over 20 minutes; It is too irritant for intramuscular use.

Dose: 100-300mg 6-8hourly after food. Children 1mg/kg.


Mechanism of action

Bronchodilator- via inhibition of phosphodiesterase enzyme resulting to relaxation

of airway smooth muscle.

Side effects

Methylxanthies causes insomnia, tachycardia, palpitations, nausea,

gastrointestinal disturbances, headache, arrthymias and convulsions especially if

given too rapidly by intravenous injections.

NB: in acute over dosage, the side effect could be life threatening and treatment

include emptying the stomach (gastric larvage) if the patient is presented within

two hours followed by administration of activated charcoal (a universal antidote). It

is not recommended by exacerbations.

Combination therapies

1. Generic name: Aminophylline/Salbutamol

Trade name: Franol

Route of administration: oral

2. Generic name: Sameterol/Fluticasone

Trade name Advir

Route of administration: inhalation

Chronic Obstructive Pulmonary Disease ( COPD)

COPD encompasses emphysema and chronic bronchitis.

Emphysema

Emphysema is characterized by destruction of the tiny alveoli, or air sacs, of the

lungs. As a result, air accumulates in the tissues and organs. Typically, air

spaces distal ( farther away from) the terminal bronchioles are enlarged.

Inflammation destroys these air sacs, which ten lose their ability to expand and

contact and their ability to pass oxygen into the blood and remove carbon dioxide.

In the early stages, shortness of breath occurs only after heavy exercise. As the

disease progresses, walking even a short distance can make the patient gasp for

air. Patients with emphysema have tachypnea ( very rapid respiration), which


gives them a flushed appearance. Major risk factors are cigarette smoking

( which destroys the wall of the lungs), occupational exposure ( as in cement

factory) air pollution, and genetic factors.

Bronchitis

Bronchitis is a condition which the lining of the bronchial airways becomes

inflamed, causing the patient to experience obstruction of air flow on expiration.

This disease is characterized by a cough that produces sputum that may be

purulent (containing pus) , green, or blood streak. Acute bronchitis is caused by

an infection especially viral and is corrected by the use of antibiotics to prevent

secondary bacterial infection. Several factors can contribute to the development

of chronic bronchitis. The most prominent of these include cigarette smoke;

exposure to occupational dusts, fumes, and environmental pollution; and bacterial

infection.

Drugs Treatment of COPD

To understand the treatment for emphysema and chronic bronchitis, you must

also understand the lungs natural defense system. when this system is

functioning properly, the host defense of the respiratory tract provide good

protection against pathogen invasion and remove potentially infectious agents

from the lungs. The lungs are normally sterile below the first bench. It is when

organisms breach this region that infection and inflammation are initiated. The

body’s defense includes a number of cells.

The ciliary carpet consists of minute hairlike process, called cilia, that beat

rhythmically to propel fluid or mucus, and any inhaled particles that have

become trapped in the fluid, over the inner surface of the airway; upward

and out.

Goblet cells secrete mucus.

Clara cells, unciliated cells at the branching of the alveolar duct into the

bronchioles, secrete enzymes that break down airborne toxins.

Epithelia cells produce a protein-rich exudates in the small bronchi and

bronchioles.


Type I pneumocytes in the alverolar membranes act as the phagocytes of

the lungs. They clear trash and organisms from the lungs,.

Type II pneumocytes synthesize and secrete surfactant.

Emphysema and chronic bronchitis sometimes occur together, and their

pharmacologic treatment is similar. The pharmacologic management of

emphysema and bronchitis is still largely empirical, with methylxanthines,

corticosteriods, beta agonists and ipratropium forming the foundation of

therapy as in Asthma. In both emphysema and chronic bronchitis, antibiotic

therapy is sometimes needed if either sputum changes from yellow to green or

fever is present. Expectorants and mucolytics are sometimes used to

stimulate respiratory secretion and counter dryness which stimulates irritation

and coughing. Drinking large amounts of water helps to break up mucus hand

enables the patient to cough up secretions;

DRUGS FOR GIT DISEASES.

The gastrointestinal (GI) tract is a continuous tube that begins in the mouth,

extends through the pharynx, esophagus, stomach, small intestine, and large

intestine, and ends a the anus.

A wide variety of diseases can affect the gi tract. Although

gastroesophageal reflux disease (GERD, or heartburn) and the various conditions

known collectively as peptic diseases may be the most common, several other

diseases, including gastritis and inflammatory bowl disease, are also important.

GERD

This is a common problem. Symptoms include radiating burning or pain in the

chest and an acid taste. GERD patients also have recurrent abdominal pain,

which may move about n the epigastric area. They may have nonspecific

epigastric discomfort that is worse before measles and may awaken the patient

form sleep.

The primary mechanism responsible for meal related symptoms of

esophagitis ( irritation of the esophagus) is the reflux ( backflow) of acidic stomach


contents through an incompetent lower esophageal sphincter. This sphincter is

normally in a state of relative contraction. During swallowing, it relaxed enough to

allow the forward passage of food and drink into the stomach. Then it contracts

again preventing the reflux of the stomach contents. Heartburn occur when the

spinster becomes incompetent ( unable to keep itself sufficiently contracted).

Even with competent sphincter, the likelihood of reflux increases during

pregnancy as the uterus exerts upward pressure on abdominal organs, including

the stomach; the gastric contents a are pushed toward the lower esophageal

sphincter and up into the esophagus. Factors that may contribute to the

malfunctioning of the lower esophageal sphincter include overeating, eating on

the run, eating late at night, drinking alcohol, smoking cigarettes, and consuming \

various foods.

Pharmacologic Treatment of GERD

The treatment of GERD is categorized as phase I and phase II treatments. Phase

I include lifestyle modifications and or use of an antacid. Antacids neutralize the

acidic stomach contents so that if reflux does occur, the content will be less

irritating to the esophageal lining.

Phase II treatment employ medications to try to improve gastric motility and

decrease acid production in the stomach. Examples of phase II drugs include

Proton

Antacids. Antacid therapy has several shortcomings, including the need for

frequency of dosing and patient compliance. For patients with an active bleeding,

antacid must be given every hour between meals for 6 to 8 weeks. Eg

Magnesium hydroxide ( Phillips milk of Magnesia), Aluminum hydroxide

H2 Receptor Antagonist.

Gastric acid secretion and pepsin secretion occur in response to histamine ,

gastrin, foods, distention, or caffeine stimulation. When these processes result

from histamine, they can be blocked by an H2 histamine receptor antagonist. The

mechanism of action is competitive inhibition of histamine at H2 receptor on the

stomach gastric secreting cells which inhibits gastric acid secretion. E.g


Cimetidine ( Tagament etc) , Ranitidine ( Zantac etc) , Famotidine (Famodar,

pepcid etc).

Side effects:

H2 Receptor Antagonists may cause diarrhea, dizziness, rahs tiredness.

Gynacomastia (breast enlargement), reduced libido in men. occasional reversible

liver damage and confusion has been reported.

Proton pump Inhibitors.

Acidity in gastric secretion is maintained by an enzyme known as the parietal cell

H K-ATPase pump . this term indicates that this enzyme pumps acidic hydrogen

ions ( H+) or protons, into the stomach; pumps nonacidic potassium (K+) ions out;

and uses up energy ( ATP) to do so a proton pump inhibitor a drug that blocks

this enzyme reduces stomach acidity. They must be taken on daily basis and not

when needed. Eg. Omeprazole ( Meprasil), Lansoprazole ( Lansogard),

Rabepraxole, Pantoprazole etc.

Side effects:

Generally, proton pump inhibitors are very safe. In high doses, the common side

effect reported include diarrhea, nausea, abdominal pain, headache and skin

rashes

Peptic Disease.

The term is used to refere to a broad spectrum of disorders of the upper GI

tract caused by the action of acid and pepsin, a stomach enzyme that assist in

degrading food proteins.

An ulcer is a local defect or excavation of the surface of an organ or tissue.

A peptic ulcer is an ulcer formed along any part of the GIT tract exposed to acid

and the enzyme pepsin. There are three common types of peptic ulcers: gastric,

duodenal and stress ulcers. Many factors, including bacterial infections and sever

physiological stress, can contribute to the development of ulcers. Medications

can also cause ulcers.


Gastric Ulcers.

. A gastric ulcer is a local excavation in the gastric mucosa. These lesions have

malignant potential, occur more often n men than women, and become more

frequently with aging. They are prevalent in smokers. A contributing factor for

may patients is the bacterium Helicobacter pylori.

Duodenal Ulcers.

A duodenal ulcer is a peptic lesion situated in the duodenum. Duodenal ulcers

occur more in hypersecretors and are more difficult to treat than gas tic ulcers

because of the difficulty of getting medication into the duodenum.

Stress Ulcers.

A stress ulcer is a peptic ulcer, usually gastric, that occur in the clinical setting in

patients who are under severe physiological stress form serious illness, such as

sepsis, burns, major surgery, chronic disease or chronic infection.

Drug induced Ulcers. Several drugs can cause ulcers eg. NSAIDs

Pharmacologic Treatment of H. Pylori

Research has shown that Helicobacter pylori is responsible is responsible for the

majority of peptic ulcers. It also plays a role in chronic active gastritis and gastric

cancer. Therefore, treatment regiments aim at eradication of the bacterium. The

main\stay of therapy for ulcers include antacids, H2 receptor antagonists, and

proton pump inhibitors. Once a positive diagnosis has been made, H. pylori is

eradicated using the following triple eradication regiment on the basis of efficacy

and simplicity

Antibiotics + H2 receptor antagonist + Pronto pump inhibitors for I week.

The decision on choosing an eradication regiment for a particular patient should

take into account local resistance to antibacterial , cost and availability of the

necessary drugs. Egs of a triple therapy of H. pyroli eradication are:


Omeprazole 40mg od

Metronidazole 400mg tid x

Amoxicillin 500mg tid

Or

Omeprazole 20mg bd

Clarithromycin 500mg bd x

Amoxicillin 1g bd

The most commonly used agents for H. pylori are

Antibiotics: Amoxicillin, Clarithromycin, , Metronidazole and Tetracycline

H2 receptor antagonists: Cimetidine, Ranitidine

Pronton pump inhibitors : Omeprazole, Ransoprazole, Labeprazole

ENDOCRINE SYSEM DRUGS.

The endocrine system consists of glands and other structures that

elaborate, or produce secretions called hormones and release them directly into

the circulatory system. The various hormones are responsible for the specific


regulatory effects on organs and other tissues of the body. Through the work of

hormones, the endocrine system maintains homeostasis of the body by regulating

the physiologic functions involved in normal daily living and in stress.

Diabetes Mellitus.

Diabetes Mellitus is not one disease but rather is a heterogenous group of

syndrome characterized by an elevation of fasting blood glucose caused by a

relative or absolute deficiency in insulin. If left untreated, diabetes can cause a

range of serious conditions and eventually death.

The pancreas contains specialized cells, called the islets of Langerhans

that produce insulin. Insulin helps cell burn glucose for energy, combines with

membrane receptors to allow glucose uptake, enhances transport and

incorporation of amino acids into protein, increase ion transport into tissues, and

inhibits fats breakdown. Thus, insulin is critical in maintaining blood glucose

levels, as well as having other metabolic roles.

In persons with diabetes, either the secretion or the utilization of insulin is

inadequate, which leads to excessive blood glucose levels. The normal glucose

level is around 100mg/dL. At elevated levels the kidneys will not be able to

reabsorb the excess, and glucose will spill into the urine. Level consistently

above 140 -160mg/dL are associated with long term effect of diabetes. An

elevated blood sugar level is known as hyperglycemia.

Diabetes is a devastating disorder that can damage all major organ

systems. Over time, diabetes can destroy eyesight, kidneys, and peripheral

circulation.

Types of Diabetes.

Diabetes mellitus can be separated into two groups Insulin-Dependent

Diabetes Mellitus (IDDM) and Non-insulin-Dependent Diabetes mellitus ( NIDDM)

based on their requirement for insulin.

Type I Diabetes (Insulin Dependent Diabetes Mellitus)


Type I diabetes occurs most commonly in children and young adults, but it

may occur at any age. The average age of diagnosis is 11-12 years. These

patients are insulin dependent; that is they have no ability to produce insulin. This

group comprises 5-10% of diabetic population. Individuals with IDDM require

insulin t avoid life-threatening ketoacidosis.

Many patients show a “honeymoon” period following initial treatment when

the symptoms transiently disappear and little or no insulin is required. This

remission results from a temporary return of insulin secretion which may last for

weeks or moths.

The metabolic changes in IDDM are mainly hyperglycemia and

ketoacidosis is left untreated. Hyperglycaemia is caused by increased hepatic

production of glucose combined with diminished peripheral utilization. Ketosis

results from increased mobilization of fatty acids form adipose tissues combined

with accelerated hepatic synthesis of ketone bodies viz: 3-hydroxybutyrate,

acetoacetate and acetone from ketogenic amino acids eg. Leucine and Lysine

Diagnosis of IDDM

Patients with IDDM can usually be recognized by the abrupt appearance of

polyuria ( frequent urinating), polydipsia ( excessive thirst) and polyphagia

( excessive hunger) often triggered by stress or an illness. The symptoms are

usually accompanied by fatigue, weight loss, and weakness. The diagnosis is

confirmed by a fasting blood glucose greater then 140mg/Dl (7.8mmol/L)

commonly accompanied by ketoacidosis which can be life-threatening.

Type II Diabetes (Insulin Non-Dependent Diabetes Mellitus)

Type II comprises 80-90% of diabetic cases. Most patients are over 40

years of age, with the majority being female. Patients with type II diabetes may

have relative insulin insufficiency (impaired insulin secretion); however, insulin

receptor resistance on cells may be the primary culprit. The peripheral target

tissues are resistant to insulin produced. Glucose is not absorbed because the

cells do not respond to insulin. The blood glucose concentration is raised with


glycosuria ( glucose in urine) but ketoacidosis is not common and the symptoms

are often those of late complications of diabetes. Most type II diabetics are

overweight, and the best treatment is to lose weight.

Comparism of Type I and Type II Diabetes Mellitus.

IDDM NIDDM

Synonym Type I juvenile onset

diabetes

Type II adult onset.

Age Childhood or puberty Frequently after 35yrs

Nutritional status Frequently

undernourished

Obesity usually present

Prevalence 10-20% 80-90%`

Genetic

predisposition.

Moderate Very strong.

Defect -pancreatic cell

destroyed

Inability of -pancreatic cell to

produce insulin, insulin

resistance

Ketosis Common Rare

Acute complication. Ketoacidosis Hyper-osmolar coma

Oral hypoglycemia Unresponsive Responsive

Insulin therapy Always necessary Usually not required.

Gestational diabetes

Gestational diabetes occurs during pregnancy and increases the risk of fetal

morbidity and death. The onset occurs during the second and third trimesters.

Gestational diabetes can be treated with diet, exercise, and insulin. Usually, it

disappears after the birth of the baby, but 30 – 40% of women who have

gestational diabetes will develop type II diabetes in 5 – 10 years. Oral

contraceptives raise blood glucose levels, especially in these women, so whether

they should use this type of birth control is debatable.


Secondary diabetes

Secondary diabetes is caused by drugs. Among these drugs are oral

contraceptives, beta blockers ( e.g propranolol), diuretics ( eg furosemide) ,

calcium channel blockers ( e.g Nifedipine) , glucocorditcoids ( e.g Prednesolone),

and phenytoin. Secondary diabetes may return to normal when the drug is

disconteined. The use of these drugs in diabetes should be done with caution.

Long term Complications of untreated DM include:

Retinopathy – here the vessels become damaged, resulting in insufficient

blood supply; rupture causes loss of sight.

Neuropathy is the result of a lack of blood flow to nerves, leaving them

unable to function,. Symptoms are dull aching to sharp stabbing pains.

Vascular problems lead to atherosclerosis of peripheral coronary and

cerebrovascular vessels. The decrease blood flow causes neuropathy and

slows healing, especially in the feet and legs. Wounds that fail to heal can

lead to amputation.

Dematologic involvement is often expressed as boils, acne, or fungal

infections.

Nephropathy, or kidney damage, occurs n 10-21% of diabetics and is

primary cause of end-state renal disease.

Treatment of Diabetes Mellitus.

The goal of treatment of diabetes is to approximate non-diabetic physiology

as closely as possible. The treatment consists of diet, exercise, and

medications. Blood glucose monitoring is very important to prevent both acute

and log-term complications and to guide treatment for reaching target fasting

blood glucose goals. To avoid long term complications, diabetes should be

controlled to maintain fasting blood glucose levels between 80-120mg/dL.

Patients with Type I diabetes must receive insulin. Those with Type Ii diabetes

may be able to control the disease through diet and exercise alone, but

commonly they have to add a drug and eventually may need insulin.


ANTI DIABETIC DRUGS.

Insulin.

Mechanism of action.

Insulin lowers the concentration of glucose in the blood mainly by:

a. Facilitating glucose transport across cell membrane resulting in increase

uptake of glucose by the tissues.

b. Facilitating glycogen synthesis from glucose in liver muscles and fat

c. Inhibit gluconeogensis.

Sources of insulin.

There are three sources of insulin, bovine (extracted insulin from beef

pancreas), porcine (extracted insulin from pork pancreas and is very similar to

human insulin), and human. Human insulin is prepared semi-synthetically by

enzymatic modification of porcine insulin or biosynthetically by recombinant

DNA technology using Escherichia coli or yeast.

Method of Insulin Administration:

Insulin is usually administered subcutaneously, however, IM or IV

administration is possible e.g in diabetic emergencies such as ketoacidosis or

surgery if a more rapid effect is wanted.

Injection Technique.

A volume of air corresponding to the prescribed dose of insulin is injected into

the vial. Turn vial and syringe upside down and draw up the prescribed dose

of insulin. Remove syringe from vial and expel any air from syringe. Lift up a

skin fold and inject the insulin under the skin. Keep the needle under the skin

for a few seconds to make sure that all insulin has been injected. If blood

appears after withdrawing the needle, press the injected site lightly with a

finger.


Subcutaneous injection into the abdominal wall ensures a faster absorption

tan from other regions of the body. An injection should be followed by a meal

or snack containing carbohydrate within 30 minutes to avoid hypoglycaemia.

Insulin preparations.

For clinical use insulin have been classified traditionally into short, intermediate

and long acting insulin.

Short acting, soluble, regular or neutral insulin.

These are human or purified animal insulins and have the advantage of being

administered by intravenous, intramuscular as well as subcutaneous routes.

Following subcutaneous injection, soluble insulin has a rapid onset of action

(after 30 – 60 minutes). They are used in diabetic emergencies ( e.g

diabetic coma) and at the time of surgery. Soluble insulins include. Pork

Actrapid, Human Actrapid, Humilin S etc.

Intermediate acting insulins.

These insulins act for a varying periods depending on the mix of rapid and

slow acting components. They have an onset of action of approximately 1-2

hours, a peak action of 3-12 hours, and duration of action of 16-24 hours. E.g

Isophane and biphasic insulins.

Long acting insulin.

Protamin Zinc Insulin (PZI) is an example of a long acting insulin. Its action is

prolonged. Starting after 4hours lasting for 24-36hours. Human insulin zinc

suspension is the choice of preparation when long action is desires.

Human insulin does not contain impurities and is preferred in pregnancy

because impurities in insulin from animal sources can cross the placenta and

damage the islet tissues of the fetus.


Insulin Dosing.

The dose, frequency of administration and type of insulin type to use

depends on numerous factors which vary greatly between individuals. Blood

glucose monitoring is recommended.

Total daily dose of insulin is 0.6-1 mcg/Kg body weight. 2/3 of total insulin

dose is usually given in the morning before breakfast and the 1/3 in the

evening before supper. The overall dose is usually adjusted according to

response.

Storage conditions.

Insulin preparations not in use should be stored in a refrigerator, between

2oC to 8oc at which temperature they will retain the biological and antimicrobial

effect until the date of expiry printed on the pack. Insulin should not be frozen

and frozen insulin must not be used.

Insulin vials may be stored at room temperature ( up to 25oC) for up to six

weeks after first use but should be protected from excessive heat or direct

sunlight.

Insulin vials should be stored horizontally. This is because the insulin in

certain preparations e.g suspensions can settle during storage. If this should

occur while the bottles are stored in an upright position, it can be difficult to re-

disperse the insulin uniformly in the liquid. Moreover, insulin suspension

should not be shaken to re-disperse it but gently swirls between the palms

Adverse effects

1. Hypoglycaemia ( which is the most dangerous side effect in DM treatment)

2. Local reaction – irritation t the site of injection

3. Immunogenic response. Non human insulin can stimulate the production of

anti-insulin antibodies which may lead to hypersensitivity reaction and to

insulin resistance.

4. Weight gain.


Every diabetic should be aware of the risk of hypoglycemia ( blood glucose

<70mg/dL or <2.5mmol/dL. Hypoglycemia can be caused by any of several

factors

skipping of meals

too much exercise

a poorly adjusted medication regiment

concurrent use of alcohol and or other drugs

Symptoms of Hypoglycaemia.

The symptoms of hypoglycaemia, usually considered as blood glucose

concentration of < 45mg/dL (i.e <2.5mmol/L) can be divided into two

categories.

Adrenergic symptoms.

Anxiety, palpitation, tremor, and sweating are mediated by epinephrine

(Adrenaline) release regulated by the hypothalamus in response to

hypoglycaemia. Usually Adrenergic symptoms occur when glucose levels fall

abruptly.

Neuroglycopenic Symptoms

Neuroglycopenia ( the impaired delivery of glucose to the brain) results in

impairment of brain function causing headache, confusion, slurred speech,

blurred vision, seizure, coma, and death. Neuroglycopenic symptoms often

results from gradual decline in blood glucose often to the levels below

400mg/dL. The slow decline in glucose deprives the of fuel but fails to trigger

on epinephrine response.

Types of Hypoglycaemia

1. Postprandial Hypoglycaemia.

It is cause by an exaggerated insulin release following a meal prompting a

transient hypoglycaemia with mild adrenergic symptoms. The plasma glucose

levels return to normal even if the patient is not feed. The only treatment


usually required is that the patient ea\t frequently small meals rather than the

usual three large meals.

2. Fasting hypoglycaemia.

Low blood glucose occurring during fasting is rare but is more likely to

present a serious medical problem. Fasting hypoglycaemia tend to produce

neuroglycopenic symptoms and which may be due to an increased rate of

glucose utilizations by the peripheral tissues due to oral hypoglycemic agents

eg. Biguanides and Sulfonylureas. Behaviours associated with alcohol

intoxication - agitation, and impaired judgment are also common.

Treatment of Hypoglycaemia.

Treatment of hypoglycaemia necessitates giving the patient additional

sugars. Milk or sugars in any form (fruit juices, soft drinks, or candy) are highly

effective. Glucose tablets are available and type I diabetics should have then

on hand.

Oral Hypoglycemic Agents.

Oral hypoglycemic agents cause the pancreas to release stored insulin. Thy

are not effective in type I diabetes because there is no insulin available for the

body to release. Oral hypoglycemic agents are divided into

Sulfonylureas. .

Sulfonylurea drugs increase insulin release

These are subdivided into first generation sulfonylureas and second generation

syulfonylureas.

Examples of first generation sulfonylureas are: Tolbutamide and

Chorpropamide ( diabenese

Examples of second generation sulfonylures are: Glipizide, Glyburide,

Glimepiride ( Amaryl), Glibenclamide ( Daonil, gliben-J etc)

Side effects.

Hypoglycaemia, headache


Biguanides.

Biguanides decreases intestinal absorption of glucose and improves insulin

sensitivity. One of these compounds Metformin (Glucophage) rarely causes

hypoglycemia and has a favorable effect on serum lipids. Others include

phenformin, and Bufomin. Only Metformin is on essential drugs list.

Side effects.

Lactic acidosis, ( especially in patients with renal impairment),

Thiazolidinediones.

Thiazolidinediones ( or Glitazones) lower blood glucose by improving cellular

response to insulin. Examples include Piloglitazone , Rosiglitazone

MOA: Glitazones reduces blood glucose concentrations by increasing insulin

sensitivity in muscles and adipose tissues, and inhibiting hepatic

gluconeogensis.

Side effects.

Headache, pharyngitis, hypoglycaemia and upper respiratory tract infection

have been reported.

Inhibitors of GIT glucose absorption.

Acarbose lowers blood glucose by delaying the hydrolysis of ingested

complex carbohydrates and disaccharides and the absorption on of glucose.

REFERENCES.

Agarwal S.L and Agaral Sunil ( 2002). Pharmacology for Undergraduates. Satish

Kumar jain new Dehil India.

Don A. B and Mary M. L (2010). Pharmacology for Technicians. Paradigm

Publishing. St. Paul. Los Angeles USA.


Pever, J. T (2003). Fundamentals of Pharmacology for Health Workers. Selfers

Publishers, Mkd Nigera.

Hardman J. G etal (ed) ( 2001). Goodman & Gilman’s The Pharmacological Basis of

Therapeutics 10th edition. McGraw Hill. USA


basic and essential pharmacology

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