a concise review of mutual effects of drugs and liver on each other

2. Drugs pharmacology in Liver disease
By
M. H. Farjoo M.D, Ph.D.
Shahid Beheshti University of Medical Sciences

3.  Introduction
 Pharmacokinetic Changes in Liver Disease
 Absorption and Liver
 Metabolism in Liver
 Protein Binding
 Age Effect
 Laboratory Tests
 Liver Disease and Kidney
 Liver Diseases: Acute/Chronic Hepatitis & Cirrhosis
 Modification of Drug Therapy in Liver Disease
 Specific Drugs
Drugs pharmacology in Liver disease

4.  Acute liver impairment interferes with drug
metabolism and elimination.
 Chronic liver impairment affects all parameters of
pharmacokinetic.
 Impaired liver function greatly increases the risks of
adverse drug effects.
 On the other hand, drug-induced liver injury (DILI)
can impair liver function.
Introduction

5. Classifications of drug-induced liver injury (DILI)
Type of classification Examples
Clinical laboratory
Hepatocellular
Cholestatic
Mixed hepatocellular/cholestatic
Mechanism of hepatotoxicity
Direct hepatotoxicity
Idiosyncratic
Immune-mediated
Metabolic
Histologic findings
Cellular necrosis or apoptosis
Cholestasis
Steatosis
Fibrosis
Phospholipidosis
Granulomatous
Sinusoidal obstruction syndrome

6.  Many drugs change liver function tests without
clinical signs of liver dysfunction.
 Hepatotoxicity is potentially life threatening.
 Liver is able to function with as little as 10% of
undamaged hepatic cells.
 With severe hepatic impairment, extrahepatic
metabolism becomes more important.
Introduction

7.  Clients at risk for impaired liver function include:
 Primary liver disease (eg, hepatitis, cirrhosis).
 Diseases that impair blood flow to the liver (heart
failure, shock, major surgery, or trauma).
 Hepatotoxic drugs.
 Malnourished people or those on low-protein diets.
Introduction

8.  Clinical signs for hepatotixicity should be sought
(nausea, vomiting, jaundice, hepatomegaly).
 Hepatotoxic drugs should be avoided if possible:
(acetaminophen, INH, statins, methotrexate,
phenytoin, aspirin and alcohol).
Introduction

9.  There are two patterns of change in liver disease:
 Drugs metabolized rapidly with high extraction in a
single pass through the liver.
 Drugs metabolized slowly with poor extraction in a
single pass through the liver.
Pharmacokinetic Changes in Liver Disease

10. Elimination of drugs

12.  In high extraction group:
 Clearance is limited by hepatic blood flow.
 The predominant change for oral drugs is increased
bioavailability.
 The initial and maintenance doses of such drugs
should be reduced.
 With severe liver impairment the t½ of drugs in this
class may lengthen.
Pharmacokinetic Changes in Liver Disease

13.  In low extraction group:
 The rate-limiting factor is metabolic capacity.
 The major change is prolongation of t½.
 So, the interval between doses may need to be
lengthened
 The time to reach steady-state (5 * t½) is
increased.
Pharmacokinetic Changes in Liver Disease

14.  Some oral drugs are extensively metabolized in the
liver.
 This process is called the first-pass effect or
presystemic metabolism.
 With cirrhosis, oral drugs are distributed directly into
the systemic circulation.
 This means that oral drugs metabolized in the liver
must be given in reduced doses.
Absorption and Liver

15. presystemic clearance
Mechanism of presystemic clearance.After drug
enters the enterocyte, it can undergo metabolism,
excretion into the intestinal lumen, or transport into the
portal vein. Similarly, the hepatocyte may accomplish
metabolism and biliary excretion prior to the entry of
drug and metabolites to the systemic circulation.

18.  Most drugs are metabolized by enzymes in the liver
 They are called the cytochrome P450 [CYP] or the
microsomal enzymes.
 CYP system consists of 12 groups:
 Nine of them metabolize endogenous substances.
 Three of them metabolize drugs.
 The three groups that metabolize drugs are: CYP1 to
CYP3.
Metabolism in Liver

19.  The CYP3 metabolizes 50% of drugs, the CYP2 45%,
and the CYP1 group 5%.
 They catalyze oxidation, reduction, hydrolysis, and
conjugation with glucuronic acid or sulfate.
 Excretion decreases when the liver cannot metabolize
lipid-soluble drugs into water-soluble ones to be
excreted by the kidneys.
 An impaired liver cannot synthesize adequate amounts
of metabolizing enzymes.
Metabolism in Liver

20. Conjugation Pic.

21.  Dosage should be reduced for drugs that are
extensively metabolized in the liver including:
 Cimetidine and Ranitidine
 Diazepam and Lorazepam
 Morphine and Meperidine (Pethidine)
 Phenytoin
 Propranolol
 Verapamil.
Metabolism in Liver

22.  With chronic administration, some drugs increase
metabolizing enzymes in the liver: enzyme induction.
 Enzyme induction accelerates drug metabolism and
larger doses is required.
 Rapid metabolism also increases the production of
toxic metabolites.
 In one study, enzyme induction occurred within 1-3
weeks (to synthesize new enzymes?).
Metabolism in Liver: Enzyme Induction

23. Metabolism in Liver: Enzyme Induction
 In another study, induction occurred within a few days
and finished over 2–3 weeks.
 Both the time for onset and offset of induction, and
recovery after induction (or inhibition) depends on
enzyme turnover.
 Inducing substances are usually lipid soluble, and have
a long t½.

24. Enzyme Inducers
 Barbecued meats
 Tobacco smoke
 Ethanol (chronic use)
 Insecticides
 Barbiturates (phenobarbital)
 Phenytoin
 Carbamazepine
 Primidone
 Rifampicin
 Griseofulvin

25.  Metabolism can be decreased by enzyme inhibition.
 It occurs with co-administration of drugs that
compete for the same metabolizing enzymes.
 In this case, smaller doses of the slowly metabolized
drug is needed to avoid toxicity.
 Enzyme inhibition occurs within hours or days.
Metabolism in Liver: Enzyme Inhibition

26. Enzyme Inhibitors
 Amiodarone
 Cimetidine
 Ciprofloxacin
 Erythromycin
Fluvoxamine
 Fluconazole
 Fluoxetine (Prozac)
 Grapefruit Juice
 Ketoconazole
 Metronidazole
 Ritonavir (Norvir)
 Cotrimoxazole
 Isoniazid (INH)
 Diphenhydramine
 Paroxetine
 Quinidine
 Terbinafine

27. Drugs Acting by Enzyme Inhibition

28. enzyme induction and inhibition Pic.

29.  If hepatic blood flow ↓ => delivery of drug to
hepatocytes ↓ => drug metabolism ↓ => drug toxicity ↑
 Some drugs alter liver blood flow and indirectly affect
liver function:
 Epinephrine decreases blood flow by constricting
hepatic artery and portal vein.
 β blockers decrease blood flow by decreasing
cardiac output, and constricting portal vain.
Metabolism in Liver

30.  The impaired liver does not synthesize albumin
adequately.
 Liver impairment causes accumulation of substances
(bilirubin) that displace drugs from protein-binding
sites.
 When protein binding ↓ => free drug ↑ => drug
distribution to sites of action & elimination ↑
 => onset of drug action ↑
 => duration of action ↓
 When protein binding ↓ => peak blood levels and
adverse effects ↑
Protein Binding

31. Protein binding Pic.

32. Protein binding Pic.

33.  Pharmacokinetics differs in neonates, especially
prematures, because their organs are not fully
developed.
 Until 1 year, liver function is still immature.
 Children of 1 to 12 years have increased activity of
metabolizing enzymes.
 After 12 years of age, children handle drugs similarly
to adults.
 In elderly many drugs are metabolized more slowly
and accumulate with chronic administration.
Age Effect

34.  Many patients with DILI are asymptomatic and are
only detected by laboratory testing.
 Albumin, PT (or INR), and bilirubin together, have a
better predictive value than each test alone.
 AST or ALT were NOT correlated with hepatic drug
clearance.
 In hepatocellular injury, there is a disproportionate
elevation of AST or ALT .
 Because these enzymes reflect hepatic damage, not
hepatic function.
Laboratory Tests

35.  Patients with chronic DILI may develop severe
cirrhosis.
 Even hepatic encephalopathy may occur (sign of acute
liver failure).
 AST or ALT levels <2 times normal, are self limiting.
 For AST or ALT >3 times, withdraw the drug, even in
asymptomatic patients.
 In cholestatic injury ALP is elevated.
Laboratory Tests

36. Laboratory Tests
 DILI is alarming if any of the following is true:
 ALT >3 times normal
 ALP >2 times normal
 Total bilirubin >2 times normal (whatever ALT or
ALP).
 PT >1.5 times control
 Albumin <2.0 g/dl

37.  Renal function are depressed in liver disease.
 In advanced cirrhosis, mechanisms are activated to
maintain blood pressure.
 This causes intrarenal vasoconstriction that affect
sodium excretion and water retention.
Liver Disease and Kidney

38.  The water retention leads to ascites, edema, and renal
failure (hepatorenal syndrome).
 So reducing the doses for drugs that are eliminated by
the kidney in cirrhosis accompanied by ascites.
 Cirrhotic patients are also at increased risk of acute
renal failure after being treated with ACEI and
NSAIDs
Liver Disease and Kidney

39. Hemodynamic Abnormalities In
Decompensated Cirrhosis

40.  In general, drug elimination during acute viral
hepatitis is either normal or moderately impaired.
 Drug elimination is impaired most significantly in
chronic hepatitis B, but in the late stages of disease.
 Viral hepatitis or alcohol-related liver disease, have
more impact on metabolizing activity than cholestatic
conditions.
Hepatitis

41.  Chronic liver disease is secondary to chronic alcohol
abuse or chronic viral hepatitis.
 There is a decrease in CP450, but is compensated by
increase in liver size so metabolism is not impaired.
 Cirrhosis causes collagen deposition, and reduction in
liver size, so total cytochrome P450 is reduced.
 Cirrhosis affects drug metabolism more than any
other form of liver disease does.
Chronic Liver Disease and Cirrhosis

42.  Deposition of collagen in hepatic sinusoids results in
functional shunting of blood past the hepatocytes.
 These changes can interfere significantly with the
hepatic uptake of drugs and metabolites.
 Cirrhosis causes up to 50% decrease in cytochrome
P450 content, and/or shunting of blood away from
functioning hepatocytes.
 Shunts reduce drug delivery to liver, but increase
delivery to the systemic circulation.
Chronic Liver Disease and Cirrhosis

43.  Vasopressin constricts splanchnic blood vessels.
 Systemic, vasoconstriction are predictable
complications necessitating treatment withdrawal.
 In cardiovascular disease and uncontrolled
haemorrhage, simultaneous administration of TNG
(SL or IV) allows continued use of vasopressin.
 Vasopressin is cleared rapidly from the circulation so
is given by continuous infusion.
Complications of Cirrhosis
Variceal Bleeding

44.  Somatostatin and octreotide reduce splanchnic blood.
 Octreotide does not have the risk of cerebral or
cardiac ischemia.
 Propranolol is a prophylactic drug for variceal
bleeding.
 It induces splanchnic vasoconstriction via unopposed
α adrenergic vasoconstriction.
 It is extracted in a single pass by the liver so its
bioavailability is less predictable in cirrhosis with
portal hypertension.
Complications of Cirrhosis
Variceal Bleeding

45.  Salt restriction is effective; fluid restriction is
unnecessary unless the Na+ falls below 125 mmol/L.
 Bed rest (reduces plasma renin activity) is effective,
 Cirrhotic patients exhibit a reduced responsiveness to
loop diuretics.
 This is related to decrease in renal function, which is
often unrecognized in these patients.
Complications of Cirrhosis
Ascites

46.  Spironolactone is not dependent on GFR for efficacy,
so is the most useful diuretic, but maximum efficacy
is seen at 2 weeks.
 If spironolactone does not provide adequate diuresis,
and renal function is conserved, furosemide may be
added.
 Each liter of ascites removed, should be matched by
6–8 g albumin given before or with paracentesis.
Complications of Cirrhosis
Ascites

48.  In the pathophysiology ammonia is a key player.
 Ammonia is derived from colonic urease-containing
bacteria that normally undergoes hepatic extraction.
 Lactulose is an osmotic laxative to speed up clearance
of toxic substances from GI tract.
 Colonic bacteria metabolize it to lactic and acetic
acids, which inhibit ammonia producing organisms
 The correct dose is that which produces 2-4 soft
stools daily (usually 30–60 mL daily).
Complications of Cirrhosis
Hepatic Encephalopathy

49.  Neomycin and metronidazole inhibit urease
producing bacteria, but their use is limited by
toxicity.
 The non-absorbable antibiotic Rifaximin is effective
over a prolonged period without significant toxicity.
Complications of Cirrhosis
Hepatic Encephalopathy

50.  The loading dose of IV drugs need not to be altered in
hepatic disease.
 The maintenance dose should be lowered to reflect
the reduction in hepatic clearance.
 Prescribing of most drugs is safe in compensated liver
disease.
 If in doubt, check the PT, albumin and bilirubin.
 Generally, for drugs with significant hepatic
metabolism, reduce the dose to 25–50% of normal.
Modification of Drug Therapy in Liver Disease

51. Some Drugs Requiring a Dose Reduction in Patients with
Moderate Cirrhosis

53. Some Features of Toxic and Drug-Induced Hepatic Injury

54.  Take particular care with:
 Impaired hepatic function (hypoalbuminaemia,
increased INR).
 Current/recent hepatic encephalopathy.
 Fluid retention and renal impairment.
 Drugs with high hepatic extraction, high protein
binding, low therapeutic ratio, and CNS
depressants.
Modification of Drug Therapy in Liver Disease

55.  Sedatives, antidepressants, and antiepileptics should
be used with extreme caution in advanced liver
disease.
 Treatment of alcohol withdrawal in established liver
disease is hazardous.
 Opiates can precipitate hepatic encephalopathy in
decompensated liver disease.
 For pain control, doses should be reduced to 25–50%.
Modification of Drug Therapy in Liver Disease

56.  Codeine can precipitate hepatic encephalopathy
through constipation alone and accumulates with
renal impairment.
 NSAIDs may exacerbate impaired renal function and
fluid retention, and precipitate GI bleeding.
 Antacids that contain large quantities of sodium can
precipitate fluid retention and cause ascites.
 Aluminium- or calcium-based preparations and
antimotility drugs cause constipation and may
precipitate encephalopathy.
Modification of Drug Therapy in Liver Disease

57.  Potentially hepatotoxic drugs include:
 Acetaminophen
 Isoniazid
 Sodium Valproate
 Phenytoin
 Amiodarone
 Erythromycin
 Oral Contraceptives
 Trimethoprim-Sulfamethoxazole
Specific Drugs

58.  A single dose of 10–15 g, produces liver injury and
25 g is fatal.
 Maximal hepatic failure occurs 4–6 days after
ingestion, and aminotransferase levels may approach
10,000 units.
 Treatment is gastric lavage, supportive measures, and
oral activated charcoal or cholestyramine.
 Neither of these agents is effective if given >30 min
after acetaminophen ingestion.
Acetaminophen

59.  Administration of cysteine, or N-acetylcysteine reduces
the severity of hepatic necrosis.
 Therapy should begin within 8 h of ingestion but may
be effective after 24–36 h.
 If hepatic failure occurs despite N-acetylcysteine
therapy, liver transplantation is the only option.
Acetaminophen

60. Acetaminophen
metabolism
Metabolism of acetaminophen (top
center) to hepatotoxic metabolites.
(GSH, glutathione; SG, glutathione
moiety).

62.  In ~10% of adults elevated serum aminotransferase
levels develop during the first few weeks.
 In ~1% of treated patients, an illness similar to viral
hepatitis develops .
 The case-fatality rate may be 10%.
 Isoniazid hepatotoxicity is enhanced by alcohol,
rifampin, and pyrazinamide.
Isoniazid

63.  It is associated with severe hepatic toxicity and rarely,
fatalities, predominantly in children.
 Elevations of serum aminotransferase levels occurs in
45% of patients but have no clinical importance.
 Its metabolite, 4-pentenoic acid, is responsible for
hepatic injury.
 Hepatotoxicity is more common in persons with
mitochondrial enzyme deficiencies
 It may be ameliorated by IV carnitine, which valproate
therapy depletes.
Sodium Valproate

64.  Phenytoin rarely causes severe hepatitis leading to
fulminant hepatic failure.
 Hepatic injury is usually manifested within the first 2
months after phenytoin therapy.
 Aminotransferase and ALP levels is increased and
represent the potent enzyme–inducing properties of
phenytoin.
Phenytoin

65.  Clinically important liver disease develops in <5% of
patients.
 It has a half-life of up to 107 days so liver injury may
persist for months after stopping the drug.
Amiodarone

66.  The important adverse effect is a cholestatic reaction.
 It is more common in children than adults.
 Most of these reactions have been associated with the
estolate salt.
 The reaction usually begins during the first 2 or 3
weeks of therapy.
Erythromycin

67.  Combination pills of estrogenic and progestational
steroids lead to intrahepatic cholestasis.
 It occurs in a small number of patients weeks to
months after taking these agents.
 The lesion is reversible on withdrawal of the agent.
 The two steroid components act synergistically on
hepatic function but the estrogen is more responsible.
 OCPs are contraindicated in patients with a history of
recurrent jaundice of pregnancy.
Oral Contraceptives

68.  In most cases, liver injury is self-limited.
 The hepatotoxicity is attributable to the
sulfamethoxazole component of the drug.
Trimethoprim-Sulfamethoxazole

70. Thank you
Any question?