Cholinergic Receptors

Cholinergic Receptors: Types Muscarinic receptors Nicotinic receptors Based on selective activation and antagonism.

Subtypes and characteristic of cholinoceptors Receptor Type Other Names Location Structual Features Postreceptor Mechanism M1 M 1a Nerves Seven transmembrane segments, G protein-linked IP3,DAG cascade M2 M 2a, Cardiac M2 Heart,nerves, smooth muscle Seven transmembrane segments,G protein-linked Inhibition of cAMP production, activation of K+ channels

Seven transmembrane segments, Receptor Type Other Names Location Structual Features Postreceptor Mechanism M3 M2b, glandular M2 Glands, smooth muscle, endothelium Seven transmembrane segments, G protein-linked IP3 , DAG cascade m41 ?CNS Inhibition of cAMP production

Seven transmembrane segments, Receptor Type Other Names Location Structual Features Postreceptor Mechanism m51 ?CNS Seven transmembrane segments, G protein-linked IP3 , DAG cascade NM Muscle type, end plate receptor Skeletal muscle neuromuscular junction Pentamer ( α2βδγ)2 NA+, K+ depolarizing ion channel

α and β subunits only as α2β2 or α3β3 Receptor Type Other Names Location Structual Features Postreceptor Mechanism NN Neuronal type, ganglion receptor Postganglionic cell body, dendrite α and β subunits only as α2β2 or α3β3 NA+, K+ depolarizing ion channel

Receptors and signal transduction in the ANS: Nicotinic Receptors b g d

Receptors and signal transduction in the ANS Cholinergic Receptors Nicotinic Muscarinic M1 M3 M5 M2 M4

Receptors and signal transduction in the ANS: Muscarinic receptors are 7 transmembrane domain, G-protein coupled receptors

Receptors and signal transduction in the ANS: Muscarinic receptors (M1, M3, M5) NH 3 (+) Phospho - G lipase C q PIP 2 COOH IP Diacylglycerol 3 Increase Ca 2+ Activate Protein Kinase C Response

Receptors and signal transduction in the ANS: Muscarinic Receptors (M2 and M4)

The major groups of cholinoceptor-activating drugs

Cholinergic agonists Two (2) types Direct – Indirect occupy and activate receptors Indirect inhibit acetylcholinesterase levels of Ach increase Ach stimulates receptors

Esters of Choline

Esters of Choline hydrophilic differ in breakdown by Ach’esterase acetylcholine - very susceptable methacholine - 3X less susceptible bethanechol - not susceptible methacholine & bethanechol longer duration of action than Ach mostly activate muscarinic receptors

Direct Esters of choline – mostly activate muscarinic receptors methacholine bethanechol Alkaloids – activate both muscarinic and nicotinic receptors pilocarpine nicotine

Properties of choline esters Susceptibility to Cholinesterase Muscarinic Action Nicotinic Action Acetylcholine chloride ++++ +++ Methacholine chloride + None Carbachol chloride Negligible ++ Bethanechol chloride

Alkaloids (pilocarpine and nicotine) Highly lipid soluble well absorbed from GI tract get into brain Capable of both muscarinic and nicotinic receptor activation

Effect of direct-acting cholinoceptor stimulants Organ Response Eye Sphincter muscle of iris Ciliary muscle Contraction (miosis) Contraction for near vision Lung Bronchial muscle Bronchial glands Contraction (bronchoconstriction) Stimulation

Organ Response Heart Sinoatrial node Atria Atrioventricular node Ventricles Decrease in rate (negative chronotropy) Decrease in contractile strength (negative ionotropy),Decrease in refractory period Decrease in conduction velocity, Increase in refractory period Small decrease in contractile strength

Organ Response Blood vessels Arteries Veins Dilation (via EDRF), Constriction (high-dose effect) Urinary bladder Detrusor Trigone and sphincter Contraction Relaxation

Organ Response Gastrointestinal tract Motility Sphincters Secretion Increase Relaxation Stimulation Glands Sweat, salivary, lacrimal, nasopharyngeal

Eye pupillary sphincter muscle contraction (miosis) ciliary muscle contraction opens drainage canals in anterior chamber lowers intraocular pressure lens thickens for near vision

CV Effects Direct effects on heart Reduced vascular resistance – decreased SA and AV conduction velocity decreased force of atrial contraction Reduced vascular resistance – activation of receptors on endothelium generation of nitric oxide (NO) NO causes vascular muscle relaxation Effects on BP modified by reflexes

Cardiac Conduction - Ach Increased K+ conduction – slows conduction SA node AV node Decreased inward Ca++ current – reduces force of contraction Slowed pacemaker rate opposed by reflexes Ventricles are less directly affected (parasympathetic innervation of ventricles much less than atria)

Respiratory Effects bronchial smooth muscle contraction respiratory gland secretion asthmatics highly sensitive

GI Effects Increased secretion Increased motility - diarrhea gastric glands salivary glands Increased motility - diarrhea

Cholinergic receptors in the brain Brain has muscarinic receptors Esters don’t penetrate Alkaloids penetrate well Brainstem and spinal cord contain nicotinic receptors Mild alerting from smoking Seizures in overdose

Clinical Uses of Cholinergic Agonists Glaucoma – physostigmine once used GI and urinary stimulation - bethanechol myasthenia gravis edrophonium for diagnosis or testing pyridostigmine for treatment

SLUDGE: Toxicity Salivation Lacrimation Urination Defecation Gastric Emptying

Cholinergic Blockers More selective than agonists; may block muscarinic or nicotinic receptors selectively

Cholinergic Blockers muscarinic blockers - very useful in medicine ganglionic blockers - not used much neuromuscular blockers - used for skeletal muscle relaxation in surgery

Antimuscarinic Drugs alkaloids – naturally occurring tertiary amines atropine scopolamine tertiary amines dicyclomine benztropine quaternary amines - ipratropium

Antimuscarinic Drugs tertiary amines & alkaloids lipid soluble good absorption from mucous membranes and skin penetration into brain wide distribution e.g. brain & periphery highly selective for muscarinic receptor quaternary amines - opposite of above

Antimuscarinic Drugs alkaloids – naturally occurring tertiary amines atropine scopolamine tertiary amines dicyclomine benztropine quaternary amines - ipratropium

Atropine & Scopolamine plant origin atropine - Atropa belladonna scopolamine - Hyoscyamus niger well absorbed from mucous membranes or skin competes with Ach for muscarinic receptors organs differ in sensitivity to these drugs

Atropine most sensitive intermediate sensitivity - heart tissues salivary glands bronchial glands sweat glands intermediate sensitivity - heart tissues least sensitive - parietal cells highly selective for muscarinic receptors

Atropine - CNS sedation in therapeutic doses hallucinations in toxic doses bradycardia when given parenterally antimotion sickness effects antiparkinsonism effects

Atropine - Eye relaxes pupillary sphincter muscle unopposed sympathetic effects mydriasis or dilation paralysis of the ciliary muscle - cycloplegia reduction in lacrimal secretion - dry eye

Atropine Heart & Cardiovascular System initial bradycardia - central effect (?) tachycardia due to blockade of vagal slowing Opposes ach effects on SA depolarization Opposes ach effects on AV conduction ventricles are less affected overall - little affect on BP

Atropine respiratory tract some bronchodilation reduction of respiratory secretions a quaternary drug (Ipatropium) is given as an aerosol to patients with asthma genitourinary tract - ureter and bladder relaxation sweat glands - suppressed by atropine

Atropine dry mouth slight, if any, decrease in gastric secretion GI motility decreased decreased gastric emptying constipation

Atropine Poisoning dry as a bone blind as a bat red as a beet very dangerous in children - hyperpyrexia

Therapeutic Uses antiparkinsonism effects motion sickness - scopolamine given via transdermal patch eye examinations - usually something short-acting (e.g. phenylephrine) is used rather than atropine asthma - ipatropium aerosol insecticide poisoning