Polytherapy in epilepsy

The epic of Polytherapy in epilepsy

Dr Mohammad A.S Kamil Consultant neurologist

INTRODUCTION

Seizure free without side effects every one happy.

Uncontrolled epilepsy disappointed peoples except drug companies .

Has the Epileptologist got more options?

• Times have changed-data in 1992 strongly discouraged polytherapy.

• Most drugs produced interactions, both pharmacokinetic and pharmacodynamic

• What’s different in 2013?

• Many more AEDs, many more mechanisms means greater potential for synergy between drugs

• Some new AEDs have low potential for pharmacokinetic AND pharmacodynamic interactions

• New drugs may produce less side effects when added to other drugs

Let us sink deep into targets

Sodium channels blockers

• Blockade of voltage-gated sodium channels is the most common mechanism of action among currently available AEDs.

• fast inactivation pathway phenytoin , carbamazepine, lamotrigine, oxcarbazepine, topiramate, felbamate,zonisamide, rufinamide and lacosamide.

• Sodium valproate and gabapentin may also have inhibitory effects on neuronal sodium channels.

• Selectively influences slow inactivation lacosamide .Recent evidence suggests that this drug can be usefully combined with sodium channel blockers that act on fast inactivation.

Calcium channels blockers

• The efficacy of ethosuximide and zonisamide in generalised absence epilepsy is believed to be mediated by blockade of the low voltage-activated T-type calcium channel in the dendrites of thalamocortical relay neurones. Sodium valproate may have a similar action.

• gabapentin and pregabalin exert their effects via high-voltage-activated ( HVA) calcium channels.

• Lamotrigine limits neurotransmitter release by blocking both N- and P/Q-types of the (HVA) calcium channel and levetiracetam exerts a partial blockade of N-type calcium currents.

• Phenobarbital, felbamate, and topiramate are also believed to influence HVA calcium channel conductance, although their effects are less well characterised in terms of channel subtypes or interaction with specific protein subunits.

GABA –ergic drugs

• Activation of the ionotropic GABAA receptor resulting in an enhanced response to synaptically released GABA is a major AED mechanism.

• Phenobarbital and the benzodiazepines share this effect.

• They bind to distinct sites on the receptor complex and differentially influence the opening of the chloride ion pore.

• Barbiturates prolong the duration of chloride channel opening.

• benzodiazepines increase the frequency of opening.

• In addition, phenobarbital is capable of direct activation of the GABA A receptor in the absence of GABA, an effect which is believed to underlie its sedative properties.

• Stiripentol has been identified as a subunit selective GABA A enhancer with a preference for a3-B3-g2 containing receptors.

• Felbamate and topiramate also modulate GABA responses at the GABAA receptor.

GABA – ergic drugs

• Vigabatrin is an irreversible inhibitor of the mitochondrial enzyme GABA-transaminase, which is responsible for the catabolism of GABA.

• Tiagabine prevents the removal of GABA from the synaptic cleft by blockade of GABA transport.

• These distinct mechanisms result in the globalelevation of brain GABA concentrations and the Although these drugs target neurones and glial cells, vigabatrin has marginally higher affinity for neuronal GABA transaminase, whereas tiagabine is slightly more effective in

• Sodium valproate, gabapentin and topiramate have also been reported to influence GABA turnover by increasing neurotransmitter synthesis and/or release.

• Potassium channel opener, particularly KCNQ2-5 channels Retigabine(ezogabin).

• Perampanel Noncompetitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors on postsynaptic neurons.

• Levetiracetam Precise mechanism unknown; binds synaptic vesicle protein 2A, a presynaptic protein, on synaptic vesicles.

Carbonic anhydrase inhibitor

• The acid–base balance and maintenance of local pH is critical to normal functioning of the nervous system.

• Various isoenzymes of carbonic anhydrase play an important role in this regard.

• They are responsible for catalysing the bi-directional conversion of carbon dioxide and water to bicarbonate and hydrogen ions (CO2 + H2O$HCO3 + H+).

• The forward reaction is rapid, whereas the rate of the reverse reaction is more modest.

• As a result, inhibition of carbonic anhydrase influences the latter more significantly, producing a localised acidosis and increased bicarbonate ion concentration.

• This, in turn, attenuates excitatory neurotransmission by reducing NMDA receptor activity and enhances inhibitory neurotransmission by facilitating the responsiveness of GABA A receptors.

• Acetazolamide is a classical carbonic anhydrase inhibitor which has been employed as an AED for more than 50 years.

• Topiramate and zonisamide share this mechanism, but are significantly less potent and have greater selectivity for individual isoenzymes.

Drug options by epilepsy syndrome seen in adult

practice (modified from NICE). Drugs to be avoided

(may worsen seizures) Other drugs Second line drugs First line drugs Epilepsy syndrome

Carbamazepine,Phenytoin

Oxcarbazepine,Tiagabine

Vigabatrin

Clonazepam

Clobazam Levetiracetam

Topiramate Lamotrigine,Sodium valproate

Ethosuximide Juvenile absence epilepsy

Carbamazepine,Gabapentin

Oxcarbazepine,Phenytoin

Pregabalin,Tiagabine

Vigabatrin

Acetazolamide Clobazam

Clonazepam Lamotrigine,Sodium valproate

Levetiracetam,Topiramate Juvenile myoclonic epilepsy

Tiagabine

Vigabatrin Acetazolamide

Phenobarbital,Phenytoin

,Primidone

Clobazam,Clonazepam

Oxcarbazepine,Zonisamide Carbamazepine,Lamotrigine

Sodium valproate,Levetiracetam

Topiramate

Generalized tonic–clonic

seizures only

Acetazolamide,

Clonazepam,Gabapentin

Phenobarbital,Primidone

Clobazam,Gabapentin

Levetiracetam,Phenytoin

Pregabalin,Tiagabine

Carbamazepine,Lamotrigine

Oxcarbazepine,Levetiracetam

Sodium valproate,Topiramate

Focal epilepsies: cryptogenic,

symptomatic

Topiramate

Zonisamide Carbamazepine,Lamotrigine

Oxcarbazepine,Sodium

valproate

Benign epilepsy with

centrotemporal spikes

Levetiracetam

Topiramate Carbamazepine,Lamotrigine

Oxcarbazepine,Sodium

valproate

Benign epilepsy with

occipital paroxysms

Drug options by seizure type (modified from NICE).

Drugs to be avoided

(may worsen seizures Other drugs that

may be considered Second line drugs First line drugs Seizure type

Tiagabine

Vigabatrin Acetazolamide

Phenobarbital

Phenytoin

Clobazam

Clonazepam Carbamazepine,Lamotrigine

Levetiracetam,Oxcarbazepine


Generalized tonic–clonic


Oxcarbazepine,Pregabalin

Tiagabine,Vigabatrin

Phenobarbital Clobazam

Clonazepam

Topiramate

Ethosuximide

Lamotrigine

Sodium valproate

Absence


Oxcarbazepine,Pregabalin

Tiagabine.Vigabatrin

Clobazam,Clonazepam

LamotriginePiracetam

Zonisamide

Sodium valproate

Topiramate Levetiracetam Myoclonic

Carbamazepine

Oxcarbazepine Acetazolamide

Phenobarbital,Phenytoin Clobazam,Clonazepam

Levetiracetam,Topiramat Lamotrigine

Sodium valproate Tonic

Carbamazepine

Oxcarbazepine,Phenytoin Acetazolamide

Phenobarbital Clobazam,Clonazepam

Levetiracetam,Topiramate Lamotrigine

Sodium valproate Atonic

Acetazolamide,Clonazepam

Phenobarbital,Phenytoin Clobazam,Gabapentin,

Pregabalin,Tiagabine,

Zonisamide

Carbamazepine,Lamotrigine

Levetiracetam,Oxcarbazepine


Focal with/without

secondary

generalization

Now to choose the drug for the type of epilepsy and patient

status.

Drugs that should be

particularly avoided Drugs that are particularly suitable Patient characteristics

Gabapentin, lamotrigine, valproate Clobazam, carbamazepine, lacosamide, levetiracetam, oxcarbazepine, phenytoin,

topiramate, zonisamide Patients with severe partial-onset seizures

Phenobarbital, phenytoin, primidone,

valproate (for its effects on hair) Patients who wish particularly to avoid cosmetic

effects

Levetiracetam Clobazam (and other benzodiazepines), carbamazepine, gabapentin, phenobarbital,

pregabalin, valproate Patients with prominent anxiety

Levetiracetam, vigabatrin, phenobarbital Carbamazepine, lamotrigine, valproate Patients with prominent depression

Acetazolamide topiramate, zonisamide Patients with renal stones

Topiramate, valproate Patients with migraine

Gabapentin, pregabalin, valproate Topiramate, zonisamide Patients with the need to lose weight (or not to

gain weight)

Carbamazepine, clobazam, levetiracetam, oxcarbazepine, phenytoin, tiagabine Patients with foreign tissue lesional epilepsy (e.g.

tumour)

Carbamazepine, oxcarbazepine Patients with hyponatraemia

Acetazolamide, carbamazepine, felbamate,

lamotrigine, oxcarbazepine, phenytoin,

zonisamide

Clobazam, gabapentin, lacosamide, levetiracetam, pregabalin, topiramate,

vigabatrin Patients at particular risk from allergy

Carbamazepine, lacosamide, lamotrigine,

oxcarbazepine Patients at particular risk of heart disease

Phenobarbital, phenytoin Gabapentin, levetiracetam, pregabalin Patients at risk from osteoporosis

Clobazam, gabapentin, lacosamide, levetiracetam, pregabalin, topiramate,vigabatrin Patients in whom the risk of hepatic enzyme

interactions have to be avoided (e.g. those co-

mediated with antibiotics, immunosuppressive

drugs, oncological drugs, antipsychotics, etc.)

Pharmacokinetic interaction (another dive)

• Pharmacokinetics is the study of the effect of the body on a drug.

• Pharmacodynamics is the study of the factors that relate to the efficacy and safety of the drug and determines the relationship between concentration and effect.

Relationship between Pharmacokinetics pharmacodynamics

Dose

Receptor site: Brain

Total serum concentration

Unbound serum concentration Pharmacologic response

Protein bound concentration Therapeutic outcome

seizure freedom

Absorption Distribution

Metabolism

Excretion

BLO

OD

BR

AIN

BA

RR

IER

Potential Adverse Effects Antiepileptic Drug

Sedation, depression, and paradoxical hyperactivity in children; neurologic toxicity(such as dysarthria,

ataxia, and nystagmus) with increasing doses; rare hematologic Toxicity Phenobarbital and

other barbiturates

Nystagmus; ataxia; diplopia; drowsiness; impaired concentration; gingival hyperplasia; hirsutism; acne;

hepatotoxicity and idiosyncratic reactions including lupuslike reactions and aplastic anemia Phenytoin

Nausea; abdominal discomfort; anorexia; drowsiness; dizziness; numerous idiosyncratic reactions; rarely,

hematologic toxicity Ethosuximide

Nausea; dizziness; drowsiness; diplopia; weight gain; rash; Stevens-Johnson syndrome; toxic epidermal

necrolysis; hyponatremia; leukopenia; rare cases of hepatotoxicity; other idiosyncratic reactions Carbamazepine

Dose-related tremor (less with controlled-release formulations); hair loss; weight gain; nausea; vomiting;

hepatotoxicity; acute hemorrhagic pancreatitis; thrombocytopenia; hyperammonemia; less commonly,

lethargy

Valproate

Headache; fatigue; dizziness; drowsiness; depression; permanent visual field deficits Vigabatrin

Headache; nausea; dizziness; weight loss; fulminant hepatic failure; aplastic anemia Felbamate

Somnolence; dizziness; fatigue; weight gain Gabapentin

Hypersensitivity reactions; Stevens-Johnson syndrome (increased occurrence with rapid titration); dizziness;

nausea; insomnia; headache Lamotrigine

Dizziness; tremor; abnormal thinking; nervousness; abdominal pain; rare psychosis;

rare nonconvulsive status epilepticus Tiagabine

Drowsiness; paresthesias; metabolic acidosis; oligohidrosis; renal calculi (most commonly reported

idiosyncratic reaction); rare hepatic failure; impaired language fluency and cognition; weight loss; rarely acute

glaucoma

Topiramate

Dizziness; somnolence; asthenia; headache; irritability; behavioral problems; depression; psychosis Levetiracetam

Fatigue; headache; dizziness; ataxia; diplopia; nausea; vomiting; rash; hyponatremia; Stevens-Johnson

syndrome Oxcarbazepine

Fatigue; dizziness; somnolence; anorexia; abnormal thinking; rash; Stevens-Johnson syndrome; renal calculi;

aplastic anemia; oligohidrosis Zonisamide

Dizziness; somnolence; weight gain Pregabalin

Fatigue; vomiting; loss of appetite; somnolence; headache; aggravated seizures; status epilepticus Rufinamide

Dizziness; headache; nausea; diplopia Lacosamide

Urinary retention; dizziness; somnolence; fatigue; confusion; vertigo; tremor; abnormal coordination Ezogabineb

Dizziness; somnolence; irritability; falls; ataxia; risk of severe changes in mood and behavior, including

aggression, hostility, anger, and homicidal ideation and threats Perampanel

Is it polytherapy always safe?

1. Phenobarbital and valproate: Sedation and weight gain can be difficult to combat.

2. Phenytoin and carbamazepine:Dizziness and diplopia are common, and maintaining therapeutic levels can be difficult because of a bidirectional induction of metabolism.

3. Valproate and lamotrigine: Requires adjustment of lamotrigine dose because of increased levels oflamotrigine that can cause dizziness and increase the risk of Stevens-Johnson syndrome; however, this combination has been noted to be very efficacious in some patients.

4. Topiramate, lamotrigine, or zonisamide and enzyme-inducing AEDs (eg, carbamazepine, phenytoin): When adding drugs to enzyme inducers, doses of the additive drugs will need to be substantially higher because of increased clearance.

Constitution to treat epilepsy

Before an AED trial has been declared a failure, it is important to review a number of questions:

Is it the drug of choice for the type of epilepsy?

Has the medication been titrated to the maximum tolerated dose?

Has the patient been compliant with the medication?

Are the breakthrough seizures provoked by factors that can be corrected, such as sleep deprivation, alcohol or drug abuse, or concomitant use of a medication known to reduce the seizure threshold?

Rational

polypharmacy in

epilepsy

involves

combining drugs

Have different

mechanisms of

action

Do not have

complex

pharmacokinetic

interactions

Do not have a

similar adverse

effect profile

Can be

combined in

minimum doses

to produce

maximum effect

The best evidence in favour of a

synergism with a particular

AED combination is

The best studied antagonistic combination

sod

ium

va

lpro

ate

wit

h la

mo

trig

ine

LTG

an

d C

BZ

Some useful combination

• Sodium valproate with ethosuximide for absence seizures.

• Phenobarbital with phenytoin for tonic–clonic seizures .

• Vigabatrin with tiagabine for refractory epilepsy .

• Lamotrigine with topiramate for a range of seizure types .

• Carbamazepine with valproate or vigabatrin for focal seizures .

FINALY

• Choose the drug of choice for the type of epilepsy.

• Treat patient not epilepsy.

• Try two monotherapies before going to polytherapy.

• Please always ask and insist about compliance.

• Initial combination therapy is to combine first line drugs with different mechanism of action for the type of epilepsy.

• If there is no improvement add third drug.

Health & Medicine

Polytherapy in epilepsy