Pharmacology

Question 1

State the 2 general MOA of Antiepileptics

Answer 1

1) Decrease membrane excitability by altering Na+ and Ca2+ conductance during action potentials.

2) Enhance effects of inhibitory GABA neurotransmitters.

Question 2

State the MOA of Phenytoin

Answer 2

Blockade of voltage depedent Na+ channels -> prevents influx of Na+ and action potential

Question 3

State which of the 1st line anti-epileptics can be used for all types of seizures except absence seizures.

Answer 3

Phenytoin, Carbamazepine

Question 4

State which of the 1st line anti-epileptics can be used for all types of seizures including absence seizures.

Answer 4

Valproic acid
Lamotrigine (not 1st line but still can use)

Question 5

State the characteristics of Phenytoin that necessitates dose titration and monitoring

Answer 5

1) Narrow therapeutic range (plasma concentration 40-100 μM)

2) Saturation kinetics and consequent non-linear relationship between dose and plasma concentration

Question 6

Is Phenytoin teratogenic?

Answer 6

Yes

Question 7

State MOA of Carbamazepine

Answer 7

Blockade of voltage depedent Na+ channels

Question 8

State the quirks of Carbamazepine (2)

Answer 8

• Hepatic enzyme (CYP450) inducer, T½ shortens with repeated doses -> accelerates elimination of other drugs
• Pharmacogenomics effects in Stevens Johnson Syndrome/ Toxic Epidermal Necrolysis ((HLA)-B* 1502)

Question 9

State the MOA of Valproate

Answer 9

• Blockade of voltage dependent Na+ and Ca2+ channels AND
• Inhibits GABA transaminase -> increased GABA

Question 10

State the potential DDI mechanism of Valproate (applies to other 1st gen ASM also)

Answer 10

• Strongly bound to plasma proteins, displaces other antiepileptics -> increase bioavailability of other antiepileptic

Question 11

State the dose related side effects of antiepileptics (9)

Answer 11

CNS effects
* Drowsiness, confusion, nystagmus (eyes become non-aligned), ataxia, slurred speech, nausea, unusual behaviour, mental changes, coma

Question 12

State the non-dose related side effects of antiepileptics (6)

Answer 12

1) Hirsutism,
2) Acne,
3) Gingival hyperplasia (increased growth of gums),
4) Folate deficiency,
5) Osteomalacia (softening of bone),
6) Hypersensitivity reactions (including Stevens Johnson syndrome)

Question 13

State the MOA of Benzodiazepines

Answer 13

• Enhance inhibitory effects of GABA by binding to allosteric site of GABA receptor and -> increased Cl- influx -> hyperpolarization and decreased neuron firing

Question 14

What is the reversal agent for Benzodiazepines?

Answer 14

Flumazenil (Benzodiazepine site inhibitor)

Question 15

State the ADRs of Benzodiazepines/ Phenobarbital (3 main)

Answer 15

1) Acute toxicity/ overdose
o Can cause severe respiratory depression (e.g CV collapse, lung collapse), especially used concurrently with alcohol
o Treatment is by flumazenil, a benzodiazepine site antagonist
2) Side effects during use:
o Drowsiness, confusion, amnesia
o Impaired muscle coordination (impairs manual skills)
3) Tolerance and dependence
o Tolerance depends on frequency of use. Therefore, tolerance develops faster for epilepsy than for use to induce sleep
o Dependence can develop. Withdrawal effects include disturbed sleep, rebound anxiety, tremor and convulsions
o Important to withdraw gradually
o Has abuse potential

Question 16

State the MOA of Barbiturates

Answer 16

Also potentiate GABAA mediated Cl- currents, but at a site distinct from benzodiazepines -> Flumazenil will not work if overdosed on Phenobarbital

Question 17

State the indication for Barbiturates in Epilepsy (2)

Answer 17

• Use as a sedative hypnotic has largely been replaced by benzodiazepines due to barbiturates’ tendency to develop tolerance and dependence
• Use as AED mainly for pediatric or neonatal patients (IV loading dose followed by IV or oral maintenance doses) -> highly limited use as AED

Question 18

State the duration of actions for the different Barbiturates (Long-acting, Short, Ultrashort) and what are their uses

Answer 18

o Long acting (1-2 days) -> Anticonvulsant
 E.g Phenobarbital
 Preferred so no need to dose so often
o Short (3-8hrs) -> Sedative & Hypnotic
 E.g pentobarbital and amobarbital
o Ultrashort (20 min) -> I.V induction of anesthesia
 E.g Thiopental

Question 19

MOA of Lamotrigine

Answer 19

• Blocks voltage gated sodium channels, inhibits release of glutamate, impedes sustained repetitive neuronal depolarization

Question 20

State the indications of Lamotrigine (2)

Answer 20

• Indicated for adjunctive or monotherapy treatment of partial seizures and generalised seizures, including tonic clonic seizures
• Monotherapy of typical absence seizures
• Adjunctive or initial AED for Lennox-Gastaut syndrome (severe childhood epilepsy)

Question 21

MOA of Cafergot

Answer 21

• Tonic action on vascular smooth muscles in the external carotid network. Leads to vasoconstriction by stimulating alpha adrenergic and 5-HT receptors (especially 5-HT1B and 5-HT1D receptors -> agonist on these receptors)

Question 22

Which of the antimigraine drugs are indicated for acute treatment?

Answer 22

Cafergot, Sumatriptan

Question 23

Which of the antimigraine drugs are indicated for prophyalaxis treatment?

Answer 23

Erenumab

Question 24

ADR of Cafergot (4)

Answer 24

• Common:
  o Nausea and vomiting
• Rare:
  o Hypersensitivity , myocardial infarct, ergotism (vascular ischaemia)

Question 25

What are the DDI of Cafergot?

Answer 25

• Substrate of CYP3A. Should not be used with other CYP3A inihibitors like macrolide antibiotics -> elevated exposure to ergot toxicity (vasospasm and tissue ischaemia + other vasoconstrictive effects)
• Should NOT be used with other vasoconstrictor agents (including ergot alkaloids, sumatriptan and other 5HT1 agonists).

Question 26

State the PK characteristics of Cafergot (AD)

Answer 26

• Oral (also rectal).
• Rapidly absorbed (maximum plasma concentrations reached in 1.5-2 hr).
• High plasma protein binding -> stuck in plasma = low absolute bioavailability (2-5%)

Question 27

MOA of Sumatriptan

Answer 27

• Selective vascular serotonin (5-HT1B and 5-HT1D) receptor agonist -> constricts cerebral vessels +
• Inhibits trigeminal nerve activity and inhibits vasoactive peptides released by trigeminal neurons -> inhibition of nociception (inhibition of central pain amplification)

Question 28

ADR of Sumatriptan (~12)

Answer 28

• Common
  o Dysgeusia (unpleasant taste), transient BP increase, flushing, sensation of cold, pressure, tightness
  o Sleepy, tired, dizzy
  o Pain or tightness in throat/jaw
  o Vertigo
• Rare
  o Minor disturbances in liver function tests
  o Heart attack
  o Seretonin syndrome

Question 29

State the PK characteristics of Sumatriptan (ADM)

Answer 29

• Oral, nasal, IV.
• Rapidly absorbed, low plasma protein binding.
• Eliminated primarily by oxidative metabolism mediated by monoamine oxidase A (MAO).

Question 30

MOA of Erenumab

Answer 30

• Monoclonal antibody calcitonin gene related peptide (CGRP) inhibitor. Blocks CGRP receptors.

Question 31

What are the PK characteristics of Erenumab? (Administration, onset of effect, kinetic type)

Answer 31

• Subcutaneous injection (monthly).
• Clinical benefit typically within 3 months. Linear kinetics at therapeutic doses (as CGRP receptor binding is saturated).

Question 32

ADR of Erenumab (4)

Answer 32

• Hypersensitivity reactions, injection site reactions, constipation, pruritis