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Drug Use in Chronic Liver Disease

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Drug Use in Chronic Liver Disease Dr Ian Coombes University of Queensland Safe Medication Practice Medication Unit Diagnosis and Plan Decompensated ALD with ... – PowerPoint PPT presentation

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Title: Drug Use in Chronic Liver Disease


1
Drug Use in Chronic Liver Disease
  • Dr Ian Coombes
  • University of Queensland
  • Safe Medication Practice Medication Unit

2
Objectives
  • After this session you will be able to
  • Describe the relationship between chronic liver
    disease and the development of a number of
    complications.
  • Discuss the strategies commonly used to manage
    these complications
  • Describe the influence of liver disease on the
    pharmacokinetics of drugs

3
Chronic liver disease (CLD)
  • Inflammation of the liver for gt than 6 months
  • Have permanent structural changes in the liver
  • Eventually leads to reduced liver function

4
Blood supply
  • Liver receives 25 of resting cardiac output
  • Blood enters via
  • hepatic artery (25) portal vein (75)
  • carries blood from gut
  • rich in absorbed nutrients
  • portal flow increases after meals
  • Blood leaves via
  • hepatic vein
  • Also leaving liver
  • hepatic ducts
  • carry bile to gall bladder

5
Normal Situation
Systemic Circulation
Urea
Collateral
Splanchnic Circulation
GIT
Bacteria
Protein NH3
6
Causes Of Chronic Hepatic Failure
  • Viral Hepatitis
  • Hepatitis C
  • Hepatitis B / D
  • Alcohol
  • Autoimmune Disease
  • Primary Biliary Cirrhosis (PBC)
  • Primary Sclerosing Cholangitis (PSC)
  • Autoimmune Hepatitis

7
  • Hereditary Metabolic Disorders
  • Haemochromatosis - Iron overload
  • Wilsons Disease - Copper accumulation
  • Alpha - 1 - antitrypsin deficiency
  • Fatty Liver
  • Venous Outflow Obstruction (Budd-chiari Syndrome)
  • Drugs
  • eg methyldopa, isoniazid, nitrofurantoin,
    methotrexate, amiodarone
  • Cryptogenic

8
Major complications of liver disease
  • Portal hypertension
  • Ascites
  • Bleeding
  • Encephalopathy
  • Hepato-renal syndrome
  • Effects on drug handling and sensitivity

9
Complications of ALD Portal hypertension
  • Increased resistance to flow through the portal
    system ? blood forced down alternate channels
  • Collateral circulation
  • Portosystemic shunting

10
Consequences of portal hypertension
  • Ascites
  • Hepatic encephalopathy
  • Increased risk of spontaneous bacterial
    peritonitis
  • Increased risk of hepatorenal syndrome
  • Splenomegaly-mild panyctopenia
  • Portacaval anastomoses (oesophageal varices,
    haemorrhoids, caput medusae)

11
Complications of CLD Ascites
  • Caused by
  • ? albumin
  • Portal hypertension
  • ? renal perfusion
  • Na/water retention
  • ? aldosterone
  • Treatment
  • Diuretics (spironolactone/frusemide)
  • Ascitic taps
  • shunts

12
Starlings Forces control of fluid movement in
CV system
Arteriolar Level Capillary Bed Venule
Albumin
CO2
OPgtBP
BPgtOP
O2 Nutrients
Movement of fluid controlled by hydrostatic
pressue (BP) and Oncotic pressure (OP -
generated by albumin). When albumin decreases
(due to liver disease fluid remains in tissue
bed ascites (as driven by portal hypertension).
13
Complications of CLD Bleeding
  • Caused by
  • Portal hypertension
  • Oesophageal / Gastric / Rectal varices
  • Variceal bleeding mortality after 1st bleed 50
  • 60 re-bleed in 1 year
  • Decreased clotting factors
  • Liver site of clotting factor production
  • Increased prothrombin time/INR
  • Infection can exacerbate bleeding
  • Endotoxin mediated

14
Complications of CLD- Hepatic encephalopathy
  • May be precipitated by
  • GI bleeding, constipation, high dietary protein
    load
  • Electrolyte disturbances
  • Infection
  • Drugs
  • Renal impairment
  • Pathogenesis incompletely understood
  • Ammonia
  • Treatment
  • Lactulose/neomycin
  • Avoiding sedating agents

15
Diseased Liver
Systemic Circulation
Urea
Cirrhosis
Collateral
Splanchnic Circulation
Portal Hypertension
GIT
Bacteria
Protein NH3
Drugs
Portal systemic shunting
16
Complications of CLD- Hepatorenal syndrome
  • Acute oliguric RF with portal HT ascites
  • Intense vasoconstriction occurs in otherwise
    normal kidneys
  • Caused by
  • Pathogenesis unknown
  • Related to altered renocortical blood flow
  • Treatment
  • Avoid precipitating drugs treatments
  • No effective treatment poor prognosis
  • terlipressin

17
Investigation of CLD
  • Signs and symptoms, history
  • Liver enzymes
  • Plasma protein, coagulation factors, auto
    antibodies
  • Imaging ultrasound, cholangiography
    (endoscopic, percutaneous, MR)
  • Liver biopsy

18
Classification of CLD
  • Child-Pugh classification (modified version).
  • Point score correlates with survival.

19
What the points mean!

20
Management of CLD
  • Treatment of underlying cause if possible
  • Adequate nutrition
  • Prevention and symptomatic treatment of
    complications
  • Liver transplantation

21
Drug Use in Chronic Liver Disease
  • Disease severity
  • Pharmacokinetic response
  • absorption
  • distribution
  • elimination
  • hepatic clearance
  • Pharmacodynamic response
  • Potentially hepatotoxic drugs

22
Consider
  • Is it hepatically cleared?
  • First pass?
  • What are the side effects?
  • Constipation
  • CNS side effects
  • Renal toxicity
  • Is it hepatotoxic?
  • Idiosyncratic or dose related?

23
PHARMACOKINETIC CONSIDERATIONS IN LIVER DISEASE
  • Five variable will affect the pharmacokinetics of
    a
  • drug in liver disease.
  • HEPATIC BLOOD FLOW
  • REDUCTION IN HEPATIC CELL MASS
  • PORTAL SYSTEMIC SHUNTING
  • CHOLESTASIS
  • DECREASE IN PROTEIN BINDING

24
1. HEPATIC BLOOD FLOW
  • Reduction occurs in
  • cardiac failure
  • cirrhosis
  • hepatic venous outflow obstruction
  • portal vein thrombosis
  • Large decrease in blood pressure e.g. shock
  • HIGH RISK DRUGS gt60 first pass clearance

25
Hepatic Extraction of drugs
26
2. REDUCED HEPATIC CELL MASS
  • Associated with both acute and chronic liver
    disease
  • Decrease first pass metabolism of drugs
  • with a high hepatic extraction increase in
    bioavailability
  • Decrease elimination of drugs with a low hepatic
    extraction i.e. capacity limited drugs lead to
    increase in half-life.

27
3. PORTAL SYSTEMIC SHUNTING
  • 80 blood entering liver portal vein,
  • Bioavailability of drugs with high extraction can
    increase significantly,
  • Peak plasma concentrations will be increased,
  • Half-life will be prolonged,
  • Elimination delayed may lead to toxicity

28
4. CHOLESTASIS
  • Failure of passage of bile salts to
  • duodenum. Directly affects hepatocellular
  • function drug clearance.
  • Lack of bile - reduces absorption of lipid
    soluble drugs
  • Reduced plasma protein binding of drugs
    competition with bile salts.

29
5. REDUCTION IN PROTEIN BINDING
  • Majority of plasma proteins (PP) synthesised by
    liver,
  • Reduction in PP decrease binding potential
    increase in free drug concentrations e.g.
    phenytoin
  • If drug highly extracted no increase in plasma
    conc but for other drugs will result in
    increase in free drug plasma concs.
  • Competition may also occur for binding sites e.g.
    bile salts.

30
Case 1
  • 48 year old 86 kg man
  • PC massive abdominal distension and pain
  • HPC - ? abdominal distension, pain and lethargy,
    confusion
  • PMH includes
  • Alcoholic liver disease/haemochromatosis
  • Social history
  • Lives alone
  • Alcohol abuse
  • Allergies - NKA

31
Case 1 continued
  • On examination
  • HR 84 reg BP 115/70 mmHg RR 18/min
  • Temp 37.7?C
  • Ascites, abdominal pain
  • Mild confusion
  • Medications
  • Omeprazole 20mg bd
  • Lactulose 20mL tds prn
  • Thiamine 100mg daily
  • Vitamin K 10mg daily
  • Spironolactone 100mg daily

32
Laboratory Tests
  • UEs
  • Sodium 130 mmol/L ?
  • Potassium 3.9 mmol/L
  • Creatinine 130 micromol/L ?
  • Glucose 4.3 mmol/L
  • Haemotology
  • Hb 100 g/L ?
  • WCC 16.7 x 109/L ?
  • Platelets 256 x 109/L
  • INR 1.9 ?

33
Laboratory Tests
  • LFT/Gastro
  • Total Protein 61 g/L
  • Albumin 23 g/L ?
  • Bilirubin 86 umol/L ?
  • ALT 63 U/L ?
  • GGT 96 U/L ?
  • ALP 107 U/L
  • AST 143 U/L ?

34
Diagnosis and Plan
  • Decompensated ALD with increasing ascites and
    mild encephalopathy
  • Lactulose 30mL 3-4 times daily
  • Ascitic tap with albumin cover
  • Fluid restrict 1.5L/day
  • Low salt
  • Weigh daily
  • Add frusemide 40mg mane

35
  • Which lab tests indicate liver disease? Which
    tests are used to assess disease severity?
  • What are the common complications of chronic
    liver disease (seen in this patient any others)
    and describe briefly the main forms of treatment
    for each of the complications. Consider current
    therapy
  • What pharmacokinetic changes occur in chronic
    liver disease that effect drug metabolism?
  • What are the pharmacodynamic changes that occur
    in chronic liver disease that effect drug dosing?
  • What are the potential problems with
    aminoglycoside and analgesic use in this patient?
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