Cholinergic transmission and cholinergic drugs l Pharmacology of cholinergic drugs on Autonomic Nervous System l Study Pharma l

 Autonomic Nervous System:

Autonomic nervous system is a part of Peripheral Nervous System that regulates all the involuntary actions of the body.

Autonomic nervous system divided into two parts:

1. Sympathetic nervous system        2. Parasympathetic nervous system

Cholinergic transmission:

Acetylcholine is one of the neurohumoral transmitter that transmits the information from neurons to neurons, neurons to effector cells (where we wants to produce action).

Synthesis of Acetylcholine (Ach):

Acetylcholine synthesized inside the neuron cells, Acetyl coenzyme-A combined with choline molecule in the presence of catalytic enzyme choline-acetyl transferase and forms acetylcholine.

Storage of Acetylcholine (Ach):

After acetylcholine is formed then it stored under the synaptic vesicles by a transporter VAT (vesicle associated transporter) in the axon terminal of neurons.

Release of Acetylcholine (Ach):

After the actin potential generated in the neuron cell that cause synaptic vesicles to fused with the synaptic membrane of axon terminal of the neuron and release of neurotransmitter that is acetylcholine, binds to their specific receptors that present on effector cells or neurons.

Cholinoceptors or cholinergic receptors:

There are two main receptors by which acetylcholine binds and show effects.

1. Muscarinic           2. Nicotinic

Muscarinic receptors:

Muscarinic receptors are present on the effector cells for binding to cholinergic drugs and stimulated by muscarine and blocked by atropine.

Where present- Muscarinic receptors are presents on heart, blood vessels, eye, smooth muscle, respiratory tract, gastrointestinal tract, glands, urinary tract and in the CNS (central nervous system).

Muscarinic receptors works through G-protein coupled receptor (GPCR).

Types- Muscarinic receptors are divided into 5 subtypes: M1, M2, M3, M4 and M5.

M1 subtype receptor:

M1 subtype receptor  is a neuronal receptor present on ganglion cells as well as in the CNS especially in cortex, hippocampus, corpus striatum region.

Function:

Major role of M1 subtype receptor is promotes all gastric secretions, relaxation of lower esophageal sphincter by vagal stimulation, intestinal secretion, learning, memory, etc.

M2 subtype receptor:

M2 subtype receptor present on heart as cardiac receptor and present in presynaptic neuron and act as auto-receptor.

Function:

Role of M2 subtype receptor is mediates vagal bradycardia, fall in B.P.

M3 subtype receptor:

M3 subtype receptor present on smooth muscle in blood vessels, in gastrointestinal tract, in urinary tract also.

Function:

Function of M3 subtype receptor is cause vasodilation of blood vessels, contraction of smooth muscles of respiratory tract, tone of peristalsis of gastrointestinal tract.

The first three subtypes M1, M2 and M3 receptors are present on prejunctional nerve ending, on the effector cells, also exhibits both peripheral organs and in the CNS and M4 and M5 subtype receptors are present on nerve ending that function the regulates other neurotransmitter release.

Nicotinic receptors:

Nicotinic receptors are present on effector cells and stimulated by nicotine and blocked by tubocurarine.

Where present- Nicotinic receptors are present on ganglionic cells (in both sympathetic as well as parasympathetic) and also present on skeletal muscles.

Nicotinic receptors works through ligand gated ion channel.

Types- Nicotinic receptors are divided into 2 subtypes: Nm and Nn.

Nm subtype receptors:

Nm subtype receptors are present on skeletal muscles, stimulated by PTMA (phenyl trimethyl ammonium) and blocked by tubocurarine.

Function:

Stimulation cause contraction of skeletal muscles.

Nn subtype receptors:

Nn subtype receptors are neuronal receptor present on ganglion cells (in both sympathetic as well as parasympathetic),stimulated by DMPP (dimethyl phenyl piperazinium) and blocked by hexamethonium

Function:

Primary pathways to transmission by ganglion cells.

Cholinergic drugs: (Cholinomimetics, parasympathomimetic)

Cholinergic drugs are which works similar like acetylcholine, by direct interacting with cholinergic receptor or by increasing the availability of acetylcholine at that sites.

Cholinergic agonist:

Cholinergic agonist which directly bind to their receptors, act as similar like acetylcholine.

Categories of cholinergic agonist:

Choline esters- Acetylcholine, Carbachol, Methacholine, Bethanechol.

Alkaloids- Muscarine, Pilocarpine, Areoline.

Pharmacology of Cholinergic agonist: (Acetylcholine act as prototype)

Drug interaction and their action depends on muscarinic and nicotinic receptors.

Muscarinic action:

1. Heart: ( M2 receptor present )

- Acetylcholine hyperpolarize SA nodes cause decrease in diastolic rate, rate of impulse results in bradycardia.

- AV nodes and His Purkinje fibers refractory period increases and conduction velocity decreases, P-R interval increases results partial to complete AV block occurs.

2. Blood vessels: ( M3 receptor present )

- Blood vessels are dilated because of the activation of M3 receptors which cause to produce EDRF (Endothelial Dependent Relaxing Factor) that is Nitric oxide.

- Stimulation of cholinergic nerves to penis induced vascular dilation of Cavernosal vessels in penis which cause erection of penis.

3. Smooth muscles: ( M3 receptor present )

- Smooth muscles of organs shows contraction due to activation of M3 receptors.

- Tone of peristalsis of Gastrointestinal tract increases cause abdominal cramp and evacuation of bowel.

- Peristalsis movement increases in ureter cause contraction of detrusor muscles and bladder trigone and sphincter relaxes, results in urination occur.

- Smooth muscles of bronchial tract shows contraction, results in bronchospasm, bronchial asthma, dyspnoea occurs.

4. Glands:

- All body secretion increases due to activation of M3 receptors and some of by M2 receptors cause sweating, gastric secretion, lacrimation, salivation.

5. Eyes:

- Contraction of circular muscles of iris increases, resulting miosis shows contraction of pupils ultimately spasm of accommodation, increased aqueous outflows facility, reduction in intraocular tension.

Nicotinic action:

1. Autonomic ganglia: ( Nn receptor present )

All the sympathetic and parasympathetic stimulation by Nicotinic neuronal receptors. At higher dose, it will cause tachycardia, rise in B.P. due to sympathetic stimulation.

2. Skeletal muscles: ( Nm receptor present )

Activation of Nm receptors cause contraction of skeletal muscles.

 Uses:

- In hypertension, given cholinergic drug like bethanechol to reduce BP, results in normalize the condition.

- In urinary retention, give cholinergic drugs to promote urination.

- Peripheral resistance of blood flow, give cholinergic drugs to cause dilate the blood vessels to maintain the blood flows.

Adverse drug effects:

- Over secretion like salivation, lacrimation, defecation, urination,

Cholinomimetics Alkaloids:

- Pilocarpine:

> It is obtained from plant Pilocarpus microphyllus. 

> It has muscarinic action and also stimulates ganglia. 

> At small doses cause fall in BP, stimulates all body secretion.

> At higher doses cause rise in BP,  tachycardia due to ganglionic stimulation. 

> Used  to treat glaucoma

> Side effect when treating glaucoma by giving Pilocarpine is cause spasm of accommodation, pain in eyes, blurriness, unable to see for few minutes. 

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