Lec 16. Adrenergic Antagonists II, Dr. Parmar- FS PDF

Adrenergic Antagonists I Lecture - 16 Mayur S. Parmar, Ph.D. Assistant Professor of Pharmacology Department of Foundational Sciences Email: [email protected] l Phone: 813-574-5357 Dr. Kiran C. Patel College of Osteopathic Medicine Nova Southeast...

Adrenergic Antagonists I Lecture - 16 Mayur S. Parmar, Ph.D. Assistant Professor of Pharmacology Department of Foundational Sciences Email: [email protected] l Phone: 813-574-5357 Dr. Kiran C. Patel College of Osteopathic Medicine Nova Southeastern University, Tampa Bay/Clearwater Campus Learning Objectives 2  Synthesis and release of Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Fourth Edition, 4e, 2017 norepinephrine Adrenergic Antagonists from the adrenergic neuron. Adrenergic antagonists' drugs interact with either α - or β - adrenoceptors to prevent or reverse the actions of endogenously released norepinephrine or epinephrine or exogenously administered sympathomimetic agents.  α blockers  Nonselective α blockers (α1 and α2)  Selective (α1 or α2)  β blockers  Nonspecific β blockers (β1 and β2)  Selective β blockers (β1)  Mixed Blockers Inactive metabolites  α& β 3 α-blockers Adrenergic Antagonists 4 α-adrenergic Antagonists Key Points:  α blockers are based on selective affinity for α1 versus α2 receptors or a lack thereof.  They may be reversible (e.g., phentolamine and prazosin) or irreversible (e.g., phenoxybenzamine) in their interaction with these receptors.  Drugs that block α1-adrenoceptors profoundly affect blood pressure.  Because normal sympathetic control of the vasculature occurs largely through agonist actions on α1-adrenergic receptors, blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance.  This lowered blood pressure induces reflex tachycardia. Note: Selective α2-adrenergic blockers have limited clinical utility. 5 α-adrenoceptor Antagonists: Nonselective  Phenoxybenzamine  Phentolamine 6 Phenoxybenzamine Long duration of action; irreversible Mechanism of action:  Blocks α1-receptors > α2-receptors; forms a covalent bond with α-receptor and causes irreversible receptor blockade; noncompetitive Pharmacological effects:  Cardiovascular:  Prevents α1 receptor vasoconstriction of peripheral blood vessels caused by endogenous catecholamines → leads to This may lead to decreased peripheral resistance → resultant reflex tachycardia (mediated by the baroreceptor reflex). cardiac arrhythmias  By blocking presynaptic α2-receptors on the sympathetic nerve terminals in the heart, it causes an increase in the release and anginal pain. of norepinephrine, which in turn increases heart rate and cardiac output (mediated by β1-receptors).  Thus, this drug is unsuccessful in maintaining lowered blood pressure in hypertension, and it is no longer used for this purpose. Therapeutic uses:  Presurgical treatment of hypertension specifically caused by pheochromocytoma.  Preferred/initial choice for the management of pheochromocytoma-associated hypertension and sweating.  Sometimes effective in treating Raynaud disease and frostbite. 7 Phenoxybenzamine Adverse effects: Adverse effects:  Orthostatic hypotension.  Myocardial ischemia.  Reflex Tachycardia (mediated by the baroreceptor reflex). Note: To manage tachycardia, concomitant use of β blocker can be useful.  Inhibit ejaculation.  Caution in patients with cerebrovascular or cardiovascular disease. Contraindications:  Severe hypotension.  Hypersensitivity to the drug. 8  Adverse effects: Phentolamine Short duration of action Mechanism of action:  Competitive, reversible antagonist of α1- and α2-receptors. Pharmacological effects: of phentolamine are very similar to those of phenoxybenzamine. Therapeutic uses:  Used for short-term management of pheochromocytoma-associated hypertension and sweating.  Prevent rebound hypertension due to abrupt discontinuation of clonidine.  Control hypertension - cocaine withdrawal treatment.  Treat hypertensive crisis due to ingesting tyramine-containing foods in patients taking monoamine oxidase inhibitors.  Used locally to prevent dermal necrosis following extravasation of norepinephrine.  Reversing dental anesthesia.  Antidote to an overdose of α-agonists (e.g., dopamine, epinephrine, norepinephrine, and phenylephrine). Adverse effects: Contraindications:  Orthostatic hypotension.  Severe hypotension  Inhibit ejaculation.  Coronary artery disease  Reflex Tachycardia. 9 Adrenoceptor Antagonists: α1-selective  Prazosin  Doxazosin  Terazosin  Alfuzosin  Tamsulosin  Silodosin 10  By Unknown author - National Cancer Institute, AV Number: https://commons.wikimedia.org/w/index.php?curid=5581217 CDR462221, Public Domain,  α1A-receptors are found in the prostate.  α1B-receptors are found in the prostate and vasculature.  α1D-receptors are found in the vasculature.  By blocking the α1A and α1B- receptors in the prostate, the α-blockers cause prostatic smooth muscle relaxation, which leads to improved urine flow. 11 Prazosin Short duration of action Mechanism of action:  Selective competitive blockers of the α1 (both α1B and α1A) receptor. Pharmacological effects:  Decrease peripheral vascular resistance and lower blood pressure by causing relaxation of both arterial and venous smooth muscle.  Unlike phentolamine and phenoxybenzamine, these drugs cause minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Therapeutic uses:  Hypertension (↓ vasoconstriction →↓ blood pressure)  Benign prostatic hyperplasia (relaxation of bladder neck muscles →↓ bladder outlet obstruction and easier micturition).  Off-label: Nightmares and insomnia associated with PTSD or acute stress. Adverse effects:  Orthostatic hypotension (first dose effect; within two hrs.), but little or NO reflex tachycardia.  First-dose is adjusted to one-third or one-fourth of the normal dose and given at bedtime (to ensure that the patient remains supine).  Monitoring the blood pressure is important during the initial administration of the medication. Patients should avoid sudden changes in position.  Dizziness.  Intraoperative floppy iris syndrome. 12  13 https://meetings.ami.org/2018/project/intraoperative-floppy- iris-syndrome-ifis-during-cataract-surgery/ Terazosin, Doxazosin  Terazosin and doxazosin have a longer duration of action  Doxazosin is the longest acting (22 hrs.), while Terazosin’s half-life is 9-12 hrs. Mechanism of action:  Selective competitive blockers of the α1-(both α1A and α1B) receptor. Pharmacological effects:  Decrease peripheral vascular resistance and lower blood pressure by causing relaxation of both arterial and venous smooth muscle.  Unlike phentolamine and phenoxybenzamine, these drugs cause minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Therapeutic uses:  Hypertension.  Benign prostatic hyperplasia. Adverse effects:  Orthostatic hypotension.  First-dose syncope; start with a low dose and gradually increase.  Dizziness.  Intraoperative floppy iris syndrome.  Hepatitis, angioedema (doxazosin only). 14 Tamsulosin, Alfuzosin, Silodosin Mechanism of action:  Competitively blocks α1A-receptors in bladder and prostate → relaxes prostatic and bladder smooth muscle → facilitates bladder emptying. Pharmacological effects:  All have less pronounced effects on blood pressure because they are less selective for α1B-receptors in the blood vessels and more selective for α1A-receptors in the prostate and bladder.  Blockade of the α1A-receptors decreases tone in the smooth muscle of the bladder neck, and prostate and improves urine flow. Therapeutic uses:  Approved only for benign prostatic hyperplasia. Adverse effects:  Intraoperative floppy iris syndrome (worst outcome with tamsulosin).  Priapism.  Retrograde ejaculation (Silodosin; reversible upon discontinuation).  Rhinitis (Tamsulosin only). Note: Tamsulosin should be taken with food, while terazosin does not need to be taken with food. 15 Adrenoceptor Antagonists: α2-selective Yohimbine 16 Yohimbine  Found as a component of the bark of the Yohimbe tree. Mechanism of action:  Selective competitive α2-antagonist. Pharmacological effects:  Elicits increased central sympathetic activity.  Increases norepinephrine release. Therapeutic uses:  Obsolete use for erectile dysfunction.  Use in research only. Adverse effects:  May cause anxiety.  Excess pressor effect if norepinephrine transporter is blocked. 17  α-adrenoceptor Antagonists: Contraindications  Hypersensitivity to the drug.  Hepatic impairment.  Severe renal impairment (Silodosin only).  DO NOT USE Alfuzosin in patients at risk for QT prolongation – prolongs QT intervals. α-adrenoceptor Antagonists: Drug interactions  Tricyclic antidepressants may increase the risk of postural hypotension.  Concurrent use with strong 3A4 inhibitors (Silodosin or alfuzosin only) 18  Books:  Basic & Clinical Pharmacology, 15e Resources  Lippincott® Illustrated Reviews: Pharmacology, 7e  Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Fourth Edition, 4e 19