On the World Health Organization's List of Essential Medicines and a prototypical drug of its class, propranolol is a non-cardioselective beta blocker and it is typically synthesized as a racemic mixture of 2 enantiomers where the S(-)-enantiomer has approximately 100 times the binding affinity for beta adrenergic receptors. It can be administered intravenously to the bloodstream or orally, where it passes through hepatic portal circulation, and enters the bloodstream to act on peripheral cells. This pathway focuses on cardiovascular effects of propranolol but as a relatively lipophilic drug, it can accumulate in the brain. In the brain, it antagonizes serotonergic receptors and inhibits (via receptor antagonism) adrenergic receptors - its psychiatric effects are under research currently. It may also be used for infant hemangioma. In the periphery, propranolol can target beta-1, beta-2, and beta-3 adrenergic receptors (hence its reduced selectivity compared to newer beta blockers, which has clinical implications in the treatment of dysrhythmias) to interfere with the normal epinephrine to adrenergic receptor binding, thus acting as a competitive antagonist - its cardiovascular effects on the beta-1 adrenergic receptor are responsible for its primary therapeutic use as a class II antidysrhythmic agent. It is also an antihypertensive and antianginal agent. In bronchial and vascular smooth muscle, propranolol can compete with epinephrine for beta-2 adrenergic receptors. By competing with catecholamines for adrenergic receptors, it inhibits sympathetic stimulation of the heart. The reduction of neurotransmitters binding to beta receptor proteins in the heart inhibits adenylate cyclase type 1. Because adenylate cyclase type 1 typically activates cAMP synthesis, which in turn activates PKA production, which then activates SRC and nitric oxide synthase, its inhibition causes the inhibition of cAMP, PKA, SRC and nitric oxide synthase signaling. Following this chain of reactions, we see that the inhibition of nitric oxide synthase reduces nitric oxide production outside the cell which results in vasoconstriction. On a different end of this reaction chain, the inhibition of SRC in essence causes the activation of Caspase 3 and Caspase 9. This Caspase cascade leads to cell apoptosis. The net result of all these reactions is a decreased sympathetic effect on cardiac cells, causing the heart rate to slow and arterial blood pressure to lower; thus, propranolol administration and binding reduces resting heart rate, cardiac output, afterload, blood pressure and orthostatic hypotension. By prolonging diastolic time, it can prevent re-infarction. One potentially less than desirable effect of non-selective beta blockers like propranolol is the bronchoconstrictive effect exerted by antagonizing beta-2 adrenergic receptors in the lungs. Clinically, it is used to increase atrioventricular block to treat supraventricular dysrhythmias. Propranolol also reduce sympathetic activity to manage hyperthyroidism, anxiety and tremor. As a result, propranolol is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Propranolol Pathway (New - beta blocker) References