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PHARMACOKINETICS AND HEPATIC DISEASE

1. Hepatic Anatomy and Pathophysiology:

Cl	=	Q x	(Ci - Co)
			__________
			Ci
	..
	=	Q x	E

Cirrhosis is the most important hepatic disorder that influences drug disposition, whereas hepatitis and biliary obstruction are of lesser importance.

Physiological consequences of cirrhosis:

Liver cell mass and function.

Hepatic blood flow.

Serum albumin.

 

2. Drug Metabolism Overview:

Phase I:

Eg. Hydroxylation.

- Accomplished by cytochrome - P450 dependent mixed-function oxidase enzyme system.

- Can be influenced by genetic, environmental and disease-state factors.

Phase II:

Eg. Glucuronidation.

Drug conjugation is less disturbed by above factors.

Cl	=	Q x	E
	..
	=	Q x	fu . Cl
			__________
			Q + fu.Cl

High extraction ratio (eg. Lignocaine, Propranolol):

ClH QH

Low extraction ratio (eg. Phenytoin, Warfarin):

ClH fu . Cli

Changes in blood flow, protein binding, and intrinsic ability of the liver to remove a drug are therefore all factors that can influence the hepatic elimination of a drug. This influence varies depending on whether the drug is highly or poorly extracted by the liver.

 

3. High Clearance Drugs and Hepatic Disease:

plasma level of drug (especially if taken orally)

(a) hepatic blood flow clearance 

(b) Intra-hepatic and extra-hepatic shunting of blood “first pass” effect oral bioavailability.

Eg. Verapamil orally

Cl by 50% 

F by 240% 

Plasma levels by (2.4 / 0.5) = 4.8 - fold

Table 1: Examples of drugs with high hepatic extraction ratios showing the influence of cirrhosis on clearance, bioavailability and degree of accumulation after doses by mouth·
Drug	Clearance†	Bioavailability†	Degree of Accumulation after Doses by Mouth
Pethidine	60%	160%	270%
Pentazocine	50%	350%	700%
Chlormethiazole	70%	1150%	1700%
Metoprolol	76%	170%	220%
Propranolol	60%	160%	280%
Labetolol	70%	190%	270%
Verapamil	50%	250%	490%
Lignocaine	60%	--	--
· Other drugs which have not been studied but would be predicted to behave in a similar manner include Alprenolol; Oxprenolol; Ergot alkaloids; Glyceryl trinitrate; Isosorbide dinitrate; Hydralazine; Nifedipine; Perhexilene; Prazosin; Codeine; Papaverine; Dextropropoxyphene Naloxone; Tricyclic antidepressant agents; and Pentoxifylline.  † Percentage of normal value.

Hence, the extent of dosage reduction in liver disease for drugs with a high hepatic clearance is dependent on the route of administration.

The chemical consequences are that a two-fold dose reduction may be necessary for the intravenous route, but a five to ten-fold reduction in dosage may be required by mouth.

4. Low Clearance Drugs and Hepatic Disease:

(a) Cl (hepatic cell mass and function).

(b) Often fu (serum albumin).

(c) No significant change in F.

Overall, total Cl ( fu . Cl) is generally reduced two to four-fold.
Therefore, total plasma levels are generally increased by two to four-fold.

However, free (active) plasma levels may be increased by much more (Cl).
Therefore, highly bound drugs may need > 2 or 4-fold dosage reduction.

Table 2: Examples of drugs with a low hepatic extraction ratio showing the influence of cirrhosis on hepatic clearance·
Drug	Clearance†
Chlordiazepoxide	40% (unbound)‡
Diazepam	25% (unbound)
Desmethyldiazepam	50%
Nitrazepam	70% (unbound)
Hexobarbital	50%
Chloramphenicol	35%
Cefoperazone	50%
Clindamycin	50%
Metronidazole	40%
Naproxen	40% (unbound)
Sulindac	30%
Azapropazone	50% (unbound)
Paracetamol	80%
Triamterene	10%
Bumetanide	30%
Theophylline	30%
Valproic acid	50% (unbound)
Pancuronium	75%
· Other drugs which have not been studied but would be predicted to behave in a similar manner include Phenytoin; Quinidine; Mexiletine; Amiodarone; Miconazole; Ketoconazole; Isoniazid; Tinidazole; and Rifampicin.  † Percentage of normal value.  ‡ Based on unbound concentrations in plasma.

5. General Guidelines:

- Patients with chronic liver disease may require a two to four-fold reduction in the dose of drugs with a low hepatic clearance, irrespective of the route of administration.

- For drugs with a high hepatic clearance, a two-fold dose reduction may be necessary for IV administration but a larger reduction (eg. 5 or 10-fold) when given by mouth.

- If possible, use TDM to individualise therapy.

- Drugs that only undergo Phase II conjugation metabolism (eg. Lorazepam, Oxazepam, Temazepam, Clofibrate) and drugs that are primarily cleared by the kidneys (eg. Digoxin, Gentamicin) can be prescribed in normal doses to patients with chronic liver disease.

6. Other Liver Diseases:

Drug clearance is often unaffected

Eg. Acute viral hepatitis
Cholestasis

7. Other Pharmacokinetic Parameters:

(a) Vd mayor in liver disease:

(i) fu

(ii) presence of ascites - ECF volume

Vd

 

(b) t½ can alsoor in liver disease:

t½	=	0.693 Vd
		__________
		Cl

Where 

Vdor
Cl or

Thence, clearance is a more reliable indicator of the eliminative capacity of the liver in hepatic disease.

 

8. Altered Drug Responses (Pharmacodynamics) in Hepatic Disease:

Eg:- 

(a) ­ sensitivity to oral anticoagulants.

(b) ­ CNS sensitivity to depressants.

(c) ­ risk of hypokalaemia with loop diuretics.

9. Biochemical Tests to Predict Altered Drug Metabolism in Hepatic Disease:

In renal disease, Creatinine clearance is a reliable guide to altered drug clearance by the kidney, but in spite of the large number of hepatic function tests (eg. bilirubin and albumin levels, enzyme levels, prothrombin index), none of these in isolation has been able to reliably predict the degree of alteration of drug clearance in a patient with liver disease.

It is only possible to generalise : patients with the greatest derangements in liver function tests (eg. hypoalbuminaemia, abnormal coagulation) will have the most marked fall in drug clearance, and patients with mild cirrhosis will have little, if any, decline in drug clearance.