General Pharmacology: Adverse Drug Reactions, Tolerance, and Drug Interactions

Overview of Adverse Drug Reactions (ADR)

Adverse Drug Reactions (ADRs) are critical clinical considerations driven by a variety of factors related to the drug, the patient, and external variables. Understanding the complex interplay of these factors is essential for safe therapeutics.

• Factors Influencing Drug Response and ADRs:

  • Drug Dosage: The quantity of the substance administered influences the amount available at the target site.

  • Pharmacokinetics: The amount of drug available at the target site.

  • Patient History: Previous history of disease.

  • Genetics: Individual genetic makeup (Pharmacogenetics/Pharmacogenomics).

  • Interactions: Drug-drug interactions, drug-food interactions, and drug-supplement interactions.

  • Patient Profile: Age, medical conditions, and living conditions.

• Possible Effects of Interactions:

  • Decreased action of drug(s).

  • Increased action of drug(s).

  • Cause of specific adverse effects and side effects.

Classification of Adverse Drug Reactions

ADRs are generally categorized into two main types based on predictability and relationship to pharmacological action.

Unpredictable (Type B or Bizarre) Reactions

These reactions are based on patient abnormalities rather than the known pharmacological actions of the drug.

• Idiosyncrasy (Pharmacogenetics):

  • Defined as an unpredictable abnormal response due to a genetic abnormality.

  • Characteristics: Less common, non-dose related, more serious, requires immediate drug withdrawal.

  • Occurrence: Can occur on the very FIRST exposure to the drug.

  • Examples of Idiosyncrasy:

    1. Isoniazid Metabolism: Differences between slow acetylators and rapid acetylators. Slow acetylators are prone to peripheral neuropathy, while rapid acetylators associated with hepatotoxicity.

    2. Succinylcholine Apnea: Occurs in patients with a deficiency in the pseudo-cholinesterase enzyme. This leads to increased levels of $Succinylcholine$, causing prolonged depression of respiratory muscles.

• Allergy (Hypersensitivity):

  • Defined as an unpredictable abnormal response resulting from an Antigen/Antibody ($Ag/Ab$) reaction.

  • Mechanisms: The drug or its metabolite acts as a complete Antigen ($Ag$) or a Hapten.

  • Key Features:

    • Not all drugs cause it and not all patients experience it.

    • Does NOT occur on the first exposure (requires sensitization).

    • NOT dose-dependent.

    • The drug must not be reused.

    • Cross-Allergy: Occurs between related drugs, such as $Penicillin$ and $Cephalosporins$.

Predictable (Type A or Augmented) Reactions

These are based on the known pharmacological properties of the drug.

• General Characteristics: Augmented but qualitatively normal responses; common, dose-related, reversible, and mostly preventable.

• Side Effects: Unwanted but often unavoidable pharmacodynamic effects occurring at therapeutic doses. They are not serious and are predictable from the drug profile. Dosage reduction usually helps.

• Secondary Effects: Indirect consequences of a primary drug action. Example: Suppression of bacterial flora by antibiotics leads to superinfections.

• Over-Dose: An exaggerated normal action of the drug caused by high blood levels. Example: Hypoglycemia resulting from a large dose of $Insulin$.

• Supersensitivity (Intolerance): Appearance of characteristic toxic effects at therapeutic doses. Example: Supersensitivity to $Adrenaline$ in patients with thyrotoxicosis.

Tolerance and Dependence

Tolerance

Tolerance is a state of decreased or failed response to a drug. To recapture the original response, one must increase the dose or stop the drug for a duration.

• Congenital Tolerance:

  • Rabbits are naturally tolerant to $Atropine$ .

  • Black races show tolerance to mydriatics.

• Acquired Tolerance: Occurs with repeated use in an individual initially responsive (e.g., $Morphine$, nitrates).

• Cross Tolerance: Development of tolerance to pharmacologically related drugs (e.g., $Penicillin$ and $Cephalosporin$, or $Morphine$ and $Pethidine$).

• Resistance: Tolerance of microorganisms to the inhibitory action of antimicrobials.

• Tachyphylaxis (Refractoriness): Rapidly developing tolerance following repeated administration at short intervals.

  • Mechanism: Depletion of endogenous stores/receptors (acute tolerance).

  • Example: $Ephedrine$ releases $Noradrenaline$; once stores are exhausted, increasing the dose does not restore the action.

• Mechanisms of Tolerance:

  • Pharmacokinetic: Decreased absorption, increased metabolism (enzyme induction), or increased elimination.

  • Pharmacodynamic: Receptor downregulation (desensitization) or formation of antibodies.

Receptor Regulation

• Downregulation (Desensitization): Sustained agonist activity leads to endocytosis and recycling/degradation of receptors.

• Upregulation (Supersensitization): Sustained antagonist activity or withdrawal leads to an increase in the total number of receptors, producing an exaggerated response.

Drug Dependence

Dependence is a state of periodic or chronic intoxication detrimental to the individual and society.

• Habituation (Psychic Dependence): Sudden cessation leads to psychic craving but no physical harm (e.g., tobacco, coffee, tea).

• Addiction (Physical & Psychic Dependence): Sudden cessation leads to withdrawal or abstinence syndrome (e.g., barbiturates, opiates, ethanol).

• Components of Addiction:

  1. Euphoria: Sense of happiness and forgetfulness.

  2. Tolerance: Due to increased enzyme production.

  3. Psychic Dependence: Habituation.

  4. Physical Dependence.

  5. Withdrawal Symptoms: Symptoms opposite to the drug's pharmacological actions.

Specific Pathological Drug Effects

• Iatrogenic Diseases: Drug-induced diseases. Example: Cushing’s syndrome from large doses of $Cortisone$.

• Carcinogenicity: Capacity of a drug to produce genetic defects and cancer.

• Teratogenicity: Drug-induced fetal abnormalities, especially during the first trimester ($3$ months).

  • FDA Categories:

    • Class A: No risk.

    • Class B, C, D: Varying levels of evaluated risk; in Class D, benefits may outweigh risks.

    • Class X: Absolute contraindication.

• Cytotoxic Reactions:

  • Hepatotoxicity: Associated with $Halothane$ and $Paracetamol$.

  • Nephrotoxicity: Associated with $NSAIDs$ and aminoglycosides.

Drug-Drug and Nutritional Interactions

Pharmacokinetic Interactions

• Absorption:

  • pH: Gastric acidity increases absorption of weak acids (e.g., $Aspirin$); intestinal alkalinity increases absorption of weak bases (e.g., $Amphetamine$).

  • Complexation: $Tetracycline$ chelates with $Ca$, $Mg$, $Al$, or ferrous iron, decreasing absorption.

  • Binding: $Cholestyramine$ binds drugs; Activated charcoal adsorbs drugs (decreasing absorption of oral hypoglycemics and anticoagulants).

  • Motility: $Metoclopramide$ (increases emptying) increases $Paracetamol$ absorption but decreases $Digoxin$ absorption. $Atropine$ (decreases emptying) generally decreases drug absorption.

• Distribution: Drugs like $Aspirin$, sulfonamides, and clofibrate displace other drugs from plasma protein binding sites, potentially leading to bleeding (from anticoagulants) or hypoglycemia (from hypoglycemics).

• Metabolism:

  • Inducers: $Phenobarbitone$, $Phenytoin$, $Rifampicin$, chronic alcohol, St. John’s Wort.

  • Inhibitors: $Estrogen$, $Erythromycin$, $Cimetidine$, $Omeprazole$, $Chloramphenicol$, acute alcohol.

• Excretion:

  • Probenecid: Inhibits active tubular excretion of $Penicillins$, prolonging their duration.

  • pH Changes: Acidification of urine (via $NH_4Cl$) increases excretion of weak bases; Alkalinization (via $NaHCO_3$) increases excretion of weak acids.

Pharmacodynamic Interactions

• Addition ($1+1=2$): Combined effect equals the sum of individual effects (e.g., $Aspirin$ + $Paracetamol$).

• Synergism (1+1>2): Combined effect is greater than the sum (e.g., ethanol + barbiturates leading to severe CNS depression).

• Potentiation (0+1>1): One drug with no effect enhances the effect of another (e.g., $Physostigmine$ + $Acetylcholine$).

• Antagonism:

  • Chemical: Neutralization or chelation.

  • Physiological: Opposite effects on the same function via different receptors (e.g., $Adrenaline$ vs $Histamine$ on smooth muscle).

  • Pharmacological Competitive: Antagonist competes for the same site; reversible; surmountable by increasing agonist concentration. Shifts curve to the right (decreases potency; no change in $E_{max}$). Examples: $Atropine$ vs $Acetylcholine$, $Naloxone$ vs $Morphine$.

  • Pharmacological Non-competitive: Antagonist not displaced; non-parallel shift to the right; decreases $E_{max}$ (decreases efficacy).

    • Reversible: Ends by metabolism (e.g., $Nicotine$, $Succinylcholine$).

    • Irreversible: Covalent binding; ends by receptor re-synthesis (e.g., $Phenoxybenzamine$).

• Reversal: Example: Adrenaline reversal where adding an $\alpha$-blocker ($Prazosin$) leaves only the $\beta_2$ action, dropping blood pressure from $160/120/100$ levels to around $40/120$.

Pharmaceutical Incompatibility (In Vitro)

• Formulation: $Calcium$ chelates $Tetracycline$.

• IV Infusion: $Phenytoin$ is incompatible with $5\%$ glucose (causes crystals/emboli); must use $0.9\%$ saline.

• Syringe Mixing: Mixing basic and acidic drugs (e.g., $Heparin$ and $Protamine$; $Thiopentone$ and $Succinylcholine$; $Penicillin$ and aminoglycosides) causes neutralization.

Drug-Nutrient Interactions

• Altered Intake: Nausea, altered taste, changed appetite, or increased mineral intake (e.g., sodium in antacids).

• Altered Absorption: Drugs may alter pH (inhibiting $Iron$ or $B_{12}$ absorption), speed gut transit, or kill gut flora (reducing $Vitamin K$ and $B$ vitamins synthesis).

• Altered Excretion: Diuretics ($Lasix$) increase loss of $Na$, $K$, $Cl$, $Mg$, and thiamin.

• Altered Metabolism:

  • $Isoniazid$ causes $Vitamin B_6$ deficiency.

  • Anticonvulsants ($Phenytoin$, $Phenobarbital$) impair $Vitamin D$ hydroxylation, risking rickets or osteomalacia.

Questions & Discussion

• Case 1 (Iron Deficiency): A $60$-year-old lady taking ferrous fumarate ($300\,mg$ bid) for anemia ($Hb. 8\,g/dl$) showed no improvement because she took antacids for epigastric distress. Antacids increase gastric pH, which inhibits the absorption of iron.

• Case 2 (Diabetes and Aspirin): A $50$-year-old man on $Glibenclamide$ ($5\,mg$ bid) took $Aspirin$ ($650\,mg$ 6 hrly) for toothache. He experienced hypoglycemia symptoms (anxiety, sweating, palpitation). Explanation: $Aspirin$ displaces $Glibenclamide$ from plasma protein binding sites, increasing its free concentration.

• Case 3 (OCP Failure): A $30$-year-old mother on oral contraceptives ($0.15\,mg$ levonorgestrel + $30\,μg$ ethinylestradiol) became pregnant while treated for TB with $Rifampin$. $Rifampin$ is a potent hepatic microsomal enzyme (HME) inducer that increases the metabolism of contraceptive hormones, rendering them ineffective.

• Case 4 (Myocardial Infarction): A $68$-year-old woman on $Clopidogrel$ and $Omeprazole$ suffered an MI. $Omeprazole$ is a CYP inhibitor. Since $Clopidogrel$ is a pro-drug requiring CYP activation, its antiplatelet activity was reduced, leading to the cardiac event.

Pharmacogenetics vs. Pharmacogenomics

• Pharmacogenetics: The study of the relationship between genetic factors and drug response (e.g., Idiosyncrasy and Genetic Polymorphism like acetylation enzymes).

• Pharmacogenomics: A broader term relating to how the whole genome affects drug response, aiming for "individualized medicine" to tailor drugs and doses to a patient's genetic makeup and avoid adverse reactions.

Adverse Drug Reactions (ADRs) are significant clinical factors arising from interactions between drug properties, patient characteristics, and external variables. Key factors include drug dosage, pharmacokinetics, patient history, genetics, and interactions (drug-drug, drug-food, drug-supplement). ADRs can lead to decreased or increased drug efficacy and specific adverse effects.

ADRs are classified into:

1. Unpredictable (Type B):

   • Idiosyncrasy: Genetic factors cause abnormal responses (e.g., varying reactions to Isoniazid).

   • Allergy: Antigen/Antibody reactions causing unpredictable responses.

2. Predictable (Type A): Based on drug pharmacology, these reactions are common and dose-related (e.g., side effects).

Tolerance refers to reduced drug response needing increased doses. It can be congenital, acquired, or due to cross-tolerance. Drug Dependence encompasses both physical and psychic dependencies leading to withdrawal symptoms upon cessation.