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810 > Dosing in Liver Disease > Flashcards

Dosing in Liver Disease Flashcards

1
Q

General Considerations for Dosing in Liver Disease

A
  1. Is this an acute or chronic liver injury?
    * *2. What are the ADME properties of the drug?
    * *3. What are the pathophysiological changes in the patient that might affect the drug?
  2. What is the therapeutic window of drug?
  3. What are the implications of under dosing or over-dosing?
  4. Are there specific monitoring parameters for the drug?7. Are there safer alternative therapies?
  5. What is the potential for drug interactions with the patient’s existing medications/herbs/supplements?
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2
Q

Absorption in Cirrhosis

A

Rate of absorption may be slowed due to impaired gastric motility, generally amount absorbed is not affected.

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3
Q

Distribution in Cirrhosis

A
  • Presence of ascites alters volume of distribution for hydrophilic drugs (increases) and may require higher initial dose (ex: beta-lactam antibiotics) with dosing based on actual body weight
  • Hypoalbuminemia: albumin and alpha-1 glycoprotein produced in liver. Drugs that are highly protein bound will be affected.
  • Can be difficult to predict- check total and free levels of drug if available (ex. phenytoin, valproic acid)
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4
Q

Metabolism and Cirrhosis

A

-Metabolic capacity can vary depending on the severity of the disease
-In patients with cirrhosis, changes in liver structure cause disrupted vasculature and formation of nodules of regenerating hepatocytes.
-Consequences: decreased hepatocyte function, chronic hepatocyte damage, and blood shunting
from functioning hepatocytes
-Expect to see reduced metabolism of hepatically metabolized drugs because of loss of hepatocytes and because blood may be bypassing liver (similar to traffic being diverted from particular area due to on-going
construction)

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5
Q

Phase I Metabolism + Cirrhosis

A

Phase I metabolism (drug metabolizing enzyme reactions through cytochrome P450 including oxidation, reduction, and hydrolysis) is MORE likely to be affected in cirrhosis.

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6
Q

Phase II Metabolism + Cirrhosis

A

Phase II metabolism (conjugation reactions such as glucoronidation, sulfation, methylation, acetylation) are LESS likely to be affected in cirrhosis.

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7
Q

Clinical Clues of Metabolic Changes

A
  • Affected by fibrotic changes in the liver
  • Clinical events such as varices or presence of ascites
  • Changes in hepatic synthetic function (loss of function) seen with increased INR: coagulopathy & decreased albumin
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8
Q

Elimination

A

Drug elimination by excretion into bile and elimination in feces or reabsorption into blood stream (enterohepatic cycling)

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9
Q

Impaired Elimination

A
  • Alterations difficult to predict
  • Clues for impaired elimination include elevations of alkaline phosphatase (Alk Phos) and bilirubin (specifically direct bilirubin)
  • Severe elevations of bilirubin suggest cholestasis (impaired excretion through bile)
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10
Q

Renal Effects from Impaired Elimination

A
  • Patients with liver failure likely have some degree of renal impairment
  • Kidneys also have metabolic function and may compensate for hepatic damage
  • Avoid nephrotoxic drugs in patients with cirrhosis/liver failure to avoid precipitating renal failure. Combination of acute hepatic and acute renal failure is called hepatorenal and is rapidly fatal
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11
Q

Hepatorenal

A

Combination of acute hepatic and acute renal failure, rapidly fatal

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12
Q

Assessment of Liver Function

A
  • *NO SINGLE TEST TO ASSESS LIVER FUNCTION**

- Combination of synthetic functions, liver enzymes, thrombocytopenia, elevated levels of certain proteins

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13
Q

Liver Disease

A
  • Ranges from hepatitis, fibrosis, and cirrhosis

- Dosing adjustments may or may not be necessary

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14
Q

Hepatitis

A

Inflammation, associated with decreased hepatocyte function. Clinical significance varies based on severity (acute vs. chronic)

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15
Q

Cirrhosis

A
  • On-going inflammation leading to changes in hepatic structure
  • Chronic liver disease with replacement of liver tissue with fibrosis, scar tissue, and regenerative nodules.
  • Occurs after prolonged periods of fibrosis
  • Severity of cirrhosis varies
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16
Q

Decompensated v.s. Compensated Cirrhosis

A
  • Cirrhosis is further defined as either compensated or decompensated depending on whether the patient has had clinical events as a result of the liver damage.
  • Cirrhosis becomes clinically evident (considered decompensated) with development of hepatic encephalopathy, portal hypertension and its sequelae including varices (potential for variceal bleeding) and ascites, or development of jaundice (seen with elevated bilirubin)
17
Q

Synthetic Functions of Liver

A
  • Albumin: production declines with progressive liver damage
  • INR: progressive increases in INR consistent with loss of production of clotting factors
  • Bilirubin: increases with increasing congestion (blockage- fibrotic changes) within the liver
18
Q

Thormbocytopenia

A
  • Platelets <150,000
  • In a patient with known liver disease, should be considered a marker of cirrhosis until proven otherwise
  • Cirrhotic changes in liver cause disruption in blood flow which causes portal hypertension
  • With portal hypertension, platelets are sequestered in spleen- evidenced by low platelet count
19
Q

Liver Enzyme Levels

A
  • Liver enzymes (AST, ALT) to determine level of inflammation for acute injury
  • Only gives idea of how much inflammation happening at that moment, does NOT indicate how much damage already happened
  • Patients with cirrhosis often do not have markedly elevated AST or ALT (often near normal values) because there has been so much damage that there aren’t many hepatocytes left to “leak out” enzymes
20
Q

APRI/FIB-4

A

Used to identify if advanced fibrosis or cirrhosis is likely

21
Q

MELD

A

Used to assess 3 month mortality and evaluation for liver transplantation

22
Q

Child-Pugh (CP) Score

A

-Used to assess and classify severity of cirrhosis; often
used for recommendations on drug dosing (also known as Child Turcotte Pugh or CTP)
-Only scoring system for which any drug dosing
recommendations are available
-Should only be used if a patient is identified as a cirrhotic.

23
Q

Child Pugh Scores + Function Interpretation

A
  • 5-6 (A) = Mild dysfunction
  • 7-9 (B) = Moderate dysfunction
  • > 9 (C) = Severe dysfunction
24
Q

CP Score: Encephalopathy

A
  • None (or no history of) = 1
  • Moderate^ = 2
  • Severe* = 3
25
Q

CP Score: ^ and *

A
  • ^ = Includes patients who are medically controlled

- * = Refractory to treatment/ poorly controlled

26
Q

CP Score: Ascites

A
  • Absent = 1
  • Mild- moderate^ = 2
  • Severe* = 3
27
Q

CP Scores: Bilirubin (mg/dL)

A
  • <2 = 1
  • 2-3 = 2
  • > 3 = 3
28
Q

CP Score: Albumin (g/dL)

A
  • > 3.5 = 1
  • 2.8-3.5 = 2
  • <2.8 = 3
29
Q

CP Score: PT Prolongation (INR)

A
  • 0-4 (<1.7) = 1
  • 4-6 (1.7-2.3) = 2
  • > 6 (>2.3) = 3
30
Q

CP Score + Dosing

A
  • Child Pugh Class B: Consider moderate dose reduction (approx. 25%)
  • Child Pugh Class C: Consider significant dose reduction (approx. 50%)
31
Q

Acute v.s. Chronic Liver Disease

A
  • If chronic, then is the patient cirrhotic? If yes, then do Child Pugh to understand level of liver disease and guide dosing
  • If not chronic liver disease, need to consider why liver damage occurring and if expected to resolve
  • Acute injury: Temporary decrease in function with anticipated recovery to normal or near normal function.
  • Acute injury can be associated with markedly abnormal labs (AST and ALT)
32
Q

Contaminants to Consider

A
  • Acute alcohol can compete for metabolism
  • Chronic alcohol can increase enzyme activity
  • Consider other drugs (medical or otherwise), herbs, supplements
33
Q

Are the most common drugs which cause adverse drug reactions or cause severe complications in patients with cirrhosis predominantly metabolized in the liver?

A

No.

34
Q

Furosemide

A
  • Electrolyte abnormalities

- Electrolyte disturbances and hepatorenal syndrome

35
Q

ACE-I

A
    • RAS effect

- Hypotension

36
Q

NSAIDs

A
  • Renal failure
  • Increased risk of bleed
  • Hepatorenal syndrome
  • Fatal GI bleeds; anemia
37
Q

Aminoglycosides

A
  • Renal failure

- Hepatorenal syndrome

810 (22 decks)

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