General Pharmacology: Adverse Drug Reactions and Drug Interactions PDF

Adverse effects of drugs  Type A: augmented and dose dependent  Type B: bizarre and unpredictable (not related to the normal pharmacology of the drug)  Type C (chronic): chronic effects after long use of the drugs  Type D (delayed): delayed effects of the drugs  Type E (end dose): en...

Adverse effects of drugs  Type A: augmented and dose dependent  Type B: bizarre and unpredictable (not related to the normal pharmacology of the drug)  Type C (chronic): chronic effects after long use of the drugs  Type D (delayed): delayed effects of the drugs  Type E (end dose): end of use effects (effects of sudden stoppage of drug use)  Type F (failure of therapy): tolerance  Adverse effects of drugs Type A  Side effect: unavoidable, undesirable normal action produced by therapeutic dose of the drug. E.g. dry mouth induced by atropine when used as antispasmodic  Supersensitivity: exaggerated normal action in response to small therapeutic dose of the drug. E.g. supersensitivity to adrenaline in hyperthyroid patients  Adverse effects of drugs Type A  Secondary effect: undesirable secondary to normal action of the drug. E.g. broad spectrum antibiotics may cause superinfection and diarrhea due to inhibition of intestinal flora  Over-dose: exaggerated normal response due to increase of the drug dose  Adverse effects of drugs Type A  Cytotoxicity: cardiotoxicity (halothane), hepatotoxicity (halothane), nephrotoxicity (gentamicin), neurotoxicity (streptomycin), bone marrow inhibition (chloramphenicol)  Iatrogenic (drug-induced) disease: chlorpromazine (may cause parkinsonism), cortisone (may cause cushing syndrome)  Drug –drug interactions  Adverse effects of drugs Type B Allergy (hypersensitivity)  Definition: Unpredictable abnormal response to drugs due to antigen-antibody reaction  Characters: not all patients, not all drugs, not dose- dependent, not first exposure and not to reuse the drug again, cross allergy between related drugs  Manifestations: fever, rash, angioneurotic edema, bronchial asthma and anaphylactic shock  Adverse effects of drugs Type B Idiosyncrasy  Definition: Unpredictable abnormal response to drugs due to genetic abnormality  Occurs on first exposure  Examples: hemolytic anemia (aspirin, phenacetin, primaquine,sulphonamides,chloramphenicol), malignant hyperthermia (succinylcholine, halothane), succinylcholine apnea and peripheral neuritis (isoniazid)  Adverse effects of drugs Type C Drug dependence  Habituation: psychic dependence, sudden stop of the drug leads to psychic craving for the drug and examples include smoking, tea and coffee  Addiction: psychic and physical dependence, sudden stop of the drug leads to withdrawal symptoms that may be fatal and examples include morphine, barbiturates and ethanol  Adverse effects of drugs Type D  Teratogenicity: ability of the drug to cause fetal malformations when given to pregnant mothers, e.g. aspirin and thalidomide (FDA :A,B,C,D,X)  Carcinogenicity: tobacco smoking → bronchogenic carcinoma Type E  withdrawal symptoms: sudden stop of addicting drugs as morphine  sudden stop of cortisone after long use → acute addisonian crisis  Adverse effects of drugs Type F Tolerance  Definition: failure of the responsiveness to the usual dose of the drug  Types: congenital (species, racial, individual) and acquired (bacterial resistance to antibiotics, cross tolerance, tachyphylaxis)  Mechanisms of acquired tolerance: decrease absorption, increase metabolism or excretion, down-regulation of receptors (decrease in number and sensitivity) and target cell adaptation  DRUG INTERACTIONS Pharmacokinetic drug interactions  Drug interactions affecting absorption: Tetracyclines bind metals as calcium, magnesium and aluminum → decrease their absorption  Drug interactions affecting distribution: Drugs with high affinity binding to plasma proteins e.g. aspirin and sulphonamides can displace other drugs e.g. warfarin from their plasma proteins binding sites increasing their action (changing from bound to free) and may lead to toxicity of these drugs  DRUG INTERACTIONS Pharmacokinetic drug interactions  Drug interactions affecting metabolism: some drugs stimulates hepatic microsomal enzymes (hepatic microsomal enzymes inducers) leading to increased metabolism of other drugs e.g rifampicin while other drugs inhibits hepatic microsomal enzymes(hepatic microsomal enzymes inhibitors) leading to decreased metabolism of other drugs e.g chloramphenicol  DRUG INTERACTIONS Pharmacokinetic drug interactions Drug interactions affecting excretion: Alkalinization of urine by sodium bicarbonate increases excretion of acidic drugs e.g. aspirin while acidification of urine by ascorbic acid increases excretion of basic drugs e.g ephedrine  DRUG INTERACTIONS Results of drug interactions  Addition or Summation (1+1=2): The resultant action=sum of individual drug actions e.g. acetylcholine + histamine on intestinal contractility  Synergism (1+1>2): the resultant action >sum of individual drug actions. E.g. ethyl alcohol + barbiturates causes severe CNS depression  Potentiation (1+0>1): one drug has no action (0) but increaes the effect of another drug(>1). E.g. physostigmine + acetylcholine  DRUG INTERACTIONS Results of drug interactions  Antagonism: antagonism may be chemical (neutralization of heparin by protamine sulphate and chelation of Hg or As by BAL), physiological or pharmacological (kinetic or dynamic)  Reversal: adrenaline and phentolamine on blood pressure  DRUG INTERACTIONS Pharmacodynamic drug interactions  Pharmacological Antagonism (2 drugs with opposite actions operating on the same receptor): the antagonist may be competitive or non-competitive. Non-competitive antagonist may be reversible or irreversible  Physiological Antagonism (2 drugs with opposite actions operating on the different receptors): Caffeine antagonizes CNS depressant effect of barbiturates  Types of antagonists  Competitive: the antagonist can be displaced from the receptor by increasing agonist concentration. E.g. atropine  Non-competitive: the antagonist cannot be displaced from the receptor by increasing agonist concentration. It may be reversible (the block ends by metabolism of the antagonist, e.g. succinylcholine) or irreversible (the block ends by synthesis of new receptors, e.g. phenoxybenzamine)