Polytherapy in epilepsy
Published on: Mar 4, 2016
Transcripts - Polytherapy in epilepsy
The epic of Polytherapy in
Dr Mohammad A.S Kamil
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
• 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
• 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
• 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
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
• Potassium channel opener, particularly KCNQ2-5 channels
• 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
• 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 drugsSecond line drugsFirst line drugsEpilepsy syndrome
Juvenile absence epilepsy
Juvenile myoclonic epilepsy
Focal epilepsies: cryptogenic,
Benign epilepsy with
Benign epilepsy with
Drug options by seizure type (modified from NICE).
Drugs to be avoided
(may worsen seizures
Other drugs that
may be considered
Second line drugsFirst line drugsSeizure type
Now to choose the drug for the
type of epilepsy and patient
Drugs that should be
Drugs that are particularly suitablePatient characteristics
Gabapentin, lamotrigine, valproateClobazam, carbamazepine, lacosamide, levetiracetam, oxcarbazepine, phenytoin,
Patients with severe partial-onset seizures
Phenobarbital, phenytoin, primidone,
valproate (for its effects on hair)
Patients who wish particularly to avoid cosmetic
LevetiracetamClobazam (and other benzodiazepines), carbamazepine, gabapentin, phenobarbital,
Patients with prominent anxiety
Levetiracetam, vigabatrin, phenobarbitalCarbamazepine, lamotrigine, valproatePatients with prominent depression
Acetazolamide topiramate, zonisamidePatients with renal stones
Topiramate, valproatePatients with migraine
Gabapentin, pregabalin, valproateTopiramate, zonisamidePatients with the need to lose weight (or not to
Carbamazepine, clobazam, levetiracetam, oxcarbazepine, phenytoin, tiagabinePatients with foreign tissue lesional epilepsy (e.g.
Carbamazepine, oxcarbazepinePatients with hyponatraemia
Acetazolamide, carbamazepine, felbamate,
lamotrigine, oxcarbazepine, phenytoin,
Clobazam, gabapentin, lacosamide, levetiracetam, pregabalin, topiramate,
Patients at particular risk from allergy
Carbamazepine, lacosamide, lamotrigine,
Patients at particular risk of heart disease
Phenobarbital, phenytoinGabapentin, levetiracetam, pregabalinPatients at risk from osteoporosis
Clobazam, gabapentin, lacosamide, levetiracetam, pregabalin, topiramate,vigabatrinPatients 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.
Receptor site: Brain
Total serum concentration
Unbound serum concentration Pharmacologic response
Protein bound concentration Therapeutic outcome
Potential Adverse EffectsAntiepileptic Drug
Sedation, depression, and paradoxical hyperactivity in children; neurologic toxicity(such as dysarthria,
ataxia, and nystagmus) with increasing doses; rare hematologic Toxicity
Nystagmus; ataxia; diplopia; drowsiness; impaired concentration; gingival hyperplasia; hirsutism; acne;
hepatotoxicity and idiosyncratic reactions including lupuslike reactions and aplastic anemia
Nausea; abdominal discomfort; anorexia; drowsiness; dizziness; numerous idiosyncratic reactions; rarely,
Nausea; dizziness; drowsiness; diplopia; weight gain; rash; Stevens-Johnson syndrome; toxic epidermal
necrolysis; hyponatremia; leukopenia; rare cases of hepatotoxicity; other idiosyncratic reactions
Dose-related tremor (less with controlled-release formulations); hair loss; weight gain; nausea; vomiting;
hepatotoxicity; acute hemorrhagic pancreatitis; thrombocytopenia; hyperammonemia; less commonly,
Headache; fatigue; dizziness; drowsiness; depression; permanent visual field deficitsVigabatrin
Headache; nausea; dizziness; weight loss; fulminant hepatic failure; aplastic anemiaFelbamate
Somnolence; dizziness; fatigue; weight gainGabapentin
Hypersensitivity reactions; Stevens-Johnson syndrome (increased occurrence with rapid titration); dizziness;
nausea; insomnia; headache
Dizziness; tremor; abnormal thinking; nervousness; abdominal pain; rare psychosis;
rare nonconvulsive status epilepticus
Drowsiness; paresthesias; metabolic acidosis; oligohidrosis; renal calculi (most commonly reported
idiosyncratic reaction); rare hepatic failure; impaired language fluency and cognition; weight loss; rarely acute
Dizziness; somnolence; asthenia; headache; irritability; behavioral problems; depression; psychosisLevetiracetam
Fatigue; headache; dizziness; ataxia; diplopia; nausea; vomiting; rash; hyponatremia; Stevens-Johnson
Fatigue; dizziness; somnolence; anorexia; abnormal thinking; rash; Stevens-Johnson syndrome; renal calculi;
aplastic anemia; oligohidrosis
Dizziness; somnolence; weight gainPregabalin
Fatigue; vomiting; loss of appetite; somnolence; headache; aggravated seizures; status epilepticusRufinamide
Dizziness; headache; nausea; diplopiaLacosamide
Urinary retention; dizziness; somnolence; fatigue; confusion; vertigo; tremor; abnormal coordinationEzogabineb
Dizziness; somnolence; irritability; falls; ataxia; risk of severe changes in mood and behavior, including
aggression, hostility, anger, and homicidal ideation and threats
Is it polytherapy always safe?
1. Phenobarbital and valproate: Sedation and weight gain can be difficult to
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
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
Do not have
Do not have a
The best evidence
in favour of a
synergism with a
The best studied
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 .
• 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.