β - Adrenoceptor Antagonist Drugs
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*- Adrenoceptor Antagonist Drugs
*The -receptorblocking drugs differ in their relative affinities for 1 and 2 receptors.Some have a higher affinity for 1 than for 2 receptors. Since none of the clinically available -receptor antagonists are absolutely specific for 1 receptors, the selectivity is dose-related; it tends to diminish at higher drug concentrations. Other major differences among antagonists relate to their pharmacokinetic characteristics and local anesthetic (membrane-stabilizing) effects.
*Pharmacokinetics AbsorptionMost of the drugs in this class are well absorbed after oral administration; peak concentrations occur 13 hours after ingestion. BioavailabilityPropranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low .Bioavailability increases as the dose is increased, suggesting that hepatic extraction mechanisms may become saturated. Because the first-pass effect varies among individuals, there is great individual variability in the plasma concentrations achieved after oral propranolol.
* Selectivity Partial Agonist Local Anesthetic tAcebutolol 1 Yes Yes 34hoursAtenolol 1 No No 69 hoursBisoprolol 1 No No 912 hoursEsmolol 1 No No 10 minutesLabetalol None ( blocker) Yes Yes 5 hoursMetoprolol 1 No Yes 34 hoursNadolol None No No 1424 hoursPenbutolol None Yes No 5 hoursPindolol None Yes Yes 34 hoursPropranolol None No Yes 3.56 hoursSotalol None No No 12 hoursTimolol None No No 45 hours
*Distribution and ClearanceThe antagonists are rapidly distributed and have large volumes of distribution. Propranolol and penbutolol are lipophilic and readily cross the blood-brain barrier .Most antagonists have half-lives in the range of 310 hours. Esmolol, which is rapidly hydrolyzed and has a half-life of approximately 10 minutes. Propranolol and metoprolol are extensively metabolized in the liver, with little unchanged drug appearing in the urine.Atenolol and pindolol are less completely metabolized.
*Nadolol is excreted unchanged in the urine and has the longest half-life (up to 24 hours). The half-life of Nadolol is prolonged in renal failure. The elimination of drugs such as propranolol may be prolonged in the presence of liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition.The pharmacodynamic effects of these drugs are sometimes prolonged well beyond the time predicted from half-life data.
* Pharmacodynamics Effects on the Cardiovascular SystemBeta-blocking drugs given chronically lower blood pressure in patients with hypertension .These drugs do not usually cause hypotension in healthy individuals with normal blood pressure.
Beta-receptor antagonists have prominent effects on the heart and are very valuable in the treatment of angina and chronic heart failure and following myocardial infarction.
*In the vascular system, -receptor blockade opposes 2-mediated vasodilation. This may acutely lead to a rise in peripheral resistance from unopposed -receptor-mediated effects as the sympathetic nervous system is activated in response to the fall in cardiac output. Nonselective and 1-blocking drugs antagonize the release of renin caused by the sympathetic nervous system.Chronic drug administration leads to a fall in peripheral resistance in patients with hypertension.
*Mechanism of ActionIncludes a reduction in myocardial contractility, heart rate, and cardiac output. Blockade of the -1 receptors of the juxtaglomerular complex, reduce renin secretion and thereby diminishing production of circulating AngII. This action contributes to the antihypertensive action of this class of drugs,.Some members have additional effects unrelated to their adrenergic receptors blockade. Labetalol is an receptor antagonist, and Nebivolol promotes endothelial cell dependent vasodilation via activation of the NO pathway
*Effects on the Respiratory TractBlockade of the 2 receptors in bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. Beta1-receptor antagonists may have some advantage over nonselective antagonists. However, no currently available 1-selective antagonist is sufficiently specific to completely avoid interactions with 2 adrenoceptors. Consequently, these drugs should generally be avoided in patients with asthma.Many patients with chronic obstructive pulmonary disease (COPD) may tolerate these drugs quite well and the benefits, for example in patients with concomitant ischemic heart disease, may outweigh the risks.
*Effects on the EyeBeta-blocking agents reduce intraocular pressure, especially in glaucoma. The mechanism is decreased aqueous humor production. Without treatment, glaucoma results in damage to the retina and optic nerve, and eventually blindness. Two major types of glaucoma are recognized: open-angle and closed-angle (or narrow-angle). The closed-angle form is associated with a shallow anterior chamber, in which a dilated iris can occlude the outflow drainage pathway. This form is associated with acute and painful increases of pressure, which must be controlled on an emergency basis with drugs or prevented by surgical removal of part of the iris (iridectomy).
*The open-angle form of glaucoma is a chronic condition, and treatment is largely pharmacologic.Glaucoma is treated by:1- reduction of aqueous humor secretion. 2- enhancement of aqueous out-flow. Five general groups of drugs have been found to be useful in reducing intraocular pressure:1-cholinomimetics2- agonists3- blockers4- prostaglandin F2 analogs.5- diuretics
*The prostaglandin analogs and the blockers are the most popular. This popularity results from convenience (once- or twice-daily dosing) and relative lack of adverse effects (except, in the case of blockers, in patients with asthma or cardiac pacemaker or conduction pathway disease).The use of drugs in acute closed-angle glaucoma is limited to cholinomimetics, acetazolamide, and osmotic agents preceding surgery. The onset of action of the other agents is too slow in this situation
*Metabolic and Endocrine EffectsBeta-receptor antagonists inhibit sympathetic nervous system stimulation of lipolysis. The effects on carbohydrate metabolism are less clear, though glycogenolysis in the human liver is at least partially inhibited after 2-receptor blockade. blockers should be used with caution in insulin-dependent diabetic patients.
*Effects Not Related to Beta-BlockadeIt has been suggested that some intrinsic sympathomimetic activity is desirable to prevent untoward effects such as asthma or excessive bradycardia. Pindolol and some other blockers are partial agonists.They may be useful in patients who develop symptomatic bradycardia or bronchoconstriction in response to pure antagonist -adrenoceptor drugs.Local anesthetic action, also known as "membrane-stabilizing" action, is a prominent effect of several blockers .
*However, the concentration in plasma is too low for the anesthetic effects to be evident. These membrane-stabilizing - blockers are not used topically on the eye, where local anesthesia of the cornea would be undesirable. Sotalol is a nonselective -receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (used to treat both ventricular & supraventricular arrhythmias).
*Specific Agents Propranolol is the prototypical -blocking drug. it has low and dose-dependent bioavailability. A long-acting form of propranolol is available; prolonged absorption of the drug may occur over a 24-hour period. The drug has negligible effects at and muscarinic receptors; however, it may block some serotonin receptors in the brain, though the clinical significance is unclear. It has no partial agonist action at receptors.
*Metoprolol, Atenolol.Are 1-selective antagonists.These agents may be safer in patients who experience bronchoconstriction in response to propranolol, but, since their 1 selectivity is modest, they should be used with great caution in patients with a history of asthma. However, in selected patients with chronic obstructive lung disease the benefits may exceed the risks, eg, in patients with myocardial infarction. Beta1-selective antagonists may be preferable in patients with diabetes or peripheral vascular disease when therapy with a blocker is required, since 2 receptors are probably important in liver (recovery from hypoglycemia) and blood vessels (vasodilation).
*Nebivolol Is the most highly selective 1-adrenergic receptor blocker, and it has the additional quality of eliciting vasodilation. This may be due to stimulation of the endothelial nitric oxide pathway.Nadolol has a very long duration of action. Its spectrum of action is similar to that of timolol. T