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 com...
Has the Epileptologist got more options?
• Times have changed-data in 1992 strongly discouraged polytherapy.
• Most drugs ...
Let us sink deep into targets
Sodium channels blockers
• Blockade of voltage-gated sodium channels is the most common
mechanism of action among currentl...
Calcium channels blockers
• The efficacy of ethosuximide and zonisamide in generalised absence
epilepsy is believed to be ...
GABA –ergic drugs
• Activation of the ionotropic GABAA receptor resulting in an enhanced response to
synaptically released...
GABA – ergic drugs
• Vigabatrin is an irreversible inhibitor of the mitochondrial enzyme GABA-
transaminase, which is resp...
• Potassium channel opener, particularly KCNQ2-5 channels
Retigabine(ezogabin).
• Perampanel Noncompetitive antagonist of ...
Carbonic anhydrase inhibitor
• The acid–base balance and maintenance of local pH is critical to normal functioning of the
...
Drug options by epilepsy syndrome seen in adult
practice (modified from NICE).
Drugs to be avoided
(may worsen seizures)
O...
Drug options by seizure type (modified from NICE).
Drugs to be avoided
(may worsen seizures
Other drugs that
may be consid...
Now to choose the drug for the
type of epilepsy and patient
status.
Drugs that should be
particularly avoided
Drugs that are particularly suitablePatient characteristics
Gabapentin, lamotrig...
Pharmacokinetic interaction (another dive)
• Pharmacokinetics is the study of the effect of the body on a drug.
• Pharmaco...
Relationship between
Pharmacokinetics pharmacodynamics
Dose
Receptor site: Brain
Total serum concentration
Unbound serum c...
Potential Adverse EffectsAntiepileptic Drug
Sedation, depression, and paradoxical hyperactivity in children; neurologic to...
Dizziness; tremor; abnormal thinking; nervousness; abdominal pain; rare psychosis;
rare nonconvulsive status epilepticus
T...
Is it polytherapy always safe?
1. Phenobarbital and valproate: Sedation and weight gain can be difficult to
combat.
2. Phe...
Constitution to treat epilepsy
Before an AED trial has been declared a failure, it is important to
review a number of ques...
Rational
polypharmacy in
epilepsy
involves
combining drugs
Have different
mechanisms of
action
Do not have
complex
pharmac...
The best evidence
in favour of a
synergism with a
particular
AED combination
is
The best studied
antagonistic
combination
...
Some useful combination
• Sodium valproate with ethosuximide for absence seizures.
• Phenobarbital with phenytoin for toni...
FINALY
• Choose the drug of choice for the type of epilepsy.
• Treat patient not epilepsy.
• Try two monotherapies before ...
Polytherapy in epilepsy
Polytherapy in epilepsy
Polytherapy in epilepsy
of 27

Polytherapy in epilepsy

neurology epilepsy
Published on: Mar 4, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Polytherapy in epilepsy

  • 1. The epic of Polytherapy in epilepsy Dr Mohammad A.S Kamil Consultant neurologist
  • 2. INTRODUCTION Seizure free without side effects every one happy. Uncontrolled epilepsy disappointed peoples except drug companies .
  • 3. 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
  • 4. Let us sink deep into targets
  • 5. 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.
  • 6. 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.
  • 7. 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.
  • 8. 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.
  • 9. • 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.
  • 10. 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.
  • 11. 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 Carbamazepine,Phenytoin Oxcarbazepine,Tiagabine Vigabatrin Clonazepam Clobazam Levetiracetam Topiramate Lamotrigine,Sodium valproate Ethosuximide Juvenile absence epilepsy Carbamazepine,Gabapentin Oxcarbazepine,Phenytoin Pregabalin,Tiagabine Vigabatrin AcetazolamideClobazam 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
  • 12. 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 Tiagabine Vigabatrin Acetazolamide Phenobarbital Phenytoin Clobazam Clonazepam Carbamazepine,Lamotrigine Levetiracetam,Oxcarbazepine Sodium valproate,Topiramate Generalized tonic– clonic Carbamazepine,Gabapentin Oxcarbazepine,Pregabalin Tiagabine,Vigabatrin PhenobarbitalClobazam 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
  • 13. Now to choose the drug for the type of epilepsy and patient status.
  • 14. Drugs that should be particularly avoided Drugs that are particularly suitablePatient characteristics Gabapentin, lamotrigine, valproateClobazam, 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 LevetiracetamClobazam (and other benzodiazepines), carbamazepine, gabapentin, phenobarbital, pregabalin, valproate 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 gain weight) Carbamazepine, clobazam, levetiracetam, oxcarbazepine, phenytoin, tiagabinePatients with foreign tissue lesional epilepsy (e.g. tumour) Carbamazepine, oxcarbazepinePatients 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, 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.)
  • 15. 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.
  • 16. 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 BLOODBRAINBARRIER
  • 17. 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 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 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 Lamotrigine
  • 18. 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; psychosisLevetiracetam 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 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 Perampanel
  • 19. 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.
  • 20. 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?
  • 21. 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
  • 22. The best evidence in favour of a synergism with a particular AED combination is The best studied antagonistic combination sodiumvalproatewithlamotrigine LTGandCBZ
  • 23. 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 .
  • 24. 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.

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