Antiadrenergics Lecture Notes PDF

Antiadrenergics Pranaya Mishra PhD [email protected] 1 2 Learning Objectives • Describe the receptor affinities for various adrenergic antagonists. • Explain the mechanism of action of nonselective and selective αadrenergic antagonists. • Explain the mechanism of action of nonselective and sel...

Antiadrenergics Pranaya Mishra PhD [email protected] 1 2 Learning Objectives • Describe the receptor affinities for various adrenergic antagonists. • Explain the mechanism of action of nonselective and selective αadrenergic antagonists. • Explain the mechanism of action of nonselective and selective βadrenergic antagonists. • Explain the mechanism of action of indirect-acting antiadrenergic drugs. • Describe the pharmacologic effects of nonselective and selective α-adrenergic antagonists. • Describe the pharmacologic effects of nonselective and selective β-adrenergic antagonists. • Relate the effects of adrenergic antagonists to the blockade of specific receptors. 3 Learning Objectives • Describe the significant pharmacokinetic features of αadrenergic and β-adrenergic antagonists. • Describe the main adverse effects of α-adrenergic and βadrenergic antagonists. • Describe the main drug interactions between adrenergic antagonists and other autonomic drugs. • Outline the main contraindications of α-adrenergic and βadrenergic antagonists. • Describe the main therapeutic uses of α-adrenergic antagonists. • Describe the main therapeutic uses of β-adrenergic antagonists. 4 Diseases Treated with Autonomic Drugs • Hypertension • Ophthalmic hyperemia • Hypotension • Shock • Heart failure • Angina • Arrhythmias • Pheochromocytoma • Benign prostatic hyperplasia • Nasal congestion (red eyes) • Myasthenia Gravis • Urinary retention • Urinary incontinence • Glaucoma • Asthma • COPD • Dry mouth • Sialorrhea 5 This list is not comprehensive; however, many of the most common uses are listed. Adrenergic blockers α blockers Irreversible e.g., Phenoxybenzamine ß blockers Reversible Non-selective e.g., Phentolamine Selective α1 blockers e.g., Prazosin, Terazosin, Doxazosin, Tamsulosin α2 blockers e.g., Yohimbine 6 ß-blockers Non-selective (ß1 +ß2 blockers) 1. without intrinsic sympathomimetic activity e.g., Propranolol, Timolol, Sotalol, Nadolol 2. with intrinsic sympathomimetic activity e.g., Acebutolol, Pindolol Selective ß1-selective (cardioselective) e.g., Atenolol, Acebutolol, Esmolol, Metoprolol ß2-selective e.g., Butoxamine 3. with additional α-blocking property e.g, Labetalol, Carvedilol 7 α blockers 8 α blockers GENERAL EFFECTS OF α BLOCKADE on CVS: • • • • blockade of vasoconstriction – TPR - hypotension cause reflex tachycardia (due to fall of BP) postural reflex is interfered – postural hypotension Dale’s vasomotor reversal (Epinephrine reversal) 9 Other Actions of α blockade • relaxation of trigone & spinchter muscles in the base of urinary bladder and prostate -------> decrease resistance to urinary outflow • nasal stuffiness and miosis • increase intestinal motility --------> diarrhea • failure of ejaculation (impotence) 10 Nonselective α blocker (antagonists) Phenoxybenzamine : • non-selective, irreversible α1 and α2 blocker • Actions - prevents vasoconstriction - causes reflex tachycardia • Selectively used in Pheochromocytoma (prior to surgical removal, to preclude hypertensive crisis) • Dale’s vasomotor reversal (Epinephrine reversal) 11 Epinephrine reversal: • Epinephrine, when given in high doses, increases blood pressure (vasopressor effect) by acting on the α1 receptors. Epinephrine has an effect on ß2 receptors also (at low doses, epinephrine stimulates only ß2 predominantly). So, when α1 blockers are given before epinephrine (high dose), it will not be able to act on α1 receptor and won’t exhibit a vasopressor effect, instead epinephrine will cause a drop in BP (vasodepressor effect). 12 α1 effect Blood pressure Epinephrine in high dose ß2 effect 13 Epinephrine reversal: "vasomotor reversal of Dale” Blood pressure Epinephrine Phenoxybenzamine DROP in BP: Predominant ß2 effect 14 Nonselective α blocker (antagonists) Phentolamine • a competitive (reversible), non-selective α blocker (both α1 and α 2 blocker) • like phenoxybenzamine, produces postural hypotension and causes epinephrine reversal • also used in Pheochromocytoma (prior to surgical removal, to preclude hypertensive crisis) • causes reflex tachycardia, which is mediated by baroreceptor reflex and by blocking of α2 receptors of the cardiac sympathetic nerves 15 Nonselective α blocker (antagonists) Phentolamine Adv effects: • can trigger arrhythmias and anginal pain C/I: • patients with decreased coronary perfusion 16 Therapeutic uses: α blockers – only used for the acute hypertension (in hospital; given IV) – opposing catecholamines actions in Pheochromocytoma – Raynaud’s disease 17 Raynaud’s disease 18 Adverse effects • Postural hypotension • Nasal stuffiness • Sexual dysfunction (inhibit ejaculation) • Tachycardia • Contraindicated in ↓ coronary perfusion 19 α1 selective blockers • Prazosin • Terazosin • Doxazosin – long acting • Tamsulosin (α1A antagonist) 20 α1-selective blockers α1 blocker Prazosin Duration of action High first pass metabolism 6 hrs Terazosin 20 hrs Doxazosin 30 hrs 21 α1-selective blockers Uses : • as antihypertensive agent (Prazosin, Terazosin, Doxazosin; Tamsulosin has least effect on BP) • in Raynaud disease • in benign prostatic hypertrophy (BPH): Tamsulosin is a more potent inhibitor of α receptors found on the smooth muscle of the prostate (α1A) --------> decrease tone in the smooth muscle of the bladder neck and prostate---------> improves urine flow Silodosin - α1A selective blocker (uroselectivity), approved by FDA in 2008 for BPH. 22 Adverse effects of α1 blockers • “First dose” effect: syncope (fainting) (greater hypotensive effect when administered first time) o may be minimized by adjusting the first dose to 1/3rd or 1/4th of normal dose, and by giving the drug at bedtime • Orthostatic (postural) hypotension • Headache, dizziness • Reflex tachycardia (less compared to non-selective blockers) • Nasal stuffiness/congestion • Sexual dysfunction (less with selective agents) • Miosis 23 Selective α2 blockade • Yohimbine o selective, competitive α2 blocker o sexual stimulant (aphrodisiac) o can be used in postural hypotension and sexual impotence (but no clinical utility) • Mirtazapine (used as antidepressant) 24 α blockers Uses : • Pheochromocytoma • Hypertension • BPH • Raynaud’s disease 25 Distribution of Adrenoceptor Subtypes Receptor Type α1 α2 Tissue Action Most vascular smooth muscle Contraction Pupillary dilator muscle Contraction (mydriasis) Prostate; urinary sphincter Contraction Adrenergic and cholinergic nerve terminals Ciliary epithelium Inhibits transmitter release Pancreatic β-cells ↓ insulin secretion Platelets Aggregation Fat cells Lipolysis Action in the presence of α-antagonists: Fill in the blank spaces. ↓aqueous humor production 16 ß blockers 27 ß-blockers Non-selective (ß1 +ß2 blockers) 1. without intrinsic sympathomimmetic activity, e.g., Propranolol, Timolol, Sotalol, Nadolol 2. with intrinsic sympathomimmetic activity e.g., Acebutolol, Pindolol 3. with additional α-blocking property e.g, Labetalol, Carvedilol Selective ß1-selective (cardioselective) e.g., Acebutolol, ß2-selective e.g., Butoxamine Atenolol, Esmolol Metoprolol 28 Propranolol • well absorbed after oral administration • undergo extensive first-pass metabolism • lipophilic and enters the brain • excreted in urine as glucuronide metabolites 30 Propranolol: Pharmacological actions 1. On CVS Heart: • decrease force of contraction (negative inotropic) • decrease rate of contraction (negative chronotropic) • directly suppresses SA and AV nodal activities--------> bradycardia • HR, SV, CO 31 Propranolol • cardiac work in angina) decreased O2 consumption (useful Blood vessels: • blocks ß2 mediated vasodilatation 32 Blood pressure • does not decrease BP in normal individual, but decrease BP in hypertensive patients • decrease both, systolic and diastolic BP • no postural hypotension occurs (as no effect on α1adrenergic receptors) 33 Propranolol 2. Kidney: • decrease renin release from kidney (ß1-action) (very useful property in reducing compensatory BP elevation) • ß-blockers are often combined with a diuretic in treatment of HTN*** 34 Propranolol 3. Respiratory tract: bronchoconstriction and can precipitate bronchial asthma (ß2 action). (ß-blockers are thus contraindicated in patients with bronchial asthma) • Bronchoconstriction is minimal in normal individual but can be life threatening in patients with asthma or COPD 4. Eyes: decrease the IOT due to decreased aqueous humor production 5. CNS: sedation, lethargy, depression, forgetfulness, sleep disturbances (dreams and nightmares) 6. Skeletal muscle: antagonizes the epinephrineinduced tremors 35 Propranolol 7. Metabolic effects: • blocks epinephrine induced glycogenolysis (fasting hypoglycemia) • by decreasing insulin release (ß2-blockade), causes hyperglycemia after meal • Propranolol should be used with great caution in diabetics: because propranolol blocks the sympathetic signs and symptoms such as sweating, palpitations (tachycardia) induced by hypoglycemia • all ß-blockers mask tachycardia - a warning signal of hypoglycemia 36 Therapeutic Uses: Propranolol • HTN • Angina (except Prinzmetal’s angina) • MI o Prophylactic use post-MI • Cardiac arrhythmias (Class II: Propranolol, Acebutolol, Esmolol) • Migraine - Prophylactically 37 Therapeutic Uses: Propranolol • Hyperthyroidism: o may be live saving in protecting against severe cardiac arrhythmias in acute hyperthyroidism (thyroid storm) ▪ Chance of thyroid storm increases during surgical removal of thyroid (Prior admin of ß-blockers is desirable) • Pheochromocytoma (along with α blockers) • Performance anxiety o blocks peripheral manifestations of anxiety (palpitations, tremors) • Essential tremors • Glaucoma (Timolol) 38 Adverse Effects CVS • Bradycardia • AV block • Abrupt discontinuation of propranolol can precipitate angina, arrhythmia and HTN PROPRANOLOL SHOULD BE WITHDRAWN GRADUALLY AFTER LONG TERM USE 39 Adverse Effects Respiratory • causes bronchoconstriction • should not be used in asthmatic and COPD patients Metabolic • fasting hypoglycemia (diabetics being treated with insulin & persons prone to hypoglycemia must use propranolol with caution) • increases blood lipid levels (LDLs, TGs) Other adverse effects: • sexual dysfunction • fatigue and exercise intolerance 40 C/I - Asthmatics and COPD - Diabetics - Raynaud’s disease - Prinzmetal angina 41 Drug Interactions 1. Digitalis and Verapamil additive depression of SA and AV node-----cardiac arrest 2. Insulin and oral hypoglycemics aggravate hypoglycemic effects mask warning sign (tremor and tachycardia)*** 3. Indomethacin and other NSAIDs annul antihypertensive actions of ß-blockers 42 Drug Interactions 4. Cimetidine inhibits metabolism of Propranolol 5. TIMOLOL potent non-selective ß-blocker reduces the production of aqueous humor in the eye and hence used topically for the treatment of chronic open-angle glaucoma 43 6. NADOLOL: very long duration of action Same effects and adverse effects as propranolol. 44 ß1–selective Antagonists • • • • Acebutolol Atenolol Esmolol Metoprolol They can be used in hypertensive patients with asthma & COPD and do not cause bronchoconstriction at therapeutic doses. 45 ß1–selective Antagonists Pharmacological actions • • • • • • preferentially block ß1-receptors decrease BP in hypertensive patients increase exercise tolerance in angina no bronchoconstriction effect no effect on PR no effect on CHO metabolism (this effect would be through ß2, so no impact) 46 ß1–selective Antagonists Therapeutic Uses: • HTN patients (with impaired pulmonary functions and diabetic patients receiving insulin and other oral hypoglycemic agents) • ANGINA • MI Adverse effects: • bradycardia 47 Atenolol • Lower lipid solubility • Less CNS entry • Excreted unchanged in the urine Therapeutic Uses: • HTN*** • Angina • MI 48 Metoprolol Orally / IV Therapeutic Uses: • HTN*** • Angina • Acute MI 49 Esmolol • Shortest acting • I.V. administration to treat acute supraventricular tachycardia 50 Antagonists with Partial Agonist Activity (ISA) • PINDOLOL • ACEBUTOLOL o o o o act as partial agonists less bradycardia (ß1) slight vasodilation or bronchodilation (ß2) minimal change in plasma lipids (ß2) Therapeutic Uses: HTN with moderate bradycardia in DM cases 51 Antagonists with Partial Agonist Activity (ISA) Therapeutic Uses: • effective in hypertensive patients with moderate bradycardia • CHO metabolism less affected than Propranolol, hence valuable in the treatment of HTN in diabetics 52 ß-blocker with K+-channel blockade Sotalol • Used as antiarrhythmic (Class III) 53 a & b blockers LABETALOL & CARVEDILOL • • • • Peripheral vasodilation -- ↓ B.P Do not alter serum lipid and glucose levels Can be used in HTN emergency Good point – Does not cause reflex tachycardia • Bad point – Same contraindications of non-selective beta blockers 54 Indirect Acting Antiadrenergic Drug Metyrosine Mechanism of action • Inhibition of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis. Clinical uses • Pheochromocytoma – before surgery, or long-term management for malignant pheochromocytoma. Adverse effects • orthostatic hypotension • sedation 55 Distribution of Adrenoceptor Subtypes Rec ept or Typ e β1 Tissue Action Heart Increases force and rate of contraction Kidney; juxtaglomerular cells Increases renin release Respiratory and uterine smooth muscle Eye; ciliary epithelium Promotes smooth muscle relaxation Skeletal muscle Vasodilation; promotes potassium uptake Activates glycogenolysis β2 Liver Action in the presence of β-antagonists Fill in the blank spaces: ↑ aqueous humor production 24 Questions? 57 THANKS! 58