LIVER DISEASE

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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
PHASE I
EXCRETION OF
DRUGS
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
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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.

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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.

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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
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Hepatic drug
Clearance
High clearance Drugs Low clearance Drugs
Lidocaine Phenytoin
Propronolol Warfarin
Morphine Theophyllin
Antipsychotic Aminodarone
Beta blockers Anti convalcents
Ca channel blockers Anti Parkinson
Nitrates Anti thyroids
Opoids Benzodiazepines
Tricycles anti depressants Quinidine
Retinoids
Rifamcin
Spiranolactone
Sulfonylureas
Proton pump inhibitors

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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 that is doubled in patients
with chronic liver failure.

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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.
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Increased risk of gastrointestinal
bleeding and
may aggravate fluid retention.
Avoid NSAIDs in severe liver disease
NSAIDs Meloxicam
Celecoxib Nabumetone
Diclofenac Naproxen
Etodolac Phenylbutazone
Ibuprofen Piroxicam
Indometacin Rofecoxib
Ketoprofen Sulindac
Ketorolac Tenoxicam
Mefenamic acid Tiaprofenic Acid
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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

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 Opioid analgesics ACE inhibitors:
Codeine
Morphine
Captopril
Dextropropoxyphene Enalapril
Diphenoxylate
Fentanyl
Fosinopril
Methadone Quinapril
Nalbuphine Ramipril
Pethidine
Tramadol
Trandolapril
Avoid or reduce dose.
May precipitate coma.
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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

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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

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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

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

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