약물요법-정사준

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1 Pharmacotherapeutics New Antiepileptic Drugs in Childhood Epilepsy Sajun Chung, MD Department of Pediatrics, Kyunghee University College of Medicine E - mail : sajchung@khmc.or.kr J Korean Med Assoc 2009; 52(6): Abstract Many new antiepileptic drugs (AEDs) have been developed in the last two decades, contributing to the optimal treatment for childhood epilepsy. The goal of the treatment is to achieve seizure-free without any side effects, that deteriorates the quality of life by causing negative consequences. The new AEDs have not shown better efficacy, but generally seem to be better tolerated, having fewer systemic reactions and better pharmacokinetics than the established AEDs. The new AEDs have a broad spectrum of activities, which offer new opportunities to patients who have not shown any favorable responses to the established ones. There are more choices when trying to select AEDs for epileptic seizures and syndromes. Majority of the new AEDs have more than one action mechanism. AEDs acting selectively through the GABAergic system are tiagabine and vigabatrin; acting by inhibition of voltagedependent Na and Ca 2 channels are lamotirigine, oxcabarbazepine and topiramate; and acting by inhibition of glutamate-mediated excitation are felbamate, topiramate. The pharmacokinetic parameters of the new AEDs compared to the established AEDs, new AEDs have improved in terms of longer half-lives, permitting less frequent daily dosing, reduced potential for drug interactions. Considerations in selecting an AEDs are not only dependent on seizure types or syndromes, side effect profile, action mechanism, drug interaction, pharmacokinetic profile, facility of drug initiation, but also on age and sex of patients. Patients with worsened seizure frequency or development of new types of seizure after the introduction of AEDs, should be questioned on the previously diagnosed seizure types or syndromes. Keywords: New antiepileptic drugs; Action of mechanism; Pharmacokinetics/pharmacodynamics; Side effects; Seizure aggravation. 611

2 Chung SJ Table 1. List of the established and newer antiepileptic drugs Established drugs Carbmazepine (1954) Newer drugs Felbamate (Carter-Walalce, 1993) Diazepam (1965) Gabapentin (Pfizer Inc, 1995) Phenobarbital (1912) Lamotrigine (GlaxoSmithKline, 1996) Phenytoin (1938) Primidone (1954) Levetiracetam (UCB,2000) Oxcarbazepine (Norvatis,1990) Valproate (1967) Pregabalin (Pfizer,1985) Tiagabine (Abott, 1997) Topiramate (Janssen -Ortho, 1996) Vigabatrin (not in USA) (Ovation Pharmaceuticals, 1985) Zonisamide (Eisai, 1989) 612

3 New Antiepileptic Drugs in Childhood Epilepsy Table 2. Correlation between animal models and proposed mechanisms of action of antiepileptic drugs Seizures type KInds of AEDs Experimental Proposed mechanism Tonic/clonic Absence Partial New AEDs Established AEDs model of action seizures Maximal FBM, GBP, CBZ, PHT, VPA, PB Limit sustained electroshock LTG, OXC, repetitive firing by TPM, ZNS inhibiting volatage NA + channels scptz FBM, GBP, VPA, ESM, PB, BZD Enhance GABA TGB, LTG, TPM Electrical FBM, GBP, CBZ, PHT, VPA, Multiple kindling LTG, OXC, PB, BZD VGB, ZNS scptz, subcutaneous pentylenetetrazole. Table 3. Summary of the principal molecular actions of newer antiepileptic drugs CLB FBM GBP LEV LTG OXC TGB TPM VGB ZNS Established drugs Inhibits voltage- + +? PHT, VPA, gated Na + channels CBZ, PB Inhibits T-type + EsM, VPA Ca2 + channels Inhibits L, N, P, Q +(L) +(L) PB, DZP, PHT type Ca 2+ channels Enhance GABAA-R PHT, DZP, PB mediated Cl - currents Inhibits presynaptic +++ GABA reuptake Increase brain GABA +++ VPA inhibiting GABA-Tr Inhibits Ca 2+ current/ PB? NMDA-R Inhibits Na + current/ + AMPA/Kainate-R Inhibits brain carbonic AZM anhydrase activity Increase K + channels + + DZP Others (SV2A ligand) + R, receptor; Tr, transaminase; KA, kainate; CAH,carbonic anhydrase; +++, well documented action, major part of AEDs effect; ++, effect probably of clinical significance; +, effect only tentatively. 613

Chung SJ Figure 1. An excitatory synapse. the putative major sites of action of various AEds. MDA: N-methyl-D-asparate, AMPA: a-amino-3-hydroxy-4-isoxazo-lepropionic acid (2).

4 Chung SJ Figure 1. An excitatory synapse. the putative major sites of action of various AEds. MDA: N-methyl-D-asparate, AMPA: a-amino-3-hydroxy-4-isoxazo-lepropionic acid (2). GABA-T Figure 2. An inhibitory synapse. the putative major sites of action of various AEds. GABA: - aminobutyric acid, GABA-T, GABA transaminase, GAD: glutamic acid decarboxylase (2). 614

5 New Antiepileptic Drugs in Childhood Epilepsy Table 4. Pharmarcokinetic parameters of newer and established antiepileptic drugs F (%) Tmax (h) Vd (L/kg) Protein T (h) Tse (d) Therapeutic Maintenance dose binding (%) range (serum) (mg/kg/d) ug/l umol/l Infant Children Newer AEDs CLB > 90 1~ ~ ~75 60~ ~1 0.25~0.75 FBM > 90 2~ ~ GBP 30~60 2~ ~ ~90 LEV > 90 1~2-6~8 2 20~8 - LTG > 90 1~ ~60 3~ ~8 OXC > ~15 2 8~20 30~80 15~60 20~50 TGB > 90 1~ ~9 1~ ~1 (adult) TPM > 90 1~ ~30 3~ ~2-2~10 VGB ~ ~ ~150 40~80 ZNS - 2~ ~70 10~ ~20 Established AEDs CBZ 75~85 4~12 0.8~ ~50 20~30 3~12 12~50 10~40 10~40 CNZ > 90 1~ ~ ~75 60~ ~ ~0.5 DZP > ~ ~ ~2500 0~0.5 ESM > 90 1~ < 10 30~ ~ ~700 20~40 15~45 PB > ~ ~ ~30 4~130 3~5 3~5 PHT 0.7~1.2 74~90 40~60 10~20 5~15 4~7 VPA > 90 1~ ~93 5~ ~ ~700 20~40 15~60 F: bioavailability, Tmax, time interval ingestion and maximal serum concentration; Vd, volume of distribution, T, elimination of half - life; Tse, steady - state time. 615

6 Chung SJ Figure 3. Plasma concentration of a drug following repeated oral drug administration (4) as a function of interval of administration measured as multiples of elimination half - life. Figure 4. Relationship between serum drug concentration (ordinate) and drug dose (abscissa) for a drug observing (B) first- order kinetics (linear) and (A, C) zero- order kinetics (4) A, PHT, ZNS; B, FBM, ESM, PB, TPM, VPA,OXC, LEV, ZNS; C, LTG, VPA. 616

7 New Antiepileptic Drugs in Childhood Epilepsy Table 5. Pharnacokunetic interactions between new AEDs and established drugs Effects of the addition of FBM GBP LEV LTG OXC TPM TGB VGB ZNS CBZ ESM PB PHT VPA FBM _ GBP _ LEV _ LTG _ OXC _ TPM _ TGB _ VGB _ ZNS _ CBZ * * * _ * ESM _ PB _ PHT _ VPA _ * CBZ- epoxide elevated only, CBZ may be decreased., no significant pharmacokinetic interaction expected; or, (marked) decrease or increase in serum concentrations expected. On levels of 617

8 Chung SJ Table 6. The changes of concentration by the interaction between new AEDs and other drugs FBM GBP LTG LEV OXC TGB TPM VGB ZNS Antacids G-1 Cimetidine G-2 Cyclosporine O -1 Dihydropyrine? Digoxin T-1 Ethinyl estradiol F -1 O-2 T-2 Haloperidol T-3 Macrolides Proxyphene Ritonavir L-1 Sertraline L-2 Wafarin F- 2, no interaction, F -1, decrease in progestin; F - 2, increase in wafarin; G -1and G -2, decrease in GBP L-1, decrease in LTG; L- 2, increase in LTG; O -1, decrease in cyclosporine; O - 2, decrease in ethinyl estradiol; T-1, decrease in digoxin; T- 2, decrease in ethinyl estradiol; T - 3, increase in haloperidol. 618

9 New Antiepileptic Drugs in Childhood Epilepsy Table 7. Risks and adverse effects of antiepileptic drug dherapy Risks of AED therapy Systemic Toxicity Side effects and adverse effects (dose related, idiosyncratic) Chronic toxicity Teratogenicity Physical injuries High Cortical functions Cognitive and behavior change Psychosocial Need for daily medication Labeling as epileptic Economic/Temporal Cost of medication and time Risks of Seizures Accidents (drive, bathing, burns) sports injuries (swimming, bicling) Impairment in postictal state Restriction on school/social activities Time lost due to seizure and recovery Discrimination in employment 619

10 Chung SJ Table 8. Commandments in the pharmacological treatment of epilepsy (7) Choose the correct drug for the seizure type or epilepsy syndrome Start at low dosage and increase incrementally Titrate slowly to allow tolerance to central nervous system side-effects Keep the regimen simple with once- or twice-daily dosing, if possible Measure drug concentration when seizures are controlled or if control is not readily obtained (if possible) Counsel the patient early regarding the implications of the diagnosis and the prophylactic nature of drug therapy Try two reasonable monotherapy options before adding a second drug When seizures persist, combine the best tolerated first-line drug with one of the newer agents depending on seizure type and mechanism of action Simplify dose schedules and drug regimens as much as possible in patients receiving polypharmacy Aim for the best seizure control consistent with the optimal quality of life in patients with refractory epilepsy Table 9. Choice of antiepileptic drugs in children according to seizure type Seizure type First line Second line/add-on Tonic - clonic LTG, TPM, VPA, PHT, CBZ, OXC, LEV Absence LTG, VPA, ESM, CLB, ZNS Myoclonic VPA, LTG,TPM, ZNS, CLB, PB Partial seizures OXC, CBZ, GBP, TPM, LTG, ZNS, CLB, PHT, LEV Unclassiiable VPA LTG, TPM, LEV, ZNS 620

11 New Antiepileptic Drugs in Childhood Epilepsy Table 10. Summary of Pediatric epilepsy syndromes and treatments* Neonatal seizures Febrile convulsions Infantile spasms Lennox-Gastaut BECTS (rolandic epilepsy) CJAE JME Partial seizures GTC Phenobarbital and phenytoin commonly used. Topiramate or levetiracetam Long-term prophylactic therapy after simple febrile seizures's is not recommended. FAmilies can be advised to have rectal diazepam available for use as needed ACTH, predinisolone, pyridoxine, vigabatrin (tuberous sclerosis), nitrazepam, topiramate, lamotrigine Topiramate and Lamotrigine (may exacerbate myoclonic seizures in some patients) topiramate + low to moderate doses of lamotrigine (considered for synergistic action) Carbamazepine, Gabapentin may be first choice because of lack of toxicity compared with carbamazepine. Ethosuximide, valproic acid, and lamotrigine are commonly used; Initial choice may be based on perception of tolerability, potential cognitive effects and systemic toxicity, and urgency of need for rapid control Valproic acid is currently the drug of choice. there is evidence of effectiveness of lamotrigine as monotherapyand of topiramate as adjunctive therapy Carbamazepine or oxcarbazepine considered an acceptable first drug by many, followed by lamotrigine, or topiramate, with choice based on tolerability. Strongest evidence favors topiramate among the newer AEDs. showed equivalent efficacy of oxcarbazepine and phenytoin. Lamotrigine was shown to be efficacious for GTC seizures in Lennox -Gastaut syndrome. * based on less than class I and class II evidence (5). BECTS, benign epilepsy of childhood with centrotemporal spikes; CJAE, childhood and juvenile absence epilepsy; JME, juvenile myoclonic epilepsy; GTC, generalized tonic-clonic seizures. Table 11. Efficacy of newer antiepileptic drugs for a particular seizure syndromes (1) FBM GBP LEV LTG OXC PGB TGB TPM VGB ZNS Initial +a? +a +a +a monotherapy Refractory partial +a +a +a +a +a +a +a +a +a +a seizure Idiopathic +a +a +a +a GTC seizures absence seizures + + Myoclonic seziures +a Lennox-Gastaut +a + + Infantile spasms +a Progressive + myoclonicepilepsies Secondary generalized GTC: genralized tonic- clonic, +, effective, not approved; a: Indication approved by either the US Food and Drug Administration (FDA) or European Medicines Agency (EMEA) 621

12 Chung SJ Table 12. Comparison of recommendations for treatment of pediatric epilepsy (10) Seizure type or syndrome PECS* ILAE SIGN NICE FDA approved Partial - onset OXC, CBZ A: OXC PHT, VPA, CBZ CBZ, VPA, LTG PB, PHT, CBZ B: none LTG, TPM, OXC OXC, TPM OXC, TPM C: CBZ,PB,PHT VGB, CLB TPM, VPA BECTS OXC, CBZ A, B: none not mentioned CBZ, OXC, LTG, None C: CBZ,VPA VPA Childhood ESM A, B: none VPA, ESM, LTG VPA, ESM, ESM, VPA absence C: ESM, LTG, VPA Juvenile VPA, LTG A, B, C: none VPA, LTG, TPM VPA, LTG TPM myoclonic Lennox-Gastaut VPA, TPM, LTG not reviewed not mentioned LTG, VPA, TPM FBM, TPM, LTG syndrome Infantile spasms VGB, ACTH not reviewed not mentioned VGB, steroid FBM, TPM, LTG BECT, BECTS, benign epilepsy of childhood with centrotemporal spikes. * Pediatric Expert Consensus survey. Drugs rated as treatment of choice listed International League Against Epilepsy, Recommendations listed according to levels of evidence supporting the efficacy options. Level A, B, C (French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drug I: treatment of new onset epilepsy. Neurology 2004; 62: ) SIGN: scottish intercollegiate guideline network. Diagnosis and manegement of epilepsies in children and young people; A national clinical guideline Edinburgh, SIGN: MArch (Copies available at: http.// pdf/ sign81.pdf) National Institute for Clincal Excellence, Technology Appraisal Guidance 79. Newer drugs for epilepsy in children ( guidance) and Clinical guidance 20. The epilepsies: The diagnosis and mangement of the epilepsies in adults and children in primary and secondary care, October 2004 ( / uk/ CG020NICE guideline). II FDA approval for each selzures type or epilepsy syndrome. 622

13 New Antiepileptic Drugs in Childhood Epilepsy Table 13. Reasons for pseudoresistance to antiepileptic drugs drug therapy Wrong diagnosis (syncope, arythmia, maligering, underlying brain lesions, pseudoseizures) Wrong drugs (inappropriate for seizure type, kinetic/dynamic interactions) Wrong dose (too low, side effects preventing dose increase) Wrong patient (poor compliance with medication, inappropriate life style-alcohol or drug abuse) Table 14. Combinations of drug reported to be useful in refractory epilepsy Combination Indicatiom VPA + ESM Generalized absences CBZ + VPA Complex partial seizures VPA + LTG Partial/generalized seizures TPM + LTG Partial/generalized seizures VGB + LTG Partial seizures VGB + TGB Partila seziures Table 15. Combination therapy according to action mechanisms of antiepileptic drugs Na channel blocker + Multiple mechanisms VPA + CBZ VPA + LTG TPM + LTG TPM + CBZ Na channel blocker + GABAnergic drugs VGB + CBZ TGB + CBZ VGB + LTG GABAnergic + Multiple mechanisms VGB + VPA VGB + TPM Multiple + Multiple VPA + TPM GBP + VPA 623

14 Chung SJ Table 16. Idiosyncratic reactions and long term side effects of the new antiepileptic drugs Drugs Principal side effect Serious adverse effects Clobazam sedation, dizziness, irritability, depression, disinhibition Felbamate anorexia, GI symptoms, Irritability, insomnia, nausea, headahe, aplastic anemia, hepatic failure Gabapentin weight gain, behavioral changes, GI upset somnolence, fatigue, ataxia, dizziness, Lamotrigine headache, tremor, vomiting, insomnia allergic -toxic reaction, Rash, dizziness,tremor, ataxia, GI upset, (Stevens -Johnson syndrome) Levetiracetam behavioral changes, psychosis, tremor, allergy, sedation Oxcarbazepine rash, hyponatremia, weakness, rash, dizziness, diplopia, ataxia, headache, Tiagabine confusion, dizziness, GI upset, anorexia weakness stupor or spike wave stupor Topiramate Cognitive disturbance, renal stones, paresthesia, glaucoma, tremor, weight loss, language dysfunction hypohidrosis headache, fatigue, GI upset, renal calcli Vigabatrin depression, psychosis, depression, Irreversible visual field defects, weight gain, tremor, behavioral change, sedation, weight gain, GI upset, psychosis Zonisamide fatigue, paresthesia, renal stones somnelence, headache, dizziness weight loss, photosensitivity Table 17. Suggested mechanisms for an antiepileptic drug-induced seizure aggravation (11) Clinical circumstances and mechanisms and AED-induced seizure aggravation Paradoxical intoxication (chronic dose-related or acute idiosyncratic) Paradoxical reaction Inappropriate drug choice/increased epileptiform discharges AED-induced encephalopathy Mechanisms underlying seizure aggravation/ specific drug effect Increased GABA-mediated transmission (vigabatrin, tiagabine, gabapentin) Blockade of voltage- gated sodium channels Secondary loss of efficacy due to tolerance Mixed seizure disorders with multiple seizure types 624

15 New Antiepileptic Drugs in Childhood Epilepsy Table 18. AED - induced aggravation of seizures or epileptic syndromes (11) GBP LTG OXC TGB VGB BZP CBZ PHT VPA Absence Myoclonic JME LGS/MAE BECTS SMEI/ESES ++ + LKS/ESES + + +, limited; ++, moderate; +++. significant. JME, juvenile myoclonic epilepsy; LGS, Lennox-Gastaut syndrome; MAE, myoclonic astatic epilepsy; BECTS, benign epilepsy of childhood with centrotemporal spikes; SMEI, severe myoclonic epilepsy of infancy; LKS, Landau-Kleffner syndrome; ESES, electrical status epilepticus of sleep. 625

16 Chung SJ List of abbreviations ACTH adrenocorticotropic hormone, AEDs antiepileptic drugs AZM acetazolamide BZD benzodiazepine; CBZ carbamazepine CLB clobazam CNZ clonazepam DZP diazepam ESM ethosuximide FBM Felbamate GABA Y-aminobutyric acid GBP Gabapentin LEV Levetiracetam LTG Lamotrigine OXC oxcarbazepine PB phenobarbital PHT phenytoin PTZ pentylenetetrazol TGB Tiagabine TPM topiramate VGB vigabatrin VPA valproic acid ZNS Zonisamide 11. Ben -Menachem E. Strategy for utilization of new antiepileptic drugs. Curr Opin Neurol 2008; 21: Rho JM, Sanker R. The pharmacologic basis of antiepileptic drug action. Epilepsia 1999; 40: Meldrum BS. Update on the mechanism of action of antiepileptic drugs. Epilepsia 1996; 37 (S6): S4-S Bourgeois BFD. Pharmacokinetics and pharmacodynamics of antiepileptic drugs. In: Wyllie E, ed. The treatment od epilepsy. practice & practice. 3rd ed. Pholadelphia:Lippincott Williams & Wilkins, 2001: French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A, Glauser TA. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology; Quality Standards Subcommittee of the American Academy of Neurology. American Epilepsy Society. Efficacy and tolerability of the new antiepileptic drugs I: treament of new onset epilepsy. Neurology 2004; 62: Beyenburg S, Bauer J, Reuber M. New drugs for treatment of epilepsy: a practical approach. Postgrad Med J 2004; 80: Brodie MJ, Schachter SC, Kwan P. Fast Facts:Epilepsy. 3rd. ed. Oxford: Health Press, O Dell C, Shinnar S. Initiation and discontinuation of antiepileptic drugs. Neurol Clin 2001; 19: Sankar R. Initial treatment of epilepsy with antiepileptic drugs;pedaitric issues. Neurology 2004; 63 (S4): S30- S Wolfig AA. Monotherapy in children and infants. Neurology 2007; 69 (S3): Sazgar M, Bourgois BFD. Aggravation of epilepsy by abtiepileptic drugs. Pediatr Neurol 2005; 33: Peer Reviewers Commentary 626

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract