Antiepleptic, neuropathic, antihypertensive medications
Tom McPharlin R.Ph.
Harborview Medical Center
June 2012
Causative factors
Structural damage to brain– Trauma– Stroke: ischemia, hemorrhage– Anoxia– Toxins– Tumors– Metabolic disorders– Prolonged seizures– Infection
Idiopathic – genetics (Channelopathy) Cryptogenic – no identifiable reason
Drugs that decrease seizure threshold
Penicillin’s (HD)Quinolones (HD)DisulfiramDantroleneAntipsychotics
– chlorpromazine– clozapine (titrate!)– perphenazine
Tramadol (renal fx!)
Buproprion (OD)Anticonvulsants (OD)ClomipramineEthanol withdrawalBenzo withdrawalIllicit street drugs
– Amphetamines– Cocaine– Ecstasy
Drugs that decrease seizure threshold
Drugs that decrease sz threshold
Drugs that decrease sz threshold
Treatments for epilepsy
Medication (AEDs)
Surgery
Electrical stimulation
Ketogenic diet
AED treatment Select proper AED for type of epilepsy
– Pharmacokinetic profile– Drug/Disease state interaction– Expected adverse effects– Patient preference
Use one agent until therapeutic effect OR toxicity
If inadequate control with first medication then add second drug slowly to therapeutic dose then start SLOWLY decreasing the first agent
AEDs
Broad Spectrum Agents
– Felbamate– Lamotrigine– Levetiracetam– Rufinamide– Topiramate– Valproate– Zonisamide
Narrow Spectrum Agents
Carbamazepine Gabapentin Lacosamide Oxcarbazepine Phenytoin Pregabalin Tiagabine
Ethosuximide (absence)
Pharmacology of AEDs
GABA :– major inhibitory neurotransmitter– underexcited
Glutamate (NMDA, Kinate, AMPA) :– major excitatory neurotransmitter– overexcited
Sodium, Calcium, Potassium ? ChannelSerotonin system?
Mechanism of action of AEDs
Status Epilepticus (SE)
Old definition: – continuous seizure lasting > 30 min
Newer definition: continuous, generalized, convulsive seizure lasting longer than 5 min (Lowenstein, 1999)
Refractory SE: sz lasting > 2 hours OR doesn’t respond to first-line treatment (two drugs)
Mortality: 8-32%
Progression of SE
Neuronal injury 1st phase – generalized tonic-clonic seizures
– Increase in autonomic activation– Increase in cerebral blood flow
2nd phase – failure of cerebral autoregulation– Decrease in cerebral blood flow– Clinical manifestations restricted twitching
Longer sz untreated, greater neurologic damage, more difficult to treat.
Complications
Cardiac dysrhythmiasPulmonary edemaHyperthermiaRhabdomyolysisAspiration Pneumonia
Treatment of SE
VA cooperative trial 1998– SF Emergency Medical Service 2001– Recommend lorazepam as 1st-line
Refractory– Evidence more limited– Drug of Choice (DOC): pentobarbital, midazolam and
propofol continuous infusion– Alternative drugs: Valproate , Levetiracetam ,
lacosamide IV infusions
Diazepam vs Lorazepam
Drug Dose Onset DurationPoints to
remember
Diazepam0.15-0.25mg\
kg1 – 3 min. 15-30 min
Redistributes out of CNS.Lipid soluble
Lorazepam 0.1mg\kg 3-10 min. 12-24 hours
Needs to be refrigerated.
Water soluble, less
likely to leave CNS.
Treatment algorithm 1st: Lorazepam 0.1 mg/kg 2nd: Phenytoin (fosphenytoin) 20mg/kg IV (monitor BP)
Sz not controlled then:(+/- additional 5mg/kg Phenytoin?)
Valproate 20-45mg/kg IV loador
Levetiracetam 1000-3000 mg IV x1• or
Lacosamide?? 200-400mg IV x1
- Intubation after this point –
Midazolam bolus 0.2mg/kg: 0.1mg/kg/hr continuous dripor
Propofol Bolus 1-2mg: 2mg/kg/hr continuous drip (MAX 48 HR)or
Pentobarbital Bolus 5-15mg/kg: 1mg/kg/hr continuous drip
Hirsch, et al. Treatment of SE 2002/NCC guidelines
SE and treatment
RSE treatment
FDA Indications for AEDs for seizure type
AED Partial (2nd generalized) Primary generalized
PHENYTOIN X NO
CARBAMAZEPINE X NO
OXCARBAZEPINE X NO
TIAGABINE X NO
GABAPENTIN X NO
PREGABALIN X NO
VALPROATE X X
LAMOTRIGINE X X
TOPIRAMATE X X
ZONISAMIDE X NO
LEVETIRACETAM X X
Efficacy of newer AEDsClincal comparability of new AEDs in refractory partial epilepsy:A systematic review and meta-analysis Epelpsia 2011
Drug Interactions
Inducers (2-3 weeks for max effect):– Carbamazepine– Phenytoin– Phenobarbital– Primidone (phenobarbital)– Oxcarbazepine, topiramate (>200mg/day), Rufinamide (3A4)
Inhibitors (mostly immediate):– Valproate– Felbamate– Stiripentol– Rufinamide?
Drug InteractionsProtein Binding:
– Phenytoin, Valproate, Carbamazepine, Tiagabine, Oxcarbazepine
Drug transporters (Pgp, MRP2, MRP3):– Induced by the AED inducers– Increased secretion of agent (renal,gut,brain)
Important interactions:– Valproate with Lamotrigine (increase t1/2) – Valproate and carbapenems (decrease vpa lvls)
Drug Interactions - OCPsOCPs and Inducer AEDs
– Estrogen decreased by Inducers No effect: gabapentin, levetiracetam, zonisamide,
lamotrigine, topiramate (dose <200mg/day) No effect on estrogen eluting IUDs
– High dose OCPs recommended (Ovral) OCPs effects on AED:
Lamotrigine levels decreased by 50% with OCPs– Estrogen component – Rebound effect on the 7 days off OCPs = toxicity?
Valproate levels (free and total) increased
Drug Interactions: Enzyme inducer AEDs
AED blood levels
Used as a guideUseful when:
– Assessing compliance– Drug interactions– Phenytoin dosing?! (FREE level)
Therapeutic/Toxic levels defined by patient
Most significant AED adverse effects
AED Adverse effects
Phenytoin Sedation, hersutism, gum hyperplasia, drug interaction (DI), rash
Carbamazepine Sedation, rash, DI, hyponatremia
Tiagabine Dizziness
Gabapentin Sedation, Weight gain
Valproate Weight gain, teratogenesis
Lamotrigine Rash
Topiramate Cognitive slowing, weight loss, mood
Zonisamide Cognitive slowing, weight loss
Levetiracetam Mood change
Pregabalin Weight gain, sedation
Oxcarbazepine hyponatremia
AEDs and teratogenicity
HLA-B 1502
Majority of Asians with SJS/TEN had allele– No association with Macro Papular Eruptions
Frequency:– 10-15% in China, Thailand, Malaysia,
Indonesia, Philippines and Taiwan– 2-4% in India– <1% in Japan and Korea
Asians should be screened prior to starting CBZ, Phenytoin and ?? Lamotrigine
HLA-A 3101 allele
Japanese – Associated with SJS-TEN
European descent– High rate of hypersensitivity rxn including SJS-
TEN
Specific AEDS in Depth
Phenytoin (Dilantin)
Absorption: 100% ; nonlinear – Exception: tube feedings = 50% decrease absorption
Distribution: highly protein bound (weakly) Metabolism: Hepatic Clearance: nonlinear kinetics (Michaelis-
Menton); CYP2C9 (major); half-life 18-24 hours; consider special population (elderly, nutritional).
Lots of Drug Interactions!!! (Inducer) Can worsen absence and Juvenile Myoclonic
seizures
Phenytoin Dosing
Loading dose: 18-20mg/kg– If given orally: saturable absorption 400-500mg– Dilute in 0.9% NaCl (will ppt in dextrose)– Max rate 50mg/min (hypotension rate-dep.)– Lower rate if elderly or multiple CV complications
25mg/min Maintenance: usually 300 – 400mg/day
(5mg/kg/day) Therapeutic Index: 10-20mcg/mL
– free (1-2mcg/mL) Given q HS (max oral 400-500mg)
Phenytoin Toxicity
Plasma level related– Nystagmus
(> 20mcg\mL)– Ataxia (>30 mcg\mL)– Confusion (> 40mcg\mL)– Encephalopathy– Seizure– Hypotension (rate)
Non-dose related – GI toxicity– Rash – Gingival hyperplasia– Hirsutism– Folate deficiency and megaloblastic anemia– Osteoporosis– Hepatotoxicity– Teratogenesis
Tube Feedings
Decreases Phenytoin (PTN) bioavailability– Binding to enteral feeding – ca, casinates– Binding to actual tubing– 50% decrease in bioavailability
Pharmacotherapy 1998;18(3):637-645 and/or Neurology 1978: ….
Fosphenytoin (Cerebyx)
Prodrug (inactive) of phenytoin Advantages:
– Soluble and stable in all IV solutions– Faster rate of infusion 150mg/min– Can be given IM (still use IV for SE)
Disadvantage– Must be converted by liver to gain activity– Units are expressed in PE (phenytoin equivalents)
Carbamazepine (CBZ)
Absorption: 75%Metabolism: hepatic – CYP3A4, 1A2,2C8
– Epoxide – active metaboliteAuto inducer: takes 4-6 weeks Dosing: 200mg BID; inc. q3-5daysTI: 4-12 mcg/mL
– not useful for epoxide metabolite –NOT reflected
CBZ Toxicity
DiplopiaDrowsinessDizzinessBlurred visionPoor mental performanceNystagmusAtaxia
Anticholinergic SEAntidiuretic hormone like activityAltered lipidsThrombocytopeniaHepatitisRashesOsteoporosis
Phenobarbital
Indicated for generalized onset myoclonic & partial/gen. onset tonic-clonic
Not used commonly as sz prophylaxis or maintenance
Studies have shown longer ICU\hospital stays Used more in practice in EtOH withdrawal and SE Load dose: 18mg/kg Maintenance: 120 – 180mg QD Half-Life: Approximately 3 days
Valproic Acid (VA)
Absorption: 100%Distribution: highly protein boundMetabolism: Hepatic
– Clearance: hepatic glucuronidation/beta-oxidation, CYP450 (minor)
Drug interactions: inhibitor and protein binding displacer
VA Dosing
Loading: 18-45mg/kgMaintenance: 500mg PO BID to TID
– Pft/iv dose q8 h to q6 hTI: 50-100+ mcg/mL (free is active form
but not measured)Available as:
– Divalproex sodium po (Depakote) 250, 500mg– Valproic acid syrup pft (tid to qid)– Valproic acid IV formulation (tid to qid)
VA Toxicity GI effects Drowsiness/confusion Tremor Weight gain Hyperammonemia (without LFT changes) Inhibition of platelets and lowering of count Hepatotoxic Pancreatitis Teratogenic
Ethosuximide (Zarontin)
Generalized absenceDose: 500 – 1500mg PO QdayTI: 40-100mcg/mLAbsorption = 100 %Metabolized by liver (CYP450)Half-life 40-60 hours
Ethosuximide Toxicity
GI: nausea/vomitingHeadachesPsychotic episodesRashEPS – parkinsonism, bradykinesia
Newer AED’s
Gabapentin (1993) Lamotrigine (1994) Topiramate (1996) Tiagabine (1997) Levetiracetam (1999) Oxcarbazepine (1999) Zonisamide (2000) Pregabalin (2001) Lacosamide (2009)
Lamotrigine (Lamictal) Partial seizures and primary generalized Start low 25mg PO QDay and titrate slowly to
150mg PO Q Day (approximate max 400 mg)
– Different with inducer (50mg) or inhibitor (25 mg qod) on board
Haven’t established definitive blood levels Toxicity
– Skin rash: erythematous, morbilliform rash occurring within 4-6 weeks.
– Enhanced by VPA; starting at higher doses and\or rapid dose escalation may increase toxicity
Topiramate (Topamax)
Adjunctive for partial seizures and primary generalized
Start at 25mg PO BID, increase weekly by 25-50mg to 200mg PO BID or more– RSE: MUCH faster and higher!
Drug levels do not correspond to efficacyRenally eliminated
Topiramte Toxicity
GI: diarrhea and weight lossCNS: mental slowing, fatiguePsychosisAcidosisKidney stone formation
Levetiracetam (Keppra)
Adjunctive for partial seizures and primary generalized
Case reports in SE – IV formulation Start dose at 500mg PO BID, inc. q2wk to
1500mg PO BID (possibly more) Drug levels do not correspond to efficacy Few DI – not metabolized by CYP or UGT Renally cleared – Dose adjust r/t GFR!! SE: Drowsiness, dizziness, agitation
Oxcarbazepine (Trileptal)
Similar to CBZUsed successfully as monotherapy for
partial and sec generalized tonic/clonic seizures. NOT primary generalized.
Dose: 300-600mg PO BIDADR: similar to CBZ, increased
hyponatremia – cross sensitivity rxn occurs in 25% of pts who had rash from CBZ
Zonisamide (Zonegran)
Adjunctive for partial seizuresStart at 50mg PO BID, inc. q1-2wks to
200mg PO BID (or more)Few drug interactionsSE: somnolence, headache, fatigue, rashLong half-life: 63 hours
Lacosamide (Vimpat)
FDA approved for adjunctive treatment of partial-onset seizures (and diabetic neuropathic pain)
Both IV and POWorks on slow inactivation Na channelSchedule VBID dosing (200-400mg/day) IV/poNew….limited formulary.
SPECIAL POPULATIONS
Epilepsy and Women
Reproductive Health– Catamenial Epilepsy– Infertility (ie. PCOS)– Contraception (ie. drug interactions)– Pregnancy (ie. frequency of seizures to mom)
Fetal MalformationsOsteoporosisCosmetic Reasons
Women and contraceptives (drug interactions)
Oral Contraceptives Pills (OCP’s)– Interacts with lamotrigine by 40-50% reduction
of lamotrigine blood levels– Patient on Enzyme inducing AED’s:
Use at least 50-60 mcg of estrogen (older OCP’s) Tricycle (3 month consecutive cycle without 7 day
placebo) with 4 days placebo between tricycles Does not apply to Depot forms (use normal dose)
Pregnancy Planned pregnancy important!!
– 50% are unplanned pregnancies Use mono therapy with lowest dose Avoid if possible:
– Use of valproic acid (Depakote) Dose effect?: High dose > 1000 mg more likely than
lower doses– Possibly carbamazepine?
Risk of birth defects is 2-3% in general population– Monotherapy has odds ratio (OR) of 2.8– Poly therapy has OR of 4.2
Folic Acid supplements ~ 5 mg/day
Cosmetic Considerations Phenytoin – Gingival hyperplasia,
hirsutism, coarse facial features
Changes in Weight:
Weight Gain Neutral Weight Loss
Valproic acid Lamotrigine Topiramate
Gabapentin Levetiracetam Zonisamide
Carbamazepine Phenytoin Felbamate
Tiagabine
Vigabatrin
Asconape JJ. Seminars in Neurology. 27-39.
Drug Interactions1A2 2C9 2C19 2D6 3A4 UGT
PHT Inducer Inducer Inducer Inducer
PB Inducer Inducer Inducer Inducer Inducer
CBZ Inducer Inducer Inducer Inducer Inducer
VPA Inhibitor Inhibitor Inhibitor inhibitor Inhibitor
LTG Wk inducer
TPM Wk inhibitor
Wk inducer
GBP
LEV
OXC inducer
Anderson GD. Annuals of Pharm 1998
Epilepsy and Elderly Sedation, behavioral disturbances, and cognitive
impairment significantly accentuated – More sensitive and s/e can develop at levels not
considered to be high. Pharmacokinetics:
– Metabolism: slower (both CBZ and VA converted to active metabolite)
– Renal clearance: lower– Lower albumin affecting binding of AED; more free
levels Drug Interactions: 2/3 of pts over 60 are taking 7
medications Osteoporosis
Discontinue?
Factors:– Type of seizure
Primary generalized sz (except JME)
– Age at onset– > 2 yrs of seizure freedom on AED (>60% success)– No prior attempt being unsuccessful– Etiology– Normal Neurologic exam– Control of seizure (frequency, duration, severity)– Normal EEG’s
QUESTIONS?
Neuropathic pain and drug therapy
TCAsAEDsSNRIsLidocaine patch 5%Botulinum toxinCapsaicin Patch
IMPORTANT 4-8 week trial for efficacy!
Agents in neuropathy
Studies
NNT and NNH
Side effects
TCAs (amitriptyline > nortrip, desipramine)– Drowsiness, confusion (caution elderly=falls)– Dry mouth– Orthostatic hypotension – Weight gain– Urinary retention– EKGs for patients over 40 (screen & routine)– CAUTION in patients with cardiac disease
Increase risk of MI, sudden cardiac death >100mg\/day
Side effects
AEDs (gabapentin, pregabalin)– Drowsiness– Dizziness, cognitive or gait impairment– Peripheral edema
Side effects
SNRIs (duloxetine, venlafaxine)– Nausea– Dizziness– Dry mouth– Sexual dysfunction– EKG in patients with CV risk (venlafaxine)– Blood pressure increase at high doses
(venlafaxine)
Specific agents
Nortriptyline, desipramine:– Start 25 mg qhs increase q3-5 days– Maximum 150 mg– Drug level?????
Duloxetine:– Start 30 mg qhs increase in a week– Target dose 60 mg qd (60mg qd = 60mg bid)– Max 60 mg bid
Specific agents
Venlafaxine:– Start XR 37.5 mg qd increase 75 mg q week– Maximum 225 mg qd– Efficacy at 150-225 mg/day
Gabapentin:– Start 100-300 mg qhs OR 100-300 mg q8h– Increase q day to week depending on tolerance– Max dose 3600 mg qd (1200mg q8 h)– RENALLY ELIMINATED
Specific agents
Pregabalin:– 50 mg tid or 75 mg bid increase 3-7 days as
tolerated– Target 200 mg tid or 300 mg q12 h
Efficacy 300mg/day = 600 mg/day?? Increase s/e– RENALLY eliminated
Lidocaine patch 5%– Qday off for 12 hours– Maximum of 3 patches
Specific agents
Opoids:– Methadone ???
Tramadol– Start 50 mg qid based off tolerance– max 400 mg/day– Less efficacious than opioids?– RENALLY eliminated = seizures
Combination therapy
LOW threshold to start!No one medication is effective for allAdverse effects limit doseCombos studied:
– Gabapentin + MS– Pregabalin + oxycodone– Nortriptylene + gabapentin– Pregabalin + lidocaine patch– Valproate + glyceryl trinitrate spray
Tom’s tips
Antibiotics
Vancomycin: – Weight based – load 20-30 mg/kg (max 2 to 2.5G load) – then 15 mg/kg (actual wt.) q 12h (q8 h dosing?)
Zosyn:– Dosing for pseudomonas is 4.5 G q6 h– Dose based off GFR– Possible use Cefepime due to increase
resistance
Antibiotics
Acyclovir:– 10 mg/kg based off IDEAL body wt.– ALWAYS IV fluids ~ 80 mL/h
Cipro (fluroquinalones) NOT pftDexamethasone for pneumococcal
meningitis?? I say YES! – Dex 10 mg iv/po q6 h for 4 days
Phenytoin or phosphenytoin
Dose 18-20 mg/kg (guess wt)– 1mg/kg = 1 point in total level (little less than)
Monitor free levels especially in ICU– About $1-2 more with total at HMC and UW
Normal ratio 1:10 but can change based off:– Albumin– Other bound drugs – BUN and Tb
Phenytoin or phosphenytoin
Dose: x mg IV = x mg PO = x mg BID pftOsteoporosis: use 800-1200 IU Vit D with
CaPhenytoin rate = 50mg/min OR 25mg/min
– Cardiovascular patients or elderly– Hypotension….SLOW rate!
Phosphenytoin rate = 150 mg/min
More AEDs !
Valproate:– Check NH4 levels if altered mental status– Decrease l-carnitine stores
Carbamazepine drug levels:– Do NOT reflect active metabolite 10,11
epoxide– Roughly 10% of parent drug unless inducer on.
Phenobarbital:– GREAT for AWS! Binding difference!
Drug Interactions!
Aspirin with NSAID reduced effectiveness of ASA
Plavix + ASA: unless stent should use ASA 81 mg – decrease risk for GI bleed
Plavix + PPI = CONTROVERSIAL..avoid??...unless of course GI bleed then Pantoprazole
Meropenem + valproate = 60% decrease in valproate levels
Treatment of hypertension
What’s in store?
CHEP 2009 guidelinesCombination therapyTreatment of resistant hypertensionHypertension in the old – therapy?Blood pressure variability and riskThiazide is a thiazide? NO!!
CHEP guidelines 2009
CHEP guidelines 2009
CHEP guidelines 2009
CHEP guidelines 2009
Combination therapy
A = ACEI or ARB
B = B-Blockers
C = Calcium Channel Blockers
D = Diuretic
Combination therapy
Complementary classes are 5-times more effective in lowering bp than increasing 1 drug– AB-CD system
Combination therapy with lower doses– Antihypertensive produce dose dependant s/e
Adherance:– Kaiser study showed adherence inversely related to
number of medications; 77%, 70%, 63%, 55%– Drops with increasing number of doses; 71%, 61%, 50%,
31%.
Combination therapy
RAAS inhibitor (ACEI, ARB) + Diuretic– Additive blood pressure reduction– Diuretics reduce intravascular volume
Activates RAAS = vasoconstriction, Na/H2O retention– RAAS inhibitor – attenuates diuretic s/e
RAAS inhibitor + CCB– Additive blood pressure reduction– RAAS inhibition improves s/e of CCB (edema)
CCB=arteriolar dilation, RAAS inhibition = venodilation
Treatment of resistant htn
Definition: Failure to reach goal bp despite full doses of an appropriate 3 drug regimen including diuretics
Incidence not known– ALLHAT 27% required 3 or more medications
Potential causes:– Longstanding htn– Secondary htn– Non-adherance to therapy– Interfering medications (NSAID, Sympathomimetics)– Lifestyle factors (Na intake, etoh, obesity, SA)
Combination therapy
Studies have shown at least 75% require combination therapy:ALLHAT = 26% monotherapyHOT = 33% monotherapyLIFE = 10% monotherapyHigh blood pressure is usually multifactorialVolume, Cardiac performance, vascular resistance
RAASMeta-analysis shows monotherapy reduced bp by 9.1/5.5 mm Hg
Little differences between classesVALUE trial showed better outcomes throughout 5 yr f/u in those that reached goal within first 6 months of tx
Blood pressure variability
Patients with episodic hypertension have increased risk of vascular events– Benefits of medication may partly be due to reduced
variability in blood pressure.– Acute ischemic stroke, variability linked to
hemorrhagic transformation– Moderate to high SBP variability showed increased
white matter disease– SD of SBP was shown to be independent predictor of
stroke after adjustment for mean SBP.
Blood pressure variability
ALLHAT trial:– Small differences in mean SBP between groups– Large differences in SD of SBP
Paralleled group differences in stroke risk Amlodipine < chlorthalidone < lisinopril
ASCOT-BPLA– Mean SBP were similar– Large difference in SD of SBP correlated to primary outcome– amlodipine < atenolol
MRC trail – showed b-blockers had no effect on stroke risk despite reduction
in mean sbp. Diuretic group had effect.– Correlated to SD of SBP
Thiazide is a thiazide?
Mr Fit trial:– “The data leading to the protocol change indicated that in the nine
clinic whose staff prescribed hydrochlorothiazide predominantly, the trend of mortality was unfavorable for SI men compared with UC men, whereas it was favorable in the six clinics whose staff primarily used chlorthalidone. “
Accomplish trial:– “A possible explanation for the difference between the outcomes of
this trial and those of ALLHAT is that chlorthalidone (which was used in ALLHAT) may differ from hydrochlorothiazide (which was used in the ACCOMPLISH trial) in its effect on outcomes independently of its effect on blood pressure.”
Thiazide is a thiazide?
HCTZ:– T1/2 = 5.6 -14.8 hrs– Duration = 6-12 hrs
Chlorthalidone:– T1/2 = 40-60 hrs– Duration = 24-72 hrs
Indapamide:– T1/2 = 14-18 hr– Duration = <36 hrs
Questions???
THANKS!!