OIA1013 Introduction to ANS Pharmacology

1Introduction to Autonomic Pharmacology

Learning Outcomes

Understand the synthesis, storage, release, and termination of action of major autonomic transmitters.

Identify major types of autonomic receptors and their locations in the body.

Describe the physiological effects of parasympathetic and sympathetic system stimulation.

Overview of the Autonomic Nervous System (ANS)

The ANS operates largely autonomously and is not under conscious control.

It is distributed throughout the body and consists of two main divisions: sympathetic and parasympathetic.

Sympathetic division originates from thoracic and lumbar regions (T1–T12, L1–L5).

Parasympathetic division originates from cranial and sacral regions (Cranial nerves III, VII, IX, X and S2, S3, S4).

The sympathetic system is often referred to as the 'fight or flight' system, while the parasympathetic system is known as the 'rest and digest' system.

Neurotransmitters in the ANS

Acetylcholine (ACh) is the primary neurotransmitter for cholinergic transmission, found in all preganglionic fibers and parasympathetic postganglionic fibers.

Noradrenaline (NA) is the primary neurotransmitter for adrenergic transmission, found in sympathetic postganglionic fibers, except for sweat glands.

Both ACh and NA play crucial roles in transmitting signals across synapses in the ANS.

Neurotransmitters Transmission

Cholinergic Transmission

Terminal cholinergic neurons contain small membrane-bound vesicles (ACh) & large dense-cord vesicles (Cotransmitters) initially synthesized in neuron cell body which is carried & may be recycled.

Mechanism of Cholinergic Transmission

1. Synthesis & Storage

ACh synthesised by choline acetyltransferase (ChAT) from acetyl-CoA (in mitochondria) & choline (transport by choline transporter (CHT): rate-limiting step)

Hemicholinium inhibits CHT

ACh actively transported from cytoplasm to vesicles (stored by vesicle- associated transporter (VAT): inhibited by vesamicol

2. Release ACh

Voltage-gated Ca2+ channels open: Ca2+ influx

Ca2+ interacts with VAMPs & SNAPs: fusion of vesicle membrane with terminal membrane, causing opening of pore into synpase

Opening pore & in rush of cations: exocytotic expulsion of ACh into synaptic cleft

Botulinum toxin: enzymatic removal of amino acids from fusion proteins

3. ACh action termination

ACh bind & activate cholinoceptor

ACh diffusers with acetylcholinesterase (AChE): metabolised into acetate & choline -> action terminated where products are recycled

Inhibition of AChE is important therapeutic effect of several drugs

Cholinergic Receptors (Muscarinic & Nicotinic)

Adrenergic Transmission

Noradrenaline (NA): primary transmitter at sympathetic postganglionic neuroeffector cell synapse (except sweat gland)

Some NA may convert to adrenaline in adrenal medulla

Adrenergic receptors (on visceral effectors innervated by sympathetic postganglionic axon) bind both NA (neurotransmitters & hormone) & adrenaline (hormone only)

In dopaminergic neurons, synthesis terminates with dopamine

Mechanism of Adrenergic Transmission

1. Synthesis & Storage

Tyrosine transport into nerve ending by sodium-dependent carrier

Hydroxylation of Tyrosine Hydroxylase (TH) to DOPA: rate-limiting step

Decarboxylated to DA & hydroxylated to NA

TH inhibited by metyrosine

NA & DA Transport into vesicles by vesicular monoamine transporter (VMAT) & stored

MAO (in mitochondria) inactivates portion of DA & NA in cytoplasm

Reserpine inhibit VMAT: depletion of transmitter stores.

2. Release of NA

Calcium-dependent mechanism (same as ACh)

Noradrenergic & dopaminergic neurons lack receptors for Botulinum & not transport toxin to nerve terminal

NA release can be blocked by guanethidine & bretylium

3. Termination of NA action

Not involve mechanism (in ACh) but diffusion & reuptake

NA diffuse out of cleft & metabolised by MAO & COMT

or

NA transport to cytoplasm by norepinepinephrine transporter (NET) & uptake (blocked by cocaine & certain antidepressants)

Discussion questions

1/6

What are the key differences between the sympathetic and parasympathetic divisions of the autonomic nervous system?

Difficulty: Easy

2/6

How do neurotransmitters like acetylcholine and noradrenaline function in the autonomic nervous system?

Difficulty: Medium

3/6

Discuss the synthesis and release mechanisms of acetylcholine in cholinergic transmission.

Difficulty: Medium

4/6

What role do presynaptic and postsynaptic receptors play in the integration of autonomic function?

Difficulty: Hard

5/6

Analyze the physiological effects of sympathetic activation on the body during stress.

Difficulty: Medium

6/6

How does the autonomic nervous system maintain homeostasis through negative feedback mechanisms?

Difficulty: Hard