A multitude of host & environmental factors influence drug response. Understanding of these factors can guide choice of appropriate drug & dose for individual patient.
Variation in response to the same dose of a drug between different patients and even in the same patient on different occasions will occur. The range of variability may be marked or limited depending on the pharmacokinetic & Pharmacodynamic characteristics of the drug. Drugs mostly disposed by metabolism are most effected (e.g. propanolol) while those excreted by the kidneys are least effected (e.g. atenolol).
1. Physiological Factors.
2. Pathological Factors (Diseases)
3. Genetic Factors
4. Environmental Factors
5. Interaction with other drugs
There exists no specific dose. The decision lies with the doctor. Giving optimum dose is mandatory for desired results. Pharmacopoeia gives the guidelines and ranges. All factors affecting absorption and biotransformation may influence the outcomes of drug actions.
1. Physiological Factors
The adult dose is for people between 18 and 60 years of age. The tissues of an infant & child are highly sensitive to large number of drugs. Children under 12 yrs require fraction of adult dose because:
- Drug metabolizing enzyme system is inefficient in them (Glucuronidation takes 3 months to develop)
- Their barriers are not fully developed (BBB, blood aqueous barrier), thus are more sensitive to CNS stimulants. All parts of the body are affected by the drug.
- Infants have an immature renal tubular transport system. Penicillin, streptomycin and amino glycosides are not administered. After one year of age, elimination by kidneys is increased.
- Hepatic metabolizing capacity is also under developed. Chloramphenicol may cause grey baby syndrome.
The dose for a child is calculated from the adult dose up to 8 yrs of age. The average adult dose is for an individual of medium built. For very thin or obese individual the dose may be modified using either the body surface area or body weight. i.e.
Surface area is found from height and weight, and is around 1.7-1.8/m2.
Dose to be prescribed = Body surface area (m2) x adult dose
Dose to be prescribed = Wt in kg x A.D
Child dose= Body surface area in m2 of child x A.D
1.7 (average body surface area in AD).
The drug dosage of newborn is decreased because:
a. gastric acid secretion are not adequate e.g.
GIT absorption of ampicillin and amoxicillin is greater in neonates due to decreased gastric acidity
b. liver microsomal enzymes (glucuronyl transferase) are deficient
Administration of Chloramphenicol may lead to Grey baby syndrome because of inadequate glucouronidation of chloramphenicol resulting in drug accumulation
c. Plasma protein binding is less
d. GFR & tubular secretions are not adequate.
e. There is immaturity of blood brain barriers in neonates.
Sulfonamides may lead to hyperbilirubinemia and kernicterus
In children Tetracyclines may cause permanent teeth staining
Corticosteroids may lead to growth & development retardation
Antihistaminics may cause hyperactivity.
Geriatric age group (> 60 yrs)
Patient requires special consideration because physiological changes occur with age are to be kept in mind such as:
- Reduced body weight
- Reduced body fat
- Reduced intestinal motility & mesenteric blood flow.
- Reduced renal & hepatic functions
- Altered mental functions
Elderly often require lesser doses than adults because they are prone to suffer from adverse drug reactions. If liquid preparations are available, they should be preferred as are convenient for absorption.
Liver functions are impaired. Drugs like diazepam, theophylline having lower therapeutic index, may have much larger half lives (2 hrs in normal 90 hrs in old)
Kidney functions are also impaired. Drugs like Digoxin, lithium and amino glycosides have decreased excretion
Plasma protein binding is decreased leading to greater amounts of active drugs.
Increased sensitivity to CNS depressants like diazepam, morphine also occurs
Testosterone increases the rate of biotransformation of drugs.
Decreased metabolism of some drugs in female (Diazepam) occurs. Females are more susceptible to autonomic drugs (estrogen inhibits choline esterase). Drugs used for ulcer may cause increased prolactin.
During menstruation, salicylates and strong purgatives should be avoided as they may increase bleeding.
In pregnancy following are to be considered:
- Cardiac output
- GFR and renal elimination of drugs.
- Volume of distribution
- Metabolic rate of some drugs
Lipophilic drugs cross placental barrier & are slowly excreted. During pregnancy, uterine stimulants, strong purgatives and drugs likely to have teratogenic effects should be avoided, especially during first trimester no drug should be given unless absolutely necessary.
During labour, morphine should be avoided as it crosses placental barrier and depresses respiration in newborn.
d. Plasma Protein Binding
Malnutrition causes decreased amino acids, decreased proteins leading to decreased binding sites for drugs.
e. Body weight
Dose is given per kg body weight. Average muscular weight is between 50 and 100 kg, with 70 kg being the average.
During lactation, drugs may be excreted through milk and may affect the infant e.g. some purgatives, penicillin, chloramphenicol and oral anticoagulants.
Drugs are better absorbed in empty stomach. To prevent gastric irritation most drugs are taken after or between foods, which affects the outcomes. Antimotion drugs are taken on empty stomach. Helminthes (for evacuation of worms) are also taken on empty stomach.
Allergy is the abnormal response of drug resulting from antigen-antibody reaction, leading to liberation of histamine and histamine-like substances; therefore, there may be skin rashes, urticaria, bronchoconstriction and fall of blood pressure. Allergic reactions may occur immediately or may be delayed for many days.
Immediate and acute allergic reactions lead to acute anaphylactic shock which is dangerous for patient and may even be fatal e.g. penicillin, sera, vaccines. Steps which can be taken include:
- History taking of previous allergic reactions
- Test dose should be given first
- Drugs required to deal with emergency should be kept ready
Sometimes skin rashes or urticaria along with fever and pain in joints and swelling of lymph nodes may occur after a few days. This is delayed type of allergy called serum sickness type reaction.
i. Drug Dependence (Drug addiction)
Drug dependence is a state of periodic or chronic intoxication which is detrimental to person and society. It becomes almost impossible to carry out normal physical functions without the drug.
Components of phenomenon of addiction include:
- Euphoria- sense of happiness and forgetfulness
- Tolerance- due to increased production of enzymes
- Psychic dependence (Habituation)- person desires but in absence of drug no harm occurs
- Physical dependence-
- Withdrawal symptoms (Abstinence syndrome)- symptoms opposite pharmacological actions of drug develop in absence of drug
2. Pathological Factors
Diseases cause individual variation in drug response
(A) Liver Disease
In liver diseases, prolong duration of action occurs because of increased half life. Plasma protein binding for warfarin, tolbutamide is decreased leading to adverse effects
If hepatic blood flow is reduced, clearance of morphine- propanolol may be affected.
Impaired liver microsomal enzymes may lead to toxic levels of Diazepam, rifampicin and theophylline
(B) Renal Disease
GFR, tabular function and plasma albumin may be affected leading to abnormal effects of digoxin, lithium, gentamycin and penicillin
Plasma protein binding of drugs is reduced along with the amount of microsomal enzymes, leading to increased portion of free, unbound drug e.g. Warfarin
3. Genetic Factors
Genetic abnormalities influence the dose of a drug and response to drugs. It affects the drug response in individuals at 2 levels.
- At the level of receptors
- At the level of drugs metabolizing enzyme
Thus, interfering with the functions such as rate of plasma drug clearance.
Pharmacogenetics is the study of the relationship between genetic factors and drug response.
Idiosyncrasy is the abnormal drug reaction due to genetic disorder. It is the unpredictable response seen on first dose of drug on hereditary basis. This may be due to
- Succinylcholine apnea
- Glucose 6-phosphate dehydrogenase deficiency.
All individuals do not respond in similar way to same drug. Idiosyncrasy is used to describe abnormal drug response on administration of first dose.
The existence in a population of two or more phenotypes with respect to the effect of a drug. E.g. Acetylation enzymes deficiency
Acetyl transferase (non-microsomal) affects Isoniazid, sulphonamides, etc.
Slow acetylator phenotype may show peripheral neuropathy .
Rapid acetylator phenotype may show hepatitis
Succinyl choline is a skeletal muscle relaxant. Succinylcholine apnea may occur due to paralysis of respiratory muscles.
Occurs by succinyl choline due to inherited inability to chelate calcium by sarcoplasmic reticulum resulting in Ca release, muscle spasm and rise in temperature.
In case of Debrisoquine
- Extensive metabolizers (EM) need larger dose.
- Poor metabolizers (PM) – need smaller dose.
Deficiency of Glucose-6 phosphate dehydrogenase (G-6-PD)
G-6-PD Deficiency in RBCs leads to haemolytic anaemia upon exposure to some oxidizing agents like
- Antimalarial drug, primaquine
- Long acting sulphonamides
- Fava beans ( favism).
4. Environmental Factors
a. Route of Administration
Some drugs are incompletely absorbed after oral intake, when given intravenously; their dose has to be reduced. Examples include morphine and magnesium sulphate. Magnesium sulphate when given orally is osmotic purgative, but its 20% solution is injected intravenously to control the convulsions in eclampsia of pregnancy.
b. Time of Administration
Hypnotics (producing sleep) act better when administered at night and smaller doses are required. Amonoglycosides like streptomycin when given intravenously cause neuromuscular blockage, which is not observed after intramuscular injection.
c. Effect of Climate
Metabolism is low in hot and humid climate. Purgatives act better in summer while diuretics act better in winters. Oxidation of drugs is low at higher altitudes.
d. Racial Differences
Castor oil, a purgative, is ineffective in Chinese. The dilating effect of ephedrine in fair people on pupil is absent in Negroes.
e. Preparation of Drug
Drugs in solid forms disintegrate slowly. Onset of action is rapid when drug is given in liquid form.
f. Age of Drug
Action may be modified if kept for longer durations. Outdated tetracyclines give rise to excretion of amino acids in urine. Chloroform and carbon tetrachloride become toxic if kept for long durations.
g. Acidic or Basic Medium
If GIT has decreased acidity, acidic drugs like benzyl penicillin are not effective orally.
h. Effect of Disease
Certain drugs are only effective in disease conditions. These include antipyretics like aspirin and paracetamol, which do not reduce temperature in case of healthy individuals.
Iron is better absorbed in iron deficiency anemia. As the anemia improves, it has less response.
Hyper susceptibility to Drugs
Variations in individuals leading to prolonged effects of drugs. Examples include diazepam, 2 mg of which are used as antianxiety producing no hang overs. In hyper susceptible individuals, the drug has prolonged action causing hangovers and hypnotic actions.
Opioids like morphine cause analgesia and sedation in 10 mg dose effective for 4-6 hours. In hyper susceptible individuals, effect might be prolonged to 10-12 hours. These are individual based variations.
Hypersensitivity is the quantitatively abnormal response with certain groups of drugs. Response is seen in sub therapeutic doses not capable of producing pharmacological actions. This has immunological basis, e.g. allergy. 25% of the drugs show hypersensitivity.
Hematological disorders can occur more pronounced in atopic individuals, who are already exposed to antigens, e.g. ashthemics are more prone to allergic reactions.
Nearly all drugs show hypersensitivity in some category, which might be self limiting or even life threatening. Penicillin when administered may cause anaphylactic shock. High molecular weight drugs have a greater tendency to show hypersensitivity. History taking is helpful in predicting hypersensitivity. Test dose can be given intradermally and localized reactions can be seen.
Resistance to normal therapeutic dose of drug, producing lesser response to normal therapeutic dose is known as tolerance. This is acquired character. Examples include morphine, person is initially responsive, if continued, changes occur at cellular and pharmacokinetic level, reducing the action. Thus one has to increase the dose of drug to overcome.
Alcoholics do not respond to hypnotics and analgesics, dose of which has to be increased many folds. In fact they may even tolerate toxic levels.
A person tolerant to drugs resembling in chemical structure is known as cross tolerance. Those drugs resembling in chemical structures show cross tolerance. If a person is tolerant to morphine, he also shows tolerance to pathedine (synthetic derivative) and codeine.
Complete cross tolerance is observed in cases like diazepam and flurezepam
Incomplete cross tolerance occurs with the drugs sharing the same pharmacological properties. Examples include barbiturates and general anesthetics, site of action is CNS, incomplete cross tolerance may be observed although they are not resembling chemically, but having same pharmacological properties.
Repeated administration of a drug at short intervals of time leads to a rapidly developing tolerance. This occurs with indirectly acting drugs. On repeated administration, depletion of endogenous receptors occurs. It is also known as acute tolerance. Example includes ephedrine, which acts by releasing noradrenalin from adrenergic stores. After repeated administration, these stores are exhausted and pharmacological action is not restored even on increasing the dose.
5. Interactions of Drugs
Synergism is the facilitation/potentiation of pharmacological response by concomitant use of two drugs.
The total effect will be more than the sum of their individual effects. Examples are:
- Acetylcholine + physostigmine. Physostigmine inhibits the action of esterase prolonging the effect of acetylcholine.
- Levodopa (Parkinsonism) + carbidopa/benserazide. Levo dopa is decarboxylated peripherally, carbidopa inhibits the decarboxylase.
- Sulfonamide (effective against some microorganisms) when combined with trimethoprim is effective against a wider range of microorganisms.
The action is more than the normal therapeutic effect.
II. Additive Effect (Summation)
In this case the total pharmacological action of two drugs will be equal to the sum of their individual effect on simultaneous administration. The response is not more than their total algebraic sum. e.g.
- Aspirin + paracetamol as analgesic/ antipyretic
- Ephedrine + theophylline as bronchodilator
- Nitrous oxide + ether as general anesthetic
- Antihypertensive drugs
- Cardiac stimulants
When two drugs, administered simultaneously, oppose the action of each other on the same physiological system, the phenomenon is called antagonism. It can be of following types.
1. Chemical antagonism:
It involves reduction of the biological activity of a drug by a chemical reaction with another agent e.g. between acids and alkalies: BAL and arsenic. Antacids, used for dyspepsia involve administration of sodium bicarbonate to react with hydrochloric acid. In cases of heavy metal poisoning chelating agents are used like dimerzapam.
In iron poisoning deproxamine is given which binds sulphydral groups forming insoluble complexes which can be easily detoxified.
2. Pharmacological antagonism
Pharmacological antagonism is of two types:
I. Competitive or reversible antagonism.
In this type of antagonism the agonist and antagonist compete with each other for the same receptors. The extent of antagonism will depend on the relative number of receptors occupied by the two compounds. Other features are:
a. Antagonist has chemical resemblance with agonist.
b. Antagonism can be overcome by increasing the concentration of the agonist at receptor site. It means the maximal response to agonist is not impaired.
c. Antagonist shifts the dose response curve to right
d. Emax of agonist is obtained with high concentration of agonist
e. Duration of action is short. It depends on drug clearance
Example is of acetyl choline and atropine antagonism on muscarinic receptors. In presence of antagonist, log dose response curve of agonist shifts to right, indicating a higher concentration of agonist is required for same response. Maximum height of the curve can be attained by overcoming the action of antagonist. This leads to a parallel shift of log dose response curve towards right.
II. Non competitive antagonism:
Here an antagonist inactivates the receptor in such a way so that the effective complex with agonist cannot be formed irrespective of the concentration of the agonist. This can happen by various ways:
- The antagonist might combine at the same site in such a way that even higher concentration of the agonist can not displace it.
- The antagonist might combine at a different site of R in such a way that agonist is unable to initiate characteristic biological response
- The antagonist might itself induce a certain change in R so that the reactivity of the receptor site where agonist should interact is abolished.
Other features of this antagonism are:
- Antagonist has no chemical resemblance with agonist.
- Maximum response is suppressed
- Although antagonist shifts the dose response curve to right, the slope of the curve is reduced.
- The extent of antagonism depends on the characteristics of antagonist itself and agonist has no influence upon the degree of antagonism or its reversibility
- Emax of agonist is decreased even with high concentration of agonist
- Duration of action is long which depends upon new receptor synthesis.
Example is of phenoxybenzamine and adrenaline at alpha adrenergic receptors.
III. Physiological antagonism:
In this interaction of two drugs, both are agonists, so they act at different receptor sites. They antagonize the action of each other because they produce opposite actions. Classical example of physiological antagonism is adrenalin and histamine. Former causes bronchodilatation while later broncho Constriction. So adrenalin is a life saving drug in anaphylaxis.
Clinical significance of drug antagonism
- It helps to correct adverse effects of a drug e.g. ephedrine and phenobarbitone.
- It is useful to treat drug poisoning e.g. morphine with naloxone
- It guides to avoid drug combinations with reduced drug efficacy such a as penicillin and tetracycline combination