Cholinergic drugs

Nervous system

CENTRAL NERVOUS SYSTEM PERIPHERAL NERVOUS SYSTEMS

Sensory fiber motor fiber

involuntary voluntary sympathetic parasympathetic

function

Sympathetic and parasympathetic are complemantary

Composition: pre,ganglion and post Chemicals are Ach and NA

Cholinergic drugs

Drugs produce similar effects to acetylcholine

Classification

a. Direct cholinergic agents

b. Indirect

c. Cholinestrase reactivator

Effects of acetylcholine

A. Muscarinic effects Contaraction of smooth muscle Peripheral vasodilation Increase secretion of saliva, exocrine Dcrease the contraction of the heart

B. Nicotinic Stimulation of skeletal muscle tone

Trans acetylcholine active on muscarinic and nicotinic receptors

A. Direct cholinergic agents

Mode of action

Choline esters Cholinomimetic alkaloid

Methacholine

Carbachol

[Cholinomimetics & parasympathomimetics]

Pilocarpine

SAR

CH3

N+

O CH3

OCH3

CH3

Acetyl choline

Metacholine

CH3

N+

O CH3

OCH3

CH3

CH3

• CH3 on beta carbon increase muscarinic

• Long duration

• Uses: Mythenia gravis, paroxysmal tachycardia

Synthesis

O

+ N

HO

CH3

N+

O

CH3

N

O

Carbachol

Long duration Uses: glucoma Synthesis

CH3

N+

O NH2

OCH3

CH3

Bethanicol

Bioisoster of methacholine

Long durationMainly muscarinic

Uses:abdominal distention,urinary distention

O

CH3

N

O

H2N

2 .Cholinomimetic alkaloid

pilocarpine

O

N

NO

CH3

CH3

Uses: glucoma, antagonises mydriatics

cevimeline

For treatment of dry mouth in Sjogren’s syndrome

Similar to pilocarpinO

S

N

B.Indirect acting [anticholinesterase]

Carbamates

Physostigmine

Neostigmine methyl sulphate

Pyridostigmine

Neostigmine bromide(prostigmin)

Edrophonium

Organophosphorus

Physostigmine acts by interfering with the metabolism of acetylcholine. It is an inhibitor of acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction. It indirectly stimulates both nicotinic and muscarinic receptors. (Find the structure and uses).

Neostigmine bromide(prostigmin)

N+

CH3

CH3O

O

NCH3

CH3

CH3

Synthesis

OH OH

+ NH

CH3

CH3

OH N

CH3

CH3

O

Cl Cl

N

CH3

CH3O

O

ClNH

CH3

CH3

N

CH3

CH3O

O

NCH3

CH3

CH3Br

N+

CH3

CH3O

O

NCH3

CH3

CH3

Br-

III

IIIIV

V

Neostigmine methyl sulphate

Uses Contraindication

Bradycardia, cardiac disease, hypotension, parkinsonism.

Pyridostigmine bromide(mestinon)

N

O

O

N

B r+

Synthesis

Uses: Mysthenia gravis

N

OH+ C l

O

N

N

O

O

N CH3

Br

N

O

O

N

B r+

I II IVIII

Edrophonium Chloride

Short and rapid-acting cholinergic drug .Uses:myasthenia gravis , emergency treatment (short action)

Side effects: bradycardiaa, hypotension,increase saliva

Cholinesterase reactivators

N+

CH3

NOH

2)]-Hydroxyimino(methyl-[1-methylpyridinium chloride

Synthesis

NC l

+ N NH

+ OH

(I) (II)

-H2O

NN H

+

(III)

N N+ O H

NH2OH.HCl

Cholinergic blocking agents[Anticholinergic]

Act at different sites

Postganglionic of parasympathetic(Antimuscurinic)

At ganglionia of sympathetic and parasympathetic

(ganglion blockers)

Neuromuscular junction of voluntry system

(neuromuscular blocking agents)

I. Antimuscarinics[similar to Ach & alkaloid]

There effects will be : Mydriatic Antispasmodic antisecretory

1. Antimuscarinics similar to Acetyl choline

R C O (CH2)n N

O

5 AAntimuscarinic:aminoalcohol,aminoamides,

papaverine derivatives.Aminoalcohols:esters,ethers,carbamates.

Esters:solaneceous alk.,synthetic analouges,esters of other alc.

2 .Alkaloid antimuscarinics

Atropine, Hyoscin

Uses of Antimuscarinics:

Antispasmodic

Antisecretory

Antiparkinsonism

mydriatics

Esters of other aminoalcohol

CyclopentolateUses:

mydriatic ,cycloplegicN

O

OOH

2-(dimethylamino)ethyl 2-(1-hydroxycyclopentyl)-2-phenylacetate

Aminoalcohol ethers

OrphenadrineUses:

Antihistaminic,antiparki-nsonism.

N

O

N,N-dimethyl-2-(phenyl(o-tolyl)methoxy)ethanamine

Oxybutynin

used to relieve urinary and bladder difficulties, including frequent urination and inability to control urination

Homework : find the structure and mechanism of action

Papaverine and related compounds .

N

H3CO

H3CO

OCH3

OCH3

Vasodilator relax smooth muscle.(GIT,bronchi,uretures,biliary system).

Trihexyphenidyl

Uses Parkinson’s disease

OH

N

1-cyclohexyl-1-phenyl-3-(piperidin-1-yl)propan-1-ol

Ipratropium bromide

Uses Bronchodilator

Ganglionic blocking agent

Hexamethonium

N+

N+ Cl-

Cl-

Neuromuscular bloking agents

Decamethonium bromide

Assay :volhard

N+

N

Br-

Br-

+

Neuromuscular blocking agents

C

C

O

O

O

O

N+

N+ Cl-

Cl-

Succinylcholine

ON+

ON+

O

N+

3I-

gallamine triethiodide

Uses