FACTORS MODIFYING

DRUG EFFECTS

On administration of a drug ,a predicted response is obtained but some timesIndividuals may vary considerably in their responsiveness such as. . . . . . respond differently to drugs both from time to time and from other individuals. Some would show less than the usual response , and some may show more than usual response.

INTRODUCTION

QUANITATIVELY: The plasma concentration and/or action of drug is increased or decreased. Most of the factors introduce this type of change and can be dealt with by adjustment of drug dosage.

QUALITATIVELY: The type response is altered. e.g. drug allergy or idiosyncrasy. This is less common but often precludes further use of that drug in the affected patient.

TWO TYPES OF FACTORS

Body weight.Age.Sex.Species and race.Genetics.Route of administration.Time of administration.Environmental factors.Pathological state.Psychotic factors.Cumulation.Tolerance.Drug resistance.

The various factors are . . .

• It influences the concentration of the drug attained at the site of action.

• The average adult dose refers to individuals of medium built.

• For exceptionally obese or lean individuals and for children dose may be calculated on body weight(BW) basis:

Individual dose=BW(kg)/70Xaverage adult dose

BODY WEIGHT

It has been argued that body surface area(BSA) provides a more accurate basis for dose calculation, because total body water, extracellular fluid volume and metabolic activity are better paralleled by BSA

Individual dose=BSA(m2)/1.7xaverage adult dose.

The BSA of an individual can be calculated from DUBOIS FORMULABSA(m2)=BW(kg)0.425xHeight(cm)0.725x0.007184

BODY SURFACE AREA . . .

IN CHILDREN;• The dose of a drug for children is often calculated from the

adult dose

YOUNG`S FORMULA:• Child dose = age/age+12xadult dose

DILLINGS FORMULA:• Child dose =age/20xadults dose

• It can also be calculated (more accurately) on the basis of BW and BSA.

AGE. . .

Children are growing and are susceptible to special adverse effects of drugs. e.g. Tetracycline cause permanent staining of teeth. • corticosteroids cause suppression of growth and

development of retardation.

• Androgens may promote early fusion of epiphysis resulting in stunting of stature.

EFFECTS OF DRUGS IN CHILDREN

Hepatic drug metabolising system is inadequate in newborns

Chloramphenicol can produce gray baby syndrome

Blood brain barrier is more permiable – drugs attain higher concentrations in the CNS

accumulation of unconjugated bilirubin causes kernicterus.

GIT absorption of ampicillin and amoxicillin is greater in neonates due to decreased gastric acidity

IN NEWBORNS

Drug absorption may also be altered in infants because of lower gastric acidity and slower intestinal transit.

Transdermal absorption is faster because their skin is thin and more permeable.

Therefore infant doses must be learned as such and are not derived from any formula.

IN INFANTS . . . .

Decreased liver function (diazepam, theophylline)

Decreased kidney function (digoxin , lithium)

Decreased plasma protein binding

Increased sensitivity to CNS depressants (diazepam, morphine)

IN OLD AGE PEOPLE . . . .

Evidences show that men and women may respond differently to same drugs.

This may be due to body size, and amount of body fats.But there are also some less easily explained differences in

gender –specific drug response.Aspirin shows greater benefit in men than women in

cardiovascular diseasesbenzodiazepines decrease metabolism of some drugs in

females.Testosterone increases the rate of metabolism in males. females are more susceptible to autonomic drugs ( estrogen inhibits choline estrase)

GENDER

There are many examples of differences in responsiveness to drugs among different species;

Rabbits are resistant to atropine, rats and mice are resistant to digitalis and rat is more sensitive to curare than cat. These differences are important while extrapolating results from experimental animals to man. Among human beings some racial differences have been observed e.g. blacks require higher and mongols requires lower concentration of atropine and Ephedrine to dilate their pupil. Indians tolerate thiacetazone better than whites

SPECIES AND TRACES

GENETICS Pharmacogenetics; it is the study of relationship

between the genetic factors and drug response.

Pharmacogenomics; it is the use of genetic information to guide the choice of drug and dose on an individual basis.

It intends to identify individuals who are either more

likely or less likely to respond to a drug, as well as those who require altered dose

of certain drugs.

Some genetic defects which lead to discontinuous variation in drug responses

e.g.G-6-PD is responsible for haemolysis with primaquine, and some oxidizing drugs like sulfonamides,dapsone,quinine,nalidixic acid.The low activity of CYP2C9 variants metabolize warfarin at a

slow rate and are at higher risk of bleeding.

Acute intermittent porphyria precipitated by barbiturates is due to genetic defect in repression of porphyrine synthesis.

Malignant hyperthermia after halothane is due to abnormal ca2+ release channel (ryanodine receptor) in the sarcoplasmic reticulum of skeletal muscle.

GENETIC DEFECTS

Route of administration governs the speed and intensity of drug response

Parenteral administration is often restored to for more rapid, more pronounced and predictable drug action.

A drug may have entirely different uses through different routes.

e.g. magnesium sulfate given orally cause purgation, applied on sprained joints decreases swelling

while intravenously it produces CNS depression and hypotension.

ROUTE OF ADMINISTRATION . . .

Subjective effects of drugs may be markedly influenced by the setup in which it is taken.

Hypnotics taken at night and in quiet familiar surroundings may work more easily.

.It has been shown that corticosteroids taken as a single morning dose cause less

pituitary-adrenal supression.

TIME OF ADMINISTRATION

Not only drugs modify disease processes several diseases can influence drug disposition and drug action.

GASTROINTESTINAL DISEASES:These can alter the absorption of orally administered drugs. The changes are Complex and drug absorption can increase or

decrease, e.g. in coeliac disease absorption amoxicillin is decreased but that of cephalexin and cotrimoxazole is increased. Thus malabsorption syndrome not necessarily reduce

absorption of all drugs. Gastric stasis occurring during migraine attack retards the absorption of ingested drugs.NSAIDs can aggravate peptic ulcer disease.

PATHOLOGICAL FACTORS

Bioavailability of drugs having high first pass metabolism is increased due to loss of hepatocellular function and portocaval shunting.

Serum albumin is reduced –

protien binding of acidic drugs(diclofenac, warfarin) is reduced and more drug is present in the free form.

Metabolism and elimination of some drugs (morphine, lidocaine, propronolol) is decreased-their dose should be reduced.

LIVER DISORDERS

Clearance of drugs that are primarily excreted unchanged (aminoglycosides, digoxin, phenobarbitone) is reduced parallel to decrease in creatinine clearence.

Binding of acidic drugs is reduced, but that of basic drugs is not much affected.

The permiability of blood brain barrier is increased in renal failure

( opiates, barbiturates,phenothiazines, benzodiazepines etc).

KIDNEY DISORDERS

Several environmental factors affect drug responses.

Exposure to insecticides, carcinogens, tobacco smoke and consumption of charcoal broiled meat are well known to induce drug metabolism.

Type of diet and temporal relation between ingestion and meals can alter drug absorption.

e.g. food interferes with absorption of ampicillin, but fatty meal enhances absorption of griseofulvin.

ENVIRONMENTAL FACTORS

Efficacy of a drug can be affected by patient`s beliefs, altitudes and expectations

.This is particularly applicable to centrally acting drugs e.g.nervous and anxious patient requires more general anasthetic. Alcohol generally impairs performance but if punishment

(which induces anxiety) is introduced, it may actually improve perfomance.

Psychotic factors . . .

Any drug will cumulate in the body if rate of administration is more than the rate of elimination.

However, slowly eliminated drugs are particularly liable to cause cumulative toxicity.

e.g. prolonged use of chloroquine causes retinal damage.Full loading dose of digoxin should not be given if

patient has received it within the past week.A course of emetine should not be repeated within 6 weeks.

CUMULATION

Requirement of higher dose of a drug to produce a given response.

It’s an adaptive biological phenomenon

Drug tolerance may be two types1)Natural2)Acquired

Natural tolerance– the individual is inherently less sensitive to the drug.

E.g. black races are tolerant to mydriatics

TOLERANCE

Acquired tolerance:This occurs by repeated use of a drug in an individual who was initially responsive.Body is not capable of developing tolerance to most drugs but the phenomenon is very easily recognized in the case of CNS depressants. An uninterrupted presence of the drug in the body favours development of tolerance. However, significant tolerance does not develop to atropine, digitalis,cocaine,sodium nitroprusside, etc.Cross tolerance: It is the development of tolerance to pharmacologically related drugse.g. alcoholics are relatively tolerantto barbiturates and general anasthetics.

Tolerance develops to sedative action of chlorpromazine but notto its antipsychotic action.

Tolerance occurs to the sedative action of phenobarbitone but not as much to its antiepileptic action.

Tolerance occurs to anaphylatic and euphoric action of morphine,but not to its constipating and miotic actions.

DRUG RESISTANCE: It refers to tolerance of microorganisms to inhibitory action of antimicrobials, e.g. staphylococci to pencillin.

REFERENCEKD.TRIPATHI

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