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!!