ANTIADRENERGIC DRUGS

     Drugs that interfere with the sympathetic nervous system act at various sites, including the central nervous system (CNS), postganglionic sympathetic nerve endings, and peripheral alfa - and B -receptors.
     Normally, when a sympathetic nerve is stimulated, norepinephrine is released, which traverses the synapse and stimulates postsynaptic alfa - and B-receptors. Norepinephrine within the synapse can also bind to presynaptic B - and alfa 2- receptors, providing a feedback mechanism that modulates further release of the hormone. The B -receptor increases, and the alfa 2-receptor inhibits further, norepinephrine release.
     The consequences of receptor stimulation depend on the organ involved. The effect of alfa1-receptor stimulation on vascular smooth muscle is vasoconstriction, whereas B2 stimulation causes vasodilation. In the CNS, alfa2 stimulation inhibits sympathetic outfl ow to the periphery, thereby contributing to vasodilation.

Central Adrenergic Inhibitors (CNS Alfa 2-Agonists) 
     Alfa 2-Receptors are located in the presynaptic neurons of the CNS. When stimulated by an alfa2-agonist, they lead to diminished  sympathetic outfl ow from the medulla. This action reduces peripheral vascular resistance and decreases cardiac stimulation, resulting in a fall in blood pressure and heart rate. CNS alfa2-agonists were once among the most commonly used antihypertensive drugs but have
largely given way to better tolerated agents. They are not sufficiently potent to serve as vasodilators in the treatment of heart failure.
     The drugs in this group are all available as oral preparations, and clonidine can also be prescribed as a skin patch that is applied and left in place for 1 week at a time, facilitating drug compliance. Side effects of CNS alfa2-agonists include sedation, dry mouth, bradycardia, and, if the drug is stopped suddenly, the possibility of a sudden, paradoxical rise in blood pressure.

Sympathetic Nerve-Ending Antagonists
     Reserpine was the fi rst drug found to interfere with the sympathetic nervous system. It inhibits
the uptake of norepinephrine into storage vesicles in postganglionic and central neurons, leading to norepinephrine degradation. The antihypertensive effect results from the depletion of catecholamines, which causes the force of myocardial contraction and total peripheral resistance to decrease.
     Reserpine’s CNS toxicity represents its chief drawback. It often produces sedation and can impair concentration. The most serious potential toxicity is psychotic depression. Newer, better tolerated antihypertensive agents have largely supplanted the use of reserpine and other sympathetic nerve-ending antagonists.

Peripheral Alfa-Adrenergic Receptor Antagonists
     Peripheral alfa -antagonists are divided into those that act on both alfa1- and alfa2-receptors, and those that inhibit alfa 1 alone. Alfa1-Selective receptor antagonists (prazosin, terazosin, doxazosin) are occasionally prescribed in the treatment of hypertension. Their selectivity for the alfa1-receptor explains their ability to produce less refl ex tachycardia than nonselective agents. Normally, drug-induced vasodilation results in baroreceptor-mediated stimulation of the sympathetic nervous system and an undesired increase in heart rate. This effect is amplifi ed by drugs that block the presynaptic alfa2-receptor, because feedback inhibition of norepinephrine release is prevented. However, alfa 1-selective agents do not block the negative feedback on the alfa 2-receptor. Thus, further norepinephrine release and reflex sympathetic side effects are blunted.
     Historically, the principal indication for alfa 1- antagonists has been in the treatment of hypertension. However, in a large prospective, randomized trial, patients treated with the alfa 1- antagonist doxazosin experienced more adverse cardiac outcomes than those treated with a thiazide diuretic. Thus, alfa1-antagonists have fallen out of favor in the management of hypertension. Terazosin and doxazosin are mainly used today to treat the symptoms of benign prostatic hyperplasia, because the drugs also beneficially relax prostatic smooth muscle tone.
     Phentolamine and phenoxybenzamine are nonselective alfa -blockers. They are used in the treatment of pheochromocytoma, a tumor that abnormally secretes catecholamines into the circulation. Otherwise, these drugs are rarely used because the alfa2-blockade impairs the normal feedback  inhibition of norepinephrine release, an undesired effect, as indicated earlier.

B-Adrenergic Receptor Antagonists
     The B -adrenergic antagonists are used for a number of cardiovascular conditions, including ischemic heart disease, hypertension, heart failure, and tachyarrhythmias.
     Because catecholamines increase inotropy, chronotropy, and conduction velocity in the heart, it follows that B -receptor antagonists decrease inotropy, slow the heart rate, and decrease conduction velocity. When stimulation of the B-receptors is low, as in a normal resting person, the effect of blocking agents is likewise mild. However, when the sympathetic nervous system is activated (e.g., during exercise), these antagonists can substantially diminish catecholamine-mediated effects.
     The B-blockers can be distinguished from one another by specific properties: (1)
the relative affi nity of the drug for B 1- and B 2- receptors, (2) whether partial -agonist activity is present, (3) whether the drug also has vasodilator properties (e.g., via alfa 1-receptor blockade), and (4) differences in pharmacokinetic properties. The goal of B1-selective agents is to achieve myocardial receptor blockade, with less effect on bronchial and vascular smooth muscle (tissues that exhibit B2-receptors), thus producing less bronchospasm and vasoconstriction in susceptible patients. Agents with partial B -agonist effects (also termed intrinsic sympathomimetic activity) tend to slow the heart rate less than other B-blockers.
     During short-term use, nonselective -antagonists tend to reduce cardiac output because they decrease heart rate and contractility as well as slightly increase peripheral resistance (via B2-receptor blockade). B -Antagonists that have partial agonist activity (such as pindolol) or those that possess some alfa -blocking activity (such as labetalol) can actually lower peripheral resistance by interacting with their respective B2- and alfa -receptors.

Clinical Uses
Ischemic Heart Disease
     The beneficial effects of B -blockers in ischemic heart disease are related to their ability to decrease myocardial oxygen demand. They reduce the heart rate, blood pressure (afterload), and contractility. The negative inotropic effect is directly related to blockade of the cardiac B -receptor, which results in decreased calcium influx into the myocyte. B -Blockers also improve survival following acute myocardial infarction. Agents with intrinsic sympathomimetic activity are less beneficial in this
regard than B-blockers without it.

Hypertension
     B-Blockers are effective antihypertensive agents. Despite their widespread use in this capacity, the mechanisms responsible for blood pressure lowering are not completely understood. With initial use, the antihypertensive action is thought to result from a decrease in cardiac output, in association with slowing of the heart rate and mild decrease in contractility. However, with chronic administration, other mechanisms are likely at work, including reduced renal secretion of renin and possibly CNS effects.

Heart Failure
     The negative inotropic effect of B -blockade would be expected to worsen heart failure symptoms in patients with underlying left ventricular systolic dysfunction. However, trials in patients with all classes of clinically stable heart failure have actually shown a survival benefit with chronic B-blocker administration using carvedilol, metoprolol, or bisoprolol. The mechanism may relate to blunting of the cardiotoxic effects of excessive circulating catecholamines. Because of the potential risk of transiently worsening heart failure in tenuous patients, B -blocker therapy should be started at low dosage, augmented slowly, and carefully monitored.
     Other conditions that benefit from B-blocker therapy include tachyarrhythmias (as discussed later) and hypertrophic cardiomyopathy.

Adverse Effects
     Fatigue may occur during B -blocker therapy and is most likely a CNS side effect. B -Blockers with less lipid solubility (e.g., nadolol) do not penetrate the blood–brain barrier and may have fewer CNS adverse effects than more lipid-soluble drugs, such as propranolol. Other potential adverse effects relate to the predictable consequences of B -blockade:
 1. B 2-Blockade associated with use of nonselective agents (or large doses of B 1-selective blockers) can exacerbate bronchospasm, worsening preexisting asthma or chronic obstructive lung disease.
2. The impairment of AV nodal conduction by B1-blockade can cause conduction blocks.
3. B 2-Blockade can precipitate arterial vasospasm, which can result in Raynaud phenomenon or worsen symptoms of peripheral vascular disease.
4. Abrupt withdrawal of a B -antagonist after chronic use could precipitate myocardial ischemia in patients with CAD.
5. Undesirable reduction of high-density lipoprotein (HDL) cholesterol and elevation of triglycerides can occur through an unknown mechanism. This effect appears to be less pronounced with B -blockers that have partial B -agonist activity or combined B - and alfa -blocking properties.
6. B 2-Blockade may impair recovery from hypoglycemia in diabetics suffering an insulin reaction. In addition, B-blockers may mask the sympathetic warning signs of hypoglycemia, such as tachycardia. If B-blockers are used in diabetics, B 1-selective agents are generally preferred.

     Other potential side effects include insomnia, depression, and impotence. Finally, B -antagonists should be used with caution in combination with nondihydropyridine CCBs (verapamil or diltiazem), because both types of drugs can impair myocardial contractility and AV nodal conduction, possibly precipitating heart failure or AV conduction blocks.