Presentation on theme: "Antiepleptic, neuropathic, antihypertensive medications"— Presentation transcript:
1 Antiepleptic, neuropathic, antihypertensive medications Tom McPharlin R.Ph.Harborview Medical CenterJune 2012Introduce myself
2 Causative factors Structural damage to brain TraumaStroke: ischemia, hemorrhageAnoxiaToxinsTumorsMetabolic disordersProlonged seizuresInfectionIdiopathic – genetics (Channelopathy)Cryptogenic – no identifiable reasonEx. Of cryptogenic would be lennox-gastaut syndrome
3 Drugs that decrease seizure threshold Penicillin’s (HD)Quinolones (HD)DisulfiramDantroleneAntipsychoticschlorpromazineclozapine (titrate!)perphenazineTramadol (renal fx!)Buproprion (OD)Anticonvulsants (OD)ClomipramineEthanol withdrawalBenzo withdrawalIllicit street drugsAmphetaminesCocaineEcstasy**all drug that affect the CNS have the potential of causing a sz. Obviously drugs taken in toxic doses also vary and cannot be completely listed.
7 Treatments for epilepsy Medication (AEDs)SurgeryElectrical stimulationKetogenic diet
8 AED treatment Select proper AED for type of epilepsy Pharmacokinetic profileDrug/Disease state interactionExpected adverse effectsPatient preferenceUse one agent until therapeutic effect OR toxicityIf inadequate control with first medication then add second drug slowly to therapeutic dose then start SLOWLY decreasing the first agent
10 Pharmacology of AEDs GABA : Glutamate (NMDA, Kinate, AMPA) : major inhibitory neurotransmitterunderexcitedGlutamate (NMDA, Kinate, AMPA) :major excitatory neurotransmitteroverexcitedSodium, Calcium, Potassium ? ChannelSerotonin system?Complex and multifactorial…but if you know these basic principles it will help in the understanding of how the drugs work.fine balance in the brain between factors that begin electrical activity and factors that restrict it, and there are also systems that limit the spread of electrical activityTx: benzo bind to GABA receptor and increase GABA transmissionBarbituates bind directly to GABA receptor
12 Status Epilepticus (SE) Old definition:continuous seizure lasting > 30 minNewer 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%Has been defined as a continuous seizure lasting 30 minutes or as two or more discrete seizures between which consciousness is not fully regainedNewer thought has proposed that SE be defined as a continuous, generalized, convulsive seizure lasting longer than 5 min, or two or more seizures during which patient does not return to baseline consciousness. (Lowenstein, 1999)new def based on rationale that typical, generalized tonic-clonic sz rarely lasts > 5min, spontaneous termination becomes less likely in sz of >5 in, and that longer the seizure continues the more difficult the sz becomes to control and greater degree of neuronal damage- unreasonable to wait 30 minutes to start treat SE…. Metabolic demands of brain increase 3-5 fold when exhausted causes brain damage-sz recurrence is a significant risk-
13 Progression of SE Neuronal injury 1st phase – generalized tonic-clonic seizuresIncrease in autonomic activationIncrease in cerebral blood flow2nd phase – failure of cerebral autoregulationDecrease in cerebral blood flowClinical manifestations restricted twitchingLonger sz untreated, greater neurologic damage, more difficult to treat.Neuronal injuray1st phase – generalized tonic-clonic szIncrease in autonomic activation – ie. Hypertension, hyperglycemia, sweating, salvationIncrease in cerebral blood flow which incr the metabolic demands of the brain2nd phase – 30 min later failure of cerebral autoregDecrease in cerebral blood flow – which causes an increase in ICP and systemic decrease in BPSz at this point cont but clinical manifestations are restricted to minor twitching (looks like a coma)Ends in brain death
15 Treatment of SE VA cooperative trial 1998 Refractory SF Emergency Medical Service 2001Recommend lorazepam as 1st-lineRefractoryEvidence more limitedDrug of Choice (DOC): pentobarbital, midazolam and propofol continuous infusionAlternative drugs: Valproate , Levetiracetam , lacosamide IV infusionsMention potential of IV valproic acid and case studies and potential use of topamaxTx successful if clinical and electrical evidenc of sz activity stopped within 20 min after starte of tx and id not recur during the period fomr 20-60min.
16 Diazepam vs Lorazepam Drug Dose Onset Duration Points to remember mg\kg1 – 3 min.15-30 minRedistributes out of CNS.Lipid solubleLorazepam0.1mg\kg3-10 min.12-24 hoursNeeds to be refrigerated.Water soluble, less likely to leave CNS.Diazepam:Rapid onsetCan be given rectallyDis: short duration of action, depresses cons, active metaboliteLorazepam:Also has rapid onset of action but a longer duration than diazepamDis: needs to be refrigerated therefore often not in Medic trucks
17 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 loadorLevetiracetam mg IV x1Lacosamide?? mg IV x1- Intubation after this point –Midazolam bolus 0.2mg/kg: 0.1mg/kg/hr continuous dripPropofol Bolus 1-2mg: 2mg/kg/hr continuous drip (MAX 48 HR)Pentobarbital Bolus 5-15mg/kg: 1mg/kg/hr continuous drip2Hirsch, et al. Treatment of SE 2002/NCC guidelines
20 FDA Indications for AEDs for seizure type Partial (2nd generalized)Primary generalizedPHENYTOINXNOCARBAMAZEPINEOXCARBAZEPINETIAGABINEGABAPENTINPREGABALINVALPROATELAMOTRIGINETOPIRAMATEZONISAMIDELEVETIRACETAM
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): CarbamazepinePhenytoinPhenobarbitalPrimidone (phenobarbital)Oxcarbazepine, topiramate (>200mg/day), Rufinamide (3A4)Inhibitors (mostly immediate):ValproateFelbamateStiripentolRufinamide?
24 Drug Interactions Protein Binding: Phenytoin, Valproate, Carbamazepine, Tiagabine, OxcarbazepineDrug transporters (Pgp, MRP2, MRP3):Induced by the AED inducersIncreased 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 AEDsEstrogen decreased by InducersNo effect: gabapentin, levetiracetam, zonisamide, lamotrigine, topiramate (dose <200mg/day)No effect on estrogen eluting IUDsHigh dose OCPs recommended (Ovral)OCPs effects on AED:Lamotrigine levels decreased by 50% with OCPsEstrogen componentRebound effect on the 7 days off OCPs = toxicity?Valproate levels (free and total) increased
30 HLA-B 1502 Majority of Asians with SJS/TEN had allele Frequency: No association with Macro Papular EruptionsFrequency:10-15% in China, Thailand, Malaysia, Indonesia, Philippines and Taiwan2-4% in India<1% in Japan and KoreaAsians should be screened prior to starting CBZ, Phenytoin and ?? Lamotrigine
31 HLA-A 3101 allele Japanese European descent Associated with SJS-TEN High rate of hypersensitivity rxn including SJS-TEN
33 Phenytoin (Dilantin) Absorption: 100% ; nonlinear Exception: tube feedings = 50% decrease absorptionDistribution: highly protein bound (weakly)Metabolism: HepaticClearance: 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 seizuresGold standard in sz prophylaxis and treatment. ….Small change in dose or F can result in disproportionate change in steady-stateFosphenytoin (Cerebyx) – prodrug of Phenytoinunlike phenytoin higly soluble and stable in all IV solutions due to presence of a phosphate grouplower need for reduction infusion rates, can be infused rapidly over minutes 150mg\minadvantage: can be given IM but it still should be given IV for SEdisadvantage, must be converted by liver to gain pharmacological activityAbsorption: F~ 1 ; nonlinear; tube feedingsDistribution: highly protein bound (consider following people renal failure, pregnancy, liver dx, alcoholics, ICU, elderly)Clearance: nonlinear kinetics (Michaelis-Menton); CYP2C9 (major); half-life hours; consider special pop. (hepatic failure, elderly(low metabolism need smaller dose/kg), children (high met: larger dose/kg)
34 Phenytoin Dosing Loading dose: 18-20mg/kg If given orally: saturable absorption mgDilute in 0.9% NaCl (will ppt in dextrose)Max rate 50mg/min (hypotension rate-dep.)Lower rate if elderly or multiple CV complications 25mg/minMaintenance: usually 300 – 400mg/day (5mg/kg/day)Therapeutic Index: 10-20mcg/mLfree (1-2mcg/mL)Given q HS (max oral mg)infusion rate limited by cardiotoxic side effects (main advantage of fosphenytoin) max 50mg\minSome disadvantages: poorly soluble in water. Dissolved in propylene glycol and sodium hydroxide (lye). These are responsible fro pain during infusion, phlebitis, and skin sloughing after extravsation, and hypotensionoriginally formulated to be an IM preparation rather than IV, however when given IM extremely painful and poorly absorbed (don’t give IM)
35 Phenytoin Toxicity Plasma level related Non-dose related Nystagmus (> 20mcg\mL)Ataxia (>30 mcg\mL)Confusion (> 40mcg\mL)EncephalopathySeizureHypotension (rate)Non-dose relatedGI toxicityRashGingival hyperplasiaHirsutismFolate deficiency and megaloblastic anemiaOsteoporosisHepatotoxicityTeratogenesisPlasma level relatedNystagmus (> 20mcg\mL) – rapid involuntary movement of eyesAtaxia (>30 mcg\mL) – shaky movements and unsteady gaitConfusion (> 40mcg\mL)EncephalopathyNon-dose relatedGI toxicity (give with food)Rash (Cross sensitivity with other agents???)Gingival hyperplasiaHirsutismFolate deficiency and megaloblastic anemiaOsteoporosis – give with Ca/Vit DHepatotoxicity – ass with rash and fever and lymphadenopathyTeratogenesis – fetal hydantoin syndrome cleft palate and enlarged facial bones
36 Tube Feedings Decreases Phenytoin (PTN) bioavailability Binding to enteral feeding – ca, casinatesBinding to actual tubing50% decrease in bioavailabilityPharmacotherapy 1998;18(3): and/or Neurology 1978: ….
37 Fosphenytoin (Cerebyx) Prodrug (inactive) of phenytoinAdvantages:Soluble and stable in all IV solutionsFaster rate of infusion 150mg/minCan be given IM (still use IV for SE)DisadvantageMust be converted by liver to gain activityUnits are expressed in PE (phenytoin equivalents)
38 Carbamazepine (CBZ) Absorption: 75% Metabolism: hepatic – CYP3A4, 1A2,2C8Epoxide – active metaboliteAuto inducer: takes 4-6 weeksDosing: 200mg BID; inc. q3-5daysTI: 4-12 mcg/mLnot useful for epoxide metabolite –NOT reflectedIndications: GTC and partial sz disorders, trigeminal neuralgia, bipolar dxProminent features: poor conc-dose relationship, active metabolite, and autoinducerAbsorption: has low water solubility so absorption is low. Dissolution-rate dependent; food enhances F and suspension is abs faster than tablets
39 CBZ Toxicity Diplopia Drowsiness Dizziness Blurred vision Poor mental performanceNystagmusAtaxiaAnticholinergic SEAntidiuretic hormone like activityAltered lipidsThrombocytopeniaHepatitisRashesOsteoporosisDiplopiaDrowsinessDizzinessBlurred visionPoor mental performanceNystagmusAtaxiaHyponatremia defined as sNa of <135. Potential mechanism is that it increases sensitivityo osmorecptors to ADH or have direct effect on receptors. Closely linked to age. Incidence increases with age. See it develop in first 90 days.
40 PhenobarbitalIndicated for generalized onset myoclonic & partial/gen. onset tonic-clonicNot used commonly as sz prophylaxis or maintenanceStudies have shown longer ICU\hospital staysUsed more in practice in EtOH withdrawal and SELoad dose: 18mg/kgMaintenance: 120 – 180mg QDHalf-Life: Approximately 3 daysWater soluble and inexpensiveDownside isCNS depression leading to respiratory compromiseSide effects: rash/steven-johnson, blood dyscraias, angioedemaLot of Drug interactions
41 Valproic Acid (VA) Absorption: 100% Distribution: highly protein bound Metabolism: HepaticClearance: hepatic glucuronidation/beta-oxidation, CYP450 (minor)Drug interactions: inhibitor and protein binding displacerBroad spectum anticonvulsant. Best for myoclonic jerking, absence. Also been used for migraines and psych illness such as bipolar. Also indicated for generalized myoclonic, partial/generalized onsetFree level monitoring has been recommended since free is the active form however conc-effect relationship have shown to be variable fpr both free and total levelsMany formulationsDepacon – IV formulationDepakote – oral preparation
42 VA Dosing Loading: 18-45mg/kg Maintenance: 500mg PO BID to TID Pft/iv dose q8 h to q6 hTI: mcg/mL (free is active form but not measured)Available as:Divalproex sodium po (Depakote) 250, 500mgValproic acid syrup pft (tid to qid)Valproic acid IV formulation (tid to qid)Start low to avoid GI Side effects and drowsiness. Increase 25-30% every 7 days until targe dose reached
43 VA Toxicity GI effects Drowsiness/confusion Tremor Weight gain Hyperammonemia (without LFT changes)Inhibition of platelets and lowering of countHepatotoxicPancreatitisTeratogenicGI effects – take with foodDrowsiness/confusionTremorWeight gainHyperammoniemia – explain mechanism and antidote L-carnitineInhibition of platelets and lowering of countHepatoxic –PancreatitisTeratogenic- spinal bifida
44 Ethosuximide (Zarontin) Generalized absenceDose: 500 – 1500mg PO QdayTI: mcg/mLAbsorption = 100 %Metabolized by liver (CYP450)Half-life hours
46 Newer AED’s Gabapentin (1993) Lamotrigine (1994) Topiramate (1996) Tiagabine (1997)Levetiracetam (1999)Oxcarbazepine (1999)Zonisamide (2000)Pregabalin (2001)Lacosamide (2009)Older agents can cause a lot of SE and also:narrow Therapeutic windowPharmacokinetic and pharmacetuical prop making administration difficult and complexDrug interactionsCross-reactivity between agentsAll these have lead to finding newer agentsProblem with these agents. Research is poor in head to head trials with older agents. No IV formulations available.Gabapentin – not going to talk a whole lot about since we generally don’t use it on our service. Division between coasts opinion.
47 Lamotrigine (Lamictal) Partial seizures and primary generalizedStart 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 boardHaven’t established definitive blood levelsToxicitySkin rash: erythematous, morbilliform rash occurring within 4-6 weeks.Enhanced by VPA; starting at higher doses and\or rapid dose escalation may increase toxicityIndicated for partial sz but also being used in other psych disorders, migraine, and painDown side is that it can take weeks for beneficial effects to occur
48 Topiramate (Topamax)Adjunctive for partial seizures and primary generalizedStart at 25mg PO BID, increase weekly by 25-50mg to 200mg PO BID or moreRSE: MUCH faster and higher!Drug levels do not correspond to efficacyRenally eliminatedAlso starting to be used as monotherapy for sz and in psych (bipolar), peripheral neuropathies, essential tremor and migraines.
49 Topiramte Toxicity GI: diarrhea and weight loss CNS: mental slowing, fatiguePsychosisAcidosisKidney stone formation
50 Levetiracetam (Keppra) Adjunctive for partial seizures and primary generalizedCase reports in SE – IV formulationStart dose at 500mg PO BID, inc. q2wk to 1500mg PO BID (possibly more)Drug levels do not correspond to efficacyFew DI – not metabolized by CYP or UGTRenally cleared – Dose adjust r/t GFR!!SE: Drowsiness, dizziness, agitationIV formulation – add on therapy or transitional mediation
51 Oxcarbazepine (Trileptal) Similar to CBZUsed successfully as monotherapy for partial and sec generalized tonic/clonic seizures. NOT primary generalized.Dose: mg PO BIDADR: similar to CBZ, increased hyponatremia – cross sensitivity rxn occurs in 25% of pts who had rash from CBZDoes not work on absence or myoclonic szhyponatremia more common with OXC vs CBZLeudopenia is less common with OXUnlike CBZ there is no autoinductionSeems to be equally effective with CBZ in tx of partial and sec generalized sz with fewer SE and fewer DIBest if used in tx of localization related epilepsy
52 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 hoursSulfa compound ---- cross-reactivity with sulfa drugs??? Some-Studies in partial and sec generalized tonic/clonic szADRs: infrequent. But 2% of pts have been found to have renal calculi, dizziness and mental slowing depending on rate of escalationRenally excreted after conjugationHalf life of 2-3 days as monotherapy or days with enzyme inducers
53 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 ( mg/day) IV/poNew….limited formulary.
55 Epilepsy and Women Reproductive Health Osteoporosis Cosmetic Reasons Catamenial EpilepsyInfertility (ie. PCOS)Contraception (ie. drug interactions)Pregnancy (ie. frequency of seizures to mom)Fetal MalformationsOsteoporosisCosmetic ReasonsMany sex-specific concerns. Sz have been linked to menarche, menstrrual cycles, and menopause. Family planning is affected by both seizures and AEDsSex hormones alter neuronal excitabilityEstorgen inhibits aminobutyric acid and potentiates glutamate resulting in heightened excitability (pro-convulsive)Progesterone (anti-convulsive) has opposite effect; its metoboites potentiate barbiturate-like ligands at the aminobutyric acid channel resulting in increased inhibition with reduced epileptiform discharges and fewer sz. Consequentely sz frequency can be altered at puberty, during a menstrual cycle, pregnancy, and menopauseCBZ, PHT, PB and VA all alter endogenous steroid hormones. Newer drugs like lamotrigine and GABA do not and thus have been advantageous.Contraception: higher failure rate of hormonal contraception, esp with enzyme inducing AED: ie. Barbs, PTN, CBZ, OBZ, lesser extent felbamate and topiramate.Can still use OCP but must use higher does with 50mcg of estradiol rather than typical 20-35mcg.Hormonal contraceptives have not been reported to interfere with sz controlGood alternative agents to use with OCP are VA, gabapentin, lamotrigine, levetiracetam or benzoslow dose tiagabine does not interact but may with higher dosesPregnancy: goal is to remain sz-free. 2-3 fold increase in common complications of preganacy occurs in women with eopilepsy. High rate of spontaneous abortions and lower fertility rates. Generalized tonic-clonic sz are harmful to devleoping fetus…causing alterations in blood pressure, oxygenation, and electrolytes.Effects of preg on epilepsy: 25% will experience inc in sz. Most commonly seen by the end of 1st trimester or beginninf of second trimester. Reasons are multifactorial: med compliance, lowered AED levels , sleep deprivation and stressdecline in levels due to accelerated hepatic metobolism, N/V, changes in plasma volume, absorption, and protein binding. Although total levels decline, free levels may increase b/c of lowered serum albumin. Thus both free and total levels should be checkedFolic acid def: PTN, CBZ, and barbs interfere with absorption/metabolism of folate. Needed to prevent neural tube defects and cleft palateFetal Malformation: major defects include fetal hydantion syndrome cleft palate and enlarged facial bones. , cardiac defects, cleft lip, skeletal malforamtion. AR are greater with polytherapy vs monotherapy, higher vs lower AED levels, and AED-treated vs untreated women.Osteoporosis – women are already at a higher risk than men for issues of osteo. But AEDs can cause additive damage by inducing the metabolism of vitamin D. ie PTN, PB, CBZ and primadone.Reports of valproic acid causing decrease in bone mass. Mech still uncertain but may be associatate with an increase in ionized calcium which via negative feedback mechanisms reduces secratio of PTH and suprersses formatino of vitamin d.
56 Women and contraceptives (drug interactions) Oral Contraceptives Pills (OCP’s)Interacts with lamotrigine by 40-50% reduction of lamotrigine blood levelsPatient on Enzyme inducing AED’s:Use at least mcg of estrogen (older OCP’s)Tricycle (3 month consecutive cycle without 7 day placebo) with 4 days placebo between tricyclesDoes not apply to Depot forms (use normal dose)
57 Pregnancy Planned pregnancy important!! 50% are unplanned pregnancies Use mono therapy with lowest doseAvoid if possible:Use of valproic acid (Depakote)Dose effect?: High dose > 1000 mg more likely than lower dosesPossibly carbamazepine?Risk of birth defects is 2-3% in general populationMonotherapy has odds ratio (OR) of 2.8Poly therapy has OR of 4.2Folic Acid supplements ~ 5 mg/day
58 Cosmetic Considerations Phenytoin – Gingival hyperplasia, hirsutism, coarse facial featuresChanges in Weight:Weight GainNeutralWeight LossValproic acidLamotrigineTopiramateGabapentinLevetiracetamZonisamideCarbamazepinePhenytoinFelbamateTiagabineVigabatrinWeight gain:VPA, Gabapentin – have the highest maximal within 6 mo.CBZ, tiagabine, vigabatrin – have been associatedWeight loss: Topiramate, Zonisamide, FelbamateAsconape JJ. Seminars in Neurology
59 Drug Interactions 1A2 2C9 2C19 2D6 3A4 UGT PHT Inducer PB CBZ VPA InhibitorinhibitorLTGWk inducerTPMWk inhibitorGBPLEVOXCinducerEnzyme Induction: results in an increase in rate of metabolism of affected drug, decrease in serum conc of parent drug, and poss loss of efficacy. If the affected drug has an active metabolite, induction can cause an increase in drug therapeutic effect or cause toxicity.Takes about 1-2 weeks to see inductive effect and the same amount when discontinuing med.Enzyme inhibition: usually occurs b/c of competition at the enzyme site.Most abundant isoenzyme is 3A4; involved in metabolism of more than 50% of all drugsProtein-binding displacement interactions: clinically sig interactions occur only in highly protein-bound drugs. PTN and VA are the most important in these reactions.Phenytoin: increases met of CYP2C AND CYP3A subfamilies and UGT enzymes- warfarin: see an initial increase in INR due to competitively inhibits metabolism of warfarin and displaces warfarin from albumin-binding sites. After 1-2 weeks induction of 2C9 occurs and INR drops.PB:Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations.CBZ: also induces it own metabolism through 3A4 to CBZ-10,11-epoxideRiva R, Albani F, Contin M, Baruzzi A. Epilepsy Center, University Department of Neurology, Bologna, Italy. Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial beta-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.Anderson GD. Annuals of Pharm 1998
60 Epilepsy and ElderlySedation, behavioral disturbances, and cognitive impairment significantly accentuatedMore 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: lowerLower albumin affecting binding of AED; more free levelsDrug Interactions: 2/3 of pts over 60 are taking 7 medicationsOsteoporosisClassically sz disorders were thought to have the highest occurance in infancy and childhood. As people are starting to live longer seeng a trend increasing in the elderly. Condiation at greatest risk were Alzheimers, cerebrovascular dx and brain tumors.Post-traumatic epil has highest incidenct in yr age group; up to 50% of individ with head injury will develop sz (Jennett, 1975) important prognositc factors include prolonged period of unconsciousness, evidnce of contusion or penetrating head injuriesPt over 65, vascular dx is most common reason and depends on area or stucture in CNS injured. Highest incidence of sz is associated with embolic strokes, AVM, ICH, and arteritis (Foster and Booker, 1983)Some association with degenerative dementias causeing szAnd as we age renal and hepatic medical disordesr are common leading to szDrug overdosesmore susceptible to neruotoxic effects of AED including gait disturbance, sedation, tremor
61 Discontinue? Factors: Type of seizure Age at onset Primary generalized sz (except JME)Age at onset> 2 yrs of seizure freedom on AED (>60% success)No prior attempt being unsuccessfulEtiologyNormal Neurologic examControl of seizure (frequency, duration, severity)Normal EEG’s
67 Side effects TCAs (amitriptyline > nortrip, desipramine) Drowsiness, confusion (caution elderly=falls)Dry mouthOrthostatic hypotensionWeight gainUrinary retentionEKGs for patients over 40 (screen & routine)CAUTION in patients with cardiac diseaseIncrease risk of MI, sudden cardiac death >100mg\/day
68 Side effects AEDs (gabapentin, pregabalin) Drowsiness Dizziness, cognitive or gait impairmentPeripheral edema
69 Side effects SNRIs (duloxetine, venlafaxine) Nausea Dizziness Dry mouthSexual dysfunctionEKG in patients with CV risk (venlafaxine)Blood pressure increase at high doses (venlafaxine)
71 Specific agents Venlafaxine: Gabapentin: Start XR 37.5 mg qd increase 75 mg q weekMaximum 225 mg qdEfficacy at mg/dayGabapentin:Start mg qhs OR mg q8hIncrease q day to week depending on toleranceMax dose 3600 mg qd (1200mg q8 h)RENALLY ELIMINATED
72 Specific agents Pregabalin: Lidocaine patch 5% 50 mg tid or 75 mg bid increase 3-7 days as toleratedTarget 200 mg tid or 300 mg q12 hEfficacy 300mg/day = 600 mg/day?? Increase s/eRENALLY eliminatedLidocaine patch 5%Qday off for 12 hoursMaximum of 3 patches
73 Specific agents Opoids: Tramadol Methadone ??? Start 50 mg qid based off tolerancemax 400 mg/dayLess efficacious than opioids?RENALLY eliminated = seizures
74 Combination therapy LOW threshold to start! No one medication is effective for allAdverse effects limit doseCombos studied:Gabapentin + MSPregabalin + oxycodoneNortriptylene + gabapentinPregabalin + lidocaine patchValproate + glyceryl trinitrate spray
76 Antibiotics Vancomycin: Zosyn: 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 hDose based off GFRPossible use Cefepime due to increase resistance
77 Antibiotics Acyclovir: Cipro (fluroquinalones) NOT pft 10 mg/kg based off IDEAL body wt.ALWAYS IV fluids ~ 80 mL/hCipro (fluroquinalones) NOT pftDexamethasone 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 ICUAbout $1-2 more with total at HMC and UWNormal ratio 1:10 but can change based off:AlbuminOther bound drugsBUN and Tb
79 Phenytoin or phosphenytoin Dose: x mg IV = x mg PO = x mg BID pftOsteoporosis: use IU Vit D with CaPhenytoin rate = 50mg/min OR 25mg/minCardiovascular patients or elderlyHypotension….SLOW rate!Phosphenytoin rate = 150 mg/min
80 More AEDs ! Valproate: Carbamazepine drug levels: Phenobarbital: Check NH4 levels if altered mental statusDecrease l-carnitine storesCarbamazepine drug levels:Do NOT reflect active metabolite 10,11 epoxideRoughly 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 bleedPlavix + PPI = CONTROVERSIAL..avoid??...unless of course GI bleed then PantoprazoleMeropenem + valproate = 60% decrease in valproate levels
89 C = Calcium Channel Blockers D = Diuretic Combination therapyA = ACEI or ARBB = B-BlockersC = Calcium Channel BlockersD = Diuretic
90 Combination therapyComplementary classes are 5-times more effective in lowering bp than increasing 1 drugAB-CD systemCombination therapy with lower dosesAntihypertensive produce dose dependant s/eAdherance:Kaiser study showed adherence inversely related to number of medications; 77%, 70%, 63%, 55%Drops with increasing number of doses; 71%, 61%, 50%, 31%.
92 Treatment of resistant htn Definition: Failure to reach goal bp despite full doses of an appropriate 3 drug regimen including diureticsIncidence not knownALLHAT 27% required 3 or more medicationsPotential causes:Longstanding htnSecondary htnNon-adherance to therapyInterfering medications (NSAID, Sympathomimetics)Lifestyle factors (Na intake, etoh, obesity, SA)
93 Combination therapyStudies have shown at least 75% require combination therapy:ALLHAT = 26% monotherapyHOT = 33% monotherapyLIFE = 10% monotherapyHigh blood pressure is usually multifactorialVolume, Cardiac performance, vascular resistanceRAASMeta-analysis shows monotherapy reduced bp by 9.1/5.5 mm HgLittle differences between classesVALUE 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 eventsBenefits of medication may partly be due to reduced variability in blood pressure.Acute ischemic stroke, variability linked to hemorrhagic transformationModerate to high SBP variability showed increased white matter diseaseSD 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 groupsLarge differences in SD of SBPParalleled group differences in stroke riskAmlodipine < chlorthalidone < lisinoprilASCOT-BPLAMean SBP were similarLarge difference in SD of SBP correlated to primary outcomeamlodipine < atenololMRC trailshowed 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? Accomplish trial: 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.”