Adrenergic Antagonists Lecture PDF

Adrenergic Antagonists By Imad Addeen M. Taj Addeen Faculty of Pharmacy Adrenergic Antagonists These are agents that inhibit responses mediated by noradrenaline or adrenaline or exogenously administered sympathomimetic agents at alpha (α-) or beta (β-) adrenoceptor. They...

Adrenergic Antagonists By Imad Addeen M. Taj Addeen Faculty of Pharmacy Adrenergic Antagonists These are agents that inhibit responses mediated by noradrenaline or adrenaline or exogenously administered sympathomimetic agents at alpha (α-) or beta (β-) adrenoceptor. They are also called adrenoceptor antagonist, sympatholytics or adrenergic blocking agents. They prevent the adrenergic agonist from binding with its receptor (α-and β-adrenoceptors) by either reversible or irreversible competitive antagonism. They are classified according to their relative affinity for alpha- and beta- adrenoceptor, into: Alpha (α)–blockers: α-adrenoceptor blocking agents and Beta (β)-blockers: β-adrenoceptor blocking agents.  Alpha (α)-blockers Classification According to their relative selectivity to alpha-adrenoceptors they can be classified into four types:  1. Non-selective α-blockers like phentolamine, tolazoline and phenoxybenzamine 2. Relative selective alpha-1 (α1)-blockers such as prazosin, terazosin, doxazosin and alfuzosin  3. Selective alpha-1 (α1A)-blockers e.g., tamsolusin and silodosin  4. Selective α2-blocker e.g. yohimbine Alpha (α)-blockers Pharmacological Effects The predominant effect of alpha blockers is in cardiovascular system and include lowered peripheral vascular resistance and blood pressure (α1 effect). They are used to treat hypertension. They also relax smooth muscle in the bladder neck, prostate capsule, and prostatic urethra and decrease resistance to outflow of urine. They are used to treat benign prostatic hyperplasia. Alpha (α)-blockers/Specific drugs Nonselective alpha (α)-blockers Specific agents: Phentolamine and phenoxybenzamine. Phentolamine It is a competitive, non-selective antagonists that are equiactive at both α1-and α2-receptors. Phentolamine reduces peripheral resistance and decreases blood pressure. Phentolamine is approved for the diagnosis of pheochromocytoma and for the prevention and management of hypertensive episodes associated with pheochromocytoma. Alpha (α)-blockers/Specific drugs Pheochromocytoma is a tumor of the adrenal medulla that secrets excessive amounts of catecholamines. Symptoms include hypertension, tachycardia, and arrhythmias. Phenoxybenzamine It is nonselective (α1- and α2-), noncompetitive antagonists (irreversible) α-adrenoceptor blocking agent, with some selectivity for α1-receptors. Phenoxybenzamine binds covalently (irreversibly) with α1- and α2- adrenoceptors resulting in a long-lasting (15-50 hours) blockade. It is used to treat sweating and hypertension associated with pheochromocytoma. The use of phenoxybenzamine and phentolamine has diminished in the recent years (why ??) This is related to blockade of α2-receptors which enhances release of noradrenaline. Alpha (α)-blockers/Specific drugs Prazosin, terazosin, doxazocin and alfuzosin are relative selective while tamsulosin and silodosin, are selective α1A- antagonists. Prazosin, terazosin, and doxazocin are used for the management of hypertension. Terazosin, doxazocin, alfuzosin, tamsulosin and silodosin are used for the management of benign prostatic hyperplasia (BPH). Alpha (α)-blockers/Specific drugs Prazosin Prazosin is the prototype of competitive antagonists with relative selectivity for α1-receptors. Prazosin reduces peripheral resistance and blood pressure. This drug is administered orally. It has a slow onset (2-4 hours) and a long duration of action (10 hours) and is extensively metabolized by the liver (50% during first pass). Alpha (α)-blockers/Specific drugs Terazosin, doxazosin and alfuzosin They are relatively α1-selective blockers, with higher selectivity than prazosin Their half lives about three hours They may produce postural hypotension They produce vasodilatation with less tachycardia than prazosin They produce relaxation of smooth muscle of the bladder neck and prostate capsule. So, they facilitate micturition. For this action, they can be used in case of urine retention associated with benign prostatic hyperplasia (BPH) in which prostate compresses the urethra and prevent micturition. Alpha (α)-blockers/Specific drugs Tamsolusin and silodosin They are selective for α1A–adrenoceptors in the sphincter of urinary bladder. α1A stimulation leads to contraction of the sphincter, so, no micturition α1A blockade leads to relaxation of the sphincter. So, it facilitates micturition Tamsolusin and silodosin are used clinically in treating urine retention associated with benign prostatic hyperplasia (BPH) and they are better here than prazosin, terazosin and doxazosin They cause less hypotension than prazosin Alpha (α)-blockers Therapeutic Uses 1.α1-adrenoceptor antagonists are used to treat mild and moderate essential hypertension (Prazosin and terazosin). 2. Phentolamine and phenoxybenzamine are used to treat hypertension of pheochromocytoma. β-receptor antagonists are often used to prevent the cardiac effects of excessive catecholamines after an α-receptor blockade is established. 3. Prazosin, terazosin, doxazosin and alfuzosin are used to treat urinary obstruction of benign prostatic hyperplasia (BPH) in patients who are poor candidates for surgery. 4.Tamsulosin and silodosin may have greater efficacy to treat urinary obstruction of BPH, due to their selective action at α1A-receptors. Alpha (α)-blockers Therapeutic Uses 5. Phentolamine is used to treat reversible peripheral vasospasm (Raynaud syndrome). 6. It is used to treat erectile dysfunction in combination with papaverine. α2-receptor antagonists (e.g. yohimbine) have no important therapeutic uses (why ??). Because its selective α2-receptor blockade increases release of noradrenaline. Therapeutic Uses of Selected Alpha Adrenoceptor Antagonists Alpha (α)-blockers Adverse Effects Phentolamine and phenoxybenzamine may cause postural hypotension, reflex tachycardia, arrhythmias, angina, and diarrhoea. These drug should be used cautiously in patients with a peptic ulcer or with coronary artery disease. Prazosin, terazosin, and doxazosin produce postural hypotension and bradycardia on initial administration (first- dose hypotensive effect); these drugs produce no significant tachycardia. Nasal congestion due to vasodilatation (α1–adrenoceptor effect). Sexual dysfunction; α1–adrenoceptor stimulation cause ejaculation. Beta (β)- blockers All β-blockers are competitive antagonism catecholamines and other adrenomimetic at β-adrenoceptors. β– blockers can be classified into the following: Non selective beta-blockers: propranolol, timolol, nadolol and pindolol Selective β1-blockers: atenolol, esmolol, metoprolol, practolol, acebutolol and bisoprolol. Beta (β)- blockers Pharmacological Effects on Cardiovascular System They decrease the heart rate (negative chronotropic effect). They decrease myocardial contractility and cardiac output (negative inotropic effect), and They reduce conduction velocity (negative dromotropic effect). β -adrenoceptor antagonists lower blood pressure, possibly due to their combined effects on the heart (β1blockade), the kidney (renin-angiotensin system), and inhibition of sympathetic outflow from the CNS. These drugs reduces sympathetic-stimulated increases in heart rate and contractility and cardiac output. β- adrenoreceptor antagonists lengthen AV conduction time and refractory peroid and suppress automaticity. Beta (β)- blockers Pharmacological Effects in Respiratory System β-blockers increase airway resistance (bronchoconstriction) as a result of β2-receptor blockade. This respiratory effect is more pronounced in asthmatic patients. Pharmacological Effects in The Eye They cause contraction of the ciliary muscle leading to opening of the canal of Schlemm this increases outflow of aqueous humor and decreases its production. All these leads to decreased intraocular pressure (IOP). Endocrine and Metabolic Effects β-blockers inhibit lipolysis ( β3 effect). They inhibit glycogenolysis in the liver (β2) and glucagon secretion (they may cause hypoglycaemia). In insulin–dependent diabetics (type 1), β-blockers mask the symptoms of hypoglycemia (sweating, tachycardia and tremors). Pharmacological Effects of Beta blockers Intrinsic Sympathomimetic Activity (ISA) Some of the β-blockers produce some action of β-agonist e.g., Pindolol and carteolol So, they are less dangerous when given to patients with bronchial asthma (β2-agonists activity) or excessive bradycardia Membrane Stabilizing Action (MSA) Some β-blockers stabilize the cell membrane by blocking Na+ channels. Therefore, produce “local anesthetic action” e.g., propranolol and pindolol Beta (β)-adrenoceptor blockers Specific drugs: Propranolol (Inderal)R It is the prototype β-adrenoreceptor antagonist. Propranolol is a nonselective competitive antagonist at β1-and β2- receptors. Propranolol have low bioavailability (˂ 50%) because of extensive first-pass metabolism. Propranolol is used in long-term treatment of hypertension, but it is not useful for hypertensive crisis. This drug is used to treat supraventricular and ventricular arrhythmias and is administered intravenously for the emergency treatment of arrhythmias. Propranolol is 90% bound to plasma proteins. It has membrane stabilizing action (MSA) Beta (β)-adrenoceptor Antagonists/Specific drugs Metoprolol, Betaxolol, Bisoprolol, Atenolol, Acebutolol, Esmolol and Nebivolol They are selective β1-receptor antagonists. Their advantages over nonselective blockers is that, they can be used to treat cardiovascular disease in asthmatic patients. Atenolol has little local anaesthetic activity (MSA); it enters the CNS poorly. Betaxolol is used topically for chronic open-angle glaucoma. Esmolol is ultrashort-acting (half-life is 10 minutes) due to esterase metabolism, it is administered by IV infusion. Beta (β)-adrenoceptor Antagonists/Specific drugs Timolol, Levobunolol, Metipranolol and sotalol They are nonselective β-blockers. Nadolol has a longer duration of action. Timolol, metipranolol and levobunolol are used topically for treatment of glaucoma. These drugs have no local anaesthetic activity. Sotalol is used to treat arrhythmias. Pindolol, carteolol, and penbutolol are nonselective antagonists with partial β2-agonists activity (ISA) Beta (β)- blockers 1. They are used to treat hypertension, often in combination with a diuretic or vasodilator. 2. Timolol, propranolol, and metoprolol are used to reduce the incidence of myocardial infarction. 3. β-blocker are used for prophylaxis and treatment of supraventricular and ventricular arrhythmias. 4. They are also used to treat angina pectoris. 5. Topical application of timolol, betaxolol, levobunolol, and carteolol reduces intraocular pressure in glaucoma. 6. Propranolol is used to control clinical symptoms of hyperthyroidism. 7. Propranolol relieves acute anxiety and panic symptoms. 8. Propranolol, timolol, and metoprolol are beneficial in the prophylaxis of migraine. Therapeutic Uses of Selected Beta Adrenoceptor Antagonists Beta (β)- blockers Adverse Effects and Contraindications Nonselective blockers may cause bronchoconstriction. They can precipitate heart failure or heart block. Propranolol, and other β-receptor blockers, cause sedation, depression, sleep disturbances (hallucination and night mares) as well as rare drug allergies. Burning or dryness of eyes after topical application of timolol to the eye. β-adrenoreceptor antagonists may cause sexual dysfunction. They are contraindicated for asthmatics and COPD patients. Beta (β)- blockers Adverse Effects and Contraindications Beta-blockers are contraindicated in peripheral vascular disease and heart failure. These drugs may augment insulin action in diabetics and mask tachycardia and other symptoms associated with hypoglycemia. All agents of β-adrenoreceptor antagonists should be administered with extreme caution in patients with preexisting compromised cardiac function because they can precipitate heart failure or heart block. Beta (β)- blockers Adverse Effects and Contraindications On chronic use of β–lockers, abrupt withdrawal causes the β- adrenoceptors to become “supersensitive” and even the circulating catecholamine can stimulate them to increase risk of angina and cause severe arrhythmias. So, withdrawal should be very gradual over weeks i.e., tapered withdrawal is recommended. Drugs with Combined β- and α- Blocking Activity Labetalol, bucindalol, carvedilol and medroxalol Labetalol is a competitive antagonist (partial agonist) that blocks β-receptors and α1-receptors (3:1 to 7:1 ratio). Labetalol reduces heart rate and myocardial contractility, decreases total peripheral resistance and lowers blood pressure. Labetalol is approximately one-third as potent as propranolol as a β-blocker, and one-tenth as potent as phentolamine as an α-blocker This drug is administered orally or IV and undergoes extensive first-pass metabolism. Drugs with Combined β- and α- Blocking Activity Labetalol may be used to reverse hypertension crisis due to sudden increase in α-receptor stimulation caused by, for example, an overdose with sympathomimetic agonists or pheochromocytoma. Because it possesses both α- and β-blocking activity, labetalol is useful for the preoperative management of patient with pheochromocytoma. The adverse effects of labetalol include postural hypotension, and gastrointestinal disturbances Carvedilol also has mixed activity but is equiactive at β- receptors and α1-receptors