The cholinergic Agonist:

    The preganglionic fibers terminating in the adrenal medulla, the autonomic ganglia both parasympathetic and sympathetic and the postganglionic fibers of the parasympathetic use ACETYLCHOLINE as a neurotransmitter. In addition, ACETYLCHOLINE innervates the muscle of the somatic system and also play important role in the CNS.

                                   

Neurotransmission at Cholinergic Neuron:

1.Synthesis of ACETYLCHOLINE:

      Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by energy-dependent carrier system that cotransports sodium and is inhibited by the drug HEMICHOLINIUM. Choline has quaternary nitrogen and a permanent positive charge thus cannot diffuse through the membrane. Choline acetyltransferase catalyzes the reaction of the choline with acetyl coenzyme A to form acetylcholine an ester in the cytosol. The ACh is then stored in the storage vesicles. The released ACh interacts with cholinergic receptors on effector cells and activates them. In the synaptic cleft, the ACh is rapidly hydrolysed by Acetylcholinesterase AChE enzyme.

                             

CHOLINESTRASE:

It is an enzyme and has two types:

1.True cholinesterase:

It is found in cholinergic neurons, ganglia, RBCs and neuromuscular junction. It rapidly hydrolysis ACh and methacholine into choline and acetate in the synaptic cleft.

2.Pseudocholinesterase or Butyrylcholine:

It is found in plasma, liver and glial cells. It can hydrolyse ACh but does not hydrolyse methacholine. Hydrolysis is slow.

2.Cholinergic receptors:

These are of two types:

1.MUSCARINIC RECEPTORS               2.NICOTINIC RECEPTORS

MUSCARINIC RECEPTORS:

There are five subclasses. M1 found in gastric glands, autonomic ganglia and CNS. M2 is found in the heart. M3 is present in smooth muscles, exocrine glands and epithelial cells. M4 & M5 are present in CNS.

M1 & M3 are Gq coupled while M2 is Gi-coupled.

 

                                       

NICOTINIC RECEPTORS:

These are of 2 subtypes:

Those present at the neuromuscular junction are called Nm and all others are called Nn. These are ionotropic receptors they activate sodium channels and cause depolarization of the cholinergic neuron.

Directly acting Cholinergic Agonist:

1.Choline esters                                                 2.Alkaloids

Acetylcholine                                                      Pilocarpine

Bethanechol                                                         Muscarine

Carbachol

Acetylcholine:

It is quaternary ammonium so it can not penetrate membranes. It is the neurotransmitter at parasympathetic and somatic as well as autonomic ganglia. It is rapidly metabolized by cholinesterase. ACh has both muscarinic and nicotinic activity.

Actions of ACh:

HEART:  

 It mimics the effects of vagal stimulation. It decreases heart rate and cardiac output.

Blood pressure:

Injection of ACh causes vasodilation and lower blood pressure.

Other actions:

In the gastrointestinal tract, it increases salivary secretion, increases gastric acid and stimulates intestinal secretions and mobility. It also enhances bronchial secretion and causes bronchoconstriction.

It causes constriction of ciliary muscles of an eye for near vision and constriction of sphincter pupillae muscle, causing miosis.

Bethanechol:

It is not hydrolysed by AChE and is inactivated bt other esterases. It lacks nicotinic actions but does have strong muscarinic activity.

Therapeutic uses;

It is used to stimulate the atonic bladder, neurogenic atony as well as megacolon.

Adverse effects:

sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain. diarrhoea and bronchospasm. Atropine sulfate is used to overcome its side effects.

Carbachol:

It has both muscarinic and nicotinic actions, a poor substrate of AChE. It is used to provide miosis for eye surgery. It may first stimulate and then depress these systems.

Pilocarpine:

It is a tertiary amine and is stable to hydrolysis by AChE. It can penetrate CNS and has muscarinic activity.

Therapeutic uses:

It is a drug of choice for the emergency lowering of intraocular pressure for both open and closed-angle glaucoma. It is also used in xerostomia and Sjogren syndrome.

Adverse effects:

blurred vision, night blindness, profuse sweating and salivation. Atropine is used to counteract the toxicity of pilocarpine.