Polytherapy in epilepsy
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Transcript of 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
Sodium valproate,Topiramate
Generalized tonic–clonic
Carbamazepine,Gabapentin
Oxcarbazepine,Pregabalin
Tiagabine,Vigabatrin
Phenobarbital Clobazam
Clonazepam
Topiramate
Ethosuximide
Lamotrigine
Sodium valproate
Absence
Carbamazepine,Gabapentin
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
Sodium valproate,Topiramate
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.