8.Adrenergic Antagonists 2.pdf

Adrenergic antagonists 2 Dr Suprava Das, Associate Professor, Department of Pharmacology Learning Outcomes Explain the pharmacological actions of propranolol on: CVS, kidney, respiratory system, metabolism, eye, skeletal muscles and CNS. *** Explain the advantages of selective β1 blockers over...

Adrenergic antagonists 2 Dr Suprava Das, Associate Professor, Department of Pharmacology Learning Outcomes Explain the pharmacological actions of propranolol on: CVS, kidney, respiratory system, metabolism, eye, skeletal muscles and CNS. *** Explain the advantages of selective β1 blockers over non- selective beta blockers. ***  Explain the therapeutic uses of beta blockers. *** Apply pharmacological actions of beta blockers to provide rationale for their contraindications. *** Apply the changes seen on prolonged use of beta blockers and disease features to provide rationale for the consequences of sudden withdrawal of beta blockers. *** 2  Introduction  All β-blockers are competitive antagonists They block the β receptor mediated effects of sympathetic stimulation and adrenergic drugs Non-selective β-blockers act at both β1 and β2 receptors Cardio-selective or selective β- blockers block primarily β1 receptors There is no absolute selectivity, and it depends on the dose Manipal University College Malaysia 3  β1 Adrenoceptors β2 Adrenoceptors Distribut Postsynaptic – Postsynaptic - lungs, ion heart & Juxtaglomerular uterus, skeletal muscle apparatus in kidney blood vessels Effect Excitatory Inhibitory Agonist Epinephrine, Norepinephrine, Epinephrine, Dobutamine Salbutamol Antagoni Propranolol, Atenolol Propranolol st  Effects of β receptor stimulation β1 β2 Tachycardia Vasodilatation Increased myocardial contractility, Decreased peripheral increase in COP and increase in BP resistance Increased release of renin  Bronchodilatation increase in BP Uterine relaxation Myocardial oxygen requirement is Glycogenolysis in increased. muscle & liver  Effects of β receptor blockade β1 block β2 block Decrease heart rate & force Slight constriction of skeletal of contraction  decrease muscle BV causing increase in COP & decrease BP. peripheral resistance. Decrease oxygen requirement Bronchospasm – Contraindicated of the heart. in bronchial asthma Decrease renin secretion  decrease intraocular tension by decrease in BP decreasing aqueous humor formation. Delay recovery from hypoglycemia. β receptor blockers are not vasodilators. They lower BP by decrease of COP & decrease in renin secretion. (β1). selective β1 blockers can block β2 receptors at higher doses. Β-Blockers  Classification  Non-selective β-blockers: Propranolol, Timolol, Pindolol, Sotalol Cardio-selective (β1-selective) blockers: Atenolol, Bisoprolol, Metoprolol, Esmolol, Acebutolol, Celiprolol, Betaxolol, Nebivolol Β-blockers with additional vasodilatory effect (α1-blocking action): Labetalol, Carvedilol Β-blockers with intrinsic sympathomimetic (partial agonist) activity: Pindolol, acebutolol, labetalol, celiprolol, and carteolol Β-blockers with membrane stabilizing (local anaesthetic) activity: Propranolol, acebutolol, carvedilol, labetalol, metoprolol, pindolol 4  Β-Blockers – Pharmacological Actions (Propranolol)  CVS: ↓ HR, Conduction rate, FOC, CO, → ↓ BP ↓ A-V conduction, ↑ PR interval ↓ cardiac work → ↓ O2 requirement of the myocardium Oppose β2-mediated vasodilation  Kidney: ↓ renin release → ↓ production of angiotensin II & aldosterone → ↓ BP Manipal University College Malaysia 5 Heart rate continuously recorded in a spectator watching a live football match, showing the effect of beta blocker.  Heart rate (HR) in a patient with ischemic heart disease measured while watching television. Measurements were begun 1 hour after receiving placebo (upper line, red) or 40 mg of oxprenolol (lower line, blue). Not only was the HR decreased by the drug, it also varied much less in response to stimuli. Β-Blockers – Pharmacological Actions  Respiratory effects: Blockade of β2 receptors→ ↑ bronchial airway resistance → bronchospasm in patients with asthma and COPD Cardio-selective β-blockers are less likely to cause bronchospasm  Eye: ↓ secretion of aqueous humour – ↓ IOP in glaucomatous eye (β2) – topical (no effect on pupil size) Local anaesthetic action – membrane stabilizing effect (Blockade of Na+ channel) 1 1  Β-Blockers – Pharmacological Actions  Metabolic effects: Inhibits stress induced / β receptor induced glycogenolysis and↓ glucagon secretion Delay recovery from hypoglycaemia in diabetics Masking of warning signs and symptoms (tremor, tachycardia, sweating, anxiety) of hypoglycaemia Should be used cautiously in diabetics on insulin and hypoglycaemic agents Chronic use → ↓HDL and LDL ratio → ↑ risk of CAD(coronary artery disease) Manipal University College Malaysia 8  Β-Blockers – Pharmacological Actions  Skeletal muscles: ↓ blood flow to skeletal muscles → skeletal muscle fatigue (β2) Inhibits tremors CNS: ↓ anxiety symptoms – short term (Non-selective, propranolol) Behavioral changes, forgetfulness, ↑ dreaming, nightmares – long term Manipal University College Malaysia 13  β-Blockers with Intrinsic Sympathomimetic Activity (ISA) The presence of ISA results in less resting bradycardia and less of a reduction in cardiac output than β- blockers without ISA. In the long term, partial β-agonists may produce arterial vasodilation and increase arterial compliance, possibly leading to additional beneficial effects in the treatment of hypertension. β-blockers with ISA do not have adverse effects on plasma lipoproteins during long-term treatment The presence of ISA could counteract the up-regulation of β- adrenoceptors often observed with β- blockers without ISA. Manipal University College Malaysia 14  Advantages of Selective β-Blockers over Non-selective β-Blockers ↓ bronchoconstriction Safer in diabetics Less chances of precipitating Raynaud’s disease Less changes in lipid profile Less liable to impair exercise capacity However, the selectivity is not absolute as it depends on the dose of β-blocker Manipal University College Malaysia 15  Therapeutic Uses of β-Blockers Essential Hypertension: preferred in patients with angina, MI or cardiac arrhythmia Congestive heart failure (CHF): Bisoprolol, metoprolol & carvedilol have shown to reduce mortality rate in chronic heart failure Angina pectoris: β-blockers reduce myocardial O2 demand by decreasing heart rate, myocardial contractility. Improve exercise tolerance and reduce frequency of anginal attack Myocardial infarction (MI): Limit the size of the infarct and on long term use reduce reinfarction and mortality Cardiac Arrhythmias: Mainly used in atrial arrhythmias i.e., atrial flutter, fibrillation, and paroxysmal supraventricular tachycardia (PSVT) Manipal University College Malaysia 16 Therapeutic Uses of β-Blockers  Migraine prophylaxis: Propranolol  Performance related anxiety: Propranolol Glaucoma: Timolol, betaxolol, carteolol, levobunolol; Timolol is most frequently used. Hyperthyroidism / thyrotoxicosis: Signs and symptoms like tachycardia, palpitation, tremor, anxiety etc. reduced. Also used in thyroid storm. Pheochromocytoma: Used to control the cardiac manifestations, but must be used with α-blockers  Alcohol withdrawal  Essential tremor (non-selective): Propranolol may be beneficial 14  Therapeutic Uses of β-Blockers  Esmolol: Ultra-short acting selective β blocker Its half-life is about 10 minutes It is used only I.V for rapid control of ventricular rate in supraventricular arrhythmias. It is useful in hypertensive emergencies particularly perioperatively  Labetalol: Competitive blocker at β1, β2 and α1 adrenergic receptors Used orally for hypertension and I.V for hypertensive emergency, safer to be used in pregnancy and used in pregnancy induced hypertension(PIH) Manipal University College Malaysia 18  Therapeutic Uses of β-Blockers  Carvedilol: Like labetalol it blocks β1, β2 and α1 receptors It has antioxidant, antiproliferative, membrane stabilizing and vasodilatory properties Has cardioprotective effect and reduces mortality in patients with CHF  Nebivolol Third generation selective β1 blocker Has vasodilating activity No membrane stabilizing and intrinsic sympathomimetic action No unfavourable effects on lipid profile Used for control of hypertension and congestive cardiac failure Manipal University College Malaysia 19  Adverse Effects of β-Blockers  Bradycardia  Coolness of hands and feet in winter  CNS: mild sedation, vivid dreams and rarely depression  Alteration in lipid profile (↑ Total TG, LDL, ↓ HDL) Rebound hypertension, angina, MI can occur by abrupt withdrawal after chronic use. This is due to up-regulation (super-sensitivity) of β receptors to catecholamines  Reduced exercise capacity  GI upset, nightmares, forgetfulness, sexual distress Manipal University College Malaysia 20  Regulation of sympatheic activity Pre-synaptic regulation – Immediate – by α2 receptors. Post-synaptic regulation – follows prolonged drug use by either increasing or decreasing the receptor number. Several other mechanisms are also possible. – Up-regulation (Increased response) – Down regulation (Decreased response) Up-regulation - Prolonged exposure to an antagonist (deprivation of stimulation by agonist) results in increase in no. of receptors. This leads to supersensitivity to the agonist when the antagonist is discontinued.  Post-synaptic regulation - Receptor up-regulation Clinical implication of Up-regulation: Following abrupt withdrawal of β blockers eg. Propranolol (for Hypertension) - angina & myocardial infarction (ischemic heart disease) may be precipitated due to increased no. of sympathetic receptors & activity. When the antagonist is withdrawn, the endogenous catecholamines act on the receptors (increased in no. due to the antagonist) & produce enhanced action. Hence, betablockers should not be stopped abruptly.  Presynaptic regulation Down regulation - Presynaptic α2 receptor stimulation by NE at the synapse results in inhibition of further release of NE thereby regulating the sympathetic activity.  Post-synaptic regulation - Receptor down-regulation Down-regulation: Prolonged exposure to β receptor agonists in bronchial asthma results in decrease in no. of receptors & decrease in response, i.e. tolerance. Clinical implications: development of tolerance to bronchodilatory action of Salbutamol during long term treatment of asthma.  Post synaptic Receptor regulation Before drug treatment Normal Receptors After chronic agonist Receptor down regulation After chronic antagonist Receptor upregulation  Contraindications of β-Blockers  Bronchial asthma & COPD  Patients on insulin & oral hypoglycaemic drugs with poor glycaemic control  Prinzmetal’s angina (unopposed α action) Partial & complete heart block, Myocardial insufficiency (careful administration)  Topical use in glaucoma in asthmatic patients  Raynaud’s disease Manipal University College Malaysia 26