Lecture 33: clinical pharmacist epilepsy freya

Front: (Card 1) What is the clinical definition of epilepsy?

A diagnosis of epilepsy requires:

• At least two unprovoked seizures occurring more than 24 hours apart.

• 1st Class Note (from transcript): The 24-hour rule is key. Having multiple seizures within 24 hours does not typically increase the risk of future seizures and may be considered a single event. Presenting in status epilepticus also does not automatically lead to an epilepsy diagnosis.

Front: (Card 2) Which age groups are most likely to be diagnosed with epilepsy?

Back: There are two main peaks for diagnosis:

1. Childhood (0-10 years): Often due to congenital malformations or metabolic problems.

2. Older Adults (Over 70-71 years): This is a rapidly increasing population. Seizures are often "secondary" to other events like strokes, falls (leading to head injuries), or brain tumours.

Front: (Card 3) What is the difference between a provoked, acute symptomatic, and remote symptomatic seizure?

Back:

• Provoked: Caused by a clear, transient factor (e.g., toxins, alcohol/drugs, certain medications, or metabolic issues like low sodium).

• Acute Symptomatic: A seizure occurring within 7 days of an acute brain insult (e.g., TBI, stroke, CNS infection). Recurrence risk is low (e.g., 33% after stroke).

  • Remote Symptomatic: A seizure occurring more than 7 days after the insult. Recurrence risk is high (e.g., 71.5% after stroke).

Clinical Importance: This distinction dictates treatment. We often do not treat an acute symptomatic seizure with long-term AEDs, as the risk of recurrence is low. A remote symptomatic seizure has a high risk of recurrence and is much more likely to be treated.

Front: (Card 4) Why is the distinction between acute vs. remote symptomatic seizures critical for treatment decisions?

Back: The risk of recurrence is vastly different.

• Acute: Has a much lower risk of a second unprovoked seizure (e.g., 33% after stroke). We often do not treat with long-term AEDs, as it's seen as a one-off event.

• Remote: Has a very high risk of recurrence (e.g., 71.5% after stroke). This is much more likely to be treated as epilepsy.

Front: (Card 4) What is SUDEP, and what are the biggest risk factors?

Back:

SUDEP (Sudden Unexpected Death in Epilepsy) is a significant cause of early death, usually following a convulsive seizure.

• Mechanism: Believed to be post-seizure respiratory arrest. Studies show that stimulation or arousal (like touching the face) can restart breathing.

• Key Risk Factors:

  • Generalized Tonic-Clonic Seizures (GTCS), especially if frequent.

  • Nocturnal (night-time) GTCS.

  • Unwitnessed seizures (e.g., living alone or sleeping alone).

Front: (Card 5) When should pharmacological therapy (AEDs) be initiated?

Back:

The decision is highly individualised and made with a specialist. It's a discussion of risks vs. benefits, based on:

• Risk of Recurrence:

  • After 1st unprovoked seizure: ~33%

  • After 2nd unprovoked seizure (within 1 year): ~76%

• Clinical Factors:

  • High risk if EEG shows discharges or MRI shows structural lesions (>90% risk)¹⁵.

  • Patient lifestyle (e.g., driving, university, job).

Example: A patient with 2 seizures 3 years apart might decline treatment, while a patient with 2 seizures 10 months apart is very likely to accept.

Front: (Card 6) What are the fundamental principles of AED therapy, and why is the first choice so critical?

Principles:

Monotherapy: Use one drug where possible.

Titrate Slowly: Start low and go slow to minimise side effects.

Lowest Effective Dose: Use the minimum dose that controls seizures.

Why 1st Choice is Critical: The chance of achieving seizure freedom drops dramatically with each new drug tried.

• 1st ASM: 50.5% become seizure-free.

• 2nd ASM: Only 11.6% become seizure-free

  3rd ASM: Only 4.4% become seizure-free.

Front: (Card 7) What are the NICE first-line monotherapy options for newly diagnosed GTCs?

• Sodium Valproate

• Lamotrigine

• Levetiracetam

*1st Class Note: Valproate is the most effective drug for Genetic Generalised Epilepsy (GGE), but it is "falling out of favour" as a first-line choice, especially in women, due to its high teratogenicity risk

What is the mechanism, and what are the key PK interactions for Lamotrigine (LTG)?

• Mechanism: Blocks voltage-gated sodium channels, preventing the release of excitatory neurotransmitters (glutamate).

• Pharmacokinetics (PK):

  • Hepatic metabolism (glucuronidation).

  • Long half-life (~24h).

• Key Interactions:

  • Valproate (Inhibitor): Doubles LTG half-life (increases levels).

  • Inducers (Carbamazepine, Phenytoin): Halve LTG half-life (decrease levels).

  • Oestrogen (e.g., COCP) / Pregnancy: Increase LTG clearance (decrease levels)

Front: (Card 9) What is the single most important side effect of Lamotrigine, and how is it managed?

The RASH.

• What: A maculopapular rash, typically in the first 8 weeks. Carries a rare (0.3%) but life-threatening risk of Stevens-Johnson Syndrome (SJS).

• Risk Factors:

  1. Fast titration.

  2. Starting while on Valproate (which doubles LTG levels).

• Management:

  • Action: Withdraw the drug immediately.

  • Prevention: Requires a very slow titration (e.g., 25mg ONCE daily for 2 weeks). The titration must be even slower if the patient is also taking valproate. Must re-titrate if stopped for >5 days.

Front: (Card 10) Is routine Therapeutic Drug Monitoring (TDM) useful for AEDs? When is it helpful?

No, it is not usually useful routinely. The transcript notes that concentration doesn't always correlate well with seizure control. It is helpful in specific situations:

• To check compliance.

• To confirm suspected toxicity.

• In cases of unexplained loss of seizure control.

• To manage high doses or known drug interactions.

• During pregnancy (especially for Lamotrigine)

Front: (Card 10) What is the mechanism, place in therapy, and key risk profile for Sodium Valproate (VPA)?

• Mechanism: Broad spectrum via multiple mechanisms:

  1. Blocks Na+ channels.

  2. Inhibits GABA transaminase (increases inhibitory GABA).

  3. Modifies T-type Ca2+ channels (making it effective for absence seizures).

• Place in Therapy: The most effective drug for Genetic Generalised Epilepsy (GGE).

• Key Risks:

  • Teratogenicity: Highest risk of all AEDs (see special populations).

  • Side Effects: Weight gain, hair loss (usually temporary), dose-related tremor.

  • Interactions: It is a potent enzyme inhibitor (e.g., doubles lamotrigine levels).

Front: (Card 11) What is the mechanism, PK profile, and key side effect of Levetiracetam (LEV)?

• Mechanism: Binds to synaptic vesicle protein SV2A, reducing neurotransmitter release in a state of hyperactivation.

• Pharmacokinetics (PK):

  • Renally cleared (requires dose reduction in renal impairment).

  • NO hepatic metabolism and few significant drug interactions. This is its main advantage.

• Key Side Effect:

  • Psychiatric/Behavioural: Tiredness, anxiety, agitation, depression, emotional lability, and psychosis. This is the "main sort of limiting side effect".

• Clinical Pearl: A major benefit over lamotrigine is its fast titration (can increase every 5-7 days). It's also the 1st choice drug in Status Epilepticus (after benzodiazepines).

Front: (Card 12) What are the NICE first-line monotherapy options for newly diagnosed focal seizures?

Back:

• Lamotrigine

• Levetiracetam

Second-line monotherapy includes Carbamazepine, Oxcarbazepine, and Zonisamide

Front: (Card 13) What is the PK profile and what are the 3 key "must-know" side effects for Carbamazepine (CBZ)?

• Mechanism: Binds to Na+ channels, preventing high-frequency firing.

• PK Profile: Its use is "really limited" by its interactions.

  1. Auto-induction: Induces its own metabolism in the first 3-5 weeks, causing levels to drop.

  2. Potent CYP3A4 Inducer: Reduces levels of many drugs (e.g., DOACs, COCP).

• Key Side Effects:

  1. Hyponatremia: Very common (~20%) due to an antidiuretic effect.

  2. Rash (SJS): High risk in patients with the HLA-B*1502 allele (requires genetic screening for patients of Han Chinese or Thai origin).

  3. Blood Dyscrasias: Rare risk of agranulocytosis and aplastic anaemia. Patients must report fever, sore throat, or bruising.

Why is Phenytoin (PHT) use limited, and what are its key side effects (long-term vs. toxicity)?

• Why Limited: It has "tricky pharmacokinetics". It follows saturable (zero-order) kinetics, meaning metabolism gets "saturated". Small dose increases can lead to large, toxic jumps in serum levels. It is also a potent enzyme inducer.

• Side Effects:

  • Long-Term Use: Gingival hyperplasia (gum overgrowth), hirsutism (hair growth), Vitamin D deficiency (osteoporosis), anaemia.

  • Toxicity Signs: Nystagmus (eye movement), diplopia (double vision), slurred speech, ataxia (poor coordination)

Front: (Card 15) What is the key clinical limitation of Topiramate?

• Mechanism: Broad spectrum, multiple mechanisms (Na+ block, GABA augmentation, AMPA antagonism).

• Use: Broad spectrum AED, but not usually first-line due to poor tolerability.

• Key Side Effects:

  1. Cognitive ("Dope-a-max"): "Cognitive slowing," decreased attention, memory impairment, and significant "word-finding difficulties".

  2. Weight loss & reduced appetite.

  3. Kidney stones (1 in 10 men).

  4. Teratogenic (now requires a PPP) .

Front: (Card 16) What is the interaction between Enzyme-Inducing AEDs (EIAEDs) and the Combined Oral Contraceptive (COCP)?

Back:

• EIAEDs: Carbamazepine, Phenytoin, Phenobarbital, Primidone, and Topiramate (>200mg/day) ⁷⁶.

• Interaction: EIAEDs are CYP450 inducers. They increase the metabolism of the oestrogen and progesterone in the COCP⁷⁷.

• Result: This leads to contraceptive failure (risk of pregnancy).

• Management: COCP is not recommended⁷⁸. The most reliable and unaffected methods are IUDs (intrauterine devices) or the depot injection^79797979

Front: (Card 17) What is the reverse interaction between Lamotrigine (LTG) and the COCP?

This is a "reverse" interaction:

• The oestrogen in the COCP induces the clearance (metabolism) of lamotrigine.

• Result: This lowers the patient's lamotrigine levels, leading to a potential loss of seizure control (breakthrough seizures).

• Clinical Note: This is also why lamotrigine levels typically fall during pregnancy, often requiring a dose increase.

Front: (Card 18) What are the teratogenic risks of Sodium Valproate (VPA) that require a Pregnancy Prevention Programme (PPP)?

Valproate is the most teratogenic AED. It carries two distinct, high-incidence risks:

1. Major Congenital Malformations: 1 in 9 babies (11%) will have a birth defect (e.g., spina bifida, heart defects, cleft palate) .

2. Neurodevelopmental Disorders: 3-4 in 10 children (30-40%) may have problems with development (e.g., low IQ, delayed walking/talking, autism).

• PPP: Because of this, it must not be used in women of child-bearing potential unless the conditions of the Pregnancy Prevention Programme (PPP) are met (e.g., no other effective treatment, specialist approval, highly effective contraception)

Front: (Card 19) What are the "safest" and "riskiest" AEDs to use during pregnancy?

• Riskiest (Avoid):

  1. Sodium Valproate: Highest risk (11% malformations, 30-40% neurodevelopmental).

  2. Topiramate: High risk (4-9% malformations); also now requires a PPP.

  • (Also Phenytoin, Carbamazepine).

• Safest (Preferred):

  • Lamotrigine (has the lowest known teratogenicity).

  • Levetiracetam.

• Management: ALL women on AEDs planning pregnancy should take high-dose folic acid (5mg) daily.

Front: (Card 20) What are the key pharmacological considerations for treating epilepsy in the elderly?

• Cause: Seizures are typically secondary to stroke, falls, or neurodegenerative disorders.

• Diagnosis: Can be "tricky" as the presentation is often subtle (e.g., confusion, blank spells) rather than convulsive.

• PK: Altered pharmacokinetics, including reduced protein binding (which increases free levels of highly-bound drugs like Phenytoin).

• Management:

  • Require lower doses and slower titrations.

  • High risk of interactions (polypharmacy) and cognitive side effects.

  • Preferred AEDs: Lamotrigine and Levetiracetam (better tolerated).

Front: (Card 21) What are the MHRA categories for brand prescribing, and what is the "real-world" clinical practice?

Back:

• Category 1: Patient must be maintained on a specific brand (e.g., Carbamazepine, Phenytoin, Phenobarbital).

• Category 2: Need for brand continuity is based on clinical judgement and patient factors (e.g., Lamotrigine, Valproate, Topiramate).

• Category 3: Clinically relevant differences are considered very low (e.g., Levetiracetam, Lacosamide, Gabapentin).

• 1st Class Note (from transcript): In reality, "we don't really stick to this very well". It is very difficult for pharmacies to source specific brands. The "general consensus" is that it is better for the patient to take any brand of their AED than to miss doses because their specific brand is unavailable.

Brivaracetam (BRV): How is it related to Levetiracetam, and when is it used?

• Relation: Structurally similar to LEV with the same SV2A mechanism , but with 20x higher affinity and better brain permeability.

• Use: As an adjunctive therapy for focal seizures.

• Clinical Pearl: Often used when Levetiracetam is effective for seizures but poorly tolerated (i.e., due to its psychiatric side effects). A "straight switch" is possible. It has fewer psychiatric side effects than LEV.

Front: (Card 17) What are the NICE first- and second-line monotherapy options for newly diagnosed focal seizures?

• First-line: Lamotrigine or Levetiracetam.

• Second-line: If first-line is unsuccessful, try monotherapy with:

  • Carbamazepine

  • Oxcarbazepine

  • Zonisamide

Lacosamide (LCM): Mechanism, key monitoring requirement, and side effects.

• Mechanism: Narrow spectrum. Blocks Na+ channels by enhancing slow channel activation (different from CBZ/PHT).

• Use: For focal seizures (monotherapy or adjunct). Its use is "increasing considerably".

• Monitoring: ECG prior to treatment. It can prolong the PR interval and is contraindicated in 2nd/3rd degree AV block.

• Side Effects: Dizziness, headache, diplopia, N+V. Generally well-tolerated, but side effects are worse when combined with other Na+ channel blockers

Perampanel: Mechanism and key psychiatric side effects.

• Mechanism: Selective noncompetitive AMPA glutamate receptor antagonist.

• Use: Adjunctive for focal seizures. A 3rd/4th line drug you "won't see very many patients on".

• Side Effects: The "main one" to worry about is psychiatric disorders. Aggression, anger, anxiety, and confusion are "not uncommon" (~20% at high doses).

Zonisamide: Key structural feature, mechanisms, and PK.

• Structure: Sulphonamide derivative (so caution in sulfa allergy).

• Mechanism: Broad spectrum. Multiple mechanisms (Na+ block, T-type Ca2+ channel block, weak carbonic anhydrase inhibitor).

• PK: Very long half-life (~60 hours)

Front: (Card 24) When are benzodiazepines (Clobazam, Clonazepam) used in chronic epilepsy management?

• As adjuvant therapy only, not monotherapy.

• 1st Class Note (Transcript): They are often used short-term (e.g., a 3-day course of Clobazam) for "clusters" of focal seizures to prevent them from progressing to a secondary generalisation.