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DRUG TOXICITY

DRUG TOXICITY. Dr. Naila Abrar. LEARNING OBJECTIVES. By the end of this session you should be able to: define drug toxicity; know the types of toxicity; comprehend the reasons that may lead to toxicity of drugs; and recognize the toxic effects of drugs in the body organ systems.

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DRUG TOXICITY

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  1. DRUG TOXICITY Dr. Naila Abrar

  2. LEARNING OBJECTIVES By the end of this session you should be able to: • define drug toxicity; • know the types of toxicity; • comprehend the reasons that may lead to toxicity of drugs; and • recognize the toxic effects of drugs in the body organ systems.

  3. The Renaissance physician Paracelsus (1493-1541) is famously credited with offering the philosophical definition of poisons: "What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison."

  4. Toxic Effect Change in the body which is either too extensive to be compatible with life or is irreversible causing long lasting or permanent damage

  5. TYPES Acute Chronic Absolute Relative

  6. REASONS OF DRUG TOXICITY Over dosage Improper storage Precipitation or aggravation of infections Drug interactions

  7. Dose-Dependent Reactions Pharmacological, pathological, or genotoxic. Incidence and seriousness of the toxicity is proportionately related to the concentration of the drug in the body and to the duration of the exposure. Drug overdose provides a dramatic example of dose-dependent toxicities.

  8. Pharmacological Toxicity • CNS depression (barbiturates) Anxiety Sedation Somnolence Coma • Hypotension produced by nifedipine • Tardivedyskinesia (antipsychotics) -dependent upon duration of exposure. • Can also occur when the correct dose is given: • Phototoxicity associated with exposure to sunlight in patients treated with tetracyclines, sulfonamides, chlorpromazine, and nalidixic acid.

  9. Pathological Toxicity Acetaminophen CYP nontoxic glucuronide + sulfate conjugates & highly reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) • At therapeutic dosing, NAPQI binds to nucleophilic glutathione; but, in overdose, glutathione depletion may lead to the pathological finding of hepatic necrosis

  10. Genotoxic Effects Ionizing radiation and many environmental chemicals are known to injure DNA, and may lead to mutagenic or carcinogenic toxicities. Cancer chemotherapeutic agents

  11. Functional alteration • Delirium with high dose of atropine • Structural alteration/damage • Hepatic necrosis with high dose of paracetamol

  12. DRUG TOXICITY IN VARIOUS ORGAN SYSTEMS Liver Kidneys Hematopoietic system Skin Gastrointestinal tract Nervous system Cardiovascular system Lungs Eyes

  13. LIVER • Acute hepatic injury • Hepatocellular necrosis • By direct action (halothane, chloroform) • Indirect action by interference with certain metabolic pathways (MTX) • Cholestatic jaundice (OCP) • Hypersensitivity (indomethacin, ketoconazole) • Chronic hepatic disease • Chronic active hepatitis (isoniazid, methyldopa, paracetamol, sulphonamides) • Hepatic cirrhosis (ethyl alchohol)

  14. KIDNEY • Acute renal damage • Glomerulonephritis (phenylbutazone, hydralazine) • Acute tubular necrosis (aminoglycosides, amphotericin, paracetamol) • Acute interstitial nephritis (sulphonamides, thiazides) • Non-acute renal damage • Nephrotic syndrome (gold, mercurials, probenicid) • Analgesic nephropathy (papillary necrosis) • Crystalluria (sulphathiazole, chemotherapy- urate released) • Renal stones (alkali with Ca with milk, Vit D) • Lupus erythematosus (hydralazine, isoniazid) • Retroperitoneal fibrosis (methysergide)

  15. HEMATOPOIETIC SYSTEM • Bone marrow depression (chloramphenicol) • Aplastic anemia, thrombocytopenia. granulocytopenia, pancytopenia • Megaloblastic anemia (phenytoin, MTX) • Hemolytic anemia (methyldopa, phenytoin, levodopa, mefenamic acid) • Agranulocytosis (cytotoxic drugs, clozapine) • Thrombocytopenia (cyotoxic drugs) • Leukemia (immunosuppressive therapy)

  16. SKIN & APPENDEGES • Drug eruptions • Acneform • Pigmentation • Eczematous • Exfoliative dermatitis • Erythemanodosum • Urticaria • Psoriasis • Photosensitivity (sulphonamides, teracyclines) • Erythemamultiforme • Steven Johnson syndrome (sulphonamides) • Systemic lupus erythematosus(sulphonamides, grisefulvin, hydralazine) • Alopecia(cytotoxic drugs, carbimazole, chloroquine)

  17. Phototoxic reaction

  18. Drug induced vasculitis

  19. GASTROINTESTINAL TRACT Nausea Vomiting Diarrhea Abdominal cramps (digitalis, bromocriptine, levodopa, morphine, NSAIDS) GI bleeding (NSAIDS) Ulcer (indomethacin, corticosteroids) Pseudomembranous colitis

  20. NERVOUS SYSTEM Extra pyramidal symptoms (chlorpromazine, metoclopramide) Ototoxicity(aminoglycosides, furosemide, salicylates) Peripheral neuropathy (isoniazid) Hallucinations (digitalis) Convulsions (isoniazid, lignocaine) Ataxia (streptomycin, phenytoin, lithium) Nystagmus(phenytoin)

  21. CARDIOVASCULAR SYSTEM Cardiac arrhythmias (halothane, chloroform, amitriptyline, imipramine, digitalis, thioridazine) Hypertensive crises (clonidine, tyramine containing foods with MAOI) Myocardial depression (emetine, chloroform)

  22. LUNGS Bronchoconstriction(beta blockers) Allergic form of asthma (penicillin, aspirin) Pulmonary fibrosis (methsergide, busulphan, nitrofurantoin) Pulmonary edema (I/V fluids)

  23. EYES Optic neuritis (ethambutol, quinine) Retinal damage (chloroquine, thioridazine)- bulls eye apperarance Increased IOP (atropine, corticosteroids)

  24. TERATOGENICITY Capacity of a drug to cause fetal abnormalities when administered to the pregnant mother.

  25. TOXIDROMES Anticholinergics Cholinesterase inhibitors Beta blockers Digoxin Opioids Ethylene glycol & methanol Alcohol Sedative hypnotic drugs Aspirin Acetaminophen Amphetamines & other stimulants

  26. PHARMACOVIGILANCE Science & activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problem • Post marketing surveillance • Drug alerts, medical letters • Change in labels indicating restrictions, warnings etc

  27. Therapeutic drug monitoring • Relation of plasma concentration to the effects of the drug • Low therapeutic index • Toxicity at higher concentrations even within TD • Aminoglycosides • Digoxin • Lithium • Sample taken at steady state

  28. Thank you!

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