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Drug toxicity
This document discusses drug toxicity and its underlying mechanisms. It covers several topics: - Drug toxicity can occur through both on-target and off-target adverse effects as drugs may bind to unintended receptors. Factors like dosage, genetics, and drug interactions influence toxicity. - On-target effects arise from exaggerated pharmacologic action on the intended receptor. Off-target effects occur when a drug binds unrelated receptors. - Drugs and their metabolites may also cause toxicity. For example, acetaminophen is normally detoxified but high doses overwhelm the pathways, allowing a toxic metabolite to accumulate and damage liver cells. - The document uses examples like statins, antihistamines, and thalidom
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Drug toxicity
- 1. DRUG TOXICITY By ImadNmeir Supervised by Dr. Rita Mouawad HOLY-SPIRIT UNIVERSITY OF KASLIK Faculty of sciences Department of pharmacology and cosmetology 1
- 2. TABLE CONTENT Introduction • Toxicologyand pharmacology • Drug toxicity • Adverse effects of drugs Mechanism • Introduction • Factors affecting drug toxicity • Classification • On-target adverse effect • Causes • Miscellaneous • Off-target adverse effect • Reason as drug causing it • Reason as body causing it • Production of toxic metabolism • Drug metabolism Acetaminophen toxicity • Biotransformation in normal dose levels • Biotransformation with large doses 2
- 3. INTRODUCTION Drug toxicity andits science3
- 4.
- 5. DRUGS Therapeutic • Used correctly Toxic •Supratherapeutic- doses • Genetic predispositions • Inappropriate use • Non-selective actions 5
- 6. ADVERSE EFFECTS OFDRUGS All drugs have adverse effects Most are undesirable From nuisance to life threatening Subject of focus of drug toxicology Inappropriate drug behavior 6
- 7. MECHANISM OF DRUGTOXICITY Introduction7
- 8. FACTORS AFFECTING DRUGTOXICITY Patient’s Age Genetic factors Pathological conditions Dose Drug-drug interaction 8
- 9. EXAMPLES The veryyoung and the very old may be more susceptible to the toxic effects of a drug because of age-dependent differences in pharmacokinetic profiles or in drug metabolizing enzymes. Liver or kidney dysfunction will affect drug pharmacokinetics Genetic difference may yield difference in drug metabolism or in receptor activity, as well differences in activities of repair mechanism 9
- 10. CLINICAL DETERMINATION ISNOT STRAIGHT FORWARD a patient treated with antibiotic may develop skin rash, high fever, and other morbidities for several reasons: Allergic reactions to antibiotics Recurrence of infection 10
- 11. DRUG TOXICITY CLASSIFICATION “OnTarget” adverse effect Drug binding in its intended receptor Inappropriate posology or Inadequate kinetics or Incorrect tissue “Off Target” adverse effect Binding to a receptor that it was not intended 11
- 12.
- 13. MECHANISM OF DRUGTOXICITY On-Target adverse effect13
- 14. CAUSES OF ON-TARGETEFFECTS Exaggeration in pharmacologic action Alteration in the pharmacod ynamics Alteration of the pharmaco kinetics Dosing error 14
- 15. SUBCLASS AND IMPORTANTDETAILS OF ON- TARGET EFFECTS May expose unknown functions of the biological target Drug action on the same receptor but on different tissue than the target one 15
- 16. EXAMPLE: HMG COAREDUCTASE INHIBITOR Used to decrease blood cholesterol levels Target organ: liver Inhibition of HMG CoA reductase Rate limiting step in isoprenoid synthesis Have muscle toxicity as side effect HMG CoA reductase is important for muscle protein posttranslational modification regulation Lipidation through geranyl-geranylation 16
- 17. EXAMPLE: ANTIHISTAMINE DIPHENHYDRAMINE Used to reduce allergic reaction Minimize histamine release by interacting with H1 receptors. Pass the blood-brain barrier Causes drowsiness by interacting with H1 receptor in the brain. 17
- 18. MECHANISM OF DRUGTOXICITY Off-Target adverse effect18
- 19. REASONS FOR OFF-TARGETADVERSE EFFECT FROM DRUGS PERSPECTIVE Rare are the rugs with a single molecular targets. The presence of enantiomers Each enantiomer is treated as a compound Different enantiomers have different affinities which give different functions 19
- 20. EXAMPLE: ANTIHISTAMINE TERFENADINE Inhibits histamine release in the blood Also inhibits cardiac potassium channels Causes fatal cardiac arrhythmias Withdrawn from the market Now usage of fexofenadine Have affinity to cardiac potassium channels but to a much lesser degree than terfenadine 20
- 21. EXAMPLE: R ANDS THALIDOMIDE Effective sedative S-thalidomide is a potent teratogen Cause of this is: anti-angiogenic property of S- thalidomide 21
- 22. REASONS FOR OFF-TARGETADVERSE EFFECTS FROM BODY PERSPECTIVE Unintentional activation of a different receptor other than the target one. Usage of genetically modified animals which lack the target receptor. 22
- 23. EXAMPLE: BETA-BLOCKERS Beta1receptors: causes increase in heart rate and myocardium contractility Beta2 receptors: smooth muscle relaxation and dilatation of these tissues Some Beta1 antagonist exert activity on beta 2 receptors May cause airway constriction with asthma patients Non-selective Beta blockers are not given to these patients then 23
- 24. MECHANISM OF DRUGTOXICITY Production of toxic metabolites24
- 25. DRUG METABOLISM Metabolized in theliver Gives active compound Undesired actions 25
- 26. EXAMPLE: LOSARTAN ANDEBASTIN Losartan is converted to the active E3174 Ebastin is converted to carebastine Both are active inside the body and may cause damage. 26
- 27. ACETAMINOPHEN Mechanism of Acetaminophentoxicity27
- 28. WITH NORMAL DOSES Acetaminophen enterthrough the digestive tract Heavily metabolized by the liver by Liver enzymes P450 will metabolize it into intermediate “N- acetyl-p- benzoquinoneimine (NAPQI)” NAPQI is then immediately conjugated with glutathione Then it is further conjugated with glucuronate and sulfate Finally it is excreted from the body 28
- 29. WITH HIGH DOSEADMINISTERED The high levels of acetaminophen will saturate the conjugation enzymes First the glucuronate transferase and the sulfate transferase will be saturated This will eventually saturate the glutathione transferase When that happens high levels of NAPQI will accumulate inside the cell NAPQI will react with other hepatic proteins giving other toxic compounds This will cause hepatotoxicity and will cause death This is solved by giving the patient N-acetylcysteine 29