pharmacology at a glance - pharmacyconcepts.in

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PHARMACOLOGY AT A

GLANCE

PHARMACOLGY KEY POINTS FOR GPAT/NIPER/ PHARMACIST/

DRUG INSPECTOR

Dr Rajesh Choudhary

M. Pharm. (Pharmacology)

Ph. D. (Pharmacy)

i www.youtube.com/pharmacologyconceptsbyrajeshchoudhary

Contents Chapter 1. General Pharmacology………………………….……………..01-15

Chapter 2. Autonomic Nervous System…………………………...……….16-24

Chapter 3. Cardiovascular System………………………………………….25-41

Chapter 4. Autacoids………………...…………………...…………………..42-45

Chapter 5. Gastrointestinal Drugs………………………...…...……………46-49

Chapter 6. Chemotherapy………………………………………………..….50-78

Chapter 7. Central Nervous System……………………………………….79-96

Chapter 8. Antiasthematic Drugs…………………………………….……97-98

Chapter 9. Hormone, Vitamin, Enzyme, & Nucleic Acid…………….99-111

Chapter 10. Important Drug Interactions……………………………....112-118

1 www.youtube.com/pharmacologyconceptsbyrajeshchoudhary

Chapter 1

General Pharmacology

Pharmacology: Pharmacology: made up by Greek words- “Pharmacon = Drug” and “ Logos =

Discourse in”

Definition: Pharmacology is the branch of Medical or biological Sciences concerned with the study of

“Drug” action or interaction between Drug and Living System (Human, Animals, Microbes)

Pharmacy: It is the art and science of compounding and dispensing of a drug. “Science of Drug”.

Clinical Pharmacology: study the effects of drug in Human, and mainly focused on clinical efficacy,

potency, and ADR.

Toxicology: Study the poisonous effect of drug

Pathophysiology: Altered physiology during a disease

Biopharmaceutics: study of the physiochemical properties of drugs and the biological effects they

produce

Pharmacoepidemiology: is the study of the utilization and effects of drugs in large numbers of

people; it provides an estimate of the probability of beneficial effects of a drug in a population and the

probability of adverse effects

Pharmacoeconomics: is the study of therapeutic cost between drug therapeis for a diseases.

Benefit-cost ratio (BCR) = Therapeutic Benefits/ Therapeutic Cost

For a dug BCR should be high as much as possible

Pharmacogenetics: study of inherited genetic differences in drug effect. Genenic variations may

affect the effect of drug.

E.g. Fast acetylated enzyme gene causes the higher elimination of isoniazid (INH) thus dose of INH is

required high as compared to slow acetylated gene

Pharmacovigilance (PV): is related to the collection, detection, assessment, monitoring, and

prevention of adverse effects with pharmaceutical products. It is a Part of Phase IV Clinical Trial.

Major Objectives:

Assessment of Drug Safety

Assessment of Risk-benefit ratio (RBR) over the populations

Benefits of PV:

Prevention of drug related toxicity, morbidity, and mortality

Understanding of drug induced diseases

Detect early signals/warning to serious ADR

Improve the health benefits

DRUG: It is a French words- “Drugue = a dry herb”

Definition: It is the biological active compounds, which alter or correct the pathophysiological state of

a disease for health benefit. And that is used for diagnosis, prevention, treatment, or cure of a disease

DRUG NOMENCLATURE

❏ chemical name: describes the chemical structure, the same in all countries

❏ drug company code: a number, usually for drugs that are not sold

❏ non-proprietary name: shortenend form of chemical name, listed in pharmacopea

❏ proprietary name: the brand name or registered trademark


❏ street name: drugs of abuse

DRUG ADMINISTRATION AND SITE OF ACTION

❏ different routes of administration are chosen depending on

• desired onset of action

• systemic or local effects

• patient characteristics

• properties of the drug

ROUTE ADVANTAGE DISADVANTAGE/WARNINGS

Sublingual -The effect starts immediately,

-NO first-pass elimination

-The absorption may decrease if emesis happens.

Oral -Easy, reliable, economic -First-pass elimination occurs,

-Emesis, diarrhea, heavy constipation may cause

decrease in absorption

Rectal -The effect starts immediately,

-NO first-pass elimination,

-Suitable for patients with heavy emesis

or when the oral route is not an

appropriate route.

-Unpleasant way of application

-Risk of rectal bleeding

-Increased bacteremia risk for

immunosuppressive patients

-Decreased absorption in diarrhea and

constipation.

Inhalation -The effect starts immediately,

-suitable for general anesthetics and

bronchodilators

-Intubation and special equipment are required

Intramuscular -The effect starts immediately, -Edema, local irritation or pain

-Risk of infection

Intravenous -The effect starts immediately,

-Bioavailability is 100%

-Irritation or pain

-Risk of infection

-Solution must be dissolved well

-Risk of embolism

Subcutaneous -Absorption is slower compared to im inj. -Edema, local irritation or pain

-Volume shouldn’t exceed 2 ml

-Risk of infection

Intranasal -The effect starts immediately,

-NO first-pass elimination.

-Local irritation

-Suitable for administration of small doses of

drugs

Transdermal -Enables for slow and long-term drug

application

-The effect starts very slowly

-Local skin reactions can be seen

Percutaneous -Suitable for local effect. -The effect starts very slowly

-Local skin reactions can be seen

PHARMACOKINETICS (ADME)

❏ “ADME”: absorption, distribution, metabolism, excretion

❏ definition: the manner in which the body handles a drug

❏ examines the rate at which drug concentrations change in the body by observing


1. input processes

• absorption: movement of drug into the body from the site of administration

2. output processes: responsible for drug delivery and removal from the body

• distribution: movement of drug from intravascular to extravascular compartment

• metabolism: chemical transformation of drug

• elimination: removal of drug from the body

ABSORPTION PRINCIPLE: The amount of drug that reaches the systemic circulation (bioavailability) is highly

dependent on absorption. Properties of the drug, route of administration and patient factors should

be considered to ensure clinical effectiveness.

❏ most drugs are absorbed into the systemic circulation via passive diffusion

❏ other mechanisms of absorption include: active transport, facilitated diffusion, pinocytosis/phagocytosis

❏ absorption rate and amount depends on

local blood flow at admininstration site (eg. sublingual vessels provide significant blood flow therefore

rapid absorption)

lipid solubility: greater lipid solubility = increased rate of diffusion through membranes (e.g.

anesthetics are very lipid soluble therefore have a rapid onset of action)

molecular size: small size, water soluble drugs can pass through channels in membranes, large

molecules cannot (e.g. aminoglycosides are large molecules and are not absorbed through intestinal

mucosa and are therefore not orally active)

local pH and drug ionization: charged molecules do not cross membranes (e.g. lactulose ionizes

ammonia to ammonium and keeps it in the bowel)

total surface area for absorption: the small intestine has villi which increase the surface area for

absorption, and hence is the primary site of absorption for most oral drugs

Bioavailability

❏ the percentage of dose given that reaches the systemic circulation in unchanged form

❏ the administered dose does not equal active dose

❏ drugs with a low bioavailability may be ineffective orally

e.g. pencillin G is destroyed by gastric enzymes and needs to be administered IV

❏ fate of oral drug: GI Tract ––> portal vein ––> liver (metabolism) ––> systemic circulation

First Pass Effect

❏ metabolism of orally administered drug in the liver before it reaches the systemic circulation

❏ significant first pass metabolism limits a drug’s bioavailability

❏ drugs with a high first-pass effect include: chlorpromazine, levodopa, morphine, propranolol,

lidocaine, hydralazine, nortriptyline, and organic nitrates

❏ drugs with low hepatic extraction (little or no first pass effect) include: diazepam, digoxin, phenylbutazone,

phenytoin, theophylline, tolbutamide, warfarin

PRINCIPLE: Some drugs have uncommon distribution parameter (e.g. Vd, protein binding,

storage in fat depots) and have to be dosed carefully to avoid toxicity while ensuring

therapeutic efficacy.

❏ definition: process by which drugs are carried throughout the body to reach target sites of action

Volume of Distribution (Vd)

❏ actual volume of distribution (Vd): the anatomic volume that is accessible to drug, e.g. total body

water of 40 L


❏ apparent volume of distribution (Vd) is a calculated value that does not correspond to an anatomical

space, a drug with a large Vd (larger than 40 L) must distribute in other tissues besides body water

• e.g. Amiodarone; Vd=400L in a 70kg person

Protein Binding

❏ drug molecules in the blood are in two forms:

• bound to plasma proteins, mainly albumin

• free

❏ principles of protein binding

• only free drug can distribute into tissues and exert its action, and is subject to metabolism and

elimination

• affinity of a protein binding site for a drug determines bound/unbound concentrations, and

reversibility of interaction

• saturation of binding sites may result in a large increase in unbound drug concentration, which

could cause toxicity

• if albumin concentration is decreased (liver failure or nephrotic syndrome), dose of highly

bound drug must be lowered to avoid toxicity

• competition for binding sites between drugs and endogenous substrates can result in

interactions and toxicity

• significant drug interactions can occur due to competitive protein binding

e.g. ASA displaces several drugs which are highly bound to plasma proteins such as

phenytoin, increasing risk of toxicity

• in general, only drugs that are highly protein bound, e.g. > 90%, are involved in drug

interactions due to competitive binding

Plasma Proteins:

o Albumin

o Alfa-1 Acid Glycoprotein (AAG/α-AGP)

o Lipoproteins

o Globulines

1. Albumin

The most important protein (59% of total) that binds the drugs in blood is albumin for most of

the drugs.

Especially, the acidic drugs (salicylates, vitamin C, sulfonamides, barbiturates, penicillin,

tetracyclines, warfarin, probenesid etc.) are bound to albumin.

It has 4 binding site:

A. Warfarin site: NSAIDs, Sulfonamides, Phenytoin, Bilirubin.

B. Diazepam site: BDZs, fatty acid, Tryptophen, Probenecid, Penicilline.

C. Digitoxin site: digitalis alkaloid

D. Tomoxifen Site: tomoxifen

If the two drugs have same binding site, thus it can give rise the displacment interaction and

further cause drug accumulation, and toxicity.

2. Alfa Acid Glycoprotein Basic drugs (streptomycin, chloramphenicol, LA, TCAs, Prazosin etc.) are bound to alpha-1

and alpha-2 acid glycoproteins.

3. Lipoproteins (chylomicron, LDL, HDL) Acidic- Diclofenac

Neutral- Cyclosporin A

Basic- Chlorpromazin

4. Globulines

1) α-1 (Transcortin)- Corticosteroids, thyroxine, cynocobalamine

2) α-2 (Ceruloplasmin)- Vit A, D, E, K

3) β-1 (Trasferin)- Fe2+


4) β-2 – Caritinoids

5) γ-globulin- Antigens

Some drugs like Phenytoin, Phenobarbital are bind with blood hemoglobin.

Depots

❏ a part of the body (e.g. a type of tissue) where drug molecules tend to be stored

❏ fat tends to be a depot for very lipid soluble drugs (e.g. diazepam)

Barriers

❏ body structures that limit/prevent diffusion of drug molecules,

❏ e.g. blood-brain barrier (BBB), placental barrier

METABOLISM (BIOTRANSFORMATION)

PRINCIPLE: Drugs that are metabolized by similar enzymes, eg. the same cytochrome P450

isoenzymes, have the potential to interfere with each other’s metabolism. When in doubt, especially

for new drugs, look up metabolic route and then anticipate the interaction before writing the

prescription.

❏ conversion of a drug into another form may result in

• activation of pro-drug: eg. codeine to morphine, nitroglycerine to NO

• maintenance of activity, eg. diazepam is metabolized to an active metabolite

• inactivation, eg. procaine to PABA

❏ main site of biotransformation in the body is the LIVER.

❏ drug metabolizing enzyme pathways generally mediate 2 types of reactions

• Phase I reactions

• oxidation-reduction and hydrolysis

• introduce or unmask polar chemical groups therefore increase water solubility

• mediated by cytochrome P450 enzymes

• P450’s are found in the endoplasmic reticulum or cell cystoplasm

• phase II reactions

• conjugation with polar endogenous substrates e.g. glucoronic acid, glutathione

• increases water solubility and renal elimination

Table 3. Organ Distribution of Drug

Metabolizing Enzymes

Site Relative Activity

Liver

Lung

Kidney

Intestine

Term Placenta

Adrenal Glands

Skin

100

20-30

8

6

5

2

1

Table 2. Examples of Important Highly

Protein Bound Drugs

Name % Bound

Salicylic Acid

Phenytoin

Propranolol

Diazepam

Warfarin

82

90

93

99

99.5


Clinical Pearl

❏ Cytochrome P450 isoenzyme CYP 3A4 metabolizes about 50% of all drugs, hence if a drug

which is metabolized by 3A4 is prescribed, double check for possible interactions if any other drug

is added to the regimen.

Drug Interactions are Often Due to Interactions in Biotransformation Pathways

❏ Phase I (Cytochrome P450 enzymes)

1. erythromycin inhibits the CYP3A4 enzyme, and predisposes to cisapride toxicity and possible

fatality

2. cimetidine inhibits P450 enzymes, leading to increased levels of theophylline, diazepam,

warfarin, phenytoin

3. phenobarbital induces P450 enzymes, which could decrease levels of other drugs

(see below: Enzyme Induction)

4. the SSRIs could inhibit CYP 2D6 (and 3A4), and therefore increase serum levels of other

drugs metabolized by these enzymes, e.g. benzodiazepines, carbamazepine, phenytoin

5. the new HIV drugs, the protease inhibitors, are metabolized by cytochrome P450 enzymes, (e.g.

indinavir is metabolized by CYP 3A4), and hence could interact with other drugs metabolized by this

route

❏ Phase II (Conjugation reactions):

1. Acetaminophen is 95% metabolized to inactive glucuronic acid and sulfate conjugates,

and 5% oxidized by P450, generating a reactive metabolite which is then conjugated with glutathione.

If glutathione stores are depleted, eg. massive dose of acetaminophen, the reactive metabolite remains

unconjugated and causes hepatocellular damage. In concurrent ingestion of alcohol and large doses of

acetaminophen, a double whammy situation occurs. Alcohol induces the P450 enzymes, and hence the

generation of the reactive metabolite; alcoholics tend to be deficient in nutrients, notably glutathione,

hence depletion occurs more readily, resulting in massive hepatocellular damage in this situation

❏ Enzyme Induction

• over 200 unrelated drugs have the ability to increase the activity of drug biotransforming enzymes

generally reducing activity/intensity of drug action

• reflects de novo synthesis of P450 and other biotransforming enzymes

• induction of P450 can stimulate multiple iso-enzymes specifically or non specifically

❏ other factors affecting drug metabolism

• age

• early in fetal life drug metabolizing enzyme levels are low

• elderly have reduced rates of metabolism due to reduced hepatic function

• nutrition

• inhibition or drug metabolizing enzymes with decreased

protein, decreased fatty acids

Table 4. Examples of Inducing Agents

Inducing Agent Substance Induction

Cyt P450

whose metabolism is increased

PCH(polycyclic hydrocarbon)

Barbiturate

INH, rifampicin, alcohal

Anticonvulcant, barbiturate

Clofibrate

Cyp 1A1

Cyp 2B1

Cyp 2E1

Cyp 3A

Cyp 4A

Phenytoin

Phenytoin, oral contraceoative

Coumarins, phenobarbitone

Phenytoin

cholesterols


• alcohol, vitamin deficiency states

• induction of P450 with chronic ingestion

• inhibition of P450 with acute ingestion

• radiation

• sex

• race

Clinical Pearl

❏ The very young and the very old are very sensitive to the actions of drugs.

ELIMINATION PRINCIPLE: Dosing of drugs needs to be adjusted according to the elimination characteristics of

the patient (e.g. in renal impairment) in order to avoid toxicity from drug or metabolite

accumulation.

❏ routes of elimination include

• stool (e.g. corticosteroids from biliary system)

• lungs (e.g. general anesthetics eliminated by expiration)

• skin and mucous membranes (e.g. rifampin in tears)

❏ KIDNEYS are the main organ of drug excretion through

• glomerular filtration: passive, pore size about 400-600 Angstroms

• tubular secretion: active, against concentraion gradient, saturable, two distinct transport mechanisms

for weak acids and weak bases

• e.g. acids: penicillin, salicyclic acid, probenecid, chlorothiazide

• e.g bases: quinine, quaternary ammonium compounds (e.g. choline)

• tubular reabsorption: can be active or passive (depending on charge)

❏ elimination rate depends on renal function (assessed clinically, using serum creatinine levels)

• the Cockroft-Gault equation can estimate creatinine clearance (CrCl) for males as:

CrCl (mL/min) = (140-patient's age in yrs) x IBW (kg)/50 x SCr (μmol/L)

• for females above equation x 0.85

❏ drug interactions due to interference with filtration, secretion, reabsorption

• probenecid significantly reduces renal excretion of penicillin by competing for the weak acid transport

• lithium is renally eliminated through glomerular filtration, much of the filtered load is reabsorbed at

the proximal renal tubule. Sodium competes for thereabsorption site with lithium. Hence, thiazide

diuretics, which can cause hyponatremia and reduced sodium load in the renal tubule, increase the

reabsorption of lithium and can predispose to increased serum lithium levels and lithium toxicity


PHARMACOKINETICS CALCULATIONS

❏ definition: the quantitative description of the rates of the various steps of drug disposition (ie.how drugs

move through the body)

❏ the pharmacokinetic principles of ADME (absorption, distribution, metabolism and elimination) can be

graphically represented on the concentration vs time graph (see Figure 1)

❏ many kinetic parameters are measured using IV dosing, there is no absorption phase, and distribution for

most drugs is rapid, therefore the elimination is the main process measured.

❏ the concentration axis is converted to a log base 10 concentration to allow for easier mathematical

calculations

❏ equations from the graph

• t1/2 (Half-life) = the inverse of the slope of the line (k) x 0.693

• Vd (volume of distribution) = dose/concentration at time 0

• Cl (clearance) = k x Vd

Half-Life (t1/2)

❏ defined as the time it takes for blood level of a drug to fall to one-half (50%) of the level measured at some

prior time

❏ for most drugs, half-life correlates with the elimination phase

❏ in general it takes 5 half lives to reach steady state with repeated dosing or for drug elimination once dosing

is stopped

Steady State

❏ The concentration at which the same amount of drug entering the system is eliminated from the system

❏ time is important for therapeutic monitoring as drug levels are only reliable when the drug has reached this

steady state

❏ any change in drug dose and interval will change the steady state level

❏ special situations

• drug with long half-life and the need to rapidly increase blood levels – give a loading dose (e.g.

phenytoin)

• drugs with a very short half-life and the need for a long term effect – multiple, frequen repeated doses

are too inconvenient thus use a continuous infusion (e.g. nitroprusside)

Elimination Kinetics

❏ first-order kinetics (the most common type)


• a constant fraction of drug is eliminated per unit time

• the amount of drug eliminated is based on the concentration of drug present

• this relationship is linear and predictable

❏ zero-order kinetics (less common, associated with toxicities)

• non-linear kinetics

• a constant amount (number of molecules) of drug is eliminated per unit time

• clearance slows as drug concentration rises

• some drugs can follow first order kinetics until elimination is saturated (usually at large doses) and the

clearance decreases

• some drugs follow non-linear kinetics at therapeutic levels e.g. phenytoin

PHARMACODYNAMICS

❏ definition: the relationship between the drug concentration and effect (what the drug does to the body)

Agonists Have Two Main Properties

❏ affinity: the ability of the agonist to “bind to” the receptor

❏ efficacy: the ability to cause a response via the receptor interaction

e.g. the ß2-agonist (salbutamol) bind to ß2-receptors (i.e. has affinity) and result in activation of

smooth muscle relaxation (ie. has efficacy)

Antagonists

❏ have affinity (can bind to a receptor) but no efficacy

❏ chemical antagonism: direct chemical interaction between agonist and antagonist prevents agonist binding to

receptor

• e.g. chelator agents for removal of heavy metals

❏ functional antagonism: interaction of 2 agonists that act at different receptors independent of each other but

have opposite physiological effects

• e.g. acetylcholine at the muscurinic receptor decreases HR, constricts pupil, stimulates intestinal

motility

• epinephrine at the adrenergic receptor increases HR, dilates pupil, decreases intestinal motility

❏ competitive antagonism (most common in clinical practice) (see Figure 3)

• antagonist acts at same receptor (i.e. binds) displacing agonist

• antagonist binding is reversible and can be overcome

❏ non-competitive antagonism (see Figure 4)

• irreversible binding of antagonist to receptor

• allosteric effect: changes ability of the agonist to bind to the receptor through various mechanisms

such as changing the conformation of the receptor


• increasing concentrations of agonist cannot reverse the antagonism

Dose-Response Relationship

❏ pharmacodynamic principles measuring efficacy and potency can be quantified using dose-response curves

❏ with gradual dose response relationships the response of the drug reflects the number of receptors that are

effectively occupied

❏ efficacy

• the maximum intensity of response to a drug, eg. if Drug A causes a greater maximum intensity of

response than Drug B (regardless of dose), then Drug A is more efficacious than Drug B

• ED50 (effective dose-50%) the dose or drug that gives rise to the designated response in 50% of the

subjects

• ED50 is easier to measure than maximum effect and is used to determine efficacy

❏ potency

• a comparison of the ED50 of two or more drugs that have parallel log dose-response curves

• the drug that reaches the ED50 at the lower dose is the more potent

• potency is a term that is often misused (confused with efficacy)

• potency is not important if you can increase the dose of the less potent drug without causing side

effects

Effectiveness and Safety

❏ the two most clinically relevant properties of any drug are effectiveness and safety

❏ effectiveness


• similar to efficacy but in real populations (i.e. not experimental)

❏ safety (see Figure 6)

• LD50 (lethal dose-50%): defined as the dose of a drug needed to cause death in 50% of a test

population of subjects (e.g. usually rodents)

• TD50 (Toxic Dose - 50%): defined as the dose needed to cause a harmful effect in 50% of the

subjects

Therapeutic Index (TI) (see Figure 6)

❏ defined as TD50/ED50

❏ reflects the “margin of safety” for a drug - the likelihood of a high dose causing serious toxicity/death

❏ the larger the TI, the safer a drug

❏ factors can change the ED50, LD50 or the TD50

• presence of interacting drugs

• changes in drug absorption, distribution, metabolism, elimination

• e.g. amoxicillin has a large TI, therefore therapeutic monitoring is not needed, whereas warfarin has a

small TI and must have accurate therapeutic monitoring

Variability in Drug Action

PRINCIPLE: not everyone experiences the same response to the same dose (route of adminstration,

dosage interval, etc. may need to be adjusted in some cases).

❏ some common causes of variable responses to a drug

• age: (see geriatric pharmacology)

• gastric pH and gut motility (affects absorption of certain drugs)

• body composition (changes in fat, muscle, water content)

• plasma protein levels (affects various aspects of pharmacokinetics)

• renal, liver function (affects excretion and metabolism respectively)

• gender: mainly due to presence or absence of certain enzymes, hormones, etc.

• genetics: presence/absence of one or more genes needed to form enzymes, other proteins, hormones,

etc.

• overall health - presence/absence of other diseases

• use of other drugs (i.e. interactions)

• nutritional status - excess or deficiency of key vitamins, minerals, etc.

• compliance

TARGETS FOR DRUG ACTION


The protein targets for drug action on mammalian cells that are divided into:

receptors

ion channels

enzymes

carrier molecules (transporters).


Type 1: ligand-

gated ion

channels

Type 2: G-protein-

coupled receptors

Type 3: receptor

kinases

Type 4: nuclear

receptors

Location Membrane Membrane Membrane Intracellular

Effector Ion channel Channel or enzyme Protein kinases Gene transcription

Coupling Direct G-protein Direct Via DNA

Examples Nicotinic

acetylcholine

receptor, GABA A

receptor

Muscarinic

acetylcholine

receptor,

adrenoceptors

Insulin, growth factors,

cytokine receptors

Steroid receptors

Structure Oligomeric

assembly of

subunits

surrounding

central pore

Monomeric

dimericor structure

comprising seven

transmembrane

helices

Single transmembrane

helix linking

extracellular receptor

domain to intracellular

kinase domain

Monomeric

structure with

separate receptor-

and DNA-binding

domains


ADVERSE DRUG REACTIONS (ADRs)

❏ classification of adverse drug reactions

• type A: predictable

• type B: unpredictable

Type A

❏ side effects: excessive but characteristic pharmacological effect from usual dose of a drug

❏ overdose / toxicity: exaggerated but characteristic pharmacological effect from supratherapeutic dose

❏ teratogen: drug may produce developmental defects in fetus

❏ characteristics

• account for 80% + of all ADRs

• extension of pharmacological effect

• dose-related and generally not severe

• usually do not require discontinuation

• dose reduction or titration may help minimize effect

• e.g. a common side effect of beta-blockers is bradycardia (an extension of its therapeutic effect)

Response

Type B

❏ idiosyncratic: uncharacteristic response to drug, unrelated to pharmacology

❏ pseudoallergenic: mimics immune-mediated reaction

❏ allergic / immune-mediated: does not occur on first exposure (up to 7d), immediate with subsequent

exposure, may occur with low dose, resolves within 3-4 days of discontinuation

• characteristics

• usually more severe

• usually require discontinuation

• not dose-related

• e.g. sulpha based drugs (such as septra) can cause an idiosyncratic Stevens Johnson Syndrome (SJS)

Approach to Suspected ADRs

❏ history and physical examination: symptoms, timing, risk factors, medication related, dechallenge and

rechallenge information is needed, look up previous reports in the literature

❏ differential diagnosis: therapy or disease pathophysiology

❏ treat the adverse drug reaction: stop the drug, supportive care, symptomatic relief

PHARMACOKINETIC CALCULATIONS

❏ Volume of Distribution (Vd)

Vd = dose/concentration at time 0

❏ λ = rise

run

= log (C1 – C2)

t2 – t1

❏ Clearance (CL)

CL = k x Vd

❏ Half-life (t1/2) = 0.693 x 1/k

❏ Ideal Body Weight (IBW)

for males = 50 kg + [2.3kg x (no. of inches > 5 ft)]

for females = 45.5 kg + [2.3kg x (no. of inches > 5 ft)]

❏ Loading Dose (LD)

LD = IBW x dose/kg

Or LD = Cp x Vd/F where Cp = target plasma drug concentration

Vd = volume of distribution

F = bioavailability (F = 1 for IV drugs)


❏ Maintenance Dose (MD)

MD = IBW x Dose per kg/τ (dosing interval)

For renally impaired:

MD = CrCl (patient)/ CrCl (normal) x Dose for normal patient or MD = Cp x CLcr/ F


Chapter 2

Autonomic Nervous System

❏ Atuonomic nervous system (ANS) is divided into sympathetic and parasympathetic branches

❏ Efferent fibers originate in nuclei in the CNS

❏ Sympathetic preganglionic fibers exit the CNS through thoracic and lumbar spinal nerves and

terminate in

1. paravertebral ganglia that lie in a chain along the vertebral column - sympathetic trunk

2. prevertebral ganglia

❏ Parasympathetic preganglionic fibers exit through cranial nerves and sacral nerves and terminate on

ganglion cells located near or within the innervated organs

❏ Most organs are innverated by both sympathetic and parasympathetic nerves having opposing

effects

❏ All preganglionic fibers release acetylcholine which acts on

• preganglionic fibers to all ganglia in the ANS and adrenal medulla

• postganglionic parasympathetic fibers to effector organs

• postganglionic sympathetic nerves to sweat glands

❏ Postganglionic fibers release either acetylcholine or norepinephrine

Parasympathetic Nervous System ❏ acetylcholine is the neurotransmitter of the parasymathetic nervous system

❏ acetylcholine receptors include

• nicotinic located in autonomic ganglia, adrenal medulla and neuromuscular junction (NMJ)

• muscarinic

• M1 located in the CNS & GI GIglands

• M2 non-neuronal receptors located on cardiac muscle

• M3 on GI smooth muscles and secretary glands

❏ acetylcholines action is terminated by metabolism in the synaptic cleft by acetylcholine esterase

and in the plasma by butyrocholinesterase

❏ parasympathomimetics can be divided into three groups

1. choline esters e.g. carabachol, methacholine

2. alkaloids e.g. pilocarpine

3. anticholinesterases e.g. neostigmine, phsyostigmine


PARASYMPATHOMIMETICS

M1 (Neural) M2 (Cardiac) M3 (Glandular/

smooth muscle')

M4 M5

Location

Autonomic ganglia,

Glands (GI)

Cerebral cortex

Heart (atrium)

CNS

Exocrine glands (

salivary, etc)

Smooth muscles

(gastrointestinal tract,

eye, airways, bladder)

Blood vessels

CNS CNS (substantia nigra)

Salivary glands

Iris/ciliary muscle

Cellular Mechanism

GqPCR, ↑IP3,

DAG

Excitation (slow

epsp)

↑Ca2+ , ↓K+

conductance

GiPCR, ↓cAMP

↓Ca2+

conductance

GqPCR, ↑IP3, DAG

↑Ca2+ conductance

Gi PCR,

↓cAMP

GqPCR, ↑IP3

Functional

Response

CNS excitation

(?memory),

Gastric secretion

Cardiac

inhibition,

Neural

inhibition,

Central

muscarinic

effects (e.g.

tremor,

hypothermia)

salivary secretion,

Gastrointestinal

smooth muscle

contraction,

Ocular

accommodation

(Miosis),

Vasodilatation

(EDRF)

Enhanced

locomotion

Not known

Agonists Acetylcholine, Carbachol, Oxotremorine, Talsaclidine

Antagonists

Atropine

Dicycloverine

Tolterodine

Oxybutynin

Ipratropium

Pirenzepine

Mamba toxin MT7

Atropine

Dicycloverine

Tolterodine

Oxybutynin

Ipratropium

Gallamine

Atropine

Dicycloverine

Tolterodine

Oxybutynin

Ipratropium

Darifenacin

Atropine

Dicycloverine

Tolterodine

Oxybutynin

Ipratropium

Mamba toxin

MT3

Atropine

Dicycloverine

Tolterodine

Oxybutynin

DRUGS AND THEIR DESCRIPTION

DRUGS MECHANISM INDICATION/DESCRIPTION ADR

Cholin esters

Acetylcholine M (GPCR) and

N (LGIC)

M1,M3-

GqPCR

M2-GiPCR

Clinically Not Used Bradycardia (reduce

Automatecity and Coductivity)

negative Iono, Chrono, Drono-

tropic

Carbachol M and N Glaucoma

Bethenachol M Post operative atony of GI and Bladder

Scoplamine toxicity

Methacholine

[S (+) isomer)

M Diagnosis of bronchial hyperreactivity

Pilocarpine M Glaucoma

Retinal detachment

Miotic action (pupil constriction)

Cholinesterase inhibitor/AntiChE

Carbamates

Physostigmine Mainly M

action

Glaucoma

Miotic action

Antidote for Atropine/belladonna, TCAs

and Phenothiazines poisoning


Neostigmine

Pyridistigmine

Mainly N

Action

Mysthenia Gravis

Post operative Ilius

Endrophonium Diagnosis of MG

Rivastigmine

Donepezil

Tacrine

ALZHEIMER

Galantamine

(Alkaloid)

ALZHEIMER

Organophosphate

Isofluorophate

Echotheophate

Glaucoma Orgnaphosphorus Poisoning

Antitodes-

Atropine

Oximes (pralidoxime)

Hydroxylamine

Hydroxamic acide

Diazepam

Parathion

Malathion

Insecticides

Tuban

Sarin

Soman

Nerve gases

CONTRAINDICATION OF CHOLINOMIMETICS

Asthma

Hyperthyroidism

Ulcer

Coronary Artery diseases

ACETYLCHOLINE NEUROTRANSMISSION MODULATORS

DRUGS MECHANISM INDICATION/DESCRIPTION

Vesamicol Inhibit vesicle transport of Ach Inhibit the Cholinergic

Neurotransmission Botulin toxin Inhibit Release (exocytosis) of Ach

Hemicholinium Inhibit Cholin transport

Ach esterase (ChE) and Butyryl ChE

(Pasma; BuChE)

Hydrolysis of Ach

PARASYMPATHOLYTICS (MUSCURINIC BLOCKERS) DRUGS MECHANISM INDICATION/DESCRIPTION ADR

Atropine

[(±) hyoscyamine]

M blocker Antisecretory (preanesthetic)

Mydriatic & Cyclopegic

action

Organophosphorus and

Mushroom poisoning

Antispasmodic

Digitalis toxicity [for

vegolytic action (M2

blocker)--- Atropine and

Gallamine]

Belladona/Atropine poisoning

Cycloplegia (blurred vision)

Photophobia

Tachycardia

Urinary retention

Atonia

Psychotic behavior

Antidotes: Physostigmine

Contrainication:

Arrhythmetic Patients

Glaucoma

**Belladona poisoning is diagnosis by administration of Methacholine (5mg) or Neostigmine (1mg) that fail to

induce typical muscirinic effect

** l- isomer belladonna alkaloid is more active that d-isomer

Scopolamine

[(-) hyoscine]

M blocker Marked CNS effect than

Atropine

Cycloplegia (blurred vision)

CNS Depression effect


Motion sickness

Antisecretory

NARCO TEST

Loss of short term memory

(for Narco test)

Homotropin

Cyclopantolate

M3 blocker Mydriatic & Cyclopegic

action

“Tropium”

(4o Ammonium

analogue)

Ipratropium

Tiotropium

Oxytropium

M3 blocker Asthma (Brinchodilator)

Cimetropium M3 blocker Reduce tone of GI, bilary and

urogenital tract

Dicyclomine M3 blocker Antispasmodic

Anti-secretory

Motion Sickness

Pirenzepine M1 blocker Peptic Ulcer

Propanthelin M3 and M1 blocker Anti Sapsmodic

Peptic Ulcer

Adjuvant to X-ray

examination of GIT

Benztropine

Trihexyphenidyl

Beperiden

Anti-Parkinsonian

GANGLIONIC BLOCKER (NN BLOCKER) DRUGS MECHANISM INDICATION/DESCRIPTION

Mechylamine NN blocker Smoking Cessation by nicotine patches (Nicotine + Mechylamine)

NEUROMUSCULAR (NM) BLOCKER DRUGS MECHANISM INDICATION/DESCRIPTION ADR

Curare derivatives

(Nondepolarizing/

Competetive

blocker)

d-Tubocurarin

Atracurium

Vencuronium

Nm blocker Skelatal muscle relaxant ADR:

Muscular paralysis

Contraindicated with

Stigmines—decrease potency

Halogenated Anesthetic—

increase neuromuscular

bloking action

Aminoglycoside—increase

potency/actn

CCB-- increase potency/actn

Succinylcholine

(Depolarizing/ Non

comp. blocker)

Nm Agonist Post operative muscular pain Hyperkalamia

Increase IOP

Central acting

Mehenesin Antidote for Stychnine

poisoning

Muscle relaxant

Baclofen GABAB Agonist

(GiPCR)

Anti-Spasticity in Spinal

cord injury


Alcohalism (reduce alcohol

withdrawal symptoms)

Dentrolene RyR (Rynodine) receptor

blocker- Ca2+ release

from SR

Malignant hyperthermia

Muscle spasticity Contraindication:

Liver, lungs, CVS diseases

Pregnancy and Lactating

female

Sympathetic Nervous System

❏ norepinephrine is the major neurostransmitter of the Sympathetic system

❏ receptors include

• ß1 predominately in cardiac tissue

• ß2 predominately in smooth muscle and glands

• α1 predominately on post-synaptic receptors in smooth muscles and glands

• α2 predominately on pr-synaptic terminals as well as post-synaptic terminals in the brain,

uterus and vascular smooth muscle

❏ each receptor has a different sensitivity to sympathomimetics

❏ norepinephrines actions terminated by reuptake into the nerve terminal, diffusion from the synaptic

SYMPATHOMIMETICS



Noradrenaline α1 and β1

Septic shock

Hypotension

Reflux bradycardia

Contraindication

Hypertension

Hyperthyroidism

Angina

Arrhythmia

(-) Adrenaline α and β Hypotension

Anaphylaxis

Asthma

Open Angle Glaucoma

(Depivefrine)

Reflux Tachycardia

Cerebral Haemorage

Palpitation

Contraindication

Hypertension

Hyperthyroidism

Angina

Arrhythmia

Isoprenaline Β Cardiogenic Shock

Heart Block

(Bradyarrhythmia)

Contraindication

Hypertension

Hyperthyroidism

Angina

Arrhythmia

Dopamine Large dose- α1

Medium dose- β1

Small dose- D1R

Cardiogenic Shock in

oliguric renal failure

CHF (+ionotropic)

Relax the renal smooth

muscle by D1 receptor

Dobutamine β1 agonist (GsPCR) Cardiogenic Shock

Heart failure (CHF)- +

ionotroic

Cardiac stress testing

Salbutamol

Albutrol

Turbutaline

Bitolterol (Colterol)

Metaproterenol

(Orciprinaline)

β2 agonist

(GsPCR)

Bronchodilator (Asthma)

Ritrodine

Isoxuprine

Terbutaline

β2 agonist

(GsPCR)

Uterine relaxant to prevent

premature laour birth

Phenylephrine α1 agonist

(GqPCR)

Hypotension

Supraventricular tachycardia

(due to reflux vegal action)

Nasal decongestion, Rhinitis

Reflux bradycardia

“Imidazolines”

Nephzoline

Xylometazoline

Oxymetazoline

α1 agonist

(GqPCR)

Nasal decongestion, Rhinitis,

Sinustis

1R2S (-) Ephedrine

α and β Asthma

Nasal decongestant

Urinary incontinence

Acticity of Ephedrine: (-) Ephedrine > (±) Ephedrine > (+) Ephedrine > (+) Pseudoephedrine > (±) Pseudoephedrine > (-)

Pseudoephedrine

Dex-Amphetamine

(Central acting)

α and β Major depression

Obesity (loss of appetite)

Narcolepsy

Orthostatic hypotension


ADHD/ADS (Attention

deficiat hyperactivity

disorder)

Fenfluramine Anorectic agent used in

obesity

No CNS effect

α-methyl dopa α2 agonist

Nor-ad synthesis inhibitor

Hypertension in pregnancy

ADRENERGIC NEUROTRANSMISSION MODULATOR

Guanethidine Vesicle release

(Exocytosis) inhibitor

Decrease the Adrenergic

neurotransmission

Reserpine Glandular/vasicular

uptake inhibitor


neurotransmission

Cocain

TCAs (desipramine)

Antihistamins

Axonal uptake/

NET inhibitor

(Nor-epinephrine

transporter)

Increase the Adrenergic

neurotransmission

MAO (intra and

exracellular)

COMT

(extracellular)

Metabolism of

catecholamines


neurotransmission

MAO- A Inhibitor

Moclobemide

Clorgyline

Inhibit metabolism of

Nor-Ad, Dopamine and

5HT

Depression

Dysthemia Cheese reaction with dairy

products, beer, meet, fish that

contains tyramine and dopa

Enhance the sympathetic

action

Hypertensive crisis MAO-B Inhibitor

Selegiline


phenylalkylamines

Parkinson

COMT inhibitor

Tolcapone

Entacapone


Nor-ad and dopamine

Parkinson

SYMPATHOLYTICS DRUGS MOA INDICATION ADR CONTRAINDICATIO

α1 Blockers α1 Blockers

Selective Uses

in

Peripheral vascular

diseases

Pheochromocytom

a

Benign prostatic

hypertrophy (BPH)

Hypovolemic

Shock (Secondary

shock)

Postural

Hypotension

Reflux

Tachycardia

Edema due to

reduce GFR)

Reduce semen

ejaculation

Non selective

Phenoxybenzene

Phentolamine

Hypertension

Dihydroergotamine

Dihydroergotoxin

Migrane

Cognition

Enhancer

**Hydrogenated amino acid ergot alkaloids have α1 blocking activity while natural amino acid ergot alkaloids

having vasoconstriction property

** α1 blocking activity -- Dihydroergotoxin > Dihydroergotamine

*** Vasoconstriction---- Ergotamine > Ergotoxin

Selective α1-

ZOSIN

Prazosin

Terazosin

Hypertension


Doxazosin

Alfuzosin

Silodosin

Benign

prostatic

hypertrophy

(BPH)

β-Blockers

Non selective (β1

and β2 blocker)

Propranolol

[R (-) enatioer]

Angina

MI

Hypertension

Arrhythmia

Anxiety

Hyperthyrodism

Migrane

Pheochromocytom

a

Bronchoconstrictio

n

Bradycardia

Sexula dysfunction

Fatigue

Rebound

hypertension due to

sudden withdrawal

CHF

Asthma

Hyperlipidemia

Interacion:

+CCB/Digitalis Cardiac

arrest

+ Insulin/oral hypoglycemic

increase hypoglycemia

+ Alfa 1 agonist- marked

hypertensive action

Timilol Galucoma

Satolol Class II

antiarrhythmic and

having K+ channel

blocking property

Selective β1

blocker

Atenolol [S (-)]

Metaprolol [S (-)]

Nebivolol

Acebutalol (with

ISA)

Esmolol (with ISA)

Angina

MI

Hypertension

Anxiety

Hyperthyrodism

Pheochromocytom

a

Bradycardia

Sexula dysfunction

Interacion:

+CCB/Digitalis Cardiac

arrest

α1 + β blocker

Labetalol (having 4

diastereomers)

5 time more

potent

β>> α1

blocking

Pheochromocytom

a

Hypertension

Clonidine

withdrawal

Sexula dysfunction

(ejaculation failure)

Postural

Hypotension

Hepatotoxic

Carvidilol β and α1

blocking

CHF

Hypertension

Angina

Block Ca Channel


Chapter 3

Cadiovascular System

Fig. Smooth muscle contraction/relaxation

Fig. Cardiac muscle contraction


DRUGS ACTING ON CVS DISOERDERS

CHF/HYPERTENSION/ANGINA

INOTROPIC DRUG – Used in CHF

Force of contraction of ventricular walls by increasing intracellular Ca2+ ion


Digitalis

Aglycdn- Genin

(Digitoxigenin and

Digoxigenin)

Glycan- dogotoxose

Inhibit Na+K+ATase

pump

+Inotropic Action: Inhibition

of Na+K+ATpase pump

indirectly inhibit NCX which

further leads to increasing

intracellular Ca2+ ion in

myocardial tissues

– Chronotropic Action: by

hypokalemia and vegal

stimulation.

USED IN

CHF

Rapid Atrial Fibrillation

CONTRAINDICATED IN:

Arrhythmia

Hypokalemic patients

Elderly, renal and hepatic

dysfunction patient

Wolff Parkinsion White

Syndrome (arrhythmia MI

Thyrotoxicity

Myxoedema

Hypokalamia

Gynacomasteia (anti-

androgenic effect)

Treatment of Digitalis toxicity

V. arrhythmia—Lidocain,

phenytoin

SV tachycardia- propranolol

AV block: Atropine

Digoxin Antibody: DIGIBIND

(Digoxin-Fab)

INTERACTION:

+ Diurectic: marker hypokalemia

cause Tachyarrhythmia (reversed

by infuse 20-100 mM KCl/hour.

K+ also antagonize the digitalis

induced enhanced automaticity.

+ Ca2+ : Synergisms action

+ Quinidine, Verapamil,

Captoprol, Amioderone: increased

Plasma conc. of ditalis-- toxicity

PDE-III inhibitor

Amrinone

Milrinone

Inhibit the

phosphodiesterase enz

yme(PDE III)

+cCMP action

+Ionotropic by +cAMP in heart

Vasodilation by +cAMP in

vessels

CHF

Thrombocytopenia

Arrhythmia

Contraindicated in

Arrhythmia

PDE-V inhibitor

Sildenafil

+cGMP action Erectile dysfunction

*PDE III is responsible for dedradation of cAMP and PDE V is responsible for degradation of Cgmp

Beta 1 agonist:

Dobutamine

Dopamine

+ β1 (GsPCR) on

heart

+cAMP action

+Ino and Chronotropic effect

Used in

CHF

Cardiogenic shock

VASODIALATERS

-dilate the blood vessels and decrease the preload and afterload

Nitrates

Glyceryl trinitrate

(GTN)

Isosorbiddinitrate

Sod.nitropruside

(arterio-venodilator)

+ Gunylyl clycalse

+ cGMP action--

+MLCP

Veinodilator

Angina

Hypertension

Erectile dysfunction

Methemoglobinemia

Palpitation and Flushing

Reflux tachycardia (not used in

CHF)

drug dependence -MI and

sudden death if sudden

withdrawal due to coronary and

vessels spasm

nitropruside –cyanide toxicity.

Interaction:


+ Sildanafil—makred hypotension.

Ca2+ Channel

Blockers

Block L-type Ca

channel Arteriodilator

DHPs (lipophiloc)

Nifedipine

(Prototype)

“Vaso-selective”

Mainly act on blood

vessels than heart

Decrese TPR, Fall in BP

Reflex sympathetic stimulation of

heart predominates producing

tachycardia, increased contractility

and C.O. Coronary flow increased.

Used in

Hypertension

Angina

Raynaud’s epidode

Prevent premature labour

(nifedipine)

Hypotension

Palpitation and Flushing due to

sympathetic stimulation

Reflux Tachycardia

Ankle edema (is not due to

fluid retention, but because of

greater dilatation of

precapillary than postcapillary

vessels.

Decrease insulin release

(contraindicated in diabetes)

Other DHPs

S (-) Amlodepine

Felodipine

Nitrendipine

Nimodipine

Indication is similar as nifedipine but having some advantages:

Early vasodilator side effects (palpitation, flushing, headache, postural dizziness) are largely

avoided

Greater vassoselective action

Additionaly it release NO from endothelial cells and inhibit PDE. Thus, it enhances vasorelaxant

effect

Highy lipid solubility, selectively relax the cerebral vasculature. Used for neurological deficit

subarachnoid haemorrhage or ruptured congenital intracranial aneurysms.

Verapamil

(phenylalkylamine)

Heart selective

Mainly act on heart

than blood vessels

Verapamil has liltle

alfa blocking action.

- Iono, - Chrono, - dronotropic

Cardiac depressant action (decrease

HR, conducton)., but CO is

maintained by reflux sympathetic

action.

Coronary flow increased

Used in

Angina

Tachy Arrhythmia

Hypertension

Migraine

ADR

Bradycardia

Cardiac arrest

Contraindicated in:

Heart block

Bradyarrythmia

Interaction:

+ Beta blocker: Sinus depression,

conduction defects or asystole may

occur.

Diltiazem

(Benzothiazepine)

Heart selective L type

calcium channel

blocker

- Iono, - Chrono, - dronotropic

Consistent fall in BP, Coronary

flow increased

Used in

Angina

Tachy Arrhythmia

Hypertension

ADR

Bradycardia

Cardiac arrest

Contraindicated in:

Heart block

Bradyarrythmia

K+ Channel opener

Nicorandil

Pinacidil

Diazoxide

Cromakalim

Minoxidil

Produce

hyperpolerization. Arteriodilator

Angina

Hypertension

CHF

Alopecia (minoxidil)

Erectile dysfunction

Premature labour

Decrease insulin secretion

(diazoxide)

Palpitation

Flushing

Contraindicated With:

Oral hypoglycemic

Nicorandil: activates ATP sensitive K+ channels (KATP) and acts as a NO donor—relaxes blood vessels by increasing

cGMP. Thus, arterial dilatation is coupled with venodilatation. Coronary flow is increased; Nicorandil is believed to exert

cardioprotective action by simulating ‘ischaemic preconditioning’ as a result of activation of mitochondrial KATP channels.

RAAS modulator/inhibitor- RAS action is inhibited by-


Sympathetic inhibition (β1 receptor)- decrease renin release

Renin inhibitor- Aliskerin

ACE Inhibitors (ACEIs)

Ang II Type I receptor blockers (ARBs)

Pro Renin Receptor (PRR) inhibitors

Fig. Renin Angiotensin System

ACE inhibitor

Captopril (proline

derivative)

Enalapril (prodrug)

Ramipril

Inhibit the

conversion of Ang-

I to Ang-II

Indirect Arterio &

Veinodilators

Ang II and Bradykinin and

in long term Ang (1-7)

Malignant HTN

Hypertension

CHF

MI

Diabetic nepropathy

Scleroderma crisis

Persistant Cough due to

bradykinin

Hyperkalaemia

hypotension

Angiodema

Dysgeusia-alter taste

Foetopathic- hypoplasia of organ

Acute renal failure

Granulocytopenia and Proteinuria

Contraindicated in

Renal stenosis

Pregnancy

ARBs

Losartan

Olmesartan

Telmisartan

Irbesartan

Block the AT1

receptor (GqPCR)

Indirect Arterio &

Veinodilators

Hypertension

CHF

MI

Diabetic nepropathy

Scleroderma crisis

Hypotension

Hyperkalaemia

Foetopathic- hypoplasia of organ

Contraindicated in

Renal stenosis

Pregnancy

Natriuretic peptides: for compensate blood pressure NPs are released and produce natriuresis and vasodilatory effects.


Natriuretic

peptides

NP receptors Act on NPRs

Enz-linked receptoer (GC-

linked receptor)

They induce natriuresis

Vasodilation

Act on NPRs

CHF

Atrial natriuretic

peptide (ANP)

Release from Atria

Brain natriuretic

peptide (BNP)

Nisiritide

Release from

Ventricle

C-type natriuretic

peptide (CNP)

Release from blood

vessels

Sympathetic modulators:

α 1 blokers, β blockers, and α2 agonist can also be used in HTN to reduce BP by reducing TPR and/or cardiac work.

**For details please see Sympathetic system Section

DIURETICS Mainly used in CVS disorders to reduce peripheral edema, preload, venous return and volume retention

Figure: Nephron and Sites for Solute reabsorption


Figure: Site of drug action of diuretics


Figure: Diuretics Overview

DRUGS MECHANISM INDICATION

/DESCRIPTION

ADR

Loopdiuretics

Furosemide

Bumetanide

Ethacrinic acid

Block Na+K+2Cl-

Co-transport pump

(SITE II: apical mem.

of ascending loop of

Henle)

It secrete by OAT in

proximal tubules and act on

ALH.

Max. natriuresis effects:

excreation of Na+, K+, Ca2+,

and Mg2+

Used in

CHF

Hypertension

Edema

Hypercalcaemia and renal

calcium stone

Ototoxicity (hearing loss) Hypokalamia

Hypocalcemea

Alkalosis

Carbohydrate intolerance

Impaired lipid metabolism

+RAAS

Contraindicated in:

Pregnancy – miscarriage

Thiazides

Hydrochlorthiazide

Block Na+Cl-

Symport pump

(SITE III: DCT)

Decrease the Plasma volume,

TPR and C.O. (not preffer in

CHF)

Used in

Hypertension

Edema

Hypercalciuria

Ototoxicity (hearing loss) Hyperglycemia

Hyperlipidemia

Hypokalamia

Hypercalcemea

Hyperurecemia

Brisk Diuresis- Mental

disturbance and hepatic coma

Contraindicated in:

Renal failure (GFR<30 ml)

Diabetes

Hyperlipidemic

Pregnancy- miscarriage

Liver disease

CAIs

Acetazolamide

Inhibit carbonic

anhydrase

SITE I: proximal

tubules

Glaucoma

To Alkalinise urine

Epilepsy

Periodic paralysis

Glaucoma

Hypokalaemia

Hypersensivity reaction

Hyperurecemia

Contraindicated in:

Liver disease

COPD

K sparing diuretics

Spiranolactone

(Canerenon)

Aldosterone receptor

antagonist

Inhibit Na+ channe

Act on DT/CT (Site IV)

Adjuvant in other

CVS/diuretics drugs those

cause the K+ loss

Edema

Hypertension

CHF

Hyperkalaemia

Gyancomastia

Hirsutism

Impotence

Menstrual irregularities

Contraindicated:

o Renal insufficiency

o Cirrhotics

o Peptic ulcer

Eplerenone Aldosterone receptor

antagonist

New Aldosterone antagonist

having lesser side effect on

hormone disturbance

Hyperkalaemia

Amiloride

Inhibit renal epithelial

Na+ channel

Act on DT/CT (Site IV)

Adjuvant in other


cause the K+ loss

Edema, Hypertension, CHF

Symptomatic improvement in

cystic fibrosis

Hyperkalaemia


Triamterene Act on DT/CT (Site IV)

Adjuvant in other


cause the K+ loss

Edema, Hypertension, CHF

Hyperkalaemia

Impaired glucose tolerance

Photosensitivity

Interaction with K sparing diuretics:

K+ supplement/ACEIs /ARBs/NSAIDs-- dengerous Hyperkalaemia

Aspirin block it action by inhibit tubular secretion of Canerenone

It increase the plasma digitoxin concentration

Amiloride block the Li+ entry so mitigates diabetes insipidus induced by Li+

Osmotic Diuretic

Mannitol

(only iv)

Increase the osmotic

pressure

Glaucoma

To reduce intracranial

pressure

Acute renal failure

Pre/post ocular and brain

surgery

Poisoning along with slaine

Hyponatraemia

Contraindicated in

Acute tubular narcosis

Anuria

Pulmonary edema

CHF

Cerebral haemorrhage

Isosorbid

Glyerol

Oral active osmotic

diuretics

Glaucoma

To reduce intracranial

pressure

Haemolysis (in i.v.; glycerol)

ANTICOGULANT/THROMBOLYTIC AGENTS Mainly used in MI/Angina

DRUGS MECHANISM USE/INDICATION ADR/INTERACTION/

CONTRAINDICATIO

Anticogulants

Heparin (perenteral) + antithrombin III

Block the factor X and

thrombin

MI/Angina

Anticogulation in vivo and

in vitro

Antiplatelet

Leaemia clearing

Rheumatic heart diseases

Cerebrovascular diseases

Defibrination syndrome

ADR

Bleeding

Trombocytopenia

Alopecia

Osteophoresis

Contraindicated in:

Bleeding disorder

Sever Hypertension

Subacute bacterial endocarditis

Ocular and neurosurgery

Warfarin (oral)

Inhibit synthesis of Vit

K and cloting factors

MI/Angina

Anticogulation in vivo only Antiplatelet

Rheumatic heart diseases


Defibrination syndrome

Alopecia

Dermititis

Commercial- Recemic wrfarin

[R(+)&S(-) enantiomer]

Potency- S (-) > R (+) warfarin

Fibrinolytics

(plasminogen

activator)

Contraindicted of Fibrinolytics (Stk) in

Subacute bacterial endocarditis

Hemophilia or other bleeding disorder


Brain tumor

https://www.rxlist.com/script/main/art.asp?articlekey=6875


Aneurysm,

High blood pressure

Streptokinase (Stk)

Source-Beta

hemolytic

streptococci

Inhibit fibrin formation

by activating

plasminogen

Inhibit fibrin formation

by activating

plasminogen

Used in

MI/Angina

Vein thrombosis

Pulmonary embolism

Strock

ADR

Antigenic action

Allergy

Hypotension and arrhythmia

Bleeding

Urokinase (uPA)

(serine protease)

Source- urine &

cultured human

kidney

ADR

Allergy

Bleeding

Recombinant t-PA

(serine protease)

Alteplase

Reteplase

Tenecteplase

ADR

Mild hypotension

Bleeding

Contraindication

Uncontrolled hypertension

Thrombocytopenia

Cerebral hemorrhage

Antiplatelets

Aspirin COX1 and TXA2

synthesis inhibitor

Low dose of aspirin (50-150

mg/day or 300 mg

twice/week) act as an

Antiplatelet agent Angina

Dipyridamole Inhibit PDE

Block Adinosine

uptake and degragation

+ cAMP potentiates PGI2

and inhibit platelete

aggregation

Angina

Thromboembolism

Ticlopidine

(Thienopyridine)

Clopidogrel

inhibit ADP and

fibrinogen induce

aggregation

Indirect inhibit P2Y (GiPCR;

purinergic receptor).

Unstable Angina

Stroke

Other thrombotic diseases

Abaximab

Eptifibatide

Tirofeban

Glycoprotein (GP)

IIb/IIIa receptor

blocker

Coronary artery diseases

Unstable angina

MI

Other thrombolism


ANTIHYPERLIPIDEMICS

“Statins”

Lovastatin

Atorvastatin

Simvastatin

HMG-CoA reductase

inhibitor

Reduce cholesterol synthesis

Should be taken at bed time

because HMG-CoA

reductase activity is higher in

midnight

Type IIa, IIb and V

CAD

Sleep disturbance

Muscle tenderness

Myopathy

“Fibric acids”

Gemfibrozil

act on PPARα

Enhance the lipoprotein

lipase synthesis and fatty

Myopathy

Eosinophilia


Fenofibrate

Bezafibrate

acid oxidation

Increase LDL receptor

expression

Decrease TG synthesis

Type III, IV, and V

Impotance

Blurred vision

Bile acid

sequestrants:

Cholestyramine

Colestipol

Decrease bile acid absorption

Increase LDL receptor

Niacin Niacin receptor

(GiPCR)

Decrease production of

VLDL by inhibiting TGs

synthesis

Decrease lipolysis in

adipocytes

Ezetimibe Block Cholestrerol

transport protein

(NPC1C1)

Decrease the both bile and

dietary cholesterol


ANTIARRHYTHMICS Vaughan Williams & Singh gave a four class system for antiarrhythmic agents. D.C. Harrison proposed a modified

subgrouping of class I agents.

CLASS I : Membrane stabilising agents (Na+ channel blockers).

Class 1A : The drugs of this group prolong action potential duration. e.g. quinidine, procainamide, disopyramide

& moricizine.

Class I B : The drugs of this group shorten action potential duration e.g. lidocain, phenytoin, tocainide and

mexiletine.

Class 1C : The drugs of this group have no effect on action potential duration. (i.e., slow phase O depolarisation

e.g. Encainide, Flecainide, indecainide and propaferone.

CLASS II : ‘’ adrenergic blockers e.g. propranolol, metoprolol, sotalol

CLASS III : Drugs that prolongs the action potential duration (potacium channel blockers) e.g. Amiodarone, Bretylium

tosylate.

CLASS IV : Calcium channel blockers, e.g. Verapamil, diltiazem, nifedipine.


The important cardiac arrhythmias are:

1. Extrasystoles (ES) are premature ectopic beats due to abnormal automaticity or afterdepolarization arising from an

ectopic focus in the atrium (AES), A-V node (nodal ES) or ventricle (VES). The QRS complex in VES is broader and

abnormal in shape.

2. Paroxysmal supraventricular tachycardia (PSVT) is sudden onset episodes of atrial tachycardia (rate 150–200/min)

with 1:1 atrioventricular conduction: mostly due to circus movement type of reentry occurring within or around the A-V

node or using an accessory pathway between atria and ventricle (Wolff-Parkinson-White syndrome or WPW).

3. Atrial flutter (AFI) Atria beat at a rate of 200–350/min and there is a physiological 2:1 to 4:1 or higher A-V block

(because A-V node cannot transmit impulses faster than 200/min). This is mostly due to a stable re-entrant circuit in the

right atrium, but some cases may be due to rapid discharge of an atrial focus.

4. Atrial fibrillation (AF) Atrial fibres are activated asynchronously at a rate of 350–550/min (due to electrophysiological

inhomogeneity of atrial fibres), associated with grossly irregular and often fast (100–160/min) ventricular response. Atria

remain dilated and quiver like a bag of worms.

5. Ventricular tachycardia (VT) is a run of 4 or more consecutive ventricular extrasystoles. It may be a sustained or

nonsustained arrhythmia, and is due either to discharges from an ectopic focus, after-depolarizations or single

site (monomorphic) or multiple site (polymorphic) reentry circuits.

6. Torsades de pointes (French: twisting of points) is a life-threatening form of polymorphic ventricular tachycardia with

rapid asynchronous complexes and an undulating baseline on ECG. It is generally associated with long Q-T interval.

7. Ventricular fibrillation (VF) is grossly irregular, rapid and fractionated activation of ventricles resulting in

incoordinated contraction of its fibres with loss of pumping function. It is fatal unless reverted within 2–5 min; is the most

common cause of sudden cardiac death.

8. Atrio-ventricular (A-V) block is due to depression of impulse conduction through the A-V node and bundle of His,

mostly due to vagal influence or ischaemia.

First degree A-V block: Slowed conduction resulting in prolonged P-R interval.

Second degree A-V block: Some supraventricular complexes are not conducted: drop beats.

Third degree A-V block: No supraventricular complexes are conducted; ventricle generates its own impulse; complete

heart block.

Drug of Choice

PSVT- Adenosine

Atrial flutter- Cardioversion

Atrial Fibrillation - Cardioversion

Atrial extra systole- Quinidine

Ventricular extrasystole

Due to MI------- Lignocaine

Due to Digitalis--- Lignocaine

Ventricular tachycardia- Ligocaine, CaCl2

Wolff-Parkinson-White syndrome- Cardioversion, procainamide

Sinus bradycardia- Atropine

Cardiac arrest- Adrenaline, dobutamine

Heart block- Isoprenaline

Atrial fluter - Didoxine

Ventricular fibrillation/digitalis arrhythmia - MgCl2

Torsades de point: MgSO4


DRUGS MOA INDICATION ADR/CONTRAINDICATION

Class I

Quinidine

(+) Quinine alkaloid

Antimalerial- (-)

isomer

Open state Na+

channel blocker

(Ia)

Block AV conduction, prolong

APD (due to K+ ch. Block),

ERP/APD>1

Quinidine increases P-R and Q-T

intervals and tends to broaden

QRS complex.

Other Action:

fall in BP (due toweak α1

adrenergic blockade and direct

cardiac depression),

decreased skeletal muscle

contractility,

uterine contractions,

neurological effects like ringing in

ears, vertigo, deafness, visual

disturbances and mental changes

(Cinchonism).

Used in

Atrial and Ventricl arrhythmia

Prevention of paroxysmal

recurrent atrial fibrillation

(triggered by vagal overactivity),

ADR

Cardiac arrest

Idosyncracy and hypersensitivity

INTERACTION:

+digitalis: Rise in blood levels and

toxicity of digoxin due

todisplacement from tissue binding

and inhibition of P-glycoprotein

mediated renal and biliary clearance

of digoxin.

Marked fall in BP in patients

receiving vasodilators.

Risk of torsades de pointes is

increased by hypokalaemia caused

by diuretics.

Synergistic cardiac depression with

β blockers, verapamil, K+ salts.

Quinidine inhibits CYP2D6:

prolongs t½ of propafenone and

inhibits conversion of codeine to

morphine.

Lidocain Block the Na+

channel in both

state

Mainly in

inactivated state

(Ib)

Supress of automaticity in

ectopic foci.

Not affect AV conduction only

affects cardiac contractile

muscle.

QT interval may decrease.

Used in V. arrhythmia and

digitalis induced arrhythmia.

Propafenone Block Na+

channel in open

state

Long recovery

time

(Ic)

Depresses impulse transmission

and has profound effect on His-

Purkinje as well as accessory

pathway conduction

Used in PSVT

Precipitate CHF and Asthma

Neurological disturbance

Visual disturbance

Potent proarhythmic drug

Class III

Amiodarone K+ channel

blocker

(III)

Amiodarone is a broad spectrum

antiarrhythmic agent belonging to

class IA, II, III and IV

Increase APD and ERP

Used in ventricular and

supraventicular arrhythmias

Blue baby syndrome

Bretylium Tosylate K+ channel

blocker

(III)

Bretylium tosylate is an

adrenergic neuron blocker.

It prolongs ventricular action

potential duration and effective

refractory period.

It is used in ventricular

tachycardia, ventricular

fibrillation and in ventricular

premature beats


SHOCK Shock (Inadequate perfusion and oxygenation of cells) is a life-threatening condition that occurs when the body is not

getting enough blood flow and there's insufficient circulation of oxygen in body. This can damage multiple organs. It

typically occurs when blood pressure falls to a very low level, either from reduced cardiac output, or from reduced

effective circulating blood volume. As blood pressure falls, brain and other organs don't get enough blood or oxygen to

function, and they begin to fail. Shock can arise from a number of causes. It is a life-threatening medical emergency and

must be treated early to avoid serious complications and even death.

types of Shock:

1. Cardiogenic: heart fails to pump blood out due to MI.- Adrenaline, dobutamine, dopamine (preffered in

oligouric cardiogenic shock)

2. Obstructive: heart pumps well, but the output decreased due to an obstruction (in or out of heart).

3. Hypovolemic: heart pumps well, but not enough blood volume.- fluid replacement by plasma, saline, or blood

4. Distributive: heart pumps well, but there is peripheral vasodilation due to loss of vessel tone.

5. Anaphylactic shock: hypersensitivity/allergic reaction leads marked vasodilation and increase capillary

permeability.- Adrenaline, Antihistamines (H1 blocker; diphenhydramine), Corticostreroids, and inhaled

Oxygen.

6. Septic Shock: shock by bacterial infection charecterised by decreased vascular resistance.-

Antibiotics/Noradrenaline with fluid replacement. Isoprenaline used for improve tissue perfusion.

Classification of drugs used for treatment of shock:

There are 3 categories of drugs that play a role in treating shock:

1. Vasoconstrictors: Epinephrine, Norepinephrine, Methoxamine HCl,

2. Cardiotonic drugs: Digoxin, Dobutamine, Dopamine. (refer section ‘Congestive cardiac failure’)

3. Fluid replacement agents: Whole blood. IV solutions of electrolyte.

Others:

Glucagon improve haemodynamic state, used in acute heart failure, MI

Dextron: plasma expenders, used in hypovolumic shock.

Oxygen: Used in cardiogenic shock to create positive pressure ventilation.


BLOOD COGULANTS AND ANTICOGULANTS

Figure: Process of Blood cloting/cogulation


Vitamin K is essential for synthesis of Factors II, VII, IX and X

Function of vitamin K Synthesis of clotting factor II, VII, IX and X and make the γ–carboxylation of these which

is essential for the ability Ca2+and to get bound to phospholipid surface → further cascade of coagulation.

Deficiency of vitamin K Due to liver disease, obstructive jaundice, malabsorption, long term antimicrobial

therapy E.g., Tetracyclines, β–lactams etc.

Local haemostatics (Synaptics): Substances used to stop bleeding from a local approachable site; E.g., tooth pocket, open

wounds etc. Thrombin, Fibrin, Russels viper venom, Vasoconstriction: 1% adrenaline, and Astringent: tannic acid

ANTICOAGULATING AGENTS Prevents blood clotting in vitro or in vivo or both

1. Used in vitro:

a. Organic acid: Heparin

b. Organic acid salt: EDTA, Sod. Citrate, sod. oxalate

2. Used in vivo:

a. Perenteral:

Heparin: Heparinoids, Heparan sulfate, Danaproid, Lepirudin, Ancord

b. Oral anti–coagulants:

Coumarin derivetives: Warfarin (Coumadin), Acenocumarol, Indendione phenindione

Danaparoid (Heparan sulfate) A heparin of different structure, it may be safer in hypersensitivity to heparin.

Phenindione Used as oral anticoagulant. It produce serious toxic effecs; E.g., rashes, fever, hepatitis, nephropathy,

agranulocytosis orange urine.

Direct thrombin inhibitors (DTIs)

Hirudin and bivalirudin these are bivalent DTIs that bind at both the catalytic or active site of thrombin as well as at

a substrate recognition site → prevents formation of fibrin and cotting of blood.

Argatroban is a small molecule thrombin inhibitor that is FDA approved for use in patients with heparin–induced

thrombocytopenia (HIT) with or without thrombosis and coronary angioplasty in patients with HIT.


Chapter 4

Aotacoids

Autacoids are also known as local harmones, and generally act locally at the site of synthesis and release.

Autacoids are involved in the inflammatory and immunological response.

CLASSIFICATIONS:

1. Amines: Histamine and Serototine (5HT)

2. Lipid derivetives (Eicosanoids): Prostaglandins, Leukotrienes, Platelet activating factor (PAF), and

Thromboxanes

3. Peptides: Plasma Kinins (Bradykinin, Kallidin), Angiotensins, vasopressin, substance-P, slow reacting

substance of anaphylaxix

4. Others: Cytokines, gastrin, somatostatin, vasoactive intestinal peptides, cholestokines.

HISTAMINE Histamine is also known as tissue amines, which present in human, animals, plants (Stinding nettle),

bacteria and insect venom.

English scientists George Barger and Henry H. Dale first isolated histamine from the plant fungus ergot in

1910, and in 1911 they isolated the substance from animal tissues.

Dale in 20th century observed the pharamacological action of histamine mainly, Allergic and hypersensitive

reactions.

In humans histamine is found in nearly all tissues of the body, where it is stored primarily in the granules of

tissue mast cells. The blood cells called basophils also harbour histamine-containing granules.

Mast cell (slow turnover) relrase – Skin, GI mucosa, lungs, liver, and placenta

Non-Mast cell (Fast turn over)- Brain, gastric mucosa, and epidermis.

H1 and H2 reeptor classified by Asch and Schild, 1966

Sir James Black, 1972- developed first H2 blocker (Burimamide)

In 1983, H3 autoreceptor locate in brain.

Histamine (β-imidazolyl ethyamine)

L-Histidine

Decarboxylase

N-methyl histamine

Imidazole acetic acid


Histamine

N-me. transferase

Diamine oxidase

https://www.britannica.com/biography/Henry-Dale

https://www.britannica.com/science/ergot


H1 H2 H3

Selective agonist 2-(m-fluoro phenyl)

histamine

2-me-histamine (8:1,

H1:H2)

2-thyazolyl ethylamine

(90:1, H1:H2)

Dimaprit, Impromidine R--methyl histamine

Selective antagonist Mepyramine Ranitidine, Roxatidine Imetit, Thioperamide

Effector pathway GqPCR (IP3/DAG) GsPCR (cAMP) GiPCR

Distribution Smooth muscles: intestine,

bronchi, uterus

Stomach, Uterus, Heart Brain

Action Allergic reaction

Smooth muscle

contration (intestine,

bronchi, uterus)

Blood vessels: Large

artery constrict and

small artery and veins

dilated via EDRF (NO)

Intradermal inj shows:

Flush, wheal and flare

action.

Enhance the capillary

permeability.

In brain acts as a

neurotransmitter.

Stimulate afferent nerve

endng and ganglionic

cell.

In adrenal medulla –

release Catacholmines

GI seceretion

Heart: +chrono and

+inotropic

Blood vessel: dilation

Uterus : relax

Autoreceptor: decrease

Histamine release at

presynaptic (Sedation)

Decrease Ach release in

intestine

Decrease Nor-Ad

release


ANTIHISTAMINIC (H1 Receptor Antagonist)

H1 antagonists are lipophilic, therefore, they cross blood brain barrier easily and produce sedation.

Clinically H1 antihistamines are classified into three categories depending on the use or degree of

sedation they produce. Antihistamic drugs oppose the action of histamine by blocking H1 receptor. Sedative Nonsedative Antivertigo

Highly sedative Moderately Sedative Mild Sedative

Diphenhydramine

Dimenhydrinate

Promethazine

Trimeprazine

Meclizine

Buclizine

Antazoline

Pheniramine

Cyproheptadine

Clemastine

Methdilazine

Chlorpheniramine

Triprolidine

Cyclizine

Mepyramine

Cetirizine

Astemizole

Terfenadine

Cinnarizine

SEROTONIN

5-Hydroxytryptamine or 3-(2-aminoethyl)-1H-indol-5-ol

Serotonin 5HT1

5HT2

5HT3

5HT4

GiPCR: inhibit cAMP/PKA pathway

GqPCR: activate IP3/DAG pathway

Ligand gated cation channls

GsPCR: activate cAMP/PKA pathway

5-CT, Sumatriptan, Buspirone

α-methyl 5-HT

2-methyl 5-HT

5-methoxy tryptamine, Metaclopramide

Methiothepin, Cyanopindolol

Methysergide, Ketanserine

Ondansetron, Tropisetron, Zacoprid

GR113808, RS39604

Some importance physiological role of serotonins, and its antagonists.

Migraine: serotonins produce the migraine due to its vasoconstriction effects; therefore, the methylsergide

(5HT-2 antagonist) and sumatriptan (5HT-1 agonist) can effectively control the attack.

Raynaud’s: release of serotonins from platelet trigger acute vasospastic episodes of larger arteries,

ketanserin (5HT-2 antagonist) has prophylactic values in Raynaud’s.

5HT-3 antagonist (Ondansetron, Tropisetron, Zacoprid) are widely used in cytotoxic drug or radio therapy

induce emesis, as an antiemetic drugs.

5HT-4 Agonist/Prokinetics (Cisapride, Mosapride, Renzapride) are used as an antiemetic drugs


EICOSANOID

Eicosanoid Effect

PGD2 Promotion of sleep9 l

PGE2 Smooth muscle contraction; inducing pain, heat, fever; bronchoconstriction

PGF2α Uterine contraction

PGI2 Inhibition of platelet aggregation; vasodilation; embryo implantation

TXA2 Stimulation of platelet aggregation; vasoconstriction

LTB4 Leukocyte chemotaxis

Cysteinyl-LTs Anaphylaxis; bronchial smooth muscle contraction.

Drug Type Use

Alprostadil PGE1 Erectile dysfunction, maintaining a patent ductus arteriosus in the fetus.

Carboprost PG analogue Labour induction, abortificient in early pregnancy.

Dinoprostone PGE2 Labor induction

Iloprost PGI2 analogue Pulmonary arterial hypertension

Misoprostol PGE1 analogue Stomach ulcers, labour induction, abortifacient

Montelukast LTreceptor antagonist Asthma, seasonal allergies

Travoprost PG analogue Glaucoma, ocular hypertension

Zafirlukast LT receptor antagonist Asthma

http://en.wikipedia.org/wiki/Bronchoconstriction

http://en.wikipedia.org/wiki/Contraction_(childbirth)

http://en.wikipedia.org/wiki/Prenatal_development#Fertilization_and_embryogenesis

http://en.wikipedia.org/wiki/Chemotaxis

http://en.wikipedia.org/wiki/Alprostadil

http://en.wikipedia.org/wiki/Carboprost

http://en.wikipedia.org/wiki/Dinoprostone

http://en.wikipedia.org/wiki/Induction_(birth)

http://en.wikipedia.org/wiki/Iloprost

http://en.wikipedia.org/wiki/Pulmonary_hypertension

http://en.wikipedia.org/wiki/Misoprostol

http://en.wikipedia.org/wiki/Montelukast

http://en.wikipedia.org/wiki/Receptor_antagonist

http://en.wikipedia.org/wiki/Asthma

http://en.wikipedia.org/wiki/Allergy

http://en.wikipedia.org/wiki/Travoprost

http://en.wikipedia.org/wiki/Glaucoma

http://en.wikipedia.org/wiki/Hypertension

http://en.wikipedia.org/wiki/Zafirlukast

http://en.wikipedia.org/wiki/Receptor_antagonist

http://en.wikipedia.org/wiki/Asthma


Chapter 5

Gastrointestinal Drugs

ANTI ULCER

Figure 46.1: Secretion of HCl by gastric parietal cell and its regulation

C.Ase.—Carbonic anhydrase; Hist.—Histamine; ACh.—Acetylcholine; CCK2—Gastrin cholecystokinin receptor; M.—Muscarinic receptor; N—Nicotinic receptor; H2—Histamine H2 receptor; EP3—Prostaglandin receptor; ENS—Enteric nervous system; ECL cell Enterochromaffin-like cell; GRP—Gastrin releasing peptide; + Stimulation; – Inhibition.

H2 receptor

blocker

The histamine H2 receptor antagonists act on H2 receptors in the stomach, blood vessels and other

sites. They are competitive antagonists of histamine and are fully reversible. These agents completely

inhibit gastric acid secretion induced by histamine, or gastrin. However, they only partially inhibit

gastric acid secretion induced by acetylcholine or bethanechol. They also inhibit the secretion of

pepsin and IF

Drug MOA Indication ADR Contraindication

Cimitidine

(Imidiazole ring)

H2 (GsPCR)

Blocker

Prototype H2

blocker

Peptic Ulcer

Zollinger

Ellison

Syndrome

Bradycardia

Bronchospasm

Antiandrogenic

effects:

Metabolic Enz Inhibitor

Decrease the metabolism

of others and cause drug

toxicity


GERD

Prophylaxis of

aspiration

pneumonea

Gynaecomastia, loss

of libido, impotency

Cross the BBB and

produce CNS effects

Ranitidine (Furan

ring)

H2 blocker Used similar as cimitidine but having less or

No CNS and Antiandrogenic effects

Fomatidine

(thiazole ring)

Competitive and

Non competitive

H2 blocker

Proton Pump

inhibitors (PPIs)

This class of drug binds to the H+/K+-ATPase enzyme systeni (proton pump) of the parietal cell,

suppressing secretion of hydrogen ions into the gastric lumen. The membrane-bound proton pump is

the final step in the secretion of gastric acid. They not affect the secretion of pepsin, gastrin, IF and

GI motility. PPIs do not affect the cholinergic and histaminergic transmission. E.g. Omeperazole,

pentaperazole, Rebeprazole, Esomeprazole.

Omeperazole

(benzimidazole)

Prototype PPI At neutral pH it is inactive and activate at

pH < 5

Peptic Ulcer

Zollinger Ellison Syndrome (First choice)

GERD

Prophylaxis of aspiration pneumonea

ADR:

Long treatment –

Atrophic gastritis

(hypergastrinemia).

Caranoid tumor cause the

over secretion of gastric

juice.

Gynaecomastia

Erectyle dysfunction

Osteophoresis (impaired Ca2+

absorption)

Prostaglandin

and prosta

cycline

Prostaglandins E2 and I2, produced by the gastric mucosa, inhibit secretion of HCI and stimulate

secretion of mucus and bicarbonate (Cytoprotective effect). A deficiency of prostaglandins is

thought tobe involved in the pathogenesis of peptic ulcers.

Mesoprostol PGE2 NSAIDs

induced Ulcer

Uterine Bleeding

Cisaprost PGI2

Antacids Antacids are weak bases that react with gastric acid to form water and a salt, thereby diminishing

gastric acid. H+ binding groups such as CO32-, HCO3- or OH- together with their counter ions are

contained in antacid drugs. The acid-neutralizing ability of an antacid depends on its capacity to

neutralize gastric HCl (Acid neutralizing capecity) and on whether the stomach is full or empty

(food delays stomach emptying, allowing more time for the antacid to react).

**Acid Rebound action is common with antacids, becoze increase the gastic pH >4 cause the

relase the gastrin and pepsin to overcome the gastric pH for optimal peptic activity (pH 2-4)

Acid neutralizing capecity (ANC): no of mEq of 1N HCl that brought upto pH 3.5 within 15 min

by a unit dose (g) of an antacid.

NaHCO3

(ANC)1g = 12

mEq HCl

Systemic

antacid

Alkalosis

Increase Na+

overload

Acid Rebound action

Contraindicated with

CHF and Edema

Drug interactions:

Concurrent administration

of antacids and other drugs

are avoided. By altering

gastric and urinary pH or

delaying gastric emptying,

antacids can affect rates of

dissolution and absorption,

bioavailability, and renal

elimination of many drugs.

With tetracycline, Al3+

compounds can form

Al(OH)3 gel ANC = 1-2.5

mEq HCl

Used in

hyperphosphate

mia and

phosphate

stone

Constipation

Decrease GI

emptying

Hypophosphatemia-

Osteomalacia

CaCO3 ANC = 20 mEq

HCl

Marked Acid

rebound action


Milk Alkali

Syndrome

insoluble complexes that

are not absorbed.

Antacids can increase the

rate of absorption of some

drugs, for example,

levodopa.

ANTI EMETICS

Emesis: Vomiting is controlled by vomitting centre (CTZ) located in medulla oblongata. Activation of 5HT3, H1, M, and

D2 receptors triggers the CTZ and evoke the emesis while opoid (u) receptor suppress the emesis

Emetic agents:

Apomorphine: act on CTZ by activating dopaminergic activity on CTZ. ADR- CNS and Respiratory depression. i.m./s.c.

only

Ipecacuanha: Emesis by reflex action

DRUG MOA DESCRIPTION ADR/CONTRINDICATION

Anticholinergic M receptor

antagonist

Motion and morning sickness

Hyoscine Motion sickness

Dicyclomine Motion and Morning sickmess

Anti Histaminics H1 antagonist Motion, morning, and post operative emesis

Promethazine

Diphenhydramine

Dimenhydrinate

Used in Motion Sickness and Chemo

induced emesis

Block Central Cholinergic thus block the

extrapyrimdal effects

Sedative drugs

Doxylamine Sedative anti histaminics with prominent

central anticholinergic ction

Morning sickness along with pyridoxime in

early pregnancy


Foetal malformation

Taretogenicity

Cyclizine

Cinnarizine

Motion sickness

Anti vertigo

Neuroleptics Central D2

Blockers

Chlorpromazine Block the D2 as well as M and H1 R

Broad spectrum anti emetics

Prochlorperazine Labyrithing suppressant

Selective anti vertigo

PROKINETICS

ANTIEMETICS

The drugs, which are act on 5HT4 agonist and D2 antgonist are known as prokinetics. They increase

the GI motililty, transit and emptying and improve lower esophagal sphincter (LES) tone

Metachlorpromide

(Procainamide

analogue)

Introduce as

gastric hurrying

agent

D2 antagonist

5HT4 agonist

5HT3 antagonist

D2 antagonist:

Suppress CTZ

Improve GI emptying and LES tone

(dopamine: inhibitory action on GIT)

5HT4 agonist: increase the Ach release.

Prokinetic effect

Improve Gastric hurrying and LES tone

5HT3 antagonist:

Suppress CTZ

USES:

Antiemetics

Gastrokinetics

GERD

Dyspepsia

ADR:

Gynaecomastia

Glactorrhoea

Parkinsonism

Interaction:

Abolish the therapeutic

effect of L-dopa

Decrease the absorption of

drugs like Aspirin, BDZ

Domperidone Peripheral D2

antagonist

Lesser Antiemetic and prokinetic action.

Prokinetic action is related to D2

antagonism only

ADR:

Glactorrhoea

Hyperprolactemaemia

arrhythmia

Cisapride Strong 5HT4

agonist

Week 5HT3

antadonist

Improve Gastric hurrying and LES tone,

additionally increase the colon transit.

Prokinetic action mainly

Used in GERD, dyspepsia, and constipation.

ADR:

Arrhythmia(Torsades depoint)

Mosapride Strong 5HT4 Ag

Week 5HT3

antadonist

Similar as cisapride but having no

arrhythmatic effect

Tegaserod Selective partial

5HT4 agonist

Mainly increase colon and gstric transit

Lesser effect on LES tone

Used in constipation, irritable bowl

syndrome

5HT3 Antagonist

Ondansetron

Antiemetic action only

Not use in motion and morning sickness


Chapter 6

Chemotherpy

CHEMOTHERAPEUTIC AGENTS/ANTIBIOTICS

The term chemotherapy was coined by Ehrlich at the beginning of the 20th century to explain the use of

synthetic chemicals to destroy infective agents.

The drugs in this class are differing from other drugs including antihypertensive, antianginals, antiulcer etc. The

chemotherapeutic drugs are designed to act on pathogenic microorganism, due to analogy between

cancerous or malignant cell with pathogenic microbes therefore the treatment of neoplastic diseases with the

drugs is also include in chemotherapy.

Definitions:

Chemotherapy: is the use of synthetic or natural agents to destroy or inhibit the growth of infective agents (e.g.

bacteria, fungi, virus, helminthes and protozoa) and cancerous cells.

Chemotherapeutic agents: are chemicals which are designed to inhibit the growth or destroy the infective

agents without significantly affecting the host.

Antibiotics: are substance produced by microorganism that in suppress the growth or destroy the other

microorganism at low concentration.

Antimicrobial agents (AMA): are the synthetic or natural substances that are used to treatment of various

infections e.g. bacterial, fungal and viral.

History

Phase 1: Emperical phase

Chaulmoongra oil is used by Hindus in leprosy

Chenopodium by Aztecs for intestinal worms

Cinchona bark for fever

Phase II: Ehrlich pase (1890-1935)- Dyes and Organometalic compounds

Arsenicals—atoxyl for sleeping sickness

Arsphenamine (1906) and Neoarsphenamine (1909)—for syphilis

Ehrlich coined the term “ Chemotherapy”

Phase III: Modern era

Domagk (1935) – Prontosil (a sulphonamide dye)—for pyogenic infection. And he noticed that p-

amino benzene sulphonamide is an active metabolie. Sulfapyridine (M &B 693) is first sulphonamide

marketed in 1938.

Antibiotic phenomeno – by Pasteur (1877) – anthrax bacilli in urine was inhibited by air burn bacteria.

In 1940s- Waksman and his students research the Actenomycetes as the source of Antibiotics and

discovered Streptomycin in 1944.


Domagk, Fleming , and Waksman--- got NOBEL PRIZE for their discoveries.

* commensals: Many microorganism are not pathogenic in normal condition they share our body spaces (e.g.

the gut) these are called commensals, even if host is immune compromised they become pathogenic

**Prions: This is a proteinacious agent which causes diseases but resist to all attempt to chemotherapeutic

agents.

MOLECUALR BASIS OF CHEMOTHERAPY

Bacteria is the most infective micro-organism, and cause most of the infective diseases like UTI,

Pneumonia,

Becterial Cell

1. Cell walls- Contains peptidoglycan except mycpplasma it contains mycolic acid

2. Plasma membrane-

Similar to eukaryotes phospholipid bilayer and proteins

Selective perimiability by selective transport system for specific nutrients and drugs.

It dose not contains Sterols and thus it may alter the penetration of some chemical agens

3. Ribosomes (70s)—50s + 30s—protein synthesis

4. Chromosome – single circular chromososme DNA

5. Capsule- Grame negative bac.- prevent penetration and attack of lysozymes

Biochemical Reaction

Class I


The utilisation of glucose or some alternative carbon source for the generation of energy (ATP) and

simple carbon compounds (such as the intermediates of the tricarboxylic acid cycle), which are used as

precursors in the next class of reactions.

Similar to human for energy production pathway (Embden-Meyerhof pathway and the tricarboxylic

acid cycle) thus not promosing target

Second, even if the glucose pathways were to be blocked, a large variety of other compounds (amino

acids , lactate, etc.) could be used by bacteria as alternatives.

Class II

The utilisation of the energy and precursors to make all the necessary small molecules: amino acids ,

nucleotides, phospholipids, amino sugars, carbohydrates and growth factors.

Better target becoz some pathways are exist in only paracytes not in human.

Bacteria- synthesis some essential amino acis (folic acid) and Growth factor (Vitamins)

Ex- Folate, Pyrimidine, and Purin analauges.

Folate

The synthesis of folate is an example of a metabolic pathway found in bacteria but not in humans.

Folate is required for DNA synthesis in both bacteria and in humans. Humans cannot synthesise it but

obtain it from the diet and have evolved a transport mechanism for taking it up into the cells. By

contrast, most species of bacteria, as well as the asexual forms of malarial protozoa, have not evolved

the necessary transport mechanisms and they cannot make use of preformed folate. They must, of

necessity, synthesise their own folate by de Novo synthesis pathway

Sulfonamides (PABA analauge) compete with PABA for the enzyme (DHFS) involved in folate

synthesis and thus inhibit the metabolism of the bacteria

Trimethoprime (Folate analauge) Compete with Dihydro folate for the enzyme (DHFR)

PABA---(DHFS)- DH Folate---(DHFR)-- TH Folate---(+purine/pyrimidine)-----DNA/RNA

SENSIVITY OF FOLATE ANALAUGE/ANTAGONIST

IC50 valuses for

DHFR

Human Protozoa Bacteria

Trimethoprime 260 0.07 0.005

Pyrimethamine 0.7 0.0005 2.5

Methotrixate 0.001 0.1 INACTIVE

Purine and Pyrimidine Analauge

Ex.- Antimetabolite neoplastics - 5FU, Mercaptopurine, Thioguanine, Flucytosine

Class III

Assembly of the small molecules into macromolecules: proteins, RNA, DNA, polysaccharides and

peptidoglycan.

Good target for selective toxicity

Synthesis of Peptidoglycan, protein, and Nuclic acid, DNA&RNA

http://www.studentconsult.com/content/bookcontent.cfm?ID=HC044003


Peptidoglycan –

Gram-positive bac. contains up to 40

layers thick peptidoglycan. Each layer

consists of multiple backbones of

amino sugars-alternating N-

acetylglucosamine and N-

acetylmuramic acid residues.

Peptidoglycan synthesis inhibitors-

Beta lactums- penicillin,

cephalosporin, carbepenam,

monobactum

Glycopeptide- Vancomycin

Other- Bacitracin

Protein Synthesis-

Protein synthesis takes place in the ribosomes-cytoplasmic nucleoprotein structures. Ribosomes are

different in eukaryotes and prokaryotes and this provides the basis for the selective antimicrobial action

of some antibiotics.

The bacterial ribosome consists of a 50S subunit and a 30S subunit. The other elements involved in

peptide synthesis are messenger RNA (mRNA), which forms the template for protein synthesis, and

transfer RNA (tRNA), which brings the individual amino acids to the ribosome. The ribosome has

three binding sites for tRNA, the A, P and E sites.

DNA---(transcription)----mRNA---------(Translation)--------Protein



Nucleic Acid Synthesis


The nucleic acids of the cell are DNA and RNA.

There are three types of RNA: mRNA, tRNA and ribosomal RNA (rRNA). (The rRNA is an integral

part of the ribosome, being necessary for its assembly, having a role in the binding of mRNA and

having peptidyl transferase activity.) All are involved in protein synthesis.

Each nucleotide consists of a base linked to a sugar (deoxyribose) and a phosphate. There are two

purine bases, adenine (A) and guanine (G), and two pyrimidine bases, cytosine (C) and thymine (T).

The chain is made up of alternating sugar and phosphate groups with the bases attached

Initiation of DNA synthesis requires first the activity

of a protein that causes separation of the strands.

The replication process inserts a positive supercoil.

This is relaxed by DNA gyrase (also called

topoisomerase II and IV)

It is possible to interfere with nucleic acid synthesis in five

different ways:

by inhibiting the synthesis of the nucleotides

by altering the base-pairing properties of the

template

by inhibiting either DNA or RNA polymerase

by inhibiting DNA gyrase

by direct effects on DNA itself.

Inhibition of the synthesis of the nucleotides

e.g. Folate analauge (DHFR Is), Antimetabolites

Alteration of the base-pairing properties of the template

Agents that intercalate in the DNA have this effect.

Examples are the acridines (proflavine, acriflavine),

which are used topically as antiseptics

The acridines double the distance between adjacent

base-pairs and cause a frameshift mutation. whereas some purine and pyrimidine analogues cause

mispairing.


Inhibition of either DNA or RNA polymerase

Actinomycin D) binds to the guanine residues in DNA and blocks the movement of RNA polymerase,

thus preventing transcription and consequently inhibiting protein synthesis. It is used in cancer

chemotherapy in humans. NOT BLOCK THE BAC. RNA POLYMERASE

Bacterial RNA Polymerase Inhibotors- Rifampicin, Rifamycin- TB

Acyclovir (Guanine analauge)- DNA polymerase inhibitors ---- Herpes

RNA retroviruses have a reverse transcriptase (viral RNA-dependent DNA polymerase) that makes a

DNA copy of the viral. Zydovudin, Didanosine- R. transcriptase inhibitors.

Foscarnate- Viral RNA polymerase inhibitor.

Inhibition of DNA gyrase (Topoisomerase IV)- Quinolones (ofloxacine, ciprofloxacin, Norfloxacin)

Direct effects on DNA itself – Alkelying agents, nitrogen mustard derivatives and nitrosoureas

THE FORMED STRUCTURES OF THE CELL AS POTENTIAL TARGETS

Cell Membrane-

Polymixins are cationic detergent antibiotics that have a selective effect on bacterial cell membranes

Fungal cells, unlike mammalian and bacterial cells, have large amounts of ergosterol in the plasma

membrane. The ergosterol facilitates the attachment of polyene antibiotics (e.g. nystatin and

amphotericin), which act as ionophores and cause leakage of cations.

Ergosterol synthesis inhibitors- Azoles (itraconazole, Ketakonazole)- ltering membrane fluidity and

thus the function of membrane-associated enzymes.

Microtubules/Microfilament

The benzimidazoles (e.g. albendazole ) have anthelminthic action by binding selectively to parasite

tubulin and preventing microtubule formation

The vinca alkaloids vinblastine and vincristine are anticancer agents that disrupt the functioning of

microtubules during cell division

Muscle fibres are affected by:

o Piprazine (Avermectins) (anthelminthics), which increase Cl- permeability GABA agonist in

Nemotodes muscle.

o Pyrantel (anthelminthic) stimulates nematode nicotinic receptors, eventually causing muscle

paralysis





CLASSIFICATION:

Antimicrobial agents can be classified in many ways:

A. BASED ON MECHANISM OF ACTION

(1) Inhibition of cell wall synthesis

(a) β-lactums: Penicillins, Cephalosporins, Carbapenems*, Monobactams*

(b) Glycopeptides: Vancomycin, Teicoplanin

(c) Others: Bacitracin, Cycloserine

*beta lactamase resistant beta-lactum antibiotics

(2) Cell membrane function inhibitors

(a) Polypeptides: Polymyxins, Bacitracin, Colistin

(b) Polyenes: Amphoterecin B, Hamycin, Nystatin

(3) Inhibition of protein synthesis

(a) Aminoglycoside: Streptomycin, Kanamycin, Amikacin, Neomycin, Gentamicin—30s

(b) Tetracyclines: Tetracycline, Oxytetracycline, Demeclocycline, Doxycycline---30s

(c) Macrolides: Erythromycin, Roxithromycin, Clarithromycin, Azithromycin----50s

(d) Lincosamides: Lincomycin, Clindamycin

(e) Oxazolidione: Linezolid

(f) Others: Chloramphenicol----50s

(4) Inhibition of nucleic acid synthesis

(a) Sulphonamides: Sulfadiazine, Sulfamethoxazole, Sulfadoxine, (DHFS Is)

(b) Quinolones: Nalidixic acid, Ciprofloxacin, Ofloxacin, Lomefloxacin, Gatifloxacin (DNA Gyrase

inhibitors)

(c) Others: Metronidazole, Rifampicin, Idoxorudine, Acyclovir, Zydovudine, Bleomycine

B. BASED ON SUSEPTIBLE MICROORGANISM

(1) Antibactarial: β-lactum antibiotics, Aminoglycosides, Tetracyclines, Sulfonamides etc.

(2) Antifungal: Amphotericin B, Ketoconazole, Clotrimazole, Griseofulvin, Terbinafine

(3) Antivirals: Acyclovir, Idoxuridine, Amantadine, Zidovudine, Nevirapine, Indinavir

(4) Antiprotozoal: Metronidazole, Chloroquine, Pyrimethamine, Diloxanide, Pentamidine

(5) Antitubercular: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol, Streptomycin

(6) Antileprotic: Depsone, Rifampicin, Ethionamide, Minocyciline

(7) Anthelmintic: Mebendazole, Albendazole, Pyrantel, Levamisole, Praziquantel

C. BASED ON SPECTRUM

(1) Narrow spectrum: Penicillin G, Streptomycin, Erythromcin

(2) Broad spectrum: Tetracyclines, Chloramphenicol, Ampicillin, Amoxycillin

D. BASED ON ACTION

(1) Bactereostatics: Sulfonamides, Tetracyclines, Erythromycin, Chloramphenicol

(2) Bactereocidal: Aminoglycosides, Penicillins, Co-trimazole, Cephalosporins, INH, Rimapin

E. BASED ON SOURCE

1) Fungi: Penicilin, Cephelosporin, Griseofulvin

2) Bacteria: Polymixin B, Bacitracin, Colistin, Aztreonam

3) Actinimycetes: Aminoglycosides, Tetracyclines, Macrolides, Polyenes, Chloremphenicol.

RESISTANCE TO ANTIMICROBIAL AGENTS:


Drug resistance is an insensitivity of a microorganism to an AMA.

(1). Natural Resistances: occurs due to lake of metabolic process or target site in microbes for particular drugs,

e.g. gram negative bacteria bacilli are unaffected by penicillin G, M. tuberculosis is insensitive to tetracyclines.

(2). Acquired Resistance: occurs due to use of an AMA over a period of time leading to development of

resistance by either mutation or gene transfer in microorganism. Mechanism of drug resistance as follows:

(a) Production of enzyme by microorganism that inactivate the drug action (e.g. β-lactamase/penicillinase,

which inactivates the β-lactum antibiotics; Acetyl transferases, which inactivate chloramphenicol;

Kinases which inactivate aminoglycosides).

(b) Alteration of drug binding site in the microorganism, e.g. aminoglycosides, penicillins and

erythromycin.

(c) Reduction of drug uptake by bacterium, e.g. tetracyclines.

(d) Alteration of enzymes, e.g. Dihydrofolate reductase becomes insensitive to trimethoprim.

ANTIBIOTICS/AMA Cell Wall Synthesis Inhibitors

Penicillin:

Penicillin was first discovered by Alexander Fleming in 1928 and fisrt antibiotic to be used clinically in 1941.

Penicillin antibiotics are obtained from the mould Pencillium notatum and P. chrysogenum (highest yield).

-lactam ring is strained ring and is sensitive to acid hydrolysis and penicillinase (-lactamase) [produced by S.

aureus].

Stable penicillins have been prepared by minimising the sensitivity of -lactam ring to acid hydrolysis,

penicillinase and amidase.

The basic structure of pencillins consists of a thiazolidine (A) ring linked to a -lactam ring (B) . The two rings

together constitute the basic nucleus 6-aminopenicillanic acid.

Basic nucleus of penicillins

*1-bond is broken by amidase.

*2-bond is broken by penicillinase/ beta lactamase

SAR :

1. Intact -lactam ring is essential for antibacterial activity.

2. Side chain of penicillin is also essential for antibacterial activity, (side chain determines the stability of the

penicillin against degradation by acid and penicillinase).

3. Substitution of electron withdrawing group in the position of the acyl group increases the resistance to acid

hydrolysis.

*All of the natural penicillins are strongly dextrorotatory

Penicillins Inhibit peptidoglycan

synthesis by inhibit

transpeptidase enz.

Streptococcal

infaction:

Pharyngitis, Scarlet

fever, Rheumatic

ADR:

hypersensitivity (allergic reaction)

Jarisch-Herxheimer reaction

CH3

CH3

COO

H

A

S

N O

H

N R C

O

B

*2

*1 Acyl

group 6-amino penicillanic acid


Inhibit NAM-NAG

cross link formation

fever, Subacute

bactrerial

endocardites (SABE)

Meningitis

Dephtheria

Tetanus

Prophylactic use for

Rheumatic fever and

Surgical infection

Resistance

Production of penecillinase enzyme

Penicillin binding proteins are

located deeper.

Cephalosporines:

These are -lactam antibiotics closely related (structurally and functionally) to the penicillins. Cephalosporins

have 7-amino cephalosporanic acid nueleus and are obtained from the fungus Cephalosporium.

7-amino cephalorosporanic acid

General structure of cephalosporins

Substitution can be made at R1 and R2 to obtain stable cephalosporins.

Source: Cephelosporium

**Cephamycin a beta lactum antibiotic obtained by Streptomyces.

Classification : Cephalosporins are classified as first, second, third and fourth generation antibiotics. This

classification is based on antibacterial spectrum and periods of their introduction.

(1) First Generation Cephalosporins : These have greater activily against gram positive and less activity against

gram negative microorganisms. These are effective against E.coli, Proteus, Klebsiella, Staphylococci, Streptococci

and Pneumococci. These are ineffective against Salmonella, Shigella, Anaerobes and Pseudomonas. These were

developed in 1960s.

Orally- Cephalexin,Cephaloridine, Cephradine, Cefadroxil and Cephapirin.

Perenteral- Cephalothin, Cefazolin

(2) Second Generation Cephalosporins : These have greater activity against gram negative microorganism

including H. influenza, Enterobacter aerogenes and some Neisseria species. They are mainly used in the gram

negative infections. Second generation cephalosporins were introduced subsequent to first generation

cephalosporins. These are inactive against anaerobes and Pseudomona aerugionosa.

Orally- Cefaclor, Cefuroxime axetil

Perenteral- Cefuroxime, Cefoxitin

(3) Third Generation Cephalosporins : These antibiotics offer wider coverage against gram negative bacilli and

are less active on gram positive cocci. These were introduced in 1980s.

Orally- Cefixime, Cefdirin

Perenteral- Ceftriaxone, Cefotaxime, Ceftrazidime, Ceftizoxime and Cefoperazone.

(4) Fourth Generation Cephalosporins : These are newly developed cephalosporins, have same properties like

CH2 O C

CH3 O

O

COOH

N

S H2N

O COO

H

N

S R2 C N

O H

R1


those of third generation cephalosporins but more resistant to -lactamases. Fourth generation cephalosporins are

inactive against methicillin resistant Staphylococci.

perenteral: Cefepime and Cefprome. Cefepime is similar to third generation cephalosporins but more resistant to

beta-lactamases. It is used in serious gram negative infectons.

Cefelosporins Inhibit peptidoglycan

synthesis by inhibit

transpeptidase enz.

Alternate to Penicillin

RTI, UTI, Soft tissue

infection

Surgical

prophylaxix—1st gen

Maningitis by H.

influenza and

Pseudomonas—2nd

and 3rd gen.—cross

BBB

Gonorrhoea—

Ceftriaxone (3rd)

Typhoid

ADR:

hypersensitive reactions

Nephrotoxicity occurs specially with

cefadrine (3rd).

Drug induced alcohol intolarace

Bleeding-hypoprothrombinemia

Resistance

Alteration on Beta lactum binding

protein (differ from pen binding

protein-avoid cross resistence)

Exess Production of beta lactamase

Carbapenam induce the formation of

long filamentaus bac.

Structure and inhibit

cell wall synthesis.

Beta lactamase

resistant antibiotics

Gram negative inf- H.

influenza, and

Pseudomonas.

Unffective against G

+ bac

Hepatotoxic,

alter taste (test senserory affect)

Monobactams Beta lactamase

resistant antibiotics

infections of skin,

urinary tract, lower

respiratory tract,

endocarditis &

septicemia.

Neurotoxicity

Tinnitis—sound on ear

Vencomycine Allergic reaction (Red man syndrome)

Thromboflabitis

Anaphylactoid

Superinfection with G (-)

Serious reaction—VIII (auditory)

Cranial nerve (Chochlea) toxicity

Fetal urecemia

Protein Synthesis Inhibitors

1. Aminoglycoside: 30s-- decrease polysome formation, disrupt in codon

2. Tetracycline: 30s--- compete with the tRNA for A site on 30s

3. Chloramphenicol: 50s—decrease transpeptidation

4. Macroides: 50s—decrease translocation

5. Lincosemide: 50s---decrease peptidyl transferase and cause

Premature detachment of ribosomal to mRNA


Aminoglycoside act on 30 s Ribosomal

unit decrease polysome

formation, disrupt in

codon

effective against gram

negative aerobic

bacilli

Gram positive

bacteria are resistant

to aminoglycoside

antibiotics(except S.

aureus and S.

epidermidis)

Active only in aerobic

condition

TB, SABE, Plague

Tularemia (1st

choice)

ADR

Ototoxicity: damage VIII cranial nerve

(cochlear and vestibular damage)

Nephrotoxicity

Neuromuscular blockade

Fetal ototoxicity during pregnancy

Bacterial Resistance:

inactivation through microbial enzymes

failure of penetration

Interaction

+ loop diuretic- increase oto and nephro

toxicity

+ Amphoterecin B- Nephro toxicity

+ Vancomycin—Ototoxicity

+ During renal disease—kidney damage.

Tetracycline act on 30 s Ribosomal

unit compete with the

tRNA for A site on

30s

Used in cholera,

chlamydial infections,

gonorrhoea, syphilis,

acne, rickettsial

infection, Whippler

disease, Leptospirosis

Irritative: Diarrhoea, oesophageal

ulceration, GI pain

temporary inhibition of long bone

growth in infants,

Nephrotoxicity, Hepatotoxicity,

"fatty liver of pregnancy" in pregnant

women,

superinfection of respiratoxy tract,

Jarisch- Herxheimer reaction,

Phototoxicity

Discolration of teeth and bone

Vestibular toxicity- atexia (lake of

voluntary co-ordinate) by minocycline

Chloramphenicol act on 50 s Ribosomal

unit

decrease

transpeptidation

used in Enteric fever,

pyogenic meningitis,

Anaerobic infection,

intraocular infection

bone merrow depression,

Aplastic anemia

Gray baby syndrome in new born child.

Macroides act on 50 s Ribosomal

unit

decrease

translocation

1st choice-

Mycoplasma

pneumonia infection,

Whooping Cough,

Chancroid

GIT disturbance

Hearing impairment

Hypersensitivity

Lincosemide act on 50 s Ribosomal

unit

decrease peptidyl

transferase and cause

premature detachment of

ribosomal to mRNA


Folate Synthesis Inhibitors

Sulphonamide:

In landmark discovery in 1930s, Domagk introduces a dye prontosil (sulfonamide-chrysoidine) which are

effective against streptococcal infection in mice. Prontosil is an inactive prodrug gives an active product

sulfanilamide after metabolism. Many sulphonamides have been developed and used extensively, but because of

bacterial resistance, their current utility is limited, except cotrimoxazole (combination of sulfamethoxazole and

trimethoprim). In the UK, only sulfamethoxazole, sulfadiazine and trimethoprim are used clinically

Trimethoprim: Trimethoprim is a diaminopyrimidine which is related to antimalarial drug like pyrimethamine,

they are selective bacterial dihydrofolate reductase (DHFR) and further inhibit the thymidylate synthesis.

Trimethoprim is absorbed from gut and distributed widely in body fluids and tissues. It is more concentrated in

prostatic and vaginal fluids, which are more acidic in nature than plasma. Therefore it has more antibacterial

activity in prostatic and vaginal fluids than other AMAs.

Cotrimoxazole: Co-trimoxazole contains sulphamethoxazole and trimethoprim in 5:1 proportion.

Sulfamethoxazole with trimethoprim produces sequential blocking of DHFS and DHFR in folic acid synthesis,

resulting in marked enhancement of the activity of both drugs. It is indicated for treating infection of the urinary,

gastrointestinal & respiratory tracts. Combination of the two, i.e; sulphamethoxazole and trimethoprim produce

bactericidal/bacteriostatic action.

Sulfonamides Inhibit the dihydro

folate synthetase and

dihydropterote

synthetase ezyme

inflammatory bowel

diseases

infected burn

urinary tract infection,

respiratory tract

infection

malaria

ADR:

photosensitivity,

urticaria,

hepatitis,

bone marrow depression, Stevens-

Johnson syndrome, crystalluria

kernicterus (pregnancy)

Resistance

Increased production of PABA by the

resistance bacteria


Dihydrofolate synthetase has less

affinity for sulphonamides

Decreased permeability of

sulphonamides to the resistant bacteria

Developed efflux system in resistant

bacteria for sulphonamides.

Trimethoprime DHFR inhibitor Used alone or

combination with

sulfonamides

sulphamethoxazole and

trimethoprim in 5:1

Quinolones and Fluoroquinolones

Nalidixic acid and its congeners are known as quinolones. These are entirely synthetic antimicrobials. These are classified

as (Classified by Kucess, Bennet and Kemp) :

(1) First Generation Quinolones : These have limited antibacterial spectrum. e.g. Nalidixic acid, Miloxacin, Oxolinic acid,

Flumequine, Pipemidic acid, Rosoxacin.------- Gram negetive

(2) FluroQuinolones (Fluoroquinolones) : These are quinolones containing fluorine atom at 6 position and piperazene

substitution at 7 position (known as fluoroquinolones). These have extended antibacterial spectrum----- Gram negative and

positive

A. First generation: Ciprofloxacin, Norfloxacin, Pefloxacin, Ofloxacin, Amifloxacin

B. Second Generation: Levofloxacin, Lomafloxcin, Sparfloxacin, Moxifloxacin

Mechanism of Action : Quinolones block bacterial DNA synthesis by inhibiting bacterial (DNA gyrase) topoisomerase IV.

DNA gyrase having two subunit A (for nicking of DNA) and B (for introducing negative supercoils). FQs bind with A and

interfere with the cutting of DNA.

Inhibition of topoisomerase II prevents the relaxation of positively supercoiled DNA (required from normal transcription and

replication) in human. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the

daughter cells during cell division in bacteria.

“Floxacins”

Ciprofloxacin

Ofloxacin

Norfloxacin

DNA Gyrase

(topoisomerase IV)

inhibitors

UTI,

Gonorrhoea,

Typhoid,

Soft tissue infection,

Respiratory infection,

TB,

ADR:

Phototoxicity

Damge the growing cartilage and tendon

in infant

Skin/hypersensitivity (allergic reactn

Drug Interaction (Ciprofloxacin):

Plasma conc increased of theophyllin,

caffine, warfarin due to decrease

metabolism.

NSAIDs increased CNS toxicity of FQs-

-Seizures

ANTICANCER These are the drugs used in the treatment of cancer also known as antineoplastic agents. Cancer or

neoplasm (new growth) is an abnormal and uncontrolled growth or cell division.

The effective utelising of anticancer agent requires an uderstanding of the pathogenesis of cancer cells, cellula

kinetics and pharmacology of the drugs. Cancer cells are generally characterized by their

Uncontrolled proliferation (decreare apoptpsis, increase telomerase (RNA dependent DNA polymerase


expression).

Uncontrolled differenciation and loss of the function

Invasiveness – Tendency to spread over healthy cell

Metastesis- Spead to different part of body

Normal cells are converted into cancer cells by mutation of the nomal base sequences of DNA which can be

inherited or acquired and that lead to uncontrolled proliferation of the cells and become a tumor cells by

inactivation of tumor suppression gene (Antioncogene) or convertion of proto-oncogene (control normal cell

devision, apoptosis and deffrentiation) to oncogene. Thus may lead to several changes in cellular system like:

Over expression of growth fector receptor on the cells.

Production of their own extracellular growth factor

Production of cell cycle transducer e.g. cyclin-dependent kinases (cdks), cdk inhibitors and cyclins

Inhibit apoptosis

Tumor directed angeogenesis


Chemotherapy of cancer is difficult and different from infectious diseases in that

(i) Metabolic pathways of microbes are different from host tissue cell. Chemotherapeutic agents selectively

inhibilt these metabolic pathways without affecting host cells.

(ii) Immune mechanism and other host defences play an important role in killing microbes.

But this is not true for cancer cells.

(i) Metabolic pathways of cancer cell and host cell is same and

(ii) Immune mechanism & other host defences play negligible role in killing cancer cell.

Principles of Chemotherapy : Chemotherapy of cancer is directed towards the arrest of metabolic sites

essential for cell replication, e.g. availabilty of purine* and pyrimidine* precursor for DNA and RNA

synthesis.


A. non specific : e.g. Alkylating agents, Actinomycin-D—they kill at resting and dividing phase

B. cell cycle specific such as:--- they Kill at actively dividing cell

(a) G1 phase: proceed of DNA synthesis, e.g. Vinka alkaloids

(b) S phase: DNA synthesis, e.g. Antimetabolites, hydroxyurea

(c) G2 phase: terminal of DNA synthesis, e.g. Daunorubicin, Bleomycin, Etoposide

(d) M phase: mitotic phase, e.g. Vinka alkaloids, taxol.

G1--------S---------G2------M--------G1

G1 (Gap 1)/ Growth Phase I: Proceed DNA Synthesis

S (Syntesis Phase): DNA synthesis phase

G2 (Gap 1)/ Growth Phase I: terminal of DNA synthesis/ proof reading

M (Mitotic Phase): Prophase, Metaphase, Anaphase, Telophase, Cytokinesis

CLASSIFICATION :

(1) ALKYLATING AGENTS : have reactive carbonium ion that react with electron donor (-NH2, -OH, -SH)

and form covelent bond with nucleophilic substance and also cause intra or inter-sand/cross linking.

(a) Nitrogen mustards: Mechlorethamine, Cyclophosphamide, Chlorambucil, Ifosfamide,

Melphalan

(b) Nitrosoureas : Carmustine, lomustine

(c) Alkylsulphonates : Busulfan

(d) Ethylenimines : Thiotepa

(e) Triazenes : Dacarbazine

(2) ANTIMETABOLITES :

(a) Folate antagonists : methotrexate (MTX)

(b) Purine analogues : 6-mercaptopurine, 6-thioguanine, Azathioprim, flutarabine, pentostatin, cladribine.

(c) Pyrimidine analogues : 5-fluorouracil, floxuridine, cytarabine, Raltitrexed, Pemitrexed

(3) Natural products :

(a) Plant products : Vinca alkaloids (vincristine & vinblastine), Podophyllotoxin, Etoposide, Taxol, and


Camptohecin (Topotecan, Irinotecan)

(b) Antibiotics : Actinomycin-D, Doxorubicin, Daunorubicin, Bleomycin, Mithramycin, Mitomycin-C.

(c) Hormones and antihormones :

Glucocoricoide: Prednisone

Estrogen: Fosfestrol, Diethylstilbesterol, Ethinyl estradiol

Anti-Estrogen: Tamoxifen

Anti-Androgen: Flutamide, Bicalutamide

Progestins: Medroxy progesterone, Hydroxy progesterone Acetate

GnRH analogue: Naferelin, Goserelin

5-alfa reductase Inhibitors: Finasteride, Dutasteride

(d) Enzymes : L-asparginase

(e) Biologic response modifiers : Interferons (, and )

(4) Miscellaneous agents : Cisplatin, hydroxyurea, procarbazine,

General ADR

BMS- thrombocytopenia, grnulocytopenia, aplastic anaemia (decrease new blood cells)

Lymphocytopenea- decrease Lymphocytes: decrease cell mediated and Humoral immunity

GIT- Vometting, Ulcer, diarrhea

Alopecia

Gonades- decrease spermato and Oogenesis--- impotency

Teratogenic

Carcinogenicity—secondary cancer—leukemia, Lymphomas

Hyperurecemia

Resistance to anticancer drugs :

Resistance developed due to:

Decreased accumulation of cytotoxic drugs in cells via energy-dependent drug transport proteins defect,

i.e. P-glycoprotein.

A decrease in the amount of drug taken up by the cell (e.g. in the case of methotrexate).

Insufficient metabolic activation of the drug, e.g. mercaptopurine, flurourecil and cytarabine.

Increase in inactivation, e.g. . mercaptopurine and cytarabine.

Increased concentration of target enzyme (methotrexate).

Decreased requirement for substrate (crisantaspase).

Increased utilisation of alternative metabolic pathways (antimetabolites).

Rapid repair of drug-induced lesions (alkylating agents).

Altered activity of target, for example modified topoisomerase II (doxorubicin).

Mutations in various genes, giving rise to resistant target molecules. For example, the p53 gene and

overexpression of the Bcl-2 gene family (several cytotoxic drugs).

Future Aspect for Cancer Chemotherapy:

Angiogenesis and metalloproteinase inhibitors, tumour cells produce metalloproteinases and

angiogenic factors that facilitate tumour growth.

Cyclo-oxygenase (COX) inhibitors, The COX-2 isoform is overexpressed in about 85% of cancers,

chronic use of cyclo-oxygenase (COX) inhibitors protects against cancer of the gastrointestinal tract

and possibly other sites as well.

Activation of tumour suppression gene (p53) as anticancer target.

Antisense oligonucleotides, antisense oligonucleotides are synthetic sequences of single-stranded

DNA complementary to specific coding regions of mRNA, which can inhibit gene expression. An

antisense drug, augmerosen, down-regulates the antiapoptotic factor Bcl-2.

Alkylating Agents Alkylating the DNA stands


Bifunctional alkylating agents can cause intrastrand cross linking of two nucleophilic site

such as N7 of guanine, N1 & N3 of Adenine and N3 of Cytosine in the DNA strand.

Cyclophosphamide

(Nitrogen mustered)

Used in Hodgkin's disease, carcinoma of lung and

other solid tumors

Bladder damge due to toxic metabolite

acrolein

Antidote- Mesna

Carmustine

(Nitrosourea)

Brain tumours (because of its ability to cross

blood-brain-barrier)

Hodgkin's disease,

multiple myeloma and

non-Hodgkin's lymphomas.

Antimetabolites block vital cellular metabolic reactions

Cell cycle specific act on S phase

Methotrexate (MTX) Folate antagonist

Block DHFR

acute lymphoblastic leukemia

choriocarcinoma

Burkitt’s lymphoma

Purin analauges

6-Mercaptopurine Inhibit Purin & DNA

synthesis

Leukemia Interaction:

**The purine analogues (5MP and

Azathioprim) are also metabolized by

Xanthin oxidase thus allopurinol decrease

the required dose of 5MP and Azathioprim

6-thioguanine It inhibit purine

nucleotide

interconversion

Azathioprime Marked effect in T-

lymphocytes and

suppressed cell

mediated immune

system

Used a

immunosupresant in

organ transplant and

R.arthritis

Pyrimidine Analouge

5-fluorouracil inhbit thymidylate

synthetase

Inhibition of DNA synthesis results in “thymineless death” of

cells.

Used in the carcinoma of stomach, colon, rectum, breast and

ovaries

Cytarabine inhibits DNA

polymerase

Ara-cytosine triphosphate is active metabolite

Used in the treatment of acute nonlymphoblastic leukemia.

Cytarabine is used as an antiviral agent in the treatment of Herpes

infection and encephalitis.

Others

Pemetrexed

Raltitrexed

inhbit thymidylate

synthetase, DHFRn,

and GARFT

Inhibit the DNA and RNA synthesis

malignant pleural mesothelioma (Lung cancer)

Natural products

A. Plants

Vinca alkaloids depolymerisation of

microtubules

Mitotic inhibitor (M Phase)

Vinca alkaloids are "spindle poisons"

Taxols (Paclitaxel and

Docetaxel)

Enhance the

polymerization of

microtubules

Taxol was isolated from Pacific Yew tree bark

Act on Interphase

Podophyllotoxin and Inhibit Topoisomerse Podophyllotoxin is obtained from root of the May apple


Etoposoide II (Podophyllum peltatum).

Etoposide is a semisynthetic derivative of podophyllotoxin.

act on G2 phase

Campothecins:

Irinotecan and

Topotecan

Inhibit Topoisomerse I Source: Camptotheca acuminate

act act on S phase and arrest cycle at G2 phase

B. Antibiotics

Actinomycin-D Streptomyces chrysomallus

block DNA dependent RNA polymerase

Intercalate the DNA stands

Doxorubicin and

Daunorubicin

anthracycline antibiotic

Streptomyces coeruleorubidus and S. peucetius

interfere on topoisomerase II (DNA gyrase)

enzyme

Intercalate the DNA stands

Bleomycin metal chelating glycopeptide antibiotic

Streptomyces verticillus

It produce DNA strand breakage

Bleomycin is inactivated by

bleomycin hydrolase

C. Hormones and antihormones Hormones are not cytotoxic, but modify the growth of hormone

dependent tumours

Prednisone

(glucocorticoid)

It is used in acute childhood leukemia and

lymphomas.

Prednisolone is active metabolite

Diethylstilbesterol

(Estrogens)

prostate tumours and breast cancer.

Megestrol

(progestogens)

endometrial carcinoma

Tamoxifen Estrogen receptor

antagonist

induces production of

transforming

growth factor

(TGF-)*

used in breast cancer

D. Enzymes

L-asparaginase destroy asparagine isolated from bacteria E. coli and Erwinia carotovora

Orthers

Interferons Inhibit protein

synthesis

Produce TIP (translation inhibitory protein)

Interferon is effective in hairy cell leukemia, melanoma, Kaposi's

sarcoma

Cisplatin denaturation of DNA

chain

testicular and ovarian tumours and bladder cancer

Hydroxyurea inhibit ribonucleotide

reductase

depletion of deoxynucleoside triphosphate pools.


ANTI VIRAL

These are the agents used in the treatment of viral infections.

Viruses are obligate intracellular parasites that depend on metabolic processes of host cells for their replication.

Virus consist of either RNA or DNA enclosed in a protein coat and a lipoprotein coat.

Component of virus particle or virion

PATHOGENIC VIRUSES:

DNA viruses:

o Poxviruses: smallpox,

o Herpesviruses (Vercella Zoster, H. Simplex, CMV): chickenpox, shingles, cold sores, glandular

fever),

o adenoviruses (sore throat, conjunctivitis) and

o papillomaviruses (warts).

RNA viruses: o orthomyxoviruses (influenza),

o paramyxoviruses (measles, mumps, respiratory tract infections),

o rubella virus (German measles),

o rhabdoviruses (rabies),

o picornaviruses (colds, meningitis, poliomyelitis),

o retroviruses (acquired immunodeficiency syndrome [AIDS], T-cell leukaemia),

o arenaviruses (meningitis, Lassa fever),

o hepadnaviruses (serum hepatitis) and

o arboviruses (arthropod-borne encephalitis and various febrile illnesses, e.g. yellow fever).


VIRUSES AND THEIR HOST CELLS:

1. ATTACHMENT

Formed vacuoles. Attachment is facilitated by poly peptide binding site on the envelop or capside wich

interact with the receptor of host cell.

These receptors are generally for cytokines, NTs, hormone, and ion channels.

Reduce the attachment---- immune gamma-glycoproteins Agents inhibiting host cell penetration by virus. e.g. HBIG (Hepatitis B immunoglobulin), HRIG

(Human rabies immunoglobulin), Varicella-Zoster immunoglobulin.

Example of viral infection and Receptor

a. HIV: Helper T-lymphocytes CD4 glycoprotein,


CCR5 receptor for chemokines MCP-1 and RANTES,

CXCR4 chemokine receptor for cytokine SDF-1.

b. Rebies virus: Acetylcholine receptor on skeletal muscle.

c. Adenovirus: MHC molecules.

d. Infantile diarrhoea virus: β-Adrenoceptors.

HOST DEFENCES

Skin is a first barrier for virus, most viruses are unable to penetrate, therefore wounds, mucous membranes are

most favorable target site. After virus entry host produces innate and adaptive immune response.The infected

cell presents, on its surface, viral peptides complexed with major histocompatibility complex (MHC) class I

molecules. This complex is recognised by T lymphocytes, which then kill the infected cell by lytic proteins

(perforins, granzymes) or by triggering the apoptotic pathway. The latter it also activate the as tumour necrosis

factor (TNF)-α and natural killer (NK) cell.

Host Diffence Against Virus

2. Uncoating – Uncoating of viral DNA/RNA by host cell

The formed virus-receptor complex enter to the host cell by receptor mediated endocytosis after

removal of coat by host enzyme.

Prevented by Amentadine/Rimentadine (used in RTI, influenza, Resp. Syncital virus)

Agents binding to surface coats of viruses and stabilising the protein coat so that subsequent uncoating

of virus in host cell does not occur. e.g. Disoxaril.

3. Replication, Synthesis and protein synthesis:

a. Reverse Transcriptase Is

Viral RNA produce vDNA by Reverse transcriptase enzyme that is inhibited by Reverese transcriptase

(vRNA dependent DNA polymerase) inhibitor (Anti-retro virus—RNA virus):

o NRTIs -Non nucleoside RTIs: Zidovudine (AZT), Lamivudine, Stavudine, Didanosin, Abacavir

o Non NRTIs: Nevirapine, Delavirdine, efavirenz

b. Protease Inhibitor (HIV 1- protease inhibitor)- “NAVIR”

A protease (also called a peptidase or proteinase) is any enzyme that

performs proteolysis; protein catabolism by hydrolysis of peptide bonds

Protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1

protease) and blocking proteolytic cleavage of protein precursors that are necessary for the

production of infectious viral particles. EX- Ritonavir, indinavir, Saquinavir, Lopinavir

Hepatitis C virus NS3/4A protease inhibitor- “PREVIR”): asunaprevir, boceprevir,

grazoprevir, paritaprevir, simeprevir

https://en.wikipedia.org/wiki/Enzyme

https://en.wikipedia.org/wiki/Proteolysis

https://en.wikipedia.org/wiki/Protein

https://en.wikipedia.org/wiki/Catabolism

https://en.wikipedia.org/wiki/Hydrolysis

https://en.wikipedia.org/wiki/Peptide_bond

https://en.wikipedia.org/wiki/Proteases

https://en.wikipedia.org/wiki/HIV-1_protease

https://en.wikipedia.org/wiki/HIV-1_protease

https://en.wikipedia.org/wiki/Virion

https://en.wikipedia.org/wiki/Asunaprevir

https://en.wikipedia.org/wiki/Boceprevir

https://en.wikipedia.org/wiki/Grazoprevir

https://en.wikipedia.org/wiki/Paritaprevir

https://en.wikipedia.org/wiki/Simeprevir


c. DNA Synthesis Inhibitors

Inhibit the DNA synthesis (Anti-Herpes simplex and cytomegalovirus CMVvirus): Idoxuridine,

Vidarabine, Acyclovir, Ganciclovir.

HSV1- oral, ocular, and Facial infection

HSV2- Genital infection

d. vRNA polymerase inhibitor (Anti-Herpes virus )- Foscarnate

e. Protein Synthasis inhibitor

Agent inducing production of intracellular enzymes which inhibit the translation of viral-mRNA to

viral protein. e.g. Human leucocyte interferon.

Agent inhibiting 'late' structural protein synthesis in Variola virus. e.g. Methisazone

4. Assembly- by virus particle and budding

Agents preventing assembly of enveloped mature viral particles. e.g. Rifampicin

Amentadine: inhibit the maturation of viral protein

5. Release- by lysis

(1) Idoxuridine : It is a substituted pyrimidine (Thymidine) analogue.

Mechanism : Inhibit DNA sunthesis.

Idoxuridine gets phosphorylated within the cell and the triphosphate derivative is incorporated into DNA (of

both viral and mammalian). Such DNA is more susceptible to breakage and results in faulty transcription.

Uses : Used in the treatment of superficial H. simplex keratoconjunctivitis as 0.5% eye ointment applied

every 4 hrs during day and once at bedtime or as 0.1% eyedrops, 1 drop instilled in conjunctival sac every hour

during day and every 2 hours during night.

(3) Acyclovir : Guanine analogue

It is active against Herpes viruses particularly Herpes simplex virus (HSV) type-l and type-2.

Mechanism of Action : The Herpes viruses contain a specific thymidine kinase which phosphorylates

acyclovir to its monophosphate. Further phosphorylation is by host cell guanosine monophosphate kinase to

the diphosphate, which is then phosphorylated to acyclovir triphosphate. Acyclovir triphosphate inhibit Herpes

virus DNA polymerase. It also get incorporated into viral DNA and terminates biosynthesis of viral DNA

strand.

Acyclovir----thymidine kinase (viral)-A. monophosphate-----Guanosine monophosphate kinase--- A.diP--

--- Acyclovir triphosphate---inhibit virus DNA polymerase

Uses : It is used in the treatment of infections due to Herpes simplex virus and Varicella-Zoster virus and

Epstein virus.

(4) Zidovudine : It is a thymidine analogue.

Mechanism: It is incorporated into the virus and inhibit vRNA dependent DNA polymerase (reverse

transcriptase) and thereby inhibit viral replication. It also inhibit the viral DNA Chain elongation and v RNA

dependant DNA polymerase.

Ziduvudin (ATZ)-------T. kinase---- Z. triphosphate-----inhibit RT

Uses : It is used in the treatment of AIDS/HIV/retrovirus.

ADR- BMS, Anaemea, Epilepsy

Interaction: ATZ + paracetamol---increase toxicity due to compete with glucorunidation.


(5) Didanosine : It is an inosine analogue., Mechanism of action is similar to zidovudine.

Didanosine-------T. kinase---- D. triphosphate-----inhibit RT

Uses : It is used in the treatment of AIDS.

ADR- Panchreatitis, peripheral neuropathy,

6) Stavudine – Thymidine analogue, Antagonise the effect of ATZ due to compete with Thymidine kinase.

7) Lamuvudine- Deoxy cytidine. Inhibit HIV RTs and Hepatitis B DNA Polymerase.

8) Nevirapine and efavirenz (NNRTIs)- More potent HIV-1 RT than ATZ. Prevent mother to baby

transmission.

(9) Amantadine : tricyclic Amine, 1-adamantanamine

It is active only against influenza - A virus. It is also used in the management of Parkinson’s disease.

Mechanism: Amantadine inhibit the initiation of transcription of an early stage between uncoating and viral

specific RNA synthesis. It also block the M2 protein (channel for virus).

Interferons : Virus infected host cells produce a group of host cell species specific proteins that have virus

nonspecific antiviral activities, these proteins are known as interferons.

Interferons inhibit viral protein synthesis while host cell protein synthesis is unaffected.

Human leucocyte interferon (IFN-) and Human fibroblast-interferon (IFN-) are produced in response to variety of

inducers. Human leucocyte interferon appears to be promising in AIDS.

ANTI TUBERCULOSIS

Tuberculosis is a serious infectious disease caused by Mycobacterium tuberculosis and M. bovis, collectively termed as

tubercle bacilli.

To achieve effective treatment of M. tuberculosis (a slow growing intracellular bacteria) require multidrug

therapy for extended periods of time and prevent the emergence of resistance.The risk of adverse reactions

therefore must be a major consideration in drug selection. A 6 month chemotherapy regimen are generally used

for tuberculosis treatment by using a combination of 4 drugs (rifampicin, isoniazid, ethambutol, and pyrazinamide for 2

months, followed by rifampicin and isoniazid for 4 months).

Multiple Drug Resistance:

Multidrug-resistant tuberculosis (MDR-TB) is TB that does not respond to antimicrobial drugs at least isoniazid and

rifampicin.The primary causes of multidrug resistance are mismanagement of TB treatment and person-to-person spread.

Inappropriate or incorrect use of antimicrobial drugs, or use of ineffective formulations of drugs, and premature treatment

interruption can cause drug resistance.

Solutions to control drug-resistant TB are to:

cure the TB patient the first time around

ensure adequate infection control in facilities where patients are treated

ensure the appropriate use of recommended second-line drugs to treat this form of TB.


CLASSIFICATION :

The chemotherapeutic agents used in the treatment of tuberculosis are classified into two groups :

1. First-Line Drugs (Primary Drugs) :

These drugs are used in initial phase. These drugs have high antitubercular efficacy. Generally three drugs are

used concurrently. Agents used as first line drugs are : e.g. Isoniazid, Rifampicin, Ethambutol, Pyrazinamide*

and Streptomycin*.

Treatment in initial phase involve use of isoniazid and rifampicin, supplemented by ethambutol or streptomycin for 8

weeks. This may be followed by continuation phase in which only isoniazid is given in combination with rifampicin,

ethambutol or streptomycin.

2. Second-Line Drugs (Reserved Drugs) :

These are indicated when the causative agent is resistant to the primary drugs. These drugs have low

antitubercular efficacy and high toxicity. e.g. Paraaminosalicylic acid (PAS), Ethionamide, Cycloserine,

Thiacetazone, Capreomycin, Kanamycin, Amikacin and Rifabutin.

Recent Clinical trials developing drugs:

Fluoroquinolone: Gatifloxacin, Moxifloxacin

Nitromidazole: Delamanid

Oxazolidinone: Linezolid

Refamycin: Refapentin

Treatment of tuberculosis involve use of combination of two or more drugs because of following reasons :

(1) Different drugs have different mechanisms of action which give an additive antibacterial effect.

(2) In combination therapy, the dose of each drug is reduced and thus minimise the chance of individual

drug toxicity.

(3) Emergence of acquired bacterial resistance can be delayed by combining two or more drugs.

Isoniazid (INH) inhibiting mycolic

acid synthesis

Bacteriostatic

Isoniazid is the primary

drug for chemotherapy of

pulmonary or

extrapulmonary

tuberculosis

Peripheral neuritis

Neurotoxicity ( prophylactically

prevented by pyridoxine)

Hepatotoxicity

Rifampicin inhibiting DNA

dependent RNA

polymerase

TB

Rifampicin is also used

with dapsone and

clofazimine in the

treatment of leprosy

Combination of

doxycycline and rifampin

is the first line therapy of

brucellosis.

Second/third choice drug

for MRSA, diphtheroids

and Legionella

infections.

Hepatotoxicity

Respirtory syndrome

Cutaneous Syndrome

Purpura, haemolysis, shock, renal

failure

Flu syndrome

Abdominal Syndrome

Ethambutol inhibits synthesis

of arabinogalactan

Drug contains two

chiral cen

Ocular Toxicity (optic neuritis)

Hepatotoxicity

Hyperurecemia

Pyrazinamide Hepatotoxicity

Hyperurecemia


Paraaminosalicylic

acid

folate synthesis

antagonist

WHO has recommended a four drug combination during the first two months for patients 34-50 kg.

Isoniazid 300 mg

Rifampicin 450 mg

Pyrazinamide 1500 mg

Ethambutol 800 mg

Anthelmintics 1. Drugs used in Round Worm (Nematodes) Infection : e.g. Mebendazole, Albendazole, Pyrantal pamoate,

Thiabendazole, Piperazine, Levamisole, Diethylcarbamazine, Tetramizole and Metronidazole.

2. Drugs used in Tapeworm (Cestode) Infection : e.g Niclosamide, Praziquantel and Albendazole.

3. Drugs used in Fluke (Trematode) Infection : e.g. Praziquantel, Bithionol and Niclosamide.

Mebendazole

Albendazole

(benzimidazole)

inhibit

microtubule

synthesis

irreversibly impair glucose uptake

Broad spectrum of anthelmintic activity

Pyrantel pamoate depolarising

neuromuscular

blocking agent

broad spectrum anthelmintic

it causes release of acetylcholine and inhibition of cholinesterase, this

results in stimulation of ganglionic receptors & worm paralysis and

expulsion from the hosts intestinal tract.

Thiabendazole

(benzimidazole)

It inhibit enzyme fumarate reductase which is important for microtubule

aggregation

It is vermicidal and ovicidal.

Piperazine Piperazine

causes paralysis

of ascaris by

blocking

acetylcholine at

the myoneural

junction

ARD: Piperazine forms N-mono nitroso

piperazine metabolite which is

carcinogenic.

ANTI MALARIALS

Malaria is a protozoal disease infected by Plasmodium specieses (P. falciparum, P. vivex, P. malariae and P.

ovale). Malaria is transmitted in human via a bite from an infected female Anopheles mosquito.

Antimalarial drugs are used to prophylaxis, treatment and prevention of relapses of malaria.

1. 4-Aminoquinolines: Chloroquine, Amodiaquine, Piperaquine.

2. 8-Aminoquinolines: Primaquine, Bulaquine.

3. Quinoline-methenol: Mefloquine, Cinchona alkaloids (Quinine and Quinidine).

4. Nephthoquinone: Atovaquone.

5. Biguanides: Proguanil, Chlorproguanil.


6. Diaminopyrimidines: Pyramithamine.

7. Sulfones and Sulfonamides: Dapsone, Sulfamethopyrazine, Sulfadoxine.

8. Endoperoxides: Artemether, Artesunate, Arteether- Sesquiterpine lactones

9. Amino alcohols: Halofantrine, Lumefantrine.

10. Tetracyclines: Tetracycline, Doxycycline

11. Mannich Base: Pyronaridine.

Quinine H bond complex

with DNA and

inhibit DNA and

protein synthesis

Suppressive and

Clinical cure for

vivax

Cerebral malaria

and chloroquine

resistant P.

falciparum

ADR

Myocardial depression

Black water fever

Cinchonism

Idiosyncrasy

Hypoglycemia

Optic nervetitis

Tinitis (sound in ear)

Chloroquine Intercalate the

DNA stands

inhibit DNA and

protein synthesis

Form complex

with haem that

cause damage

the plasmodium

membrane and

increase the

intravascular

pH.

Malaria (except

P. falciparum)

Rheumatoid

arthritis

ADR:

Photooxicity

Ocular toxicity

Pigmentation

Cardiac depression

Resistance:

P. falciparum are resistant to chloroquine due to

alteration of chloroquine transporter protein (CG2)

that cause the decrease the ability to penetration.

Contraindicated in liver disease patients

Mefloquine inhibit DNA and

protein synthesis

Malaria

including

chloroquine

resistant P.

falciparum.

Sinus bradycardia

Haemetological and hepatic toxicity

Primaqune Used as Prevent Haemolysis in subject with inherited deficiency of


to relapse

Radical cure

G6PD enzyme

Pyrimethamine Inhibit DHFR Used alone or

combination

with

Sulfadoxine in

20:1 ratio

Malaria

including

chloroquine

resistant P.

falciparum

Sulfadiazine +

pyrimethamine

– 1st choice for

Toxoplasmosis

(Toxoplasma

gondii)


Chapter 7

Central Nervous System

Location of Cranral Nerves


NEUROTRANSMITTERS

Neurotransmitter are the endogeneous chemical that transmit signals across a synapse from one neuron to another (target)

neuron. There are three main categories of neurotransmitter involved in the brain pathophysiology.

(A) Amino Acids:

(i) Excitatory amino acids: Gulatamate, Aspartate

(ii) Inhibitory amino acids: GABA, Glycene

(B) Biogenic Amines: Dopamine, Norepinephrine, Serotonin

(C) Peptides: Vasopressin, Somatostatin, Neurotensin, Enkephalines, Endorphine, Dynorphin

(D) Misc: Acetylcholin, Nitric Oxide, Histamine

*Acetylcholine and norepinephrine are widly distributed in peripheral nervous system and little on CNS. They generally

regulate the periphery physiological functions.

* Nitric Oxide (NO) is a potent vasodialator act as a EDRF (endothelial derived releasing factor). It dose not bind on

any surface receptors, it activate the guanilyl cyclase enzyme which are responsible for conversion of AMP to cAMP.

Neurotransmitter Metabolism:

** Most of the neurotransmitters are made up of amino acides except Acetylcholine

Nitric Oxide:

L-Argenine Nitric oxide synthase (NOS)

NADPH O2

Nitric Oxide (NO)

L- Citrulline

Acetylcholine:

Choline Choline acetyltransferase (CAT)

Acetyl CoenzymeA

Acetylcholine

CoenzymeA

Glutamine Glutamate GABA

Glutamic acid decarboxylase

Glycene

Glyoxylate

α-Oxoglutarate

Glutaminase

Glutamine

synthatase

Amino Acids:

GABA-

transaminase

Metabolite


Biogenic amines:

Tryptophane 5-Hydroxy

tryptophane

5-Hydroxy tryptamine

(Serotonin)

5-Hydroxy indol acetic acid

(5HIAA)

Hydroxylase Decarboxylase

MAO, ADH

Tyrosin hydroxylase DOPA-decarboxylase Dopamine β-hydroxylase

Tyrosine DOPA Dopamine

Norepinephrine

N-methyl Transferase

Epinephrine

Histamine:

L-Histidine

Decarboxylase

N-methyl histamine



Histamine

N-me. transferase

Diamine oxidase


*Dominergic neurons lake of β-hydroxylase therefore dopamine can not convert into norepinephrine and epinephrine,

whereas, adrenergic neurons take place.

Neuropeptides

They are the neuronal signaling small protein molecules, co-released with other classical neurotransmitters, which

modulate the neurotransmitters activity.

Examples: Norepinephrine- Galanin, enkephalin, neuropeptide Y

Epinephrine- neuropeptide Y, neurotensin

GABA- Somatostatin, cholecystokinin, neuropeptide Y

Dopamine- cholecystokinin, neurotensin

Serotonin- Subtance P, enkephalin

Acetylcholine- VIP, Subtance P

COMT

Dopamine 3-methoxydopamine

MAO, ADH MAO, ADH

COMT

Dihydroxyphenylacetic acid Homovanillic acid

(DOPAC) (HVA)

MAO MAO

Norepinephrine 3,4-dihydroxy Mandalic acid Epinephrine

COMT COMT CMOT

MAO MAO

Nor-metanephrine 3-methoxy, 4-hydroxy Metanephrine

Mandelic acid

ADH- Aldehyde dehydrogenase

MAO- Mon amine oxidase

CMOT- Catechol-O-methyl transferase

:


ANTIPSYCHOTICS

DRUGS MOA DESCRIPTION/USES ADR/Contraindications/

Interactions

NEUROLEPTICS: Centrally D2 Blockers

Phenothiazenes

Chlorpromazene

(CPZ)

[Largacitil]

D2 blocker

Also having

Antiadrenergic (α1

blocking)

Anticholinergic (M

blocking)

Antihistaminergic

(H1 blocking)

Schizophrenia, mania and major

psychosis.

As antiemetic (Promethazene,

Triflupromazene)

Anticough agents.

As preanaesthetic agent.

Aggressive or destructive

behaviour in children

Anxiety

Alcoholic hallucinosis,

Huntington’s syndrome, Giles de

la Tourette’s syndrom

ADR

Extrapyrimidal side effects

(trifluphenazene, pimozide) due to

D2 blockade on basal ganglia

Postural hypotension, Palpitation ,

tachycardia(due to α1 blocking)

Hyperprolactemia (due to D2

blocking)

Hypersensitive reaction:

Cholestatic jaundice,

Photosenetivity, urticarial

Contraindications

Cardiovascular disease,

Glaucoma,

Benign prostatic hypertrcphy


History of seizures

**Potent central anticholinergic neuroleptic drug having less extrapyrimidal effect (Parkinsonism, dyskinesia, akathisia,

muscle dystonia)

Anticholinergic activity: Thioridazene>CPZ> Triflupromazene> Trifluperazene`= haloperidol

Butyraphenone

Haloperidol

D2 blocker

NEUROLEPTIC

Having low Antiadrenergic (α1

blocking)

Anticholinergic (M blocking)

Schizophrenia, mania and major

psychosis

Alcoholic hallucinosis,

Huntington’s syndrome, Giles de

la Tourette’s syndrome

Extrapyrimidal side effects

(trifluphenazene, pimozide)

Hyperprolactemia (due to D2

blocking)


Cholestatic jaundice

ATYPICAL ANTIPSYCHOTICS

Clozapine Low D2 blocking and

Potent 5-HT2 bloking

activity

Selective D4 blocking activity

(basal ganglia)

Low D2 blocking activity

5HT2 and α1 blocking activity

Anticholinergic activity

Potent H1 blocking activity

Improve the cognitive function

Schizophrenia and major

psychosis

ADR

Sedation

High dose induce epilepsy

Weight gain

Postural hypotension, tachycardia

Precipitation of diabetes


agranulocytosis, myocarditis

Contraindication

Diabetes

Epilepsy

Aripiprarzole Partial agonist of D2

and 5HT1A

Antagonist of 5HT2

Improve the cognitive function


psychosis

ADR

Increase blood suger

Precipitation of diabetes

Contraindication

Diabetes

Epilepsy

Ziprasidone Antagonistic activity on D2,

5HT1D, 5HT2A, H1, α1

Agonist on 5HT1A

Inhibit 5HT and Nor-Ad reuptake

(antidepressant and anxiolytic

action)


psychosis

Mania

Sedation

Weight gain

Increase blood suger

Hypotension


ANTIPSYCHOTICS/NEUROLEPTICS (Major Tranquillisers)

These are the agents that inhibit or diminishes symptoms of psychosis through antagonism of dopamine (D2)

receptors. These are also known as antipsychotics, major tranquillisers or ataractics.

In psychosis there is an abnormality in the central neurotransmitters (particularly dopamine). Over production

of dopanine or increase in dopamine receptor activity in mesolimbic/mesocortical pathway is the cause of

psychosis.

PSYCHOSES

a. Acute and chronic organic brain syndrome (Cognitive disorder) :

Delirium: Breif state of excitement and mental confusion, Hallucination

Dementia: Alzeimer or defective memory.

b. Functional disorders: memory, emotion, and behavioral changes.

Schizophrenia (spilt mind): splitting the perception and interpretation from reality.

Paranoid state: false believe

AFFECTING DISORDERS

Change in the mood

Mania: irritable mood/Angery, hyperactivity, reduce sleep, uncontrolled thought and speech

Depression: sedness, guilty feeling, delf-destructive thought

Bipolar disorder- both mania and depression

NEUROSES

Anxiety

OCD

Phobic disorder

Reactive depression

Post traumatic disorder

** Over dopaminergic activity in limbic system---Schizophrmia and mania

***Loss of monoaminergic (NA/5HT)-- depression

Mood stabilizer/antimanic

DRUGS MOA USES ADR/CONTRAINDICATIONS

Lithium carbonate

(Li+)

Decrease the release of

NA and DA

Affect Na+ in brain

Mania

Prophylaxix of

Bipolar disorder

(mania+ depression;

Manic depressive

illness)

ADR

Thrust, polyurea

Seizures like event

CNS toxicity

Interaction:

+diuretics: Li+ tubular reabsorption

+insulin/sulfonylurea- enhance

hypoglycemia

+ Succinylcholin/curare- prologation of

paralysis

+ Haloperidol- acute brain encephalopathy

* *presently Li+ is not use due to its toxicit. The alternatives to Li+: Carbamezapine, Sod. Valproate, Lamotriagine,

Topiramate, Atypical antipsychotics


ANTIDEPRESSANTS

Depression and mania are affective (emotional) disorders in which there is pathological change in mood state. The

common symptoms of mental depression are feeling of guilt, anxiety, tension, emotional withdrawal and motor retardation.

Person may suffer from complete or partial loss of memory, sexual desire diminishes, there is loss of appetite & weight and

may suffer from insomnia. The depression could be of following types :

(a) Manic : There is extreme excitement, excessive elation, agitation, hyperactivity, overtalkativeness followed

by severe depression.

(b) Endogenous : There is no external reason. It is due to biochemical changes.

(c) Reactive : Depression is due to anxiety.

(d) Drug induced : Some drugs may produce depression e.g. reserpine.

Theorie of Depression

The Monoamine Theory: The monoamine hypothesis proposed that depression is caused by reduction of

monoamine neurotransmitter (noradrenaline and serotonine) at certain brain areas and mania caused by exess

of these neurotransmitters.

CLASSIFICATION :

Antidepressants are classified into three groups :

(1) Monoamine oxidase inhibitors (MAO inhibitors) : e.g. Phenelzine, Pargyline, Tranylcypromine,

Isocarboxazid.

MAO-A Is- Moclobemide, clorgyline--- for inhibit metabolism of NA and 5HT--- antidepressant

MAO-B Is- Selegiline--- for inhibit metabolism of DA-- antiparkinson

(2) Tricyclic antidepressants (TCAs): e.g.

NSRIs- Amitriptyline, Imipramine, Dothiepin, Trimipramine & Clamipramine.

NRIs- Nortriptyline, Desipramine, Doxepin, Amoxapin, Reboxetine

3) SSRIs: Fluoxetine, Fluvoxamine, Paroxetin, sertaline

(3) Atypical antidepressants (second generation antidepressants) : e.g. Trazodone, Mianserin, Mirtazapine

Tricyclic antidepressant (TCAs)

NA+5HT reuptake

inhibitor (NSRIs)

Imipramine

Amitryptyline

Clomipramine

Inhibit NET and SERT

[NA and 5HT

transporter)

Also having

anticholinergic

Imipramine is a

analogue of CPZ

Depression

OCD and Phobic

state (Clomipramine)

Neuropathic pain

(Amitryptyline)

Attenion deficit-

hyperactivity

disorder in children

(ADHD) (first line

drug)

Enuresis

(Imipramine)

Migrane

(Amitriptyline)

Pruritus (topical

doxepin)

Sedation (Anti H1)

Anticholinergic side effect

dengerous CVS action:

Tachycardia/arrhythmia

Postural hypotension

Myocardial depression

Acute TCAs poisoning antidotes:

Diazepam- for CNS activity

Propranolol/lidocain- for reduce cardiac

activity

Physostigmine- for antichoinergic toxicity

Contraindication:

CVS Disorders

Interactions:

+ sympathomimetic—enhance the action

+Guanethidine/clonidine—abolish their

antihypertensive action

+Alcohal/antihistamines—marked

depression

+penytoin/NSAIDs/phenylbutazone/CPZ can

NA reuptake

inhibitor (NRIs)

Desipramine

Nortryptyline

Inhibit NET

Also having

anticholinergic


displace the TCAs Protein biding sites and

cuse toxicity

+MOA Is- hypertensive crises

Selective serotonine reuptake inhibitor (SSRIs)

Fluoxetine

Inhibit SET Depression (first line

drug)

OCD and Phobic

state

Anxiety

ADR

Sexulal dysfunction (ejaculation)

Interctions:

These are metabolic enzyme inhibitors

they elevated the plasma conc. Of others

like TCAs, haloperidol, warfarin, beta

blockers etc.

Serotonine syndrome- agitation,

restlessness, sweating, twitching

followed by convulsion with other

serotonergic/MAO drugs drug.

MAO Inhibitors

Two forms of MAO have been identified. MAO-A-preferentially deaminates 5HT/NA and MAO-B-

preferentially deaminates phenylethylamine.

MAO-A inhibitors : Chlorgiline and moclobemide.

MAO-B inhibitors : Selegiline.

Nonspecific MAO inhibitors : Tranylcypromine, phenelzine and isocarboxazid.

Depression is due to deficiency of monoamine transmitters (e.g. noradrenaline & 5HT) in the brain. MAO

inhibitors inhibit MAO & thereby increase the availability of noradrenaline & 5HT.

* Pargyline is used in the treatment of hypertension rather than is depression.

Uses : MAO inhibitors are rarely used now because of toxicity and lower antidepressant activity than tricyclic

antidepressants. May be used in major depression not responding to tricyclic antidepressants

Interactions

(1) Patients taking MAO inhibitors should be warned to avoid tyramine containing food and beverages

(cheese, liver, wine, beer etc.).

(2) The MAO inhibitors should not be administered with or immediately following other MAO inhibitors

or antidepressants can produce hypertensive crisis.

(3) The MAO inhibitors potentiate the effects of phenothiazines, thiazides, procaine, insulin, antiparkinson

agents, morphine, barbiturates etc.

ANXIOLYTICS/MINOR TRANQUILLISERS

Anxity is emostional condition that are characterized by the normal fear response to threatening stimuli,

comprises several components, including defensive behaviours, autonomic reflexes, arousal and alertness,

corticosteroid secretion and negative emotions.

Anxiolytics are the drugs used to treat anxiety. Pharmacologically anxiolytics are sedative-hypnotic in type.

CLASSIFICATION : Anxiolytics are classified into two groups.

(1) Benzodiazepines : e.g. Diazepam, Alprazolam, Oxazepam, Chlordiazepoxide, Lorazepam, Chlorazepate

dipotassium, Prazepam & Halazepam.

(2) Others : e.g. Meprobamate, Buspirone & -Blockers.


Benzodiazepines

Diazepam

Alprazolam (repid

elimination)

Chlordiazepoxide

Lorazepam

BZD/GABAA agonist

Increase frequency Cl-

channel opening

Anxiety

Sedation

Muscle relaxant

Anticonvulsant

Cognitive impairment

Physical dependance

Hydroxyzine H1 blocker anxiolytic

Sedation

Antiemetic

Antimuscurinic

Spasmolytic

Used in urticaria and

pruritus

Buspirone

(Azaprione)

Modulate 5HT1A

receptor

Week D2 blocking

action

Non sedative

anxiolytic

Partial agonist of

5HT1A presynaptic

autoreceptor

Antagonist of post

synaptic 5HT1A

receptor

Anxiety

OCD

Presently SSRIs is drug of choice for social anxiety

SEDATIVES/HYPNOTICS Barbiturates

Phenobarbitone

Pentobarbitone

MOA:

Allosteric

picrotoxicin/GABAA

agonist

Increase duration Cl-

channel opening

GABA facilitatory action

GABA mimetic action

Decrease Ca2+ dependant NT release (N type

Ca2+ channel)

Sedation---Sleep----anesthesia----Coma

Decrease REM and NERM (3, 4 stage).

Used: Epilepsy, GA, Hypnotics/ Insomnia,

adjuvant with antipsychotics

Respiratory depression

Tolarence and psychological

dependence

Hypersensetivity/ idosyncracy

Mental confusion

Withdrawal symptoms

Acute Barbiturates poisoning:

Res./CVS/CNS collaps.

Antidote: Alkaline diuresis (NaHCO3)+

mannitol Haemodialysis,

Contraindication:

Liver and kidney diaseases

Pulmonary insufficiency (emphysema)

Pregnancy

Obstructive sleep apnoea

Interactions :

Barbiturates is a metabolic inducer.

Sod.valproate increase the plasma conc of

barbiturates

Benzodiazepines

Allosteric

BDZ/GABAA agonist

GABA facilitatory action

Increase frequency Cl- channel opening

Decrease REM and NERM (3, 4 stage) sleep

Increase NERM (2stage) sleep

Vertigo

Cognitive impairment

Physical dependence


Nitrazepam- increase REM sleep

Anxiety

Hypnotic/Sedation-Insomnia

Preanesthetics

Muscle relaxant

Anticonvulsant

Prevent Alcohol withdrawal symptoms

BDZ Antagonist: Flumazenil (used in BZD

overdose)

GABA, Muscimol: GABAA Agonist

Bicuculin: GABAA Antagonist

Barbiturates: allosteric picrotoxine/barbiturate GABAA Agonist

Picrotoxin: allosteric picrotoxine/barbiturate GABAA Antagonist

BZD: Allosteric BDZ/GABAA agonist

Flumazenil: Allosteric BDZ/GABAA antagonist

β-carboline (DMCM): Allosteric BDZ/GABAA inverse agonist

Zopiclone

(Cyclopyrolate ring)

+ BZD1 subtype

receptor

Dose not alter REM

Prolong NERM (3

and 4)

Insomnia

Zolpidem

(imidazopyridine)

+ BZD α1 subunit

receptor

Insomnia

Ramelteon

melatonine

Melatonin receptor

agonist

Insomnia

ANTICONVULSANT/ANTIEPILEPTICS

Epilepsy: It is a groups of CNS disease which characterized by Seizures, which is associated with episodic high

frequency discharge of impulse by a group of neurons in brain. The form of seizure is depend upon on the parts

of brain affected. Involvement of the motor cortex produce convulsion; involvement of the hypothalamus

causes peripheral autonomic discharge; and involvement of the reticular area causes loss of consciousness.

Convulsion:

Epilepsy is classified in two categories:

(1) PARTIAL SEIZURES: Impulse discharge begins locally and often remains locally. Symptoms depending

on brain area.

(i) Simple partial seizure- cortical focal epilepsy, without loss of consciousness.

(ii) Complex partial seizure- temporal lobe epilepsy; psychomotor epilepsy charectrized by involuntary

muscle contractions, abnormal sensory/autonomic discharge, alter mood and behaviours.

(iii) Simple partial or complex partial seizure secondarily generalized- The partial seizure occurs first and

evolves into generalized tonic-clonic seizure with loss of consciousness.

**An epileptic focus in the motor cortex causes repetitive jerking of a particular muscle groups is sometime

called ‘jacksonian epilepsy’.

(2) GENERALISED SEIZURES: Involved in whole brain.

(i) Generalized tonic-clonic/grand mal seizure: commonest, the usual sequence occurs is aura—cry—

unconsciousness—tonic spasm—clonic jerking followed by prolongation sleep and CNS depression.

(ii) Absence/petit mal seizure: mainly in children, momentry loss of consciousness, ‘freez’ conditions.

(iii) Atonic/akinetic seizure: loss of conscious with relax all muscles.

(iv) Myoclonic seizure: shock like momentry contraction of all muscels

(v) Infantile spasm: mainly showed in infants, intermittent muscle spasm and progressive mental

deterioration.

Anticonvulsant/Antiepileptic agents: The drugs which are used to prevent or treat convulsion or seizure.

(1) Barbiturate: Phenobarbitone

(2) Deoxybarbiturate: Primidone


(3) Benzodiazepines: Clonazepam, Clobazam, Diaze

(4) Hydantoin: Phenytoin

(5) Succinamide: Ethosuximide

(6) Carboxylic acid: Sodium valproate

(7) Iminostilbene: Carbamazepene, Oxcarbamazepene

(8) Phenyltriazine: Lamotrigine

(9) Cyclic GABA analougue: Gabapentin

(10) Newer drugs: Topiramate, Vigabatrin (γ-vinyl GABA), Tiagabin, Levatiracetam, Felbamate,

Zonisamide (Sulphonamide analouge)

*Primidone is converted into active metabolites phenobarbitone and phenylethylmelonamide (PEMA).

Phenobarbitone Activate GABAA

mediated Cl- ion

channel,

All type of seizures except Absence seizure

High dose reduce Ca2+ entry and anti glutamate activity

Primidone

(deoxybarbiturate)

+ GABAA Phenobarbitone + phenyl ethyl malonamide are active metabolites

Used as an adjuvant to phenytoin or carbamazepine for Partial Seizure

and General tonic-clonic

Diazepam Facilitate the GABAA

mediated Cl- ion

channel

First choice of Febrile and Status epilepsy

Phenytoin

(Hydantoin)

Barbiturate analuge

Block of Na+ channel

(Voltage gated)

High dose anti

glutamate activity

Neuronal membrane

stabilizer

All type of seizures

except Absence

seizure

Foetal hydantoin syndrome

Steven Jhonsan syndrome

Gum hypertrophy

Cardiac dysrrhythmia

Hypoglycemia (decrease insulin release)

Hirsutism

Contraindication:

Pregnancy

CVS disorder

Interaction:

+ Valproic acid displace the protein binding

and reduce metabolism- icrease plasma conc.

+barbiturates increase phenytoin metabolism

and phenitoin increase barbiturates

metabolism

Ethosuximide Inhibit T-Type Ca2+

channel

Effective only in Absence Seizure

Act on thalamocortical region

Valproate

(aliphatic carboxylic

acid)

Prolongation of Na+

channel inactivation,

Inhibit T-Type Ca2+

channel,

Induce GABA

mediated action

through inhibit its

degradation by

GABA-transaminase.

Preferred in Absence,

Myoclonic and

Atonic seizures

Broad spectrum

anticonvusant

ADR

Alopecia

Increase blood ammonia

Thrombocytopenia

Interaction:

+Mentabolic enzyme inducer

+Displace the phenytoin from protein

binding site

+ increase feotal abnormality with

carbamezapine


Carbamazepine

(iminostilbine)

Prolongation of Na+

channel inactivation

All type of seizures

except Absence

seizure, preferred in

Generalized tonic

clonic, and Cortex

partial seizure

Mood disorder

(Mania)

Increase antidiuretic

hormone action

Trigeminal related

neuralgias

Feotal abnormality

Lamotriagine

(phenytriazene)

Prolongation of Na+

channel inactivation,

Direct block of presynaptic voltage sensitive Na+ channel and

prevent release of excitatory amino acids

All Type

Gabapentin

(Lipophilic GABA

derivative)

enhance the GABA

release in brain

inhibit T type Ca2+

chhanel

Partial Seizure

Mania

Migrane

Diabetic neuropathy

Neuralgia

Vigabatrin GABA-transaminase

inhibitor,

Potentiation of GABA

action

Antagonism of Glutamate receptor

Prolongation of Na+ channel inactivation

Partial seizure

Topiramate Weak carbonic

anhydrase inhibitor

Antagonism of Glutamate receptor,

Prolongation of Na+ channel inactivation,

Potentiation of GABA action

Partial seizure, tonic-clonic, myoclonic

All type of seizures except Absence seizure

Tiagabine

(GABA analogue)

Inhibit GABA uptake

through block GABA

transporter (GAT-1)

Partial seizure

Levetiracetam

(piracetam analogue)

???mechanism is

unknown

May be + GABA and

– ion channel

Partial seizure

Zosinamide

(Sulphonamide

derivertive)

It may inhibit T-Type Ca2+ channel ,

Prolongation of Na+ channel inactivation

Felbamate

(meprobamate)

Inhibit NMDA receptor mediated Na+ channel,

Potentiation of GABA action

NEURODEGENERATIVE DISORDERS

Neurodegeneration disorders are group of diseases characterized by neuronal loss and generally an

accumulation of insoluble intracellular or extracelluar material in certain area of brains.

The neurodegenerative disorders are:

(A) Parkinson’s Disease (PD)- disable motor co-ordination due to loss of nigrostraital inhibitory

dopaminergic neurons.

(B) Alzheimer’s Disease (AD)- the most common cause of dementia, in which the neuronal injury is primarily

in the hippocampus and cortex, specially


(C) Huntigton’s Disease (HD)- motor disorder characterized by execessive and abnormal movements

resulting from the loss of specific straital neurons.

(D) Amyotrophic lateral sclerosis (ALS)- progressive weakness and muscle atrophy due to degeneration of

spinal, bulber, and cortical neurons.

** Proteins associated with neurodegenerative disorders.

PD- α-Synuclein AD- β-Amyloid

HD- Huntingtin ALS- Superoxide dismutase (SOD)

**Excitotoxicity: Over expression of extracellular Glutamic acid (Glutamate) can cause of neuronal toxicity

and lead to neuronal death is called exocitotoxicity. These can leads to pathogenesis of various

neurodegenerative diseases including PD, AD, Epilepsy. Thus, the antagonism of glutamate overactivation is

help to prevent neurotoxicity and enhance neuroprotection and cognition.

Extracellular glutamate is regulated by various transporters.

VGluTs (vesicular glutamate transporters): responsible for uptake of the excitatory amino acid (EAA) like

glutamate.

EAATs (excitatory amino acid transporters): responsible for neuronal uptke, dysfunction of EAATs

implicated with neurodegenerative disorders.

System-X (glutamate antoporter): exchange of extracellular glutamate to intracellular glutamate (1:1).

**Overload of intracellular Ca2+ ion can also produce excitotoxic effect through over activation of

Ca2+signaling pathways.

ANTIPARKINSONIANS

Parkinsonism is a progressive neurodegenerative disorder of muscle movement, characterized by tremors,

muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements). Parkinson’s

disease occurs due to reduction in the activity of the inhibitory dopaminergic neurons in the substantia nigra and

corpus striatum parts of the brain's basal ganglia system that are responsible for motor control. An imbalance

between cholinergic (excitatory) and dopaminergic (inhibitory) neurons in straitum give rise to motor defect.

Anti parkinson’s agents are restore these imbalance, as well as enhance the dopamine level or

dopaminergic activity in the brain.

Ach

+ GABA

Dopamin

e

Neostraitu

m

Substantia

nigra Degenerate in Parkinson’s

disease


CLASSIFICATION

(1) Drugs affecting the dopaminergic neuronal activity

(i) dopamine precursor: Levodopa

(ii) Peripheral decarboxylase inhibitors: Carbidopa, Benzserazide

(iii) Dopamine receptor agonist: Bromocriptin, Ropirinol, Pramipexole, Piribedil

(iv) MAO-B inhibitors: Selegiline

(v) COMT inhibitors: Entacapone, Tolcapone

(vi) Dopamine facilitator: Amentadine

(2) Drugs affecting the cholinergic neuronal activity

(i) Central anticholinergic: Trihexiphenidyl, Procyclidine, Biperiden

(ii) Antihistaminics: Orphenadrine, Promethazine

Levodopa + Dopaminergic

neurotransmission

+ dopamine receptor

+ D2 is responsible

for Antiparkinson

Peripherally it

converted into

dopamine by dopade-

carboxylase thus it is

given along with

Carbidopa/Benzseri

de (peripheral

dopa-decarboxylase

inhibitor)

Postural hypotension (central α2 action)

Cardiac arrhythmia

Angina

Contraindication

Cardiac patients

Psychotic patients

Interaction:

+ pyridoxine- abolish therapeutic effect

+ Phenothiazenes- block effect

+ phenelzine (MOAI-

hypertensive crises)

Bromocriptin

(Ergot derivative)

D2 agonist

Partial agonist &

antagonist of D1

Parkinson Hypotension

Hallucination

Nasal stiffness

Ropinirole D2/D3 agonist Parkinson

Entacapone COMT-Inhibitors

(peripheral)

Parkinson

Tolcapone COMT-Inhibitors

(peripheral/central)

Parkinson

Amentadine + dopamine synthesis,

release, reuptake

Parkinsion

Antiviral (influenza)

** if dopamine release is

already maxmimum then

it has no effect.

Deprenyl (Selegiline) Inhibit MAO-B it inhibit the

metabolism of

dopamine in the brain

Parkinson

ANTI-ALZHEIMER

It is a another neurodegenerative disorder which affects mostly olders and it is the most common causes of

dementia. It is occurs due to atrophy of cortical and subcortical area is associate with deposition of β-amyloid

protein and formation of neurofibrillary tangles. In alzheimer’s disease there is marked choninergic deficiency

in the brain.

The cognition enhancer or cerebroactive drugs are acts on several mechanism: (1) increase cerebral blood fow,

(2) modulation of neuronal metabolism, (3) enhancement of neurotransmission, (4) improvement of cerebral

function, e.g. memory.


CLASSIFICATION:

(1) Nootropic (Cognition enhancer): Piracetam, Aniracetam

(2) Metabolic enhancer: Nicergoline, Piribedil, Dihydroergotoxine

(3) Vasoactive cerebral protector: Ginkgo biloba, Pyritinol

(4) Cholinesterase inhibiors: Tacrine, Rivastigmine, Donapezil, Galantamine

No-Otropics

Piraetam

Aniracetam

(Cyclic GABA

analauge)

+ Glutamate release Alzheimer

Cognitive enhancer

Anti-ChE

Rivastigmine

Donepezil

Tacrine

Inhibit Choline

esterase

Restore the cholinergic (nicotinic) neurotransmission in the brain

Alzheimer

Dihydroergotoxin Block adrenergic

system

Improve cerebral blood flow

Increase release Ach in brain

Enhance the DA and 5HT neurotransmission

Protecting the alter neuron metabolism (metabolic enhancer)

Piribedil Dopaminergic agonist Metabolic enhancer

Alzheimer

Parkinson

Pyritinol

(pyrithioxine)

Vasoactive cerebral protector

Enhance the cholinergic transmiss

Activate cerebral metabolism by increase the glucose transport across

the BBB

Ginkgo biloba

(Ginkgolide B)

PAF antagonist Vasoactive cerebral protector

Prevent cerebral thrombosis in infant

ANTI-MIGRANE

5HT1D Agonist

Sumatriptan

Zolmitriptan

Ergotamine

5HT1D Agonist Cerebral /Craneal vasoconstrictor (large artery)

Block trigeminal (facial) neuro-transmission

Used in migrane attack

Used in migrane prophylaxix

5HT2 blocker

Methylsergede

Pizotifen

5HT2 Antagonist

NARCOTIC/OPOID ANALGESICS

Narcotic analgesics are semisynthetic and synthetic compounds that have been developed with morphine like

properties. Morphine is an alkaloid isolated from opium (Papaver somniferum).

Opium contains two basic types of alkaloids :

(i) Phenanthrene type : e.g. Morphine, Codeine etc.

(ii) Benzylisoquinoline type : e.g. Papaverine & Noscapine

Morphin

e

HO OH

O

H

N-CH3

B

A C

1 11

10 16

9

8

7

6 5 4 3

2 12

15 14

13


CLASSIFICATION :

Narcotic analgesics are classified into following categories :

1. Natural alkaloids : e.g. Morphine, Codeine.

2. Semisynthetic opioids : e.g. Hydromorphone, Hydrocodone, Diacetylmorphine (Heroin).

3. Synthetic opioids : e.g. Levorphanol, Pentazocine, Pethidine (Meperidine), Methadone,

Fentanyl, Dipipanone

Morphine opoid receptor

(GiPCR)

Analgesia

Increase the pain

threshold

Anti Tussive/ Cough

suppressant

(Codeine)

Antidiarrhoeal

Respiratory depression (µR)

Euphoria (µ R)

Sedation

Pin point pupil (pupil constriction- µ

and k R)

Acute morphine poisoning: res.

Depression and coma

Antidotes: Nalaxone, Naltraxone

OPIOID

RECEPTOR

Subtype 1 & 2 1 & 3 -

Selective agonist

Morphine, -Endorphin Dynorphin A & B,

Ketocyclazocine,

Butorphanol

Met/Leu enkephalin

Selective antagonist

-funaltrexamine

(irreversible antagonist),

Nalorphine.

Norbinaltorphimine

-

Effector pathway

G.protein coupled,

decrease cAMP formation

and open K+ channels.

G.protein coupled,

decrease cAMP

formation and inhibit N

type Ca++ channels.

G.protein coupled,

decrease cAMP formation

and open K+ channels.

Distribution

Thalamus, nucleus tractus

solitarious, nucleus

ambigus etc.

Spinal & supraspinal

region

Spinal region and

myenteric plexus

Opoid receptors

Mu (µ)-- analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression, euphoria,

sedation and dependence)

The δ-receptors are probably more important in the periphery but may also contribute to analgesia.

The κ-receptors contribute to analgesia at the spinal level and may elicit sedation and dysphoria; they produce relatively

few unwanted effects and do not contribute to dependence. Some analgesics are relatively κ-selective.


μ δ Κ

Analgesia

Supraspinal +++ - -

Spinal ++ ++ +

Peripheral ++ - ++

Respiratory depression +++ ++ -

Pupil constriction ++ - +

Reduced Gl motility ++ ++ +

Euphoria +++ - -

Dysphoria - - +++

Sedation ++ - ++

Physical dependence +++ - +


Chapter 8

Antiashthematic Drug

Bronchial asthma is characterized by episodes of bronchospasm or reversible over reactivity of air way smooth muscles

due to variety of stimuli, resulting in narrowing of air tubes often accompanied by increased secretion, mucosal oedema

and mucus plugging. Bronchospasm is due to inflammation of bronchial mucosa which inturn causes release of mediators

such as:

Histamine- + H1 receptor, smooth muscle constriction.

PAF- increase platelet aggragation.

Leucotriens (LTC4, LTD4)- bronchospasm.

Thromboxane- increase airway response.

Cytokines- + T-CD4 and Th2 (immune cells)- promotion of inflammatory growth cells.

Interleukins (IL-4, IL-2)- + TGF, responsible for cell mediated immune response.

Neuropeptides (Substance-P)- increase of vascular permeability and mucosal secretions.

Misc- prostaglandins, TNFα, protease enzymes

1. Bronchodilators:

(a) β2 agonists: These drugs produce bronchodilation through β2 receptor stimulation. Stimulation of these receptors

increases cAMP formation in bronchial muscle cell and produce relaxation. In addition increased cAMP in mast cells and

other inflammatory cells decreases mediator release. There are two categories of β2 agonists:

(i) Short acting: Orciprenaline, salbutamol, terbutaline, bitolterol, procaterol, pirbuterol etc.

These drugs are given by inhalation route rather than the oral route. However, terbutaline, orciprenaline etc. are also

available as tablets. Oral route is not encouraged because the systemic effects are persistent. Inhalation route produce

minimal side effects.

(ii) Long acting: Salmeterol and formoterol are long acting drugs and the effects last for about 12 hours.

Adrenaline, noradrenaline or isoprenaline are not absorbed from g.i.t. so they are never given orally. Isoprenaline is

sometime given by sublingual route. These agents are metabolized by MAO or COMT and the final product 3-

methoxy 4-hydroxy mandelic acid is excreted in urine.

Ephedrine an extremely popular drug in past is hardly used today because of cardiotoxicity, hypertensive and CNS

related adverse effects.

Contraindication: These agents are contraindicated in patient suffering from angina pectoris, hypertension,

thyrotoxicosis.

B. Theophylline: The exact mechanism of action of theophylline is not known. The proposed mechanisms are:

(a) Inhibition of phosphodiesterases: Phosphodiesterases which degrades cyclic nucleotides intracellularly are blocked by

theophylline. Bronchodilation occur due increased cAMP.

(b) Blockade of adenosine receptors: Theophylline combines with the adenosine receptors and blocks it resulting in

bronchodilation.


C. Anticholinergics : Anticholinergic drugs cause bronchodilation by blocking cholinergic constrictor tone and bronchial

mucous secretion. They are less efficacious than β2 agonists, but can add to their response. Atropine produces many side

effects including dryness of mouth, hypotension, hallucination, photophobia, urinary retention etc. Atropine also damages

the cilia; therefore the use of atropine in the treatment of asthma is discontinued. However, ipratropium is almost free from

side effects and does not produce cilliary damage; it is also not absorbed from GIT and therefore has to be given by

inhalation route.

2. Leukotriene modifiers:

The cysteinyl leukotrienes (LT-C4/D4/E4) are important mediators of bronchial asthma. Two cysteinyl leukotrienes receptor

antagonist (montelukast, zafirlukast), and 5-LOX inhibitors (zileuton) are recently available. The plasma t1/2 of

montelukast is 3-6 hrs, while that of zafirlukast is 8-12 hrs. Dose–10 mg OD.

3. Mast cell stabilizers: Sodium cromoglycate, Ketotofen

These drugs inhibit degranulation of mast cell by triggering stimuli. Release of mediator of asthma like histamine, LTs,

PAF, interleukins etc. from mast cell as well as other inflammatory cell is prevented. Sodium chromoglycate is a mast cell

stabiliser, insoluble in water and is given as aerosol. It is a prophylactic drug and has no bronchodilator action. Dose:

Sodium chromoglycate is administered as an aerosol 1 mg per dose, 2 puffs 4 times a day. It is rapidly excreted unchanged

in urine and bile. Its chief use is in the asthma of childhood, also used in allergic rhinitis.

4. Glucocorticoids: Glucocorticoids like beclomethasone, flunisolide, triamcinolone, fluticasone and budesonide are given

by inhalation and act to decrease the inflammatory process in the airways. In addition, the corticosteroids increase the

sensitivity of the β2 receptors. With increased sensitivity of the β2 receptors, the β2 receptor agonist drugs become more

effective. The glucocorticoids are contraindicated in patients with hypersensitivity to the corticosteroids, acute

bronchospasm, status asthmaticus or other acute episodes of asthma. These are used cautiously in patients with

compromised immune systems, glaucoma, kidney or liver disease, convulsive disorders, or diabetes, those taking systemic

corticosteroids and during pregnancy.

Some people with severe asthma have high eospinophil levels in their lungs. Asthmatics in this group are not

common, but generally have serious symptoms requiring regular hospitalization and injected medication.

Mepolizumab is an antibody that blocks eosinophil production.

Bronchial thermoplasty is a novel intervention in which controlled thermal energy is delivered to the airway wall

during a series of bronchoscopies, resulting in a prolonged reduction of airway smooth-muscle mass.

Methylxanthines are extensively metabolized in liver by demethylation and oxidation.

Adenosine causes contraction of smooth muscles in CVS and bronchi. It also causes release of mediators from mast

cells. Adenosine receptors have been discovered. Theophylline block the adenosine receptors.

In the past cysteinyl leukotrienes were known as slow reacting substance of anaphylaxis (SRS-A).

Glucocorticoids do not relieve bronchospasm immediately (only control it). While β2 receptor agonists relieve

bronchospasm immediately. β2 receptor agonists, therefore, are known as “relievers” and glucocorticoids as

“controllers”.


Chapter 9

Hormone, Enzyme, Vitamin, & Nucleic Acid

HORMONES

Hormones are the informational molecules, transported through blood and acts only on the target organ. Many

substances function both as hormones and neuro-transmitters; these are therefore considered together. They

have a variety of chemical forms, but can be divided into three broad categories :

(1) Water-soluble small molecules : e.g. adrenaline, noradrenaline, histamine, 5-HT etc.

(2) Peptides and proteins : e.g. enkephalines, insulin, prolactin and gonadotropins etc.

(3) Hydrophobic organic molecules: e.g. steroids, vitamin D3 derivatives, thyroid hormones etc.

Endocrine tissue : The production, storage and secretion of hormones is the sole function of many endocrine

organs. Endocrine glands are also known as ductless glands.

Following is the list of structures and functions of some of the hormones secreted by mammalian endocrine

tissues :

Gland Hormone Structure Functions/biochemical role

Anterior pituitary

Thyroid stimulating

hormone(TSH)

Follicle stimulating

hormone(FSH)

Leuteinizing hormone

Prolactin

Adrenocorticotrophic

hormone(ACTH)

Growth hormone

(Somatotropins)

Lipotrophins(LPH)

Glycoprotein dimer

Glycoprotein dimer

Glycoprotein dimer

Polypeptide

Polypeptide

Single chain polypeptide

Polypeptides

Stimulates thyroid hormone

production

Stimulates growth of ovarian

follicles

Spermatogenesis

Stimulates lactation

Stimulates adrenal steroid

synthesis

Stimulates growth of

cartilages and bones

Stimulate lipolysis

Posterior pituitary Vasopressin(anti diuretic

hormone,ADH)

Oxytocin

Peptide

Octapeptide

Blood pressure, water

Balance

Uterine contraction, milk

ejection

Intermediate lobe Melanocyte stimulating

hormone (MSH)

Polypeptide Pigmentation of skin,

stimulate pituitary hormone

production

Hypothalamus Releasing factors Polypeptides Stimulate pituitary hormone

Pineal Melatonin N-acetyl -5-methoxy

Tryptamine

Regulates circadian rhythms

Thyroid T4(thyroxine)and T3(Tri

iodothyronine)

Iodinated amino acid

derivatives

Stimulate many processes

Parathyroid Calcitonin,calcitonin gene

related peptide(CGRP)

Parathyroid hormone or

parathormone (PTH)

Polypeptides

Polypeptide

Ca2+and PO4 metabolism

Vasodilator

Gland Hormone Structure Functions/biochemical role


Adrenal cortex Glucocorticoids

Mineralocorticoids

Steroids

Steroids

Metabolism of macro

molecules, many effects

Control of ionic composition

of plasma

Adrenal medulla Adrenaline

Nor adrenaline

Catecholamine

Catecholamine

Fat and carbohydrate

metabolism, smooth muscle

contraction

Lipid release, arteriole

contraction

Pancreas Insulin

Glucagon

Somatostatin

Polypeptide

Polypeptide

Peptide

Carbohydrate fat ,protein

metabolism

Inhibits release of insulin

Growth hormone

Testes Andogens(testosterone) Steroid Male secondary sex

characteristics

Ovaries Oestrogens,

Progestins(progesterone)

Steroid Female secondary sex

characteristics

Placenta Oestrogens,progestins

Chorionic gonadotrophin,

Placental lactogen,

Relaxin

Steroids Maintenance of pregnancy

Stimulates ovaries,

Stimulate lactation

Muscle tone

Gastrointestinal

tract Gastrin

Secretin

Cholecystokinin

Motilin

Vasoactive intestinal

peptide(VIP)

Gastric inhibitory peptide

Polypeptide

Polypeptide

Polypeptide

Polypeptide

Polypeptide

Polypeptide

Gastric acidification

Bicarbonate secretion

Secretion of digestive

enzymes

Gastrointestinal muscle

control

Inhibits gastric acidification

Inhibits gastrin secretion

Heart ANP Polypeptide Smooth muscle relexation ,

diuresis

Liver Angiotensin Polypeptide Essential hypertension

Kidney D3 Steroid derivative Calcium metabolism, bone

deposition

Hormone synthesis and secretion :

Hormones/peptide are generally stored in endocrine cells within membrane bounded secretory granules, and

released by exocytosis. The signal for exocytosis may be neural (for e.g. stimulation of the adrenal medulla), or

it may occur in response to changes in the plasma concentrations of other hormones or metabolites (for e.g.,

secretion of insulin and glucagon). In contrast, steroid hormones are not stored in significant quantities in

steroidogenic tissue but are released as they are synthesized.

Mechanism of Hormone Action :

Considered at the molecular level, hormones and neurotransmitters have several different mechanisms of action

:

1. Binding of the hormone to the receptor may lead to a change in the concentration of an intracellular second

messenger, which activates a protein kinase, catecholamines and many peptide hormones act in this way.

2. The receptor itself may be a protein kinase; this is true if receptors for insulin and growth factors.

3. The hormone receptor complex may enter the cell by endocytosis, and exert its effect after degradation.


4. The receptor may be a soluble protein in the cytoplasm or nucleus, that controls transcription of DNA to m

RNA. This applies to steroid hormones, thyroid hormones and 1, 25-dihydroxy vitamin D3.

Hormones with second messengers :

Many hormones dot not enter their target cells but act by raising the intracellular concentration of another

substance, known as second messenger; this acts the allosteric effector of anther protein, such as protein

kinase, which in turn regulates the activity of metabolic enzymes. This ‘chain of command’

Hormone – receptor – second messenger – protein kinase – target enzyme, constitutes a cascade system,

since one hormone molecule can produce many molecules of second messengers, and each molecule of

protein kinase can phosphorylate many molecules of its substrate. Further more, there is an important

control and amplification stage between the receptor and the second messenger, since the receptor does not

& itself produce the second messenger but controls its synthesis by a separate enzyme, and this control is

mediated by a third type of protein, called as G-Protein.

VITAMINS

These are compounds of varying complexity which cannot be made by the organism and have to be supplied in

small quantities in the diet.

A useful working definition is that a vitamin is an organic compound that is chemically different from the main

nutrients (fats, carbohydrates and proteins), is required in minute quantities in the diet, and absence of which

causes a specific deficiency disease. Many vitamins, especially those of the B group, function as coenzymes,

but not all vitamins have a coenzyme function.

Vitamins are broadly grouped in to two categories viz.

(1) Fat soluble vitamins : These includes vitamin A, D, E and K.

(2) Water soluble vitamins : These includes vitamin B complex and vitamin-C.

Vitamin Designation Deficiency disease

Water soluble vitamins

Thiamine

Riboflavin

Pantothenic acid

Nicotinic acid(Niacin)

Pyridoxine

Folic acid

Cyanocobalamine

Ascorbic acid

Biotin

Fat soluble vitamins

B1

B2

B3

B5

B6

B12

C

H

Beriberi

Cheilosis ,corneal opacity

Chick dermatitis

Pallegra

Dermatitis in rats

Megaloblastic anaemia

Pernicious anaemia

Scurvy

Dermatitis


Retinoids

Calciferols

Tocopherols

Phyllaquinones,

menaquinones

A

D

E

K

Night blindness, xerophthamia

Rickets , osteomalacia

Abortion,degeneration of muscles,sterlity

Clotting deficiency

Name of vitamin Name of co-enzyme Types of reactions

Thiamine Thiamine pyrophosphate Decarboxylation of -keto acids

Riboflavin Flavin mono nucleotide, flavin

adenine dinucleotide

Oxidation -reduction reactions

Pyridoxine Pyridoxal phosphate Decarboxylation, transamination of

amino acids

Nicotinamide Diphosphopyridine nucleotide

& triphospho pyridine nuclotide

Oxidation -reduction reactions

Pantothenic acid Coenzyme A Transference of acetyl groups

Biotin Biotin CO2 fixation reactions

Folic acid Tetrahydro folic acid Various reactions involving single chain

carbon compounds

Cynocobalamine Cobamide coenzyme Carbon chain isomerisation

FAT SOLUBLE VITAMINS :

Vitamin A (retinol) : Vitamin A is a polyunsaturated alcohol which occurs free or esterified in milk,

butter, eggs liver, cod liver oil and shark liver oil, but can also be derived from certain carotenes that occur as

yellow pigments in plants. The conversion of these to vitamin A involves oxidative cleavage in the center of

the chain. There are many carotenes, but only four of them give rise to vitamin A. These provitamins occur in

carrots, tomatoes and in grass (and hence in milk). Young children can carry out this transformation of a

limited extent only, and it is almost completely inhibited in hypothyroidism.

The presence of bile acids of other dietary fats is required for the efficient intestinal absorption of

vitamin A and its precursors and derivatives, which are transported to the liver in chylomicrons. The liver

maintains a store of fatty acyl esters of retinol, sufficient to meet the body’s needs for several months. Retional

is transported to the tissues bound to retinol-binding protein, and is reversibly converted to its aldehyde, retinal,

by alcohol dehydrogenase :

Retinol + NAD+ Retinal + NADH + H+


Functions of Vitamin A :

(1) It forms retinal pigments thus play an essential role in normal vision.

(2) It provides nutrition to epithelia in mucous membrane and glands.

(3) It prevents keratinisation of epithelia.

Deficiency diseases : Deficiency of vitamin A or retinol produces night blindness and xerophthalmia.

(i) night blindness : In this a person is unable to see at night or in dim light. This is due to the deficiency of

rhodospin formation.

(ii) Xerophthalmia : In this eye becomes dry leading to irritation and corneal xerosis.

Vitamin D

Although historically classified as a fat-soluble vitamin. The must important form of vitamin D is

cholecalciferol.

Source : Vitamin D3 is syntheszied in skin from a cholesterol derivative (ergosterol) in the presence of

ultraviolet rays of sunlight. It is also present in foods of animal origin (e.g. cod liver oil, eggs, shark liver oil).

Two substances are active when taken by mouth : vitamins D3 (cholecalciferol), a derivative of cholesterol, and

D2 (calciferol), a synthetic derivative of a plant sterol.

Cholesterol

NADPH, O2

HO 7

1

3

5

6

7-

Dehydrocholesterol UV-light

HO

7

3

1

6

8

17

24 25

CH

2

Cholecalciferol (vitamin

D3)

HO

CH

2

25-Hydroxycholecalciferol

HO

O2, NADPH

(Liver)

O2, NADPH

(Kidney)

HO

CH

2

1,25-Dihydroxycholecalciferol

HO

HO

(Kidney)

O2, NADPH

24,25-

Hydroxycholecalciferol

HO

CH

2

Ergosterol

Calciferol (vitamin

D2)


Metabolism of vitamin D and its derivatives : transformation of cholesterol into 1, 25

dihyroxycholecalciferol

The immediate precursor of vitamin D3 is 7-dehydrocholesterol, which is formed in the skin and sebum, and

converted non-enzymically to D3 by irradiation with ultraviolet light. If the skin is sufficiently exposed to

direct sunlight, enough D3 is formed to make its intake in food unnecessary.

D3 is not itself biologically active : the most important derivative is 1,25-dihydroxycholecalciferol, formed

from cholecalciferol by two NADPH-dependent hydroxylations. The liver takes up cholecalciferol from the

plasma, hydroxylates it, and resecretes 25-hydroxycholecalciferol, which is taken up and further hydroxylated

by the kidney. 1,25-Dihydroxycholecalciferol has a short half-life, and this suggests that maintenance of an

effective concentration in plasma depends upon a steady production of

7-dehydrocholesterol in irradiated skin, rather than modification of vitamin D absorbed in the gut at irregular

intervals. Prolonged exposure of the body to ultraviolet light does not cause the level of

25-hydroxycholecalciferol to rise to more that double the normal, whereas large oral doses of vitamin D may

raise it tenfold.

Functions of Vitamin D : The most important function of vitamin D is formation of teeth and bones. It

increases absorption of calcium and phosphorous and their deposition in bones.

Deficiency diseases :

(i) Rickets in children

(ii) Osteomalacia in adults.

Treatment and prevention :

(i) Exposure to sunlight

(ii) Dietary intake of Vitamin D.

Vitamin E : It is called as tocopherol

Source : Vitamin E is present in vegetable oils.

Functions :

(i) It prevents damage of membrane lipids.

(ii) It maintain normal membrane structure.

Deficiency :

(i) Its deficiency may lead to abortion and degeneration of muscles.

ii) Its deficiency can also lead to anaemia.

Vitamin K :

Source : Vitamin K is present in green leafy vegetables like spinach, raddish and coriander leaves. It is also

synthesized in our colon by intestinal bacteria.

Functions : (i) It helps in the formation of prothrombins, which is an important factor in blood coagulation.

Deficiency disease : Its deficiency can lead to excessive blood loss due to prolonged bleeding, as an important

blood coagulation factor (Prothrombins) is not formed.

Treatment : When there is a deficiency of vitamin K, it is given either by paranteral or oral route to prevent

haemorrhage.


WATER SOLUBLE VITAMINS :

Vitamin B1 : This is also known as Thiamine.

Source : It is present in yeast, cereal, grains, nuts, liver, pulses and fresh food.

Functions : (i) It forms a coezyme for metabolism of carbohydrates.

(ii) It also helps in metabolism and synthesis of pentose.

Deficiency disease : Thiamine deficeincy produces beri-beri in man. It is characterised by weakness, anorexia,

and bradycardia, with death usually caused by heart failure.

Vitamin B2 : This is also known as riboflavin

Source : It is present in yeast, liver, curd, pulses, milk and green leafy vegetables.

Functions : (i) It keeps skin healthy and normal.

(ii) It forms two derivatives, FMN and FAD which are coenzymes for dehydrogenase.

Vitamin B3 : It is also known as Nicotinic acid

Source : It is present in yeast, liver and cereal grains. It is also synthesized in the body from amino acid

tryptophan.

Functions : It forms two coezymes NAD+ and NADP+ for a number of dehydrogenases.

Deficiency : Its deficiency produces pellagra.

Vitamin B6 : This is also known as Pyridoxine.

Source : It is present in yeast, liver, cereals & eggs.

Function : vit B6 forms a coenzyme which participate in amino acid metabolism.

NH

2 N CH

2 H3

C

N

CH

3 (CH2)2O

H

Vitamin B1(thiamine,

aneurin)

+N S

H3

C Vitamin B2(riboflavin)

H3

C N

N

CH2 (CHOH)3

CH2OH

O

O

NH

N

H3

C (Pyridoxine

)

HO

N

CH2O

H

CH2O

H

H3

C

HO

N

CH2O

H

CH

O

(Pyridoxal)

Vitamin

B6

N (Nicotinic

acid)

COO

H CONH

2

(Nicotinamide

)

N


Deficiency diseases :

(i) convulsions

(ii) Anaemia.

Vitamin B5 : This is also known as Pantothenic acid. This compounds has not been shown to cure any specific

deficiency disease in man.

Vitamin H : This is also known as Biotin.

This does not cure any specific deficiency disease in man.

Folic acid :

Source : It is obtained from green leafy vegetables, yeast and liver.

Functions :

(i) It helps in DNA synthesis.

(ii) Formation and maturation of erythrocyte.

Deficiency :

(i) Megaloblastic anaemia

(ii) Gastrointestinal diseases.

Vitamin B12 : This is also known as cyanocobalamins.

Source : It is present in animal products such as meat, liver, fish. It is also synthesised in human colon. Its

deficiency occur due to a defect in gastrointestinal absorption (lack of ‘intrinsic factor’) and not due to a

deficient diet.

Functions :

(i) It promotes DNA synthesis.

(ii) It helps in maturation of erythrocytes.

(iii) Required for formation of myelin.

Deficiency disease : This occur due to a defect in gastrointestinal absorption and can lead to :

(i) Pernicious anaemia

(ii) Degeneration of spinal cord.

Treatment : It includes:

(i) Diet improvement (animal products)

(ii) Availability of ‘intrinsic factor’.

(iii) Drug therapy

Vitamin C : It is also known as Ascorbic acid.

H2

N N

OH

Folic acid (pteroglutamic

acid)

N

N

N CH

2 NH

CH

2

CO.N

H

COO

H |

CH |

CH2

|

CH2

|

COO

H

O O

OH HO

CHCH2OH

OH

Vitamin C (L-ascorbic acid)


Source : It is present in sour fruits like lemon, orange and amla. It is also present in green leafy vegetables.

Functions :

(i) It helps in the formation of collagen which is an important intracellular material of connective tissues.

(ii) It helps in wound healing because of anti-inflammatory activity.

Deficiency disease :

(i) Scurvy (characterised by swelling of gums).

Vitamin C can not be stored in body.

ENZYMES

Enzymes are non living, complex nitrogenous substances present in living ferments. All the enzymes are

proteins. The action of the enzyme is more or less like that of a catalytic agent. Without enzymes, the living

processes should be too slow to sustain life. For example, without the enzymes in our digestive tract, it would

take us about 50 years to digest a single meal.

Some examples of enzymes

Enzymes Reaction catalysed

Maltase

Cactase

Amylase

Inverters

Urease

Carbonic anhydrase

Pepsin

Trypsin

Nucleases

DNA polymerase

RNA polymerase

Maltose . . . . . . . . . . . . . . . . . . .> 2 Glucose

Lactose . . . . . . . . . . . . . . . . . . .> Glucose + Galactose

Starch . . . . . . . . . . . . . . . . . . . .> n Glucose

Sucrose . . . . . . . . . . . . . . . . . . . > Glucose + Fructose

Urea . . . . . . . . . . . . . . . . . . . . . > CO2 + NH3

H2CO3 . . . . . . . . . . . . . . . . . . . . > CO2 + H2O

Proteins . . . . . . . . . . . . . . . . . . > Amino acids

Proteins . . . . . . . . . . . . . . . . . . > Amino acids

DNA/RNA . . . . . . . . . . . . . . . > Nucleotides

Deoxynucleotido triphosphates . . . . .> DNA

Ribonucleotide triphosphates . . . . . .> RNA

Even small amounts of enzymes can be highly efficient. This is because the enzyme molecules are regenerated

during their catalytic activity. It addition to the protein structure, most active enzymes are associated with some

non-protein compounds required for their activity. These could be metal ions and smaller organic molecules

called coenzymes. Some of the metal ions involved are Zn, Mg, Fe, Cu, K and Na. Many of the coenzymes are

derived from vitamins.

Classification of enzymes :

Enzymes are classified according to the reactions they catalyse. Six classes of enzymes are as follows :


(i) Oxidoreductase : This class contains enzymes catalysing several different types of reaction, including

dehydrogenases, oxidases, mono-oxygenases and di-oxygenases.

(ii) Transferase : Enzymes in this class catalyse the transfer of acyl-phosphoryl-, glyceryl-, amino-or other

groups.

(iii) Hydrolases : This class contains enzymes which hydrolyse esters, amides, peptides etc.

(iv) Lyases : These enzymes catalyse the non-hydrolytic removal of a group the substrate, in reaction of several

types, including dehydration and scission of C-C bonds.

(v) Isomerases : These catalyses the isomerization of substrates.

(vi) Ligases : These catalyse the formation of C-C, C-N, C-O or C-S bonds in reactions requiring energy from

the hydrolysis of nucleoside triphosphates.

Biochemical role of enzymes :

(i) They are used in fermentation processes e.g. in the manufacture of beer and wine.

(ii) They are used in food industry for generation of sweet syrups from corn starch and in cheese production.

Enzyme inhibitors:

Enzyme inhibitors have pharmaceutical uses. For e.g. bacterial infection can be treated with antibiotics that

inhibit bacterial enzymes :

Some of the clinically useful enzyme inhibitors are listed below :

Inhibitor Enzyme inhibited Clinical use

Acetazolamide

Allopurinol

Aspirin

Captopril

Omeprazole

Phenelzine

Simvastatin

Warfarin

Carbonic anhydrase

Xanthine oxidase

Cyclooxygenase

Angiotensin convertase

Gastric H+-ATPase

Monoamine oxidase

HMG-CoA reducatase

Glutamate carboxylate

Diuretic

Alleviates gout

Anti-inflammatory

Antihypertensive

Reduces gastric acidification

Antidepressant

Lowers plasma cholesterol

Anticoagulant.

Assays of Enzymes :

The amount of an enzyme in a tissue or body fluid is visually determined by measuring the rate of the reaction

catalysed by a given amount of the sample, making the assumption that this rate is proportional to the amount of

enzymes present.

Assays of enzymes are of diagnostic importance.

Some examples of enzymes commonly assayed for diagnostic purposes :

Enzyme Location Cause of elevated plasma level

Acid phosphatase Prostate Prostatic cancer


Alanine

aminotransferase

Alkaline phosphatase

Amylase

Aspartate

aminotransferase

Creatine kinase

CK-1

CK-2

CK-3

-Glutamyl transferase

Lactate

dehydrogenase

LD1, LD2

LD2, LD3

LD5

Liver (muscle, heart,

kidney)

Bone, liver

Pancreas

Heart

Muscle

Red cells

Liver

Brain, bowel

Heart

Skeletal muscle

Liver, kidney,

pancreas

Heart, kidney

Liver, muscle

Hepatitis, jaundice, circulatory failure

with liver congestion

Rickets, hypoparathyroidism,

osteomalacia, obstructive jaundice,

cancer of bone or liver

Acute pancreatitis, Peptic ulcer

Myocardial infarction

Muscle damage

Anaemia

Hepatitis, circulatory failure with liver

congestion

Myocardial infarction

Muscular dystrophy

Heapatitis, alcoholic liver damage,

cholestatic liver disease

Myocardial infarction, kidney disease,

Megaloblastic anaemia, leukaemia

Liver disease, muscle damage/disease

NUCLEIC ACIDS

Nucleic acids play an important role in transmission of hereditary characteristics and the biosynthesis of

proteins. There are two classes of nucleic acids.

(i) DNA (deoxyribonucleic acid)

(ii) RNA (ribonucleic acid)

Nucleic acid are long polymers in which the monoseric units are nucleotides. The nucleotides are made up of

three chemical components.

(i) a nitrogen containing hetrocyclic base,

(ii) a five carbon sugar

(iii) and a phosphoric acid moiety.

There are two classes of nitrogen containing bases formed in nucleotides; purines and pyrimidines.

(1) Purine : The bases derived from purine are adenine (A) and guanine (G).

(2) Pyrimidine : The bases derived from pyrimidines are cytosine (C), thymine (T) and uracil (U).

The base uracil is found only in nucleotides of RNA and the base thymine is found only in nucleotides of DNA.

The second component of the nucleotides is the pentose sugar. RNA contains the sugar ribose and DNA

contains a derivative of ribose namely 2-deoxyribose.


Bases in nucleic acids :

(A) Purine

(a) Adenine (A) (b) Guanine (G)

(B) Pyrimidine

(a) Thymine (T) (b) Cytosine (C) (c) Uracil (U)

Sugars in nucleic acids

The three components of nucleotide are joined together in the following manner :

Functions of Nucleic Acids :

Nucleic acids have two important functions :

(i) Replication

(ii) Protein synthesis

(i) Replication : The genetic information for the cell is contained in the sequence of the bases A, T, G and C in

the DNA molecule. When a cell divides, DNA molecules replicate and make exact copies of themselves so that

each daughter cell will have DNA identical to that of parent cell. In this process, the two strands of DNA helix

unwind and each strand serves as a template for the synthesis of a new strand.

N

N N

N

N

N

N

H

HN

O

O

CH3

HO.CH2

H H

OH OH

H

O

OH

HO.CH2

H H

OH OH H

O

OH

Ribose 2-deoxyribose

Phosphat

e O

Sugar

Base

N

N N

N

NH

2 H

N

N NH

N

OH

H2N

NH2

O

N

N

H

N

H

HN

O

O N

N

OH

OH

or


(ii) Protein synthesis : The genetic information coded in DNA in the form of specific bases sequences has to be

translated and expressed in the form of synthesis of specific proteins, which perform various functions in the

cell. This is brought about in tow steps : transcription and translation.

(a) Transcription : The transcription involves copying of DNA sequences into a complementary RNA

molecule called messenges RNA (mRNA). The copying of DNA sequence into mRNA proceeds according to

the same base pairing principle as in replication, but with the difference that the base A pairs with U in RNA

(b) Translation : During translation mRNA directs protein synthesis in the cytoplasm of cell with the

involvement of another type of RNA molecule namely transfer RNA (tRNA) and the ribosomal particles

(RNA-proteins complexes). Several enzymes coordinates this complex process.

Codon : Sequence of 3 bases in the m-RNA molecule (Triplet) contain coded information for the various amino

acids. Such a triplet is called as Codon. Since there are 4 bases in DNA (Adenine, Guanine, Thymine and

Cytosine), 64 triplet codon are possible.

Genetic code : The DNA sequence that codes for a specific protein or a polypeptide is called a gene and thus

every protein in a cell has a corresponding gene. The relation between the nucleotide triplets (AAA, ACG,

AGC, AAU, AAG, AAC etc.) and the amino acids is called the genetic code.

Mutations : A mutation is a chemical change in DNA molecule that could lead to synthesis of proteins with an

altered amino acid sequence.


Chapter 10

Important Drug Interactions

LIST OF SOME COMMON CLINICALLY SIGNIFICANT DRUG INTERACTIONS

Interacting drugs Result Mechanism Management

Pharmacokinetic interactions 1 Ketoconazole + Antacids Reduced dissolution,

absorption and

effectiveness

of antifungal

therapy

Ketoconazole/

itraconazole

are weakly basic drugs

requiring acidic pH

for dissolution.

Increase in pH reduces

dissolution rate

Maintain a gap of atleast 2hrs

between the antifungal drugs

and antacids.

Avoid H2-receptor

antagonists.

Use alternative non-

interacting antifungals

Ketoconazole + H2-receptor

antagonists

rantidine/famotidine)

Ketoconazole + Proton-pump

inhibitor

(lansoprazole/omeprazole)

2 Bisacodyl + Antacids

Bisacodyl + Milk

GIT irritation &

vomiting

Increase in gastric pH

results in dissolution

of enteric coating

releasing irritating

bisacodyl in stomach

Maintain a gap of at least 2hrs

between the bisacodyl and

antacids/milk

3 Tetracyclines + Milk

Tetracyclines + Antacids

Tetracyclines + Iron salts

Failure of antibiotic

therapy

Tetracyclines form

poorly soluble metal

ions complexes

resulting in decreased

absorption

Maintain a gap of at least 2hrs

between the tetracycline and

antacids/ milk. Doxycycline

and minocycline are least

affected.

4 Fluoroquinolones+ Metal ion

(Al3+, Mg2+ antacids, Iron salts,

Zn- multivitamins)

Reduced absorption and

serum concentration of

fluoroquinolones

Fluoroquinolones

form poorly soluble

and absorbed

complexes

Avoid antacids use alternates

like H2-receptor antagonists.

Maintain as long gap as

possible.

5 Thiazide diuretics+

Cholestryramine/Colestipol

Reduced absorption

because of complexation

of these drugs by

cholestyramine and

colestipol.

May lead to bleeding or

thrombus formation

depending upon the

relative decrease in

absorption of warfarin or

its antagonist Vit-K

Cholestyramine and

colestipol bind these

drugs preventing their

absorption from GIT

Maintain as long gap as

possible.

Non-interacting bile acid

binder colesevlam may be

substituted for cholestyramine

and colestipol

Digoxin+


Warfarin +


Vitamin-K+


Leflunomide+


Beneficial drug

interaction

Cholestyramine and colestipol

are used to accelerate

elimination of active

metabolite of leflunomide in

women planning for

pregnancy as the active

metabolite persists for 2 years

6 Penicillamine + Antacids

Penicillamine + Iron salts

Penicillamine + Food

Chelation / adsorption of

penicillamine

Reduced absorption of

penicillamine

Maintain a gap of at least 2

hrs.

7 Atropine + Levodopa Levodopa efficacy

reduced

Atropine or other

anticholinergis

decrease gastric

emptying, more

Anticholinergics have

additive antipakinsonian

effect but they may be

omitted or prescribe


levodopa degraded

peripherally less

absorbed

Dopa decarboxylase inhibitor

8 Cathartics + Drugs

Metoclopramide + Drugs

Increased or decreased

effect of drugs

depending upon their site

of absorption and

dissolution

Catharitics and

metoclopramide

increase motility,

Anticholinergics + Drugs Anticholinergics

decrease motility.

9 Anti-infective agents + Food

Reduced absorption Binding by food,

reduced dissolution ,

decreasing access to

absorption sites

or pH alteration

Administer 1hr before or 2 hr

after meals. Penicillin V,

amoxicillin, minocycline,

doxycycline, erythromycin

ethylsuccinate unaffected by

food

Theophylline (SR formulation)

+ Food

Administer 1hr before meals.

No effect on immediate

release formulations

Enalapril, lisinopril

unaffected

Captopril+ Food

Alendronate/ Risedronate+

Food/ juice/coffee

May be taken 1 hr before any

food, beverage or medication

with plain water

10 Acarbose / Miglitol + Food Beneficial interaction

used for reducing

glucose levels in

diabetics

Decrease digestion of

ingested

carbohydrates

Maximum effectiveness when

administered at the start of

meal

11 MAOI’s (Isocarboxazid,

phenelzine, tranylcypromine) +

Tyramine rich foods (Aged

cheese, alcoholic beverages,

conc. Yeast extracts, fava

beans etc.)

Hypertensive crisis In MAO inhibited

patients higher

absorption of tyramine

from gut, which then

releases accumulated

norepinephrine from

adrenergic neurons.

Tyramine rich foods must be

avoided by patients taking

MAOI.

12 Grapefruit juice + Ca2+ channel

blockers (Feloipine,

amlodipine, nislodipine)

Hypotension Incresed serum

conentration due to

decreased first pass

metabolism because

of inhibition of

CYP3A4 enzyme by

furanocoumarins in

grapefruit juice.

Avoid use of grapefruit juice

13 Grapefruit juice + HMG-CoA

reductase inhibitors

(atorvastatin, lovastatin,

simvastatin)

Increased serum levels Avoid use of grapefruit juice.

Pravastatin unaffected

14 Grapefruit juice + Cyclosporin Increased serum levels,

nephrotoxicity

Inhibition of CYP3A4

and P-Glycoprotein

Avoid use of grapefruit juice

15 Anticoagulants (Warfarin) +

Antibiotics (Tetracyclines,

Erythromycin etc)

Bleeding Antibiotics alter GIT

flora interfering with

microbial production

of Vit-K

Monitor for bleeding time

increase dietary intake of Vit-

K

16 Digoxin +Antibiotics

(Tetracyclines, Erythromycin

etc)

Elevated serum digoxin

levels

Bacterial reduction of

digoxin in gut to

inactive metabolites is

reduced

Alternate antibiotics,

Reduction of digoxin dose


17 Oral contraceptives +

Antibiotics

Reduced serum estrogen

levels, failure of

contraceptive therapy

Estrogen component

of OC’s undergo

enterohepatic

circulation. Reduction

of microbial flora

prevents

deconjugation of

estrogen, decreasing

serum level of

estrogen

Additional means of

contraception should be

adopted when antibiotics are

being used concurrently.

18 Phenylbutazone + Warfarin Increased anticoagulant

activity, bleeding

Phenylbutazone has

greater affinity for

protein binding sites

than warfarin,

displacing it from the

binding sites leading

to increased free

serum drug

concentration.

Replace with non-interacting

NSAID.

Monitor for prothrombin time

reduce the dose of warfarin.

19 Methotrexate + Salicylates Increased serum

methotrexate levels,

cytotoxicity

Salicylates displace

methotrexate from

protein binding sites

and also decrease the

renal excretion of

methotrexate

Avoid salicylates or replace

with non interacting NSAIDs

Monitor for serum

methotrexate levels and adjust

the dose

20 Phenytoin + Valproic acid Increased free serum

phenytoin concentration

Valproic acid

displaces phenytoin

from protein-binding

sites and inhibits its

metabolism.

Phenytoin is also

reported to inhibit

metabolism of

valproic acid.

Monitor for blood levels and

adjust the dose.

21 Warfarin + Phenobarbital Decreased warfarin

levels, Increased risk of

thrombus formation

Phenobarbital induces

metabolism of

warfarin resulting in

decreased serum

warfarin level

Alternative hypnotic sedative

like diazepam may be used or

close monitoring for

combination therapy and

adjustment of dose of

warfarin.

22 Oral contraceptives +

Phenobarbital / Rifampicin /

Carbamazepine/ Phenytoin/

St.John’s wort

Risk of failure of oral

contraceptives

Phenobarbital and

rifampicin induce

metabolism of

estrogens and

progestins

Additional contraceptive

measures should be adopted.

23 HIV protease inhibitors

(ampenavir, lopinavir,

atazanavir) + Phenobarbital /

Rifampicin / Carbamazepine/

Phenytoin/ St. John’s wort

Reduction in serum

levels of protease

inhibitors

HIV protease

inhibitors metabolism

is induced by inducers

Adjust the dose of protease

inhibitors or

avoid concurrent use of

inducers like rifampicin.


24 Levodopa + Pyridoxine Abolition of therapeutic

effect of levodopa

Pyridoxine acts as co-

factor of dopa

decarboxylase,

enhances peripheral

decarboxylation of

levodopa

Peripheral dopa

decarboxylase inhibitors

(carbidopa/benserazide)

improve the brain levels of

levodopa. On peripheral

inhibition of dopa

decarboxylase, levodopa is

metabolized by catechol-O-

methyl transferase. COMT

inhibitor (entacapone) is used.

25 Alcohol+ Disulfiram

Alcohol + Metronidazole

Disulfiram reaction

characterized by

flushing, burning

sensation, throbbing

headache, dizziness,

mental confusion,

vomiting

Disufiram inhibits

alcohol

dehydrogenase

resulting in

accumulation of

acetaldehyde, which

causes distressing

symptoms. Similar

mechanism for

metronidazole

This reaction used as aversion

technique in chronic

alcoholics desiring to leave

the habit.

Patients taking metronidazole

should be cautioned to avoid

alcohol

26 Disulfiram + Warfarin

Disulfiram + Phenytoin

Increased activity or

toxicity of warfarin/

phenytoin

Inhibition of

metabolism of

warfarin/ phenytoin

Avoid the use of disulfiram in

patients on warfarin/

phenytoin or adjust their dose

27 Allopurinol+ Mercaptopurine

Allopurinol + Azathioprine

Cytotoxic effects of

azathioprine and

mercaptopurine

enhanced

Allopurinol inhibits

xanthine oxidase

which also

metabolizes

azathioprine and

mercaptopurine

Monitor closely for the

cytotoxic effects and reduce

the dose of mercaptopurine

and azathioprine

28 Cimetidine + Carbamazepine/

diazepam/ phenytoin/ warfarin/

theophylline

Increased serum levels

of carbamazepine/

diazepam/

olanzepine/phenytoin/

warfarin/ theophylline

Cimetidine by

inhibiting cytochrome

P-450 metabolism

enzymes (CYP1A2,

CYP2C19, CYP2D6)

increase the serum

levels of drugs

metabolized by them.

Cimetidine may be substituted

with non-interacting

famotidine/ nizatidine

29 Warfarin + Acetaminophen Increased risk of

bleeding

Decreased capacity of

cytochrome P-450

enzymes by

paracetamol

Clinically significant

interaction appears after 1

week of therapy. Patients

should be cautioned. Lowest

dose of acetaminophen for

shorter duration of action

30 Theophylline + Macrolides

(Erythromycin, clarithromycin,

telithromycin)

May lead to theophylline

toxicity

Erythromycin inhibits

hepatic metabolism of

theophylline.

Close monitoring.

Azithromycin does not

interact.

31 Theophylline +

Fluoroquinolones

(Ciprofloxacin)

Increased serum

theophylline levels

Ciprofloxacin inhibits

hepatic metabolism of

theophylline.

Close monitoring.

Ofloxacin does not interact.


32 Ca2+channel blockers

(Verapamil/ diltiazem) +

Carbamazepine

Increased serum

carbamazepine

Verapamil/ diltiazem

inhibit carbamazepine

metabolism

Closely monitor and adjust

the dose of carbamzepine, use

non-interacting drugs

33 Cisapride + CYP3A4

inhibitors (cimetidine/

erythromycin/ketoconazole/

ritonavir/indinavir/ grapefruit

juice)

Cisapride toxicity

characterized by

prologation of QT

interval, torsades de

pointes, syncope, sudden

death

Cisapride metabolism

is inhibited.

Potentially fetal interactions

Cisapride should be avoided.

Cisapride withdrawn in many

countries due to its drug

interaction.

34 Salicylates + Alkalizing agents

(Systemic antacids) /

Acidifying agents (ammonium

chloride etc)

Alkalizing agents

provide smaller duration

while acidifiers increase

the duration and activity

Acidic urine favors

the unionized drug

promoting

reabsorption while

alkaline urine favors

ionized fraction

promoting excretion.

Adjust the dose of salicylates.

35 Alkalizing agents + Basic

drugs like Dextroamphetamine

/ Quinidine/ Pseudoephedrine

Increased duration and

activity of basic drugs

Increased reabsorption

of basic drugs from

alkaline urine

Close monitoring.

Adjust the dose of basic

drugs.

36 Probenecid + Penicillin/

Methotrexate

Increased serum levels

of penicillin/

methotrexate

Probenecid decreases

the renal excretion by

inhibiting tubular

secretion

Probenecid-penicillin

combination used

advantageously to prolong the

duration of action of

penicillin.

Adjust the dose.

37 Methotrexate + NSAIDs Increased serum

methotrexate levels may

lead to toxicity.

NSAIDs inhibit active

tubular secretion of

methotrexate

Closely monitor the patients.

Adjust the dose of

methotrexate.

38 Lithium + NSAIDs (ibuprofen/

indomethacin/ piroxicam)

Increased serum

concentration and

toxicity of lithium

NSAIDs inhibit renal

clearance of lithium

by inhibiting renal PG

synthesis

Close monitoing. Adjust the

dose of lithium.

39 Digoxin + P-glycoprotein

inhibitors (Quinidine/

verapamil/ erythromycin/

clarithromycin/ itraconazole/

ketoconazole)

Greater serum digoxin

levels and half-life.

P-glycoprotein limits

uptake of drugs from

blood to brain and

from intestinal lumen

into epithelial cells.

Inhibition of P-

glycoprotein results in

greater absorption and

decreased elimination.

Monitor closely.

Adjust the dose

40 Digoxin + P-glycoprotein

inducers (Rifampicin/ St.

John’s wort)

Decreased serum

digoxin concentration

P-glycoprotein

inducers decrease the

absorption and

increase the clearance.

Adjust the dose with close

monitoring.

41 Loperamide + P-glycoprotein

inhibitors (Quinidine/

verapamil/ erythromycin/

clarithromycin/ itraconazole/

CNS effects of opioids Inhibition of P-

glycoprotein results in

penetration of

loperamide into brain.

Caution the patient.


ketoconazole)

Pharmacodynamic Interactions 42 Oral anti diabetic/ Insulin +

Thiazide diuretics

Hypoglycemic action of

antidiabetics attenuated

Thiazide diuretics

elevate the blood

glucose level

Adjust the dose of

antidiabetics.

43 Alcohol + CNS Depressants

(Sedative-hypnotics/

antipsychotics/ opioid

analgesics/ TCA, Sedative ant

histaminics)

Increased duration and

intestity of CNS

depression

Additive CNS

depressant effect of

alcohol and other

drugs.

Alcoholic beverages avoided.

Patient should be cautioned.

44 Sildenafil/Tadalafil/ Vardenafil

+ Nitrates

Hypotension Sildenafil by

inhibiting PDE-5

potentiates the

hypotensive effect of

nitrates

Avoid the combination

45 Digoxin + Diuretics

(Thiazides)

Cardiac arrhythmias Diuretics deplete

potassium resulting in

increased sensitivity

of heart to digoxin.

Monitor closely for serum

potassium levels.

Use potassium-sparing

diuretics. Potassium

supplementation in cases of

toxicity under intensive care

46 Digoxin + Corticosteroids

Digoxin + Cathartics

Cardiac arrhythmias Potassium depletion

by prolonged use of

cathartics and

corticosteroids

Monitor closely for serum

potassium levels.

Avoid use of cathartics. Use

alternatives like bulk

laxatives/ NSAIDs etc.

47 ACE-inhibitors( Ramipril/

enalapril/ lisinopril) +

Potassium sparing diuretics (

Triamterene/ spironolactone/

amiloride)

Hyperkalemia ACE-inhibitors raise

serum potassium level

and potassium sparing

diuretics cause

additive hyperkalemia

Monitoring of serum

potassium levels

Change the drugs

48 Lithium- Diuretics Lithium toxicity Diuretics by cuasing

sodium depletion

reduces the renal

clearnce of lithium

and increases the

activity of lithium.

Monitor serum lithium levels.

Adjust the dose

49 MAO inhibitors +

Sympathomimetic amines

Hypertensive crisis,

cardiac arrhythmias

In MAO inhibited

patients conc of

norepinephrine at

adrenergic neurons is

increased,

sympathomimetic

amines by stimulating

their releases bring out

exaggerated response

Patients on MAOI should be

cautioned against using drugs

containing sympathomimetic

amines particularly OTC

products


50 MAO inhibitors + TCA’s

Hypertensive crisis with

excitement and

hallucinations

TCA’s inhibit uptake

of amines, MAOI

prevent their

degradation additive

action

Avoidance of the

combination. Patients should

be cautioned

51 Guanethidine + TCA’s Anti-hypertensive action

of guanethidine blocked.

TCA’s inhibit uptake

of guanethidine in

adrenergic neurons.

Avoid combination.

Use non-interacting anti-

hypertensive agents


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