IC4- Antiepileptic and Migraine medications Flashcards
With regards to the process of action potential, elaborate on the resting membrane potential
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
With regards to the process of action potential, elaborate on the depolarization stage
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
With regards to the process of action potential, elaborate on the repolarization stage
Inactivation of voltage-gated Na+ channel and opening of K+ channel causing K+ efflux (absolute refractory period), restoring back the RMP
Explain the regulation of the action potential via a feedback loop
When postsynaptic receptors are activated, presynaptic autoreceptors are also activated → inhibit further transmitter release via feedback inhibition + neurotransmitter degradation by catalytic enzymes
What are the 4 types of neurotransmitters?
- Glutamate
- GABA
- Acetylcholine
- Dopamine
What type of neurotransmitter is glutamate?
Where is it found? What brain processes is it involved in?
- Excitatory
- Found in pyramidal neurons in neocortex
- Learning and memory
What type of neurotransmitter is GABA?
What is the MOA?
- Inhibitory
- GABA binds to receptors → opening of Cl- channels and allow influx of Cl- → membrane potential kept negative → no depolarisation
Where does neurotransmitter acetylcholine arise from?
What brain processes is it involved in?
- From nucleus basalis of Meynert
- Learning, arousal and reward
Where does neurotransmitter dopamine arise from?
What brain processes is it involved in?
(it is a monoamine)
- From substantia nigra
- Motor system, reward
What are the 3 functions of the BBB?
- Modulation of entry of metabolic substrates
- Control of ion movements
- Prevent toxins and peripheral neurotransmitters escaping into bloodstream from autonomic nerve endings from entering CNS
What is the difference between glucose levels in brain ECF vs blood? Why?
Glucose is a fundamental source of energy for neurons → level in brain ECF more stable than that of blood
What are the characteristics of drugs that can undergo transmembrane diffusion past the BBB?
What are some other factors that may affect transmembrane diffusion?
- 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
How is rate uptake into BBB via transporter systems compared to that of transmembrane diffusion?
Is it also affected by efflux transporters?
- Rate of uptake > 10x transmembrane diffusion
- Uptake rate regulated by cerebral bloodflow, co-factors, hormones/ peptide modulators
Yes, also affected by efflux transporters
What are the general strategies for drug transport across BBB?
- Target transporters
- Analogues of transported ligands
- BBB itself as a therapeutic target
Describe the “Trojan horse strategy” as a strategy for drug transport across BBB
Coupling a substance that cannot cross BBB to one which does
In the strategies for drug transport across BBB, what is the advantage and disadvantage of the “Trojan horse strategy”?
- Advantage: improved peripheral PK
- Disadvantage: hybrid molecule may still not be recognised by original transporter → goes into lysosome
Describe the method of using analogues of transported ligands as a strategy for drug transport across BBB
Design analogues which retain affinity of both BBB transporter and CNS target receptor while improving peripheral PK
Describe the method of using the BBB itself as a therapeutic target as a strategy
- 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)
Antiepileptics work based on 2 rationales. What are they?
- ↓ membrane excitability by altering Na+ and Ca2+ conductance during action potentials
OR - Enhance effects of inhibitory GABA neurotransmitters
What are the general dose-related SEs of antiepileptics? (9)
- Drowsiness
- Confusion
- Nystagmus
- Ataxia
- Slurred speech
- Nausea
- Unusual behaviour
- Mental changes
- Coma
What are the general non-dose related SEs of antiepileptics? (6)
- Hirsutism
- Acne
- Gingival hyperplasia
- Folate deficiency
- Osteomalacia (soft bones)
- Hypersensitivity (SJS)
Name the antiepileptic drugs (4)
- Phenytoin
- Carbamazepine
- Sodium Valproate
- Benzodiazepines
Phenytoin MOA?
Blockade of voltage-dependent Na+ channels
Indication of phenytoin?
Focal and GTC seizures, may worsen myoclonic seizures.
NOT for absence seizures!
Why does phenytoin need TDM?
What is the therapeutic range?
- Relatively narrow therapeutic range (plasma conc 40-100µm)
- Saturation kinetics
- Non-linear relationship between dose and plasma conc (explained more in IC7)
Carbamazepine MOA?
Blockade of voltage-dependent Na+ channels
Indication of carbamazepine?
Focal (first line) and GTC seizures, may worsen myoclonic seizures.
NOT for absence seizures!
DDIs of carbamazepine?
What is special about CBZ and its metabolism?
- CYP450 (CYP3A4) inducer, t1/2 shortens with repeated doses (“autoinduction”)
- Accelerates elimination of other drugs
ADEs of carbamazepine?
Hence what must we do?
- 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
Sodium valproate MOA? (2)
- Blockade of voltage-dependent Na+ and Ca2+ channels
- Also inhibits GABA transaminase → ↑ GABA
Indication of sodium valproate?
Focal, GTC, *absence and myoclonic seizures
What is something we need to take note regarding DDIs of sodium valproate?
Strongly bound to plasma proteins, displaces other antiepileptics
Benzodiazepines MOA?
What is required for it to work?
- 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!
What are the different duration of actions of benzodiazepines? (3)
- Short-acting: duration of action ~3-8h
- Intermediate-acting: duration of action ~10-20h
- Long-acting: duration of action ~1-3d
ADEs of benzodiazepines?
- Drowsiness
- Confusion
- Amnesia (memory loss)
- Impaired muscle coordination (DO NOT operate heavy machinery)
What happens when there is acute toxicity/ overdose of benzodiazepines?
What is the Tx for this toxicity/ overdose?
- Severe respiratory depression (esp if used concurrently with alcohol) →
Tx: Flumazenil (benzodiazepine antagonist)
What are the withdrawal effects of benzodiazepines?
Hence what must we do?
- Withdrawal effects of dependence developed: disturbed sleep, rebound anxiety, tremor and convulsions → must withdraw gradually
What are the different duration of actions of benzodiazepines and what are their uses?
- 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
What is the MOA of phenobarbital?
(how does it compare to BZDs)?
Potentiate GABA mediated Cl- currents, but at a site distinct from benzodiazepines
If there is a barbiturate (phenobarbital) overdose, will flumazenil work?
No, it only blocks BZDs, it cannot block phenobarbital as it acts on a site on GABA that is distinct from BZDs
How would you compare barbiturates’ ability to depress the CNS as compared to BZDs?
Hence are they still used often in clinical settings?
Barbiturates have even greater ability to depress the CNS than BZDs → dangerous
Hence slowly replaced by BZDs
Indication of Levetiracetam?
- Primarily used as: adjunctive Tx for partial onset seizures, myoclonic and primary GTC seizures
- MonoTx for partial onset seizures in newly diagnosed epilepsy
Describe PK of Levetiracetam?
- Highly soluble, permeable
- Linear PK profile with low intra- and inter-subject variability
Which antiepileptic has abuse potential?
Benzodiazepines
Should we use monotherapy of antiepileptic drugs? Or do we use a combination?
What if Tx is unsuccessful?
Try for monoTx
If unsuccessful/ pt develops ADEs, try another drug for monoTx
Is monitoring of antiepileptics routinely needed?
No
Function of routine monitoring of antiepileptic drug levels? (3)
- Assess of compliance if pt has refractory epilepsy
- Assess of SSx due to possible antiepileptic drug toxicity
- Titrate phenytoin dose
Pathophysiology of headache/ migraine?
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)
How does serotonin counter migraines? (MOA)?
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
What are the types of migraine medications? (mentioned in this IC)
- Cafergot
- Sumatriptan
When do we use these migraine specific medications?
For moderate-severe migraines where NSAIDS/ paracetamol are ineffective
What ingredients does Cafergot contain?
Contains caffeine & ergotamine
Indications for cafergot?
When is it given?
Acute Tx of migraine (given at FIRST ssx of attack)
MOA of cafergot?
- 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)
DDIs of cafergot?
Hence what should we NOT combine them with? What will happen if we do?
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)
ADEs of cafergot? (4)
Common:
- N/v
Rare:
- Hypersensitivity
- MI
- Ergotism (vascular ischaemia)
Absorption, distribution and bioavailability of cafergot?
A: rapid absorption (max plasma conc reached in 1.5-2h)
D: High plasma protein binding
F ~2-5%
Sumatriptan MOA? (4)
- 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
Absorption and elimination of Sumatriptan?
- A: rapidly absorbed, low plasma protein binding
- E: eliminated primarily via oxidative metabolism mediated by monoamine oxidase A (MAO)
C/I of sumatriptan? (3)
- Hypersensitivity to triptans
- Concurrent administration with MAOi
- MI
ADEs of sumatriptan? (7)
Common:
- Dysgeusia (unpleasant taste)
- Transient BP ↑
- Flushing
- Sensation of cold
- Pressure
- Tightness
Rare:
- Minor disturbances in LFTs
Which 1st generation ASMs are indicated for focal and GTC seizures, and may worsen myoclonic seizures? (2)
Phenytoin, Carbamazepine
Which 2nd generation ASMs are indicated for focal and GTC seizures, and may worsen myoclonic seizures? (2)
Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine
Indications of Topiramate?
Focal and GTC seizures
