Role of Pharmacokinetics in Drug toxicity (1).pptx

Toxicokinetic process and its management

1. Role of pharmacokinetics in drug toxicity management Presenter: Dr. Saurabh Maurya (JR-3) Moderator: Dr. Shoebul Haque (SR) Peer Support: Dr. Shreedhar Angadi ( JR-3) Department of Pharmacology and Therapeutics King George’s Medical University Lucknow (U.P.) India Email- [email protected] 22-02-2025 1 Dr Saurabh Maurya

2. Content Introduction Toxicokinetic processes Clinical significance Pharmacokinetic parameters and toxicity Types of drug toxicity Pharmacokinetic approach to minimize the toxicity Summary 22-02-2025 2 Dr Saurabh Maurya

3. Specific learning o bjectives At the end of this teaching-learning session, the audience will be able to : Define toxicity Differentiate between the adverse effects and toxic effects Understand toxicokinetic processes Understand the role of pharmacokinetics in drug toxicity E numerate the role of pharmacokinetic parameters in managing toxicity 22-02-2025 3 Dr Saurabh Maurya

4. Pharmacokinetics Movement of drugs in and alteration of drug by body What the body does to a drug Include absorption, distribution, metabolism and excretion 22-02-2025 Dr Saurabh Maurya 4

5. 22-02-2025 5 Dr Saurabh Maurya Unintended , noxious or undesirable harmful effects of a drug administered

6. Examples: side effects and toxic effects Drug Side effects Toxic effects Morphine Drowsiness, constipation Opioid overdose : r espiratory depression Aspirin Gastric irritation Salicylate toxicity : m etabolic a cidosis , tinnitus 22-02-2025 Dr Saurabh Maurya 6

7. Toxicokinetic process 22-02-2025 7 Dr Saurabh Maurya

8. Effect of a bsorption on drug t oxicity Faster absorption causes rapid peak plasma level and results in high toxicity risk Slow absorption causes prolonged exposure leads to cumulative toxicity Faster g astric e mptying accelerate absorption High lipid soluble drugs are more absorbed and has higher risk of toxicity 22-02-2025 Dr Saurabh Maurya 8

9. Effect of distribution on d rug t oxicity Factors involved in distribution related toxicity A . Volume of distribution (Vd) High v olume of distribution (Vd) increases tissue accumulation Leads to delayed toxicity Not easily removed by hemodialysis Example: Chloroquine → retinal toxicity 22-02-2025 Dr Saurabh Maurya 9

10. B . Protein Binding High bound drugs are largely restricted to vascular compartment Bound fraction is not available for action Hypoalbuminemia : Increased free drug, higher toxicity ( e.g . Phenytoin) Drug Displacement: Highly bound drugs cause sudden toxicity ( e.g . Sulfonamides displace w arfarin ) 22-02-2025 Dr Saurabh Maurya 10

11. Effect of metabolism on drug toxicity Metabolic processes may change from first order to zero order as dose increases e .g. Ethanol At minimum concentration At high concentration Follows first order kinetics Constant fraction of drug is metabolised Follows zero order kinetics Alcohol dehydrogenase gets saturated so rate of metabolism becomes constant Fixed amount is metabolised 22-02-2025 11 Dr Saurabh Maurya

12. Case scenario : A 45 year old male with epilepsy, well controlled on phenytoin 300 mg daily, accidentally takes 600 mg instead of his regular dose. With in few hours, he develops dizziness, ataxia, slurred speech, confusion, nystagmus. Laboratory findings: Serum phenytoin level : 35 mcg/mL (therapeutic range: 10-20 mcg/mL) 22-02-2025 12 Dr Saurabh Maurya

13. Phenytoin Metabolised by CYP2C9, CYP2C19 At therapeutic dose Follows first order kinetics At higher dose Enzymes get saturated Elimination becomes zero order 22-02-2025 13 Dr Saurabh Maurya

14. Enzyme inhibition and toxicity Enzyme Inhibitor Affected Drug Enzyme Inhibited Toxicity Fluconazole Warfarin CYP2C9 Bleeding, elevated INR Ciprofloxacin Theophylline CYP1A2 Seizures, CNS toxicity Clarithromycin Statins (e.g., Atorvastatin) CYP3A4 Rhabdomyolysis, myopathy Itraconazole Cyclosporine CYP3A4 Nephrotoxicity, immunosuppression

15. Enterohepatic cycling 22-02-2025 15 Dr Saurabh Maurya

16. Excretion related toxicity 1. Renal impairment Drug accumulation leads to toxicity e g . Aminoglycoside nephrotoxicity 2. Biliary excretion and enterohepatic circulation Prolong drug action leads to higher risk of toxicity e g . NSAID induced liver damage 22-02-2025 16 Dr Saurabh Maurya

17. 3. Urine pH manipulation T he pH of urine can affect drug elimination by altering drug solubility. Acidic urine promotes the reabsorption of weak acids, while alkaline urine promotes the excretion of weak acids 22-02-2025 Dr Saurabh Maurya 17

18. Types of drug toxicity On-target toxicity Off-target toxicity eg . Barbiturates eg . terfenadine 22-02-2025 18 Dr Saurabh Maurya

19. Parameter Toxic Implications Example Half Life Long t 1/2 Drug accumulation increased toxicity risk Amiodarone t1/2 50 days Thyroid toxicity AUC Higher AUC Prolonged drug action Higher toxicity risk Methotrexate in renal failure Bone marrow suppression C max Higher Cmax Higher toxicity risk Aminoglycosides ototoxicity T max Faster Tmax Rapid toxicity onset Immediate-release theophylline s eizure in overdose Bioavailability High Higher toxicity risk Grape fruit juice increases bioavailability of simvastatins 22-02-2025 19 Dr Saurabh Maurya Role of pharmacokinetics in drug toxicity

20. Clinical Scenario A 65-year-old male with hyperlipidemia was prescribed Simvastatin 40 mg once daily. He regularly consumed a large glass of fruit juice , and after a few weeks, developed muscle pain and weakness. What could be the reason for new symptoms? 22-02-2025 20 Dr Saurabh Maurya

21. 1 . Activated c harcoal for GI decontamination Example: Carbamazepine, theophylline o verdose It binds unabsorbed drugs in the gut, reducing toxicity. Prevents further absorption into the bloodstream. Administered orally in acute toxicity cases. Early use can significantly reduce drug exposure . 22-02-2025 21 Dr Saurabh Maurya Approach to minimize drug toxicity

22. 2. Renal function monitoring D ose reduction in CKD Example : Aminoglycosides ( gentamicin, amikacin, tobramycin ) Toxicity risks : Nephrotoxicity Prevention : Monitor serum creatinine , creatinine clearance , eGFR Management: Extended-interval dosing based on renal function 22-02-2025 Dr Saurabh Maurya 22

23. 3. Hepatic function monitoring D ose reduction in liver disease Example : Paracetamol ( a cetaminophen ) overdose Toxicity Risk: Hepatotoxicity ( NAPQI accumulation ) Prevention: Avoid high doses in liver impairment Management: N-acetylcysteine as an antidote 22-02-2025 Dr Saurabh Maurya 23

24. 4. Avoiding drug-drug i nteractions CYP enzyme interactions Example: Warfarin with CYP Inhibitors ( fluconazole, amiodarone, ciprofloxacin) Toxicity Risk: Bleeding due to increased warfarin levels Prevention: Avoid co-administration, monitor INR closely Management: Reduce warfarin dose if needed 22-02-2025 Dr Saurabh Maurya 24

25. 5 . Avoid drug-food i nteractions Example: Grapefruit juice with statins (simvastatin, atorvastatin) Toxicity Risk: Increased bioavailability → r habdomyolysis Mechanism: CYP3A4 inhibition , leading to high statin levels Prevention: Avoid grapefruit juice with statins 22-02-2025 Dr Saurabh Maurya 25

26. Examples of drug-food interaction and toxicity Drug Food Propranolol Bioavailability is higher when taken with meal MAO inhibitors Tetracyclines Tyramine rich foods ( Cheese, cured meats) Itraconazole Food enhances the absorption Metronidazole Alcohol, Metronidazole inhibits alcohol dehydrogenase leading to acetaldehyde accumulation 22-02-2025 26 Dr Saurabh Maurya

27. 6 . Therapeutic drug m onitoring (TDM) TDM is essential for drugs with a narrow therapeutic index (NTI) to avoid toxicity Drug Class Example Toxicity concern Aminoglycosides Gentamicin, Amikacin Nephrotoxicity, Ototoxicity Antiepileptics Phenytoin, Carbamazepine CNS Depression, Ataxia Digoxin Digoxin Cardiotoxicity Theophylline Theophylline Seizures, arrhythmias 22-02-2025 27 Dr Saurabh Maurya

28. 7 . Urinary a lkalinization For acidic drugs like salicylate toxicity Example: Aspirin (salicylate poisoning) Management: IV sodium b icarbonate → alkalinizes urine → increases salicylate excretion 22-02-2025 28 Dr Saurabh Maurya

29. 8 . Haemodialysis Effective for toxic drug removal Examples: Methanol, ethylene glycol, lithium overdose Goal: Rapidly clear toxic metabolites , reduce toxicity 22-02-2025 Dr Saurabh Maurya 29

30. 9 . Genetic polymorphisms a ffecting d rug m etabolism Example: Isoniazid (INH) toxicity in slow acetylators Risk : peripheral neuropathy, hepatotoxicity Prevention : genetic testing for N-acetyltransferase 2 (NAT2) polymorphisms 22-02-2025 30 Dr Saurabh Maurya

31. Summary Pharmacokinetics predicts and prevents toxicity by managing half-life, Vd , metabolic pathways, and clearance. Pharmacokinetics enhances drug safety by guiding dose adjustments, monitoring, antidote use, elimination methods, and tailored therapy. ADME factors like absorption, distribution, metabolism, excretion affect toxicity Toxicity Types: On-target, off-target, hypersensitivity, idiosyncratic Management Strategies: Dose adjustments, avoiding interactions, TDM, enhancing elimination, genetic testing 22-02-2025 Dr Saurabh Maurya 31

32. Specific learning o bjectives a chieved Learnt to differentiate adverse effect and toxic effect Defined toxicokinetic processes and their clinical implications Understood the role of pharmacokinetic parameters in drug toxicity Explained how pharmacokinetic parameters help in managing toxicity 22-02-2025 Dr Saurabh Maurya 32

33. References Katzung BG, Trevor AJ. Basic and Clinical Pharmacology. 15th ed. New York: McGraw Hill; 2021 Bruntal LL, Hilal-Dandan R, Knollmann BC, editors. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14 th ed. New York: McGraw Hill; 2022. p. 155-165 Tripathi KD, Essentials of medical pharmacology. 9 th ed. New Delhi: Jaypee Medical Publishers; 2023. p. 15-105 22-02-2025 33 Dr Saurabh Maurya

34. Questions Difference between side effect and toxicity? What impact does a high volume of distribution ( Vd ) have on drug toxicity? What is the difference between on target and off target toxicity? What are the different pharmacokinetic approaches to minimize toxicity? 22-02-2025 34 Dr Saurabh Maurya

35. THANK YOU 22-02-2025 35 Dr Saurabh Maurya