ABSTRACT
Recurrent stroke is a major public health concern and new treatment strategies are needed. While modulation of the renin angiotensin aldosterone system (RAAS) has proven effective in reducing recurrent cardiac events, its role in preventing recurrent cerebrovascular events remains unclear. RAAS is both a circulating and tissue based hormonal system that regulates homeostasis and tissue responses to injury in both the CNS and the periphery, via the activity of angiotensin II (Ang II). Vascular and hematologic effects induced by Ang II including endothelial dysfunction, vascular structural changes, inflammation, hemostasis, and fibrinolysis are increasingly linked to the occurrence of cerebrovascular events. Animal models have shown that RAAS modulation may be protective in cerebrovascular disease. The HOPE and LIFE trials support the role of blood pressure independent mechanisms of RAAS modulation for improving outcomes in a broad range of patients with cardiovascular disease but do not specifically address recurrent stroke prevention. PROGRESS, a trial of secondary stroke prevention, demonstrates that blood pressure reduction with a combination strategy including the routine use of ACE inhibitors prevents recurrent stroke. Current evidence suggests that the RAAS plays an important role in the development and progression of cerebrovascular disease. Modulation of the RAAS holds promise for the secondary prevention of stroke, however, ongoing clinical trials will better define the exact role of ACE inhibitor and angiotensin II Type 1 receptor blocker therapy in stroke survivors.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Renin-Angiotensin System/physiology , Stroke/prevention & control , Aged , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Chronic Disease , Double-Blind Method , Drug Evaluation, Preclinical , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Endothelium, Vascular/ultrastructure , Fibrinolysis/drug effects , Hemostasis/drug effects , Humans , Inflammation/drug therapy , Inflammation/physiopathology , Middle Aged , Nerve Regeneration , Randomized Controlled Trials as Topic , Rats , Receptor, Angiotensin, Type 1/drug effects , Receptor, Angiotensin, Type 1/physiology , Receptor, Angiotensin, Type 2/physiology , Renin-Angiotensin System/drug effects , Secondary Prevention , Stroke/physiopathology , Treatment OutcomeABSTRACT
Hepatic impairment can alter the pharmacokinetic profiles of cardiovascular drugs, which can lead to unwanted toxicity. In the presence of cirrhosis, portosystemic shunting occurs and cytochrome P450 activity is reduced. Impaired oxygen uptake caused by changes in the liver's sinusoids, as proposed by the oxygen limitation theory, may also explain the alteration of drug metabolism seen in cirrhosis. With congestive heart failure, sinusoidal congestion and hypoperfusion of the liver are seen. Similar to cirrhosis, the common pathway for hepatic damage in congestive heart failure seems to be liver hypoxia, which may explain the disease's effect on drug metabolism. Since routine hepatic function tests do not always relate to the liver's ability to eliminate drugs, existing guidelines for dosing cardiovascular drugs in patients with hepatic impairment are limited. This article provides guidance for dosing cardiovascular drugs in cirrhotic and heart failure patients based on available research data. Altered drug metabolism, especially in congestive heart failure, tends to be overlooked or not realized in clinical practice. Therefore, further research is needed in congestive heart failure to better elucidate safe prescribing patterns.