Cholinergic Receptors Cholinergic Receptors Types Muscarinic receptors 2

Cholinergic Receptors

Cholinergic Receptors: Types Muscarinic receptors 2. Nicotinic receptors 1. Based on selective activation and antagonism.

cholinoceptors Receptor Other Type Names M 1 a M 1 M 2 Location Nerves Structual Features Postreceptor Mechanism Seven IP 3, DAG transmembrane cascade segments, G protein-linked M 2 a, Heart, nerves, Seven Inhibition of Cardiac transmembrane c. AMP smooth M 2 segments, G production, muscle protein-linked activation of K+ channels

Receptor Type M 3 m 41 Other Names Location Structual Features Postreceptor Mechanism M 2 b, Glands, Seven IP 3 , DAG transmemb cascade glandular M 2 smooth rane muscle, segments, endotheli G proteinum linked ? CNS Seven Inhibition transmemb of c. AMP rane production segments, G proteinlinked

Receptor Type m 51 NM Other Names Location ? CNS Structual Features Postreceptor Mechanism Seven IP 3 , DAG transmem cascade brane segments, G proteinlinked Muscle Skeletal Pentamer NA+, K+ type, end muscle ( α 2βδγ)2 depolarizing plate neuromuscular ion channel receptor junction

Recep tor Type NN Other Names Location Neuronal Postganglionic type, cell body, ganglion dendrite receptor Structual Features Postreceptor Mechanism α and β subunits only as α 2β 2 or α 3β 3 NA+, K+ depolarizing ion channel

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

Receptors and signal transduction in the ANS Cholinergic Receptors Nicotinic Muscarinic M 1 M 3 M 5 M 2 M 4

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 NH 3 (M 1, M 3, M 5) Gq (+) Phospho- lipase C PIP 2 COOH IP 3 Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response

Receptors and signal transduction in the ANS: Muscarinic Receptors (M 2 and M 4)

The major groups of cholinoceptoractivating drugs Cholinoceptor stimulants Direct-acting Indirect-acting (cholinesterase inhibitors) (receptor agonists) Muscarinic Nicotinic Choline esters Ganglionic Alkaloids Neuromuscular

Cholinergic agonists �Two (2) types �Direct – ○ 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 - 3 X 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 Choline Ester Acetylcholine chloride Methacholine chloride Carbachol chloride Bethanechol chloride Susceptibility to Muscarinic Cholinesterase Action Nicotinic Action ++++ ++++ None Negligible ++ +++ Negligible ++ None

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 • Eye Sphincter muscle of iris Ciliary muscle • Lung Bronchial muscle Bronchial glands Response Contraction (miosis) Contraction for near vision Contraction (bronchoconstriction) Stimulation

Organ • Heart Sinoatrial node Atria Atrioventricular node Ventricles Response 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 • Blood vessels Arteries Veins • Urinary bladder Detrusor Trigone and sphincter Response Dilation (via EDRF), Constriction (high-dose effect) Contraction Relaxation

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

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 �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 �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 �atropine �scopolamine occurring �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 �atropine �scopolamine occurring �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 �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