Adrenergic Pharmacology

The objective of these presentations is to facilitate the understanding of sympathomimetics and sympatholytics and the adrenergic receptors at which these drugs interact to produce their therapeutic effects.

Sympatholytic Learning Objectives

The student should be able to explain or describe;

1) The pharmacologic properties and toxicities of beta-adrenergic blockers as exemplified by propranolol and metoprolol

2) The therapeutic uses of beta-adrenergic receptor blockers.

3) The pharmacologic properties, toxicities and therapeutic uses for tamsulosin and prazosin-like drugs.

4) How activation of "₂ receptors decreases sympathetic outflow and causes hypotension.

Key Drugs

Metoprolol- Toprol and various trade names - 2^nd leading prescription drug in the US in 2007- source- rxlist.com

Carvedilol- Coreg, 34^th leading prescription drug in the US in 2007- source- rxlist.com

Clonidine - Minipres and various trade names

Propranolol - Inderal and various trade names

Terazosin - Hytrin

Tamsulosin-Flomax, 40^th leading prescription drug in the US in 2007- source- rxlist.com

2) The beta blockers used in clinical therapeutics are either selective for the beta₁ receptor or nonselective beta₁ and beta₂ antagonists.

2) It was the first clinically approved beta blocker and the standard to which newer drugs have been compared.

1) Recall that the beta1-adrenergic receptor associated with the heart increases the force and rate of myocardial contraction.

2) Beta antagonists block the ability of the sympathetic nervous system to increase the contractile force and the rate of contraction.

3) The release of renin from the kidney is also regulated by the beta1-receptor. By blocking renin secretion beta1 blockers reduce the formation and hence the biological activity of angiotensin II.

4) Beta1-receptor antagonists decrease blood pressure. While the mechanism underlying this effect is not completely understood, it certainly involves a decrease in cardiac output and heart rate as well as decreasing angiotensin II levels. This reduction in blood pressure makes the beta blockers useful in the treatment of hypertension.

5) Beta blockers are also useful in treating ischemic heart disease. This is because two major determinants of myocardial oxygen consumption are the force and rate of myocardial contraction which are diminished by this class of drugs.

6) Beta blockers are given following a myocardial infarction to prevent reinfarction.

7) Certain arrhythmias are due to excess stimulation of the beta1-receptors. Thus beta blockers are useful in treating supraventricular tachyarrhythmias.

8) There are many indications for beta blockers unrelated to cardiovascular therapeutics.

9) Several clinical trials have shown that certain beta blockers, specifically, metoprolol, bisoprolol and carvedilol, can be used to treat congestive heart failure. The proposed actions for this beneficial effect include, an up regulation of the beta1 receptors, an antagonism of the effects of circulating catecholamines on hypertrophic growth and generation of reaction oxygen species.

A major disadvantage of nonselective beta blockers is the fact that they will block beta₂ receptors associated with airway or vascular smooth muscle. This unwanted action can exacerbate airway diseases (asthma, emphysema, chronic bronchitis) or peripheral vascular disease (Raynaud’s Disease). To overcome this disadvantage, "selective" beta₁ blockers have been developed. These agents have the ability to preferentially block beta₁ receptors. However, this selectivity is only relative and in higher doses selective antagonists will also block beta₂ receptors.

3) These agents increase triglycerides and decrease HDL cholesterol. However, the relevance of this effect is uncertain.

1) Beta blockers should be used with caution in patients with diabetes. This is because catecholamines utilize the beta₂ receptor to promote glycogenolysis and mobilize glucose. This effect would be blocked by non-selective beta blockers.

2) In addition all beta blockers mask the tachycardia associated with hypoglycemia. As a result the diabetic patient is deprived of one of the earliest physiologic responses to hypoglycemia.

Certain beta blockers actually have a modest degree of agonist activity. In other words these agents are partial agonists with low intrinsic activity. This is referred to as intrinsic sympathomimetic activity or ISA. These drugs may have a lesser effect on resting heart rate or cardiac output than compounds without ISA.

Prazosin and analogs(doxazosin, terazosin, trimazosin) - Selective, competitive antagonists

Prazosin and analogs are selective alpha1-receptor blockers used to treat hypertension. These agents have similar cardiovascular actions, differing only in pharmacokinetic parameters. Doxazosin, trimazosin and terazosin are more widely used than prazosin.

2)This results in a decrease in systemic arterial blood pressure due to a decrease in peripheral vascular resistance and venous return.

3) The reduction in arterial blood pressure does not result in a significant increase in heart rate.

4) Treatment with these drugs can result in fluid retention as a response to the lowering of blood pressure. Thus the drugs can be prescribed with a diuretic in the treatment of hypertension.

5) May have beneficial effects on lipid profiles by increasing HDL cholesterol and decreasing LDL cholesterol.

6) The effectiveness of this class of drugs for the treatment of hypertension was recently called into question by results from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The ALLHAT study showed that patients taking doxazosin were 25 % more like to have “cardiovascular events” and twice as likely to be hospitalized for heart failure than patients taking the thiazide diuretic, chlorthalidone.

Actions in Benign Prostatic Hyperplasia

1) Prazosin and analogs also relax the smooth muscle associated with the bladder neck and prostate. Because of this, they can be used to treat BPH.

2) Tamsulosin has a similar action and is also used to treat BPH. Tamsulosin is an example of a drug that is selective for one of the subtypes of the alpha1-adrenergic receptor. This ligand selectively blocks the alpha1A-receptor. The alpha1A-receptor is involved in regulating the smooth muscle tone associated with the prostate. Therefore, tamsulosin selectively antagonizes the receptor subtype involved in regulating prostate function and is thus less likely than the prazosin analogs to cause hypotension.

Side Effects

1) Postural hypotension occurs with greater frequency with the prazosin analogs than with tamsulosin. These effects are most likely to occur with the initial administration of prazosin analogs and is also known as first dose syncope. Orthostatic hypotension or postural hypotension occurs when systemic arterial blood pressure falls by more than 20 mmHg upon standing. In this situation, cerebral perfusion falls and an individual may become light headed, dizzy or pass out. In changing from the supine to the standing position, gravity tends to cause blood to pool in the lower extremities. However, several reflexes, including sympathetically mediated venoconstriction minimize this pooling and maintain cerebral perfusion. If these reflex actions do not occur, then orthostatic hypotension could result. By blocking the alpha₁-receptors associated with venous smooth muscle, prazosin-like drugs inhibit the sympathetically mediated vasoconstriction associated with postural changes.

2) Intraoperative Floppy Iris Syndrome (IFIS)

Phentolamine

1) Nonselective competitive alpha₁ and alpha₂ blocker

2) Used to treat pheochromocytoma

Phenoxybenzamine

1) Irreversible alpha₁ and alpha₂ receptor antagonist

2) Used to treat pheochromocytoma

SYMPATHOLYTICS WITH COMBINED ALPHA AND BETA BLOCKING PROPERTIES

1) These ligands block alpha₁ receptors as well as beta₁ and beta₂ receptors.

2) The side effect profile is what would be expected of a drug that blocks both alpha₁ and beta receptors. These include orthostatic hypotension, sedation, fatigue and other effects attributed to the blockade of beta receptors.

4) In addition to treating hypertension, several recent clinical trials have shown carvedilol to be very effective in treating congestive heart failure. There are several proposed mechanisms underlying this effectiveness. Blockade of the beta₁ receptor appears to be more relevant than alpha₁ receptor blockade. This results in an improvement in left ventricular function. One pathophysiology of heart failure is that the heart increases dimensions. These increases result in a hypertrophied heart with decreased contractile performance. Carvedilol reverses these changes. Furthermore, carvedilol has an antioxidant action and decreases reactive oxygen species.

1) These agents stimulate alpha₂ receptors in the nucleus tractus solitarius (NTS) to decrease sympathetic outflow to the heart and blood vessels.

3) Clonidine, guanfacine and guanabenz are active drugs that are direct alpha₂ receptor agonists.

4) Methyldopa is a prodrug which must first be taken up into the nerve terminal and converted to "-methylnorepinephrine. This is the same synthetic pathway that

5) Clonidine is the most widely used drug of this class. It can be given orally or in patch form. Side effects include drowsiness. This is a common occurrence for drugs that work in the CNS. Another prominent side effect of clonidine is persistent dry mouth or xerostomia. Clonidine has many other uses including opiate withdrawal, nicotine withdrawal, vascular headaches, diabetic diarrhea, glaucoma, ulcerative colitis and Tourette's syndrome. The other drugs are second-line agents used in the treatment of hypertension. Methyldopa has the particularly troublesome side effect of inducing hemolytic anemia.

2) Interferes with the vesicular storage of norepinephrine and other neurotransmitters

3) This results in an inhibition of both alpha and beta receptor dependent events.

5) This drug can produce a variety of unpleasant CNS side effects such as insomnia,

2) Long term use of guanethidine depletes catecholamines from nerve terminals.