الحلقة 3 من كورس كلنيكال فارما( ANS)

 الحلقة 3 من كورس كلنيكال فارما (جزء الجهاز العصبي اللاإرادي)

Direct-acting muscarinic agonist :-

Choline Esters:-

Acetylcholine (ACh)

Structure

Information -Ester of choline with acetate.

- Quatenary ammonium compound  carry (+ve) charge polar 

cannot penetrate membranes not pass BBB. Chemical transmitter.

Synthesis,

Storage

and Release

Synthesis:

Choline is transported from the extracellular fluid into the

cholinergic neuron by active transport (energy- dependent carrier)

system (Choline has a quaternary nitrogen and carries +ve charge

and, cannot diffuse through the membrane).

- This synthesis can be inhibited by the drug Hemicholinium.

Choline acetyltransferase enzyme catalyzes the synthesis of

acetylcholine from choline and acetyl-CoA.

Storage:

- ACh is stored into presynaptic vesicles to prevent inactivation by

active transport.

- The mature vesicle contains not only ACh but also Co-

transmitters.

-This Uptake (storage) can inhibited by Vesamicol.

Release:

-when an action potential arrives at a nerve ending

Open voltage-sensitive calcium channels on the presynaptic

membrane increase conc. Of intracellular

Ca2+promote the fusion of synaptic vesicles with the cell

membrane and release of their contents into the synaptic space by

exocytosis

This release can be blocked by botulinum toxin.

Inactivation

- Cholinesterase enzyme breakdown ACh into  Acetic acid +

Choline.

- Types of Cholinesterase enzyme:

1: True (Acetyl) cholinesterase (ACHE) found in all ACh sites.

2: Pseudo (Butyryle) cholinesterase (BCHE) found in liver &

plasma.

Pharmacological

action

Heart - (-ve) Inotropic, (-ve) Chronotropic & (-ve)

Dromotropic.

Blood

vessels

- M3 receptor in endothelium are stimulated with ACh

indirect action via (EDRF) increase NO formation

VDHypotension.

GIT - Stimulates intestinal secretions and motility

(peristalsis).

- Relaxation of sphincter.

Urinary

bladder

- Contraction of detrusor muscle (wall).

- Relaxation of sphincter.

Bronchi - Bronchoconstriction.

- Stimulates bronchial secretion.

Eye - Contraction of circular muscle Miosis

- Contraction of ciliary muscle accommodation for

near vision.

Ex.

glands

Increase all secretions e.g. lacrimation and salivation.

Nicotinic

Receptors

- NN Stimulate ganglia and adrenal medulla

increase release of adrenaline and nor-adrenaline

from adrenal medulla.

NM Stimulation of motor endplate (MEP)  Skeletal

twitches.

No clinical uses due to:

- Multiplicity of action (Non-selective) act on all ACh receptors.

-Short duration due to rapid inactivation by cholinesterase

enzyme.

Carbachol (Isopto®Carbachol)

Information - Ester of choline with carbamic acid.

- Also known as carbamylcholine.

- Totally resistant to two types of cholinesterase

enzyme.

Disadvantage - Rarely used therapeutically except in the eye as a

miotic agent due to

- Longer half-life.

- Non-Selectiveact on nicotinic and muscarinic

receptors.

uses - Used rarely except in eye drops to treat Glaucoma

Cause miosis  increase outflow of aqueous humour

through canal of schlemm decrease Intraocular

pressure (IOP).

Bethanechol(Urotone®)

Information - Ester of B-methyl choline with carbamic acid.

- Totally resistant to two types of cholinesterase enzyme.

- Selective to muscarinic receptor.

Pharmacological

action

Major action on GIT and Urinary bladder

• In GIT  Increase motility.

• In U.B Contraction wall and relaxation sphincter lead to

urination.

uses

- Postoperative non-obstructive GIT disorder to prevent

constipation.

- Postoperative non-obstructive urinary tension.

- Gastro-paresis.

- N.B: It has about a 1-hour duration of action.

Methacholine (Provocholine®)

Information - Ester of beta-methyl choline with acetic acid.

- Selective to muscarinic receptor.

uses

- used in bronchial challenge test (or Methacholine

challenge test) to diagnose asthma (increase asthma

when inhaled due to it act on M3 cause

bronchoconstriction).

Side effects - Cardiovascular effects, such as bradycardia and

hypotension (M2).

Choline Esters Susceptiblity to

cholinestrase

Muscarinic

Action

Nicotinic

Action

Ach ++++ +++ +++

Carabachol negligible ++ +++

Bethanechol negligible ++ None

Methacholine + ++++ None

All choline Esters are quaternary ammonium compounds.

 Carry charge  polar Don’t pass BBB  NO CNS effect.

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