Introduction
Different patients respond differently to the same drug and the same dose. This variation occurs because several patient-related and drug-related factors influence drug action. Understanding these factors helps in selecting the correct dose, preventing toxicity and improving treatment outcomes.
Major Categories of Factors
- Patient-related factors
- Drug-related factors
Factors Related to the Patient
1. Age
Age is one of the most important determinants of drug response.
Newborns and Infants
- Drug-metabolizing enzymes are immature, especially oxidation and glucuronidation pathways.
- Inability to metabolize chloramphenicol leads to “grey baby syndrome.”
- Renal functions (GFR, secretion, reabsorption) are low, slowing drug elimination.
Elderly Patients
People above 65 have increased risk of adverse drug reactions due to:
- Multiple diseases and polypharmacy.
- Poor compliance.
- Reduced lean body mass and total body water.
- Reduced liver blood flow and first-pass metabolism.
- Reduced renal elimination.
Drugs eliminated by kidneys (e.g., aminoglycosides, digoxin, lithium) require dose adjustment.
2. Sex
- Women may show different drug responses due to hormonal variations.
- Men usually have higher microsomal enzyme activity due to testosterone, increasing metabolism of some drugs.
3. Body Weight
Dose often needs adjustment depending on body size. Children require dose calculation using standard formulas like Clarke’s formula:
Dose for child = (Weight in pounds × Adult dose) / 150
4. Nutrition
Malnutrition, starvation, strict dieting or chronic illness can alter drug effects.
- Low albumin reduces protein binding, increasing free drug levels.
- Vitamin deficiencies may contribute to toxicity, e.g., antibiotic-induced vitamin K deficiency causing bleeding.
5. Alcohol Intake
Alcohol modifies drug metabolism:
- Acute alcohol intake: inhibits metabolism of other drugs.
- Chronic alcohol intake: increases metabolism due to enzyme induction. For example, chronic alcoholics eliminate tolbutamide faster.
6. Cigarette Smoking
Cigarette smoke contains benzopyrene, a strong enzyme inducer. It increases metabolism of drugs like theophylline and caffeine. Theophylline half-life is 8 hours in non-smokers but only 4 hours in smokers.
7. Pregnancy
Pregnancy causes changes in drug distribution and elimination:
- Increase in total body water → increased Vd for water-soluble drugs.
- Reduced albumin → higher free drug levels.
- Increased fat stores → increased Vd for fat-soluble drugs.
- Increased renal clearance → faster excretion of drugs like penicillin.
Drug effects on the fetus and risk of teratogenicity must always be considered.
8. Genetic Factors
Genetic differences may cause decreased, increased or abnormal drug responses.
- G6PD deficiency: primaquine causes hemolysis.
- Pseudocholinesterase deficiency: suxamethonium causes prolonged apnea; treated with blood transfusion.
9. Environmental Factors
Pollution increases hydrocarbon exposure, which induces microsomal enzymes and reduces drug action.
10. Pathological Conditions
Diseases significantly influence drug effects:
- In liver disease → reduced metabolism → drug accumulation.
- In kidney disease → reduced excretion → toxicity risk.
- Diseases also create conditions for drugs to act; e.g., antihypertensives act only during hypertension, antibiotics act only in infections.
Factors Related to the Drug
1. Dose
Drug action varies with dose:
- Low-dose chlorpromazine acts as an antiemetic, high dose as an antipsychotic.
- Low-dose aspirin has antiplatelet action, high dose is anti-inflammatory.
2. Route of Administration
The same drug may produce different effects depending on the route:
- Magnesium sulfate → oral: purgative; IM: sedative.
- Benzodiazepines → oral: anxiolytic; IV: anesthetic.
3. Time of Administration
Drug effect may vary with time of day. Example: sedative effect of benzodiazepines is more pronounced at night.
4. Drug Combination and Drug Interactions
Combining two drugs may produce:
- Additive effect.
- Synergistic effect.
- Antagonistic effect.
One drug may induce or inhibit the metabolism of another, affecting its action.
5. Cumulation
Occurs when a drug with slow elimination accumulates after repeated dosing, causing toxicity. Examples: digoxin, chloroquine, emetine.
6. Tolerance
Tolerance means higher doses are required to produce the same effect.
- Seen with morphine, amphetamines, alcohol, nitrates.
- Develops with repeated exposure.
Detailed Notes:
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