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PR3153 > IC4- Antiepileptic and Migraine medications > Flashcards

IC4- Antiepileptic and Migraine medications Flashcards

1
Q

With regards to the process of action potential, elaborate on the resting membrane potential

A

At rest the intracellular K+ is higher on the inside than on the outside. Hence negative RMP is due to efflux of K+ ions from inside → outside of membrane

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2
Q

With regards to the process of action potential, elaborate on the depolarization stage

A

The threshold potential opens voltage-gated Na+ channels and causes a large influx of Na+ ions.

When the action potential reaches the axon terminal, it opens the voltage-gated Ca2+ channels → Ca2+ influx → causes vesicles containing neurotransmitter to fuse with presynaptic membrane and exocytosis

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3
Q

With regards to the process of action potential, elaborate on the repolarization stage

A

Inactivation of voltage-gated Na+ channel and opening of K+ channel causing K+ efflux (absolute refractory period), restoring back the RMP

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4
Q

Explain the regulation of the action potential via a feedback loop

A

When postsynaptic receptors are activated, presynaptic autoreceptors are also activated → inhibit further transmitter release via feedback inhibition + neurotransmitter degradation by catalytic enzymes

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5
Q

What are the 4 types of neurotransmitters?

A
  1. Glutamate
  2. GABA
  3. Acetylcholine
  4. Dopamine
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6
Q

What type of neurotransmitter is glutamate?

Where is it found? What brain processes is it involved in?

A
  • Excitatory
  • Found in pyramidal neurons in neocortex
  • Learning and memory
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7
Q

What type of neurotransmitter is GABA?

What is the MOA?

A
  • Inhibitory
  • GABA binds to receptors → opening of Cl- channels and allow influx of Cl- → membrane potential kept negative → no depolarisation
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8
Q

Where does neurotransmitter acetylcholine arise from?

What brain processes is it involved in?

A
  • From nucleus basalis of Meynert
  • Learning, arousal and reward
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9
Q

Where does neurotransmitter dopamine arise from?

What brain processes is it involved in?

A

(it is a monoamine)

  • From substantia nigra
  • Motor system, reward
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10
Q

What are the 3 functions of the BBB?

A
  1. Modulation of entry of metabolic substrates
  2. Control of ion movements
  3. Prevent toxins and peripheral neurotransmitters escaping into bloodstream from autonomic nerve endings from entering CNS
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11
Q

What is the difference between glucose levels in brain ECF vs blood? Why?

A

Glucose is a fundamental source of energy for neurons → level in brain ECF more stable than that of blood

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12
Q

What are the characteristics of drugs that can undergo transmembrane diffusion past the BBB?

What are some other factors that may affect transmembrane diffusion?

A
  • Low MW (< 500 Da), high lipid solubility

Others:
- Charge, tertiary structure, degree of protein binding
- “Overexpression”/ “underexpression” of Pgp limits rate of uptake by BBB

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13
Q

How is rate uptake into BBB via transporter systems compared to that of transmembrane diffusion?

Is it also affected by efflux transporters?

A
  • Rate of uptake > 10x transmembrane diffusion
  • Uptake rate regulated by cerebral bloodflow, co-factors, hormones/ peptide modulators

Yes, also affected by efflux transporters

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14
Q

What are the general strategies for drug transport across BBB?

A
  1. Target transporters
  2. Analogues of transported ligands
  3. BBB itself as a therapeutic target
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15
Q

Describe the “Trojan horse strategy” as a strategy for drug transport across BBB

A

Coupling a substance that cannot cross BBB to one which does

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16
Q

In the strategies for drug transport across BBB, what is the advantage and disadvantage of the “Trojan horse strategy”?

A
  • Advantage: improved peripheral PK
  • Disadvantage: hybrid molecule may still not be recognised by original transporter → goes into lysosome
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17
Q

Describe the method of using analogues of transported ligands as a strategy for drug transport across BBB

A

Design analogues which retain affinity of both BBB transporter and CNS target receptor while improving peripheral PK

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18
Q

Describe the method of using the BBB itself as a therapeutic target as a strategy

A
  • Target luminal receptors of endothelial cells in BBB to synthesise CNS substances (eg neurotransmitters, cytokines)
  • Using certain drugs to bypass BBB in a diseased state (eg non lipid-soluble abx can pass through the porous capillary walls)
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19
Q

Antiepileptics work based on 2 rationales. What are they?

A
  • ↓ membrane excitability by altering Na+ and Ca2+ conductance during action potentials
    OR
  • Enhance effects of inhibitory GABA neurotransmitters
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20
Q

What are the general dose-related SEs of antiepileptics? (9)

A
  • Drowsiness
  • Confusion
  • Nystagmus
  • Ataxia
  • Slurred speech
  • Nausea
  • Unusual behaviour
  • Mental changes
  • Coma
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21
Q

What are the general non-dose related SEs of antiepileptics? (6)

A
  • Hirsutism
  • Acne
  • Gingival hyperplasia
  • Folate deficiency
  • Osteomalacia (soft bones)
  • Hypersensitivity (SJS)
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22
Q

Name the antiepileptic drugs (4)

A
  1. Phenytoin
  2. Carbamazepine
  3. Sodium Valproate
  4. Benzodiazepines
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23
Q

Phenytoin MOA?

A

Blockade of voltage-dependent Na+ channels

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24
Q

Indication of phenytoin?

A

Focal and GTC seizures, may worsen myoclonic seizures.

NOT for absence seizures!

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25
Q

Why does phenytoin need TDM?

What is the therapeutic range?

A
  • Relatively narrow therapeutic range (plasma conc 40-100µm)
  • Saturation kinetics
  • Non-linear relationship between dose and plasma conc (explained more in IC7)
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26
Q

Carbamazepine MOA?

A

Blockade of voltage-dependent Na+ channels

27
Q

Indication of carbamazepine?

A

Focal (first line) and GTC seizures, may worsen myoclonic seizures.

NOT for absence seizures!

28
Q

DDIs of carbamazepine?

What is special about CBZ and its metabolism?

A
  • CYP450 (CYP3A4) inducer, t1/2 shortens with repeated doses (“autoinduction”)
  • Accelerates elimination of other drugs
29
Q

ADEs of carbamazepine?

Hence what must we do?

A
  • SJS/ TEN (esp in asians → up to 0.6%)
    In asians with confirmed human leukocyte antigen (HLA)-B*1502 allele → up to 5%
    ∴ NEED genetic screening prior to commencing carbamazepine regimen
30
Q

Sodium valproate MOA? (2)

A
  • Blockade of voltage-dependent Na+ and Ca2+ channels
  • Also inhibits GABA transaminase → ↑ GABA
31
Q

Indication of sodium valproate?

A

Focal, GTC, *absence and myoclonic seizures

32
Q

What is something we need to take note regarding DDIs of sodium valproate?

A

Strongly bound to plasma proteins, displaces other antiepileptics

33
Q

Benzodiazepines MOA?

What is required for it to work?

A
  • Bind to another regulatory site on GABA receptor → potentiate influx of Cl- ions
  • Enhance effects of GABA neurotransmitters

Need GABA in the first place to work!

34
Q

What are the different duration of actions of benzodiazepines? (3)

A
  1. Short-acting: duration of action ~3-8h
  2. Intermediate-acting: duration of action ~10-20h
  3. Long-acting: duration of action ~1-3d
35
Q

ADEs of benzodiazepines?

A
  • Drowsiness
  • Confusion
  • Amnesia (memory loss)
  • Impaired muscle coordination (DO NOT operate heavy machinery)
36
Q

What happens when there is acute toxicity/ overdose of benzodiazepines?

What is the Tx for this toxicity/ overdose?

A
  • Severe respiratory depression (esp if used concurrently with alcohol) →

Tx: Flumazenil (benzodiazepine antagonist)

37
Q

What are the withdrawal effects of benzodiazepines?

Hence what must we do?

A
  • Withdrawal effects of dependence developed: disturbed sleep, rebound anxiety, tremor and convulsions → must withdraw gradually
38
Q

What are the different duration of actions of benzodiazepines and what are their uses?

A
  • Long acting: 1-2 days (eg. phenobarbital); function: anticonvulsant
  • Short: 3-8 hours (eg. pentobarbital and amobarbital); function: sedative and hypnotic
  • Ultrashort: 20 min (eg. thiopental); function: IV induction of anaesthesia
39
Q

What is the MOA of phenobarbital?

(how does it compare to BZDs)?

A

Potentiate GABA mediated Cl- currents, but at a site distinct from benzodiazepines

40
Q

If there is a barbiturate (phenobarbital) overdose, will flumazenil work?

A

No, it only blocks BZDs, it cannot block phenobarbital as it acts on a site on GABA that is distinct from BZDs

41
Q

How would you compare barbiturates’ ability to depress the CNS as compared to BZDs?

Hence are they still used often in clinical settings?

A

Barbiturates have even greater ability to depress the CNS than BZDs → dangerous

Hence slowly replaced by BZDs

42
Q

Indication of Levetiracetam?

A
  • Primarily used as: adjunctive Tx for partial onset seizures, myoclonic and primary GTC seizures
  • MonoTx for partial onset seizures in newly diagnosed epilepsy
43
Q

Describe PK of Levetiracetam?

A
  • Highly soluble, permeable
  • Linear PK profile with low intra- and inter-subject variability
44
Q

Which antiepileptic has abuse potential?

A

Benzodiazepines

45
Q

Should we use monotherapy of antiepileptic drugs? Or do we use a combination?

What if Tx is unsuccessful?

A

Try for monoTx

If unsuccessful/ pt develops ADEs, try another drug for monoTx

46
Q

Is monitoring of antiepileptics routinely needed?

A

No

47
Q

Function of routine monitoring of antiepileptic drug levels? (3)

A
  • Assess of compliance if pt has refractory epilepsy
  • Assess of SSx due to possible antiepileptic drug toxicity
  • Titrate phenytoin dose
48
Q

Pathophysiology of headache/ migraine?

A

Vasodilation of intracranial extracerebral blood vessels → activation of perivascular trigeminal nerves that release vasoactive neuropeptides → promote neurogenic inflammation. Central pain transmission may activate other brainstem nuclei, causing associated SSx (n/v, photophobia, phonophobia)

49
Q

How does serotonin counter migraines? (MOA)?

A

Agonist of vascular and neuronal 5-HT1 receptor subtypes known to result in vasoconstriction of meningeal blood vessels and inhibition of vasoactive neuropeptide release and pain signal transmission

50
Q

What are the types of migraine medications? (mentioned in this IC)

A
  1. Cafergot
  2. Sumatriptan
51
Q

When do we use these migraine specific medications?

A

For moderate-severe migraines where NSAIDS/ paracetamol are ineffective

52
Q

What ingredients does Cafergot contain?

A

Contains caffeine & ergotamine

53
Q

Indications for cafergot?

When is it given?

A

Acute Tx of migraine (given at FIRST ssx of attack)

54
Q

MOA of cafergot?

A
  • Tonic action on vascular SM in external carotid network → Leads to vasoconstriction by stimulating alpha-adrenergic and 5-HT receptors (5-HT1B and 5-HT1D receptors)
55
Q

DDIs of cafergot?

Hence what should we NOT combine them with? What will happen if we do?

A

CYP3A inhibitor:
- Should not be used with other CYP3A inhibitors like macrolide abx → elevated exposure to ergot toxicity → vasospasm, tissue ischemia
- Should not be used with other vasoconstrictors (eg. ergot alkaloids, sumatriptan, other 5HT1 agonists)

56
Q

ADEs of cafergot? (4)

A

Common:
- N/v

Rare:
- Hypersensitivity
- MI
- Ergotism (vascular ischaemia)

57
Q

Absorption, distribution and bioavailability of cafergot?

A

A: rapid absorption (max plasma conc reached in 1.5-2h)
D: High plasma protein binding
F ~2-5%

58
Q

Sumatriptan MOA? (4)

A
  • Selective vascular serotonin (5-HT1D and 5-HT1B) receptor agonist.
  • Selectively constricts the carotid arterial circulation, but does not alter cerebral blood flow
  • Vasoconstriction of intracranial extracerebral blood vessels
  • Inhibits trigeminal nerve activity → inhibit vasoactive peptide release
59
Q

Absorption and elimination of Sumatriptan?

A
  • A: rapidly absorbed, low plasma protein binding
  • E: eliminated primarily via oxidative metabolism mediated by monoamine oxidase A (MAO)
60
Q

C/I of sumatriptan? (3)

A
  • Hypersensitivity to triptans
  • Concurrent administration with MAOi
  • MI
61
Q

ADEs of sumatriptan? (7)

A

Common:
- Dysgeusia (unpleasant taste)
- Transient BP ↑
- Flushing
- Sensation of cold
- Pressure
- Tightness

Rare:
- Minor disturbances in LFTs

62
Q

Which 1st generation ASMs are indicated for focal and GTC seizures, and may worsen myoclonic seizures? (2)

A

Phenytoin, Carbamazepine

63
Q

Which 2nd generation ASMs are indicated for focal and GTC seizures, and may worsen myoclonic seizures? (2)

A

Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine

64
Q

Indications of Topiramate?

A

Focal and GTC seizures

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