L11 - Pharmacology of the CNS and Breathing

Question 1

List the potential targets for action of drugs affecting breathing.

Answer 1

1 - In the brain stem (central chemoreceptors).

2 - Peripheral chemoreceptors.

3 - Networks.

Question 2

What are analeptics?

Answer 2

Respiratory stimulants.

Question 3

What is doxapram and how does it work?

Answer 3

• An analeptic.

- Stimulates CO2 and O2 chemoreceptors, non-specifically enhancing electrical activity.

Question 4

Where is doxapram used clinically?

Answer 4

• With acute ventilatory failure.

- With post-operative respiratory depression.

Question 5

What is the general principle regarding the function of respiratory depressants?

Answer 5

Any agent which has a generalised CNS depressant effect has the potential to depress respiration via action at the respiratory nuclei in the brain stem.

Question 6

List 5 examples of respiratory depressants.

Answer 6

1 - General anaesthetics.

2 - Benzodiazepines, e.g. diazepam.

3 - Barbiturates, e.g. phenobarbital.

4 - Alcohol.

5 - Opioids, e.g. morphine.

Question 7

How do benzodiazepines function as respiratory depressants?

Answer 7

• Benzodiazepines bind to GABAa receptors on a different binding site to GABA and barbiturates.
• Binding increases the total conduction of chloride ions across the neuronal cell membrane when GABA is already bound to its receptor.
• Increases inhibitory action, decreasing hypoxic drive.

Question 8

How do barbiturates function as respiratory depressants?

Answer 8

• Barbiturates bind to GABAa receptors (on a different binding site to GABA and benzodiazepines), increasing the chloride channel opening time.
• At high concentrations inhibits neurotransmitter release by blocking Ca2+ channels.
• Increases inhibitory action, decreasing hypoxic drive and decreasing the excitability of central chemoreceptors.

Question 9

How does alcohol function as a respiratory depressant?

Answer 9

Ethanol increases GABAa transmission and decreases NMDA transmission.

Question 10

What opioid receptor subtypes exist at the pre-synaptic and post-synaptic membrane?

Answer 10

• Presynaptic: μ, κ and 𝛿.

- Postsynaptic: μ only.

Question 11

How do opioids function as respiratory depressants?

Answer 11

• At the presynaptic membrane, GPCRs μ, κ and 𝛿 decrease Ca2+ influx, decreasing neurotransmitter release.
• At the postsynaptic membrane, μ receptors increase potassium conductance, generating an inhibitory post-synaptic potential (IPSP).
• Decreases CO2 receptor response.

Question 12

How does tolerance to opioids change with use?

What is the significance of this?

Answer 12

• Tolerance increases with use, but will decrease again during periods of remission.
• If a patient relapses and continues on the dose they used last, effects will be greater as tolerance would have decreased since last use.

Question 13

Give an example of an opioid receptor antagonist.

Answer 13

Naloxone.