PHARMACOLOGY- PART II

DEEPTHI P.R.

1st YEAR MDS

DEPT.OF CONSERVATIVE DENTISTRY & ENDODONTICS

CONTENTS

Mechanism of drug Detoxication in the Body. Intolerance, Tolerance, Cumulative action,

Synergism, Antagonism. Dosage, Classification of Drugs

MECHANISM

OF DRUG

DETOXICATIO

N IN THE

BODY

CONTENTS

Fate of a drug

Reactions:

synthetic

non- synthetic

FATE OF A DRUG

Changes that drug undergoes & its ultimate

elimination

Alteration of a drug within a living organism:

biotransformation

Metabolism: detoxication process

3 possible fates after absorption:

FATE OF A DRUG

I. Metabolic transformation by enzymes

Microsomal/ cytosolic/ mitochondrial

Inactivate an active drug

Activate a prodrug

Generate active metabolites of an active drug

FATE OF A DRUG

II. Spontaneous change into other substances

No enzymes

III. Excretion unchanged

FATE OF A DRUG

Less polar, lipid soluble more polar, water

soluble: excretion by kidneys

Already polar & soluble: excreted as such-

aminoglycosides

Activation/ inactivation/ modification

Reactions:

Non synthetic/ Phase I/

Functionalization

Oxidation

Reduction

Hydrolysis

Cyclization

Decyclization

REACTIONS

Synthetic/ Phase II/

Conjugation

Glucuronide conjugation

Acetylation

Methylation

Sulfate conjugation

Glutathione conjugation

Ribonucleoside/ nucleotide

synthesis

REACTIONS

Phase I reactions: OH-, NH2, SH-, COO- into

drugs: water soluble & less active

Initial stages: active & more toxic products also

formed

REACTIONS

Tissues metabolising drugs: liver

Enzymes : drug metabolism- liver microsomes- sER

Esterases, amidases, glucuronyl transferases:

catalyse oxidative & reductive reactions

Variety of enzymes- CYP450 system : absorbs light

maximally at 450nm

REACTIONSDrugs – barbiturates: enzyme induction- rapid metabolism of

substrate drugs

Enzyme induction: kidney, gut, plasma, skin, lung

Non microsomal enzymes & intestinal microfloral enzymes : MAO,

alcohol dehydrogenase, xanthine oxidase

Animal species &

strain

Age & sex

Genetic determinants

Nutritional status

Altitude & temperature

FACTORS AFFECTING DRUG METAB OLISM

Route & duration of

admn

Environmental

determinants: pollutants

Drug interactions

(inducers & inhibitors)

Disease- hepatic/ renal

damage

PHASE I REACTIONS

OXIDATION

Hydroxylation: salicylic acid to gentisic acid

Dealkylation: phenacetin to p-acetaminophenol

Deamination: amphetamine to benzyl-methyl-ketone

REDUCTION

Microsomal enzymes- halothane & chloramphenicol

Non microsomal enzymes: chloral hydrate, disulfiram,

nitrites

PHASE I REACTIONS

HYDROLYSIS

Esterases: microsomal/ non microsomal/ microfloral

Pethidine, procaine, acetyl choline

CYCLIZATION

Ring structure from a straight chain compound: proguanil

DECYCLIZATION

Opening up of ring structure – cyclic drug molecule:

barbiturates, phenytoin

SYNTHETIC REACTION

Conjugation/ transfer reactions

Drug/ Phase I metabolite + endogenous

substance conjugates

Inactivation

large molecules: bile

small molecules: urine

SYNTHETIC REACTION

GLUCURONIDE CONJUGATION

Chloramphenicol, aspirin, paracetamol

Bilirubin, steroidal hormones, thyroxine

MW: excretion in bile

reabsorbed

Enterohepatic cycling: duration of action- OCPs

hydrolysis

Gut bacteria

ACETYLATION

Sulfonamides, isoniazid, PAS,

hydralazine,

Genetic polymorphism: slow

& fast acetylators

METHYLATION

Adrenaline, histamine,

nicotinic acid, methyldopa,

captopril

SYNTHETIC REACTION

GLYCINE CONJUGATION

Minor pathway-

Salicylates

GLUTATHIONE

CONJUGATION

Highly reactive

intermediates: inactivated-

paracetamol

SYNTHETIC REACTION

RIBONUCLEOSIDE/ NUCLEOTIDE SYNTHESIS:

Activation of purine & pyrimidine antimetabolites in cancer

chemotherapy

SULFATE CONJUGATION

Chloramphenicol, methyldopa, adrenal & sex steroids

ENZYMES OF INTERMEDIARY

METABOLISM

Alcohol: alcohol dehydrogenase

Allopurinol: xanthine oxidase

SCh & procaine: plasma cholinesterase

Adrenaline: mono amino oxidase

Majority: microsomal & non microsomal drug metabolising enzymes

TOLERANCE

INTOLERANCE

CUMULATIVE

ACTION

SYNERGISM

ANTAGONISM

TOLERANCE

Requirement of higher dose of a drug to produce a

given response

Refractoriness: loss of therapeutic efficiency – a

form of tolerance

Types:

Natural

Acquired

NATURAL TOLERANCE

Innate/ congenital tolerance

Species/Racial/ individual: inherently less sensitive

to the drug

Rabbits: atropine

Black races : mydriatics

Some individuals: hyporesponders –

alcohol, β-blockers

ACQUIRED TOLERANCE

Repeated administration: in initially responsive

Seen with most drugs: significant in CNS

depressants

Opiates, barbiturates, nitrites, xanthines

Not with: atropine, sodium nitroprusside, digitalis,

cocaine

TISSUE TOLERANCE

Develops unequally: different effects of same drug

Sedative action of chlorpromazine: not to

antipsychotic

Analgesic & euphoric action of morphine & not

constipating & miotic actions

CROSS TOLERANCE

Tolerance to pharmacologically related drugs

Alcoholics: barbiturates & general anesthetics

Partial: morphine & barbiturates

Complete: morphine & pethidine

APPARENT/ PSEUDO TOLERANCE

Confined to oral administration of drug

Taking small amounts of poisons orally: render

immunity to oral poisons

Mucosal changes in GIT: prevents systemic

absorption of poison

Can occur through other routes

1. Pharmacokinetic/ Drug

disposition tolerance:

Changes in absorption,

distribution, metabolism &

excretion: effective

concentration at the site of

action reduced

Barbiturates,

carbamazepine, amphetamine

MECHANSIM OF DEVELOPMENT OF TOLERANCE

2.Pharmacodynamic/

Functional/Cellular tolerance:

Target tissue changes-

Decrease in drug receptors/

down regulation or weakening

of response effectuation

Alcohol, barbiturates,

nitrates, morphine

Acute tolerance

Doses of a drug are

repeated in quick

succession: marked

reduction in response

Ephedrine, nicotine

TACHYPHYLAXIS

Slow dissociation of drug

from receptor: reduced

intrinsic activity; continued

blockade

Unidentified ‘adaptive

response’ of tissue/

compensatory homeostatic

adaptation

Rare in clinical

practice: repeated admn

in quick succession not

customary

Faster

Drug effect cant be

obtained with increased

dose

TA C H Y P H Y L A X I S V S T O L E R A N C E

More common

Slower development

Original effect obtained

with increasing dose

REVERSE TOLERANCE

Sensitisation

Intermittent dosing schedule

Greater response seen for a given dose than after

an initial dose

Repeated daily administration of cocaine/

amphetamine: gradual increase in motor activity

with constant dose

DRUG INTOLERANCE

‘Failure to tolerate’: Appearance of toxic effects of

a drug in an individual at therapeutic doses

Low threshold to the action of a drug

Single tablet of chloroquine: vomiting & abdominal

pain

DRUG INTOLERANCE

Also used: any Adverse Drug Reaction (ADR)

DRUG INTOLERAN

CE

QUANTITATIVE

AUGMENTEDPREDICTABLE

TYPE A

QUANLITATIVE BIZZARE

UNPREDICTABLE

TYPE B

IDIOSYNCRASY

ALLERGY

Dose related &

predictable :

pharmacological actions

Preventable &

reversible

Hyper response to the

main action: insulin

hypoglycemia

TYPE A ADR

Less common, not dose-

related, more serious,

require drug withdrawal

Idiosyncrasy: genetic/

unknown mechanism

Allergy: Immunological-

type I, II, III, IV

TYPE B ADR

IDIOSYNCRASY

Genetically determined abnormal reactivity:

uncharacteristic reaction with drug

Due to individual peculiarities

Chloramphenicol: non- dose related serious

aplastic anemia

ALLERGY

Type I/ Anaphylactic reactions:Urticaria angioedemabronchospasm anaphylactic shock

Type II/ Cytolytic reactions:Thrombocytopenia agranulocytosisaplastic anemia hemolysis SLE

Type III/ retarded, Arthus reaction:Rashes, serum sickness, polyateritis nodosa, SJS

Type IV/ Delayed hypersensitivity reactions:Contact dermatitis, rashes, fever, photosensitisation

Immediate stoppage of

offending drug

Mild rxns: self

subsiding

Antihistamines: type I

rxns & skin rashes

TREATMENT OF ALLERGYAnaphylactic shock/ laryngeal

angioedema:

Patient in reclining position, O2

admn at high flow rate, CPR

Inj. Adrenaline 0.5mg (0.5 ml of 1

in 100 solution) im

chlorpheniramine 10-20 mg i.m/

slow i.v

i.v. hydrocortisone sodium

succinate 100-200 mg- severe/

recurrent cases

Penicillins

Cephalosporins

Sulfonamides

Tetracyclines

Quinolones

AntiTB drugs

Phenothiazines

DRUGS CAUSING ALLERGY FREQUENTLY

Salicylates

Carbamazepine

Allopurinol

ACE inhibitors

Methyldopa

Hydralazine

Local anesthetics

CUMULATIVE ACTION

Repeated admn. Of slow excreted drug: high

concentration- toxicity

Digoxin, emetine, heavy metals

Cumulative effect desired: phenytoin in epilepsy

Passive cumulation: remain deposited in bones without

toxic effects- LEAD;Toxic: once in blood

Liver & kidney impairment : non- cumulative drugs also

cumulate

SYNERGISM

Greek: syn- together; ergon- work

Action of one drug facilitated by the other

Both may have action in same direction

Given alone: one inactive, still enhance the other

when together

2 types : additive & supraadditive

Additive:

Effect of 2 drugs: same

direction- adds up 1+1=2

Combination- better

tolerated than higher dose

of individual drug

Aspirin + Paracetamol-

analgesic/ antipyretic

SYNERGISM

Supraadditive

The effect of the combination

> individual effects 2+2=5

prolongation of duration of

action of one – time

synergism

Levodopa + Carbidopa/

benserazide- inhibition of

peripheral metabolism

ANTAGONISM

Phenomenon of opposing actions of two drugs on the same

physiological system

Effect of drugs A+B< effect of drug A + effect of drug B

One is inactive & decreases the effect of the other

Physical

Chemical

Physiological/ Functional

Receptor

ANTAGONISM

Physical:

Physical property

Charcoal adsorbs alkaloids: poisoning

Chemical:

Chemical reaction of 2 drugs: inactive product

KMnO4 + alkaloids- gastric lavage in poisoning

Chelating agents + toxic heavy metals

Physiological/ functional

Different receptors/

mechanisms- opposite

effects on same function

Opposing

pharmacological actions

Glucagon & insulin on

blood sugar level

ANTAGONISM

Receptor:

Antagonist drug blocks the

receptor action of agonist

Specific & profound

pharmacological effect

Antagonists: selective

Competitive/ non

competitive

COMPETITIVE ANTAGONISMEquilibrium type/ Reversible

Antagonist chemically similar to agonist: competes

for same binding site

No response

Reversible:

concentration of both

ACh & atropine: muscarinic

Adrenaline & prazosin: α

COMPETITIVE ANTAGONISM

Partial agonist: competes with full agonist-

submaximal response

NONCOMPETITIVE ANTAGONISM

Antagonist inactivates the receptor : effective complex with the

agonist not formed

3 ways:

Combination with same binding site: firm, not displaced by higher

agonist concentration

Combination at a different site/ allosteric site: prevent

characteristic

change by agonist

Change induced in agonist binding site: reactivity abolished

NONCOMPETITIVE ANTAGONISM

ACh & papaverine: smooth muscle

Ach & decamethonium : NMJ

Reversible/ irreversible effect

SIGNIFICANCE OF ANTAGONISM

Correcting adverse effects: chlorpromazine &

benzhexol

Treating drug poisoning: morphine with naloxone

Predicting drug combinations which would reduce

drug efficacy: penicillin & tetracycline inferior to

penicillin alone in pneumococcal meningitis

DOSAGE

CLASSIFICATIO

N OF DRUGS

CONTENTSDose

Fixed dose ratio combinations

Factors necessitating dose modification

- body size

- age

- sex

- race &genetics

- pathological states

- other drugs

DRUG DOSAGE

‘DOSE’

The appropriate amount of a drug needed to

produce a certain degree of response in a patient

Qualified in terms of the chosen response:

Aspirin: 0.3- 0.6g - headache

60-150mg - antiplatelet action

3-5g – rheumatoid arthritis

DRUG DOSAGE

Prophylactic/ Therapeutic/ Toxic dose

Inherent potency & pharmacokinetic properties :

dose

Recommended doses: ‘average’ patient

Individual patients: differ from this

Standard dose:

Same dose appropriate

for most: minor variations

& wide safety margin

OCPs, Penicillin,

chloroquine, mebendazole

DRUG DOSAGE

Regulated dose:

Finely regulated & easily

measured body function –

modified

Dosage adjusted :

measurement of parameter

Antihypertensives

Target level dose:

Response: not measurable

Certain plasma levels of

drug : achieved

Facilities unavailable: crude

adjustments – observing

patient at long intervals

Antidepressants,

antiepileptics, digoxin, lithium

DRUG DOSAGE

Titrated dose:

Dose: maximal therapeutic

effect cant be given: adverse

effects

Compromise between

submaximal therapeutic effect

& tolerable side effects

Anticancer drugs, levodopa,

steroids

Convenience & better

patient compliance

Synergistic combinations

Elimination &

counteraction of side

effects

Ensures single drug is not

administered: AIDS, TB

FIXED DOSE RATIO COMBINATIONS: ADVANTAGES & DISADVANTAGES

All components may not

be needed

Dose needs adjustment &

individualising

Time course of action of

components: different

Cause of adverse effect:

doubtful

Contraindication to one

component: whole

preparation

FACTORS MODIFYING DRUG ACTION

Different pharmacokinetic handling of drugs

Variations in number/ state of receptors

Variations in neurogenic/ hormonal tone

Genetic/ non genetic factors modify drug action:

quantitatively

qualitativelyMost factors cause such

change: dealt by adjustment of drug dosage

Less common: precludes the

use of the drug in the patient

FACTORS NECESSITATING DOSE MODIFICATION

Body size:

Average adult dose: medium built

Individual dose= x avg adult dose

Individual dose = x avg adult dose

BW (kg) 70

BSA(m2)

1.7

FACTORS NECESSITATING DOSE MODIFICATION

Age:

Child dose= x adult dose-----------(Young’s

formula)

Child dose = x adult dose-----------(Dilling’s

formula)

Age Age +12

Age 20

Low GFR, immature tubular

transport: gentamicin,

penicillin

Inadequate hepatic drug

metabolizing system:

chloramphenicol- gray baby

syndrome

Permeable blood brain barrier

Faster drug metabolism than

in adults after 1st year

PHYSIOLOGICAL DIFFERENCES FROM ADULTS REQUIRING

CAUTION:

Growth

Suppression –

corticosteroids

Stunting of stature:

androgens

Discoloration of teeth:

tetracycline

Dystonic reactions:

phenothiazines

FACTORS NECESSITATING DOSE MODIFICATION

Elderly:

Drug doses reduced: GFR~ 75% -50 years &

~50%- 75 years

Reduction in hepatic drug metabolism: oral

bioavailability

Intolerant to digitalis

Reduced responsiveness of β receptors

FACTORS NECESSITATING DOSE MODIFICATION

Sex:

Females: doses on lower side of the range

Changes altering drug disposition in pregnancy:

GI motility: delayed absorption of oral drugs

plasma albumin levels: fraction of acidic drugs and basic

drugs

RBF: faster elimination of polar drugs

Induction of hepatic enzymes: faster metabolism

Race:

Blacks require higher

& mongols lower

concentrations of

atropine & ephedrine to

dilate their pupil

FACTORS NECESSITATING DOSE MODIFICATION

Genetics:

Dose of a drug- same effect: 4-6

fold variation

Pharmacogenetics: the study of

genetic basis for variability in

drug response

Pharmacogenomics: the use of

genetic information to guide the

choice of drug & dose on an

individual basis

I. GI diseases:

Coeliac disease- Absorption

of amoxicillin

cephalexin & cotrimoxazole

achlorhydria aspirin

absorption

PATHOLOGICAL STATES

II. Liver diseases:

serum albumin: more free form

of diclofenac, warfarin

Dose reduction needed:

lidocaine, morphine, propanolol

Normal doses of CNS

depressants: toxic in cirrhotics

Oral anticoagulants: marked

PT

PATHOLOGICAL STATES

III. Renal diseases

Maintenance dose of drugs excreted unchanged &

partly unchanged: reduced or dose interval prolonged

Free form of acidic drugs : reduction in albumin level

CNS depressants : more due to permeability of BBB

Pethidine: seizures

Urinary antiseptics: systemic toxicity

PATHOLOGICAL STATES

Antimicrobials needing dose reduction

Even in mild failure Only in severe failure

Aminoglycosides Cotrimoxazole

Cephalexin Carbenicillin

Ethambutol Cefotaxime

Vancomycin Norfloxacin

Amphotericin B Ciprofloxacin

Acyclovir Metronidazole

IV. Congestive heart failure

Decreased absorption

from GIT: procainamide,

hydrochlorothiazide

Loading doses and dosing

rates of lidocaine reduced

Compensated heart; more

sensitive to digitalis

PATHOLOGICAL STATES

V. Thyroid disease:

Clearance of digoxin- roughly

parallels thyroid function

Hypothyroid: more sensitive

to digoxin, morphine, CNS

depressants

Hyperthyroid: prone to

arrhythmic action of digoxin

PATHOLOGICAL STATES

VI. Others:

Schizophrenics tolerate large doses of

phenothiazines

Head injury patients: respiratory failure- normal

doses of morphine

MI patients: prone to digitalis & adrenaline

induced arrhythmias

FACTORS NECESSITATING DOSE MODIFICATION

Other drugs:

Concurrent administration of inhibitors of hepatic

microsomal enzymes: (macrolides, chloramphenicol,

cimetidine, metronidazole)- dose reduction of drugs

metabolised: (azathioprine, warfarin, theophylline)

Propanolol: lidocaine, morphine, verapamil,

imipramine & self metabolism- reduction in hepatic blood

flow

FACTORS NECESSITATING DOSE MODIFICATION

Enzyme inducers: barbiturates, phenytoin, carbamzepine-

failure of antimicrobial therapy with metronidazole,

doxycycline, chloramphenicol

contraceptive failure

Paracetamol toxicity at lower doses: toxic metabolite

Oral anticoagulants, hypoglycemics, antiepileptics,

antihypertensives: dose adjustment

CLASSIFICATION OF DRUGS

Single, rational classification system: not possible

Requirements of chemists, pharmacologists,

doctors differ

Categorised according to the convenience of the

discussing group

I. BODY SYSTEM:

Alimentary

Cardiovascular

ANS, PNS, CNS

Respiratory system

Renal system

Blood & blood formation

CLASSIFICATION OF DRUGS

II. THERAPEUTIC USE:

Receptor blockers

Enzyme inhibitors

Carrier molecules

Ion channels

CLASSIFICATION OF DRUGS

III. MODE/ SITE OF ACTION:

Molecular interaction: glucoside, alkaloid, steroid

Cellular site: loop diuretic, catecholamine uptake inhibitor

IV. MOLECULAR STRUCTURE:

Glycoside

Alkaloid

Steroid

en. wikipedia.org

ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION SYSTEM

Controlled by the WHO Collaborating Centre for Drug Statistics

Methodology (WHOCC)

First published in 1976

Drugs into different groups: the organ or system on which they

act and/or their therapeutic and chemical characteristics

Same drug: more than one code

Eg: Aspirin- A01AD05 - local oral treatment,

B01AC06 - antiplatelet,

N02BA01 – analgesic, antipyretic

en. wikipedia.org

ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION SYSTEM

drugs are classified into groups at 5 different levels

First levelthe anatomical main group and consists of one letter.

14 main groups

Code ContentsA Alimentary tract and metabolism

B Blood and blood forming organs

C Cardiovascular system

D Dermatologicals

GGenito-urinary system and sex hormones

HSystemic hormonal preparations, excluding sex hormones and insulins

J Antiinfectives for systemic use

LAntineoplastic and immunomodulating agents

M Musculo-skeletal system

N Nervous system

PAntiparasitic products, insecticides and repellents

R Respiratory system

S Sensory organs

V Various

en. wikipedia.org

ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION

SYSTEM

Second level

the therapeutic main group and consists of two digits.

Eg: G03 Diuretics

Third level

the therapeutic/pharmacological subgroup and

consists of one letter.

Example: G03C High-ceiling diuretics

en. wikipedia.org

ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CLASSIFICATION SYSTEM

Fourth level

the chemical/therapeutic/pharmacological subgroup

and consists of one letter.

Eg: G03CA Sulfonamides

Fifth level

the chemical substance and consists of two digits.

Eg: G03CA01 Furosemide

BIBLIOGRAPHY

Pharmacology & Pharmacotherapeutics- Satoskar,

Bhandarkar, Rege: 9th edition

Essentials of Medical Pharmacology- Tripathi, 6th edition

Clinical Pharmacology- Bennett, Brown- 9th edition

Textbook of Dental Pharmacology- Sharma, Sharma,

Gupta

en. Wikipedia.com

THANK YOU!!!!