Drugs and The Liver

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Drugs and The Liver

  1. 1. • Pharmacokinetics of many drugs are altered in hepatic diseases • The extent of alteration depends on – The elimination pathway of the drug & – The severity of the hepatic disease • Awareness on the disease is very important.
  2. 2. Relationship ? Clinical application?
  3. 3. • If AST ↑ → • If ALT ↑ → indicates liver damage • If plasma protein (albumin) ↓ → indicates ↓ synthetic capacity of the liver. • but none of the tests directly measure the reflection of the disease severity.
  4. 4. • Yes .. It depends on the type of the hepatic disease as well • for example – Acute viral hepatitis – has very little effect on drug clearance .. But – Chronic hepatitis – effects on drug pharmacokinetics depending on degree of disease severity (eg. degree of cirrhosis) • It also depends on the extraction ratio of the drug by the liver.
  5. 5. • Mostly based on Child-Pugh Score • But some based on – Albumin level Best method – PT (Prothrombin time) May be useful – Bilirubin level
  6. 6. Child-Pugh classification of prognosis in cirrhosis Score 1 2 3 Encephalopathy None Mild Marked PBC/sclerosing cholangitis < 68 68-170 > 170 Other causes of cirrhosis < 34 34-50 > 50 Albumin (g/L) > 35 28-35 < 28 Prothrombin time (seconds prolonged) <4 4-6 >6 Ascites None Mild Marked Bilirubin (μmoL/L) Add the individual scores: < 7 = Child's A, 7-9 = Child's B, > 9 = Child's C
  7. 7. Survival in cirrhosis Survival % Child-Pugh Grade 1 year 5 years 10 years Hepatic death (%) A 82 45 25 43 B 62 20 7 72 C 42 20 0 85
  8. 8. Changes in bioavailability
  9. 9. • Bioavailabilty 20% means that – 100 mg (oral) of drug A = 20 mg (IV) of the same drug • One of the reasons of low bioavailability is “high first pass extraction”.
  10. 10. 1. Oral dose need to be ↓ severe hepatic disease because – There will be ↓ in 1st pass extraction →↑ bioavailability 2. In cholestasis – – Bioavailability of lipophilic drugs will be ↓ (eg. ciclosporin)
  11. 11. • Mostly concerned with the individual drug’s – – Plasma protein binding – Tissue binding – Lipid solubility
  12. 12. • In hepatic diseases, • Plasma protein (albumin) can be ↓ • Plasma protein binding of drugs can be ↓ • Free fraction of the drug can be ↑ • There can be increased drug action and effect.
  13. 13. • Actually, elimination of drugs mainly depend on renal excretion, therefore renal function mainly determines. • But for drugs which are mainly matabolised by liver, hepatic function is important for their clearance.
  14. 14. • Define as the product of blood flow (delivery of the drug to the organ of removal) and the extraction ratio. ER = Cin-Cout Cin 100-20 = 80 % = 100
  15. 15. • For High ER (i.e. ER > 70%) drugs, • Eg. Morphine (ER is 0.7 or 70%) • It is a drug mainly eliminated by liver, when it is given orally, it delivers 1st to liver, can face with first pass effect. • Its Bioavailability will be 1-ER = 0.3 or 30%
  16. 16. • In severe cirrhosis – – There is reduction in the ability of the liver to metabolize – Presence of porto systemic shunts – Bioavailability can become – 100% – Which can lead to adverse effects… • Liver diseases can change ER ratio & • There will be clinically significant changes on bioavailability of high ER drugs.
  17. 17. • In cholestasis → bile flow ↓ → accumulation of bile in liver → injury to hepatocytes + • In advanced cases of biliary cirrhosis → there is reduction in intrinsic clearance activity of liver • If bile flow is disturbed → there will be disturbance of Enterohepatic circulation (which is useful for action of some drugs)
  18. 18. • 2 phases of drug metabolism – Phase I – functionalization phase – Phase II – conjugation reactions • Phase II is a true detoxification pathway, – resulting water soluble products that are easily excreted. • Process of phase II reactions – glucoronidation, sulphation, methylation, acetylation, glutathione conjugation.
  19. 19. CYP • The enzyme used – CYP superfamily • Around 500 enzymes CYP Cytochrome P450 3 A 4 Individual gene/enzyme subfamily family
  20. 20. Clinical significance • CYP 3A4 – most important CYP involved in 50% of currently used drugs • There is strong correlation between CYP score and extent of hepatic metabolisms • In cirrhosis – CYP level can be ↓
  21. 21. • formation of porto-systemic anastomoses (Presence of shunts) + reduced hepatic metabolism → greatly increase the oral bioavailability of drugs undergo extensive 1st pass metabolism. • For eg. 2 fold increase in bioavailability of propranolol in cirrhosis compared to normal.
  22. 22. • It is difficult to come up with definite dosage guidelines • Routine liver function tests are not a good complete guide • CP score is a useful guide for determining prognosis in COL cases. – But its usefulness in predicting drug doses is less clear • Precise dose determination in liver diseases is to be based on drug to drug basis and back ground disease state.
  23. 23. • Interference with bilirubin metabolism and excretion – Steroids, androgens, estrogens, oral contraceptives – Rifampicin • Centrilobular necrosis – Paracetamol, carbon tetrachloride • Hepatocellular necrosis – Salicyclates • Fatty change in liver cells and hepatic failure – tetracycline
  24. 24. • Acute hepatocellular necrosis – Halothane (GA) – Carbamazepine, phenytoin, sodium valproate, phenobarbital (antiepileptics) – MAOI (antidepressants) – Ibuprofen (anti-inflammatory) – Isoniazid, sulphonamides, (anti infectives) – Methyldopa, hydralazine (CVS drugs) • Cholestatic hepatitis – Phenothiazine neuroleptics (Chlorpromazine)
  25. 25. • Benign liver tumor – Anabolic steroids – Oral contraceptives • Chronic active hepatitis – Isoniazid – Dantrolene • Hepatic fibrosis or cirrhosis – Methotrexate – Amiodarone
  26. 26. References • Penny North-Lewis (2008). Drugs and the Liver. 1 Lambeth High Street, London: Royal Pharmaceutical Society of Great Britain . 23135. • Palmer, KR and Penman ID. (2010). Alimentary tract and pancreatic disease. In: Colledge, NR, Walker, BR and Ralston SH Davidson's Principle and Practice of Medicine. 21st ed. London : Churchill Livingstone. 835-918. • Tripathi, KD. 2008. Essentials of Medical Pharmacology. 6th Edition. India: Jaypee Brothers Medical Publishers (P) Ltd.

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