Week 1 Antiepileptic 2 of 4 Flashcards
›Those drugs that alter synaptic function act primarily by enhancing GABA mediated neuronal inhibition:
–Phenobarbital: And other Barbiturates increase the duration of ion channel openings
–Benzodiazepines: increase frequency of GABA-mediated ion channel openings.
What delays the reuptake of GABA from synaptic clefts, effectively enhancing GABA-mediated neuronal inhibition after synaptic release of the neurotransmitter>
Tiagabine
Drug in which ›patients develop a tolerance and sedation is a common side effects?
Clonazepam
What drug is ›reserved for selected patients with uncontrolled seizures d/t its side effects?
Felbamate
What is a ›Recent benzo derivative. Unique because it does not cause significant sedation and can be used long-term d/t tolerance is relatively uncommon?
Clobazam
What drugs are used for partial seizures and has acceptable side effect profiles? (6)
›Drugs used for partial seizures and has acceptable side effect profiles:
–Carbamazepine
–Lamotrigine
–Oxcarbazepine
–Topiramate
–Zonisamide
–phenytoin
›Drugs useful for treatment of generalized seizures:
›Drugs useful for treatment of generalized seizures:
–Valproate
–Lamotrigine
–Topiramate
›Drugs effective in treatment of generalized nonconvulsive seizures and especially absence seizures:
›Drugs effective in treatment of generalized nonconvulsive seizures and especially absence seizures:
–Ethosuximide
–Lamotrigine
–valproate
What is an analog of GABA that increases synaptic GABA?
Gabapentin
What is theraputic plasma concentrations of Gabapentin?
2-20 mcg/mL
Gabapentin is ______ protein bound.
zero
Gabapentin is eliminated by?
renal
What are the uses for Gabapentin?
›Multiple uses:
–Anxiety
–Panic
–Major depression
Gabapentin has limited efficacy in ________ treatment.
epilepsy
›_________ drugs can render PO birth control less effective
›Antiepileptic drugs can render PO birth control less effective
›Seizures during pregnancy = increased ______ and ______ for mother and fetus
›Seizures during pregnancy = increased morbidity and mortality for mother and fetus
What is the goal for maternal epilepsy?
›Goal: Monotherapy with lowest dose to stop seizures
When is fetal organogenesis complete?
by 8th week
›Significant teratogenicity can happen if meds give in first 8 weeks
What are the neonatal issues with maternal epilepsy medications?
what medication has congential malformation comparable to general population?
what medication can be added during labor?
–Valproate and carbamazepine have more than double the risk of fetus with congenital malformations. Neural tube defects such as spina bifida may result
–Lamotrigine have rates of congenital malformation comparable to general population
–Clobazam may be added as needed especially during labor
›Used for patients with nonconvulsive and convulsive partial seizures. Useful in:
–Trigeminal neuralgia
–Glossopharyngeal neuralgia
Carbamazepine
›Only available PO; rapid absorption peak plasma concentrations in 2-6 hours
Carbamazepine
How much protein bound is carbamazepine?
70-80%
What is carbamazepine plasma elimination half time?
8-24 hours
›Because of Carbamazepine metabolism, increase in dosing may be needed in _________
2-4 weeks
Carbamazepine side effects?
›The usual side effects: sedation, vertigo, diplopia, n/v and chronic diarrhea in some patients.
›Rare side effects but can be life threatening:
–SIADH
–Aplastic anemia
–Thrombocytopenia
–Hepatocellular and cholestatic jaundice
–Oliguria
–HPTN
–Cardiac dysrhythmias
–WBC suppression
›High plasma concentration can have a arginine vasopressin hormone like actions resulting in hyponatremia
Carbamazepine
What happens in 10 % of pts. who take Carbamazepine?
skin rash
Carbamazepine accelerates metabolism of what drugs?
›Accelerates metabolism of:
–Valproic acid
–Ehtosuximide
–Corticosteroids
–Anticoagulants
–Antipsychotics
What drugs inhibit metabolism of carbamazepine sufficiently to cause toxic effects?
›Drugs that inhibit metabolism of carbamazepine sufficiently to cause toxic effects:
›Cimetidine
›Propoxyphene
›Diltiazem
›Verapamil
›Isoniazid
›erythromycin
What is NOT a first line drug. Reserved for pts intractable epilepsy?
Felbamate
What drug
›Used principally for poorly controlled partial and secondarily generalized seizures
Felbamate
Felbamate MOA
›MOA unknown:
May involve NMDA, GABA, and voltage-gated calcium currents
Felbamate pharmacokinetics?
›Pharmacokinetics:
–Rapid PO absorption
–Prolonged elimination half time
–Excreted unchanged by kidneys
-C-P450
Side effects of Felbamate
›Side Effects:
–Aplastic anemia
–Hepatotoxicity
–Monitor CPC, Liver Functions indicated
–Metabolized by liver cytochrome P 450 so effected by concurrent meds metabolized by cytochrome P 450
›Side Effects of what drug?
–Concomitant administration of carbamazepine or phenytoin may decrease plasma concentrations of
Felbamate
What drug is long acting. Effective against ALL seizure types EXCEPT nonconvulsive primary generalized seizures?
Phenobarbital
›Second-line drug treatment due to its side effects:
–Cognitive
–Behavioral
Phenobarbital
›Exerts antiepileptic properties:
–Partly through potentiation of postsynaptic actions of the inhibitory neurotransmitter GABA
–Inhibition of the excitatory postsynaptic actions of glutamate
–Prolongs the duration of chloride channel opening and limits spread of seizure activity and increases the seizure threshold.
Phenobarbital
PO absorption is slow but nearly complete in what drug?
Phenobarbital
Peak time concentration of Phenobaribital?
12-18 hours
Plasma proteing binding of Phenobarbital is ____ to ___.
48% to 54%
–~ 25% is eliminated by PH-dependent renal excretion with remainder inactivated by hepatic microsomal enzymes
Phenobarbital
–Principle metabolite is an inactive parahydroxyphenyl derivative excreted in urine as a sulfate conjugate.
Phenobarbital
Pheno barbital –Plasma concentration of _______are usually necessary for seizure control
–Plasma concentration of 10-40 mcg/ml are usually necessary for seizure control
Side effects of Phenobarbital?
›Side Effects:
–Sedation, irritability, hyperactivity most troublesome side effects
–Tolerance to sedation with chronic therapy
–Depression in adults, and confusion in elderly
–Megaloblastic anemia that responds to folic acid
–Osteomalacia that responds to vitamin D
–Nystagmus and ataxia with concentrations > 40 mcg/ml
–Abnormal collagen deposition causing Dupuytren (du-pew-TRNAZ) contracture may occur (mainly ring and pinky)
–Classic example of a hepatic microsomal enzyme inducer that can accelerate the metabolism of many lipid soluble drugs.
Phenytoin is a prototype of _______
hydantoins
Phenytoin is used for
›Effective tx of partial and generalized seizures
Phenytoin can be given how?
PO and IV
Phenytoin can be given acutely to achieve effective plasma concentration within ____ minutes.
20
When giving phenytoin__________ and is not accompanied by excessive sedation
high therapeutic index
MOA of Phenytoin
›MOA:
–Regulates sodium and possibly calcium ion transport across neuronal membranes
–This stabilizing effect on cell membranes is relatively selective for the cerebral cortex, although effect also extends to peripheral nerves
Pharmacokinetics of Phenytoin?
›Pharmacokinetics
–Poor water solubility may result in in slow and sometimes variable absorption from the GI (30%-97%)
–Initial adult dose is 3-4 mg/kg. Does >500 mg rarely tolerated
–Long duration so single daily so dosage
–GI intolerance may necessitate a divided dose
›Pharmacokinetics of Phenytoin:
–IV should not exceed ______ in adults
–Should not exceed ______ (or 50 mg/min) whichever is slower in pediatrics
–This is because of the risk of severe hypotension and cardiac arrhythmias
›Pharmacokinetics:
–IV should not exceed 50 mg/min in adults
–Should not exceed 1-3 mg/kg (or 50 mg/min) whichever is slower in pediatrics
–This is because of the risk of severe hypotension and cardiac arrhythmias
Plasma concentration of phenytoin?
›Plasma Concentration:
–Seizure control is usual obtain with plasma concentrations of 10-20 mcg/mL.
›Plasma Concentration of phenytoin
–For control of digitalis-induced cardiac dysrhythmias______ IV is given every 15-30 minutes until a satisfactory response or a max dose of 15 mg/kg is given
–Plasma phenytoin concentration of _______L is usually sufficient to suppress cardiac dysrhythmias
–Nystagmus and ataxia are likely with concentrations of ________
–Toxicity should be made on basis of clinical symptoms.
›Plasma Concentration:
–For control of digitalis-induced cardiac dysrhythmias 0.5-1.0 mg/kg IV is given every 15-30 minutes until a satisfactory response or a max dose of 15 mg/kg is given
–Plasma phenytoin concentration of 8-16 mcg/mL is usually sufficient to suppress cardiac dysrhythmias
–Nystagmus and ataxia are likely with concentrations of >20 mcg/ml
–Toxicity should be made on basis of clinical symptoms.
Proteing binding of Phenytoin:
›Protein Binding:
–90% to albumin
–Greater fraction remains unbound in neonates, hypoalbuminemia and in uremic patients
›Metabolism of Phenytoin
–98% is metabolized to the __________________appearing in urine as glucuronide. 2% unchanged in urine
–Concentrations of ________ follow 1st order kinetics and elimination half time is ~ 24 hours
–Concentrations of________ follow zero-order and the enzymes for metabolism become saturated and elimination becomes dose dependent. A relatively small increase in dose may result in dramatic increases in plasma concentration.
›Metabolism:
–98% is metabolized to the inactive derivative parahydroxyphenyl appearing in urine as glucuronide. 2% unchanged in urine
–Concentrations of < 10 mcg/mL follow 1st order kinetics and elimination half time is ~ 24 hours
–Concentrations of > 10 mcg/ml follow zero-order and the enzymes for metabolism become saturated and elimination becomes dose dependent. A relatively small increase in dose may result in dramatic increases in plasma concentration.
Phenytoin side effects?
›Side Effects:
–CNS toxicity manifesting as: (> 20 mcg/ml)
›Nystagmus
›Ataxia
›Diplopia
›Vertigo (cerebellar-vestibular dysfunction
–Peripheral neuropathy in 30% of pts
–Gingival hyperplasia in 20% pts and is probably the most common manifestation
principle mechanism of action Carbamazepine:
targeted seizure:
sodium ion channel blockade
partial seizures
principle mechanism of action Gabapentin
targeted seizure:
Unknown(increases GABA release) Ch.13
partial seizure, generalized seizures
Ch. 8 acts on calcium channels and inhibts glutamate release at the dorsal horn of the spinal cord.
principle mechanism of action phenobarbital
targeted seizure:
chloride ion channels
partial seizures
generalized seizures
principle mechanism of action phenytoin:
targeted seizure
sodium ion channel blockade
calcium ion channel
NMDA receptors
partial seizures
generalized seizures
principle mechanism of action Toprimate
targeted seizures
sodium ion channel blockade
enhanced GABA activity
glutamate antagonism
calcium ion channel blockade
partial/generalized seizures
principle mechanism of action valproate
targeted seizures
sodium ion channel blocker
calcium ion channels
partial / generalized seizures.
›Decreases frequency of seizures associated with Lennnox-Gastaut Syndrome and myotonic and atonic forms of epilepsy
which drug is this?
felmabate
which drug can slow metabolism of phenytoin, phenobarbital and Valproic acid
Felbamate because is a potent inhibitor of P 450 enzymes,
–If receiving Felbamate, these three drugs should be decreased by 20-30% to decrease toxicity
carbamazepine, phenytoin, and Valproic, dose should be decreased by 20-30% to prevent toxicity
