LIVER DISEASE

 

Visit www.bpharmstuf.com For more ppt s

www.bpharmstuf.com

Medications requiring dosage adjustments in hepatic disease

Liver is the principal organ responsible for processing and providing major pathways for the biotransformation of many ingested medications.

METABOLIC PROCESS INVOLVED IN THE HEPATIC EXCRETION OF DRUGS

 

  

PHASE I Enzymes cyt p 450 ,hydrolysis, oxidation, dealkylation and Reduction of drug molecules. PHASE II Involve conjugation of drug molecules E.g.: Glucorinic acid , sulphates , Amino acids, acetates
www.bpharmstuf.com 3

LIVER DISORDERS


       

HYPOPROTEINAEMIA -reduced protein binding & increased toxicity of some highly protein-bound drugs such as phenytoin & prednisolone. REDUCED CLOTTING Indicated by a prolonged prothrombin time, increases the sensitivity to oral anticoagulants such as warfarin& phenindione. HEPATIC ENCEPHALOPATHY many drugs can further impair cerebral function & drugs may precipitate These include all sedative drugs, opioid analgesics, those diuretics that produce hypokalaemia, & drugs that cause constipation. FLUID OVERLOAD Edema & ascites in chronic liver disease may be exacerbated by drugs that give rise to fluid retention, e.g. NSAIDs, corticosteroids, & carbenoxolone.
www.bpharmstuf.com 4

RELIABLE AND SENSITIVE TEST OF LIVER INJURY

Measurement: Direct and total serum albumin Direct and total serum bilurubin Serum alanine Amino transferase Alkaline phosphates. Assessment of: Protrombin time Protrombin Ratio  hepatic function  increasing INR, PTT, GGT,  A Systematic Review of the Performance Characteristics of Clinical Event Monitor Signals Used to Detect Adverse Drug Events in the Hospital Setting.

www.bpharmstuf.com

Hepatic drug Clearance

      

Liver blood flow Intrinsic enzyme metabolism capacity of liver to that drug. Hepatic excretion Ratio IN LIVER DISEASE Decrease metabolism Decreased liver blood flow Alteration of intra extra hepatic shunting
www.bpharmstuf.com 6

Hepatic drug Clearance

         

High clearance Drugs Lidocaine Propronolol Morphine Antipsychotic Beta blockers Ca channel blockers Nitrates Opoids Tricycles anti depressants

              

Low clearance Drugs Phenytoin Warfarin Theophyllin Aminodarone Anti convalcents Anti Parkinson Anti thyroids Benzodiazepines Quinidine Retinoids Rifamcin Spiranolactone Sulfonylureas Proton pump inhibitors

www.bpharmstuf.com

DRUG DOSING IN LIVER DISEASE



Abnormal function of the liver can result in alterations of drug metabolism. For example, diazepam, a commonly used medication for anxiety, sedation, and muscle spasticity, has a half-life halfthat is doubled in patients with chronic liver failure.
www.bpharmstuf.com 8

Dosage adjustments in hepatic disease

     

In hepatic disease, great potential exists. For use in a hospital system, the rules should: 1) Detect current and potential adverse drug events. 2) Avoid alert fatigue. 3) Incorporate future pharmacogenetic data into clinical decision alerts. 4) Create well defined standards by consensus guidelines for defining rules. 5) Evaluate sensitivity, specificity, and PPV of rules.
www.bpharmstuf.com 9

Increased risk of gastrointestinal bleeding and may aggravate fluid retention. Avoid NSAIDs in severe liver disease
        

NSAIDs Celecoxib Diclofenac Etodolac Ibuprofen Indometacin Ketoprofen Ketorolac Mefenamic acid

        

Meloxicam Nabumetone Naproxen Phenylbutazone Piroxicam Rofecoxib Sulindac Tenoxicam Tiaprofenic Acid
10

www.bpharmstuf.com

Anesthetics and muscle relaxants

         

Halothane Avoid if history pyrexia or jaundice Thiopental Reduce dose for induction in severe liver disease Suxamethonium chloride Prolonged apnoea may occur in severe liver disease due to reduced hepatic synthesis of Pseudocholinesterase Desflurane - reduce dose Tizanidine - Avoid in severe liver disease
www.bpharmstuf.com 11

Opioid analgesics  Codeine  Morphine  Dextropropoxyphene  Diphenoxylate  Fentanyl  Methadone  Nalbuphine  Pethidine  Tramadol Avoid or reduce dose. May precipitate coma.


      

ACE inhibitors: Captopril Enalapril Fosinopril Quinapril Ramipril Trandolapril

www.bpharmstuf.com

12

ALIMENTARY TRACT AND METABOLISM

 

      

Antacids Avoid those containing large amounts of sodium(magnesium trisilicate) and those containing calcium compounds which cause constipationasthis may aggravate encephalopath Carbenoxolone -Produce sodium & water retention andhypokalaemia Cimetidine & Ranitidine - Increased risk of confusion, reduce dose. Lansoprazol - In severe liver disease dose should not exceed 30mg daily Omeprazol - In liver disease not more than 20mg daily needed Pentoprazol - Max 20mg daily in severe hepatic impairment &cirrhosis- monitor liver function Sulphonylureas, Chlorpropamide, Glibenclamide, Gliclazide, Tolbutamide, Glipizide Increased risk of hypoglycemia in severe liver disease, Avoid or use small dose, can produce jaundice
www.bpharmstuf.com 13

Reduced dose
  

    

Leflunomide -active metabolite may accumulate Gold salts- Hepatotoxicity may occur ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS Quinolones Norfloxacin Nalidixic acid Ofloxacin Neomycin -Absorbed from gastro-intestinal tract in liver disease- increased risk of ototoxicity
www.bpharmstuf.com 14

Reduce Dose
          

Antigout agents-Antigout agents Loop diuretic Thiazides Bumetanide Chlortalidone Furosemide Hydrochlorothiazide Oral contraceptives Avoid in active liver disease & if history of pruritis or cholestasis during pregnancy Oestrogens Estradiol Norethisterone

www.bpharmstuf.com

15

 

Antimigraine agents Ergotamine and Naratripan - Max 2.5mg in 24 hours in moderate hepatic impairment avoid if severe

www.bpharmstuf.com

16

Visit www.bpharmstuf.com For more ppt s

www.bpharmstuf.com

17