Autonomic pharmacology

Question 1

Sites of transmission

Answer 1

There are two sites of transmission in the autonomic nervous system which can be targeted by drugs:

• the synapse between the pre- and post-ganglionic neurones
• the junction between the post-ganglionic neurone and target organ/tissue

Question 2

Parasympathetic neurotransmission

Answer 2

In the PSNS, acetylcholine is released at both sites of transmission. Nicotinic receptors (nAChR) are found at the ganglia, while muscarinic receptors (mAChR) are found at the target organ/tissue.

Question 3

Sympathetic neurotransmission

Answer 3

In the SNS, acetylcholine is released onto nicotinic receptors (nAChR) at the ganglia and the adrenal medulla, which is directly innervated. Noradrenaline is released at most target organs/tissues. Exceptions are sweat glands and arrector pili in the skin, which are activated by muscarinic acetylcholine receptors (mAChR).

Question 4

Nicotinic cholinergenic receptors (nAChR)

Answer 4

Important for all autonomic functions (SNS and PSNS). Ligand-gated ion channels, composed of 5 subunits. ACh binding opens the transmembrane protein pore, causing an influx of Na+. The resulting depolarisation can trigger an action potential.

Question 5

Hexamethonium

Answer 5

A selective antagonist for the neuronal sub-type of nicotinic receptor, acting as a non-competitive pore blocker. Inhibits all autonomic functions (SNS and PSNS). Used historically to treat hypertension but is no longer prescribed.

Question 6

Muscarinic cholinergenic receptors (mAChR)

Answer 6

Important for parasympathetic postganglionic transmission. G-protein coupled receptors, consisting of 7 transmembrane domains. There are 5 subtypes, of which M1-M3 are found mainly in the peripheral nervous system.

Question 7

Muscarinic agonists

Answer 7

Also known as “parasympathomimetic drugs”, which mimic the effects of the PSNS. Effects include:

• decreased heart rate
• vasodilation
• bronchoconstriction
• smooth muscle contraction
• increased secretion

Eg. muscarine- found in mushrooms, ingestion can lead to poisoning.
Eg. pilocarpine- used to treat glaucoma, acts on ciliary muscle, reduces intraocular pressure.

Question 8

Muscarinic antagonists

Answer 8

Oppose the effects of the PSNS. Effects include:

• increased heart rate
• vasoconstriction
• bronchodilation
• smooth muscle relaxation
• decreased secretion

Eg. atropine- used to treat bradycardia and muscarine poisoning, used during operations to decrease salivation and AChE inhibitor side effects.

Question 9

Adrenoreceptors

Answer 9

Important for sympathetic postganglionic transmission. G-protein coupled receptors, consisting of 7 transmembrane domains. There are 2 main types, alpha and beta, which can be further subdivided into at least 5 subtypes.

Question 10

a-adrenoreceptors

Answer 10

a1-adrenoreceptors are responsible for the contraction of smooth muscle in most blood vessels (vasoconstriction), the pupil (dilation) and the uterus when pregnant (parturition).

a2-adrenoreceptors are responsible for the auto-inhibition of pre-synaptic neurones (via negative feedback), decreasing peripheral vascular resistance (direct vasoconstriction) decreasing pancreatic secretions, and contraction of sphincters in the GI tract,

Question 11

b-adrenoreceptors

Answer 11

b1-adrenoreceptors act on the heart to increase heart rate, force of contraction, and automaticity, and on the kidney to increase renin secretion.

b2-adrenoreceptors are responsible for the relaxation of smooth muscle in the bronchi (bronchodilation), GI tract, and blood vessels to skeletal muscles and veins (vasodilation).

b3-adrenoreceptors are responsible for the relaxation of smooth muscle in the bladder (continence), and act on adipose tissue to increase lipolysis.

Question 12

Adrenergenic signal transduction pathways

Answer 12

a1 receptors are coupled with Gq proteins, activating phospholipase C which increases IP3 and DAG.

a2 receptors are coupled with Gi proteins, reducing the activity of adenylyl cyclase (AC) which decreases cyclic AMP (cAMP).

b receptors are coupled with Gs proteins, increasing the activity of adenylyl cyclase (AC) which increases cyclic AMP (cAMP).

Question 13

a1-adrenoreceptor drugs

Answer 13

a1 agonists may be used as vasocontrictors, ie. with local anaesthetics (eg. noradrenaline), or as decongestants (eg. phenylephrine).

a1 antagonists may be used to treat hypertension (eg. doxazosin), or to relax smooth muscle in benign prostate hyperplasia (eg. tamsulosin).

Question 14

a2-adrenoreceptor drugs

Answer 14

a2 agonists decrease the activity of the SNS (negative feedback), and can be used to treat hypertension (eg. clonidine).

a2 antagonists can be used to relax penile smooth muscle to treat impotence, or to enhance mood in depression by increasing noradrenaline secretion.

Question 15

b-adrenoreceptor agonists

Answer 15

Cause sympathetic effects such as stimulation of the heart, bronchodilation and relaxation of smooth muscle. Can be used to treat heart failure, cardiogenic/anaphalactic shock (eg. noradrenaline), asthma (eg. salbutamol) and to delay premature labour

Question 16

b-adrenoreceptor agonists

Answer 16

Oppose sympathetic effects. Can be used to treat hear problems such as angina, cardiac arrhythmias, hypertension, heart failure, or anxiety states (eg. metoprolol), and can be applied topically to reduce intraocular pressure in glaucoma (eg. timolol).

Question 17

Acetylcholine synthesis and release

Answer 17

At the pre-synaptic neurone:

• ACh is synthesised and packaged into vesicles.
• Depolarisation reaches the nerve terminal, causing an influx of Ca2+ through voltage-gated ion channels.
• Vesicles fuse with the membrane and ACh is released by exocytosis.

Question 18

Acetylcholine action and recycling

Answer 18

In the synapse:

• ACh crosses the synaptic cleft and binds to receptors on the post-synaptic membrane.
• ACh is broken down into acetate and choline by acetylcholinesterase (AChE).
• Choline re-enters the pre-synaptic neurone and is recycled.

Question 19

Noradrenaline synthesis and release

Answer 19

At the post-ganglionic sympathetic neurone terminal:

• Noradrenaline is synthesised (tyrosine–>DOPA–>dopamine–>NAd).
• It is packaged into vesicles by the vesicular monoamine transporter (VMAT) and released by exocytosis.

Question 20

Noradrenaline action and uptake

Answer 20

In the synapse:

• NAd crosses the synaptic cleft and binds to receptors on the post-synaptic membrane.
• The action of NAd is terminated by its reuptake into the neurone via the noradrenaline transporter (NAT), involving the co-transport of Na+ and Cl-.
• NAd can then be broken down by monoamine oxidase (MAO).

Question 21

NAT inhibitors

Answer 21

Enhance the effects of sympathetic activity by reducing the re-uptake of NAd. They may also inhibit the action of closely related dopamine (DAT) and serotonin (SERT) transporters.

eg. cocaine- increases euphoria and excitement, tachycardia, increases blood pressure, anaesthetic effect.
eg. desipramine- tricyclic antidepressant.

Question 22

MAO inhibitors

Answer 22

Most block MAO irreversibly, reducing the breakdown of NAd in the post-ganglionic sympathetic neurone. Increase levels of NAd, dopamine and serotonin in the brain and peripheral tissues.

eg. phenelzine- used to treat depression.

Question 23

Indirectly acting sympathetic amines

Answer 23

“Sympathomimetic compounds” which are tructurally related to NAd. These are transported into nerve terminals (via NAT) and vesicles (via VMAT) and displace NAd, which leaks out (via NAT). Increase the effects of sympathetic stimulation, such as vasoconstriction, bronchodilation and raised blood pressure. In the CNS, they have a similar effect on dopamine and serotonin.

eg. amphetamine- highly addictive illicit drug.
eg. tyramine- found in cheese, wine and fermented foods.