epilepsy, Gabapentinoids, phenytoin

Epilepsy definition

Neurological brain disorder

Enduring predisposition to generate epileptic seizures

• Enhanced electrical activity of neurons -> seizures

• Diagnosis usually after 2 seizures

Seizure

Brief, temporary disturbance in brain electrical activity

Caused by several neurons discharging abnormally

- Seizure does not mean pt has epilepsy

Epilepsy

Disorder characterised by recurrent seizures (>2 seizures, >24h apart)

- Isolated seizure/s or seizures relating to a 2° reversible cause e.g. alcohol withdrawal, hypoglycaemia is not epilepsy

Epidemiology of Epilepsy

5% will have a seizure (1/3rd epilepsy)

Highest incidence in neonates (congenital malformations) and elderly (2° cause)

- Neonates: genetic conditions, born with mutation that predispose them to epilepsy -> shorter life span

- Elderly: post drug epilepsy, bleed, clot, stroke, hypoxia, apoptosis

2-3x standardised mortality rate

Cause of epilepsy (aetiology)

Only 30% with defined cause

Infancy/Childhood: birth injury, metabolic error, congenital malformation

Childhood/Adolescence: Genetic syndrome, CNS infection

Young Adult: Head trauma

Older Adult: Stroke, brain tumour

prognosis of epilepsy

60% achieve seizure control with monotherapy

Some remain seizure-free post drug withdrawal

• Up to 60% in ideal candidates (several years of perfect control on monotherapy)

• After 2 years seizure free: Titrate downwards over several months (cannot drive until three months drug-free)

Seizure types, symptoms

1) Focal/Partial: seizures begin in one area of the brain.

- No definite symptoms

- Can affect autonomic function, sensory perception, motor function, behaviour

- Aware (simple), Impaired Awareness (complex)

2) Generalized: seizure occurs with all areas of the brain being hyperexcitable

- LOC + bilateral motor sx: absence (vacant stare), tonic (muscle rigidity), clonic (rhythmic movements), myoclonic (jerk), tonic-clonic, atonic (muscle flaccidity)

a) Idiopathic:

Childhood/Juvenile absence epilepsy

Juvenile myoclonic epilepsy (common epilepsy in adults, less likely to withdraw treatment)

Epilepsy with tonic-clonic seizures on awakening

b) Symptomatic: secondary

Lennox-Gastaut syndrome

3) Unknown

*Definitions:

- Tonic-clonic seizure: tonic = stiffening, comes first, then clonus = rhythmic jerking

- Absence seizures: blanking out

- Myoclonic seizures: jerking/twitching of muscles

- Infantile spasms: stiffening and movement of head and limbs back and for

Epilepsy first aid and lifestyle mod

Remove hard objects (protect from injury)

Reassure patient

Recovery position & Cover

Time seizure

Do NOT restrain or put anything in mouth

Avoid situations where a seizure may be dangerous:

• Swimming alone

• Climbing (other sports OK)

• Operating machinery

Driving a significant issue - needs discussion with the doctor

Epilepsy triggers and avoidance

Common:

- AED non-adherence

- Sleep deprivation

- Alcohol withdrawal

- TV/monitor flicker

- Systemic infection

- Head trauma

- Recreational drugs

- Menstruation

- Epileptogenic drugs (TCA's,

phenothiazines - neuroleptics, antihistamines)

Occasional:

- Dehydration

- Hyperventilation

- Flashing lights

- Diet and missed meals

- Stress

- Intense exercise

- Specific 'reflex' triggers

- BDZ/barbiturate withdrawal

pharmacist role in epilepsy

Understand treatment choice

Awareness of treatment duration

Counsel on:

- Dose: Initiation (can be complex; upwards titration)

- Common and important ADR's

- Monitoring: TDM (phenytoin), EEG, seizure diary

Lifestyle: trigger avoidance, identi-bracelet

Epilepsy treatment (partial)

1st choice: Carbamazepine

MOA: Modulates voltage gated Na+ channels

Dose:

- 100 mg CR n, increase by 100-200 mg every week to 200mg-600 mg bd

- Child: 2.5 mg/kg bd, increasing to 5-10 mg/kg bd

Increase slowly to allow for enzyme induction at start of treatment; steady-state plasma conc may not be achieved for 2-4 weeks because of autoinduction of metabolism

AE:

- Diplopia (double vision) earliest sign of toxicity

- 10% morbilliform rash (looks like measles); ↑ Asian: HLA-B*1502 allele testing (SJS and TEN risk)

- Long term: increased bone turn over, consider Ca and vit D supp, BMD, FBC monitoring for bone marrow depression

Women:

- Ensure effective contraception (eg an IUD) during tx and for 1 month afterwards (see Contraception in Epilepsy).

Pregnancy:

- Better than valproate

Epilepsy treatment (generalised)

1st choice: sodium valproate

MOA: inhibits GABA metabolism

Multiple --> block Na+ channels, enhance GABA, inhibit glutamate, block of T-type Ca2+ channels.

Dose:

- Female (child-bearing potential): 400 mg d for 1 week then 200 mg m + 400mg n (max 600 mg d)

- Male: 500 mg d for 1 week then 500 mg bd (max 1500 mg bd)

- Child: 5mg/kg bd increasing to 10mg-20mg/kg bd

AE: Sedation, hair loss, weight gain

Unpredictable DDI

Teratogenicity worse than other AED (dose-related) -> female ceiling dose

The risk of valproate-induced hepatic failure is increased in patients:

- who are children, especially if <3 years

- with congenital metabolic or degenerative disorders

- with severe seizure disorders and mental retardation

- with organic brain disease

- multiple AEDs

Epilepsy treatment (2nd, 3rd line)

Lamotrigine:

- Both focal and generalised seizures

- Mono and duo therapy

- Non- inferior to carbamazepine, suspect will become 1st line

- AE: Significant skin reactions: rash, Steven-Johnson. Tell pt to STOP then call dr. SERIOUS

Oxcarbazepine:

- fewer interactions compared with carbamazepine

- does not autoinduce metabolism

3rd line:

Topiramate: used as adjunct for both seizures

Epilepsy prophylaxis for absence seizure

1st choice: Ethosuxamide

- equal efficacy + better tolerance than valproate

- Does not prevent tonic-clonic activity (DO NOT use in mixed seizures)

Teratogenicity in epileptic drugs (High-Low)

High (significant): Valproate

High-Med (dose-related): carbamazepine, topiramate

Med (suspect): phenytoin, phenobarbitone

Low (safe): gabapentin, levetiracetam, clonazepam, lamotrigine

Dravet syndrome (DS)(epilepsy)

Onset: Febrile seizures progress to severe spontaneous generalised tonic-clonic seizures (unpredictability)

Developmental delays: delayed motor + cognitive milestones. Can occur at 1st year of life

Presentation: 5-10 minutes, Status Epilepticus (don't stop or occur in close succession)

SUDEP: 15-20%

Cause: 80% due to LOF de novo mutation in SCN1A gene, not genetic

Very rare (1/20-40k)

Lamotrigine, phenytoin and carbamazepine are contraindicated in treatment as blockage of voltage gated ion channel -> may block channel that has lost function and worsen seizures

Phenytoin MOA and when to TDM

Anticonvulsant

MOA:

Modulator of ion gated voltage channels: Na+ channel

When to monitor for drug conc:

- to confirm toxicity

- to assess compliance and therapeutic failure

- to confirm appropriate dose adjustment

- to confirm effects of drug interactions

Phenytoin AE

AE:

IV related: purple glove syndrome

Non dose related:

- Gingival hyperplasia (enlargement of gum)

- Hirsutism (hair growth in non-normal areas)

- Thickening of facial features

- Vitamin D deficiency

- Folic acid deficiency

- Osteomalacia

- Peripheral neuropathy

Dose related:

- CNS depression: agitation; sedation, confusion, ataxia, nystagmus

Asian: HLA-B*1502 allele

Phenytoin PK + PD, therapeutic range

90% of phenytoin is bound to serum albumin. The unbound fraction is responsible for drug action and is directly available to the liver for metabolism.

- Even if protein binding is reduced, free phenytoin conc will NOT increase due to metabolism by liver.

- Net effect is reduction of total phenytoin conc (bound + free). But free phenytoin conc would still be in therapeutic range

PK:

Bioavaiability: completely absorbed after oral administration (slowly)

Vd: very small distribution due to extensive protein binding (0.65 L/kg)

Capacity limited metabolism:

CL decreases with increasing plasma conc

- Vm = max metabolic rate = 7 mg/kg/day (5-15 mg/kg/day)

- Km = drug conc at half Vm = 4mg/L (range of 1-20 mg/L)

- Mediated by CYP2C9: reduce dose by 25-50% for IM and PM

Phenytoin calculations 1

Hepatic clearance: determined by fraction unbound and intrinsic clearance (CLH = fu . Clint

Estimate "normal" concentration:

C normal = C observe / 0.02 x [alb] + 0.1

- If albumin conc changed but can't measure free phenytoin conc

Total phenytoin range: 10-20 mg/L

Unbound phenytoin range: 1-2 mg/L

- CAUTION IN REDUCED ALBUMIN AND LOW PHENYTOIN CONC: as free phenytoin conc may still be in therapeutic range

- Normal albumin conc = 32-45 g/L

Phenytoin calculations 2 (important)

Oral dose rate = Vm x Css/ Km + Css

Where: Vm = max metabolic rate = 7 mg/kg/day, Km = drug conc at half Vm = 4mg/L, Css = drug conc at steady state

when dose rate > Vm, Css -> infinity (danger)

Css = (Km . F. Dose rate)/ (Vm - F.dose rate)

can also calculate Vmax by rearranging equation

Conc dependent t1/2 = 22h, t1/2 not constant because CL is conc dependent

Phenytoin role of pharm

Interpret relevant into

- Treat pt not the number. If pt is responding and doing well; dose adjustment is not needed

- Know the AE and interactions

- Use PK knowledge to make rational dose recommendation

Lennoz-Gastaut syndrome (LGS)(epilepsy)

Onset: 40% develop from West syndrome (infantile spasms). Delayed development prior to onset- worsens post-seizure. 1-8 yrs, peak 3-5yrs old

Presentation: Stiffening (tonic), Drop (atonic), Atypical absence, Generalized tonic-clonic, Status epilepticus

Cause: Structural: congenital brain malformations or brain injury/infection

Genetic: D120N mutation, metabolic (rare)

1-3 per million

Treatment for DS and

LGS (epilepsy)

Drug-resistant (often have tried 4-6 med)

Polypharmacy common (often on 3 drugs)

Other treatments:

1) Surgery

2) Vagal nerve stimulation (device)

Ketogenic diet

Tuberous Sclerosis Complex

Description: Autosomal dominant genetic condition (often mutations in TSC1 or TCS2)

Affects multiple organs including the brain due to growth of non-cancerous tumours

>90% develop epilepsy which may be intractable

Seizure types:

Infantile spasms in 1st year of life, generalised tonic-clonic, focal, tonic, atonic, absence

1/6000 people

25-50% develop autism or developmental delays

Drug-resistant (often tried 4 meds)

1st gen anti seizure drug

Barbiturate derivatives: work to tone up effects of GABAa receptors (positivities allosteric modulator), acts on the GABAa ion channel to increase mean open time. Narrow therapeutic index and large side effects profile

- Phenobarbital, phenytoin, mephobarbital

2nd gen anti seizure drugs

Benzos: also act on GABAa receptors, increase frequency of the opening of the channels -> safer profile and wider therapeutic window

Valproate: discovered by university of Utah

Carbamazepine

3rd gen anti seizure drugs

Target based compounds

University of Utah used rodents, mice and rats on uptown 32k molecules

Cannabidiol, pregabalin, levetiracetam, tiagabine, topiramate, gabapentin, lamotrigine, everolimus

MOAs of anti seizure drugs

1) Modulate voltage-gated ion channels (inhibition and enhancement of inactivation) (e.g. phenytoin, carbamazepine, lamotrigine)

2) Enhance GABA-mediated inhibition (e.g. benzodiazepines (like diazepam; tiagabine inhibits GABA transporter 1 (GAT 1))

3) Block ionotropic glutamate receptors/Decrease glutamate transmission (e.g. perampanel (AMPA-R inhib))

4) Combination of mechanisms (e.g. cannabidiol, valproate)

5) Interact with synaptic release machinery (e.g. levetiracetam binds synaptic vesicle glycoprotein (SV2A)

Preclinical models:

Screening against epilepsy targets: CB1 and CB2, GABAA, GPR55, CaV3.1, NaVs, TRPV1

Zebrafish models: PTZ seizure, DS

Mice models:DS, LGS, West syndrome

Pregabalin (pain and seizure)

Indication: neuropathic pain (PBS authority), focal (partial) seizures, secondary generalisation (adjunctive)

Dose (neuropain): 75 mg n for 3-7 days, then 150 mg d in 1-2 doses

Dose (partial seizure): 75 mg bd; if required, increase to 150 mg bd after 7 days

Max dose: 300 mg bd

PK: Rapidly absorbed

Bioavailability >90% regardless of dose

Not plasma protein bound, crosses BBB

98% excreted in urine unchanged, t1/2 = 6.3h. Linear PK.

Adjust dose in renal impairment

PD:

- Structurally related to GABA

- Don't directly bind GABA receptor - binds to α2-δ subunit of VGCC

- ↓ presynaptic Ca influx = ↓ release of excitatory neurotransmitters(glutamate, substance P)

- Pregabalin affinity 6x higher than gabapentin - faster absorption, higher activity

AE: dizziness, drowsiness, confusion, irritability

↑ opioid-related death risk

Euphoria (10% in therapeutic use), hallucinations, feeling drunk.

More significant than Gabapentin

Do not drive or operate mac

RARE: suicidal ideation, dependence, misuse, withdrawal

Purified CBD in seizures

Indicated for Drug-resistant epilepsies, ≥1 years old

Formulation:

- 98% CBD with no THC content. Approved by FDA, EMA and TGA

Dravet syndrome: 10-20mg/kg

- Evidence: 50% ↓ convulsive seizures. Seizure-freedom in 5%

LGS: 10-20mg/kg

- Evidence: ↓ seizure frequency. Seizure-freedom in 4%

TCS: 25-50mg/kg

- Evidence: % ↓ focal seizures, 49% ↓ in 50 mg/kg, 48% ↓ in 25 mg/kg. Seizure-freedom in 5%

AE: diarrhoea, somnolence (drowsiness), fatigue, vomiting, fever, abnormal liver tests (likely DDI with valproate)

Gabapentin

Indication: neuropathic pain, focal (partial) seizures, secondary generalisation (adjunctive, PBS authority)

Dose (neuropain): 100-300 mg n; if required, increase gradually every 3-7 days to 0.9-2.4 g d in 3 doses

Dose (partial seizure): 300 mg bedtime 1st day, then increase by 300 mg d to 0.9-1.8 g d in 3 doses

Max dose: 3.6 g d

PK: ↑dose = ↓bioavailability (F)

- Saturable absorption

- Mostly plasma protein unbound, crosses BBB

- Excreted in urine unchanged; not metabolised

- t1/2 = 5-7h. Adjust dose in renal impairment

PD:

- Structurally related to GABA

- Don't directly bind GABA receptor - binds to α2-δ subunit of VGCC

- ↓ presynaptic Ca influx = ↓ release of excitatory neurotransmitters(glutamate, substance P)

- Pregabalin affinity 6x higher than gabapentin: faster absorption, higher activity

AE: fatigue, sedation, dizziness, ataxia

Do not drive or operate machinery if affected.

RARE: suicidal ideation, dependence, misuse, withdrawal

Gabapentin and pregabalin role in therapy and practice points

Role in therapy:

- Often seen as opioid substitutes

- Little evidence of relieving non-neuropathic pain

- Other uses: alcohol use disorder, restless legs syndrome, PTSD, inflammatory arthritis, postoperative pain, BDZ withdrawal management

- Widespread off-label use

Practice points:

- Evidence for off-label conditions is lacking - puts pts at risk of dependence, ADRs

- Misuse potential due to euphoric and dissociative effects (esp pregabalin) >>> Caution when prescribing, esp if history of substance abuse, younger

- Potentially fatal DDI with other CNS depressants, esp opioids - use with caution and consider dose reduction

- Toxic effects: CNS depression, myoclonic jerks, dizziness, ataxia

Use in sciatica: Did not significantly reduce leg pain intensity or improve other outcomes. AE incidence significantly higher than placebo

Pregabalin misuse

Large quantities well exceeding therapeutic doses for euphoric and dissociative effects

Higher risk in younger people with prior substance abuse history + dose-dependent

Non oral routes: nasal insufflation, IV injection. To achieve high conc of drug quickly in the body, leading to higher stimulation of receptors (euphoric AE)

Higher misuse potential because:

1) Bioavailability: > 90% bioavailability regardless of dose for Lyrica and Gabapentin has saturable absorption (↑dose = ↓F)

2) More rapidly absorbed

3) Increased binding to the VGCC (site of action)

Mechanism of Seizures

Changes in

• ion channel conduction

• membrane receptor response

• messenger systems

• gene transcription

Results in

• Imbalances between excitatory (glutamate) and inhibitory (GABA) neurotransmitters

excessive Ach, NA and 5HT may also precipitate seizures

Status epilepticus

Medical emergency

5 min continuous or repetitive seizures - up to 12-30% of seizures, 20% mortality

IMMEDIATE: BDZ (IV clonazepam, diazepam, midazolam, buccal/intranasal midazolam)

FOLLOW-UP: Levetiracetam, phenytoin, sodium valproate, phenobarbital

REPETITIVE SEIZURES: PO clobazam, buccal/intranasal midazolam, PR diazepam

EPILEPSY TREATMENT Drug Options

MODULATION OF VOLTAGE-GATED CATION CHANNELS

• Na+ channel - phenytoin, carbamazepine, oxcarbamazepine, lamotrigine, topiramate, lacosamide (slow), zonisamide (slow?)

• Ca2+ channel - ethosuxamide, pregabalin, zonisamide, lamotrigine?

ENHANCE GABANERGIC SYSTEM

• GABA receptor activation - barbiturates, felbamate

• GABA receptor activation and inhibition (stereoselective) - topiramate

• GABA potentiation - barbiturates, benzodiazepines

• GABA reuptake inhibitor - tiagabine

• GABA metabolism inhibitor - vigabatrin, sodium valproate?

DECREASE GLUTAMATE TRANSMISSION

• NMDA-R inhibitor - felbamate

• AMPA-R inhibitor - perampanel

• Kainate non-NMDA inhibitor - topiramate

• Glutamate release inhibitor - lamotrigine, zonisamide

Epilepsy Prophylaxis

First drug monotherapy - 47% seizure free

Second drug monotherapy - 13% seizure free

eTG: duotherapy (add 2nd drug), consider 1st drug removal if seizure-free

Rarely triple therapy

REFRACTORY --> Consider surgery, vagal nerve stimulation and ketogenic (high-fat restrictive) diet in children (poor adherence, GI disturbance, CV risk due to selenium deficiency)

Starting epilepsy tx

Titrate upwards to therapeutic dose (phenytoin excepted) - Narrow therapeutic index

TDM: phenytoin, lamotrigine, carbamazepine in pregnancy

Long-term AED therapy AE

Increased bone turn over

Consider:

- Ca and vit D supp esp if other risk factors present

- BMD, FBC monitoring for bone marrow depression

Other Epilepsy Drugs

Levetiracetam -

- 1st line for females of child-bearing potential

- 1st line Tonic-clonic seizures where generalised or focal (partial) onset is unclear in Females (250mg)

- Less concern with cognitive deficit

- Not as effective as older AEDs

Vigabatrin - refractory epilepsy

- Significant AE: visual field defects, esp problematic in paediatric epilepsy (hard to monitor visual field)

Epilepsy Adjuncts

PARTIAL: Lacosamide, Pregabalin, Tiagabine, Gabapentin (esp in elderly), Zonisamide

GENERALISED: Phenytoin

Pregabalin Supratherapeutic use vs withdrawal symptoms

Supratherapeutic use: Dissociation, Sedation, Relaxation, Numbness, Uninhibited behaviour, Increased empathy, Hallucinations

Withdrawal: insomnia, nausea, headache, anxiety, sweating, diarrhoea

Reasons for pregabalin use amongst users of illicit drugs

attenuation (reducing) opioid/BDZ withdrawal symptoms

augmentation (enhance) of psychotropic substances

psychotropic effects of pregabalin

curiosity

mental problems

pain

epilepsy

Pregabalin Overdose

Dose-dependent CNS depression (drowsiness > coma), Dizziness, Ataxia, Confusion, Slurred speech, Myoclonic jerks, Seizures

TREATMENT

- Observation in hospital

- Supportive care - Intubation and ventilation if necessary

- Dialysis - Especially in kidney failure (renally cleared), severe toxicity