cholinergic receptors and its modulators(agonists, antagonists etc)

Dr. Asif HussainJNMCHA.M.U, Aligarh

Cholinergic receptors and modulators

Autonomic nervous system◦ Afferent neurons◦ Efferent neurons◦ Preganglionic and post ganglionic neurons◦ Involuntary in nature

1) Parasympathetic nervous system2) Sympathetic nervous system

Introduction

Somatic nervous system

◦ Sensory neurons◦ Motor neurons◦ Voluntary in nature◦ Somatic motor neurons are myelinated◦ Somatic motor neurons are cholinergic

Parasympathetic System

Ganglia close to or on target organs

Parasympathetic Innervation of Visceral Targets

• Preganglionic neurons - long

• Post ganglionic neurons - short

Acetic acid ester of choline Synthesis, storage , release and

degradation

Acetylcholine

Types of Cholinergic Receptors

1. Nicotine = agonist

2. Directly opens a Na+ Ca + K+ channels

3. Curare = antagonist

4. NM : Skeletal muscle endplate

5. NN : Ganglionic cells, adrenal medulla, CNS

(1) Nicotinic cholinergic receptor

Ionotropic Receptors

1. Work very fast; important role in fast neurotransmission

2. Each is made of several subunits (together form the complete receptor)

3. At center of receptors is channel or pore to allow flow of neurotransmitter

4. At rest - receptor channels is closed5. When neurotransmitter bind -- channel immediately opens6. When ligand leaves binding site -- channel quickly closes

Nicotinic Receptor signal transduction pathway

Ionotropic : ligand gated ion channel

Composed of 5 subunits

ACh binds to extracellular domains of α subunits

Receptor opens a central transmembrane ion channelChanges in membrane potential or ionic concentration within cell

Selectively stimulated by muscarine and blocked by atropine.

Located primarily on autonomic effector cells of heart, smooth muscles, respiratory tract etc and CNS.

Subtypes are M1 ,M2, M3, M4 & M5

(2) Muscarinic receptors

NH3

COOH

Gq

Phospho-lipase C

(+)

PIP2

IP3 Diacylglycerol

Increase Ca2+ Activate ProteinKinase C

Response

Muscarinic Receptor signal transduction pathways

M3 muscarinic receptor

C O

O

CH2 CH2 N

CH3

CH3

CH3

CH3

Acetylcholine

General Effects of Acetylcholine

Choline esters ◦ Acetylcholine◦ Methacholine◦ Carbachol◦ Bethanechol

AlkaloidsMuscarinePilocarpineArecoline

Cholinergic agonists

Blocks action of Ach on autonomic effectors and in CNS exerts through muscarinic rceptors.

Atropine is prototype drug of this class is highly selective for muscarinic receptors.

All anticholinergics are competitive antagonists.

Cholinergic antagonists

Natural alkaloid◦ Atropine◦ Hyoscine

Semisynthetic derivatives◦ Homatropine◦ Ipratropium bromide◦ Tiotropium bromide

Classification

Synthetic compoundsMydriatics: cyclopentolate, tropicamideAntisecretory-antispasmodics:

◦ Propantheline◦ Oxyphenonium◦ Glycopyrrolate◦ Dicyclomine◦ PirenzepineVesicoselective :oxybutynin, flavoxate, tolterodineAntiparkinsonian: trihexyphenidyl, biperiden

Therapeutic Uses : Cholinergic Antagonists

CVS Affect heart’s conduction system

Low Doses High Doses

Slows heart rate

↓ ↓Block inhibitory vagal effects on SA & AV Nodes

1. Sinus Bradycardia2. Sympatomatic 2nd degree heart

block

Atropine (0.05 – 1 mg/ml injection)

Therapeutic uses Continued…

CNS

1.Parkinson’s Disease

3.Motion Sickness

Parkinsonian tremor & rigidity results from Relative Excess of Cholinergic activity

Deficiency in the Dopaminergic activity in Basal ganglia-Striatum system

This vestibular disturbance involve muscarinic cholinergic transmission

Centrally acting Antimuscarinic Agents

2.Drug induced extra-pyramidal symptoms

Benzhexol, Benztropine

Scopolamine

Respiratory system

Both smooth muscle & secretory glands of Airway receive Vagal innervation & contain Muscarinic receptors

Decreased secretions from pharynx ,bronchi & bronchioles

Relaxes smooth muscles in bronchi & bronchioles

1. Asthma2. COPD3. Exercise-induced

bronchospasm

Ipratropium, Tiotropium

Gastrointestinal System

Blockade of muscarinic receptors affect motility & secretory functions of the gut

1.Decreased secretions2. Relaxation of smooth muscle3. Decreased tone & peristalsis

1.To facilitate endoscopy & GI radiology by relaxing smooth muscles ( Hyoscine)

2. As an antispasmodic in IBS & colonic divericula ( Dicyclomine)

3. Peptic ulcer disease ( Pirenzepine – selective M1

antagonist)

4. Traveler's diarrhea (atropine + diphenoxylate, Lomotil)

Genitourinary system

Relaxes smooth muscles of ureters & bladder wall

1.Bladder spasm after urologic surgery

2. Reduces involuntary voiding in neurological disorder

-Oxybutinin-Derifenacin -Solifenacin -Toltrodine

Eye

Constrictor papillae muscle is blocked by Atropine

Pupillary constrictor mucle depends on muscarinic cholinoceptor activation

Results in unopposed sympathetic dilator activity

1

2 Weaken the contraction of ciliary muscle ( Cycloplegia)

1.Referactive error measurement2. Fundoscopic examination3. To prevent synechia(adhesion) formation in uveitis & iritis

Atropine,homatropine, tropicamide,cyclopentolate

Cholinergic poisoning

- Cholinesterase inhibitors insecticide in rural communities- Consumption of wild mushrooms

1.Antimuscarinic therapy

1-2 mg Atropine sulphate i/v every 5-15 minutes until signs (dry mouth, reversal of miosis) appears

2.Cholinisterase regenerator compounds

Pralidoxime (PAM) & Diacetylmonoxime(DAM)(1-2 gm i/v infusion over 15-30 mins)

Body System Side/Adverse Effects

Cardiovascular Increased heart rate, dysrhythmias

CNS CNS excitation, restlessness, irritability, disorientation, hallucinations, delirium

Cholinergic Blocking Agents: Side Effects

Body System Side/Adverse Effects

Eye Decreased visual accommodation, increased intraocular pressure

Gastrointestinal Decreased salivation, decreased gastric secretions,

decreased motility

Genitourinary Urinary retention

Cholinergic Blocking Agents: Side Effects

Antihistamines, phenothiazines, tricyclic antidepressants, MAOIs

When given with cholinergic blocking agents, cause ADDITIVE anticholinergic effects, resulting in increased effects

Cholinergic Blocking Agents: Interactions

Ganglion blocking drugsCompetitively block action of Acetylcholine & similar agonist at nicotinic receptors of both parasympathetic & sympathetic ganglia

Effects are numerous & complex as both divisions of ANS are blocked indiscriminately

Hexamethonium –historically 1st effective antihypertensive agent

Mecamylamine ---reducing nicotine craving in patients quitting smoking

Trimethaphan ---occasionally used in hypertensive emergency & dissecting aortic aneurysm---to produce controlled hypotension

Thank You