Adrenergic Antagonists (V) PDF

**[V) ADRENERGIC ANTAGONISTS]** ***[Learning outcomes]*** **1. Describe the therapeutic uses and adverse effects of α-adrenoreceptor antagonists** **2. Describe the therapeutic uses and adverse effects of β-adrenoreceptor antagonists** **3. Contrast the differences between the nonselective and r...

**[V) ADRENERGIC ANTAGONISTS]** ***[Learning outcomes]*** **1. Describe the therapeutic uses and adverse effects of α-adrenoreceptor antagonists** **2. Describe the therapeutic uses and adverse effects of β-adrenoreceptor antagonists** **3. Contrast the differences between the nonselective and relatively β~1~-selective andrenoreceptor antagonists.** ***[Reading material]*** **The adrenergic antagonists are sometimes called adrenergic blockers or sympatholytic agents**. **They bind to adrenoreceptors [but do not trigger] the usual receptor-mediated intracellular effects. They can either attach to the adrenoreceptors reversibly or irreversibly, thus preventing its activation by endogenous catecholamines (A, NA, & DA).** **The adrenergic antagonists are classified according to their relative affinities for α or β-adrenoreceptors in the periphery.** **These agents interfere with functions of the [sympathetic nervous system] -- thus they have a profound effect on the physiology of sympathetically innervated organs**. **Several of these agents are very important in clinical medicine, particularly for the treatment of cardiovascular diseases.** ***[a) α-adrenergic blockers]*** **The α-AR blockers are either reversible (competitive) or irreversible (non-competitive) in their interaction with receptors.** **Drugs that block α-ARs profoundly affect BP due to decreased peripheral vascular resistance (α~1~ effect). A reflex tachycardia may be induced resulting from the lowered BP** b**ecause the β-ARs receptors, especially β~1~-ARs on the heart, are not affected by α blockade.** **Irreversible antagonists -- phenoxybenzamine** **Reversible antagonists -- doxazosin, phentolamine, prazosine, tamsulosine, terazosine, tolazoline, alfuzocin & lndoramine** ***1. Phenoxybenzamine*** **Phenoxybenzamine is a haloalkylamine drug that is nonselective, binding covalently to both postsynaptic α~1~-ARs & presynaptic α~2~-ARs. The block is irreversible and noncompetitive requiring the synthesis of new ARs which may take at least a day or more.** **Therefore, the actions of phenoxybenzamine last *about 24 hours* after a single administration.** **Phenoxybenzamine is a pro-drug, it is activated via biotransformation -- as a result there will be a delayed onset of blockade** **[Actions:]** **Cardiovascular effects: phenoxybenzamine prevents vasoconstriction of peripheral blood vessels via blockade of a~1~-ARs. The decreased peripheral resistance provokes a reflex tachycardia.** **Due to its lack of selectivity it also blocks presynaptic α~2~-ARs and can contribute to an increased cardiac output.** **The drug has been discontinued in many countries because it has been unsuccessful in maintaining lowered BP in hypertension.** **[Therapeutic uses:]** **Phenoxybenzamine is used in the long-term treatment of hypertension in patients with pheochromocytoma (a catecholamine-secreting tumor of cells derived from the adrenal medulla - cancer of the adrenal medulla).** It is **used prior to surgical removal of the tumor to preclude the hypertensive crisis that can result from manipulation of the tissue.** **Also used in the chronic management of these tumors -- especially if the tumor is inoperable.** **Phenoxybenzamine or phentolamine are sometimes effective in treating *Raynauds disease (spasm of the arteries causing pallor of the fingers and toes)*** **It has also been used for the treatment of benign prostatic hyperplasia (a benign enlargement of the prostate gland begins normally after age 50 years probably secondary to the effects of male hormones. If significant enlargement occurs, it may pinch off tetanic contractions of the urethra making urination difficult or impossible) -- decreasing both the obstructive symptoms of the prostate and the need to urinate** **[Adverse effects: ]** **Phenoxybenzamine can cause [postural hypotension] (orthostatic hypotension; low BP when rising from a sitting or sleeping position) often accompanied by reflex tarchycardia and other arrhythmias.** **Reversible [inhibition of ejaculation] may occur due to impaired smooth muscle contraction of the vas deferens and ejaculatory duct.** **Nasal stuffiness, nausea, and vomiting may also occur**. ***2. Phentolamine & Tolazoline*** **[Phentolamine] produces a competitive block of α~1~ & α~2~ --ARs.** **Its cardiovascular effects are very similar to those seen with phenoxybenzamine -- they are sometimes referred to as "classical" α-AR blockers to distinguish them from the more recently developed agents.** **The drug\'s action lasts for approximately 4 hours after a single administration**. **It also produces postural hypotension & causes adrenaline reversal. The drug can also trigger arrhythmias & anginal pain, and is C/I in patients with decreased coronary perfusion.** **Phentolamine also blocks the 5-HT receptors, triggers the release of histamine from the mast cells, and blocks K^+^ conductance.** **[Tolazoline] is related but somewhat *less potent than phentolamine*. Not marketed -- it stimulates secretions by salivary, lacrimal, and sweat glands as well.** **[Therapeutic indication:]** **Phentolamine can be used for the short term control of [hypertension in patients with pheochromocytoma].** **It can also be used for the treatment of [hypertensive crisis] induced by** a**brupt withdrawal of clonidine, or** f**rom ingestion of tyramine-containing foods during the use of non-selective MAO inhibitors.** **Direct intracavernous injection of phentolamine has been proposed for the treatment of male sexual dysfunction.** ***3. Prazosin, terazosin, doxazosin, tamsulosin, & alfuzosin*** **Prazosin is the prototype drug in this group of agents that contain the piperazinyl quinazoline nucleus.** **Prazosin is a potent, selective, and competitive α~1~-AR antagonist with over 1000 times greater affinity for these receptors than the than the α~2~-ARs.** **These agents exhibits greater clinical utility and have largely replaced nonselective α-AR antagonists phenoxybenzamine & phentolamine.** **[Prazosin]:The major effects of prazosin results from *its blockade of α~1~-ARs in arterioles* and *veins resulting in a fall in peripheral resistance and venous return to the heart*.** **Unlike other vasodilating drugs, prazosin does not increase the heart rate and does not promote the release of NA (has little a~2~-AR-blocking effects)** **Prazosin is well absorbed after oral administration with the *bioavailability of 50 to 70%****.* **The plasma half-life is approximately 2 to 3 hours and the duration of action is 7 to 10 hours in the treatment of hypertension**. **However, the 1^st^ dose of these drugs produces an exaggerated hypotensive response that can result in syncope (fainting) -- termed a \"first-dose syncopy\"** **This can be *minimised by adjusting the 1^st^ dose to 1/3 or 1/4 of the normal dose, and by giving the drug at bedtime****.* T**he usual dose is usually 1 mg and can be titrated to the total daily dose of 20 mg in patients with hypertension --while for benign prostatic hyperplasia (BPH) doses of 1 to 5 mg twice daily are used** **[Terazosin] is a close structural analog of prazosin, but less potent than prazosin. It retains high specificity for α~1~-AR.** **The major distinctions between the two drugs are their pharmacokinetic properties:** **Terazosin has an oral bioavailability of \>90%, elimination half-life of approximately 12 hours, and a duration of action of 18 hours**. **The initial dose of 1 mg is recommended and the dose titrated and the doses of 10 mg daily maybe required for BPH.** **[Doxazosin] is another structural analog of prazosin which is a highly selective α~1~-AR antagonist.** **The half-life of doxazosin is approximately 20 hours and its duration of action may extend to about 36 hours**. **Its bioavailability and extent of metabolism is similar to that of prazosin.** **[Alfuzosin] is a quinazoline-base α~1~-AR antagonist used extensively for the treatment of BPH**. **Its bioavailability is 64%, half-life 3 to 5 hours, and dosage is 10 mg daily.** **[Tamsulosin] is another selective α~1~-AR antagonist effective in the treatment of BPH with little effect on the BP**. **It is extensively metabolised and has a half-life of 3 to 5 hours.** **[Therapeutic indications]** - **Essential hypertension** - **Congestive heart failure -- ACE inhibitors are favored in these regard** - **BPH** - **Other indications with inconclusive evidence include:** - **Varian agina due to coronary vasospasms** - **Aortic valvular insufficiency** - **Vasospasms in patients with Raynaud's disease** **[Adverse effects]** **The major potential adverse effect of these agents is first-dose effect; marked postural hypotension, and first-dose syncope.** **These effects are seen 30 to 90 minutes following the first dose.** **Syncope also occurs with a [rapid increase in dosage or with the addition of a second] antihypertensive drug to the regimen of the patient already taking any of these agents** **Non-specific adverse effects such as headache, dizziness, and asthenia rarely limit treatment with prazosin. Tamsulosin impairs ejaculation.** ***[b) Selective α~2~-AR blockers]*** **E.g. Rauwolscine, yohimbine, idazoxan & tolazoline** **[Clinical applications]** **Their role is not yet established** - **mostly reserved for experimental pharmacology e.g. in the treatment of type-2 diabetes (α~2~-AR stimulation inhibit insulin release)** **Theoretically, through the blockade of the presynaptic α~2~-ARs, these agents could be useful in autonomic insufficiency**. **Yohimbine has been suggested to improve male sexual function (insufficient data) -- but PDE5 inhibitors (sildenafil) are more favoured**. **Yohimbine readily crosses the BBB where it acts to increase the BP & heart rate --these actions opposes those of clonidine** ***[c) β-Adrenergic Blocking Agents]*** **All clinically available β-blockers are competitive antagonists**. **They are also divided into both selective and non-selective blockers.** **Nonselective β-blockers act at both β~1~ & β~2~ --ARs, whereas cardioselective blockers primarily block β~1~-ARs. Although all β-blockers lower BP in hypertension, they do not induce postural hypotension, because the α-ARs adrenoceptors remain functional.** **They are also effective in treating angina, cardiac arrhythmias, myocardial infarction, and glaucoma, as well as in migraine headaches.** **Names of β-blockers end with "olol" except for carvedilol & labetalol.** ***[i) Propranolol: A nonselective β-antagonist]*** **Propranolol is the *prototype β-AR antagonist blocking both β~1~ & β~2~ receptors*.** **Therapeutic indications:** - **Hypertension** - **Glaucoma (open-angle glaucoma)** - **Migraine** - **Hyperthyroidism** - **Angina pectoris** - **Myocardial infarction (heart-attack)** ***[ii) Timolol, & nadolol: nonselective β antagonists]*** **Timolol & nadolol also block β~1~- & β~2~-ARs & are more potent than propranolol.** **Nadolol has a *very long duration of action*.** **Timolol reduces the production of aqueous humor in the eye. It is used topically in the treatment of chronic open-angle glaucoma and, occasionally, for systemic treatment of hypertension.** ***[iii) Acebutolol, bisoprolol, atenolol, metoprolol, & esmolol: Selective β~1~ antagonists]*** **These drugs have been developed to eliminate the unwanted bronchoconstrictor effect (β~2~ effect) of propranolol seen among asthmatic patients.** ***Cardioselective β~1~-blockers, block these receptor at doses 50- to 100-fold less than those required to block β~2~-ARs*.** **This cardioselectivity is thus most pronounced at low doses and is lost at high doses.** **Nevertheless, asthmatics treated with these agents must be carefully monitored to make certain that respiratory activity is not compromised**. **Reserved for the treatment of hypertensive patients with impaired pulmonary functions** ***[iv) Pindolol - Antagonist with partial agonist activity]*** **Ability to weakly stimulate both β~1~ & β~2~-ARs**. **Has intrinsic sympathomimetic activity (ISA).** **Stimulate the β-ARs to which it is bound and inhibit stimulation by the more potent endogenous catecholamines, A & NA.** **The result of these opposing actions is a much diminished effect on cardiac rate & cardiac output compared to that of b-blockers without ISA.** **Used for the treatment of hypertensive patients with modest bradycardia (because of a mild stimulatory effect on the heart). Valuable in diabetics (carbohydrate metabolism is less affected).** ***[v) Labetalol, bucindolol, nebivolol, celiprolol & carvedilol: ]*** **Antagonists of both α- & β-ARS. These agents reversibly block β- & α~1~-ARs and produce peripheral vasodilation, thereby reducing BP. Unlike other β-blockers (that produce peripheral vasoconstriction), they are therefore useful in treating hypertensive patients where increased peripheral vascular resistance is undesirable. They do not alter serum lipid or blood glucose levels.** **[Clinical uses]** **Labetalol is useful for treating the elderly or black hypertensive patient in whom increased peripheral vascular resistance is undesirable**. **It may be employed as an alternative to hydralazine in the treatment of pregnancy-induced hypertension.** **Labetalol is also used to treat hypertensive emergencies because it can rapidly lower blood pressure.** **[Adverse effects]** **Othostatic hypotension & dizziness (associated with α~1~-blockade)** ***[d) Drugs Affecting Neurotransmitter Release Or Uptake]*** ***i) [Reserpine]* blocks the Mg^2+^/ATP-dependent transport of biogenic amines, NA, D, & serotonin from the cytoplasm into storage vesicles. This causes an ultimate depletion of NA levels in the adrenergic neuron, because MAO degrades the NA in the cytoplasm.** **The drug has a slow onset and a long duration of action and the actions persist for many days after discontinuation of the drug.** **Reserpine is only used to treat hypertension that fails to respond to other treatments** ***[ii) Guanethidine]* acts by blocking the release of stored NA resulting in a gradual lowering of BP in hypertensive patients, & a decrease in cardiac rate.**