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PR3153 Central Nervous System > IC4 Neuropharmacology, Anti-migraine, Anti-epileptics > Flashcards

IC4 Neuropharmacology, Anti-migraine, Anti-epileptics Flashcards

1
Q

Describe the neurophysiological process of signaling

A
  1. Resting Membrane Potential
  2. Depolarization and Action Potential
  3. Repolarization
  4. Active Conduction
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2
Q

What is the distribution of ions at RMP?

A
  • K+: Intracellular > Extracellular
  • Na+: Extracellular > Intracellular
  • Cl-: Extracellular > Intracellular

K+ > Cl- Intracellularly

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3
Q

What happens at depolarization?

A

Voltage-gated sodium channels open

Influx of sodium ions down concentration gradient into cell causing the cell to be more positive (depolarized)

Once threshold is reached, more voltage-gated sodium channels open resulting in an action potential

Hodgkin-Huxley Cycle = Na influx

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4
Q

What happens at repolarization?

A

Voltage-gated potassium channels open

Potassium efflux (Absolute refractory period)

Voltage-gated sodium channels close

Become more negative

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5
Q

How does active conduction happen in unmyelinated and myelinated neurons?

A
  1. Unmyelinated - Multiple Na channels in close proximity
  2. Myelinated - Saltatory conduction at Nodes of Ranvier
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6
Q

Describe the neurochemistry of Acetylcholine

A
  1. Synthesis by choline acetyltransferase (ChAT) in presynaptic neuron
  2. Action potential causes voltage-gated calcium channels to open
  3. Calcium influx causes acetylcholine granules to be exocytosed
  4. Fate of ACh
    - Catabolism by Acetylcholinesterase
    - Feedback to presynaptic neuron to regulate release of ACh
    - Receptor on postsynaptic neuron
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7
Q

Describe how synaptic transmission occurs

A
  1. Initiation
    - Action potential, voltage-gated calcium channel opening and Ca influx
    - VAMPs release vesicles from cytoskeleton and facilitates docking, fusion and exocytosis from presynaptic membrane
    - Autoreceptor regulation (Feedback inhibition)
  2. Propagation
    - Second messenger activation
    - Depolarization and action potential
  3. Termination
    - Catalytic enzymes
    - Reuptake transporters
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8
Q

4 Major Neurotransmitters and their roles

A
  1. Glutamate - Excitatory (Learning & memory)
  2. GABA - Inhibitory
  3. ACh (Learning, arousal, reward)
  4. Dopamine - Motor system (Reward)
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9
Q

Drug effects on synaptic transmission - Different targets for agonism and antagonism?

A
  1. Neurotransmitter synthesis
  2. Enzyme degradation of neurotransmitter
  3. Neurotransmitter exocytosis
  4. Autoreceptor (Block or activate)
  5. Postsynaptic receptor
  6. Catalysis or reuptake of neurotransmitter
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10
Q

What is the function of BBB?

A

Immunologically isolate the brain

Provide stable and chemically optimal environment

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11
Q

What is the rationale of antiepileptic action?

A

Reduce excitability and enhance inhibitory GABA

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12
Q

MOA and clinical use of Phenytoin

A

Block Voltage-gated sodium channels

All seizures except Absence seizures

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13
Q

Phenytoin use in pregnancy?

A

Teratogenic

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14
Q

PK Profile of phenytoin

A
  1. Saturation kinetics
  2. Non-linear relationship of dose-plasma concentration
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15
Q

MOA and clinical use of carbamazepine

A

Block Voltage-gated Na channels

All seizures except Absence seizures

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16
Q

Carbamazepine accelerates elimination of drugs because …

A

It is a hepatic enzyme inducer (CYP450)

Its on half-life is shortened with repeated dose

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17
Q

Why is genetic screening in carbamazepine regimen important?

A

Carbamazepine has pharmacogenomic effects in SJS and TEN

Presence of HLA-B* 1502 allele

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18
Q

MOA and clinical use of Valproate

A

Block Na and Ca channels

Inhibits GABA transaminase

All seizures including Absence seizures

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19
Q

Valproate PK characteristic (one unique)

A

Strong plasma protein bound, displacing other antiepileptic

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20
Q

ADRs of Antiepileptics

A

Dose-related:
- Drowsy, confused
- Nystagmus (Eye), Ataxia (Muscle), Slurred speech
- Nausea, coma
- Unusual behavior and mental change

Non-dose related:
- Acne, hirsutism
- Gingival hyperplasia
- Folate deficiency
- Osteomalacia
- Hypersensitivity, SJS, TEN

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21
Q

MOA of Benzodiazepines

A

Enhance effects of inhibitory GABA neurotransmitters

Potentiate Chloride ion influx

Hyperpolarization and no firing

22
Q

Why are intermediate and long acting benzodiazepines used in epilepsy but not short acting ones?

A
  • Short-acting: Multiple dosing
  • Long-acting: Needed for chronic long term condition of epilepsy

Diazepam (Valium)

23
Q

Overdose and ADR effects of benzodiazepines

A

Overdose > Severe respiratory depression

ADR > Drowsy, confused, amnesia, impaired muscle coordination

24
Q

Withdrawal effects of benzodiazepines

A

Sleep disturbance, rebound anxiety, tremor, convulsions

25
Q

MOA and Drug class of Phenobarbital

A

Barbiturate - Potentiates GABA-A mediated chloride currents at distinct site from benzodiazepines

26
Q

Why are barbiturates replaced by benzodiazepines in sedation and hypnosis?

A

Due to barbiturates’ tendency to develop tolerance and dependency

27
Q

What is an antidote for benzodiazepine overdose but not barbiturate overdose?

A

Flumazenil

28
Q

In whom are phenobarbital used as AED?

A

Pediatrics or neonatal patients (IV LD and MD)

29
Q

What are the types of effect of barbiturates based on duration of action?

A

– Long acting (1-2 days) Anticonvulsant:
Eg, phenobarbital.

– Short (3-8hrs) Sedative & Hypnotic: Eg,
pentobarbital and amobarbital.

– Ultrashort (20 min) I.V induction of
anesthesia: Eg, Thiopental

30
Q

Clinical use of Levetiracetam

A

⚫ Adjunctive therapy for partial onset seizures, myoclonic and primary generalized tonic-clonic seizures

⚫ Monotherapy for partial onset seizures in newly diagnosed epilepsy

31
Q

PK Profile of Levetiracetam

A

Highly soluble and permeable.
Linear PK
Low intra- and inter-subject variability.
Route is oral of IV infusion

32
Q

Undesirable effects of Levetiracetam

A

⚫ Undesirable effects (common): Headache, vertigo, cough, depression, insomnia
⚫ Undesirable effects (rare): Agranulocytosis, suicide, delirium, dyskinesia

33
Q

Lamotrigine MOA

A

Block Na channels

Inhibit glutamate release

Impede sustained repetitive neuronal depolarization

34
Q

Lamotrigine clinical use

A

⚫ 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)

35
Q

PK Profile of Lamotrigine

A

Oral route (chewable).

Half-life is generally shorter in children.

Half-life is significantly reduced by co-administration with carbamazepine and phenytoin, increased by co-administration
with valproate

36
Q

Undesirable effects of Lamotrigine

A

⚫ Undesirable effects (common): Headache, irritability / aggression, tiredness
⚫ Undesirable effects (rare): Agranulocytosis, hallucination, movement disorders (worsens PD), SJS/TEN, hepatic failure

37
Q

Clinical use of Topiramate

A

⚫ Indicated for monotherapy of partial seizures and generalised seizures tonic-clonic seizures
⚫ Adjunctive therapy for Lennox-Gastaut syndrome (severe childhood epilepsy)
⚫ Prophylaxis of migraine headaches in adults (NOT intended for acute treatment

38
Q

PK Profile of Topiramate

A

Oral route.
Long plasma half-life.
Predominantly renal clearance
Not a potent inducer of drug-metabolizing enzymes

39
Q

Undesirable effects of Topiramate

A

⚫ Undesirable effects (common): Depression, somnolence, fatigue, nausea, weight change
⚫ Undesirable effects (rare): Neutropenia, mania, tremor, transient blindness, SJS/TEN, hepatic failure

40
Q

What is the pathophysiology of headache and migraines?

A
  1. Vasodilation of intracranial extracerebral blood vessels
  2. Activation of the perivascular trigeminal nerves
  3. Release of vasoactive neuropeptides to promote neurogenic inflammation
  4. Central pain transmission may activate other brainstem nuclei, resulting in associated symptoms (N/V, photophobia, phonophobia).
  5. Hyper-responsiveness of brain - An inherited abnormality in calcium & sodium channels and sodium/potassium pumps that regulate cortical excitability through the release of serotonin (5-hydroxytryptamine [5-HT]) and other neurotransmitters.
  6. Increased levels of excitatory amino acids such as glutamate and alterations in levels of extracellular potassium also can affect the migraine threshold
41
Q

Cafergot MOA and clinical use

A

⚫ MOA: 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)

⚫ For acute treatment of migraine (given at first symptom of attack)

42
Q

PK Profile of Cafergot

A

Oral (also rectal).
Rapidly absorbed (max plasma conc reached in 1.5-2 hr).
High plasma protein binding
Low absolute bioavailability (2-5%)

Inhibits liver CYP3A. Should not be used with other CYP3A inhibitors like macrolide antibiotics → elevated exposure to ergot toxicity (vasospasm and tissue ischaemia)

43
Q

Undesirable effects of Cafergot and DDI

A

Common: N/V
Rare: Hypersensitivity, MI, Ergotism (Vascular ischemia)
DDI: Vasoconstrictors (Ergot alkaloids, sumatriptan, 5HT1 agonists)

44
Q

MOA of Sumatriptan and Clinical use

A

⚫ MOA: Selective vascular serotonin (5-HT1d) receptor agonist.

Selectively constricts the carotid arterial circulation, but does not alter cerebral blood flow.

Inhibits trigeminal nerve activity

⚫ For acute treatment of migraine with or without aura

45
Q

PK Profile of Sumatriptan

A

Oral, nasal, IV.

Rapidly absorbed

Low plasma protein binding.

Eliminated primarily by oxidative metabolism mediated by monoamine oxidase A (MAO).

46
Q

Contraindications of Sumatriptan

A
  1. Hypersensitivity
  2. Concurrent MAO inhibitors
  3. MI
47
Q

Undesirable effects of Sumatriptan

A

Common: Dysgeusia (unpleasant taste), transient BP increase, flushing, sensation of cold, pressure, tightness

Rare: Minor disturbance in liver function test

48
Q

MOA of Erenumab

A

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

CGRP is a nociceptive neuropeptide at the trigeminal ganglion and a vasodilator

49
Q

Erenumab clinical indication

A

Prophylaxis of migraine in adults who have at least 4 migraine days per month

50
Q

PK Profile of Erenumab

A

SC injection (monthly), not given IV

Clinical benefit in 3 months

Linear kinetics

51
Q

Undesirable effects of Erenumab

A

Hypersensitivity, injection site reactions, constipation, pruritus

PR3153 Central Nervous System (2 decks)

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