Drug Handling in kidney and liver disease

1. Drug Handling in kidney and liver disease Dr. Geoff Isbister

2. Drug Action • Drugs tend to be small lipid-soluble molecules • Drugs must get access to sites of action • Drugs tend to bind to tissues, usually protein molecules • Drugs alter the actions of enzymes, ion channels and receptors

3. Drug Action • ENZYME: example Angiotensin Converting enzyme inhibitors A I ----X---------->A II lowered A II -----> Reduced BP • ION CHANNELS: example Local Anesthetics Block Na channels--->Anesthesia

4. Receptor Binding • Receptors are specialised binding sites - often on cell surface- which have specificity for certain substances (incl drugs). Drugs may activate or block the receptor • Activation of the receptor changes the activity of the cell: eg adrenaline activates the beta 1 receptors in the heart and speeds up the heart • Drugs have selectivity for receptors: eg Histamine2 antagonists- reduce histamine-induced acid secretion and heal peptic ulcers

5. Pharmacokinetics • The study of the action of the body on the drugs • Pharmacokinetics is the study of the time course of concentrations of drug in the body • The way the body handles drugs determines the dose, route and frequency of administration • The handling of drugs by the body can be split into absorption, distribution and elimination

6. Pharmacokinetics • Rate of absorption determines the time to the peak concentration • The extent of absorption determines the height of the peak concentration and the AUC

7. Pharmacodynamics • The response of the tissue to the active free concentration of drug present at the site of action • May also be changed by disease processes

8. Type of Disease • Renal disease – the nature of the disease doesn’t matter very much, the main determinant is the decline in GFR

9. Routes of elimination - Kidney • Some drugs are water-soluble and are eliminated directly by the kidney • Molecules with MW below 20000 diffuse into glom filtrate. • examples: gentamicin, digoxin, atenolol • involves no chemical change to the drug • in most cases occurs by filtration (and depends on the GFR) • in a few cases (eg penicillin) some tubular secretion contributes to elimination • Highly lipid-soluble drugs are filtered into the tubules and then rapidly re-absorbed • High protein binding will reduce filtration

10. Practical issues - treating real patients • Assessing kidney function is straightforward • serum creatinine reflects GFR • relationship between serum creatinine and GFR changes with age

11. Effects of age on renal function • There is a steady and proportional decline in average GFR with increasing age • However the serum creatinine remains unchanged • Why is this?

12. Effects of age on renal function (constant serum creatinine of 0.10 mmol/l)

13. Multiple Dosing - renally excreted drug Approx 5 half-lives to reach steady state Elderly

14. Drug Types • Water soluble - excreted unchanged (by the kidney) • Lipid soluble • filtered but fully reabsorbed in the kidney • metabolised to polar products (filtered without reabsorption)

15. A number of drugs are handled by tubular mechanisms • Two mechanisms • Active tubular secretion – important • Acidic drugs – frusemide, methotrexate, penicillins, salicylate, uric acid, probenecid • Bases – amiloride, morphine, quinine • Passive diffusion • After filtration lipid-soluble drugs will be re-absorbed passively. • Will depend on degree of ionization at certain pH levels

16. Practical Examples of dosing in renal failure

17. Gentamicin • Practice is changing - trend to once/daily dosing • The interval between doses may be >24 hours in the presence of renal failure and in the elderly • Toxicity relates to trough concentrations, particularly with prolonged therapy • Toxicity mainly affects the kidney and 8th cranial nerve

18. Digoxin • In the presence of renal impairment the dose must be reduced • The dose is given once daily • Elderly people almost invariably have some renal impairment, so they usually require dose reduction - normally a halving of dose compared with young people

19. Summary • Reduced elimination of drugs from the body in the elderly will lead to accumulation and toxicity • Disease and old age lead to reduced renal elimination of water-soluble drugs • Co-morbidity and concomitant drug therapy

20. Hepatic Disease • Metabolism by the Liver : • role of metabolism • types of metabolism • Clearance • hepatic clearance • Liver disease

21. Type of Disease • In liver disease the type of disease does matter: • Hepatitis – not much effect • Biliary obstruction – not much effect (initially) • Cirrhosis – has major effects on drug handling

22. Assessing Function • Assessing liver function is hard - no single test of how well the liver metabolises drugs • Drug metabolism most likely to be impaired when the patient has cirrhosis, and has evidence of coagulation disturbances and low albumin

23. Biotransformation • Majority produces metabolites that are : • less active • more polar and water soluble • Minority : • Pro-drugs that require metabolism to be active • active metabolites • more toxic (mutagenic, teratogenic etc.)

24. Drugs with Active Metabolites

25. Types of Metabolism • Phase 1 Reactions • usually convert the parent drug into a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Metabolite is usually inactive. • Phase 2 Reactions - Conjugation • an endogenous substrate (glucuronic acid, sulfuric acid, acetic acid, or amino acid) is attached to a functional group on the drug or phase I metabolite.

26. Absorption Elimination Metabolism Lipophilic Hydrophilic Phase I Phase II conjugate Drug Drug metabolite with modified activity conjugate Drug Inactive drug metabolite conjugate Drug

27. Phase I Reactions • Mixed Function Oxidase: • P450 enzyme system • induced and inhibited • hydroxylation and demethylation • family of isoenzymes • Monoamine Oxidase : catecholamines • Dehydrogenases :eg. Alcohol dehydrogenase

28. Phase I - P450 System • FRAGILE • High specificity • Low volume • Energy dependent • First affected by liver disease

29. Cytochrome P450 System Not a single entity Family of related isoenzymes (about 30) Important for drug interactions : Enzyme induction Enzyme inhibition Genetic polymorphism

30. Phase II ReactionsConjugation • Glucuronidation • Sulfation • Acetylation • Glutathione • Glycine

31. Phase II ReactionsConjugation • ROBUST • High volume • Low specificity • Not energy dependent • Less effected by liver disease

32. Paracetamol toxicity – failure of Phase II Conjugation pathway saturates  oxidation by P450 cytochrome pathway Formation of toxic metabolite NAPQI Initially detoxified by glutathione NAPQI accumulates and binds to tissue macromolecules - cell death Glutathione depletion

33. Sites of Biotransformation • Liver • Lung • Kidney • Large and small intestine • Placenta

34. Liver Systemic circulation 0.2 fraction escaping extraction (1-E) 1.0 0.8 fraction extracted and metabolised (E) Hepatic Clearance

35. Extraction Ratio • High extraction ratio : • Effectively removed by the liver • Limited by hepatic blood flow • High first pass metabolism • Eg. Lignocaine, propranolol, diltiazem, morphine • Less effected by changes in intrinsic clearance, such as induction and inhibition

36. Extraction Ratio • High Extraction ratio • Clearance approximates organ blood flow • Low Extraction ratio • Clearance proportional to free drug in the blood and intrinsic clearance of the liver

37. Liver Disease • Severe disease before major effects on metabolism • Liver Disease : • Hepatocellular disease • Decrease liver perfusion • Type of metabolism : • Phase I • Phase II

38. Disease Factors • Disease Type : • Acute hepatitis – little effect • Biliary Obstruction – little effect • Chronic Active Hepatitis – major effects • Cirrhosis – major effects • Indicators : • Established cirrhosis, varices, splenomegaly, jaundice, increased prothrombin time.

39. Disease Factors • Poor perfursion • Cardiac failure : limits blood flow so effects those with high extraction ratios • Eg. Lignocaine • Combination with ischaemic liver injury • Other low perfusion states : • Other causes of shock

40. Recent theories to account for impaired metabolism in cirrhosis • Intact hepatocyte mass • Sick cell theory • Impaired drug uptake/shunting theory • Oxygen limitation theory

41. Type of Metabolism • Phase I, mainly P450 • Affected first • Phase II • Severe disease before any effect • Eg. Paracetamol poisoning.

42. Other considerations • Renal function may be impaired in moderate to severe liver disease • Creatinine levels are not predictive • Pro-drug metabolism impairment • Eg ACE inhibitors • Pharmaco-dynamic disturbances • Tissues may be excessively sensitive to even low concentrations of the drug – eg morphone in the brain in the presence of severe liver disease