INTRODUCTION
Propranolol is a nonselective beta-adrenergic receptor blocking agent.
As blocking beta-adrenergic receptor sites induces reduction of
inotropic and chronotropic response in heart and dilation of blood
vessels, propranolol has been used for the treatment of hypertension,
coronary artery disease, and atrial fibrillation.[1] Propranolol is
also used to prevent variceal bleeding in cirrhotic patients. It manages
portal hypertension by decreasing cardiac output and splanchnic blood
flow, which lower the risk of variceal bleeding.[2, 3] As
gastroesophageal varices are present in about 50% of all patients with
cirrhosis, and are associated with high morbidity and mortality, all
patients with cirrhosis should be evaluated for variceal bleeding.
Guidelines recommend propranolol as a first-line medication for the
primary or secondary prophylaxis of variceal bleeding. [4, 5]
Propranolol is mainly eliminated by metabolism and cytochrome P450 (CYP)
2D6 and 1A2 primarily contribute to the metabolism. Because of its high
extraction by the liver, a large proportion of propranolol is eliminated
by pre-systemic metabolism and the bioavailability of propranolol is
only 25%.[1, 6] The systemic exposure of high hepatic extraction
drugs is influenced by hepatic blood flow, the fraction of protein
binding, and hepatic intrinsic clearance. In patients with liver
cirrhosis, the fraction of protein binding decreases because the
production of albumin, which drugs bind to, is reduced and the function
of hepatic enzymes which represents the intrinsic clearance decreases.
Moreover, the portal hypertension reduces hepatic blood flow and
increases bioavailability by reducing pre-systemic and systemic
metabolism.[7, 8] Because of these pharmacokinetic changes, when
propranolol is administered to prevent variceal bleeding, its systemic
exposure may vary according to the extent of liver dysfunction and the
extent of portal hypertension.
Despite the possibility of varying pharmacokinetics of propranolol
according to the disease progression, there is little information
available on the drug exposure or dose adjustment of propranolol in
patients with liver cirrhosis. The guideline just recommends the dose
adjusted based on the patient’s blood pressure and heart rate.[4, 5]
In this study, we investigate the factors that can affect the
pharmacokinetics of propranolol including the extent of portal
hypertension and propose a model that predicts the systemic exposure of
propranolol.