CHOLINERGIC AGONISTS

Cholinoceptor-Activating Drugs

Parasymapthomimmetics

Case Scenario

In mid-afternoon, a coworker brings 43-year-old JM to the emergency department because he is unable to continue picking vegetables. His gait is unsteady and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented.

Cholinergic agonists

Direct Actinga.Alkaloids

Muscarine, Pilocarpine*, Nicotine*, Lobeline*

b.Choline Esters

ACh, Methacholine, Carbachol, Bethanechol

In-direct ActingReversible

Edrophonium, neostigmine, physostigmine, demecarium

Irreversible

Ecothiophate, isoflurophate, Soman, parathion, malathion

Reactivator of acetylcholinesterase ---

Pralidoxime

poorly absorbed and poorly distributed into the central nervous system because they are hydrophilic. Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route), they differ markedly in their susceptibility to hydrolysisby cholinesterase. Acetylcholine is very rapidly hydrolyzed

Methacholine is resistant to hydrolysis, Carbamic acid esters Carbachol and Bethanecholmore resistant to hydrolysis by cholinesterase and have correspondingly longer durations of action.

Lobeline ………………………plant derivative similar to nicotine.

* Tertiary natural cholinomimetic alkaloids

Structural classification ---Indirect acting drugs

1. Simple alcohols bearing a quaternary

ammonium group:

Edrophonium

2. Carbamic acid esters of alcohols bearing quaternary or tertiary ammonium groups :

Carbamates:

Neostigmine, Pyridostigmine, Physostigmine, Ambenonium, Demacarium

3. Organophosphates:

Isoflurophate

Ecothiophate

Cholinergic Neurotransmitter

CHOLINERGIC NEUROTRANSMITTER

ACETYLCHOLINE

SITES WHERE Ach IS RELEASED AS TRANSMITTER:

Preganglionic fibers to adrenal medulla.

Postganglionic fibers of parasympathetic division.

Autonomic ganglia (both sympathetic and parasympathetic)

Neuromuscular junction

Cholinergic Receptors

Nicotinic (nAChR)

Muscarinic (mAChR)

Cholinoceptors are members of either G protein–linked (muscarinic) or ion channel (nicotinic) families on the basis oftheir transmembrane signaling mechanisms.

THREE MECHANISMS BY WHICH BINDING OF NEUROTRANSMITTER LEADS TO A CELLULAR RESPONSE AND EFFECT:

RECEPTORS COUPLED TO A ION CHANNEL

Cholinergic nicotinic receptors

Ions

Change in membrane potential or ionic

concentration in cell.

Ions

RECEPTORS COUPLED TO DIACYLGLYCEROL (DAG) & INOSITOL TRIPHOSPHATE

DAG IP3

Protein phosphorylation & increase in intracellular Ca

Intracellular effect

Cholinergic muscarinic receptor

Mechanism of action of

Indirect acting Cholinergic agonist

Mechanism of Action

ACETATE

ACETYLCHOLINESTERASEACETYLCHOLINE

Ach

CHOLINE

1.Choline + Acetylated Enzyme

H20

2. Acetylated Enzyme Acetate + Enzyme

ACETYLCHOLINESTERASE INHIBITORS

Actions of cholinergic agonist on

various systems

(organ system effects)

EYE:

Contraction of sphincter pupillae

muscle--- pupil constricts (Miosis).

Contraction of ciliary muscle -----------

---- accommodation of lens for

Near vision

CVS:The action of Ach on heart mimic the effects of VAGAL stimulation.

v The normal vagal activity regulates the heart by release of Ach at SA node.

Vasodilatation

SA node:

Atria:

Atrioventricular:

Ventricles: Small decrease in contractile strength.

Decrease in heart rate ( -ve chronotropic effect).

Decrease in force of contraction ( -ve Inotropic effect).

Decrease in rate of conduction in SA & AV nodes ( -ve dromotropic effect).

G.I.T: (increased secretory and motor activity)

Increase salivary secretions

Stimulates intestinal secretions

Stimulates intestinal motility.

Sphincters are relaxed

RESPIRATORY SYSTEM:

Stimulates bronchiolar secretions

G.U SYSTEM:

Increase tone of detrusor muscle

Relaxes sphincter and trigone.

Miscellaneous secretory glands

Stimulate secretion of sweat, lacrimal and nasopharyngeal glands

CNS

vTremors

vHypothermia

v Increased locomotor activity

v Improved cognition

Therapeutic Uses

of

Cholinergic agonist

EYE

Glaucoma Drugs used:Direct acting agonists Pilocarpine

Methacholine CarbacholCholinesterase inhibitors

Physostigmine Demacurium Echothiophate

Isoflurophate

Gastrointestinal and Urinary Tract

Post operative ileus

Congenital megacolon

Postoperative or postpartum nonobstructive urinary retention Reflux esophagitis Sjogren’s syndrome --- Pilocarpine / CEVIMELINE

Most commonly used choline ester:

Most commonly used Cholinesterase inhibitors:

Atony or paralysis of stomach or bowel following surgical manipulation

Bethanecol

Neostigmine

Neuromuscular junction

Myasthenia gravis

Autoimmune diseaseAntibodies against:---------- nicotinic receptors

on post junctional end platesClinical findings: Ptosis, DiplopiaDifficulty in speaking and swallowing Extremity weakness

Treatment of myasthenia gravis

Cholinesterase inhibitors

CHOLINESTERASE INHIBITORS

Diagnostic test for myastheniav EdrophoniumLong term therapy for myastheniavNeostigmine v Pyridostigmine vAmbenonium

Neuromuscular blockage(pharmacological paralysis)

caused by:Nondepolarizing neuromuscular relaxants

DRUGS USED FOR Rx

Neostigmine Edrophonium

HEART

Supraventricular tachyaryhthmiasParoxysmal supraventricular tachycardia

Drug used:

Edrophonium Adenosine / Verapamil / Diltiazem

Antimuscuranic poisoning

Atropine poisoning

Drug Used:

Physostigmine

Why Physostigmine ?why not some other cholinesterase inhibitor

Because

Physostigmine is

naturally occurring

tertiary amine

greater lipid solubility

CNS

Alzheimer's Disease

Drugs Used:

TacrineDonepezilGalantamine Rivastigmine

Alzheimer's disease (AD) or senile dementia of Alzheimer's typeneurodegenerative disease results in: a loss of mental functions due to the: deterioration of brain tissue.

Its exact aetiology (cause) is still unknown

Clinical features

usual first symptom: memory loss. behavioral changes, like confusion, disorientation, sudden periods of defiance, abusive behavior, or violence, etc. in people who have no previous history of such behavior.

Toxicity

Direct acting Muscarinic stimulantsCause predictable signs of muscarinic excess

NauseaVomitingDiarrheaSalivationSweatingCutaneous vasodilatationBronchocontriction Certain Mushrooms contain muscarinic alkaloid ---Treatment is with:Atropine – 1-2 m parenterally

Cholinergic Crises/Poisoning

Medical emergency

Especially in

Rural communities/ cultures --- Use of

Cholinesterase inhibitor (organophosphorus) insecticide

Wild Mushrooms are commonly eaten

Chemical warfare nerve gases

Mushroom poisoning ---Rapid onset (15-30 min), Delayed onset (6-12 hour)

Management of Cholinergic Crises

Decontamination

Activated charcoal

Gastric Lavage.

Atropine (to counter the muscarinic effects)

Mild symptoms of nerve agent (nerve gas) or insecticide exposure:2 mg/0.7 mL by AtroPen auto-injector into midlateral thigh followed by 2 additional 2 mg/0.7 mL (AtroPen) injections given in rapid succession are recommended 10 minutes after receiving the first injection

Pralidoxime (Cholinesterase reactivator) …… to relieve neuromuscular blockage.

v Mark I NAAK, or MARK I Kit, is United States military nomenclature for the "Nerve Agent Antidote Kit". It is a dual-chamberautoinjector

v Brand names: ATNAA (ANTIDOTE TREATMENT - NERVE AGENT, AUTO-INJECTOR) has both the

atropine and the pralidoxime in one syringe injected into the muscles of an outer thigh or into the buttocks.

Diazepam: to control seizures

Mechanical Ventilation - Respiratory paralysis