Systemic Adrenergic Agonists and Antagonist_SU.pdf

Adrenergic Agonist Agents  Adrenergic Agonist Drugs Act on receptors stimulated by epinephrine and norepinephrine  Major effects mediated by β receptors β2 β1...

Adrenergic Agonist Agents  Adrenergic Agonist Drugs Act on receptors stimulated by epinephrine and norepinephrine  Major effects mediated by β receptors β2 β1 Vasodilation Tachycardia Slight decrease in peripheral Increased myocardial resistance contractility Bronchodilation Increased lipolysis Increased glycogenolysis (liver and muscle) Increased Glucagon release Relaxation of uterine smooth muscle Activation of Alpha Adrenoreceptors  Adrenergic Agonist Actions Direct Acting Adrenergic Agonists Endogenous/Natural Occurring Epinephrine Norepinephrine Dopamine Synthetic Dobutamine Isoproterenol  Epinephrine Interacts with alpha and beta receptors Low dose/levels higher affinity for beta receptors beta receptor activity predominates (vasodilation by beta 2 receptor activity) High dose higher affinity for alpha receptors alpha receptor predominates (vasoconstrictor by alpha 1 receptor activity)  Epinephrine Pharmacokinetics Rapid onset but brief duration: IV, SC Orally ineffective Metabolites excreted in urine (Metanephrine & Vanillylmandelic Acid) Adverse effects CNS disturbances Intracerebral hemorrhage cardiac arrhythmias (digitalis) pulmonary edema Interactions Hyperthyroidism Cocaine  Actions of Epinephrine Cardiovascular system (+) inotropic and chronotropic (B1) Peripheral vasoconstriction with decrease renal blood flow (A1) Peripheral vasodilation (B2)  Actions of Epinephrine Respiratory system - Bronchodilation (B2) Liver - Glycogenolysis (B2) Pancreas - Insulin (A2) Adipose tissue - Lipolysis (B3)  Therapeutic use of Epinephrine Bronchospasm (SC) Anaphylactic shock Type I hypersensitivity reactions (Anaphylaxis) Glaucoma open angle (2% sol) intraocular pressure by increase uveoscleral outflow Anesthetics – increased duration of local anesthetic effect due to vasoconstiction  Norepinephrine Affects mostly alpha receptors Actions - Cardiovascular - vasoconstriction *Endogenous NE is reduced with baroreceptor reflex (stretching of baroreceptors due increased BP which cause decrease in sympathetic flow and thus NE levels) Therapeutic use - Acute hypotension in a hemodynamically unstable patient - It can be use as atropine pre-treatment for acute hypotension (if given after atropine it will cause tachycardia) - Cardiac arrest (adjunct Tx)  Isoproterenol Non-selective B1and B2 agonist Therapeutic use Actions Bronchial Asthma - Cardiovascular (+) inotropic (+)chronotropic Heart block or cardiac Decrease peripheral resistance arrest - Pulmonary - Bronchodilation  Dopamine A1 and B1 receptors activity D receptors activity - Dopamine 1 receptors subserve vasodilation, especially in the renal, coronary, mesenteric, and cerebral vascular beds - Dopamine 2 receptors have been located at the endings of postganglionic sympathetic nerves; upon activation inhibits norepinephrine release Actions Therapeutic use – primarily used for - Cardiovascular cardiogenic shock and acute HF (+) inotropic (+)chronotropic (B1) Adverse effects – short lived arrhythmias vasoconstriction (A) - Vasodilation of dilation of renal and nausea and splanchnic beds  Other Direct Acting Agents Fenoldopam Phenylephrine (A1) IV D1 and A2 Oxymetazoline (A) Rapid vasodilation for severe Nasal decongestant hypertension in hospitalized patients Ophthalmic (Upneeq) Dobutamine (B1) Clonidine (A2) + inotropic Essential hypertension due to CNS action Use in congestive heart failure to (diminish central adrenergic outflow)  C.O.  Other Direct Acting Agents Beta -2 agonist (bronchodilators) Metaproterenol Albuterol Pirbuterol Salmeterol and formoterol – long acting Terbutaline – also for tocolysis (bronchodilator  uterine contractions in premature labor (delay labor)  Indirect Acting Adrenergic Agents Amphetamines (“ups’ ”) Causes release of norepinephrine from presynaptic terminals and increases NE release Central stimulation  Blood pressure and heart rate Tyramine – an AA Not a clinically useful drug found in cheese and Chianti wine Cocaine - local anesthetic that blocks Na / K pump required for reuptake of norepinephrine enhancing its sympathetic activity.  Mixed - Action Adrenergic Agents Induce norepinephrine release from presynaptic terminals and activate adrenergic receptors in postsynaptic membranes Ephedrine Enhance contractility and improve motor function in Myasthenia Gravis Metaraminol Alternative drug for shock treatment May be used to treat acute hypotension Adrenergic Agonists Side Effects Arrhythmias Headache Hyperactivity Insomnia Nausea Tremors Adrenergic Antagonists  Alpha Adrenergic Blockers Actions Decrease sympathetic tone of blood vessels Results in decrease in TPR May provoke reflex tachycardia Baroreceptors in Carotid body Peripheral resistance Compensatory HR and force of contraction Phenoxybenzamine An haloalkylamine Binds irreversibly to α-adrenergic receptors Leads muscle relaxation and a widening of the blood vessels Vasodilation results in lowering of blood pressure increased blood flow to the skin, mucosa and abdominal viscera Used to control of episodes of hypertension in pheochromocytoma prior to Sx Phentolamine Competitive reversible antagonist of alpha-1 (duration of 4 hrs) Induces vasodilatation of vascular smooth muscle Used as adjunct Tx for pheochromocytomectomy IV/IM 5 mg (pre-op 1-2 hrs) Also used (off-label) for hypertensive crisis 5mg IV q 10 min Blocks alpha-1 adrenergic receptors of iris dilator, thus reduces diameter of the pupil (miosis) Ryzumvi 0.75% ophthalmic solution to reverse mydriasis induced by muscarinic antagonists Quinazoline – Based drugs Compound made up of two fused six-member simple aromatic rings Display hypotensive and anticancer activity α1-AR blockers Relaxation of smooth muscle of peripheral vasculature results in hypotensive effect by decreased TPR Relaxation of smooth muscle in the prostate and bladder sphincter decreases resistance to urinary flow, reduces discomfort associated with BPH Some studies have found to have antitumor efficacy through the induction of apoptosis in benign and malignant prostate cells – reduce to reduce tumor growth Quinazoline – Based drugs Primary use for BPH** and HTN* Prazosin (Minipress) * Terazosin (Hytrin) ** Doxazosin (Cardura)* Tamsulosin (Flomax) ** - linked to intraoperative floppy iris syndrome (IFIS), a risk factor for complications during cataract surgery, interferes with pupillary dilation Facilitates passage of kidney stones (ureterolithiasis) – off label First dose phenomenon – orthostatic hypotension, dizziness reflex tachycardia effect  Drugs Affecting Neurotransmitter Release Reserpine (Serprasil ®) Anti-hypertensive effect is by blocking the transport and storage of biogenic amines (dopamine, serotonin, NE)) causing depletion of norepinephrine from central and peripheral synapses Also reduces HR and contractility  Drugs Affecting Neurotransmitter Guanethidine Release Mechanism: Depletes the nerve ending of NE in the PNS Main effects: decrease in PVR and decrease in HR → decrease in BP Adverse effects: Orthostatic hypotension, Na+ and water retention; no CNS effects Pharmacokinetics: Poorly absorbed from the G.I. Onset slow (1-2 weeks). Metabolites excreted in urine Not used anymore; severe side effects  Beta-Adrenergic Blocking Agents 1st Generation Non-Selective Propranolol Timolol *Pindolol *Penbutolol 2nd Generation B1-Selective *Carteolol Metoprolol *Acebutolol 3rd Generation (Hybrids) Atenolol (hydrophylic) Labetalol ( & )* Betaxolol Carvedilol ( & ) Bisoprolol (Diabetics on insulin and Asthmatics ) *ISA Classification Nonselective (1st generation) Some with intrinsic sympathomimetic activity (ISA) * Cardio-selective (b-1 selective, 2nd generation) Hybrid antihypertensive drugs (Beta and Alpha blocking CV actions (3rd generation) Proposed mechanisms Block cardiac 1 receptors ➔ Lower HR ➔ lower CO Block renal 1 receptors ➔ lower renin, lower PVR Oppose action of NE released (ISA) * A group of β blockers that can stimulate β-adrenergic receptors and release NE (agonist effect) and oppose the stimulating effects of the NE released (antagonist effect) in a competitive way; they don't reduce the resting cardiac output and heart rate as effectively as Beta-blockers without ISA Clinical Uses Hypertension - Reduce cardiac output and renin secretion. Arrythmia prophylaxis after a myocardial infarction and Tx of Supraventricular tachycardias Propranolol, metropolol esmolol acebutolol and timolol - Block β1 - receptors in the heart → reduce the sympathetic effect on the heart causing : Decrease automaticity of S.A. node and ectopic pacemakers Prolong refractory period ( slow conduction ) of the A.V node Clinical Uses Angina pectoris - propranolol nadolol and other B blockers reduce heart rate and force of contraction Glaucoma - timolol and other B blockers reduce secretion of aqueous humor Migraine - propranolol provides prophylactic effect. Thyrotoxicosis - propranolol reduces cardiac rate and potential for arrythmias Labetalol (Trandate) A combined alpha-1, beta-1, and beta-2 blocker. Beta blocking action is more prominent. It also has some ISA property. Can be given i.v. for hypertensive emergencies Carvedilol (Coreg) Nonselective beta blocker and alpha-1 blocker BB of choice in the treatment of CHF Side Effects Arrhythmias Bronchoconstriction Sexual dysfunction