Factors Modifying Drug Action

FACTORS MODIFYING DRUG ACTION

Variation in response to the same dose of a drug between different patients and even in the same patient on different occasions is a rule rather than exception. One or more of the following categories of differences among individuals are responsible for the variations in drug response:

§  Individuals differ in pharmacokinetic handling of drugs: attain varying plasma/target site concentration of the drug. This is more marked for drugs disposed by metabolism (e.g. propranolol) than for drugs excreted unchanged (e.g. atenolol).

§  Variations in number or state of receptors, coupling proteins or other components of response effectuation.

§  Variations in neurogenic/hormonal tone or concentrations of specific constituents, e.g. atropine tachycardia depends on vagal tone, propranolol bradycardia depends on sympathetic tone, captopril hypotension depends on body Na+ status.

A multitude of host and external factors influence drug response. They fall in two categories viz genetic and nongenetic including all environmental, circumstantial and personal variables. Though individual variation cannot be totally accounted for by these factors, their understanding can guide the choice of appropriate drug and dose for an individual patient. be totally accounted for by these factors, their understanding can guide the choice of appropriate drug and dose for an individual patient. However, final adjustments have to be made by observing the response in a given patient on a given occasion.

The factors modify drug action either:

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

b) Qualitatively The type of 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.

The various factors are discussed below—

          1. Body Size

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:

                              BW (kg)

Individual dose = ———— × average adult dose

                                   70

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.

                            BSA (m2 )

Individual dose = ———— × average adult dose

                                  1.7

The BSA of an individual can be calculated from Dubois formula:

BSA (m²) = BW (kg)^0.425 × Height (cm)^0.725 × 0.007184

or obtained from chartform or sliderule nomograms based on BW and height.

However, dose recommendations in terms of BSA are available only for anticancer and a handful of other drugs: for the rest BW has been used as the index. Thus, prescribing on BSA basis suffers from lack of data base, is more cumbersome and has not thrived, except in few cases.

2.     Age

The dose of a drug for children is often calculated from the adult dose

It can also be calculated (more accurately) on BW or BSA basis (see above), and for many drugs, manufacturers give dosage recommendations on mg/kg basis. Average figures for children are given below.

However, infants and children are not small adults. They have important physiological differences from adults. The newborn has low g.f.r. and tubular transport is immature. As such, the t½ of drugs excreted by glomerular filtration (gentamicin) and tubular secretion (penicillin) is prolonged by 3 to 5 times. Glomerular filtration reaches adult rates by 5 month of age and tubular secretion takes about 7 months to mature. Similarly, hepatic drug metabolizing system is inadequate in newborns —chloramphenicol can produce gray baby syndrome. Bloodbrain barrier is more permeable—drugs attain higher concentration in the CNS (accumulation of unconjugated bilirubin causes kernicterus). These defects are exaggerated in the premature infant. Drug absorption may also be altered in infants because of lower gastric acidity and slower intestinal transit. Transdermal absorption however, is faster because their skin is thin and more permeable. Therefore, infant doses must be learned as such and not derived from any formula.

After the first year of life, drug metabolism is often faster than in adults, e.g. theophylline, phenytoin, carbamazepine t½ is shorter in children. Also, higher per kg dose is needed for drugs which are primarily excreted unchanged by kidney, e.g. daily dose of digoxin is about 8–12 μg/kg compared to adult dose of 3–5 μg/kg.

Solid dosage forms and aerosol inhalations are difficult to administer to young children.

Children are growing and are susceptible to special adverse effects of drugs, e.g. suppression of growth can occur with corticosteroids; androgens may promote early fusion of epiphysis resulting in stunting of stature; tetracyclines get deposited in growing teeth and discolour/deform them. Dystonic reactions to phenothiazines are more common in children.

Elderly In the elderly, renal function progressively declines (intact nephron loss) so that g.f.r. is ~ 75% at 50 years and ~ 50% at 75 years age compared to young adults. Drug doses have to be reduced, e.g. daily dose of streptomycin is 0.75 g after 50 years and 0.5 g after 70 years of age compared to 1 g for young adults. There is also a reduction in the hepatic microsomal drug metabolizing activity and liver blood flow: oral bioavailability of drugs with high hepatic extraction is generally increased, but the overall effects on drug metabolism are not uniform. Due to lower renal as well as metabolic clearance, the elderly are prone to develop cumulative toxicity while receiving prolonged medication. Other affected aspects of drug handling are slower absorption due to reduced motility of and blood flow to intestines, lesser plasma protein binding due to lower plasma albumin, increased or decreased volume of distribution of lipophilic and hydrophilic drugs respectively. Aged are relatively intolerant to digitalis. The responsiveness of adrenergic receptors to both agonists and antagonists is reduced in the elderly and sensitivity to other drugs also may be altered. Due to prostatism in elderly males, even mild anticholinergic activity of the drug can accentuate bladder voiding difficulty. Elderly are also likely to be on multiple drug therapy for hypertension, ischaemic heart disease, diabetes, arthritis, etc. which increases many fold the chances of drug interactions. They are more prone to develop postural instability, giddiness and mental confusion. In general, the incidence of adverse drug reactions is much higher in the elderly.

       3. Sex

Females have smaller body size and require doses that are on the lower side of the range. Subjective effects of drugs may differ in females because of their mental makeup. Maintenance treatment of heart failure with digoxin is reported to be associated with higher mortality among women than among men. A number of antihypertensives (clonidine, methyldopa, βblockers, diuretics) interfere with sexual function in males but not in females. Gynaecomastia is a side effect (of ketoconazole, metoclopramide, chlorpromazine, digitalis) that can occur only in men. Ketoconazole causes loss of libido in men but not in women. Obviously androgens are unacceptable to women and estrogens to men. In women consideration must also be given to menstruation, pregnancy and lactation.

Drugs given during pregnancy can affect the foetus. There are marked and progressive physiological changes during pregnancy, especially in the third trimester, which can alter drug disposition.

§   Gastrointestinal motility is reduced → delayed absorption of orally administered drug.

§   Plasma and extracellular fluid volume expands—volume of drug distribution may increase.

§   While plasma albumin level falls, that of α₁ acid glycoprotein increases—the unbound fraction of acidic drugs increases but that of basic drugs decreases.

§   Renal blood flow increases markedly— polar drugs are eliminated faster.

§   Hepatic  microsomal  enzymes  undergo induction—many drugs are metabolized faster.

Thus, the overall effect on drug disposition is complex and often difficult to predict.

4. Species and race

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 require lower concentrations of atropine and ephedrine to dilate their pupil. βblockers are less effective as antihypertensive in AfroCaribbeans. Indians tolerate thiacetazone better than whites. Considering the widespread use of chloramphenicol in India and Hong Kong, relatively few cases of aplastic anaemia have been reported compared to its incidence in the west. Similarly, quiniodochlor related cases of subacute myelooptic neuropathy (SMON)

occurred in epidemic proportion in Japan, but there is no confirmed report of its occurrence in India despite extensive use.

          5. Genetics

The dose of a drug to produce the same effect may vary by 4–6 fold among different individuals. All key determinants of drug response, viz. transporters, metabolizing enzymes, ion channels, receptors with their couplers and effectors are controlled genetically. Hence, a great deal of individual variability can be traced to the genetic composition of the subject. The study of genetic basis for variability in drug response is called ‘Pharmacogenetics’. It deals with genetic influences on drug action as well as on drug handling by the body. As the genomic technology has advanced, gene libraries and huge data bases (like ‘pharmacogenetics and pharmacogenomics knowledge base’, ‘Human genome variation database’, etc.) have been created aiming at improving precision in drug therapy.

Pharmacogenomics 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. Attempt is made to define the genetic basis of an individual’s profile of drug response and to predict the best treatment option for him/her. So far, this has been applied largely to patients with known genetic abnormalities, but the goal is ‘personalized medicine’ on a wide scale. However, a large proportion of genetic variability still remains unaccounted for.

A continuous variation with Gaussian frequency distribution is seen in the case of most drugs. In addition, there are some specific genetic defects which lead to discontinuous variation in drug responses, e.g.—

§  Atypical pseudocholinesterase results in prolonged succinylcholine apnoea.

§  G6PD deficiency is responsible for haemolysis with primaquine and other oxidizing drugs like sulfonamides, dapsone, quinine, nalidixic acid, nitrofurantoin and menadione, etc.

§  The low activity CYP2C9 variants metabolize warfarin at a slow rate and are at higher risk of bleeding.

§  Thiopurine methyl transferase (TPMT) deficiency increases risk of severe bone marrow toxicity of 6mercaptopurine and azathioprine.

§  Irinotecan induced neutropenia and diarrhoea is more in patients with UGT1A1 *28 allele of glucuronyl transferase.

§  Severe 5fluorouracil toxicity occurs in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.

§  Over expression of Pgp results in tumour resistance to many cancer chemotherapeutic drugs, because it pumps out the drug from the tumour cells.

§  Polymorphism of Nacetyl transferase 2 (NAT2) gene results in rapid and slow acetylator status. Isoniazid neuropathy, procainamide and hydralazine induced lupus occurs mainly in slow acetylators.

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

§  CYP2D6 abnormality causes poor metoprolol/ debrisoquin metabolizer status. Since several antidepressants and antipsychotics also are substrates of CYP2D6, deficient patients are more likely to experience their toxicity. Codeine fails to produce analgesia in CYP2D6 deficient, because this enzyme generates morphine from codeine.

§  Malignant hyperthermia after halothane is due to abnormal Ca2+ release channel (ryanodine

§  receptor) in the sarcoplasmic reticulum of skeletal muscles.

§  Inability to hydroxylate phenytoin results in toxicity at usual doses.

§  Resistance to coumarin anticoagulants is due to an abnormal enzyme (that regenerates the reduced form of vit. K) which has low affinity for the coumarins.

§  Attack of angle closure glaucoma is precipitated by mydriatics in individuals with narrow iridocorneal angle.

Genotype to phenotype predictability is much better in monogenic phenotypic traits such as G6PD, CYP2D6, TPMT, etc., than for multigenic traits. Majority of gene polymorphisms are due to substitution of a single base pair by another. When found in the population at a frequency of >1%, these are called ‘Single neucleotide polymorphisms’ (SNPs). Gene polymorphisms are often encountered at different frequencies among different ethnic/geographical groups.

Despite accumulation of considerable pharmacogenomic data and the fact that genotyping of the individual needs to be done only once, its practical application in routine patient care is at present limited due to prerequirement of multiple drug specific genotypic screening. Simple spot tests for some, e.g. G6 PD deficiency are currently in use.

6.      Route Of Administration

Route of administration governs the speed and intensity of drug response. Parenteral administration is often resorted to for more rapid, more pronounced and more predictable drug action. A drug may have entirely different uses through different routes, e.g. magnesium sulfate given orally causes purgation, applied on sprained joints—decreases swelling, while intravenously it produces CNS depression and hypotension.

7.      Environmental Factors And Time Of Administration

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 drug ingestion and meals can alter drug absorption, e.g. food interferes with absorption of ampicillin, but a fatty meal enhances absorption of griseofulvin. Subjective effects of a drug 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 suppression.

8.      Psychological Factor

Efficacy of a drug can be affected by patient’s beliefs, attitudes and expectations. This is particularly applicable to centrally acting drugs, e.g. a nervous and anxious patient requires more general anaesthetic; alcohol generally impairs performance but if punishment (which induces anxiety) is introduced, it may actually improve performance.

Placebo This is an inert substance which is given in the garb of a medicine. It works by psychological rather than pharmacological means and often produces responses equivalent to the active drug. Some individuals are more suggestible and easily respond to a placebo— ‘placebo reactors’. Placebos are used in two situations:

§  As a control device in clinical trial of drugs (dummy medication).

§  To treat a patient who, in the opinion of the physician, does not require an active drug.

Placebo is a Latin word meaning ‘I shall please’. A patient responds to the whole therapeutic setting; placebo effect largely depends on the physician-patient relationship.

Placebos do induce physiological responses, e.g. they can release endorphins in brain—causing analgesia. Naloxone, an opioid antagonist, blocks placebo analgesia. Placebo effects can thus supplement pharmacological effects. However, placebo effects are highly variable even in the same individual, e.g. a placebo may induce sleep on the first night but not subsequently. Thus, it has a very limited role in practical therapeutics. Substances commonly used as placebo are lactose tablets/capsules and distilled water injection.

Nocebo It is the converse of placebo, and refers to negative psychodynamic effect evoked by loss of faith in the medication and/or the physician. Nocebo effect can oppose the therapeutic effect of active medication.

9.     Pathological states

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

Gastrointestinal diseases These can alter absorption of orally administered drugs. The changes are complex and drug absorption can increase or decrease, e.g. in coeliac disease absorption of amoxicillin is decreased but that of cephalexin and cotrimoxazole is increased. Thus, malabsorption syndrome does not necessarily reduce absorption of all drugs. Gastric stasis occurring during migraine attack retards the absorption of ingested drugs. Achlorhydria decreases aspirin absorption by favouring its ionization. NSAIDs can aggravate peptic ulcer disease.

Liver disease Liver disease (especially cirrhosis) can influence drug disposition in several ways:

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

§   Serum albumin is reduced—protein binding of acidic drugs (diclofenac, warfarin, etc.) is reduced and more drug is present in the free form.

§   Metabolism and elimination of some drugs (morphine, lidocaine, propranolol) is decreased—their dose should be reduced. Alternative drugs that do not depend on hepatic metabolism for elimination and/or have shorter t½ should be preferred, e.g. oxazepam or lorazepam in place of diazepam; atenolol as βblocker.

§   Prodrugs needing hepatic metabolism for activation, e.g. prednisone, bacampicillin, sulindac are less effective and should be avoided.

The changes are complex and there is no simple test (like creatinine clearance for renal disease) to guide the extent of alteration in drug disposition; kinetics of different drugs is affected to different extents.

Drug action as well can be altered in liver disease in the case of certain drugs, e.g.

§  The sensitivity of brain to depressant action of morphine and barbiturates is markedly increased in cirrhotics—normal doses can produce coma.

§  Brisk diuresis can precipitate mental changes in patients with impending hepatic encephalopathy, because diuretics cause hypokalemic alkalosis which favours conversion of NH⁺₄ to NH₃ → enters brain more easily.

§  Oral anticoagulants can markedly increase prothrombin time, because clotting factors are already low.

§  Fluid retaining action of phenylbutazone (also other NSAIDs) and lactic acidosis due to metformin are accentuated.

Hepatotoxic drugs should be avoided in liver disease.

Kidney disease It markedly affects pharmacokinetics of many drugs as well as alters the effects of some drugs.

Clearance of drugs that are primarily excreted unchanged (aminoglycosides, digoxin, phenobarbitone) is reduced parallel to decrease in creatinine clearance (CLcr). Loading dose of such a drug is not altered (unless edema is present), but maintenance doses should be reduced or dose interval prolonged proportionately. A rough guideline is given in the box:

Dose rate of drugs only partly excreted unchanged in urine also needs reduction, but to lesser extents. If the t½ of the drug is prolonged, attainment of steady state plasma concentration with maintenance doses is delayed proportionately.

Plasma proteins, specially albumin, are often low or altered in structure in patients with renal disease—binding of acidic drugs is reduced, but that of basic drugs is not much affected.

The permeability of blood-brain barrier is increased in renal failure; opiates, barbiturates, phenothiazines, benzodiazepines, etc. produce more CNS depression. Pethidine should be avoided because its metabolite norpethidine can accumulate on repeated dosing and cause seizures. The target organ sensitivity may also be increased. Antihypertensive drugs produce more postural hypotension in patients with renal insufficiency.

Certain drugs worsen the existing clinical condition in renal failure, e.g.

§  Tetracyclines have an antianabolic effect and accentuate uraemia.

§  NSAIDs cause more fluid retention.

§  Potentially nephrotoxic drugs, e.g. cephalothin, aminoglycosides, tetracyclines (except doxycycline), sulfonamides (crystalluria), vancomycin, cyclosporine, amphotericin B should be avoided.

Antimicrobials needing dose reduction in renal failure

Even in mild failure    Only in severe failure

Aminoglycosides    Cotrimoxazole

Cephalexin         Carbenicillin

Ethambutol         Cefotaxime

Vancomycin       Norfloxacin

Amphotericin B  Ciprofloxacin

Acyclovir            Metronidazole

Thiazide diuretics tend to reduce g.f.r.: are ineffective in renal failure and can worsen uraemia; furosemide should be used. Potassium sparing diuretics are contraindicated; can cause hyperkalemia → cardiac depression. Repeated doses of pethidine are likely to cause muscle twitching and seizures due to accumulation of its excitatory metabolite norpethidine.

Urinary antiseptics like nalidixic acid, nitrofurantoin and methenamine mandelate fail to achieve high concentration in urine and are likely to produce systemic toxicity.

Congestive Heart Failure It can alter drug kinetics by—

§   Decreasing drug absorption from g.i.t. due to mucosal edema and splanchnic vasoconstriction. A definite reduction in procainamide and hydrochlorothiazide absorption has been documented.

§   Modifying volume of distribution which can increase for some drugs due to expansion of extracellular fluid volume or decrease for others as a result of decreased tissue perfusion—loading doses of drugs like lidocaine and procainamide should be lowered.

§   Retarding drug elimination as a result of decreased perfusion and congestion of liver, reduced glomerular filtration rate and increased tubular reabsorption; dosing rate of drugs may need reduction, as for lidocaine, procainamide, theophylline.

§   The decompensated heart is more sensitive to digitalis.

Thyroid Disease The hypothyroid patients are more sensitive to digoxin, morphine and CNS depressants. Hyperthyroid patients are relatively resistant to inotropic action but more prone to arrhythmic action of digoxin. The clearance of digoxin is roughly proportional to thyroid function, but this only partially accounts for the observed changes in sensitivity.

Other examples of modification of drug response by pathological states are:

§  Antipyretics lower body temperature only when it is raised (fever).

§  Thiazides induce more marked diuresis in edematous patients.

§  Myocardial infarction patients are more prone to adrenaline and digitalis induced cardiac arrhythmias.

§  Myasthenics are very sensitive to curare.

§  Schizophrenics tolerate large doses of phenothiazines.

§  Head injury patients are prone to go into respiratory failure with normal doses of morphine.

§  Atropine, imipramine, furosemide can cause urinary retention in individuals with prostatic hypertrophy.

§  Hypnotics given to a patient in severe pain may cause mental confusion and delirium.

§  Cotrimoxazole produces a much higher incidence of adverse reactions in AIDS patients.

                  10. Other Drugs

Drugs can modify the response to each other by pharmacokinetic or pharmacodynamic interaction between them. Many ways in which drugs can interact have already been considered.

                   11. Cumulation

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.

               12. Tolerance

It refers to the requirement of higher dose of a drug to produce a given response. Loss of therapeutic efficacy (e.g. of salfonylureas in type 2 diabetes), which is a form of tolerance, is often called ‘refractoriness’. Tolerance is a widely occurring adaptive biological phenomenon. Drug tolerance may be:

Natural The species/individual is inherently less sensitive to the drug, e.g. rabbits are tolerant to atropine; black races are tolerant to mydriatics. Some individuals in any population are hyporesponders to certain drugs, e.g. to β adrenergic blockers or to alcohol.

Acquired This occurs by repeated use of a drug in an individual who was initially responsive.

Body is 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. Tolerance need not develop equally to all actions of a drug, consequently therapeutic index of a drug may increase or decrease with prolonged use, e.g.:

§ Tolerance develops to sedative action of chlorpromazine but not to its antipsychotic action.

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

§ Tolerance occurs to analgesic and euphoric action of morphine, but not as much to its constipating and miotic actions.

Cross tolerance It is the development of tolerance to pharmacologically related drugs, e.g. alcoholics are relatively tolerant to barbiturates and general anaesthetics. Closer the two drugs are, more complete is the cross tolerance between them, e.g.— There is partial cross tolerance between morphine and barbiturates but complete cross tolerance between morphine and pethidine.

Mechanisms responsible for development of tolerance are incompletely understood. However, tolerance may be:

§   Pharmacokinetic/drug disposition tolerance—the effective concentration of the drug at the site of action is decreased, mostly due to enhancement of drug elimination on chronic use, e.g. barbiturates, carbamazepine, amphetamine.

§   Pharmacodynamic/cellular tolerance— drug action is lessened; cells of the target organ become less responsive, e.g. morphine, barbiturates, nitrates. This may be due to down regulation of receptors, or weakening of response effectuation.

Tachyphylaxis (Tachyfast, phylaxisprotection) is rapid development of tolerance when doses of a drug repeated in quick succession result in marked reduction in response. This is usually seen with indirectly acting drugs, such as ephedrine, tyramine, nicotine. These drugs act by releasing catecholamines in the body, synthesis of which is unable to match the rate of release: stores get depleted. Other mechanisms like slow dissociation of the drug from its receptor, desensitization/internalization or down regulation of receptor, etc. and/or compensatory homeostatic adaptation.

Drug resistance It refers to tolerance of microorganisms to inhibitory action of antimicrobials, e.g. Staphylococci to penicillin.