Adrenergic Antagonist PDF

Adrenergic antagonist P H A R M A C O L O G Y- 1 L E C T U R E ( P O - 3 1 5 / P O C - 3 1 6 ) PRESENTED BY ABEER BISHR LECTURER OF PHARMACOLOGY FA L L 2 0 2 4  Course LOs covered in thi...

Adrenergic antagonist P H A R M A C O L O G Y- 1 L E C T U R E ( P O - 3 1 5 / P O C - 3 1 6 ) PRESENTED BY ABEER BISHR LECTURER OF PHARMACOLOGY FA L L 2 0 2 4  Course LOs covered in this lecture 1-1-4-2 The pharmacological actions, side effects, drug interactions and uses of drugs acting on the autonomic nervous system and autacoids. 1-1-5-1 Utilize data from basic sciences to address therapeutic issues 3-1-4-1 Select the appropriate pharmacotherapeutic approaches based on the etiology, pathophysiology, laboratory diagnosis and clinical features of different diseases. 3-2-1-1 Recognize the pharmacological properties of different drugs.  Adrenergic antagonists Drugs that block or reduce the actions of epinephrine or norepinephrine are called sympatholytics or adrenergic receptor antagonists. These agents can alter the function and oppose the “flight-or-fight” response. The effects of the sympatholytics may be desired or unwanted effects and this depends on receptor selectivity of these compounds and the distribution of receptors that they target.  α-Receptor antagonists Non-selective α blockers (α1& α2) Selective α blocker (α1OR α2) ▪Phentolamine is a prototypical α1- adrenergic receptors antagonist: Doxazosin and prazosin competitive antagonist at both α1 - and α2 -adrenergic receptors. Phenoxybenzamine binds covalently α2 - adrenergic receptors antagonist: to both α1 - and α2 -adrenergic Yohimbine receptors (irreversible blockade).  Nonselective α-Adrenergic Receptor Antagonists A. Phentolamine &Phenoxybenzamine: Remember: α1 -adrenergic receptors in blood vessels (activation cause vasoconstriction) α2 -adrenergic receptors: presynaptic (activation inhibit NE release)  Phentolamine &Phenoxybenzamine Effect on BP: In a normal individual without hypertension, α-adrenergic receptor antagonists cause only small decreases in blood pressure but can orthostatic or postural hypotension accompanied by reflex tachycardia. Cardiac effect: - Reflex increase in heart rate (due to orthostatic hypotension). - α2-receptor blockade cause blocking to the inhibitory effect on NE release, so peripheral NE release is increased stimulating β1 cardiac receptors  Phentolamine &Phenoxybenzamine Therapeutic uses: Phenoxybenzamine is particularly useful in treatment of pheochromocytoma( which is a tumor of adrenal gland which secretes NE & E leading to signs of excessive catecholamine including hypertension, tachycardia & arrhythmias) as it causes noncompetitive blockade of α-receptors; thus, it prevents episodic surges of catecholamine releases during pre- and post-operative period. Treatment of Raynaud’s disease  Selective α1 -Adrenergic Receptor Antagonists Prazosin, doxazosin and tamsulosin are selective α1 -adrenergic receptor antagonists. They block α1 receptors in arterioles and veins, these drugs reduce peripheral vascular resistance and lower blood pressure. Blood pressure effect: They block α1 receptors in arterioles and veins, these drugs reduce peripheral vascular resistance and lower blood pressure. CVS effect: They cause less reflex tachycardia than nonselective α receptor antagonists, because selective α1 receptor antagonists can not block α2 receptor.  Selective α1 -Adrenergic Receptor Antagonists Therapeutic uses: These drugs effectively reduce blood pressure but they are not first-line antihypertensives They may be used as add-on therapy when combinations of first-line drugs do not provide effective blood pressure control. Adrenergic α1 receptor antagonists also relax smooth muscle in the prostate and bladder neck and thereby relieve urinary retention and other symptoms associated with benign prostatic hyperplasia (BPH).  Selective α1 -Adrenergic Receptor Antagonists Tamsulosin has the least effect on blood pressure because it is less selective for α1B receptors found in the blood vessels and more selective for α1A receptors in the prostate and bladder So, Tamsulosin is preferred in treatment of BPH over doxazosin Side effects of selective α1and non selective blockers  Selective α2-Adrenergic Receptor Antagonists Yohimbine: It is a selective competitive α2 -blocker. It is found as a component of the bark of the yohimbe tree and has been used as a sexual stimulant and in the treatment of erectile dysfunction.  β- Blockers (LOL) Non- selective β blocker Selective β1 blocker Propranolol Acebutolol Nadolol Atenolol Timolol Esmolol Metoprolol  β-Adrenergic Receptor Antagonists with intrinsic sympathomimetic activity Acebutolol and pindolol: Antagonists with partial agonist activity Acebutolol (β1-selective antagonist) and pindolol (nonselective β-blocker) are not pure antagonists. These drugs also have the ability to weakly stimulate both β1 and β2 receptors and are said to have intrinsic sympathomimetic activity (ISA). Therapeutic use in hypertension: β-blockers with ISA are effective in hypertensive patients with moderate bradycardia, because a further decrease in heart rate is less pronounced with these drugs.  Nonselective β-Adrenergic Receptor Antagonists The first-generation and prototypical β-adrenergic receptor blocker propranolol exerts its clinically relevant effects via the inhibition of both β1 and β2 receptors. Newer compounds differ primarily in their duration of action and subtype selectivity. Nadolol and timolol: Nonselective β antagonists that are more potent than propranolol.  Nonselective β-Adrenergic Receptor Antagonists Effects: Blocks the positive chronotropic, dromotropic, and inotropic responses to β receptor agonists and to sympathetic activation (heart is a major site of β1 -adrenergic receptor ). Reduces renin secretion. The net result of these effects β-blockers in general have antihypertensive properties of these drugs, which are effective for the treatment of hypertension (not 1st choice).  Nonselective β-Adrenergic Receptor Antagonists Therapeutic uses: Treatment of glaucoma: Timolol decreases intraocular pressure in glaucoma. How?? This occurs by decreasing the secretion of aqueous humor by the ciliary body. Nonselective β-blockers such as propranolol are also useful for the treatment of other cardiovascular diseases and are frequently used in patients with stable angina, or with various types of arrhythmias Propranolol is effective in blunting the sympathetic stimulation that occurs in hyperthyroidism.  Nonselective β-Adrenergic Receptor Antagonists Side effects: 1- Bronchoconstriction 2- Sexual dysfunction 3- Hypoglycemia 4- Hypertriglyceridemia Note that treatment with β-blockers must never be stopped abruptly because of the risk of precipitating cardiac arrhythmias, which may be severe. The β-blockers must be tapered off gradually over a period of at least a few weeks. Long-term treatment with a β antagonist leads to up-regulation of the β receptor.  Selective β1 -Adrenergic Receptor Antagonists At low doses, acebutolol, atenolol, metoprolol, and esmolol are more selective in blocking β1 receptors than β2 receptors. Thus, these agents are more likely to have effects on cardiac muscle and the conduction system than on bronchial smooth muscle.  Selective β1 -Adrenergic Receptor Antagonists Actions: They decrease blood pressure. By selectively blocking β1 receptors, these drugs decrease cardiac output & reduce renin release. In addition to its cardio-selective β blockade, nebivolol releases nitric oxide from endothelial cells and causes vasodilation. Esmolol has a very short half-life due to metabolism. It is only available intravenously and is used to control blood pressure or heart rhythm during surgery  Selective β1 -Adrenergic Receptor Antagonists Therapeutic uses: 1- Treatment of hypertensive patients with impaired pulmonary function. 2- Chronic stable angina. 3-Bisoprolol and extended-release formulation of metoprolol are indicated for the management of chronic heart failure.  Selective β1 -Adrenergic Receptor Antagonists Advantages of selective β1 blocker over Non selective β clocker?? Receptor selectivity lessens the likelihood of increasing bronchoconstriction, advantageous for patients with asthma. It is preferred in patients with peripheral vascular disease because the selective β1 agents do not inhibit β2 -mediated dilation of skeletal muscle blood vessels.  Mixed-Action α1 /β-Adrenergic Receptor Antagonists Actions: Labetalol and carvedilol are nonselective β-blockers with concurrent α1 -blocking actions that produce peripheral vasodilation, thereby reducing blood pressure Carvedilol also appears to attenuate oxygen free radical–initiated lipid peroxidation (anti-oxidant effect)  Mixed-Action α1 /β-Adrenergic Receptor Antagonists Therapeutic use: Labetalol can be used as an alternative to methyldopa in the treatment of pregnancy-induced hypertension. Intravenous labetalol is also used to treat hypertensive emergencies, because it can rapidly lower blood pressure. Carvedilol also indicated for the management of chronic heart failure.. Adverse effects: Similar to the nonselective β-blockers (e.g., bronchospasms), similar to α1 antagonists (e.g., postural hypotension).  β- blockers and hypoglycemia β-blockers can cause or exacerbate hypoglycemia in some individuals. The mechanism responsible for β-blocker–induced hypoglycemia involves inhibition of hepatic glucose production and reduction in glycogenolysis Non-selective β-blockers are more likely to cause hypoglycemia than cardio-selective ones. Nevertheless, patients on the latter should still be cautioned about the potential for drug-induced hypoglycemia. Furthermore, β-blockers have the potential for masking symptoms of hypoglycemia. The catecholamine-mediated neurogenic hypoglycemic symptoms masked by this class of medications include tremor and palpitations. Sweating, however, remains unmasked and may be the only recognizable sign of hypoglycemia in individuals treated with β-blockers.  References 1- Title: Pharmacology, Lippincott’s illustrated reviews Authors: Richard A. Harvey, Michelle A Clark, Richard Finkel, Jose A. Rey, Karen Whalen Publisher: Wolters Kluwer, Wolters Kluwer Health Edition:7th Year:2018 2- Title: Brody’s Human Pharmacology Authors: Wecker L. Publisher: Elsevier Edition:6th Year:2018