Drug toxicity

1. DRUG TOXICITY By Imad Nmeir Supervised by Dr. Rita Mouawad HOLY-SPIRIT UNIVERSITY OF KASLIK Faculty of sciences Department of pharmacology and cosmetology 1

2. TABLE CONTENT Introduction • Toxicology and 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 and its science3

4. TOXICOLOGY AND PHARMACOLOGY ToxicologyPharmacology Kinetic Dynamic Dose- response Receptors Common fields of study 4

5. DRUGS Therapeutic • Used correctly Toxic • Supratherapeutic- doses • Genetic predispositions • Inappropriate use • Non-selective actions 5

6. ADVERSE EFFECTS OF DRUGS 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 DRUG TOXICITY Introduction7

8. FACTORS AFFECTING DRUG TOXICITY Patient’s Age Genetic factors Pathological conditions Dose Drug-drug interaction 8

9. EXAMPLES  The very young 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 IS NOT 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 “On Target” 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. OTHER CLASSIFICATIONS Harmful immune response 12

13. MECHANISM OF DRUG TOXICITY On-Target adverse effect13

14. CAUSES OF ON-TARGET EFFECTS Exaggeration in pharmacologic action Alteration in the pharmacod ynamics Alteration of the pharmaco kinetics Dosing error 14

15. SUBCLASS AND IMPORTANT DETAILS 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 COA REDUCTASE 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 DRUG TOXICITY Off-Target adverse effect18

19. REASONS FOR OFF-TARGET ADVERSE 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 AND S THALIDOMIDE  Effective sedative  S-thalidomide is a potent teratogen  Cause of this is: anti-angiogenic property of S- thalidomide 21

22. REASONS FOR OFF-TARGET ADVERSE 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  Beta1 receptors: 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 DRUG TOXICITY Production of toxic metabolites24

25. DRUG METABOLISM Metabolized in the liver Gives active compound Undesired actions 25

26. EXAMPLE: LOSARTAN AND EBASTIN  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 Acetaminophen toxicity27

28. WITH NORMAL DOSES Acetaminophen enter through 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 DOSE ADMINISTERED 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

Drug toxicity

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