CHOLINERGIC DRUGS[PARASYMPATHOMIMETICS]

DR. RAMESH KRISHNANMD,PHARMACOLOGY[2 ND YEAR]

Autonomic Nervous System

Action Potential

Na+

aa

b

ACh

Acetylcholinesterase

Na+

Parasympathetic Ganglionic Synapse

Preganglionic neuron Postganglionic neuron

Receptor

nicotinemuscarine

muscarinicreceptor

The ‘master key’ for both types of ‘lock’

ACh

AC

h

Acknowlegement-Dr.Kumarasingam

M1Location 1) Gastric paracrine glands

2) CNS(Cortex, hippocampus, striatum

3) sympathetic ganglia

Molecularmechanism

Activation of PLC : ↑ IP3 & DAG :↑ Ca2+ & PKC

Functional response

↑ acid secretion↑ cognitive function(learning &memory)↑ depolarisation of autonomic ganglia

Agonists Oxotremorine

Antagonists Pirenzepine,Telenzepine

M2

Location 1)Heart 2)Smooth muscle3)Nerve terminal 4)CNS

Molecularmechanism

(-) of adenyl cyclase – ↓cAMP ,Activation of K+channel

Functional response

HEART -SA node -↓ HR : AV node - ↓ conductionAtria - ↓contraction : Ventricle- ↓ contractionSmooth muscle - ↑contraction

Agonists Methacholine

Antagonists Methoctramine, Tripitramine

M3

Location 1)Glands2)Smooth muscle3) Iris,ciliary muscle4)CNS

Molecularmechanism

Similar to M1

Functional response

Smooth muscle contractionBlood Vessel-relaxationPupil constriction , ciliary contraction

Agonists Bethanechol

Antagonists Darifenacin

M4Location CNS(forebrain)

Molecular mechanism Similar to M2

Functional response Inhibit transmitter releaseAnalgesia

Location Substantia nigra

Molecular mechanism Similar to M1 & 3

Functional response Cerebral vasodilatationFacilitates DA release

M5

Ach actions –Nicotinic

1. Autonomic ganglia:– Both Sympathetic and parasympathetic ganglia are stimulated– After atropine injection Ach causes tachycardia and rise in BP

2. Skeletal muscle– IV injection – no effect– Application causes contraction of skeletal muscle

3. CNS:– Does not penetrate BBB

Classification

Cholinoceptor stimulants

Direct-acting

(receptor agonists)Indirect-acting

(cholinesterase inhibitors)

Muscarinic Nicotinic

Choline esters

Alkaloids

Ganglionic

Neuromuscular

DIRECTLY ACTING CHOLINERGICS

CHOLINE ESTERS

• Acetylcholine

• Bethanechol

• Carbachol

• Methacholine

ALKALOIDS

• Muscarine

• Pilocarpine

• Arecoline

Acetylecholine:-

Is the neurotransmitter of the parasympathetic N.S and cholinergic nerves, it is therapeutically of no importance due to:

• 1. Multiplicity of actions.

• 2. Rapid inactivation by acetyl-cholinesterase.

• 3. Has both muscarinic and nicotinic activity.

CHOLINOMIMETIC ALKALOIDS

PILOCARPINE

• Obtained from leaves of Pilocarpus Microphyllus

• Tertiary amine Crosses BBB

• Dominant – M3 & NN

• Too toxic for systemic use

• ADR –

↑ sweating, salivation & other secretions

• Small doses ↓ BP High doses ↑ BP

USES

1. EYE - Penetrates cornea – Miosis, Ciliary muscle contraction, ↓IOP lasting 4 – 8 hrs

• 3rd line drug - Primary open angle Glaucoma

– S/E : Initial stinging ,

–Painful spasm of accomodation

• To counteract Mydriatics

• Prevent adhesions of Iris with lens/ cornea

2. As SIALOGOGUE

MUSCARINE

• Obtained from poisonous mushrooms

• Amanita muscaria & Inocybe

• Has only muscarinic actions

• No therapeutic indications

• Quarternary alkaloid↓ BBB penetration

ARECOLINE

• Betel nut

• Predominant M + slight N

• Prominent CNS effect

CEVIMELINE

• Direct acting at M3

• Lacrimal & Salivary gland epithelium

• Longer lasting Sialogogue action than pilocarpine

• ↑ lacrimal secretion in Sjogrens syndrome

INDIRECTLY ACTING PARASYMPATHOMIMETICS

ANTI CHOLINE ESTERASES

REVERSIBLE

NATURAL SYNTHETIC

CARBAMATES ACRIDINE

IRREVERSIBLE

OP CARBAMATES

ANTI CHOLINE ESTERASES

NATURAL

• Physostigmine

• Galantamine

SYNTHETIC

CARBAMATES ACRIDINE

Neostigmine TacrinePyridostigmineEdrophoniumDonepezilRivastigmine

REVERSIBLE

IRREVERSIBLE

Organophosphates• Ecothiophate

• Isoflurophate

• Parathion

• Malathion

• Diazinon

NERVE GASES

• Tabun , Sarin , soman

CARBAMATES

• Carbaryl

• Propoxur

ACh is broken by AChE

Mechanism of action :-

• 1.Acetylcholinesterase inhibitors - inhibit the AChE, responsible for breakdown of ACh

• 2.increased cholinergic activity -both nicotinic and muscarinic receptors

Mechanism of action of phosphates:-AchE

+ phosphates

Phosphorylated enzyme

Ageing-Loss of alkyl gp-resistant to hydrolysis(extremely slow reaction)

Mechanism of action of carbamates:-

AchE+ carbamates

Carbamylated enzyme+ H2O

Free enzyme + carbamic acid(slow reaction)

½ life of reactivation - carbamylated enzyme - 30 mins -less than synthesis of fresh enzyme

USES OF ANTICHOLINESTERASE DRUGS

1.MIOTIC A) GLAUCOMA

• ↑ tone of ciliary muscle ( attached to scleral spur) &

• ↑ tone of Sphincter pupillae pull on & improve alignment of trabeculae outflow facility is ↑

• Physostigmine (0.1 %)

B ) TO REVERSE EFFECT OF MYDRIATICS

C ) TO PREVENT ADHESIONS OF IRIS WITH CORNEA / LENS

2. MYASTHENIA GRAVIS

3.POST OPERATIVE PARALYTIC ILEUS / URINARY RETENTION• Neostigmine4.POST OPERATIVE DECURARIZATION• Atropine (Block M) Followed by Neostigmine5.COBRA BITE• Neostigmine + Atropine prevent Respiratory Paralysis

6.ANTI CHOLINERGIC OVERDOSAGE• TCA, Phenothiazine, Anti Histamine – Physostigmine.

7. BELLADONA POSONING

Belladona poisoning

8. ALZHEIMERS’DISEASE :-

Management of OP Poisoning :-

• Termination of further exposure

fresh air, wash the skin & mucosa with soap & water, gastric lavage

• Maintain airway- PPV if its failing

• Supportive measures

– Maintain BP

– Hydration

– control of convulsions -diazepam

1. Atropine

• Highly effective, it counteract Muscarinicsymptoms, higher doses antagonise central effects

• 2 mg IV repeated every 10 minutes till dryness of mouth

• Dilatation of pupil and HR up to 140

• Does not reverse peripheral muscle paralysis

CHOLINE ESTERASE REACTIVATORS

2.OXIMES

• Phosphorylated enzyme reacts very slowly with water

• Hydrolysis occurs a million times faster if more reactive OH groups in the form of oximes are given.

• PRALIDOXIME

• Quarternary N : Attaches to Anionic site – which remains unoccupied in OP poisoning