Download Liver Cirrhosis

Liver dysfunction
and
Drugs metabolism
Dr V.Sebghatollahi
Isfahan university of medical science
Liver Functions:
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Metabolism – Carbohydrate, Fat & Protein
Secretory – Bile acids, bile salts & pigments
Excretory – Bilirubin, drugs, toxins
Synthesis – Albumin, coagulation factors
Storage – Vitamins, carbohydrates etc.
Detoxification – toxins, ammonia, etc.
Normal Liver
Cirrhosis
Introduction
 Cirrhosis is common end result of many
chronic liver disorders.
Inflammtion – healing with fibrosis Regeneration of remaining hepatocytes form
regenerating nodules.
Loss of normal architecture & function.
INTRODUCTION
It is generally considered to be irreversible in
its advanced stages at which point the only
option may be liver transplantation.
However, reversal of cirrhosis (in its earlier
stages) has been documented in several forms
of liver disease following treatment of the
underlying cause.
Etiology of Cirrhosis
• The most common causes of cirrhosis in the
United States are:
– hepatitis C
– alcoholic liver disease
– Nonalcoholic fatty liver disease
• which together accounted for approximately
80 percent of patients on the liver
transplantation waitlist between 2004 and
2013
Etiology of Cirrhosis
• In developed countries, common causes of
cirrhosis include :
– Chronic viral hepatitis (hepatitis B, C)
– Alcoholic liver disease
– Hemochromatosis
– Nonalcoholic fatty liver disease
Pathogenesis:
• Hepatocyte injury leading to necrosis.
– Alcohol, virus, drugs, toxins, genetic etc..
• Chronic inflammation - (hepatitis).
• Bridging fibrosis.
• Regeneration of remaining hepatocytes
Proliferate as round nodules.
• Loss of vascular arrangement results in
regenerating hepatocytes ineffective.
Normal Liver - Microscopy
Cirrhosis
cirrhosis:
Liver Biopsy – Cirrhosis
Liver Biopsy – Cirrhosis
Clinical Features
Hepatocellular failure.
– Malnutrition, low albumin & clotting factors,
bleeding.
– Hepatic encephalopathy.
Portal hypertension.
– Ascites, Porta systemic shunts, varices,
splenomegaly.
Physical examination
 Spider angiomas
 Palmar erythema
 Nail changes
• Muehrcke's nails
• Terry’s nails
 Gynecomastia
 Testicular atrophy
Cirrhosis
Clinical
Features
Ascitis in Cirrhosis
Clinical Manifestations
• Muehrcke's nails
• Terry’s nails
Spider angioma
Jaundice
Gynecomastia in cirrhosis
Prominent abdominal veins.
Conclusions:
• Common end result of diffuse liver damage.
(Viral hepatitis, Alcohol, congenital, drugs, toxins & Idiopathic)
• Characterised by diffuse loss of architecture.
• Fibrous bands & regenerating nodules distort
and abstruct blood flow. (inefficient function)
• Hepatocellular insufficiency & portal
hypertension.
• Shrunken, scarred liver, ascitis, spleenomegaly,
liver failure, CNS toxicity.
Drug metabolism
Metabolism
The metabolism of drugs and other
xenobiotics into more hydrophilic
metabolites is essential for the elimination
of these compounds from the body and
termination of their biological activity.
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.
Absorption
Elimination
Metabolism
Phase I
Phase II
conjugate
Drug
Drug metabolite with
modified activity
conjugate
Drug
Inactive drug
metabolite
conjugate
Drug
Lipophilic
Hydrophilic
Biotransformation
• Generates more polar (water soluble), inactive
metabolites
• Readily excreted from body
• Metabolites may still have potent biological activity
(or may have toxic properties)
• Generally applicable to metabolism of all
xenobiotics as well as endogenous compounds such
as steroids, vitamins and fatty acids
First-Pass Metabolism
• Following nonparenteral administration of
a drug, a significant portion of the dose
may be metabolically inactivated in either
the intestinal endothelium or the liver
before it reaches the systemic circulation
• Limits oral availability of highly metabolized
drugs
Effects of Liver Disease
on Drug Metabolism
• Liver disease may have complex effects on
drug clearance, biotransformation, and
pharmacokinetics
• There is no easily available measure of liver
function, with the "liver function tests" such as
AST, ALT, GGT & alkaline phosphatase providing
an indication of liver cell damage rather than
ability of the liver to metabolise drugs.
• This contrasts with renal disease, where
estimates of renal function based on creatinine
clearance correlate with renal drug elimination.
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
• Liver Dysfunction can lead to impaired drug metabolismdecreased enzyme activity
• First pass metabolism effected – may inc 2-4 x bioavailiability
• Results in exaggerated pharmacological responses and
adverse effects
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
• Pathogenetic factors(in cirrhosis) include:
 alterations in intestinal absorption
 alterations plasma protein binding
 alterations hepatic extraction ratio
 alterations liver blood flow
 portal-systemic shunting
 alterations biliary excretion
 alterations renal clearance
• Sometimes alterations increase levels of
bioavailable drug, causing normal drug doses
to have toxic effects
• However, levels and effects for an individual
drug are unpredictable and do not correlate
well with the type of liver injury, its severity,
or liver function test results.
Thus, no general rules are
available for modifying
drug dosage in patients
with liver disease.
• Clinical effects can vary independent of drug
bioavailability, especially in chronic liver disease;
eg, cerebral sensitivity to opioids and sedatives is
often enhanced in patients with chronic liver
disease.
• Thus, seemingly small doses of these drugs given
to cirrhotic patients may precipitate
encephalopathy. The mechanism of this effect
probably involves alterations in cerebral drug
receptors
Adverse drug reactions do not appear to
be more likely in patients with advanced
liver disease
 however, such patients may tolerate any
hepatic adverse effects of drugs less well.
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