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.