Adverse effect of drugs

1. 59-291 Section 1, Lecture 9 Adverse effect of drugs • Excessive Pharmacologic Effects • overdoing the therapeutic effect • Atropine –muscarinic antagonist,desired therapeutic • Effect: reduction of gastric acid secretion but its side effects (through the same mechanism) dry mouth and urinary retention • avoid by lowering the dose

2. Hypersensitivity reactions (Drug allergies) • Type I: Mediated by IgE, drug acts as a hapten • Urticaria (hives), • atopic dermatitis, • anaphylactic shock. • Type II: Cytolytic reaction, Mediated by IgG and IgM, involves complement • Hemolytic anemia • Thrombocytopenia • Drug-induced lupus erythematosus

3. Type III: mediated by immune complexes; deposition of Ag-Ab complexes in vascular endothelium leads: • Inflammation • Lymphadenopathy • Fever (serum sickness) • e.g. Steven-Johnson syndrome; sever skin rash with immune vascultitis • Type IV: delayed hypersensitivity reactions; mediated by sensitized lymphocytes • Ampicillin-induced skin rash in patients with viral mononucleosis

4. Adverse Effects on Organs • Side effects are caused by a mechanism other than that resulting in the therapeutic effect. • Toxicity to vital organs such as liver, Kidneys • Toxicity may not be apparent until the significant organ damage has occurred • Laboratory tests should be performed to monitor the patients receiving the drugs

5. Hematopoietic Toxicity • The most frequent types of drug-induced toxicity; reversible upon drug withdraw • Agranulocytosis • Anemia • Thrombocytopenia • Pancytopenia • Aplastic anemia • e.g. Chloramphenicol; • Hypersensitivity reaction against bone marrow progenitor cells • Blocking action of ferrochelatase enzymes

6. Hepatotoxicity • Cholestatic hepatotoxicity • Caused by hypersensitivity reaction • Inflammation • Stasis of biliary system • Hepatocellular toxicity • Caused by a toxic drug metabolite • Example: Acetaminophen toxic metabolites • Serum transaminase levels should be monitored

7. Nephrotoxicity (Renal toxicity) • Interstitial nephritis • Renal tubular necrosis • Crystalluria • Nephrotoxicity reduces drug clearance, thereby higher plasma concentration of drug leading to more toxicity • Example; Cisplatin • Bladder toxicity • Less common than renal toxicity • Hemorrhagic cystitis

8. Other Organ Toxicities • Pulmonary toxicity • Respiratory depression • Pulmonary fibrosis • Cardiotoxicity • Skeletal muscle damage • Skin rashes

9. Idiosyncratic reactions • Unexpected drug reactions caused by a genetically determined susceptibility • Glucose-6- phosphate dehydrogenase deficiency • Hemolytic anemia when they are exposed to • Oxidizing drugs • Primaquine • Sulfonamides

10. Rare- mainly caused by anticancer agents Intersitital nephritis, - Crystalluria- Haemorraghic cystitis Bone marrow toxicity Red blood cells are destroyed Inflammation of the biliary system Some drug toxic to liver tissue itself

11. Drug Interactions • Pharmaceutical interactions • Chemical reaction prior to administration • Pharmacodynamic interactions • Additive effect • Synergistic effect • Antagonistic effect • Pharmacokinetic interactions • Altered drug absorption • Altered drug distribution • Altered drug biotransformation • Altered drug excretion

12. Table 4-3. Types and Mechanisms of Drug Interactions

13. What type of drug interaction is this?

14. Practice Questions • Define the synergistic effect and explain how it is different from additive effect • The effect of two drugs is greater than the sum of individual drugs. • Additive effect is equal to the sum of the individual drugs

15. List adverse effects of drugs on liver and explain what is the cause? • Cholestatic hepatotoxicity • Hypersensitivity mechanism>> inflammation • Hepatocellular toxicity • Caused by toxic drug metabolites