Epilepsy- focal

Question 1

Carbamazepine

Answer 1

• Epilepsy- first-line choice for those with focal seizures with and without secondary generalisation and for primary generalised seizures
• Trigeminal neuralgia- first choice treatment to control pain and reduce frequency and severity of attacks
• Bipolar disorder- as an option for prophylaxis in patients resistant or intolerant of other medications

Question 2

Carbamazepine

MOA

Answer 2

• The mechanism of action is not completely understood
• It appears to inhibit neuronal sodium channels, stabilising them and so resisting membrane potentials and reducing neuronal excitability
• This may inhibit 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 3

Carbamazepine

Adverse effects

Answer 3

• The most common dose-related effect is GI upset- N&V
• Neurological effects- dizziness and ataxia
• Hypersensitivity affects around 10% of people is usually a mild skin rash
• Antiepileptic hypersensitivity syndrome- usually people taking carbamazepine or phenytoin
  
  • Severe skin reactions, fever, lymphadenopathy with systemic (e.g. renal, hepatic, haematological) involvement 10% mortality
• Oedema and hyponatraemia are common

Question 4

Carbamazepine

Warnings

Answer 4

• Carbamazepine exposure in utero is associated with neural tube effect, cardiac and urinary tract abnormalities and cleft palate
  
  • Women planning pregnancy should discuss treatment with a specialist and start taking high dose folic acid supplements
• Prior Antiepileptic hypersensitivity syndrome is a contraindication to both carbamazepine and phenytoin, due to cross-sensitivity
• Carbamazepine should be prescribed with caution in patients with hepatic, renal and cardiac disease due to increased risk of toxicity

Question 5

Carbamazepine

Interactions

Answer 5

• Carbamazepine induces CYP P450 enzymes, reducing plasma concentration and efficacy of drugs that are metabolised by P450 enzymes (Warfarin, oestrogens).
• CBZ is its metabolised by these enzymes so concentration and adverse effects are increased by Inhibitors
• Complex interactions can occur with other antiepileptic drugs as most alter drug metabolism
• Drugs which alter seizure threshold- SSRI, TCA, Anti-psychotics and tramadol

Question 6

Carbamazepine

Administration and communication

Answer 6

• Switching between formulation should be avoided due to differences in bioavailability between the preparations
• Explain that treatment aims to reduce seizure frequency not cure disease
• Look for hypersensitivity reactions: rash, bruising, bleeding, high temperature or mouth ulcers (blood toxicity),
• If these occur seek medical, advise
• Advise pregnant women or those who are trying to conceive seek doctor advise

Question 7

Carbamazepine

Monitoring

Answer 7

• Treatment efficacy is monitored by comparing seizure frequency before and after starting a treatment or dose adjustment
• The most useful way to monitor safety is by asking the patient to report any unusual symptoms
• Routine FBC and LFT is unlikely to coincide with unpredictable hypersensitivity reactions
• Plasma CBZ Concentrations are not routinely measured
• Blood should be taken immediately before the next dose when CBZ concentration should be 4-12 mg/L
• Time to steady state is around 2-4 weeks after starting dose

Question 8

2nd line

Answer 8

• Lamotrigine
• Levetericetam
• Oxcarbazepine

Question 9

Give Gabapentin for refractory focal seziures

Gabapentin and pregabalin

Common indications

Answer 9

• Both drugs are used in focal epilepsies (with or without secondary generalisation), usually as an add-on treatment when other antiepileptic drugs provide inadequate control
• Both drugs are used for neuropathic pain
• Gabapentin is used for migraine prophylaxis
• Pregabalin is used in generalised anxiety disorder

Question 10

Gabapentin and pregabalin

MOA

Answer 10

• Gabapentin us closely related to GABA, the major inhibitory neurotrasmitter in the brain
• MOA although not completely understood, appears largely unrelated to GABA
• It binds with voltage-sensitive Ca²⁺ channels, where it presumably prevents inflow of Ca and in so doing, inhibits neurotransmitter release
• This interferes with synaptic transmission and reduces neuronal excitability
• Pregabalin is a structural analogue of gabapentin that has a similar MOA

Question 11

Gabapentin and pregabalin

adverse effect

Answer 11

• Gabapentin and pregabalin are generally better tolerate than other antiepileptic drugs. Their main side effects are drowsiness, dizziness and ataxia which usually improve in the following weeks

Question 12

Gabapentin and pregabalin

Warnings

Answer 12

• Both drugs depend on the kidneys for their elimination, so their doses should be reduced in renal impairement

Question 13

Gabapentin and pregabalin

Interactions

Answer 13

• The sedative effects of gabapentin and pregabalin may be enhanced when in combination with other sedative drugs (BZ)
• Other than this no other interactions

Question 14

Levetiracetam

Indications

Answer 14

• Monotherapy of focal seizures with or without secondary generalisation
• Ajunctive therapy of myoclonic seizures and tonic-clonic seizures

Question 15

• Levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores
• In addition it partially reverses the reductions in GABA and glycine-gated currents induced by zinc
• Levetiracetam binds to synaptic vesicles involved in vesicle fusion and neurotransmitter exocytosis

Question 16

Levetiracetam

Warnings

Answer 16

• Renal impairement- may need dose adjustment
• Blood cell counts- Neutropenia, agranulocytosis, leucopenia, thrombocytopenia, pancytopenia)
• Suicide
• Abnormal/aggressive behaviour

Question 17

Levetiracetam

Adverse effects

Answer 17

• Most reported- Nasopharyngitis, somnolence, headache, fatigue and dizziness
  *

Question 18

Levetiracetam

Interactions

Answer 18

• MTX- levetiracetam and MTX has been reported to decrease MTX clearance which can push to potentially toxic levels

Question 19

Topiramate

Indications

Answer 19

• Monotherapy of generalised tonic-clonic seizures or focal seziures with or without secondary generalisation
• Adjunt to tonic-clonic, focal and lennox-gastaut syndrome
• Migraine prophylaxis

Question 20

Topiramate

MOA

Answer 20

• Sodium channel blocking action
• Topiramte increased the frequency at which GABA activated GABAa receptors enhancing Cl- influx into neurones
• Topiramate antagnoised the ability of kainate to activate AMPA excitatory amino acid receptors (NB- no effect on NMDA)
• Topiramate inhibits carbonic anhydrase, this is much weaker than acetazolamide and not thought to contribute to antiepileptic effect

Question 21

Topiramate

Warnings

Answer 21

• Cautioned in
  
  • Avoid in acute porphyrias- hereditary condition with insufficent haem production.
  • Risk of metabolic acidosis
  • Risk of nephrolithiasis (kidney stones)- ensure adequate hydration

Question 22

Topiramate

Adverse effects

Answer 22

• Infection- Nasopharyngitis
• Psychiatric disorders- depression, insomnia, confusion
• CNS- paraesthesia, somnolence, dizziness
• Generic GI issues
• Skin- Alopecia, rash, pruritus
• Weight increase or decrease + fatigue
• NB- Associated with acute myopia with 2’ angle-closure glaucoma, occuring within 1 month of treatment. If intra-occular pressure increases seek specalist advice

Question 23

Topiramate

Answer 23

• Phenytoin, CBZ- CYP inducer
• COC- Topiramate can decrease efficacy of COC

Question 24

Topiramate

Monitoring

Answer 24

• Pregnancy