Autonomic pharmacology

Question 1

Why is autonomic pharmacology important?

Answer 1

The ANS innervates almost all internal organs.
It is not protected by the blood-brain barrier, so is exposed to many chemical compounds.
It produces important toxins.
There are similar methods and mechanisms of transmission in multiple different tissues.

Question 2

What is the autonomic nervous system?

Answer 2

Part of the peripheral NS.
Conveys all outputs from the CNS to the rest of the body, except to skeletal muscle,
Made up of the sympathetic, parasympathetic and enteric systems

Question 3

What does the ANS regulate?

Answer 3

Smooth muscle tone
All exocrine secretions.
Some endocrine secretions.
Heart rate and force
Certain metabolic processes.

Question 4

How do drugs affect the ANS?

Answer 4

Drugs usually act at the junction, the final point of contact between ANS nerves and the targets
This is because transmission between the ganglia is simple - Ach on nicotinic receptors, mediating transmission.

Question 5

What is the disadvantage of ANS pharmacology?

Answer 5

Similar mechanisms between sympathetic and parasympathetic system so not good targeting for selectivity.

Question 6

What are the effects of the SNS?

Answer 6

Iris - pupil dilation
Salivary glands - increased salivation
Oral mucosa - reduced mucous
Increased heart rate
Dilated lungs
Reduced motility of gut.
Bladder sphincters closed.

Question 7

What are the neurotransmitters in the ANS?

Answer 7

In the PNS, Ach is the main neurotransmitter released.
In the SNS, Ach is released from pre-ganglionic neurones to ganglions, then post-ganglionic neurones release noradrenaline.

Question 8

What are co-transmitters in the ANS?

Answer 8

In the PNS nitric oxide.
SNS - ATP is released.

Question 9

What are the postganglionic neurones?

Answer 9

Cell body is in a ganglia
It projects its axon into periphery where neurotransmitter is released from nerve terminals - by nerve terminal varicosities.
Neurotransmitter packaged into vesicles in the varicosities for exocytosis.

Question 10

How can sympathetic transmission be acted on by drugs

Answer 10

Drugs affecting noradrenaline synthesis
Inhibiting packaging
Prevention of exocytosis
Prejunctional regulation
Autoinhibition drugs
Uptake of neurotransmitters
Degradation of enzymes
Neurone blockers
Indirectly acting amines

Question 11

How can the SNS be regulated through noradrenaline?

Answer 11

Noradrenaline is synthetised from tyrosine, each enzyme in the process has an inhibitor.
Can alter the amount of noradrenaline to regulate the SNS.

Question 12

What is the process of adrenaline synthesis?

Answer 12

Tyrosine by tyrosine hydroxylase to DOPA.
DOPA to dopamine by DOPA decarboxylase.
Dopamine to noradrenaline by dopamine-B-hydroxylase.
Noradrenaline to adrenaline by phenylethanolamine/N-methyl transferase.

Question 13

What is a-methyl tyrosine?

Answer 13

a-methyl tyrosine inhibits tyrosine hydroxylase for treatment of phaeochromocytoma cancer, to reduce Ach and NO.

Question 14

What is carbidopa?

Answer 14

L-dopa, leads to increased dopamine for Parkinson’s, which increases noradrenaline and increases sympathetic transmission.
So patients are also given an inhibitor - carbidopa - of dopamine-B-hydroxylase to prevent increased noradrenaline synthesis.

Question 15

What is methyldopa?

Answer 15

Methyldopa are substrates for enzymes in the noradrenaline pathway, will interfere with SNS transmission.
It can displace noradrenaline from vesicles, used to treat hypertension in pregnancy.

Question 16

How can storage of noradrenaline be used in pharmacology?

Answer 16

Vesicles have transporters on them which package neurotransmitters - dopamine - into the vesicle.
Can inhibit packaging of neurotransmitter into vesicle.

Question 17

What is Reserpine?

Answer 17

Reserpine was used to inhibit packaging of neurotransmitter, so neurotransmitter couldn’t be released, hypertension drug.
But also stopped packaging dopamine which affected the brain.

Question 18

What is exocytosis?

Answer 18

Action potential opens VGCaC, leads to increased Ca2+ concentration, which activates proteins which initiate exocytosis - fusion of vesicles and release of neurotransmitter.

Question 19

What are exocytosis drugs?

Answer 19

Stops release of vesicles from terminals.
But mechanism between PNS and SNS are similar, so affects PNS as well.

Question 20

What is regulation of release?

Answer 20

Sympathetic terminals have receptors which substances act on and determine how many vesicles are released.

Question 21

What is autoinhibition?

Answer 21

Sympathetic nerve releases noradrenaline which then acts on a2 adrenoceptors on surface of presynaptic receptors.
This is negatively coupled to adenylyl cyclase, so inhibits further neurotransmitter release.

Question 22

What are drugs for autoinhibition?

Answer 22

Agonists of a2 receptor inhibits sympathetic transmission in the periphery.
Clonidine is used to treat hypertension, used to mimic autoinhibition.

Question 23

What are other drugs for prejunctional modulation?

Answer 23

Adenosine - the breakdown product of ATP, then inhibits release of neurotransmitter and ATP through a1 adrenoceptors.
Opioids - inhibit release of u-receptors.
Angiotensin II receptors are GPCR, increase neurotransmitter release

Question 24

What is morphine?

Answer 24

Works on opioid receptors in spinal cord to block pain pathways.
It also works on autonomic nerves through pre-junctional receptors on nerve terminals to inhibit neurotransmitter release.
Side effects are from this inhibition.

Question 25

What is the cycle of neurotransmitters?

Answer 25

Uptake: Noradrenaline is released, will act for a while then is recycled back into nerve terminal by uptake processes, on the nerve or other nerves, and is sensitive to drugs. Degradation: Neurotransmitters can then be broken down by intracellular enzymes, which can also be a target for drugs.

Question 26

What is the uptake of noradrenaline?

Answer 26

Noradrenaline is taken up into nerve terminals by noradrenaline transporter (NAT). This is secondary active transport - uses electrochemical gradient of sodium to drive recycling of noradrenaline. NAT is inhibited by cocaine, tricyclic antidepressants - desipramine, and phenoxybenzamine.

Question 27

How does cocaine affect uptake of noradrenaline?

Answer 27

Cocaine inhibits NAT, so noradrenaline stays in intracellular space for longer, and sympathetic responses are amplified, sustained action. In the brain, cocaine inhibits dopamine uptake.

Question 28

What does cocaine do?

Answer 28

Autonomic effects of increased heart rate, blood pressure, arrhythmias, and local vasoconstriction. Through inhibition of NAT, dopamine transporters, and serotonin transporters.

Question 29

What is uptake 2 of neurotransmitters?

Answer 29

Non-neuronal - cardiac and smooth muscle, endothelium. Not very selective for noradrenaline inhibition, but it can be inhibited by normetanephrine, steroid hormones, and phenoxybenzamine.

Question 30

What is metabolic degradation of neurotransmitters?

Answer 30

Intracellular enzymes Monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). These enzymes can be inhibited to prevent NAD degradation.

Question 31

What is MAO?

Answer 31

Converts catecholamines to aldehydes, which are metabolised. Inhibitors are used clinically as antidepressants, but will affect sympathetic transmission - hypotension, weight gain, insomnia. e.g. phenelzine, tranylcypromine, moclobemide.

Question 32

What are neurone blocking drugs?

Answer 32

Drugs can enter into terminal through NAT. e.g. guanethidine, bretylium. Drugs can accumulate at a high concentration and inhibit sympathetic transmission within the nerve terminal.

Question 33

What are indirectly acting sympathetic amines?

Answer 33

These drugs are transported by NAT, into terminal, and displace noradrenaline, which then leaks out via NAT (opposite direction) and act on receptors.

Question 34

What is parasympathetic transmission?

Answer 34

In periphery, on end organ, transmission is mainly cholinergic, in autonomic ganglia, also acetylcholine.

Question 35

What are nicotinic receptors?

Answer 35

Ligand gated channels. Ach binds to receptor and opens pore in membrane to allow ions through. Mainly mediate transmission in autonomic ganglia. Hard to block the receptors because it mediates both sympathetic and parasympathetic transmission.

Question 36

What are subtypes of ANS receptors?

Answer 36

Skeletal muscle Autonomic ganglia

Question 37

How does nicotine inactivate nicotinic receptors?

Answer 37

Nicotinic receptors are sensitive to nicotine, which is an agonist and activates them. Once activated, they have sustained activation, but over time the effect will switch off, so can inactivate receptors by giving nicotine for a long time.

Question 38

What is hexamethonium?

Answer 38

Hexamethonium was used to block nicotinic receptors to treat high blood pressure. But it blocks both sympathetic and parasympathetic ganglia, which causes unpredictable side effects. Non-competitive agonist - blocked the ion channel rather than the receptor, so becomes more effective as membrane is hyperpolarised.

Question 39

What are muscarinic cholinoceptors?

Answer 39

Muscarinic cholinoceptors are GPCR Mostly mediates PNS Sensitive to muscarine 7 transmembrane spanning protein.

Question 40

What are muscarinic receptor subtypes found in the periphery?

Answer 40

The receptors are found on different organs, so easy targeting. M1 - stomach, salivary glands, antagonist is pirenzepine. M2 - cardiac, antagonist is gallamine. M3 - smooth muscle.

Question 41

What are some clinical uses of antimuscarinic drugs?

Answer 41

Parasympathetic nerves causes airway narrowing, so blocking the action causes dilation, helpful for asthma. Bradycardia - slow heart rate, so blocking increases heart rate. Reduce gut motility by pirenzepine.

Question 42

What are muscarinic agonists?

Answer 42

Parasympathomimetics: Ach Carbachol Muscarine Pilocarpine

Question 43

What are poisonings of muscarinic agonists?

Answer 43

Mimic effects of PNS. Decreases heart rate Stimulate exocrine glands to increase secretions and increase gut motility.

Question 44

What is the use of Parasympathomimetics?

Answer 44

Mainly used topically - pilocarpine topically applied to eye for treatment of glaucoma.