Neurodegenerative diseases. Anxiolytics/hypnotic drugs. Antiepileptics.

Question 1

AChE inhibitors (e.g. donepezil, galantamine, rivastigmine)

Answer 1

Used in mild-moderate Alzheimer’s.

Inhibits the enzyme acetylcholinesterase , that normally breaks down or hydrolyzes Ach. By inhibiting this enzyme, it prolongs Ach in the synapse and increase cholinergic effects.

Side effects: GI symptoms (e.g. loss of appetite, nausea, vomiting, diarrhea).

Question 2

NMDA-receptor antagonist (e.g. memantine)

Answer 2

Used in moderate-severe Alzheimer’s.

Extracellular amyloid-beta is thought to block glutamate reuptake, leading to overactivation of NMDA receptors. This could lead to the memory loss seen in Alzheimer’s as NMDA receptors are important for memory consolidation. Long term, overactivation of NMDA receptors can result in neuronal cell death due to excitotoxicity.

Side-effects: confusion, headache, fatigue, vertigo (svimmelhed).

Question 3

DA replacement

Answer 3

L-dopa + decarboxylase inhibitor (carbidopa) is the first choice for older than 70y with parkinssons. The decarboxylase inhibitors are given because levodopa conversion also occurs in the periphery. Thus, by inhibiting this enzyme then there is enhanced delivery to the brain. This also minimizes the side effects of excessive DA in the periphery (decarboxylase converts levodopa into DA).

• Levodopa can pass the BBB and be taken up by DA neurons and replenish the stores, but DA can’t pass the BBB.
• Levodopa wears off after some time and starts to get more side effects. Dyskinesia (involuntary movements) does not appear initially but develop in the majority of patients within two years of starting levodopa therapy) There are on-off side effects (where there are rapid fluctuations in the clinical state where bradykinesia and rigidity may suddenly worsen acutely and then improve again).

Side effects: nausea (DA receptors expressed in the CTZ), postural hypotension, psychological effects (psychosis, confusion, nightmares, impulse control disorders)

Question 4

Dopamine 2 receptor agonists

Answer 4

Used for Parkinson’s disease.
Mimic the action of dopamine on. It is the first choice in younger patients (<70y) to avoid/postpone L-dopa induced dyskinesias (uncontrolled movement). These drugs are also used as adjuvant therapy.

Question 5

Indirect DA mimetics

Answer 5

Used for Parkinson’s disease.

MAO-B inhibitors: irreversible inhibition of DA degradation in brain. Used both as mono and adjuvant therapy.

COMT inhibitors: inhibits L-dopa degradation peripherally so more L-dopa enters the CNS.

Question 6

Benzodiazepine (anxiolytic drug and hypnotic drug)

Answer 6

Benzodiazepine site is an allosteric site enhancer so will bind to the receptor at a different part than where GABA will bind. It is a positive modulator; it increases the affinity of GABA for the receptor so GABA binds more, increasing opening frequency of the channel so that there is increased Cl- influx -> hyperpolarization and reduced neuronal excitability -> INHIBITION.

Question 7

Mechanisms to reduce excitation and inhibit the abnormal neuronal discharge (as in epileptics).

Answer 7

1. Increased GABA action (inhibitory) (e.g. benzodiazepine), works by increasing GABA inhibitory action.
2. Inhibition of “sustain repetitive firing” via blocking af Na+ channels. When a neuron fires you have too much activity, and if you block Na+ from entering neurons, you reduce firing.
3. Inhibition of Ca2+ channels. During an epileptic seizure there is too much glutamate being released, you can inhibit this by inhibiting Ca+2 channels.