DRUG TOXICITY

DRUG TOXICITYDr. Naila Abrar1LEARNING OBJECTIVESBy 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; andrecognize 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 EffectChange 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.4TYPESAcuteChronic

AbsoluteRelativeREASONS OF DRUG TOXICITYOver dosageImproper storagePrecipitation or aggravation of infectionsDrug interactionsOVER 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 failureIMPROPER 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 epianhydrotetracyclinePRECIPITATION 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. 6Dose-Dependent ReactionsPharmacological, 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 ToxicityCNS depression (barbiturates) Anxiety Sedation Somnolence ComaHypotension produced by nifedipineTardive 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 ToxicityAcetaminophen 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 EffectsIonizing radiation and many environmental chemicals are known to injure DNA, and may lead to mutagenic or carcinogenic toxicities.

Cancer chemotherapeutic agents

Functional alterationDelirium with high dose of atropine

Structural alteration/damageHepatic necrosis with high dose of paracetamolDRUG TOXICITY IN VARIOUS ORGAN SYSTEMSLiverKidneysHematopoietic system SkinGastrointestinal tractNervous systemCardiovascular systemLungsEyesLIVERAcute hepatic injuryHepatocellular necrosisBy direct action (halothane, chloroform)Indirect action by interference with certain metabolic pathways (MTX)Cholestatic jaundice (OCP)Hypersensitivity (indomethacin, ketoconazole)Chronic hepatic diseaseChronic active hepatitis (isoniazid, methyldopa, paracetamol, sulphonamides)Hepatic cirrhosis (ethyl alchohol)KIDNEYAcute renal damageGlomerulonephritis (phenylbutazone, hydralazine)Acute tubular necrosis (aminoglycosides, amphotericin, paracetamol)Acute interstitial nephritis (sulphonamides, thiazides)Non-acute renal damageNephrotic 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 SYSTEMBone marrow depression (chloramphenicol)Aplastic anemia, thrombocytopenia. granulocytopenia, pancytopeniaMegaloblastic anemia (phenytoin, MTX)Hemolytic anemia (methyldopa, phenytoin, levodopa, mefenamic acid)Agranulocytosis (cytotoxic drugs, clozapine)Thrombocytopenia (cyotoxic drugs)Leukemia (immunosuppressive therapy)

SKIN & APPENDEGESDrug eruptionsAcneformPigmentationEczematousExfoliative dermatitisErythema nodosumUrticariaPsoriasis

Photosensitivity (sulphonamides, teracyclines)

Erythema multiformeSteven Johnson syndrome (sulphonamides)Systemic lupus erythematosus (sulphonamides, grisefulvin, hydralazine)

Alopecia (cytotoxic drugs, carbimazole, chloroquine)

Phototoxic reaction

Drug induced vasculitis

GASTROINTESTINAL TRACTNauseaVomitingDiarrheaAbdominal cramps(digitalis, bromocriptine, levodopa, morphine, NSAIDS)GI bleeding (NSAIDS)Ulcer (indomethacin, corticosteroids)Pseudomembranous colitisNERVOUS SYSTEMExtra pyramidal symptoms (chlorpromazine, metoclopramide)Ototoxicity (aminoglycosides, furosemide, salicylates)Peripheral neuropathy (isoniazid)Hallucinations (digitalis)Convulsions (isoniazid, lignocaine)Ataxia (streptomycin, phenytoin, lithium)Nystagmus (phenytoin)

CARDIOVASCULAR SYSTEMCardiac arrhythmias (halothane, chloroform, amitriptyline, imipramine, digitalis, thioridazine)Hypertensive crises (clonidine, tyramine containing foods with MAOI)Myocardial depression (emetine, chloroform)LUNGSBronchoconstriction (beta blockers)Allergic form of asthma (penicillin, aspirin)Pulmonary fibrosis (methsergide, busulphan, nitrofurantoin)Pulmonary edema (I/V fluids)EYESOptic neuritis (ethambutol, quinine)Retinal damage (chloroquine, thioridazine)- bulls eye apperarance

Increased IOP (atropine, corticosteroids)

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

TOXIDROMESAnticholinergicsCholinesterase inhibitorsBeta blockersDigoxinOpioidsEthylene glycol & methanolAlcoholSedative hypnotic drugsAspirinAcetaminophenAmphetamines & other stimulants

PHARMACOVIGILANCEScience & activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problemPost marketing surveillanceDrug alerts, medical lettersChange in labels indicating restrictions, warnings etcTherapeutic drug monitoringRelation of plasma concentration to the effects of the drugLow therapeutic index Toxicity at higher concentrations even within TD

AminoglycosidesDigoxinLithium

Sample taken at steady state

Thank you!