Pharmacology of Autonomic Nervous System

In this article pharmacology and chemistry of autonomous nervous system is discussed in detail. It will help you in mastering the topic and further reinforce your GPAT preparation.

Basics terms of  autonomous nervous system (ANS)

Synapse: synapse is the junction region between two neurons. There is no protoplasmic continuity.

Myoneurol junction: the junction region between somatic motor nerves of skeleton muscle is called myoneurol junction.

Structure & gross level mode of signal transmission:

a) Synaptic junction: 

• At the synaptic region, axon of the first neuron makes synapse with - dendron/cell soma/axon of second neuron.
• At terminal part, axon of 1^st neuron shows swelling and called presynaptic knob.
• Neurotransmitters are present in vesicles.
• Region between two neuron synapatic cleft (20nm).
• ANS ganglia : axodendric synapse.
• Anterior horn of spinal cord : axosomatic synapse.

Synaptic junction

Transmission of signals:  

First neuron stimulated(Action Potential (AP) generated) ----> AP opens the voltage gated Ca²⁺ channels and presynaptic membrane ----->  Ca²⁺ enters into ICF from ECF (downhill) -----> Enter Ca²⁺ cause vesicles to attach with presynaptic membrane -----> Rupturing of vesicle by enzyme of membrane -----> Release of neurotransmitter -----> Neurotransmitter combines with the receptor----> combination of neurotransmitter and receptor.

EPSP- Excitatory post synaptic potential

IPSP-Inhibitory post synaptic potential.

Let us assume, resting membrane potential of 2^nd neuron = -80 mV

After combining of neurotransmitter = -65mV

The difference between the two is EPSP = +15 mV

After combining of neurotransmitter, if resting membrane potential falls to -60 mV then AP develops.

At molecular level: Binding of neurotransmitter to receptor ---> Opening of ligand gated channel --------> Influx of Na⁺ and other cations from ECF/ICF ---->  Hypopolarization

At ANS- Ach is always the neurotransmitter.

b) Neuromuscular junction:

Neuromuscular junction

• Neuromuscular junction is present between the motor nerve twig and the muscle cell.
• An axon of a motor nerve breaks up into many fine terminal twigs. Each such twigs supplies a muscle fibre.
• As twig approaches muscle fibre, it looses its mylein sheath and becomes swollen--> terminal bulb.
• The portion of the muscle fibre where terminal knob is impreganated -----> motor end plate(contains receptors).
• Subneurol cleft are present on motor end plate.

The transmission of signal:

AP develops in neuron ----->  reaches synapse -------> entry of Ca²⁺ in ICF ------> Release of Ach ------->  Ach + receptors -------> End plate potential  (EPP)

• EPP, assume at rest, potential of membrane = -90mV
• After lombination(2) = -65mV
• EPP(2-1) = +25mV

AP in the musucle fibre develops if the membrane potential after lombination of receptor goes to -50mV.

• Transmitter is always Ach and receptors are nicotinic (Nm)  

c) Eneteric Nervous system:

• James Langley coined the term ENS (father of ANS physiology).
• There are two  sets of local nerves are found in the gut wall-

1. Auerbach’s (myenteric) plexus- between the longitudinal and circular layer of gut muscles.
2. Meissner’s plexus- lies in submucons coat.

These two plexus consist of large no. Of neurons and do not arise from CNS.

Neurotransmitters- 5-HT, Ach, CCK, , Somatostation, NrAd and Dopamine.  

Some special issues about transmitters and transmission

a) Denervation supersensitivity: 

If a nerve supplying the target organ (skeleton, smooth, myocardium) be cut, after some days it will be seen that application of the neurotransmitter to the target organ produces an usually strong effect. 

Reasons :  a) Increase in no. Of receptor. b) No reuptake as there will be no presynaptic membrane. c) Enhanced postreceptor binding effect.

Clinical importance- Drug suppressing the postganglionic sympathetic fibres (guanethidine), when used in a increase hypertensive person for some days and then suddenly withdrawn, can precipitate a denervation supersenstivity like state.

e.g.- This person, now on slight excitement can develop reverse vasospasm & hypertension.

Sir Henry dale in 1910, used the concept of one neuron one transmitter which is now known as one nerve can produce only 1 neurotransmitter.

b) Presynaptic interactions: 

Heterotropic inhibition: 

Heterotropic inhibition

Most organs receive dual supply of sympathetic and parasympathetic nerves. When one nervons system dominates, other suppresses.

Homotropic inhibition: Consider the example of norepinephrine (NE). 

Homotropic inhibition

• There are two types of receptors: a) Presynaptic (responsible for release & reuptake) b) Postsynaptic (biological action).
• At low concentration of NE at synaptic cleft- NE binds with beta presynaptic receptors--> +ve feedback.
• Also, epinephrine released from adrenal medulla cause +ve feedback as it also binds with beta receptor.
• At high concentration NE binds with alpha receptor ---> -ve feedback (Reuptake). These presynaptic receptors are called autoreceptors.

                               Anatomy & Physiology of ANS

General introduction: The ANS has two divisions 

1. Sympathetic
2. Parasympathetic

Most organ receive dual supply of both devisions.

Effector cells include:

a.       Smooth muscles(GIT, blood vessels bronchialtree, eyes and genitourinary tract)

b.      Cardiac muscles

c.       Exocrine glands

d.   APUD cells (gut endocrine cells) ------>    Secrete GIT hormones like CCK and Gastrin.

Cannon, 1928 -------->  sympathetic system ---------> fight or fight reaction

a) Anatomy of sympathetic nervous system: 

Sympathetic nervous system

 

Anatomy of sympathetic nervous system

Receptors of sympathetic nervous system:

Receptors of sympathetic nervous system

b) Anatomy of parasympathetic nervous system (PNS):

PNS has two distint divisions:

a) Cranial

b) Sacral

In cranial, 3rd (from Edingero westphal nucleus(midbrain)), 7th (from superior salivary nucleus), 9th (Inferior salivary nucleus) and 10th ( dorsal nucleus of vagus). Together they are call cranial nerves.

Receptors of parasympathetic nervous system:

Receptors of PNS

                                                       Cholinergic drugs

• Ach is formed from----> acetyl CoA  + choline
• AcetylCoA is synthesized in mitochondria of synaptic knob.
• Choline is obtained by recycling. Acetyl CoA + Choline --------> Accetylcholine
• Ach synthesized in cytoplasm of synaptic knob and travels to vesicles and released.
• Ach is destroyed by acetylcholine esterase, AchE

There are two type of AChE:

Classification of cholinergic drugs:

Classification of cholinergic drugs on the basis of mechanism of action

Classification of cholinergic drugs on the basis of receptor

Pharmacological actions of cholinergic drugs:

a) CVS: Heart ( Decrease chronotropy & dronotrophy) 

b) Bronchii & GIT (Smooth muscles) -----> Contraction

c) Eye: Decrease intraocular pressure an used in glaucoma (Miosis- Near vision)

                                                  Antimuscranic drugs
M receptors are present:
a) M1-----> Brain
b) M2 -------> Heart
c) M3 -------> Smooth muscles of exocrine glands

Effects of antimuscranic drugs:
a) Bronchi-----> bronchodilation and decrease glandular secretion
b) Skin and sweat glands-------> increase temp. As no sweating
c) GIT-------> little effect due to ENS activity also.
d) Secretion-----> decrease salivary, gastric and other secretions

Classification of Anticholinergic drugs

Traditionally, anticholinergic are antimuscranic. So, they are ganglion blockers and neuromuscular blockers.

Ganglion blockers:

• -          Hexamethonium
• -          Trimethaphan
• -          Mecamylamine
• -          Pempidine

CVS – decrease BP and tachycardia

GIT – decrease secreation

Eye –  mydriosis and cycloplegia

Decrease sweating.

Neuromuscular blocking agents

Mechanism of action of  Neuromuscular blocking agents:

a) Non-depolarising agents: binds with Ach receptor -----> No depolarization-----> No action

b) Depolarising blockers: Binds with Ach R------> depolarization ------> contraction -----> as depolarising blockers degraded slowly, so contraction prolongs ------> there is no relaxation muscle goes for paralysis.

As for second contraction , a fresh depolarization has to occurs but this could not due to prolonged depolarization by these agents.

Drugs used against  spasticity:
a. Diazepam
b.Baclofen
c. Dantrolene.

Effects of activation of different receptors in symapthetic nervous system:

α1 receptors-

• most vascular smoothe muscles (Constriction & increased BP)
• Arrecorus pilorum ( Piloerection)
• Dilator pupillae (Dilation)
• Liver (rat) - Glycogenolysis

α2 receptors-

• Platelet (Aggregation)
• Vascular smooth muscles ( Constriction)
• Prejunctional membrane of synapse (Reuptake)

β1 receptors-

• Heart (Stimulate)
• Kidney ( increased renin secretion)
• Posterior pituatory ( Increased ADH)

β2 receptors-

• Smooth muscles (bronchial- dilation, arterioles of skeletal muscles- vasodilation, uterus- relax)
• Liver (Man)- Glycogenolysis

β3 receptors-

• Adipose tissues (Lipolysis)

Synthesis of catecholamines:

Biosynthesis of catecholamines

Mechanism of action of adrenoreceptors:

a) β1, β2 and DA1 receptors: Agonists ---------> increased Gs protein ---> activate adenyl cyclase-------> increased cAMP -------> Protein kinase --------> Biological activiy.

b) α2, DA2 and M2 receptors: Agonists ---------> increased Gi protein ---> NO adenyl cyclase---------> decreased cAMP -------> No Protein kinase --------> Biological activiy.

c) α1 & M1 receptors:  Agonists ------> Gp proteins -------> Phospholipase C ------> PIP2, IP3 & DAG------> Increased Ca2+ and protein kinase--------> Biological effect

SAR of catecholamines:

• Sympathomimetics are derivatives of β-phenyl ethyl amine
• N atom separated by 2 carbon atoms from benzene ring - increased sympathomimetic action.
• If N has alkyl group - β activity
• OH at 3 & 5 position- β2 activity
• OH group at β-carbon- β activity

Adrenoreceptors blockers:

Effects of α1 blocking: Vasodilation ( Decreased BP) ---> Tachycardia as compensatory mechanism.

• Phenoxabenzamine & Phentolamine- α1 & α2 (blockers) ---> Pheochromocytopenia.
• Prazocin & Trazocin- α1 (blockers) ----> to treat hypertention
• Labetolol- α, β, & β2 blocker ------> to treat hypertention

Pharmacology of β blocker

•  Propanolol (Non selective) Hypertention, Angina, Arrhythmia, Thyroid, AMI
• Atenolol & Metoprolol (β1) Hypertention, Angina, Arrhythmia, Thyroid, AMI
• Timolol (Non selective) Hypertention, Angina, Arrhythmia, Thyroid, AMI, Glaucoma
• Esmolol (β1) Supraventricular tachycardia
• Nadolol (Non selective) Hypertention, Angina
• Acebutolol (β1) Angina, Arrhythmia
• Pindolol (Non selective) Angina, Arrhythmia

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