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Antiepleptic, neuropathic, antihypertensive medications Tom McPharlin R.Ph. Harborview Medical Center June 2012.

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Presentation on theme: "Antiepleptic, neuropathic, antihypertensive medications Tom McPharlin R.Ph. Harborview Medical Center June 2012."— Presentation transcript:

1 Antiepleptic, neuropathic, antihypertensive medications Tom McPharlin R.Ph. Harborview Medical Center June 2012

2 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

3 Drugs that decrease seizure threshold Penicillins (HD) Quinolones (HD) Disulfiram Dantrolene Antipsychotics – chlorpromazine – clozapine (titrate!) – perphenazine Tramadol (renal fx!) Buproprion (OD) Anticonvulsants (OD) Clomipramine Ethanol withdrawal Benzo withdrawal Illicit street drugs – Amphetamines – Cocaine – Ecstasy

4 Drugs that decrease seizure threshold

5 Drugs that decrease sz threshold


7 Treatments for epilepsy Medication (AEDs) Surgery Electrical stimulation Ketogenic diet

8 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

9 AEDs Broad Spectrum Agents – Felbamate – Lamotrigine – Levetiracetam – Rufinamide – Topiramate – Valproate – Zonisamide Narrow Spectrum Agents Carbamazepine Gabapentin Lacosamide Oxcarbazepine Phenytoin Pregabalin Tiagabine Ethosuximide (absence)

10 Pharmacology of AEDs GABA : – major inhibitory neurotransmitter – underexcited Glutamate (NMDA, Kinate, AMPA) : – major excitatory neurotransmitter – overexcited Sodium, Calcium, Potassium ? Channel Serotonin system?

11 Mechanism of action of AEDs

12 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 doesnt respond to first-line treatment (two drugs) Mortality: 8-32%

13 Progression of SE Neuronal injury 1 st phase – generalized tonic-clonic seizures – Increase in autonomic activation – Increase in cerebral blood flow 2 nd phase – failure of cerebral autoregulation – Decrease in cerebral blood flow – Clinical manifestations restricted twitching Longer sz untreated, greater neurologic damage, more difficult to treat.

14 Complications Cardiac dysrhythmias Pulmonary edema Hyperthermia Rhabdomyolysis Aspiration Pneumonia

15 Treatment of SE VA cooperative trial 1998 – SF Emergency Medical Service 2001 – Recommend lorazepam as 1 st -line Refractory – Evidence more limited – Drug of Choice (DOC): pentobarbital, midazolam and propofol continuous infusion – Alternative drugs: Valproate, Levetiracetam, lacosamide IV infusions

16 Diazepam vs Lorazepam DrugDoseOnsetDuration Points to remember Diazepam mg\kg 1 – 3 min min Redistributes out of CNS. Lipid soluble Lorazepam0.1mg\kg3-10 min hours Needs to be refrigerated. Water soluble, less likely to leave CNS.

17 Treatment algorithm 1 st : Lorazepam 0.1 mg/kg 2 nd : Phenytoin (fosphenytoin) 20mg/kg IV (monitor BP) Sz not controlled then: (+/- additional 5mg/kg Phenytoin?) Valproate 20-45mg/kg IV load or Levetiracetam mg IV x1 or Lacosamide?? mg IV x1 - Intubation after this point – Midazolam bolus 0.2mg/kg: 0.1mg/kg/hr continuous drip or 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 2

18 SE and treatment

19 RSE treatment


21 Efficacy of newer AEDs Clincal comparability of new AEDs in refractory partial epilepsy:A systematic review and meta-analysis Epelpsia 2011

22 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?


24 Drug Interactions Protein 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)

25 Drug Interactions - OCPs OCPs 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

26 Drug Interactions: Enzyme inducer AEDs

27 AED blood levels Used as a guide Useful when: – Assessing compliance – Drug interactions – Phenytoin dosing?! (FREE level) Therapeutic/Toxic levels defined by patient

28 Most significant AED adverse effects AEDAdverse effects PhenytoinSedation, hersutism, gum hyperplasia, drug interaction (DI), rash CarbamazepineSedation, rash, DI, hyponatremia TiagabineDizziness GabapentinSedation, Weight gain ValproateWeight gain, teratogenesis LamotrigineRash TopiramateCognitive slowing, weight loss, mood ZonisamideCognitive slowing, weight loss LevetiracetamMood change PregabalinWeight gain, sedation Oxcarbazepinehyponatremia

29 AEDs and teratogenicity

30 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

31 HLA-A 3101 allele Japanese – Associated with SJS-TEN European descent – High rate of hypersensitivity rxn including SJS- TEN

32 Specific AEDS in Depth

33 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 hours; consider special population (elderly, nutritional). Lots of Drug Interactions!!! (Inducer) Can worsen absence and Juvenile Myoclonic seizures

34 Phenytoin Dosing Loading dose: 18-20mg/kg – If given orally: saturable absorption mg – 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 mg)

35 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

36 Tube Feedings Decreases Phenytoin (PTN) bioavailability – Binding to enteral feeding – ca, casinates – Binding to actual tubing – 50% decrease in bioavailability Pharmacotherapy 1998;18(3): and/or Neurology 1978: ….

37 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)

38 Carbamazepine (CBZ) Absorption: 75% Metabolism: hepatic – CYP3A4, 1A2,2C8 – Epoxide – active metabolite Auto inducer: takes 4-6 weeks Dosing: 200mg BID; inc. q3-5days TI: 4-12 mcg/mL – not useful for epoxide metabolite –NOT reflected

39 CBZ Toxicity Diplopia Drowsiness Dizziness Blurred vision Poor mental performance Nystagmus Ataxia Anticholinergic SE Antidiuretic hormone like activity Altered lipids Thrombocytopenia Hepatitis Rashes Osteoporosis

40 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

41 Valproic Acid (VA) Absorption: 100% Distribution: highly protein bound Metabolism: Hepatic – Clearance: hepatic glucuronidation/beta- oxidation, CYP450 (minor) Drug interactions: inhibitor and protein binding displacer

42 VA Dosing Loading: 18-45mg/kg Maintenance: 500mg PO BID to TID – Pft/iv dose q8 h to q6 h TI: 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)

43 VA Toxicity GI effects Drowsiness/confusion Tremor Weight gain Hyperammonemia (without LFT changes) Inhibition of platelets and lowering of count Hepatotoxic Pancreatitis Teratogenic

44 Ethosuximide (Zarontin) Generalized absence Dose: 500 – 1500mg PO Qday TI: mcg/mL Absorption = 100 % Metabolized by liver (CYP450) Half-life hours

45 Ethosuximide Toxicity GI: nausea/vomiting Headaches Psychotic episodes Rash EPS – parkinsonism, bradykinesia

46 Newer AEDs Gabapentin (1993) Lamotrigine (1994) Topiramate (1996) Tiagabine (1997) Levetiracetam (1999) Oxcarbazepine (1999) Zonisamide (2000) Pregabalin (2001) Lacosamide (2009)

47 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 Havent 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

48 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 efficacy Renally eliminated

49 Topiramte Toxicity GI: diarrhea and weight loss CNS: mental slowing, fatigue Psychosis Acidosis Kidney stone formation

50 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

51 Oxcarbazepine (Trileptal) Similar to CBZ Used successfully as monotherapy for partial and sec generalized tonic/clonic seizures. NOT primary generalized. Dose: mg PO BID ADR: similar to CBZ, increased hyponatremia – cross sensitivity rxn occurs in 25% of pts who had rash from CBZ

52 Zonisamide (Zonegran) Adjunctive for partial seizures Start at 50mg PO BID, inc. q1-2wks to 200mg PO BID (or more) Few drug interactions SE: somnolence, headache, fatigue, rash Long half-life: 63 hours

53 Lacosamide (Vimpat) FDA approved for adjunctive treatment of partial-onset seizures (and diabetic neuropathic pain) Both IV and PO Works on slow inactivation Na channel Schedule V BID dosing ( mg/day) IV/po New….limited formulary.


55 Epilepsy and Women Reproductive Health – Catamenial Epilepsy – Infertility (ie. PCOS) – Contraception (ie. drug interactions) – Pregnancy (ie. frequency of seizures to mom) Fetal Malformations Osteoporosis Cosmetic Reasons

56 Women and contraceptives (drug interactions) Oral Contraceptives Pills (OCPs) – Interacts with lamotrigine by 40-50% reduction of lamotrigine blood levels – Patient on Enzyme inducing AEDs: Use at least mcg of estrogen (older OCPs) Tricycle (3 month consecutive cycle without 7 day placebo) with 4 days placebo between tricycles Does not apply to Depot forms (use normal dose)

57 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

58 Cosmetic Considerations Phenytoin – Gingival hyperplasia, hirsutism, coarse facial features Changes in Weight: Weight GainNeutralWeight Loss Valproic acidLamotrigineTopiramate GabapentinLevetiracetamZonisamide CarbamazepinePhenytoinFelbamate Tiagabine Vigabatrin Asconape JJ. Seminars in Neurology

59 Drug Interactions 1A22C92C192D63A4UGT PHTInducer PBInducer CBZInducer VPAInhibitor inhibitorInhibitor LTGWk inducer TPMWk inhibitor Wk inducer GBP LEV OXCinducer Anderson GD. Annuals of Pharm 1998

60 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

61 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 EEGs


63 Neuropathic pain and drug therapy TCAs AEDs SNRIs Lidocaine patch 5% Botulinum toxin Capsaicin Patch IMPORTANT 4-8 week trial for efficacy!

64 Agents in neuropathy

65 Studies

66 NNT and NNH

67 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

68 Side effects AEDs (gabapentin, pregabalin) – Drowsiness – Dizziness, cognitive or gait impairment – Peripheral edema

69 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)

70 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

71 Specific agents Venlafaxine: – Start XR 37.5 mg qd increase 75 mg q week – Maximum 225 mg qd – Efficacy at mg/day Gabapentin: – Start mg qhs OR mg q8h – Increase q day to week depending on tolerance – Max dose 3600 mg qd (1200mg q8 h) – RENALLY ELIMINATED

72 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

73 Specific agents Opoids: – Methadone ??? Tramadol – Start 50 mg qid based off tolerance – max 400 mg/day – Less efficacious than opioids? – RENALLY eliminated = seizures

74 Combination therapy LOW threshold to start! No one medication is effective for all Adverse effects limit dose Combos studied: – Gabapentin + MS – Pregabalin + oxycodone – Nortriptylene + gabapentin – Pregabalin + lidocaine patch – Valproate + glyceryl trinitrate spray

75 Toms tips

76 Antibiotics Vancomycin: – Weight based – load 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

77 Antibiotics Acyclovir: – 10 mg/kg based off IDEAL body wt. – ALWAYS IV fluids ~ 80 mL/h Cipro (fluroquinalones) NOT pft Dexamethasone for pneumococcal meningitis?? I say YES! – Dex 10 mg iv/po q6 h for 4 days

78 Phenytoin or phosphenytoin Dose 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

79 Phenytoin or phosphenytoin Dose: x mg IV = x mg PO = x mg BID pft Osteoporosis: use IU Vit D with Ca Phenytoin rate = 50mg/min OR 25mg/min – Cardiovascular patients or elderly – Hypotension….SLOW rate! Phosphenytoin rate = 150 mg/min

80 More AEDs ! 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!

81 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

82 Treatment of hypertension

83 Whats in store? Whats in store? CHEP 2009 guidelines Combination therapy Treatment of resistant hypertension Hypertension in the old – therapy? Blood pressure variability and risk Thiazide is a thiazide? NO!!

84 CHEP guidelines 2009





89 Combination therapy A = ACEI or ARB B = B-Blockers C = Calcium Channel Blockers D = Diuretic

90 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%.

91 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

92 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)

93 Combination therapy Studies have shown at least 75% require combination therapy: ALLHAT = 26% monotherapy HOT = 33% monotherapy LIFE = 10% monotherapy High blood pressure is usually multifactorial Volume, Cardiac performance, vascular resistance RAAS Meta-analysis shows monotherapy reduced bp by 9.1/5.5 mm Hg Little differences between classes VALUE trial showed better outcomes throughout 5 yr f/u in those that reached goal within first 6 months of tx

94 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.

95 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

96 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.

97 Thiazide is a thiazide? HCTZ: – T1/2 = hrs – Duration = 6-12 hrs Chlorthalidone: – T1/2 = hrs – Duration = hrs Indapamide: – T1/2 = hr – Duration = <36 hrs

98 Questions??? Questions???


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