Lectures 20-21 Adrenergic Antagonists I-II.pdf

1 Dr. Wesam Saleh Abdel-Razaq PHBS - 301 Adrenergic Drug Antagonists I-II Development Dr. Tariq Alqahtani Dr. WesamDr. Abdel-Razaq / Dr. Mai Al Ajaji Rawan Al Na...

1 Dr. Wesam Saleh Abdel-Razaq PHBS - 301 Adrenergic Drug Antagonists I-II Development Dr. Tariq Alqahtani Dr. WesamDr. Abdel-Razaq / Dr. Mai Al Ajaji Rawan Al Nafisah PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  2 LECTURE LEARNING OUTCOMES At the end of the lectures, the students should be able to: 1. Recall different types of adrenergic receptors and the consequences of their selective pharmacological blockade. 2. Recognise the distinct pharmacological profiles of selective vs non-selective α- adrenergic receptor blockers. 3. Describe the therapeutic applications of α-adrenergic receptor blockers. 4. Describe the different types of β-adrenergic receptor blockers. 5. Recognise the distinct pharmacological profiles of selective vs non-selective β- adrenergic receptor blockers. 6. Describe the therapeutic applications of selective vs non-selective β-adrenergic receptor blockers. 7. Describe drugs with combined α- and β-adrenergic receptor blocking activity and their clinical utility. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  3 X Adrenergic Antagonists Adrenergic antagonists (also called adrenergic blockers or sympatholytic agents): – They bind to the adrenergic receptors and thus prevent their activation by the endogenous catecholamines (NE, E, D). Adrenergic antagonists are classified according to their relative affinities for α or β receptors: – α-adrenergic blocking agents – β-adrenergic blocking agents PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  4 Ritter, J. et al. (2020) Rang and Dale’s Pharmacology. Edinburgh: Elsevier. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  5 a sin PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  6 Relative Selectivity of Adrenergic Antagonists PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  7 Clinical Roles of Adrenergic Antagonists Alpha (α)-receptor antagonists: – The non-selective α-antagonists (α1 and α2) are used – prior to surgery – in the treatment of pheochromocytoma (a rare, usually benign catecholamine-secreting tumour of the chromaffin cells in the adrenal gland). - This can lead to classic sympathetic symptoms, including headaches, hypertension, tachycardia, and diaphoresis (excessive sweating). The selective α1-antagonists are used in the treatment of: Primary hypertension Benign prostatic hyperplasia (BPH) Y Selective α2 Antagonists PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  8 Clinical Roles of Adrenergic Antagonists Read Beta (β)-receptor antagonists: – Are useful in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, glaucoma, and other conditions and include: – Non-selective β-antagonists (β1 and β2) – Selective β1-antagonists – The blockade of peripheral dopamine (D) receptors is of no clinical importance at present. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  9 α – Adrenergic Antagonists PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  10 Alpha Antagonists I Adverse effects include postural hypotension, nasal stuffiness, nausea, 2 vomiting, reflex tachycardia, and male ejaculation inhibition. – Severe lowering of blood pressure (hypotension) → augmented release of NE by SNS → reflex tachycardia. – The effect is more marked in hypovolemic patients and in the standing position (less in the supine position). PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  11 Nonselective α – Antagonists Non-selective α-blockers have limited clinical application. Phenoxybenzamine: – It is used with a beta-blocker to treat inoperable or metastatic [anly] pheochromocytoma. increases NE > -. – It is a non-selective and irreversible α-receptor blocker. - – It has long-lasting effects after a single dose (24 hours – days). - – It blocks α1 receptors, reversing the vasoconstriction of - epinephrine. – It blocks presynaptic α2 receptors, leading to an increase in - cardiac output. (Why?) Thus, phenoxybenzamine is not successful in maintaining lowered blood pressure. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  12 Nonselective α – Antagonists * Dr. Phentolamine: 2It is used for the short-term management of pheochromocytoma and a hypertensive crisis due to the abrupt withdrawal of clonidine or the interaction of tyramine-containing foods with MAO inhibitors. It is a competitive blocker of both α1 and α2 receptors, with action lasting for approximately four hours after a single dose. It is contraindicated in patients with decreased coronary perfusion because it may induce reflex cardiac stimulation. (Why?) PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  13 Selective α1 Antagonists "Osin" They are selective, competitive blockers of the α1 receptor - (e.g. Prazosin, Terazosin, Doxazosin, Tamsulosin, and - - - & Alfuzosin). - Being α1-receptor-selective allows NE to exert unopposed negative feedback mediated by the presynaptic α2 receptors. Mechanism and sites of action: – Blocking α1 receptors reduces hypertension by dilating both the resistance (arterioles) and capacitance (venules) - & blood vessels. – Blood pressure is reduced more in the upright than in the supine position. – They cause minimal effects on cardiac output, renal blood flow, and GFR. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  14 Selective α1 Antagonists Therapeutic applications due to α1 receptor blocking: – Essential hypertension due to arteriole and venous vasodilation. – Benign prostatic hyperplasia as an alternative to surgery to reduce S contraction of the bladder neck and prostate capsule and improve urine flow. Tamsulosin is a selective inhibitor of α1A receptors found on the smooth muscle of the prostate, with relatively minimal effect on BP. – Congestive heart failure due to dilation of arteries and veins and decreased preload and afterload, leading to an increase in cardiac output. – Pheochromocytoma is a tumour of the adrenal gland. Raynaud’s disease is a rare peripheral vascular disorder due to vasospasms in toes and fingers that feel numb and cold in response to cold or stress. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  15 ↓ Selective α1 Antagonists PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  16 Selective α1 Antagonists Adverse effects: – Orthostatic hypotension: light-headedness and dizziness due to reduced blood flow to the brain. – First-dose effect: Due to the initial severe hypotensive response, 1% of patients may lose consciousness (30–60 minutes) after receiving their first dose (small initial dose at bedtime). – Nasal congestion due to dilation of nasal mucosa blood vessels. – Sodium and water retention due to reduced kidney blood perfusion (usually combined with diuretics). – Reflex tachycardia due to reduced BP → baroreceptor reflex → increased heart rate (usually combined with a β-blocker).  α1 antagonists are more effective when used in combination with other agents, such as diuretics and β-blockers. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  17 Selective α2 Antagonists I Selective α2 antagonists do not have much utility in clinical practice. 2  Yohimbine: only drug.  It is found in the bark of the Yohimbe tree.  It is a selective, competitive blocker of α2 receptors in the CNS that eventually increases sympathetic outflow to the periphery. Therapeutic uses: 3  It is sometimes used as a sexual stimulant for the treatment of impotence.  It is used to relieve vasoconstriction associated with Raynaud’s disease (CCBs are preferable). 4  It is contraindicated in CNS and cardiovascular disorders because it is a CNS and cardiovascular stimulant. - PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  18 β – Adrenergic Antagonists PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  19 PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  20 Relative Selectivity of Adrenergic Antagonists PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  21 Beta Antagonists (β-blockers) The names of all β-blockers end in 'olol'. – For example, propranolol, atenolol, and metoprolol. – With the exception of a few, such as labetalol and carvedilol. - - (Why?) > + B - a β-blockers can be subdivided into: – Nonselective β-blockers: inhibit both β1 and β2 receptors. – Selective (cardioselective) β-blockers: inhibit β1 receptors only. – There are no clinically useful selective β2 antagonists. (Why?) -- causes bronchoconstriction. β2 antagonists cause bronchoconstriction, particularly in asthmatic patients. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  22 Types of β-blockers PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  23 X Properties of β-blockers > - ChS. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  24 & Exam Important β-blockers. with partial agonist activity Non-selective Cardioselective (Intrinsic α and β (β1 and β2) (β1) sympathomimeti c activity) Nadolol Acebutolol Pindolol Labetalol Propranolol* Atenolol Alprenolol Carvedilol Timolol Metoprolol Oxprenolol* * High lipid solubility PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  25 Therapeutic Applications of β-blockers Heart + Blood pressure. The therapeutic applications of β-blocker are due to β1 receptors: – Hypertension: reduces cardiac output, suppresses renin release - from the kidneys,--and reduces peripheral resistance. – Angina pectoris: (paroxysmal pain in the heart region due to decreased oxygen supply to the heart) decreases cardiac workload. – Cardiac dysrhythmias: reduces the rate of SA node discharge and suppresses conduction through the AV node. – Myocardial infarction and heart failure. (How?) – Hyperthyroidism: reduces induced tachycardia. Neurologic disorders, migraine headaches, glaucoma, and other conditions (particularly propranolol). - PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  26 Consequences of β1-blocking 1. Reducing heart rate (negative chronotropic effect). - - 2. Reducing the force of contraction (negative inotropic effect). - -- 3. Reducing the velocity of impulse conduction at the AV node. Propranolol (Inderal®) was the first nonselective β-blocker shown to be effective in the treatment of hypertension and ischemic heart disease. Binds BJ directly. Cardioselective β1-blockers such as metoprolol and atenolol have been largely replacing propranolol. All β-blockers are useful for the treatment of mild to moderate hypertension without prominent postural hypotension. (because α1-receptors that control vascular resistance are unaffected). In severe hypertension, β-blockers are useful in preventing the reflex tachycardia that often results from vasodilators. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  27 Propranolol (Inderal®) Propranolol is the prototype β-adrenergic antagonist that blocks both β1 and β2 receptors with equal affinity. - Pharmacological actions: Heart: blockade of β1-receptors reduces heart rate and cardiac output. Blood vessels: blockade of β2-receptors prevents vasodilation (Is this supposed to ↑ blood pressure? ……………….. NO) (Why? ……………….. due to the reduced cardiac output) Lungs: blockade of β2-receptors in COPD or asthmatic patients induces bronchoconstriction. Liver: blockade of β2-receptors decreases glycogenolysis and glucagon secretion. Therefore, there is high caution in type-1 diabetic patients. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  28 Propranolol (Inderal®) Pharmacokinetics – After oral administration, propranolol is almost completely absorbed because it is highly lipophilic. - – It is subject to first-pass effect, and only about 25- 30% of the administered dose reaches systemic circulation. – Its volume of distribution of orally administered drugs is quite large (4 litres/Kg), and the drug readily crosses the BBB. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 187. Retrieved September 8. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  Adverse effects of Propranolol 29 (Nonselective β-blockers) Due to β1 blockade: – Bradycardia: reduces heart rate and force of contraction, can be reversed by isoproterenol and atropine. – Reduces cardiac output and may lead to heart failure, shortness of breath, night coughs, and swelling of the extremities. – AV heart block: β-blockers suppress AV conduction. Due to β2 blockade: – Bronchoconstriction: contraindicated in asthmatic patients – Inhibition of glycogenolysis: in the liver and skeletal muscles, β1-selective blockers are preferred in diabetic - patients. In addition to the previous effects, propranolol causes CNS effects, including depression, insomnia, nightmares, and hallucinations. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  30 Selective β-blockers Cardioselective β blockers: atenolol, metoprolol (Lopressor®), bisoprolol, betaxolol, nebivolol, and esmolol. They preferentially block the β1-receptors that have largely eliminated the unwanted β2-receptor effect (bronchoconstrictor) of propranolol in asthma patients. They antagonise β1-receptors at doses 50- to 100-fold less than those required to block β2-receptors. – Cardioselectivity can be lost at high doses. They share therapeutic applications with nonselective β- blockers; however, selective β-blockers are preferred in patients with asthma or diabetes. - PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  31 β-blockers with partial agonist activity Pindolol and acebutolol: physiological effect. Has a β-blocker with intrinsic sympathomimetic activity (ISA). Limited degree of receptor activation while preventing the strong endogenous agonist (catecholamines) from binding to the β-receptors to cause full activation. Therapeutically effective in hypertensive patients with moderate bradycardia. They have very little effect on resting heart rate & cardiac output. Glucose metabolism is less affected than with propranolol, making those agents valuable in the treatment of hypertensive in diabetic patients. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  32 β-blockers with concurrent α1-blocking actions  Labetalol and carvedilol: They produce additional peripheral vasodilation, thereby further reducing blood pressure. They do not alter serum lipid or blood glucose levels. Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefits in heart failure. Labetalol may be employed as an alternative to methyldopa in the treatment of pregnancy-induced hypertension. Acute administration of β-blockers can trigger heart failure or worsen the condition. However, clinical studies have shown the benefits of carvedilol, metoprolol, and bisoprolol in patients with stable chronic heart failure. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  33 Indirect-Acting Sympatholytic PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  34 Indirect-Acting Sympatholytic Agents act by interfering with NE release, reducing sympathetic stimulation of peripheral receptors (blood vessels and the heart). Adrenergic neuron-blocking agents (Reserpine and Guanethidine) – act within the sympathetic terminals, causing depletion of NE in sympathetic neurons, which impairs sympathetic functions. – However, these drugs are no longer available clinically because of intolerable toxicity. Centrally acting adrenergic drugs (Clonidine and α-Methyldopa) – act within the CNS as selective α2-receptor agonists that decrease NE release and thus reduce sympathetic outflow. -BP -. – They are used primarily for the treatment of hypertension. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  35 Ritter, J. et al. (2020) Rang and Dale’s Pharmacology. Edinburgh: Elsevier. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  36 Clonidine (Catapres®) 0.2 mg MOA: a selective α2-receptor agonist. Negative Feedback - > -. Causes bradycardia, decreases cardiac output, and promotes vasodilation. Used primarily for the treatment of hypertension that has not responded adequately to other treatments. Does not reduce renal blood flow or glomerular filtration and, therefore, is useful in the treatment of patients with renal disease. Blood pressure declines within 30 to 60 minutes after an oral dose, with the greatest decrease occurring within 2 to 4 hours. Pharmacokinetics: it is well absorbed orally (95%), given twice daily, has a relatively short half-life (8 to 12 hours), and is excreted by the kidney (duration extends up to 40 hours in patients with renal disease). PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  37 Clonidine (Catapres®) Adverse effects are generally mild. Because it may cause sodium and water retention, clonidine may be administered in combination with a diuretic. Other adverse effects include sedation, dry mouth (xerostomia), and constipation. Clonidine transdermal patch: used to maintain blood pressure control for seven days after a single application (less sedation than clonidine tab). Caution: Abrupt withdrawal of clonidine after prolonged use can result in life-threatening rebound hypertension. – It should be withdrawn gradually while other antihypertensive drugs are being substituted. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  38 Rebound Hypertension Normal After prolonged use increased number of receptors (upregulation) PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  39 α-Methyldopa (Aldomet®) It is an analogue of DOPA α-Methyldopa should be converted centrally to → α-methyl-norepinephrine. It acts as an α2-receptor agonist It reduces peripheral vascular resistance. - The maximal antihypertensive effect is in 4 to 6 hrs and can persist for up to 24 hrs. It is especially valuable in hypertensive patients with renal insufficiency and in pregnancy. Most common side effects are sedation and drowsiness, and rare adverse effects include Rang & Dale's Pharmacology, 10th Edition haemolytic anaemia and hepatic necrosis. PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah  40 Remember Drugs of ANS: – Drugs acting on the Parasympathetic Nervous System: (Cholinergic drugs) are used primarily for their effects on the GI tract, bladder, and eyes. – Drugs acting on the Sympathetic Nervous System: (Adrenergic drugs) are used primarily for their effects on the heart, blood vessels, and lung PHRB – 301 Lecture; Adrenergic Antagonists I-II Dr. Alqahtani and Dr. Al Nafisah