Nervous System

Question 1

What are the indications for gabapentin and pregabalin? (4)

Answer 1

1. Focal epilepsies - usually as an addon treatment when other antiepileptic drugs provide inadequate control as monotherapy.
2. Neuropathic pain; pregabalin in particular is recommended as a second-line option in painful diabetic neuropathy (after duloxetine) and as a first-line option in other painful neuropathies.
3. Gabapentin is used in migraine prophylaxis.
4. Pregabalin is used in generalised anxiety disorder.

Question 2

How do gabapentin and pregabalin work?

Answer 2

Despite being a closely related structural analogue of GABA (the major inhibitory neurotransmitter), gabapentins mechanism of action is due to binding to voltage-sensitive calcium channels, where it presumably prevents the inflow of calcium ions and therefor inhibits neurotransmitter release: interfering with synaptic transmission and reducing neuronal excitability.

Pregabalin is a structural analogue of gabapentin and presumably has a similar mec of action.

Question 3

What are the main side effects of gabapentin and pregabalin?

Answer 3

There are more well tolerated than other AEDs: main side effects are transient drowsiness, dizziness and ataxia which will usually improve over the first few weeks of treatment.

Question 4

When should doses of pregabalin and gabapentin be reduced?

Answer 4

Renal impairment as they are renally excreted.

Question 5

What are the important drug interactions with gabapentin and pregabalin?

Answer 5

Very few, sedative effect may be enhanced when used alongside benzo’s/other sedating drugs.

Question 6

What are the practical prescribing points wrt pregabalin and gabapentin?

Answer 6

To improve tolerability, they are started at low doses and increased over subsequent days and weeks to reach a dose that strikes the optimal balance between benefits and side effects.

Question 7

What is the only indication of the Z-drugs?

Answer 7

Short term treatment of insomnia which is debilitating or distressing.

Question 8

What is the mechanism of action of Z-drugs? What is it similar to?

Answer 8

Similar mechanism of action to benzodiazepines, despite being chemically distinct.

Their target is the GABA type A receptor which is a chloride channel that opens in response to binding by GABA - the main inhibitory neurotransmitter in the brain.

Opening the channel allows chloride to flow into the cell, making the cell more resistant to depolarisation.

Z-drugs, like BZs potentiate the effect of GABA leading to a widespread depressant effect on synaptic transmission.

Question 9

What are the important adverse effects of Z-drugs?

Answer 9

Daytime sleepiness, rebound insomnia upon stopping.

Zopiclone can cause taste disturbance.

Zolpidem can cause GI upset.

Prolonged use of Z-drugs beyond 4 weeks can cause dependence and withdrawal symptoms upon stopping.

Question 10

In who should Z-drugs be used with caution?

Answer 10

Elderly as more susceptible to drugs with central nervous system effects.

Should not be prescribed for people with obstructive sleep apnoea or those with respiratory muscle weakness or respiratory depression.

Question 11

What are the main interactions to be away of with Z-drugs?

Answer 11

Z-drugs enhance the sedative effect of alcohol, antihistamines and benzos.

They also enhance the hypotensive effect of antihypertensive medications.

Z-drugs are metabolised by CYP450 enzymes so P450 inhibitors such as macrolides can enhance sedation, while P450 inducers such as phenytoin and rifampicin can impair sedation.

Question 12

What is the interaction between Z-drugs and phenytoin and rifampicin?

Answer 12

Impaired sedation due to action as P450 inducers leading to increased metabolism of z-drugs

Question 13

What is the interacton between macrolides and Z-drugs?

Answer 13

Enhanced sedation due to macrolides inhibiting P450 metabolism of Z-drugs.

Question 14

What are the clinical indications for first generation (typical) antipsychotics? (4)

Answer 14

1. Urgent treatment of severe psychomotor agitation that is causing dangerous or violent behaviour, or to calm patients to permit assessment.
2. Schizophrenia, particularly when the metabolic side effects of 2nd gen are likely to be problematic.
3. Bipolar disorder, particularly in acute episodes of mania or hypomania.
4. Nausea and vomiting, particularly in the palliative care setting.

Question 15

How do antipsychotic drug works?

Answer 15

They block post-synaptic dopamine D2 receptors.

Question 16

D2 blockade of what pathway is probably the main determinant of antipsychotic effect by antipsychotic drugs?

Answer 16

The mesolimbic/mesocortical pathway which runs between the midbrain and the limbic system/frontal cortex.

Question 17

Blockade of D2 receptors in what zone are responsible for the use of antipsychotics in nausea and vomiting?

Answer 17

D2 receptors in the chemoreceptor trigger zone.

Question 18

What are the main drawbacks of the first generation antipsychotics? What causes this?

Answer 18

D2 blockade of the nigrostriatal pathway causes extrapyramidal side effects: acute dystonic reactions are involuntary parkinsonian movements or muscle spasms; akathisia is a state of inner restlessness; and neuroleptic malignant syndrome is rare but life-threatening.

Tardive dyskinesia occurs after months or years of treatment.

Question 19

What other side effects of first generation antipsychotics exist? (other than movement side effects)

Answer 19

Drowsiness, hypotension, QT-interval prolongation, ED and hyperprolactinaemia due to tuberhohypophyseal D2 blockade (menstrual disturbance, galactorrhoea and breast pain).

Question 20

Why should antipsychotics ideally be avoided in dementia patients?

Answer 20

They may increase the risk of death and stroke. Also should ideally be avoided in possible in parkinson patients due to their extrapyramidal side effects.

Question 21

Why should amiodarone/macrolifes not be used alongside first gen antipsychotics?

Answer 21

They all prolong the QT interval.

Question 22

Prochlorperazine, haloperidol and chlorpromazine are examples of

Answer 22

First gen antipsychotics.

Chlorpromazine has most sedative effect.

Question 23

What first gen antipsychotic is also licensed for the treatment of intractable hiccups?

Answer 23

Haloperidol.

Question 24

What is the first line treatment for focal seizures, with and without secondary generalisation and for primary generalised seizures?

Answer 24

Carbamazepine - apparent mech of action is inhibiting neuronal sodium channels.

Question 25

What is the first line treatment of trigeminal neuralgia to control the pain, and reduce the frequency and severity of attacks?

Answer 25

Carbamazepine.

Question 26

When can carbamazepine be used in bipolar disorder treatment?

Answer 26

An option for prophylaxis in patients resistant to or intolerant or other medication.

Question 27

How is carbamazepine believed to work in the treatment of Epilepsy, trigeminal neuralgia and bipolar disorder?

Answer 27

Mechanism of action is not fully understood.
Believed to inhibit neuronal sodium channels, stabilising membrane potentials and reducing neuronal excitability.

This may inhibit the spread of seizure activity in epilepsy, control neuralgic pain by blocking synaptic transmission in the trigeminal nucleus and stabilise mood in bipolar disorder by reducing electrical ‘kindling’ in the temporal lobe and limbic system.

Question 28

What are the most common side effects of carbamazepine?

Answer 28

Dose-related are GI upset and neurological effects (dizziness and ataxia).

Question 29

Carbamazepine hypersensitivity affects about what percentage of people taking the drug? How does it manifest?

Answer 29

10%, manifests as a mild maculopapular skin rash.

Question 30

Can carbamazepine be used in pregnancy?

Answer 30

Carbamazepine exposure in utero is associated with neural tube defects, cardiac and urinary tract abnormalities and cleft palate.

Women with epilepsy planning pregnancy should discuss treatment with a specialist and start taking high-dose folic acid supplements before conception.

Question 31

Why does carbamazepine interact with warfarin, oestrogens and phenytoin?

Answer 31

Carbamazapine induces cytochrome p450 enzymes, reducing plasma concentration and efficacy of drugs that are metabolised by these enzymes.

Carbamazepine itself is metabolised by these enzymes, so its concentration and adverse effects are increased by cytochrome p450 inhibitors such as macrolides.

Question 32

The efficacy of all AEDs is reduced by seizure lowering drugs such as

Answer 32

SSRIs, TCAs, antipsychotics and tramadol

Question 33

The serum concentration and adverse effects of carbamazepine are increased by what?

Answer 33

cytochrome p450 inhibitors such as macrolides, as carbamazepine is metabolised by CYP450 enzymes.,

Question 34

Can carbamazepine be prescribed generically?

Answer 34

Yes but as bioavailability can differ between formulations it isnt recommended.