Cholinergic Agonist

Cholinergic drugs (Cholinomimetic, Parasympathomimetic)

• The drugs that produced action similar to that of acetylcholine (Ach), either by interacting with cholinergic receptors (cholinergic antagonists) or by increasing the availability of Ach at these sites (anti-cholinesterase).

Cholinergic transmission

• Synthesis
• Ach is synthesized in the cytoplasm from Acetyl-CoA and choline by the catalytic action of choline acetyltransferase (ChAT).
• Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending.
• Choline is transported from the extracellular fluid into the neuron terminal by Na+ dependent membrane choline cotransporter (Carrier A).
• Drugs that block this action are Hemicholinium.
• Release
• Synthesized Ach is transported from the cytoplasm into by anti-port (molecules move in the opposite direction) that removes a proton (Carrier B).
• This action is blocked by
• Release is dependent on extracellular Ca2+ and occurs when an action potential (AP) reaches the terminal and triggers sufficient influx of Ca2+
• The increased Ca2+ concentration destabilizes the storage vesicles by interacting with the special protein VAMPs (vesicular membrane protein) and SNAPs (Synaptosome-associated protein).
• Fusion of vesicular membrane with the terminal membrane results in exocytosis, expulsion of Ach into the synaptic cleft.
• This action is blocked by Botulinum toxin.
• Destruction
• After release: Ach molecules may bind to and activate the Ach receptor (Cholinoreceptor).
• All of the Ach released will diffuse with a range of acetylcholinesterase (AchE).
• AchE very efficiently split Ach into choline and acetate.
• Most cholinergic synapses are richly supplied with AchE.
• Half-life of Ach in the synapse is very short.
• AchE is also found in other tissues, e.g. RBC
• Another cholinesterase with a lower specificity for Ach, butyryl-cholinesterase (Pseudo-cholinesterase) is found in Blood plasma, liver, glial, and many other tissues.

Cholinergic receptor

• There are two types of cholinergic receptors;

1. Muscarinic receptor
2. Nicotinic receptor

Muscarinic receptor

• It is primarily located in autonomic effector cells in the heart, eye, smooth muscles, and gland of the GIT and CNS.

Types of Muscarinic Receptors

Location of muscarinic receptor

M1:      Autonomic ganglion cells, gastric glands, and central neurons (cortex, hippocampus, curpusstriatum)

Physiological role:      mediation of gastric acid secretion and relaxation of LES (Vagal)

                                    Learning, memory, and motor function.

M2:      cardiac muscarinic receptors.

Physiological role:      mediated vagal bradycardia

                                    Auto receptor in cholinergic nerve endings

                                    CNS-Tremor, analgesia

M3:      Visceral smooth muscles, glands, and vascular endothelium. Also Iris and ciliary muscles.

Nicotinic (N) receptors

• Nicotinic action of Ach is that can be reproduced by the injection of nicotine (Nicotiana tabacum)
• Can be blocked by tubocurarine and hexamethonium
• Activation results in a rapid increase in cellular permeability to Na+ and Ca2+, resulting in depolarization and initiation of an action potential.
• Further nicotinic receptor divided into NM and NN

Classification

Acetylcholine

Pharmacological action

1. Heart (M2)

• SA node hyperpolarization: Bradycardia (decrease impulse, decrease rate of diastolic depolarization, K+ outflux, Cl– influx).
• A-V node and His-Purkinje fibres refractory period (PF-RP) is increased, and conduction is slow.
• PR interval increased and partially or complete heart block.
• Arterial fibres: decrease of contraction and RP in atrial fibres is abbreviated.
• Arterial fibrillation and flutter: predisposing
• Decrease in ventricular contractility (less prominent).

2. Blood vessel (M3)

• M3 is present in all types of blood vessels.
• Fall in BP and flushing (A redness of the skin).
• Vasodilatation by Nitric oxide (NO) release (PLC-IP3/DAG).
• Penile erection.

3. Smooth muscle (M3-contracted)

• Abdominal cramps, diarrhoea due to increased peristalsis and relaxed sphincters.
• Bronchial smooth muscle contraction: dyspnoea (difficulty in breathing).
• Voiding of bladder (incomplete relaxation of the bladder muscle and urethra).

4. Gland (M3)

• Increase secretion [sweating, salivation, lacrimation, tracheobronchial tree (damage the airway and bronchi), and gastric gland].

5. Eye (M3)

• Contraction of circular fibres of the iris (Miosis).
• Contraction of ciliary muscles.

Nicotinic 

1. Autonomic ganglia

• Both sympathetic and parasympathetic ganglia are stimulated.
• After atropine injection, Ach causes tachycardia and an increase in BP.

2. Skeletal muscle

• V. injection – no effect
• Contraction of skeletal muscle

3. CNS

• Does not penetrate blood brain barrier (BBB).
• Local injection in CNS – Complex action.

Interaction

• Anticholinesterase potentiates markedly, methanicol to a lesser extent, and has only additive action with Carbachol or bethanicol, depending upon the role of ChE in the termination of action of the particular choline ester.
• Atropine and its congeners competitively antagonize muscarinic actions.
• Acetylcholine is not used therapeutically, nonspecific.

Bethanicol 

• Used in postoperative or postpartum non-obstructive urinary retention, neurogenic bladder to promote urination, congenital megacolon, and GERD.
• Side effects: belching, colic, involuntary urination/defecation, flushing, sweating, fall in BP, bronchospasm.
• Dose: 10-40mg oral, 2.5-5mg S.C. (Urotonin, Bethacol, 25mg tab.)

Pilocarpine

• Alkaloid from leaves of jaborandi (Pilocarpus microphyllus)
• Prominent muscarinic actions and also stimulate ganglia (ganglionic muscarinic receptor).
• Caused marked sweating, salivation, lacrimation, and other secretions.
• Dilate blood vessels (Hypotension).
• High dose: increase BP and tachycardia (ganglionic action)
• On eye: produce miosis and spasm of accommodation.
• Lower intraocular pressure (IOP) in glaucoma.
• CNS toxicity.
• Diaphoretic (excessive sweating)
• Xerostomia (Dryness of mouth)
• Sjogren’s syndrome (dry mouth, dry eyes)
• To reverse the mydriasis effect of atropine.
• To break adhesion between the iris and cornea/lens alternated with mydriatic.
• Atropine is used as an antidote in acute pilocarpine poisoning (1-2 mg I.V. 8 hourly).
• Dose: Pilocarpine eye drop 0.5-4 %.

Pilocarpine in glaucoma

• Construction of the circular muscle of the iris.
• Construction of the ciliary muscle.
• Spam of accommodation fixed at near vision.

Muscarine

• Alkaloid from the mushroom Amanita muscaria.
• It has only muscarinic action.
• No clinical use.
• Mushroom poisoning due to ingestion of a poisonous mushroom.
• Early onset mushroom poisoning (Muscarine type)
• Late onset mushroom poisoning.
• Hallucinogenic type.