Autonomic Drugs Chapter 7.pptx

Autonomic Drugs UNIT 2- DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHAPTERS 3, 4, 5, 6, & 7 © 2022-2024, Dr. Susan Wrenn, All rights reserved Whalen, K., Lerchenfeldt, S., Giordano, C. (2023). Lippincott  Chapter 7 ADRENERGIC ANTAGONISTS  Ad...

Autonomic Drugs UNIT 2- DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHAPTERS 3, 4, 5, 6, & 7 © 2022-2024, Dr. Susan Wrenn, All rights reserved Whalen, K., Lerchenfeldt, S., Giordano, C. (2023). Lippincott  Chapter 7 ADRENERGIC ANTAGONISTS  Adrenergic antagonists (also called adrenergic blockers or sympatholytics) bind to adrenoceptors but do not activate Overview the receptors. These drugs attach to the adrenoceptors, thus preventing activation by endogenous or exogenous agonists. α-Adrenergic Blocking Agents α1 blockers ◦ Drugs that block α1 -adrenoceptors profoundly affect blood pressure ◦ Blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance and a reduction in blood pressure. α2 blockers ◦ These agents have limited clinical utility α-Adrenergic Blocking Agents Phenoxybenzamine ◦ Nonselective, noncompetitive (irreversible) blocker of α1 and α2 adrenergic receptors ◦ Actions ◦ Prevents α1 receptor vasoconstriction of peripheral blood vessels caused by endogenous catecholamines, which leads to decreased peripheral resistance and resultant reflex tachycardia ◦ Blocking presynaptic α2 receptors leads to increased release of norepinephrine, which increases the heart rate and cardiac output mediated by β1 receptors. ◦ Reverses the α agonist actions of epinephrine ◦ Therapeutic uses ◦ Used in the treatment of sweating and hypertension associated with pheochromocytoma ◦ Used off-label for hypertensive crisis caused by sympathomimetic amines and some urinary issues ◦ Adverse effects ◦ Postural hypotension, nasal stuffiness, GI irritation, and inhibition of ejaculation α-Adrenergic Blocking Agents Phentolamine ◦ Nonselective, competitive (reversible) blocker of α1 and α2 adrenergic receptors ◦ Effects last 4 hours ◦ Used for the diagnosis and short-term management of pheochromocytoma ◦ Used locally to prevent dermal necrosis following extravasation or norepinephrine and other vesicants ◦ Useful to treat hypertensive crisis due to abrupt withdrawal of clonidine or ingestion of tyramine-containing foods in patients taking MAOIs α-Adrenergic Blocking Agents Prazosin, terazosin, and doxazosin ◦ Selective, competitive blocker of α1 adrenergic receptors ◦ Other agents are used for BPH and are discussed in later chapters ◦ Useful in the treatment of hypertension ◦ Mechanism of Action ◦ Decrease peripheral vascular resistance and lower blood pressure by causing relaxation of both arterial and venous smooth muscle ◦ Cause minimal changes in cardiac output, renal blood flow, and glomerular filtration rate ◦ Therapeutic uses ◦ Used for hypertension, but not as monotherapy ◦ Adverse effects ◦ “First-dose” effect- exaggerated orthostatic hypotensive response ◦ Dizziness, lack of energy, nasal congestion, headache, drowsiness, and orthostatic hypotension α-Adrenergic Blocking Agents Yohimbine ◦ Selective, competitive blocker of α2 adrenergic receptors ◦ Works in the CNS to increase sympathetic outflow to the periphery ◦ See attachment for full discussion of NO-himbine β-Adrenergic Blocking Agents (- olol) ◦ All clinically available β-blockers are competitive antagonists ◦ Nonselective β-blockers act at both β1 and β2 receptors ◦ Drugs differ in intrinsic sympathomimetic activity (ISA), CNS effects, blockade of sympathetic receptors, vasodilation, and pharmacokinetics ◦ They do not induce postural hypotension because the α-adrenoceptors remain functional ◦ Effective for treating systemic as well as portal hypertension, angina, cardiac arrythmias, myocardial infarction, heart failure hyperthyroidism, and glaucoma. They are also used for the prophylaxis of migraine β-Adrenergic Blocking Agents (- olol) Propranolol ◦ Nonselective β-blocker (antagonist) ◦ Actions ◦ Cardiovascular ◦ Negative inotropic and chronotropic effects (decreases force and rate)- decrease cardiac output ◦ Directly decreases sinoatrial (SA) and atrioventricular (AV) nodal activity resulting in bradycardia that limits the dose ◦ Reduces expected sympathetic activity during exercise or stress ◦ Decreases cardiac output, workload, and oxygen consumption to make this drug useful for angina ◦ Useful for some arrythmias β-Adrenergic Blocking Agents (- olol) Propranolol ◦ Actions ◦ Peripheral vasoconstriction ◦ Nonselective blockade prevents β2-mediated vasodilation in skeletal muscles, increasing peripheral vascular resistance ◦ Reduction in cardiac output leads to decreased blood pressure, which triggers a reflex peripheral vasoconstriction ◦ In patients with hypertension, total peripheral resistance returns to normal or decreases with long-term use of propranolol as a result of down regulation of the β receptors. ◦ Gradual reduction of both systolic and diastolic blood pressures occurs in hypertensive patients β-Adrenergic Blocking Agents (- olol) Propranolol ◦ Actions ◦ Bronchoconstriction ◦ Blocking β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle ◦ Can precipitate an exacerbation in patients with chronic obstructive pulmonary disease (COPD) or asthma- contraindicated with asthma, avoid use with COPD ◦ Disturbances in glucose metabolism ◦ Decreased glycogenolysis and decreased glucagon secretion ◦ Pronounced hypoglycemia may occur after insulin injection ◦ Attenuate the normal physiologic response to hypoglycemia β-Adrenergic Blocking Agents (- olol) Propranolol ◦ Therapeutic uses ◦ Hypertension ◦ *does not reduce blood pressure in people with normal blood pressure ◦ Angina pectoris ◦ Decreases oxygen requirement of heart muscle, effective in reducing chest pain on exertion that is common in angina ◦ Useful for the management of chronic stable angina ◦ Myocardial infarction ◦ Protective effect on the myocardium ◦ Protects against 2nd MI ◦ Administration immediately following MI reduces infarct size and early mortality ◦ Reduces incidence of sudden arrhythmic death after MI β-Adrenergic Blocking Agents (- olol) Propranolol ◦ Therapeutic uses ◦ Migraine ◦ Effective in reducing migraine episodes when used prophylactically ◦ Lipophilic nature allows it to penetrate the CNS ◦ Hyperthyroidism ◦ Effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism ◦ In acute hyperthyroidism, β-blockers may be lifesaving in protecting against serious cardiac arrhythmias β-Adrenergic Blocking Agents (- olol) Propranolol ◦ Pharmacokinetics ◦ Good oral absorption ◦ Subject to first-pass; only ~25% reaches systemic circulation ◦ Readily crosses the blood-brain barrier ◦ Adverse effects ◦ Bronchoconstriction ◦ Arrhythmias ◦ Metabolic disturbances ◦ CNS effects ◦ Drug interactions β-Adrenergic Blocking Agents (- olol) Nadolol ◦ Nonselective β-blocker (antagonist) ◦ More potent than propranolol ◦ Long duration of action Timolol, carteolol, levobunolol, metipranolol ◦ Nonselective β-blocker (antagonist) ◦ Topical products used to reduce intraocular pressure in glaucoma ◦ Decrease the secretion of aqueous humor by the ciliary body ◦ Do not affect pupil size or ability of the eye to focus ◦ Used only for chronic management of glaucoma Classes of drugs used to treat glaucoma β-Adrenergic Blocking Agents (- olol) Acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, and nebivolol ◦ Selective β1 antagonists ◦ Minimize unwanted bronchoconstriction (β2 effect) ◦ Cardioselectivity is most pronounced at low doses and is lost at high doses ◦ Actions ◦ Lower blood pressure in hypertension and increase exercise tolerance in angina ◦ Fewer effects on pulmonary function, peripheral resistance, and carbohydrate metabolism- use with caution in patients with asthma ◦ Since these drugs have less effect on peripheral vascular β 2 receptors, coldness of extremities (Raynaud phenomenon), a common side effect of β-blockers, is less frequent. β-Adrenergic Blocking Agents (- olol) Acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, and nebivolol ◦ Therapeutic uses ◦ Useful in hypertensive patients with impaired pulmonary function ◦ First-line therapy for chronic stable angina ◦ Bisoprolol and the extended-release formulation of metoprolol are indicated for the management of chronic heart failure ◦ Esmolol is only available intravenously (very short half life) and is used to control blood pressure or heart rhythm in critically ill patients and those undergoing surgery or diagnostic procedures β-Adrenergic Blocking Agents (- olol) Acebutolol (selective β1 antagonists) and pindolol (nonselective β-blocker) ◦ Antagonists with partial agonist activity- ISA- intrinsic sympathomimetic activity ◦ Actions ◦ These partial agonists stimulate the β receptor to which they are bound, yet they inhibit stimulation by the more potent endogenous catecholamines, epinephrine and norepinephrine. The result of these opposing actions is a diminished effect on reduction of cardiac rate and cardiac output compared to that of β-blockers without ISA. ◦ Decreased metabolic effects ◦ Minimize the disturbances of lipid and carbohydrate metabolism ◦ Do not decrease plasma HDL levels ◦ Therapeutic Use ◦ 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 β-Adrenergic Blocking Agents (- olol) Labetalol and carvedilol ◦ Antagonists of both α- and β-adrenoceptors ◦ Actions ◦ Nonselective β-blockers with concurrent α1-blocking actions - produce peripheral vasodilation, thereby reducing blood pressure ◦ Useful in treating hypertensive patients for whom increased peripheral vascular resistance is undesirable ◦ Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefit in heart failure. β-Adrenergic Blocking Agents (- olol) Labetalol and carvedilol ◦ Therapeutic use in hypertension and heart failure ◦ Labetalol is used as an alternative to methyldopa in the treatment of pregnancy-induced hypertension ◦ IV labetalol is also used to treat hypertensive emergencies, because it can rapidly lower blood pressure ◦ Cannot be given to patients with acute exacerbation of heart failure, but are beneficial in patients with stable heart failure- work by blocking the effects of sympathetic stimulation on the heart, which causes worsening heart failure over time ◦ Adverse effects ◦ Orthostatic hypotension and dizziness associated with α1-blockade Drugs Affecting Neurotransmitter Release or Uptake Reserpine ◦ Blocks the Mg2+/adenosine triphosphate–dependent transport of biogenic amines (norepinephrine, dopamine, and serotonin) from the cytoplasm into storage vesicles in the adrenergic nerve terminals in all body tissues. ◦ This causes the ultimate depletion of biogenic amines. ◦ Sympathetic function, in general, is impaired because of decreased release of norepinephrine. ◦ Slow onset, long duration of action, and effects that persist for many days after discontinuation ◦ It has been used for the management of hypertension but has largely been replaced with newer agents with better side effect profiles and fewer drug interactions.