Aspects of Pharmacotherapy; Clinical Pharmacology and Drug Development

 Chapter - 5 

Aspects of Pharmacotherapy; Clinical Pharmacology and Drug Development

• Pharmaco- (drug) therapy is dynamic and an ever-evolving science. It requires understanding of the drug, the disease, the patient and the milieu in which it is undertaken. As such, in addition to knowledge of drug action, mechanisms and pharmacokinetics, several aspects like drug dosage, sources of variability in drug response, pharmacogenetics, influence of disease on drug action, etc. are important to optimum drug therapy.

DRUG DOSAGE

• ‘Dose’ is the appropriate amount of a drug needed to produce a certain degree of response in a patient. Accordingly, dose of a drug has to be qualified in terms of the chosen response, e.g., the analgesic dose of aspirin for headache is 0.3–0.6 g, its antiplatelet dose is 60–150 mg/day, while its anti-inflammatory dose for rheumatoid arthritis is 3–5 g per day. Similarly, there could be a prophylactic dose, a therapeutic dose or a toxic dose of the same drug.

• The dose of a drug is governed by its inherent potency, i.e., the concentration at which it should be present at the target site, and its pharmacokinetic characteristics. The recommended doses are based on population data and cater to an ‘average’ patient. However, individual patients may not be ‘average’ in respect to a number of pharmacokinetic and pharmacodynamic parameters, emphasizing the need for individualizing drug dose. The strategies adopted for different types of drugs and conditions are:

Standard dose

• The same dose is appropriate for most patients—individual variations are minor, or the drug has a wide safety margin so that large enough dose can be given to cover them, e.g., oral contraceptives, penicillin, chloroquine, mebendazole, amantadine.

Regulated dose

• The drug modifies a finely regulated body function which can be easily measured. The dosage is accurately adjusted by repeated measurement of the affected physiological parameter, e.g., antihypertensives, hypogyny ceramics, anticoagulants, diuretics, general an aesthetics. In their case, measurement of plasma drug concentration is not needed.

Target level dose

• The response is not easily measurable but has been demonstrated to be obtained at a certain range of drug concentration in plasma. An empirical dose aimed at attaining the target level is given in the beginning and adjustments are made later by actual monitoring of plasma concentrations. When facilities for drug level monitoring are not available, crude adjustments are made by observing the patient at relatively long intervals, e.g., antidepressants, antiepileptics, digoxin, lithium, theophylline.

Titrated dose

• The dose needed to produce maximal therapeutic effect cannot be given because of intolerable adverse effects. Optimal dose is arrived at by titrating it with an acceptable level of adverse effect. Low initial dose and upward titration (in most non-critical situations) or high initial dose and downward titration (in critical situations) can be practiced. Often a compromise between submaximal therapeutic effect but tolerable side effects can be struck, e.g., anticancer drugs, corticosteroids, levodopa.

Fixed dose ratio combination preparations

A large number of pharmaceutical preparations contain two or more drugs in a fixed dose ratio. Advantages offered by these are:

• Convenience and better patient compliance— when all the components present in a formulation are actually needed by the patient. It may also be cost saving compared to both/all the components administered separately

• Certain drug combinations are synergistic, e.g., sulfamethoxazole + trimethoprim; levodopa + carbidopa benderizine; combination oral contraceptives.

• The therapeutic effect of two components being same may add up while the side effects being different may not, e.g., amlodipine + atenolol as antihypertensive.

• The side effect of one component may be counteracted by the other, e.g., a thiazide + a potassium sparing diuretic. However, the amount of the latter may not be sufficient in all cases.

• Combined formulation ensures that a single drug will not be administered. This is important in the treatment of tuberculosis and HIV-AIDS. is unnecessary; if it is, the combination should not be prescribed. It can never be justified that a drug is given to a patient who does not need it in order to provide him another one that he needs.

There are many inbuilt disadvantages of fixed dose ratio combinations:

• The patient may not actually need all the drugs present in a combination: he is subjected to additional side effects and expense (often due to ignorance of the physician about the exact composition of the combined formulations).

• The dose of most drugs needs to be adjusted and individualized. When a combined formulation is used, this cannot be done without altering the dose of the other component(s).

• The time course of action of the components may be different: administering them at the same intervals may be inappropriate.

• Altered renal or hepatic function of the patient may differently affect the pharmacokinetics of the components.

• Adverse effect, when it occurs, cannot be easily ascribed to the particular drug causing it.

• Contraindication to one component (allergy, other conditions) contraindicates the whole preparation.

• Confusion of therapeutic aims and false sense of superiority of two drugs over one is fostered, especially in case of antimicrobials whose combinations should be avoided. Corticosteroids should never be combined with any other drug meant for internal use. Drug combinations that are banned in India are listed in Appendix 4.

• Thus, only a handful of fixed dose ratio combinations are rational and justified, while far too many are available and vigorously promoted. In fact, the latest WHO essential medicines list incorporates only 21 fixed dose ratio combinations (see Appendix-1). 

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:

1. 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)
2. Variations in number or state of receptors, coupling proteins or other components of response effectuation.
3. 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. 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:

• 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.
• 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—

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:

• 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

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

• or obtained from chart-form or slide-rule nomograms based on BW and heigh
• 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.

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.

• 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.

• 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 is 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 β 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.

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, β-blockers, diuretics) interfere with sexual function in males but not in females. Gynecomastia 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 (see Ch. 6 and Appendix-2). There are marked and progressive physiological changes during pregnancy, especially in the third trimester, which can alter drug disposition..

1. Gastrointestinal motility is reduced → delayed absorption of orally administered drug. 
2. Plasma and extracellular fluid volume expands—volume of drug distribution may increase. 
3. While plasma albumin level falls, that of α1 acid glycoprotein increases—the unbound fraction of acidic drugs increases but that of basic drugs decreases. 
4. Renal blood flow increases markedly— polar drugs are eliminated faster. 
5. Hepatic microsomal enzymes undergo induction—many drugs are metabolized faster.

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

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. β-blockers are less effective as antihypertensive in Afro-Caribbeans. Indians tolerate thioacetazone better than whites. Considering the widespread use of chloramphenicol in India and Hong Kong, relatively few cases of aplastic anemias have been reported compared to its incidence in the west. Similarly, guanochlor related cases of subacute myelopathic neuropathy (SMON) occurred in epidemic proportion in Japan, but there is no confirmed report of its occurrence in India despite extensive use.

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.

• 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.—

1. Atypical pseudocholinesterase results in prolonged succinylcholine apnea.
2. G-6-PD deficiency is responsible for hemolysis with primaquine and other oxidizing drugs like sulfonamides, dapsone, quinine, nalidixic acid, nitrofurantoin and menadione, etc.
3. The low activity CYP2C9 variants metabolize warfarin at a slow rate and are at higher risk of bleeding.
4. Thiopurine methyl transferase (TPMT) deficiency increases risk of severe bone marrow toxicity of 6-mercaptopurine and azathioprine.
5. Irinotecan induced neutropenia and diarrhea is more in patients with UGT1A1 *28 allele of glucuronic transferase.
6. Severe 5-fluorouracil toxicity occurs in patients with dihydropyridine dehydrogenase (DPD) deficiency.
7. Over expression of P-pg. results in tumor resistance to many cancers chemotherapeutic drugs, because it pumps out the drug from the tumors cells
8. Polymorphism of N-acetyl transferase 2 (NAT2) gene results in rapid and slow acetylator status. Isoniazid neuropathy, procainamide and hydralazine induced lupus occurs mainly in slow acetylators
9. Acute intermittent porphyria—precipitated by barbiturates is due to genetic defect in repression of porphyrin synthesis.
10. 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.
11. Malignant hyperthermia after halothane is due to abnormal Ca2+ release channel (ryanodine receptor) in the sarcoplasmic reticulum of skeletal muscles.
12. Inability to hydroxylate phenytoin results in toxicity at usual doses.
13. 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.
14. 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 G6-PD, 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 nucleotide 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 PR requirement of multiple drug specific genotypic screening. Simple spot tests for some, e.g., G-6 PD deficiency are currently in use.

Route of administration

• Route of administration governs the speed and intensity of drug response (see Ch. 1). 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.

Environmental factors and time of administrate

• 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. 

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 anesthetic; 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:  

1. As a control device in clinical trial of drugs (dummy medication).  
2. 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.

Pathological states

Not only drugs modify disease processes, but several diseases can also 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 favoring 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 (see Ch. 3) 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 β-blocker.

• 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 cirrhotic—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 (Clarr). 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 nor-pethidine 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.

1. Tetracyclines have an anti-anabolic effect and accentuate uremia. 
2. NSAIDs cause more fluid retention. 
3. Potentially nephrotoxic drugs, e.g., cephalothin, aminoglycosides, tetracyclines (except doxycycline), sulfonamides (crystalluria), vancomycin, cyclosporine, amphotericin B should be avoided.

• Thiazide diuretics tend to reduce g .f.r.: are ineffective in renal failure and can worsen uremia; 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 fa achieve high concentration in urine and are likely to produce systemic toxicity.  

1. 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.
2. 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 Lowe
3. 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
4. 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: Other examples of modification of drug response by pathological states are:

1. Antipyretics lower body temperature only when it is raised (fever). 
2. Thiazides induce more marked diuresis in edematous patients. 
3. Myocardial infarction patients are more prone to adrenaline and digitalis induced cardiac arrhythmias.
4.  Myasthenic are very sensitive to curare.
5.  Schizophrenics tolerate large doses of phenothiazines.

1. Head injury patients are prone to go into respiratory failure with normal doses of morphine. 
2. Atropine, imipramine, furosemide can cause urinary retention in individuals with prostatic hypertrophy. 
3. Hypnotics given to a patient in severe pain may cause mental confusion and delirium. 
4. Cotrimoxazole produces a much higher incidence of adverse reactions in AIDS patients.

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 (see Ch. 2, 3, 4), and a more comprehensive account of clinically important drug interactions is presented in Ch 69.

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.

1. Full loading dose of digoxin should not be given if patient has received it within the past week. 
2. A course of emetine should not be repeated within 6 weeks.

Tolerance

• It refers to the requirement of higher dose of a drug to produce a given response. Loss of therapeutic efficacy (e.g. of sulfonylureas 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 hypo responders 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.:

1. Tolerance develops to sedative action of chlorpromazine but not to its antipsychotic action.
2.  Tolerance occurs to the sedative action of phenobarbitone but not as much to its antiepileptic action.
3. 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 anesthetics. 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 (see p. 52) or weakening of response effectuation.

• Tachyphylaxis (Tachy-fast, phylaxis-protection) 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. (see p. 51, 52) and/or compensatory homeostatic adaptation.

Drug resistance It refers to tolerance of microorganisms to inhibitory action of antimicrobials, e.g., Staphylococci to penicillin (see Ch. 49).

RATIONAL USE OF MEDICINES

It is widely assumed that use of drugs by qualified Doctor of Modern Medicine would be rational. However, in reality, irrationality abounds in almost every aspect of drug use. Medically inappropriate, ineffective and economically inefficient use of drugs occurs all over the world, more so in the developing countries. As per the WHO — ‘rational use of medicines requires that the patients receive medication appropriate to their clinical needs in doses that meet their own individual requirements for an adequate period of time, and at the lowest cost to them and to their community’.

Rational use of medicines addresses every step in the supply-use chain of drugs, i.e. selection, procurement, storage, prescribing, dispensing, monitoring and feedback. However, only rational prescribing and related aspects are dealt here.

Rational prescribing

• Rational prescribing is not just the choice of a correct drug for a disease, or mere matching of drugs with diseases, but also the appropriateness of the whole therapeutic set up along with follow up of the outcome. The criteria to evaluate rational prescribing are: 

1. Appropriate indication: the reason to prescribe the medicine is based on sound medical considerations. 
2. Appropriate drug in efficacy, tolerability, safety, and suitability for the patient. 
3. Appropriate dose, route and duration according to specific features of the patient. 
4. Appropriate patient: no contraindications exist; drug acceptable to the patient; likelihood of adverse effect is minimal and less than the expected benefit. 
5. Correct dispensing with appropriate information/instruction to the patient.
6. Adequate monitoring of patient’s adherence to medication, as well as of anticipated beneicial and untoward effects of the medication.

Irrationalities in prescribing

• It is helpful to know the commonly encountered irrationalities in prescribing so that a conscious effort is made to avoid them.

1. Use of drug when none is needed, e.g., antibiotics for viral fevers and nonspecific diarrhoeas.
2.  Compulsive coprescription of vitamins/tonics. 
3. Use of drugs not related to the diagnosis, e.g., chloroquine/ciprofloxacin for any fever, proton pump inhibitors for any abdominal symptom. • Selection of wrong drug, e.g., tetracycline/ ciprofloxacin for pharyngitis, β blocker as antihypertensive for asthmatic patient. 
4. Prescribing ineffective/doubtful efficacy drugs, e.g., serrati peptidase for injuries/ swellings, antioxidants, cough mixtures, memory enhancers, etc.
5. Incorrect route of administration: injection when the drug can be given orally. 
6. Incorrect dose: either underdosing or overdosing; especially occurs in children. 
7. Incorrect duration of treatment, e.g., prolonged postsurgical use of antibiotics, stoppage of antibiotics as soon as relief is obtained, such as in tuberculosis. 
8. Unnecessary use of drug combinations, e.g., ciprofloxacin + tinidazole for diarrhea, ampicillin + cloxacillin for staphylococcal infection, ibuprofen + paracetamol as analgesic. 
9. Unnecessary use of expensive medicines when cheaper drugs are equally effective, craze for latest drugs, e.g., routine use of newer antibiotics. 
10. Unsafe use of drugs, e.g., corticosteroids for fever, anabolic steroids in children, use of single antitubercular drug. 
11. Polypharmacy without regard to drug interactions: each prescription on an average has 3–4 drugs, some may have as many as 10–12 drugs, of which many are combinations.

• Irrational prescribing has a number of adverse consequences for the patient as well as the community. The important ones are:

• Rational prescribing is a stepwise process of scientifically analyzing the therapeutic set upbased on relevant inputs about the patient as well as the drug, and then taking appropriate decisions. It does not end with handing over the prescription to the patient, but extends to subsequent monitoring, periodic evaluations and modifications as and when needed, till the therapeutic goals are achieved. The important steps are summarized in the box.

Information/instructions to the patient

• Rational prescribing also includes giving relevant and adequate information to the patient about the drug(s) and disease, as well as necessary instructions to be followed

Effects of the drug 

• Which symptoms will disappear and when (e.g., antidepressant will take weeks to act); whether disease will be cured or not (e.g., diabetes, parkinsonism can only be ameliorated, but not cured), what happens if the drug is not taken as advised (e.g., tuberculosis will worsen and may prove fatal).

Side effects 

• There is considerable debate as to how much the patient should be told about the side effects. Detailed descriptions may have a suggestive effect or may scare the patient and dissuade him from taking the drug, while not informing tantamount to negligence and may upset the unaware patient. Communicating the common side effects without discouraging the patient is a skill to be developed

Instructions 

• How and when to take the drug (special dosage forms like inhalers, transdermal patches, etc. may need demonstration); how long to take the drug; when to come back to the doctor; instructions about diet and exercise if needed; what laboratory tests are needed, e.g. prothrombin time with oral anticoagulants, leucocyte count with anticancer drugs

Precautions/warnings 

• What precautions to take; what not to do, e.g. driving (with conventional antihistaminics) or drinking (with metronidazole), orinitrate); risk of allergy or any serious reaction, etc. In the end it should be ensured that the instructions have been properly understood by the patient. Rational prescribing, thus, is a comprehensive process.

EXPIRY DATE OF PHARMACEUTICALS

• It is a legal requirement that all pharmaceutical products must carry the date of manufacture and date of expiry on their label. The period between the two dates is called the ‘life period’ or ‘shelf-life’ of the drug. Under specified storage conditions, the product is expected to remain stable (retain >95% potency) during this period. In India, the schedule P (Rule 96) of Drugs and Cosmetics Act (1940) specifies the life period (mostly 1–5 years) of drugs and the conditions of storage. The expiry of other medicines has to be specified by the manufacturer, but cannot exceed 5 years, unless permitted by the licencing authority on the basis of satisfactory stability proof.

• The shelf-life of a medicine is determined by real time stability studies or by extrapolation from accelerated degradation studies. The expiry date does not mean that the medicine has actually been found to lose potency or become toxic after it, but simply that quality of the medicine is not assured beyond the expiry date, and the manufacturer is not liable if any harm arises from the use of the product. Infact, studies have shown that majority of solid oral dosage forms (tablets/capsules, etc.) stored under ordinary conditions in unopened containers remained stable for 1–5 years (some even 25 years) after the expiry date. Liquid formulations (oral and parenteral) are less stable. Suspensions clump by freezing. Injectable solutions may develop precipitates, become cloudy or discoloured by prolonged storage. Adrenaline injection (in ampoules) has been found to lose potency few months after the expiry date of 1 year (it gets oxidized).

• There is hardly any report of toxicity of expired medicines. The degradation product of only one drug (tetracycline) has caused toxicity in man. Outdated tetracycline capsules produced renal tubular damage resembling Fancony syndrome in the early 1960s. The capsules have now been reformulated to minimize degradation.

• Loss of potency beyond the ‘life period’ of the formulation depends on the drug as well as the storage conditions. High humidity and temperature accelerate degradation of many drugs. Though, majority of medicines, especially solid oral dosage forms, remain safe and active years after the stated expiry date, their use cannot be legally allowed beyond this date.

EVIDENCE BASED MEDICINE

• Extensive scientific investigation of drugs in man and introduction of numerous new drugs over the past few decades is gradually transforming the practice of medicine from ‘experience based’ wherein clinical decisions are made based on the experience (or rather impression) of the physician to ‘evidence based’ wherein the same are guided by scientifically credible evidence from well-designed clinical studies. Evidence based medicine is the process of systematically finding, evaluating and using contemporary research findings as the basis of clinical decisions. Results of well-designed multicentric interventional trials are forming the basis of constantly evolving guidelines for disease management. Today’s physician has to be skilled in searching and evaluating the literature on efficacy, safety and appropriateness of a particular therapeutic measure (drug). Therapeutic evaluation of a drug includes:

1. Quantitation of benefit afforded by it. 
2. The best way (dosage, duration, patient selection, etc.) to use it.
3. How it compares with other available drugs. 
4. Surveillance of adverse effects produced by it. Clinical studies are basically of the following three types:

a. Clinical trials 

b. Cohort studies 

c. Case control studies

Clinical trial

• It is a prospective ethically designed investigation in human subjects to objectively discover/verify/ compare the results of two or more therapeutic measures (drugs). Depending on the objective of the study, clinical trial may be conducted in healthy volunteers or in volunteer patients. Healthy volunteers may be used to determine pharmacokinetic characteristics, tolerability, safety and for certain type of drugs (e.g., hypoglycaemic, hypnotic, diuretic) even efficacy. For majority of drugs (e.g., antiepileptic, antipsychotic, antiinflammatory, antitubercular, etc.) therapeutic efficacy can only be assessed in patients.

• The inclusion of a proper comparator (control) group in clinical trials is crucial. The control group, which should be as similar to the test group as possible, receives either a placebo (if ethically permissible) or the existing standard treatment. Separate test and control groups may run simultaneously (parallel group design), or all the subjects may be treated by the two options one after the other (cross over design) so that the same subjects serve as their own controls. In the cross over design, some patients are treated first by drug ‘A’ followed by drug ‘B’, while in others the order is reversed. This nullifies the effect (if any) of order of treatment. This design is applicable only to certain chronic diseases which remain stable over long periods.

• It is well known that both the participants and the investigators of the trial are susceptible to conscious as well as unconscious bias in favour of or against the test drug. The greatest challenge in the conduct of clinical trial is the elimination of bias. The credibility of the trial depends on the measures that are taken to minimize bias. The two basic strategies for minimizing bias are ‘randomization’ and concealment or ‘blinding’.

Randomization 

• The subjects are allocated to either group using a preselected random number table or computer programme so that any subject has equal chance of being assigned to the test or the control group. Discretion (and likely bias) of the investigator/subject in treatment allocation is thus avoided. If considered necessary, stratified randomization according to age/sex/disease severity/other patient variable may be adopted.

Blinding (masking) 

• This refers to concealment of the nature of treatment (test or control) from the subject (single blind) or both the subject as well as the investigator (double blind). For this purpose, the two medications have to appear similar in looks, number, weight, taste, etc. and are to be supplied in unlabeled packets marked for each patient. In double blind, the key/code to treatment allocation is kept by a third ‘data management’ party who is not involved in treating or recording observations. The code is broken at the completion of the trial and the results are analysed according to prespecified statistical method. However, all clinical trials need not be blinded. Those in which the nature of treatment is not concealed are called ‘open’ trials. Randomized controlled double blind trial is the most credible method of obtaining evidence of efficacy, safety or comparative value of treatments.

Inclusion/exclusion criteria 

• The characteristics of the subject/patient (age, sex, disease/symptom, severity and/or duration of illness, coexistant and past diseases, concurrent/preceeding drug therapy, etc.) who are to be recruited in the trial or excluded from it must be decided in advance. The trial results are applicable only to the population specified by these criteria.

End point 

• The primary and secondary (if any) end points (cure, degree of improvement, symptom relief, surrogate marker, avoidance of complication, curtailment of hospitalization, survival, quality of life, etc.) of the trial must be specified in advance. The results are analysed in relation to the specified end points. Higher efficacy may not always be the aim of a clinical trial. A trial may be designed to prove ‘non inferiority’ (of the new drug) to the existing treatment, and possibly afford advantages in terms of tolerability, safety, convenience, cost or applicability to special patient subgroup(s).

Sample size: 

• The number of subjects in the trial for obtaining a decisive conclusion (test better than control/control better than test/no difference between the two) must be calculated statistically beforehand. Because the trial is conducted on a sample of the whole patient population, there is always a chance that the sample was not representative of the population. 

NEW DRUG DEVELOPMENT

• In this era of bewildering new drug introduction and rapid attrition of older drugs, the doctor needs to have an overall idea of the manner in which new drugs are developed and marketed. Drug development now is a highly complex, tedious, competitive, costly and commercially risky process. From the synthesis/identification of the molecule to marketing, a new drug takes at least 10 years and costs 500–1000 million US$. The major steps/stages in the development of a new drug are given in the box.

Approaches to drug discovery

Natural sources 

• Plants are the oldest source of medicines. Clues about these have been obtained from traditional systems of medicine prevalent in various parts of the world; Opium (morphine), Ephedra (ephedrine), Cinchona (quinine), curare (tubocurarine), belladonna (atropine), Quinghaosu (artemisinin) are the outstanding examples. Though animal parts have been used as cures since early times, it was physiological experiments performed in the 19th and early 20th century that led to introduction of some animal products into medicine, e.g., adrenaline, thyroxine, insulin, liver extract, antisera, etc. Few minerals (iron/calcium salts, etc.) are the other natural medicinal substances. The discovery of penicillin (1941) opened the floodgates of a vast source— microorganisms—of a new kind of drugs (antibiotics). The use of microbes for production of vaccines is older than their use to produce antibiotics. 

• The above natural sources of medicines are by no means exhausted, search for new plant, animal and microbial products as drugs is still a productive approach, especially to serve as lead compounds.

Chemical synthesis 

• Synthetic chemistry made its debut in the 19th century and is now the largest source of medicines. Randomly synthesized compounds can be tested for a variety of pharmacological activities. Though some useful drugs (barbiturates, chlorpromazine) have been produced serendipitously by this approach, it has very low probability of hitting at the right activity in the right compound.

• A more practical approach is to synthesize chemical congeners of natural products/synthetic compounds with known pharmacological activity in the hope of producing more selective/superior drugs. Many families of clinically useful drugs have been fathered by a lead compound. Often only ‘mee too’ drugs are produced, but sometimes breakthroughs are achieved, e.g., thiazide diuretics from acetazolamide, tricyclic antidepressants from phenothiazines.

• Study of several congeners of the lead compound can delineate molecular features responsible for a particular property. Application of this structure-activity relationship information has proven useful on many occasions, e.g., selective β2 agonists (salbutamol) and β blockers (propranolol, etc.) have been produced by modifying the structure of isoprenaline, H2 blockers by modifying the side chain of histamine, ethinyl-estradiol by introducing a substitution that resists metabolic degradation, mesoprostol (more stable) by esterifying PGE1.

• Many drugs are chiral compounds. Because pharmacological activity depends on three-dimensional interaction of drugs with their target biomolecules, the enantiomers (R and S forms or d and l isomers) of chiral drugs differ in biological activity, metabolic degradation, etc. Often only one of the enantiomers is active. Single enantiomer drug could be superior to its recemate, because the additional enantiomer may not only be a ‘silent passenger’ but contribute to side effects, toxicity (dextro-dopa is more toxic than levo-dopa) load on metabolism or even antagonize the active enantiomer. Regulatory authorities in many countries, led by US-FDA, have mandated separate investigation of the enantiomers in case the new drug is a chiral molecule. Approval is withheld unless the pure enantiomers are shown to be no better than the recemate. Several drugs, originally introduced as recemates, have now been made available as single enantiomer preparations as well (see box).

Rational approach 

• This depends on sound physiological, biochemical, pathological knowledge and identification of specific target for drug action such as H+K+ATPase enzyme or glycoprotein IIa/IIIb receptor. The drug is aimed at mitigating the derangement caused by the disease, e.g., levodopa was tried in parkinsonism based on the finding that the condition resulted from deficiency of dopamine in the striatum. The purine, pyrimidine, folate antimetabolites were introduced in cancer chemotherapy after elucidation of key role of these metabolites in cell proliferation. Because virus directed reverse transcriptase is unique to retroviruses, its inhibitors have been developed as anti-HIV drugs. This approach is very attractive but requires a lot of basic research.

Molecular modelling 

• Advances in protein chemistry and computer aided elucidation of three-dimensional structure of key receptors, enzymes, etc. has permitted designing of targeted compounds, e.g., designing of selective COX-2 inhibitors was prompted by the comparative configuration of COX-1 and COX-2 enzyme molecules. Study of drug binding to mutated receptors and elucidation of configuration of drug-receptor complexes is now guiding production of improved drugs. Attempts are being made to produce individualized drugs according to pharmacogenomic suitability.

Combinatorial chemistry 

• Chemical groups are combined in a random manner to yield innumerable compounds and subjected to high-throughput screening on cells, genetically engineered microbes, receptors, enzymes, etc. in robotically controlled automated assay systems. Computerized analysis is used to identify putative drugs which are then subjected to conventional tests. This new approach has vast potentials, but has not achieved major breakthroughs so far

Biotechnology 

• Several drugs are now being produced by recombinant DNA technology, e.g. human growth hormone, human insulin, interferon, etc. Some monoclonal and chimeral antibodies have been introduced as drugs. New molecules, especially antibiotics, regulatory peptides, growth factors, cytokines, etc. produced by biotechnological methods can be evaluated as putative drugs. Other experimental approaches in new drug development are antisense oligonucleotides and gene therapy.

Preclinical studies 

• After synthesizing/identifying a prospective compound/series of compounds, it is tested on animals to expose the whole pharmacological profile. Experiments are generally performed on a rodent (mouse, rat, guinea pig, hamster, rabbit) and then on a larger animal (cat, dog, monkey). As the evaluation progresses unfavorable compounds get rejected at each step, so that only a few out of thousands reach the stage when administration to man is considered.

Clinical trials

• When a compound deserving trial in man is identified by animal studies, the regulatory authorities are approached who on satisfaction issue an ‘investigational new drug’ (IND) licence. The drug is formulated into a suitable dosage form and clinical trials are conducted in a logical phased manner. To minimize any risk, initially few subjects receive the drug under close supervision. Later, larger numbers are treated with only relevant monitoring. Standards for the design, ethics, conduct, monitoring, auditing, recording and analyzing data and reporting of clinical trials have been laid down in the form of ‘Good Clinical Practice’ (GCP) guidelines by an International Conference on Harmonization (ICH). Adherence to these provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected. The clinical studies are conventionally divided into 4 phases.

Phase I: Human pharmacology and safety 

• The first human administration of the drug is carried out by qualified clinical pharmacologists/ trained physicians in a setting where all vital functions are monitored, and emergency/ resuscitative facilities are available. Subjects (mostly healthy volunteers, sometimes patients) are exposed to the drug one by one (total 20–40 subjects), starting with the lowest estimated dose and increasing stepwise to achieve the effective dose. The emphasis is on safety and tolerability, while the purpose is to observe the pharmacodynamic effects in man, and to characterize absorption, distribution, metabolism and excretion. No blinding is done: the study is open label.

Phase II: Therapeutic exploration and dose ranging 

• This is conducted by physicians who are trained as clinical investigators on 100–400 patients selected according to specific inclusion and exclusion criteria. The primary aim is establishment of therapeutic efficacy, dose range and ceiling effect in a controlled setting. Tolerability and pharmacokinetics are studied as extension of phase I. The study may be blinded or open label and is generally carried out at 2–4 centres.

Phase III: Therapeutic confirmation/comparison 

• Generally, these are randomized double blind comparative trials conducted on a larger patient population (500–3000) by several physicians at many centres. The aim is to establish the value of the drug in relation to existing therapy. Safety, tolerability and possible drug interactions are assessed on a wider scale, while additional pharmacokinetic data may be obtained. Indications are finalized and guidelines for therapeutic use are formulated. A ‘new drug application’ (NDA) is submitted to the licencing authority, who if convinced give marketing permission.

Phase IV: Postmarketing surveillance/studies 

• After the drug has been marketed for general use, practicing physicians are identified through whom data are collected on a structured proforma about the efficacy, acceptability and adverse effects of the drug (similar to prescription event monitoring). Patients treated in the normal course form the study population: numbers therefore are much larger. Uncommon/idiosyncratic adverse effects, or those that occur only after long-term use and unsuspected drug interactions are detected at this stage. Patterns of drug utilization and additional indications may emerge from the surveillance data.

• Further therapeutic trials involving special groups like children, elderly, pregnant/lactating women, patients with renal/hepatic disease, etc. (which are generally excluded during clinical trials) may be undertaken at this stage. Modified release dosage forms, additional routes of administration, fixed dose drug combinations, etc. may be explored. As such, many drugs continue their development even after marketing.