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15. Membrane stabilizer

15. Membrane stabilizer. R3 김형준. Peripheral sensory neurons 의 정상 구조와 fx 의 지속적인 derangement -> chronic persistence of pain sensation Input 을 받아들여 CNS 로 전달하는 길에 변형이 발생 – Central sensitization

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15. Membrane stabilizer

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  1. 15. Membrane stabilizer R3 김형준

  2. Peripheral sensory neurons의 정상 구조와 fx의 지속적인 derangement -> chronic persistence of pain sensation • Input을 받아들여 CNS로 전달하는 길에 변형이 발생 – Central sensitization • Tissue injury는 A-delta와 C fibers에 영향을 주어 activation의 threshold를 감소시킴 -> perception of pain – allodynia • Pathology가 위치한 곳에 다양한 ion channel이 증가하여 neuronal membrane excitability가 증가함 -> ectopic, abnormal impulse의 발생 • Sodium channel blocking agents Antiepileptics, local anesthetics and antiarrhythmics • Calcium channel blocking agents Gabapentin, w-conopeptides and calcium channel blockers

  3. SODIUM CHANNEL BLOCKERS • Anticonvulsants, local anesthetics and antiarrhythmics • The primary agents utilized for neuropathic pain are anticonvulsants • Primary therapy or adjunctive treatment for such process as trigeminal neuralgia, CRPS, diabetic neuropathy and post herpetic neuralgia • 일반적으로 용량은 safety standards내에서 patient comfort에 맞춰 조정되어야 함

  4. SODIUM CHANNEL BLOCKERS A. Anticonvulsants 1) Phenytoin (Dilantin) • Sodium channel blocking, excitatory glutamate의 분비를 막음, inhibiting ectopic discharges • Diabetic neuropathy의 치료에 사용됨 • 치료의 효과에 대한 상반되는 결과 때문에 neuropathic pain을 위한 first-line therapy로 고려하면 안됨 • Side effects – mentation, somnolence, giddiness, nystagmus, ataxia, gum hyperplasia (unique) • Activates the P450 enzyme system -> Careful assessment of cotherapy is warranted

  5. SODIUM CHANNEL BLOCKERS A. Anticonvulsants 2) Carbamazepine (Tegretol) • 화학적 구조가 TCA와 유사 • Inhibit pain via peripheral and central mechanism • Selectively blocks active fibers, 정상적으로 작동하는 C, A-delta nociceptive fibers에는 영향을 주지 않음 • Primary therapy for trigeminal neuralgia (tic doloreux), thalamic- mediated poststroke pain, postherpetic neuralgia, and diabetic neuropathy • Side effects - nausea, vomiting and sedation • 2-4개월마다 blood tests를 시행해야 함 <- agranulocytosis and aplastic anemia

  6. SODIUM CHANNEL BLOCKERS A. Anticonvulsants 3) Oxcarbazepine • The keto-analogue of carbamazepine -> CNS (dizziness) 또는 혈액학적 (leukopenia) 부작용이 적음 • Significant hyponatremia (<125mmol/L) may develop during first 3 months • Carbamazepine에 비해 side effect가 덜하여 많이 사용됨 4) Valproic acid • GABA A receptor에 작용 • Efficacy in migraine therapy • Side effects - gastrointestinal upset, somnolence, and dizziness

  7. SODIUM CHANNEL BLOCKERS A. Anticonvulsants 5) Lamotrigine (Lamictal) • Lamotrigine은 특이하게, sodium channel blocker로 작용하면서 pain propagation과 관련된 excitatory transmitter인 glutamate의 분비를 막음 • Major use is in trigeminal neuralgia, indication for cold-induced pain • Trigeminal neuralgia 치료 시 carbamazepine의 co-drug 또는 substitute로 사용 • Carbamazepine-resistant trigeminal neuralgia • Prevention of trigeminal neuralgia in susceptible pts. • Patient suffering from diabetic neuropathy • HIV-associated polyneuropathy • Side effects – rash (m/c)

  8. SODIUM CHANNEL BLOCKERS A. Anticonvulsants 6) Topiramate (Topamax) • In addition to affecting sodium and calcium channel, enhance GABA (inhibitory) neurotransmitter, and inhibit AMPA- type glutamate (excitatory) receptor • Adjunct로 사용해야 함 • Side effects – sedation • Potential for kidney stones and ocular glaucoma 7) Levetiracetam (Kepppra) • Relatively new antiepileptic • 작용기전은 아직 밝혀지지 않음

  9. LOCAL ANESTHETICS • Block the aberrant firing of the abnormal nerves • Not block normally conducting nerves 1) Lidicaine • The usual dose is 1 to 5 mg/kg IV • Antiarrhythmic, Bradycardia and cardiac depression is a potential risk -> 장기간 사용할 때는 EKG study 필요 • 5% lidocaine is available in transdermal application • Eutetic mixture of local anesthetics (EMLA) – topical local anesthetics 2) Mexilitene • Antiarrhythmic, oral analogue of lidocaine • For diabetic neuropathy, thalamic stroke pain, spasticity and myotonia

  10. CALCIUM CHANNEL BLOCKERS • Six different calcium channel current types found in nervous tissue - L, N, P, Q, R, T 1) Gabapentin • Binds at the alpha-2-delta subunit of the L-type calcium channel • GABA와 구조적으로 유사하나 GABA 수용체에 결합하지도 작용하지도 않고, GABA의 uptake와 metabolism에도 영향을 끼치지 않음 • Allodynic, burning, lancinating pain을 가진 환자는 positive benefit을 얻을 수 있음 • Postherpetic neuralgia, diabetic neuropathiy, CRPS, radiculopathy, postlaminectomy syndrome, poststroke syndrome, phantom limb pain, multiple sclerosis and etc • Favorable side-effect profile

  11. CALCIUM CHANNEL BLOCKERS 2) Zonisamide (Zonegran) • Blocking T-type calcium channels, and sodium channels 3) w-conopeptides • Derived from the venom of a marine snail • Action on N-type calcium channels • Intrathecal administration • HIV나 cancer population에서 opioid-resistant pain의 pain relief를 위해 연구되어옴 4) Nifedipine, Verapamil, Diltiazem, Nimodipine • Decreasing central sensitization • Do not have a role as monotherapy

  12. CALCIUM CHANNEL BLOCKERS 5) Magnesium • Antagonists of the NMDA receptor, including membrane stabilizing effect

  13. NUMBERS NEEDED TO TREAT (NNT) • NNT - the number of patients treated with a certain drug in order to obtain one patient with a defined degree of relief • NNT 50% - numbers needed to obtain one patient with>50% pain relief • The “numbers needed to harm” (NNH) - the number needed to treat with a certain drug before a patient before a patient experience a significant side effect

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