Transcript Document
Cholinergic Receptors Antagonists 59-291 Section 2, lecture 3 1 • Muscarinic Receptor Antagonists – Belladonna alkaloids • Derived from plants; Atropa belladonna (the deadly night shade) • Atropine, scopolamine • Well absorbed from the gut and distributed to CNS • Systemic administration, short half life of ~ 2h • Topical ocular admin, longer half life. – Bind to iris pigments and are released over days ,darker irises bind more 2 Pharmacologic effects- muscarinic receptor antagonists inhibit parasympathetic nerve stimulation relax smooth muscle increase heart rate Increase conductivity in the heart Inhibit exocrine gland secretion These effects are dose dependent 3 Cardiac effect • Standard dose – Blocks the effect of vagus nerve • Increases heart rate • Increases AV conduction velocity • Low dose – When delivered by IV, at low dose slows heart rate • by stimulating vagal motor nucleus in the brain • Used to treat sinus bradycardia which can lead to hypotension, ischemia if left untreated 4 Central Nervous System • Atropine, scopolamine; – Block muscarinic receptors • Sedation • Excitement • Scopolamine – More sedating than atropine – Used as an adjunct to anesthesia • Atropine – Mild stimulation followed by a slower and longer-lasting sedative effect – Higher dose>> deliruim, hallucination 5 Nicotinic Receptor Antagonists • Ganglionic blocking agents (e.g. Trimethaphan) – Block NN receptors at sympathetic and parasy. – Effect on a tissue: depends on sympathetic or parasy. system is dominant – No longer are used to treat chronic hypertension – Trimethaphan is occasionally used in cases of hypertensive emergency, when extremely high blood pressure must be lowered rapidly 6 Nicotinic Receptor Antagonists • Neuromuscular blocking agents – – 1. 2. Inhibit neurotransmission at skeletal muscle Causing muscle weakness and paralysis Non-depolarizing blockers Depolarizing blockers 7 Nondeporolarizing Neuromuscular blocking agents (Curariform drugs) • Positively charged, e.g. Pancuronium, Tubocurarine • Are not well absorbed from the gut, hence they do not cause poisoning when ingested with contaminated meat • Do not cross blood-brain barrier (BBB) • Competitive antagonists of Ach at NM receptors 8 Nondeporolarizing Neuromuscular blocking agents • Paralyze small fast moving muscles of eyes and face> larger muscles of the limbs and trunk > finally the intercostal muscles and the diaphragm • Is used for relaxation of abdominal muscles for surgical procedures without producing apnea • Side effects: stimulate mast cells to release histamine> tachycardia, hypotension and bronchospasm 9 Depolarizing Neuromuscular Blocking Agents • Succinylcholine; two molecules of Ach • Binds to NM receptors and depolarizes the motor end plate • First transient muscle contraction (fasciculation) followed by a sustained muscle paralysis • Ultra-short duration action (5-10 min) due to the effect of plasma cholinesterase • Is used to produce muscle relaxation before and during surgery 10 Adrenergic Receptor Agonists • Diverse pharmacological effect: treatment of a wide spectrum of clinical conditions • Cardiovascular emergencies to common cold • Sympathetic Stimulation> release of NE, E > Adrenergic receptors> physiological effects 11 Inhibits NE release Contract vascular smooth muscle, iris, bladder sphincter muscle Relaxes bronchial, uterine, and vascular smooth muscle 12 b-Adrenergic Receptors • Activation of b1 adrenergic receptors – Positive chronotropic effect ( heart rate) – Positive inotropic effect ( contractility) – Positive dromotropic effect ( impulse conduction velocity) • Activation of b2 adrenergic receptors – Relaxation of bronchial, uterine, vascular smooth muscle cells – Potassuim uptake in skeletal muscles – Glycogenolysis • Activation of b3 adrenergic receptors – lipolysis 13 Dopamine Receptors • Dopamine receptors only activated by dopamine and not by any other adrenergic receptor agonist – D1: Muscle relaxation in vascular smooth muscles – D2: modulate neurotransmitter release 14 Imidazoline Receptors • Activated by adrenergic receptor agonists and other substances that contain imidazoline structure • Found in CNS and PNS 15 Signal transduction • Adrenergic, dopamine and imidazoline receptors are G-protien binding receptors a1 Activate phospholipase C, which catalyzes the release of IP3 and DAG from membrane phospholipid • IP3 releases Ca2+ from sarcoplasmic reticulum in a1 SM cells and muscle contraction> vasoconstriction> increase BP a2 activation> inhibition of adenylate cyclase> cAMP b and D1 receptor activation > stimulation of adenylate cyclase > cAMP 16 Practice Questions • Determine the location and function of the following adrenergic receptors a1 receptors – Postjunctional smooth muscles; – Contraction of vascular SM, iris dilator muscle, bladder sphincter muscle a2 receptors – Presynaptic neurons postganglionic neurons – Feedback inhibition of NE release b1 receptors – Cardiac cells – Positive chronotropic, inotropic, dromotropic effects 17 • What is succinylcholine? What is the effect and structure of this drug? • Nicotinic receptor antagonist • Depolarizing blocking agent • Two molecules of Ach • Binds to nicotinic receptors and causes persistent depolarization of motor end plate • Fasciculation followed by sustained paralysis 18