TEST #3 Fitzpatrick Pharm of Seizures and Epilepsy Flashcards
Abbreviations
AEDs – anti-epilepsy drugs
BZD – benzodiazepines
CBZ – carbamazepine
GABA – gamma () aminobutyric acid
GABA-T – GABA transaminase
GAD – glutamic acid decarboxylase
MOA – mechanism of action
Nav – voltage gated Na+ channels
OXCBZ – oxcarbazepine
PB – phenobarbital
PHT – phenytoin
Epilepsy
- Acquired or inherited malfunction of neuronal ion channels or neurotransmitter systems disrupting normal electrical activity in the brain.
Are AEDs Effective?
- AEDs can stop seizures from occurring in ~ 2/3 of patients; they DO NOT “CURE” epilepsy.
- There are > 32 AEDs available for therapy. About 25% of patients discontinue their medication because of significant side effects
Seizure free with:
1st drug 47%
2nd drug 13%
3rd drug or multi drugs 4%
Likelihood of AED: Drug Interactions
- About 5 out of 10 epileptic patients take 5 drugs
- There is a high propensity for Drug Interactions
Drugs Used to Treat Epilepsy
- Drugs used to treat epilepsy target neurotransmitter systems in order to SUPPRESS EXCITATORY, i.e. Glutamate Transmission, and / or ENHANCE INHIBITORY, i.e. GABA transmission.
- Because Glutamate and GABA are ubiquitous neurotransmitters throughout the CNS, the side effects of these therapies involve a broad array of brain mechanisms, from the regulation of homeostasis to alterations in higher brain functions.
Key Concepts
1) Mechanisms of Action:
- Understand AEDs molecular mechanisms
2) Hepatic metabolism:
- Role in drug-drug interactions & toxicities
3) Major & Unique Toxicities:
- Integrate with treatment concepts
Epilepsy Drugs
GENERALIZED ONSET:
1) Absence
2) Myotonic, Atonic, Clonic
3) Tonic/ Clonic
PARTIAL ONSET:
1) Tonic/ Clonic
2) Simple Complex
1) ABSENCE:
- Ethusoximide
2) MYOTONIC, ATONIC, CLONIC
- Benzodiazepines
- Clonazepam
3) TONIC/ CLONIC
- Phenytoin
- Phenobarbital
- ** Carbamazepine
4) SIMPLE COMPLEX
- ** Carbamazepine
- Gagapentin
- Pregbalin
- Oxcarbazepine
- Lacosamide
- Tiagabine
- Vigabatrin
- Ezobagin
5) BROAD SPECTRUM:
- Valproate
- Lamotrigine
- Topirimate
- Levetiracetam
- Zonisamide
*** CARBAMAZEPINE: PARTIAL ONSET Tonic-Clonic!!!!!
Mechanisms of Aciton: AEDs Antagonize Excitation by targeting:
1) Voltage gated Na+ ion channels (Nav)
2) Low-threshold (T type) Ca 2+ channels
AEDs ANTAGONIZE Voltage-dependent Na+ channels
- Phenytoin
- Carbamazepine
- Lamotrigine
- Oxcarbazepine
- Zonisamide
1) Voltage-Gated Na+ Channel BLOCKED
2) Blunt Excitation
Voltage Gated Sodium (Na+) Channel
INACTIVATION: Within a few milliseconds the channels close from inside of the neuron and go into a FAST INACTIVATED STATE FROM WHICH THEY CANNTO BE REACTIVATED…. DIRECTLY, OR INSTANTLY
DEPOLARIZATION: Na+ channels return to resting potential. During prolonged depolarization & repetitive neuronal activity, the Na+ channel goes into a SLOW INACTIVATION STATE by closing the pore from inside. This process happens on a second-to-minute time scale.
Drugs Modulate Voltage Gated Na Channels via Distinct Mechanisms
1) Prolong FAST INACTIVATION STATE of Nav ion channels:
- Traditional AED: phenytoin, carbamazepine
- New AEDs: Lamotrigine, oxcarbazepine
2) Enhance SLOW INACTIVATION of Nav
channels:
• New AED: ICOSAMIDE!!!!.
Voltage Gated Nav Channels Continued
- Voltage-gated sodium ion (Nav) channels generate the rapid, transient inward currents that drive the upstroke of the action potential of NEURONS & other excitable cells.
- Nav channels are the target of many drugs, including antiepileptics, anesthetics, analgesics, and antiarrhythmics.
Nav channels are target for drugs, used to treat Epilepsy, Seizures, Pain and Cardiac Arrhythmias.
- Drugs used to treat these disorders exhibit LITTLE or NO SELECTIVITY for Nav-channel subtypes.
- The sub-units of voltage gated NaV channels undergo CONFORMATIONAL CHANGES during the action potential.
AEDs and Nav Channels
- AEDs’ binding site is at interior side Nav channel ‘pore’
- If activation gate opens AEDs CAN ACCESS ‘pore’
- If activation gate CLOSED AEDs CANNOT ACCESS ‘pore’
- The pharmacological activity of AED Nav blockers is ‘state’ or ‘USE-DEPENDENT’…
Nav Channel Blocker: LAMOTRIGINE
- If activation gate CLOSED AEDs CANNOT access ‘pore’
- If activation gate is OPEN AEDs CAN access ‘pore’
*** The probability of Nav BLOCKADE is PROPORTION to the frequency of Nav Channel OPENING and the DOSE!!!
*** Epileptic seizures involve neurons firing at higher frequency than normal… therefore the NaV blockers ACT PREFERENTIALLY ON THE NEURONS INVOLVED IN THE DISEASE
Phenytoin and Carbazepine
- Are STATE-DEPENDENT agents that slow the recovery of Nav ion channels from inactivation.
- PHENYTOIN is most effective at depolarized membrane potentials and high-frequency action potential firing.
- The state dependence of phenytoin causes MINIMAL EFFECTS on COGNITIVE FUNCTIONS (low- frequency firing).
- CARBAMAZEPINE binds Nav LESS EFFECTIVELY, but with a much FASTER RATE than phenytoin, making carbamazepine MORE EFFECTIVE in BLOCKING High-frequency firing.
*** These differences may correlate with different clinical responses .
Lamotrigine
- The mechanism of action
of lamotrigine on Nav ion channels is similar to that of phenytoin and carbamazepine (voltage and use dependence).
- However, LAMOTRIGINE also ACTS ON OTHER MOLECULAR TARGETS, such as N- and P-type voltage-gated Ca2+ channels in cortical neurons and neocortical potassium currents.!!!!!!!!
- Therefore, its ANTI-EPILEPTIC action is NOT identical to carbamazepine and phenytoin.
Lacosamide
- Is a NOVEL AED that
effectively treats PARTIAL SEIZURES. - Lacosamide STABILIZES the SLOW-INACTIVATED STATE!!!!!!
- Other AEDs act primarily on the Fast-Inactivation state.
- In a PROLONGED train of depolarizing stimuli, lacosamide is MORE EFFECTIVE at REDUCING the AMPLITUDES and FREQUENCY of sustained repetitive firing spikes when the stimulus was prolonged to tens of seconds as opposed to less than 1 sec.
- By contrast, AEDs such as phenytoin, carbamazepine, and lamotrigine, exert their action over substantially SHORTER time scale.
T-Type Ca2+ Ion Channels (CaV3.1) Mediate Absence Seizures
- Voltage-sensitive Ca2+ channels (VSCC) mediate Ca2+ ions entry INTO EXCITABLE CELLS.
- There are 3 types of neuronal Ca2+ channel: L,N and T.
- T-type Ca channels mediate 3 Hz spike and wave
activity in the THALAMUS - the HALLMARK OF ABSENCE (PETIT MAL) SEIZURES. - AEDs that INHIBIT these T-type Ca2+ channels are particularly useful for CONTROLLING Absence Seizures
Drugs to Treat Absence Seizures
- Antagonists of T-type Ca2+ channels target CORTEX-THALAMUS oscillation
ETHOSUXIMIDE (Narrow Spectrum)!!!!!:
- ONLY used for ABSENCE SEIZURES
- ONLY limits Excitation (Ca2+ Channel)
- NON - SEDATING DRUG!!!!!!!!!!!!!!!!!!!!!
Valproate
- For many years, VALPROATE
was the only BROAD-SPECTRUM agent available and is still considered first-line therapy by many experts for generalized- onset seizures. - Unfortunately, it has ‘INTOLERABLE’ adverse effects, e.g. weight gain, tremor, hair loss, and lethargy.****
- Valproate has also been associated with NEURAL TUBE DEFECTS in the offspring of women who take it DURING Pregnancy.
Lamotrigine
- The mechanism of action
of lamotrigine on Nav ion channels is SIMILAR to that of phenytoin and carbamazepine (voltage and use dependence). - However, lamotrigine also ACTS ON OTHER molecular targets, such as N- and P-TYPE Voltage-Gated Ca2+ channels in cortical neurons and neocortical potassium currents!!!!!!!!!!!
- Therefore, its anti-epileptic action is not identical to carbamazepine and phenytoin.
ZONISAMIDE
- Is a SULFONAMIDE
derivative that is chemically and structurally unrelated to other anticonvulsants. - Its primary mechanisms of action appears to be:
1) BLOCKING voltage-dependent sodium channels
2) BLOCKING T-type calcium channels.
AEDs that Augment Inhibition
- Block GABA RE-UPTAKE or metabolism
- Potentiate GABAa receptor Cl- CURRENTS!!!!
1) TIAGABINE: INHIBITS GABA Re-uptake (Transporters)!!!!!!
2) VAGABATRIN: INHIBITS GABA METABOLISM (GABA-T)!!!!!!!!!!!
Drugs that Enhance Post-Synaptic GABAergic Neuronal Transmission
1) PHENOBARBITAL and related Barbiturates
2) PRIMIDONE (Active Metabolite = Phenobarbital)
3) BENZODIAZAPINES (Diazapam/ Lorazepam)
Phenobarbital’s Complications
*** POWERFUL, NON-SPECIFIC CNS DEPRESSION!!!!!!!
- Can cause significant SEDATION
- Can cause LETHAL RESPIRATORY DEPRESSION
- Has ABUSE and ADDICTION POTENTIAL
These liabilities prompted a search for better agents drugs …that is what led to discovery & development of benzodiazepines
Post-synaptic GABAergic Transmission
1) GABAa Receptor UNOCCIPIED = INACTIVE Cl- Channel CLOSED
2) GABAa Receptos Subunits OCCUPIED = Cl- Channel OPENS
3) HYPERPOLARIZATION blunts AP Propagation
Benzodiazepines Mechanisms of Action at Post-Synaptic GABAa Cl- Channel
- BENZODIAZEPINES (BZD) bind to distinct sites —-> ALLOSTERIC change POTENTIATE GABA binding ——–> Cl- Channels OPENS with GREATER FREQUENCY
Barbiturate Mechanism of Action at PostSYnaptic GABAa Cl- Channel
- PHENOBARBITAL (PB) binds to a distinct site and INCREASES the DURATION of Cl- CHANNEL OPENING!!!!
- TOXICITY: High Doses of Barbiturates are GABA Independent
(Lethality PB> BZD)
Differential Lethality of GABAa Receptor Agonists
1) BARBITURATE (Phenobarbital) GABA Independent
2) BENZODIAZEPINE (DIAZEPAM) GABA Dependent
Benzodiazepines (Diazepam or Lorazepam)
- Are indicated for treatment of STATUS EPILEPTICUS!!!!
Seizure Terminology
1) EPILEPTIC SEIZURES can occur WITHOUT CONVULSIONS (E.g. Absence Seizures)
2) Seizures can occur WITHOUT EPILEPSY
- Drug Withdrawal (Alcohol, Benzodiazepines, Opioids, AEDs)
- Stimulant Abuse (Cocaine)
- Poisons (Strychnine)
- Brian Tumor
- High Fever
*** STATUS EPILEPTICUS
Status Epilepticus is a Medical Emergency
Causes:
- Abrupt withdrawal of AEDS, Sedatives, for Instance during NATURAL DISASTERS
- About 40 to 50,000 deaths/ year and many thousands more of Brain Damage/ year
Status Epileptics Treatment
1) GOAL: Stop Seizure/ EEG Bursts
2) INITIAL TREATMENT: GABA-ergic agents that INCREASE INHIBITION
a) I.V: Lorazepam/ Diazepam (About 5 min)
b) In seizure hasn’t stopped: give FOSPHENYTOIN I.V. (A Na+ Channel Antagonist)
Clonazepam
- Is a benzodiazepine
drug of choice for MYOCLONIC SEIZURES and SUBCORTICAL MYOCLONUS. - It SEDATIVE effect and tolerance are similar to those of other benzodiazepines.
- It is very effective in the EMERGENCY TREATMENT of Status Epilepticus, like Diazepam, and can be given IV or RECTALLY!!!!!!!!!
Drugs with Multiple Mechanisms of Action
- Topirimate
- Valproic Acid (Valproate, Divalproate)
Valproic Acid (Older) vs Topirimate (Newer)
VALPROIC ACID:
1) Voltage Gated Na+ Channels:
- Yes
2) Ligand Gated Na+ Channels (AMPA/ Glutamate Receptor):
- No
3) T-Type Ca2+ Channels:
- Yes
4) Increases GABA:
- Yes
5) Potentiates GABAa Receptors:
- No
TOPIRIMATE:
1) Voltage Gated Na+ Channels:
- Yes
2) Ligand Gated Na+ Channels (AMPA/ Glutamate Receptor):
- Yes
3) T-Type Ca2+ Channels:
- No
4) Increases GABA:
- Yes
5) Potentiates GABAa Receptors:
- Yes
Topirimate Has Multiple Actions
- Ligand - Gated ion channels (Na+, Ca2+) Glu binding causes DEPOLARIZATION
- ** TOPIRIMATE:
a) Glutamate (AMPA) Receptor ANTAGONIST!!!!
b) GABAa Receptor AGONIST!!!!!!!!
Drugs with other mechanisms of Action
- Gabapentin
- Levetiracetam
- Pregabalin
- Ezogabine
Gabapentin
MECHANISM:
- Binds to voltage- dependent Ca+2 channels
KEY POINTS:
- No significant drug interactions
Leviteracetam
MECHANISM:
- Binds to synaptic
Vesicle protein SV2A – blunts glutamate release
KEY POINTS:
- Well- tolerated;
No CYP interaction
Pregabalin
MECHANISM:
- Multiple
KEY POINTS:
- 100% Renal CLEARANCE
Ezogabine
MECHANISMS:
- Opens voltage- gated K+ channels
KEY POINTS:
- Causes Urinary RETENTION
Why do Doctors Choose different Drugs or the same Type of Seizure?
- Seizure type is ONE determinant of drug utility
- Pharmacokinetic properties (ADME) are also a determinant of compliance, toxicity and adverse effects – PARTICULARLY INTERACTIONS WITH OTHER DRUGS ADMINISTERED TOGETHER WITH AEDS
Absorption
Distribution
Metabolism
Elimination
Two Traditional Drugs that block Voltage Gated Na+ Channels
- Phenytoin
- Carbamazepine
Phenytoin & Carbamazepine Uses For Epilepsy
- CARBAMAZEPINE & PHENYTOIN are widely used by many patients for treatment of certain types of partial or generalized Seizures disorders.
Complication with Phenytoin
** ZERO ORDER Pharmacokinetics!!!!!!
- Doubling the Dose does NOT necessarily double the Serum Level (Increase in Dose can Increase the Serum exponentially) therefore DOSE ADJUSTMENT is DIFFICULT!!!
- INDUCER of Hepatic CYP 450 Enzymes
Distinct Toxicities:
1) GINGIVAL HYPERPLASIA —> Hirsutism
2) HYPOCALCEMIA —> Osteoporosis
Complications with Carbamazepine
- INDUCER fo Hepatic CYP 45- Enzymes
1) ANAPLASTIC ANEMIA (Rare, but OFTEN FATAL) —> Idiosyncratic
- Leukopenia, Neutropenia, Thrombocytopenia (Infections, Bruising)
2) HYPOCALCEMIA —> Osteoporosis
Drug-Drug Interactions Associated With Hepatic CYP450 Induction by Carbamazepine, Phenytoin, Phenobarbital, Valproate et al.
- Induction /autoinduction of CYP450 by Carbamazepine confers RISKS for DRUG INTERACTIONS with serious consequences
***** OSTEOPENIA / OSTEOPOROSIS is a serious side effect associated with chronic administration of carbamazepine, phenytoin, phenobarbital & valproic acid.
*** These drugs INDUCE Cytochrome P450-dependent Vitamin D CATABOLISM, and thereby REDUCE CIRCULATING Vitamin D Levels.
*** The resultant DECREASED ABSORPTION of intestinal Ca2+ can trigger compensatory PTH-mediated responses that DEMINERALIZE BONE to maintain systemic Ca2+ homeostasis.
Carbamazepine Autoinduction fo CYP450
- CBZ Induces Its OWN Metabolism
- Loss of EFFICACY
- Recurrence of SEIZURES
Role of Drug Level Monitoring
- Carbamazepine levels must be monitored early in therapy.
- Dosage INCREASES up to 15 to 20 mg/kg per day may be NECESSARY after two to three months because of CYP450 AUTO-INDUCTION!!!
- Serum levels should be CHECKED e.g. EVERY Two Months until successive determinations are constant.
- Levels should be CHECKED if CBZ dosages are Changed or other Antiepileptic drug are ADDED to the treatment regimen.
AED-Drug Interactions: Oral Contraceptives
- STARTING Carbamazepine CAN INCREASE clearance of Oral Contraceptives (estrogen) metabolized by CYP isoenzymes
*** About 4 fold rise in OCP Failure Rate. Risk for UNPLANNED PREGNANCY!!!
AED-Drug Interactions: Oral Anti- Coagulants
- STARTING carbamazepine can INCREASE clearance of WARFARIN (ORAL ANTICOAGULANT) metabolized by CYP isoenzymes
- Too rapid coagulation. Elevated risk for Arterial/ Venous THROMBOSIS
AEDs’ Narrow Therapeutic Window
Carbamazepine: 3 fold
Ethosuximide: 2.5 fold
Phenobarbital: 2 fold
Phenytoin: 2 fold
Valproic acid: 2 fold
Primidone: 2 fold
** The induction process is NOT STATIC:
• Other drugs INDUCE or INHIBIT CYP
• Some foods, beverages INDUCE or INHIBIT CYP
ADME of New AEDs
MIXED CLEARANCE: Renal-Hepatic
- Topiramate/ Oxcarbazepine Levetiracetam / Zonisamide
** RENAL CLEARANCE >50% of total
- MINIMIZES Drug Interactions!!!!
Oxcarbazepine
- Is an ANALOGUE of
CARBAMAZEPINE but with the advantage of FEWER Adverse effects due to its lack of formation of an active metabolite - Metabolism of Oxcarbazepine occurs in the LIVER, but with minimal effects the CYP450 enzymes. This is advantageous in patients who require MULTIPLE DRUGS.
- NYPONATREMIA ASSOCIATED WITH BOTH OXCARBAZEPINE AND CARBAMAZEPINE is due to Increased Responsiveness of collecting tubules to antidiuretic hormone, and it is considered to be an example of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
ADME of New AEDs: Renal Clearance
- GABAPENTIN and PREGABALIN have 100% Renal Clearance!!!!
- Renal Insufficiency requires DOSE Adjustment
***Generally speaking newer AEDs have fewer problems attributable to drug interactions associated with hepatic metabolism. However, newer AEDs can still have serious toxicities
Boxed Warnings: Carbamazepine
Life-threatening:
1) Allergic reaction
(Stevens-Johnson syndrome)
2) Aplastic anemia
Boxed Warnings: Lamotrigine
Life-threatening:
1) Allergic reaction
(Stevens-Johnson syndrome)
Drug Interactions involving other Hepatic Enzyme Systems
- Valproate, lamotrigine INHIBIT CONJUGATION of drugs by UGT enzymes - causing accumulation of parent drug (e.g. EACH OTHER WHEN THYE ARE USED TOGETHER… WHICH THEY ARE OFTEN)
Adverse Effects Associated with “New” AEDS
1) LEVETIRACETAM:
- None
2) OXCARBAZEPINE:
- HYPONATREMIA (more common in elderly), rash
3) TIAGABINE:
- Stupor
4) TOPIRAMATE:
- NEPHROLITHIASIS, Open Angle Glaucoma, Hypohidrosis (mainly children)
5) ZONISAMIDE:
- Rash, renal calculi, hypohidrosis (mainly children)
Teratogenic Effects
- Several old (traditional) AEDs are Class D Teratogens:
1) Valproic Acid (Valproate)
2) Carbamazepine
3) Phenytoin
Valproic Acid and Congenital Malformations
- Associated with significantly increased risks for SPINA BIDIFA, ATRIAL SEPTAL DEFECT, CLEFT PALATE, HYPOSPADIAS, POLYDACTYLY, compared with no antiepileptic-drug use or use of other antiepileptic drugs.
