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.

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."

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 It should be understood that every drug is potentially toxic if administered in high doses, in other words a completely nontoxic drug does not exist. Very potent drugs i.e., drugs which produce a measurable pharmacological effect in very small dose and drugs with low margin of safety are more liable to produce toxic effects.

TYPES Acute Chronic Absolute Relative

REASONS OF DRUG TOXICITY Over dosage Improper storage Precipitation or aggravation of infections Drug interactions OVER DOSAGE: maybe intentional as in suicide or murder, or accidental, children are frequently poisoned if left in their reach. In hospitals over dosage can occur due to mix up of labels or miscalculation of the dose. Relative in which toxicity can occur even at usual dose e.g gentamicin in presence of renal failure IMPROPER STORAGE: e.g., paraldehyde which is a polymer of acetylaldehyde with no free aldehyde groups, on exposure to light and air, is decomposed and paraldehyde fatal poisoning may occur. Tetracycline with expired shelf life cause fanconi syndrome due to epitetracycline, anhydotetracyclin and epianhydrotetracycline PRECIPITATION OR AGGRAVATION OF INFECTION: antimicrobial drugs, corticosteroids, cytotoxic drugs due to lowering of resistance of the body may produce theses effects indirectly. Latent or dormant infection may be activated. Broad spectrum antibiotics by disturbing the normal flora of the body may selectively encourage growth of some pathogens e.g., bacterial (staphylococcus, pseudomonas), fungal (candida) and viral (zoster virus) infections may occur after drug therapy. DRUGS INTERACTIONS: simultaneous administration of a number of drugs without taking into account their synergistic action can produce toxic effects. The above mentioned causes of drug toxicity are predictable and therefore, preventable. Intelligent application of principles of drug therapy may lead to lessening the incidence of serious toxic effects of drugs.

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.

Pharmacological Toxicity CNS depression (barbiturates) Anxiety Sedation Somnolence Coma Hypotension produced by nifedipine Tardive dyskinesia (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.

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

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

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

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

LIVER Acute hepatic injury Chronic hepatic disease 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)

KIDNEY Acute renal damage Non-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)

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)

SKIN & APPENDEGES Drug eruptions Acneform Pigmentation Eczematous Exfoliative dermatitis Erythema nodosum Urticaria Psoriasis Photosensitivity (sulphonamides, teracyclines) Erythema multiforme Steven Johnson syndrome (sulphonamides) Systemic lupus erythematosus (sulphonamides, grisefulvin, hydralazine) Alopecia (cytotoxic drugs, carbimazole, chloroquine)

Phototoxic reaction

Drug induced vasculitis

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

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)

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

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

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

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

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

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

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

Thank you!