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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

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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

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• 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

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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

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• 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

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• 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

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• 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

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• Other Organ Toxicities– Pulmonary toxicity

• Respiratory depression

• Pulmonary fibrosis

– Cardiotoxicity – Skeletal muscle damage – Skin rashes

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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

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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

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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

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Type Mechanism

Drug interactions with food Altered drug absorption.

Pharmaceutical interactions (drug incompatibilities)

Chemical reaction between drugs prior to their administration or absorption.

Pharmacodynamic interactions Additive, 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 absorption Altered gut motility or secretion.

  Binding or chelation of drugs.

  Competition for active transport.

Altered drug distribution Displacement from plasma protein binding sites.

  Displacement from tissue binding sites.

Altered drug biotransformation Altered hepatic blood flow.

  Enzyme induction.

  Enzyme inhibition.

Altered drug excretion Altered 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

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What type of drug interaction is this?

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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

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• 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