CNS disorders

Question 1

Sodium valproate

Answer 1

Epilepsy treatment
Enhances GABAergic neurotransmission by inhibiting the metabolising enzymes GABA transaminase and SSA dehydrogenase.
It also blocks voltage-gated sodium, potassium and calcium channels, inhibits histone deacetylase altering gene expression, inhibits NMDA signalling, disrupts Wnt and ERK signalling, and suppresses high frequency firing.

Question 2

Lamotrigine

Answer 2

Epilepsy (as well as BD and SZ)
Blocks VGSCs in their inactivated state, suppressing high-frequency firing.
It also blocks VGCCs and inhibits 5-HT3 receptors.

Question 3

Gabapentin

Answer 3

Epilepsy (and neuropathic pain and MS)
Blocks high-voltage activated calcium channels, reducing vesicle fusion and glutamate release.
No obvious effects on GABA release, but it increases tonic GABA concentration in brain slices.

Question 4

Acetylcholinesterase inhibitors

Answer 4

Donepezil, Rivastigmine and Galantamine
Alzheimer’s disease
Increase tonic ACh to combat loss in basal ganglia

Question 5

Memantine

Answer 5

Alzheimer’s
NMDA antagonist - binds to the calcium pore of the receptor to reduce glutamate-induced excitotoxicity

Question 6

Aducanumab

Answer 6

Alzheimer’s
Monoclonal antibody against β-amyloid aggregates, reducing amyloid load
Modest effects on slowing the rate of clinical decline.

Question 7

L-dopa and Carbidopa (/benserazide)

Answer 7

Parkinson’s
L-dopa is a dopamine precursor
Carbidopa and benserazide are inhibitors of L-dopa decarboxylase that do not cross the BBB - prevent dopamine synthesis in the periphery.

Question 8

D2 agonists

Answer 8

Parkinson’s
Examples: apomorphine (D1 and D2), bromocriptine, ropinirole and pramipexole.
Directly activate D2 receptors in the basal ganglia to compensate for loss of nigrostriatal input.
Dopamine receptors outside of the basal ganglia are activated, causing side effects due to activation of the mesocortical and mesolimbic pathways. These include hallucinations and delusions, as well as compulsive and impulsive behaviour.

Question 9

MAO-B inhibitors - Selegiline

Answer 9

Parkinson’s
Prevents the breakdown of dopamine.
Used in conjunction with L-dope or D2 agonists.

Question 10

Iproniazid - MAO inhibitor

Answer 10

Depression treatment, increases monoamine concentrations

Question 11

Tricyclic antidepressants

Answer 11

Imipramine, Amitriptyline
Inhibit reuptake of 5-HT and noradrenaline
Also antagonise H1 receptors, and have anticholinergic effects (dry mouth)

Question 12

SSRIs

Answer 12

Examples: citalopram, fluoxetine, sertraline
Inhibit 5-HT reuptake by inhibiting SERTs
Citalopram binds to the central site and locks the transporter in an outward-facing configuration. It can also occupy a second allosteric site that prevents dissociation from the central site.
SSRIs can reverse changes in brain volumes, connectivity, neurogenesis and function (neuroplasticity) seen in depression.
Changes to levels of glutamate and glutamine within the CSF are also reduced.
This is because 5-HT receptor activation is linked to upregulation of BDNF.
SSRIs also directly bind to tropomyosin receptor kinase B (TRKB), a BDNF receptor.

Question 12

Atypical antidepressants

Answer 12

Examples: bupropion, venlafaxine and vortioxetine
Target different monoamine transporter and receptor combinations.

Question 13

Ketamine

Answer 13

NMDA receptor antagonist used as a fast acting antidepressant.
Works because there is hyperglutamatergic activity in depression.
Also directly binds to tropomyosin receptor kinase B (TRKB), a BDNF receptor, regulating neuroplasticity.

Question 14

Typical antipsychotics

Answer 14

Chlorpromazine and its derivatives, trifluoperazine, haloperidol, and loxapine.
Schizophrenia
D2 antagonists - treat positive symptoms but worse negative ones
Common extrapyramidal effects in the striatum include Parkinsonism, akathisia dystonia and dyskinesia

Question 15

Atypical antipsychotics

Answer 15

Examples: clozapine, risperidone, aripriprazole
Schizophrenia - treat both positive and negative symptoms and have reduced extrapyramidal effects.
These still mostly target dopamine receptors, but also have some action at 5-HT receptors, as well as α1, H1 and M1 receptors.

Question 16

Antiemetics: H1 antagonists

Answer 16

Examples: Promethazine, meclazine, diphenhydramine, dimenhydrinate
Act on vestibular nuclei of the inner ear
Used for motion sickness and pregnancy morning sickness in severe cases.
Effects in the brain cause drowsiness

Question 17

Antiemetics: M1 antagonists

Answer 17

Hyoscine (scopolamine)
Prophylaxis and treatment of motion sickness, acting at the vestibular nuclei.
Also act in the GIT to reduce gastric emptying.
Cause dry mouth and drowsiness but less sedation.

Question 18

Antiemetics: D2 antagonists

Answer 18

Examples: metoclopramide, domperidone, prochlorperazine, chlorperazine
Act in the CTZ
Can be used for chemotherapy-induced emesis.
Can cause Parkinson’s-like symptoms
Stimulate gastric emptying

Question 19

Antiemetics: 5-HT3 antagonists

Answer 19

Ondasetron blocks receptors in the GIT and CTZ
Treat chemotherapy-induced emesis

Question 20

Antiemetics: NK-1 antagonists

Answer 20

Examples: Aprepitant, Rolapritant
Act in the GIT and CTZ, used in chemotherapy-induced nausea in combination with 5-HT receptor antagonist.

Question 21

Antiemetics: Dexamethasone

Answer 21

Steroid used alongside 5-HT3 and NK-1 antagonist for chemo-induced emesis.
Mechanism of action unknown.

Question 22

Apomorphine

Answer 22

Metabolite of morphine. No effect on opioid receptors but acts as a non-selective dopamine receptor agonist.
Activation of D2 receptors triggers nausea and vomiting.
Emetic used in veterinary medicine to expel harmful ingested substances.