PCTH+301+2024+-+SNS+3-4-cyp.pdf

PCTH 301 Sympathetic Nervous System 3 (2024) Catherine Pang [email protected] Room 325, Med Sci Block C 1  Actions of mixed (α + β) adrenoceptor agonists 1. Anaphylaxis. severeallergtic inblood Int...

PCTH 301 Sympathetic Nervous System 3 (2024) Catherine Pang [email protected] Room 325, Med Sci Block C 1  Actions of mixed (α + β) adrenoceptor agonists 1. Anaphylaxis. severeallergtic inblood Interaction of antigen with IgE on mast cells. bronchi longconstriction Release of autacoids (histamine, serotonin, leukotrienes). Hypotension, bronchospasm, ↑ mucous secretion. Epinephrine (i.m.; α + β actions) Physiological “antagonist”. 1: v/c → ↑BP,  mucous secretion ( blood flow to glands), edema. β1: ↑cardiac contractility. β2: bronchodilation. 2  Actions of α1-adrenoceptor agonists i 1. Decongestion (oral or nasal administration): phenylephrine, pseudoephedrine. Vasoconstrict (v/c) mucous membrane to relieve nasal congestion. After- congestion (rebound hyperemia) occurs due to tissue ischemia. 49 How 2. Local vasoconstriction (epinephrine or phenylephrine in local anesthetic onlyhaveα receptors solution). Vasoconstricts skin and mucous membrane (for face, oral and nasal surgery) to prolong the action, and reduce the dose of a local anesthetic. 3. Ophthalmology Phenylephrine is applied to conjunctiva to cause mydriasis to allow examination of the retina. Phenylephrine does not affect accommodation (not affect ciliary muscle contraction) 3  Actions of α2-adrenoceptor agonists NOTE: α2-Adrenoceptor agonists decrease sympathetic nerve activity; they are not considered to be sympathomimetic agents. Antihypertensive: Clonidine α-Methyl dopa 0 Central α2-adrenoceptoraction: reduce sympathetic discharge from CNS. Peripheral α2-adrenoceptor action: presynaptic inhibition of norepinephrine release from the sympathetic nerve terminal. 4  Actions of 1-adrenoceptor agonists heartmusclenotgettingenoughblood oxygen 1. Cardiogenic shock (massive myocardial infarction or heart attack). Dobutamine - β1 > (β2 = α1): have been used to increase cardiac contractility/output. Note: - Norepinephrine and dopamine  TPR (α1-mediated);  tissue perfusion; - Isoproterenol HR (1+ 2). 2. Cardiac arrest musclestop beating Epinephrine is used to restore HR after cardiac arrest. 5  Actions of 2-adrenoceptor agonists 1. Asthma and COPD (chronic obstructive pulmonary disease). Salbutamol (or terbutaline): given by inhalation (or oral) to dilate the bronchioles (and to stabilize mast cells to reducing the release of mediates of allergy such as histamine and leukotrienes). Note: Glucocorticoid (e.g., betamethasone) is primary therapy to reduce edema and bronchial hyperactivity. 2. Premature labor Salbutamol, terbutaline: to transiently ( α Blocker Labetalol α1 + α2 Blocker β1 + β2 Blocker Phentolamine Propranolol Phenoxybezamine Pindolol* Ganglionic blocker α1 Blocker β1 Blocker Prazosin Metoprolol Terazosin Acebutolol* avoidblockingβ receptors Hexamethonium AVnodehavemoiireiepi.is Presynaptic inhibition (α2- Deplete NE/dopamine - Compete with NE for NE transporter (U1) adrenoceptor agonist) in storage vesicles - Deplete NE/dopamine in storage vesicles -  Action potential and NE release Clonidine Reserpine Guanethidine α-Methyl-dopa 9 *Intrinsic sympathomimetic (partial agonistic) action Blockers of α- and/or -adrenoceptors Do these drugs block the effects of endogenously released catecholamines? Yes Do these drugs block the effects of exogenously administered catecholamines? Yes 10  Irreversible (insurmountable) α-adrenoceptor blocker Phenoxybenzamine (POB, non selective α-blocker) Competes with NE for binding to α-adrenoceptors. Converted to a reactive cation → covalently bonded α-adrenoceptors (α1>α2). Effect lasts days – recovery requires synthesis of new α-adrenoceptors. Blocks receptors for serotonin, histamine and ACh at a high dose. notveryselective blockα It causes hypotension (how?), reflex tachycardia (how?), orthostatic hypotension (what is it and how?), nasal stuffiness, headache and inhibition of ejaculation. α V d inbrain 11 Phenoxybenzamine forms a reactive intermediate which covalently (irreversibly) binds to α-adrenoceptor α1-Adrenoceptor https://slideplayer.com/slide/13367821/80/images/8/Selective+a1+blockers+cause+less+reflex+tachycardia +than+Phenoxybenzamine+and+Phentolamine.jpg 12  Reversible (competitive) α-adrenoceptor blocker Non-selective antagonist (α1 = α2) Phentolamine: not important clinically. we venok BP Kif α NE β HR Alpha1-selective antagonists: less tachycardia than phentolamine. (Why?) Prazosin (t1/2=3h); Doxazosin (t1/2=20h) Terazosin (t1/2=10h) Tamsulosin (t1/2=12h; blocks α1A>α1B) Note: α1A–Adrenoceptors mediate contraction of prostate smooth muscle, whereas α1B–adrenoceptors mediate peripheral vasoconstriction. 13 Effects of i.v. phentolamine (A) on blood pressure (BP) and heart rate (HR) in an anesthetized dog. Effects of epinephrine (i.v. injected) before (B) and after (C) administration of phentolamine. Phentolamine : ↓BP (α-block) A ↑HR (reflex) Epinephrine before phentolamine: ↑BP (α/β1/β2 stimulation) B ↑HR (β1 stimulation) Epinephrine after phentolamine: ↓BP (β2); ↑HR (β1) C 14  PCTH 301 Sympathetic Nervous System 4 Catherine Pang ↑ [email protected] Room 325, Med Sci Block C 15  Therapeutic uses of α1-adrenoceptor antagonists 1. Hypertension: prazosin, acts via blockade of α1–adrenoceptors in arterioles. other Yard tumorin adrenalmedulla also ghhf irreversibleα blocker 2. Pheochromocytoma (NE and/or E secreting tumor): POB is given preoperatively to BP (via dilation of arterioles) and ↑blood volume (renal glomerular filtration), or to treat inoperable pheochromocytoma. 3. Raynaud’s syndrome: POB or prazosin (low dose) to reduce vasospasm of 00 arterioles (and tissue damage) in the hands and feet. 4. Benign prostate hypertrophy (BPH): Urinary obstruction due to enlarged prostate. Terazosin (t1/2=10h): By blocking α1A–adrenoceptors at prostate smooth muscle, it reduces urinary flow resistance → ↑urine flow. 16  https://www.urologyhealth.org/urologic-conditions/benign-prostatic-hyperplasia-(bph) Stimulation of α1–adrenoceptors at the longitudinal smooth muscle of the bladder neck and prostate narrows the bladder base and urethra, and restricts urine flow. Terazosin: Blockades of α1–adrenoceptors at the bladder and prostate smooth muscle reduce urine flow resistance. moreselective (Tamsulosin, α1A–blocker): Similar efficacy as terazosin, but causes less hypotension (α1B–adrenoceptors mediate peripheral vasoconstriction; α1A–adrenoceptors mediate contraction of bladder neck, urethra and prostate smooth muscle). 17  Common side effects of α1-adrenoceptor antagonists StimulateB Bz Heart: Reflex increased in sympathetic (β-adrenergic) drive causing tachycardia, and possibly cardiac arrhythmias and angina. reflex skin mingantimbrave Blood vessels: orthostatic hypotension, nasal stuffiness, headache. vasodilationinbrain 70 bloodinvein Genital: inhibition of ejaculation. 18  Reversible (competitive) -adrenoceptor blockers Not affect BP in normal individuals. Prevent increased HR and CO during exercise. Some have local anesthetic action. Blockers of β1+β2: Propranolol, pindolol (+ partial β agonistic), timolol (no local anesthetic action because it does not block sodium channels). bronchiole β1>β2: Metoprolol (no local anesthetic action). β1+β2>α1: Labetalol. 19  Uses of -adrenoceptor antagonists 1. Hypertension:  SNA, HR, cardiac contractility and renin release (block β1). 2. Angina/myocardial infarction/chronic heart failure: HR/cardiac work (block β1). 3. Cardiac arrhythmias: CV of AVN and ectopic beats (block β1). 4. Glaucoma (Timolol): secretion of aqueous humor, intraocular pressure (block β2). 5. Hyperthyroidism:  SNA and HR (block β1) and tremor (block β2). 6. Migraine (propranolol, prophylactic): block cerebral v/d (block β2). 7. Acute panic symptoms (propranolol): SNA (block β1) and skeletal muscle tremor (block β2). CO = cardiac output, HR = heart rate, CV = conduction velocity, AVN = AV node, SNA = sympathetic nerve activity, v/d = vasodilation. 20  Toxicities of -adrenoceptor antagonists Side effects:  HR especially in patients with sinus (SAN-induced) bradycardia and AV block; β-blockers with high lipid solubility (e.g., propranolol) cause sedation and o o depression. Cautions: Acute congestive heart failure (may worsen heart failure in patients with high β1-adrenergic tone). Asthma (can precipitate asthma attack, why?) Insulin-dependent diabetes (suppress β1-mediated increased sympathetic discharge, and β2-mediated glycogenolysis and gluconeogenesis). 21  Labetalol: non-selective blocker of adrenoceptors Blocks 1 = 2 > α1. For severe hypertension and hypertensive crisis. Decrease BP with no reflex tachycardia. (Why not?) Orthostatic hypotension is common. (Why?) Contraindicated in patients with asthma. (Why?) 22  Adrenergic neuron blockers All adrenergic neuron blockers decrease release of NE and are antihypertensive. 1. Clonidine and α-methyl dopa: Both reduce BP via stimulation of α2-adrenoceptors. Imidazoline Clonidine HCl α-Methyldopa Clonidine: acts via 1) central stimulation of α2-adrenoceptors to  sympathetic discharge; 2) stimulation of α2-adrenoceptors at presynaptic nerve terminal to  NE release; 3) stimulation of imidazoline (I) receptors. α-Methyldopa. It is converted in the body to α-methyl NE, an α2-adrenoceptor agonist. It is not an imidazoline derivative. 23  Adrenergic neuron blockers 2. Reserpine: ↓Uptake of dopamine, serotonin and norepinephrine into storage vesicles (in CNS and periphery neurons). It is rarely used except in severe hypertension because of side effects, e.g., gastrointestinal (GI) cramps (due to ↓sympathetic influence); sedation/mental depression (deplete CNS amine stores). 3. Guanethidine: It reduces release of NE from adrenergic storage vesicles (primarily via local anesthetic action), and is used in severe hypertension. It causes GI cramps, but not depression (it does not penetrate the CNS). 4. Ganglionic blockers: It is seldom used due to side effects. 24  Ganglionic blockers Block neuronal nicotinic (Nn) receptors (hexamethonium): affect ganglionic transmission of sympathetic and parasympathetic nerves. Net effects depend on predominance of parasympathetic or sympathetic tone. Hardly used due to high incidence of side effects. Drugs: Trimethaphan (t1/2