Factors affecting Drug Action
Factors affecting posology, Factors Affecting Drug Action, Or Factors Modifying Drug Dose, Or Factors Modifying Drug Response.
PHARMACEUTICS
Alok Bains
9/1/20238 min read
Posology
Author: Alok Bains
Posology is a branch of medical science that deals with the dosages of medicines. It determines the appropriate dosage, frequency of drug administration and duration of drug administration. Now a day the term posology is not used in medical practice. Word dose and dosage are used most commonly. The quantity of medicines to be administered to the patient to produce a medicinal effect is called a dose.
Factors affecting posology
Factors Affecting Drug Action Or
Factors Modifying Drug Dose Or
Factors Modifying Drug Response
Degrees of drug response vary from person to person. The degree of drug response in one individual depends upon various factors.
A. PHYSIOLOGICAL FACTORS:
The following physiological factors affect drug action and drug dose.
1. Body Weight: The average adult dose is for medium-built individuals. The dose of the drug depends upon the body surface area or body weight of a patient. The dose for individual person can be calculated by using the below formulae
Dose = B. S. A. (m2). X A.D
1.7
B.S.A. = Body Surface Area
A.D. = Adult Dose
Dose = Body Weight (Kg) X A.D.
70
Body surface area is a better parameter to calculate the dose of the drug. But it is not convenient to use. Thus body weight is preferred to calculate individual doses of drug. 70 kg is considered as average body weight.
2. Age: Adult dose is used for patients between age 18 years and 60 years. The dose of drugs varies in infant or child, adult and geriatric patients (above 60 years.). Usually, the child dose is less than the adult dose due to the following reasons:
i. Immature liver and kidney
ii. Undeveloped physiological barriers
iii. Low gastric acidity
iv. Slow intestinal motility
v. Delicate skin (for external application medicines)
vi. Slow metabolic rate
Child age is divided into various groups Ex. Neonate up to 28 days, Infants 1-24 months, Children 2-11 years, Adolescents 11-18 years.
Up to 8 years of child age, the drug dose is calculated by using the following formulae
Young’s Formula
Child Dose = Age X Adult Dose
Age+12
Dilling’s Formula
Child Dose = Age X Adult Dose
20
Cowling’s Formula
Child Dose = Age (Next birthday in year) X AD
24
Fried’s Formula
Infant dose = Age (Months) X Adult Dose
150
The dose of drugs for Patients above 60 years also requires some adjustment. Following physiological changes affect the dose of drugs in elder patients (geriatric patients):
i. Reduced body weight
ii. Reduced body fat
iii. Reduced peristaltic movement
iv. Reduced renal function
v. Reduced hepatic function
vi. Reduced metabolic rate
vii. Reduced mental function, etc
3. Sex: Some hormones and smaller body sizes of females alter drug dose-response curves. Drugs should be administered with precautions during menstruation, pregnancy, and lactation. Menstruation: Some drugs may increase bleeding. Lactation: Some drugs are excreted through milk in lactating women. These drugs may harm babies (infants). Pregnancy: Most drugs should be avoided during the first trimester of pregnancy because they may cause teratogenicity. Following physiological changes affect drug dose during pregnancy:
i. Increase in plasma volume
ii. Increase in renal blood flow
iii. Decrease in serum albumin
4. Plasma protein Binding: Absorbed drugs bind with plasma protein to form plasma protein drug complex. This complex is pharmacologically inactive. Only free drug molecules in plasma produce pharmacological effects. Thus any condition that decreases plasma protein level will cause the availability of freer drug molecules in plasma. Ex Malnutrition. In malnutrition, drug doses need to be reduced.
5. Food: Drug molecules are better absorbed in an empty stomach. But the drug produces irritation in an empty stomach. Thus most drugs are not advised on an empty stomach. The presence of food in the stomach interferes with drug absorption. Ex. Calcium-containing food blocks the absorption of tetracyclines.
6. Allergy: The body may release histamine or histamine-like substances in response to drug action. This lead to skin rashes, urticaria (Hives), bronchoconstriction, fall in blood pressure, fever, joint pain, swelling in lymph node etc. These abnormalities are symptoms of allergy. It may occur immediately or after a few days.
7. Drug Dependence (Drug Addiction): A person cannot produce normal physiological functions without a particular drug. This condition is called drug addiction. The dose of the drug needs to be increased to produce effect.
B. PATHOLOGICAL FACTORS: Physiological abnormalities of the body affect the drug dose responses. Usually following disease conditions affect drug dose response.
8. GIT Disease: Abnormalities in GIT usually decrease drug absorption. Thus drug dose is increased to produce drug effect.
9. Liver Disease: Liver disease decreases first-pass metabolism. Liver disease increases drug concentration in plasma, drug half-life, and duration of drug action. This drug dose is reduced in liver disease.
10. Kidney Disease: Most drugs and their metabolites are excreted through the kidney. In renal disease, drug and their metabolites will accumulate inside the body to produce toxicity even in normal doses. The dose of these drugs is decreased in renal disease. Some metabolites are toxic. Thus their dose should also be decreased in renal disease to avoid their toxicity.
Renal disease increases the permeability of the blood-brain barrier. Thus drugs may enter into CNS and produce toxic effects.
11. Congestive Heart Failure (CHF): Oedema in GIT and decreased blood flow in GIT occur during CHF. These conditions affect drug absorption. This requires a high dose to produce the required drug action.
12. Thyroid Disease: Thyroid hormones control the body's metabolic rate. In hypothyroidism body's metabolic rate decreases. This will increase the half-life of the drug and the concentration of the drug in the body. The half-life of the drug and concentration of the drug in the body will decrease in hyperthyroidism. Both conditions require dose adjustment.
C. ENVIRONMENTAL FACTORS
14. Route of Administration: Route of drug administration affects the pharmacodynamics of the drug. Magnesium sulfate acts as a purgative upon oral administration. It acts as an anticonvulsant upon intravenous administration. It reduces edema upon topical application as a poultice.
15. Time of Administration: The study of the drug dose-response related to the time of drug administration is called Chronopharmacology. The pharmacological effect of a drug also depends upon the time of drug administration. Ex. The human body produces endogenous corticosteroids in the morning hour. Thus degree of corticosteroid drug effects will be different in the morning and evening. A low dose of hypnotics will be required at night than daytime to produce sleep.
16. Racial Differences: Drug dose responses depend upon species and races due to genetic changes. Rabbits are resistant to atropine. The black population needs a high dose of Atropine to produce effect.
17. Genetic Factor: Drug dose responses depend upon the genes of patients. It is studied under pharmacogenetics. Chinese population produces more acetaldehyde in their body than white. Thus Chinese are more prone to flushing and palpitation than white. Propranolol is more effective among Chinese than whites.
18. Idiosyncracy: Genetic disorders may produce abnormal drug reactions upon the first dose. This drug reaction is called idiosyncrasy. It is an unpredictable drug reaction and hereditary in nature. It is used to describe unusual drug reactions in an individual upon first administration.
19. Psychological Condition: The psychological condition of the patient affects the drug dose-response. Ex. Placebo produces a therapeutic effect if the patient has faith in the physician. The anxious patient needs a higher dose than the normal patient to produce drug action.
20. Preparation of Drug: The dosage form of the drug decides the dose of the drug. Solid dosage forms need higher doses than liquid dosage forms. Liquid dosage form produces more rapid action than solid dosage form.
21. Hyper susceptibility to Drugs: Drug susceptibility varies from individual to individual. Ex. 2 mg of Diazepam acts as an anti-anxiety agent without producing a hangover. In hyper-susceptible individuals, it may cause hangovers and hypnosis. 10 mg Morphine produces analgesic and sedative effects for 4-6 hours. In hyper susceptible patients this action may prolong to 10-12 hours. Thus dose of the drug should be adjusted accordingly.
22. Hypersensitivity: Abnormal response to a drug in an individual is considered as drug hypersensitivity or drug allergy. It is an immunological problem. Ex Penicillin may produce anaphylactic shock in some individual
23. Tolerance: The requirement of a higher dose to produce a normal drug effect is called drug tolerance. There are two types of drug tolerance
Natural Tolerance: This tolerance develops with birth. It depends upon races and species. Black people require a higher dose of atropine to produce pupil dilation. Atropine does not produce pupil dilation in rabbits.
Acquired Tolerance: It develops during a lifetime. There are two types of acquired tolerance.
Acute Tolerance (Tachyphylaxis): Repeated administration of the drug in a shorter duration develops acute tolerance. It occurs with drugs that act indirectly. It usually exhausts endogenous receptors. Ex. Ephedrine produces action by releasing noradrenaline from adrenergic receptors. Repeated administration of epinephrine exhausts all noradrenaline. This develops tolerance. Even an increase in ephedrine dose does not produce pharmacological action. It is reversible tolerance. After a few days, the body starts to respond to the drug.
Chronic Tolerance: There are two types of chronic tolerance
Pharmacokinetic Tolerance: Barbiturates increase the secretion of microsomal enzymes. It increases the metabolism of other drugs. Thus patients require higher doses of drugs to produce similar effects.
Pharmacodynamic Tolerance: It occurs due to a change in the mechanism of drug action at the cellular level. Ex. Repeated administration of chlorpromazine develops tolerance for sedative effect but tolerance does not develop for antipsychotic effect.
Cross Tolerance: A repeated dose of one drug develops a tolerance for other drugs is called cross-tolerance. Ex. Alcoholics require a higher dose of sedative to produce effects. Similarly, high doses of general anesthetics are administered in alcoholics to produce anesthesia. Drugs having similar chemical structures develop tolerance for each other. This is also cross-tolerance. Ex. repeated use of morphine develops a tolerance for morphine. These patients also require a higher dose of pethidine, and codeine to produce action. Similarly, repeated use of diazepam develops tolerance for lorazepam.
D INTERACTIONS OF DRUGS WITH OTHER DRUGS,
24. Synergism: Synergism means working together. The interaction of two or more drugs to produce a pharmacological effect more than the sum of their individual pharmacological effect is called synergism. Synergism can be studied under two headings.
25. Potentiation: The interaction of two or more drugs to produce a pharmacological response greater than the sum of their individual pharmacological response is considered potentiation. Here one drug increases the effect of another drug. Ex. Levodopa and carbidopa in the treatment of parkinsonism. Levodopa is metabolized by the enzyme carboxylase. Carbidopa blocks carboxylase to prevent the metabolism of levodopa. Thus carbidopa increases the pharmacological response of levodopa. The combination of sulphamethoxazole and Trimethoprim shows a synergistic effect. This combination is called Cotrimoxazole.
26. Additive Effect (Summation): The interaction of two or more drugs to produce a pharmacological response equal to the sum of their individual pharmacological response is called the additive effect. Ex. Ephedrine and theophylline as a bronchodilator. Nitrous oxide and ether as general anesthetics.
27. Antagonism: The interaction of two drugs to oppose the pharmacological response of each other is called antagonism. An agent that opposes the action of another drug is called the antagonist. There are two types of antagonists:
Pure Antagonism: A drug with receptor affinity without producing intrinsic activity (Pharmacological response) is called a pure antagonist.
Partial Antagonism: A drug with receptor affinity and slight intrinsic activity (Pharmacological response) is called partial response. The antagonist acts by following four mechanisms:
Chemical antagonism: The chemical interaction of two drugs to inactivate the effect of each other is called chemical antagonism Ex. tetracycline and antacids. Tetracyclines interact with antacids to form chelates. Chelates are not absorbed from GIT. Thus they inactivate the pharmacological response of each other.
Physiological Antagonist: The action of two drugs at different sites or organs to produce opposite effects is called physiological antagonism. Ex. Histamine produces bronchospasm and hypotension by affecting histamine receptors. Adrenaline acts on adrenergic receptors to produce bronchodilation and hypertension. Their concurrent administration produces physiological antagonists.
Receptor level antagonism: The antagonist occupies receptors to block the action of agonists. It is of two types
Reversible Antagonism: Antagonost and agonist compete for one receptor. Usually, drugs in high concentration occupy receptors to block the action of another drug. Ex. Acetylcholine and Atropine. Both drugs produce action by combining with muscarinic receptors. Atropine action can be reduced by increasing the concentration of acetylcholine and vice versa.
Irreversible Antagonism: Antagonist and agonist compete for one receptor. The antagonist combines with the receptor by forming a covalent bond. It dissociates very slowly or does not dissociate. Thus it blocks receptors permanently or for a longer duration. Ex. Organophosphorous compound poisoning.
Author: Alok Bains