1 Cholinergic Receptors Antagonists 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 N N 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 1.Non-depolarizing blockers 2.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 N M 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 N M 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 Contract vascular smooth muscle, iris, bladder sphincter muscle Inhibits NE release Relaxes bronchial, uterine, and vascular smooth muscle

13  -Adrenergic Receptors Activation of  1 adrenergic receptors –Positive chronotropic effect ( heart rate) –Positive inotropic effect ( contractility) –Positive dromotropic effect ( impulse conduction velocity) Activation of    adrenergic receptors –Relaxation of bronchial, uterine, vascular smooth muscle cells –Potassuim uptake in skeletal muscles –Glycogenolysis Activation of    adrenergic receptors –lipolysis

14 Dopamine Receptors Dopamine receptors only activated by dopamine and not by any other adrenergic receptor agonist –D 1 : Muscle relaxation in vascular smooth muscles –D 2 : 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  1 Activate phospholipase C, which catalyzes the release of IP3 and DAG from membrane phospholipid IP3 releases Ca 2+ from sarcoplasmic reticulum in SM cells and muscle contraction> vasoconstriction> increase BP  2 activation> inhibition of adenylate cyclase> cAMP  and D 1 receptor activation > stimulation of adenylate cyclase > cAMP a1

17 Practice Questions Determine the location and function of the following adrenergic receptors  1 receptors –Postjunctional smooth muscles; –Contraction of vascular SM, iris dilator muscle, bladder sphincter muscle  2 receptors –Presynaptic neurons postganglionic neurons –Feedback inhibition of NE release  1 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