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 ( ) 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
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.

5. TYPES
Acute
Chronic
Absolute
Relative

6. 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.

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
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.

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 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)

14. 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)

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
Erythema nodosum
Urticaria
Psoriasis
Photosensitivity (sulphonamides, teracyclines)
Erythema multiforme
Steven Johnson syndrome (sulphonamides)
Systemic lupus erythematosus (sulphonamides, grisefulvin, hydralazine)
Alopecia (cytotoxic drugs, carbimazole, chloroquine)

22. Phototoxic reaction

23. Drug induced vasculitis

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

25. 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)

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

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

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

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

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

31. 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

32. 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

33. Thank you!