1. 1 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 59-291 Section 1, Lecture 9

2. 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. 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. 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. 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. 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. 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. 8 Other Organ Toxicities –Pulmonary toxicity Respiratory depression Pulmonary fibrosis –Cardiotoxicity –Skeletal muscle damage –Skin rashes

9. 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. 10 Bone marrow toxicity Red blood cells are destroyed Inflammation of the biliary system Some drug toxic to liver tissue itself Intersitital nephritis, - Crystalluria- Haemorraghic cystitis Rare- mainly caused by anticancer agents

11. 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. 12 TypeMechanism Drug interactions with foodAltered drug absorption. Pharmaceutical interactions (drug incompatibilities) Chemical reaction between drugs prior to their administration or absorption. Pharmacodynamic interactionsAdditive, synergistic, or antagonistic effects on a microbe or tumor cells. Additive, synergistic, or antagonistic effects on a tissue or organ system. Pharmacokinetic interactions Altered drug absorptionAltered gut motility or secretion. Binding or chelation of drugs. Competition for active transport. Altered drug distributionDisplacement from plasma protein binding sites. Displacement from tissue binding sites. Altered drug biotransformationAltered hepatic blood flow. Enzyme induction. Enzyme inhibition. Altered drug excretionAltered biliary excretion or enterohepatic cycling. Altered urine pH. Drug-induced renal impairment. Inhibition of active tubular secretion. Table 4-3. Types and Mechanisms of Drug Interactions

13. 13 What type of drug interaction is this?

14. 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. 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