Cholinergic Receptors Antagonists

1. Cholinergic Receptors Antagonists 59-291 Section 2, lecture 3

2. 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

3. 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

4. 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

5. 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

6. 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

7. Nicotinic Receptor Antagonists • Neuromuscular blocking agents • Inhibit neurotransmission at skeletal muscle • Causing muscle weakness and paralysis • Non-depolarizing blockers • Depolarizing blockers

8. 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

9. 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

10. 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

11. 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

12. Relaxes bronchial, uterine, and vascular smooth muscle Contract vascular smooth muscle, iris, bladder sphincter muscle Inhibits NE release

13. 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 b2adrenergic receptors • Relaxation of bronchial, uterine, vascular smooth muscle cells • Potassuim uptake in skeletal muscles • Glycogenolysis • Activation of b3adrenergic receptors • lipolysis

14. 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

15. Imidazoline Receptors • Activated by adrenergic receptor agonists and other substances that contain imidazoline structure • Found in CNS and PNS

16. 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 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 a1

17. 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

18. 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