Transcript (1)Simple partial seizures 单纯局限性发作
Welcome to Pharmacology
Chapter 18
Antiepileptic & Anticonvulsive Drugs
Section 1 Antiepileptic Drugs
Epilepsy
Epilepsy is a heterogeneous symptom complex, a chronic disorder characterized by sudden, transit and recurrent seizures which are episodes of brain dysfunction resulting from abnormal discharge of focal cerebral neuron and diffusion to normal neuronal tissues.
Somatic, sensory, automatic and psychotic
Epilepsy
Etiology incidence:0.5
%
~1
%
Primary epilepsy
Secondary epilepsy
1.
Classifications
Partial seizures (1)Simple partial seizures
单纯局限性发作
(2)Complex partial seizures
复合性局限性发作
2.
Generalized seizures (1)Absence seizures(petit mal)
失神发作（小发作）
(2)Myoclonic seizures
肌阵挛性发作
(3)Generalized tonic-clonic seizures (grad mal)
强直
-
阵挛性发作（大发作）
(4)Status epilepticus
癫痫持续状态
(1) Grand mal epilepsy Loss of consciousness and myotonia myoclonus for a few minutes.
Continuous episodes with sustained loss of consciousness is called epilepticism.
(2) Absence Involve a brief, sudden and self limiting loss of consciousness.The
patient stare and exhibits rapid eye blinking, which lasts for 3 to 5 seconds without any motor disorder.
(3) Myoclonic Consist of short episode of local muscle contractions that may reoccur for several minutes.
Simple partial
Partial
Do not lose conciousness and often exhibit abnomal activity of a single limb or muscle group.
Partial
Complex partial Exhibit motor dysfuntion and loss of conciousness.
Experimental Models
1. Electric stimulate(maximal electroshock seizure, MES): grad mal 2. Pentylenetetrazol(PTZ): absence seizure 3. Spontaneously epileptic rat(SER) 4. Kindling response: Complex partial seizures 5. Glutamate
History of Antiepileptic Drugs
1857 potassium bromide(
溴化钾
) 1912 phenobarbital 1912~1937 35 analogs of phenobarbital 1938 phenytoin 1938~1960 valproate(64), Antiepilepsrin(75) Carbamazepin(80), gabapentin(90)
The Classifications
Hydantoins Anticonvulsive barbiturates Benzodiazepines Succinimides New drugs
Electrophysiology of antiepilepsy drugs
a. inhibit discharge in focus b. inhibit diffusion in normal neuron
Mechanisms of action of antiepilepsy drugs
1.
To affect inhibitory system involving GABAergic function a. Enhancement of GABAergic transmission: reuptake or metabolism b. Direct action on the GABA-R chloride channel complex
Mechanisms
2.Modification of ion channel conductance Inhibitory of Na + and/or Ca 2+ channel N-type Ca 2+ channel L-type T-type absence seizures
Mechanisms
c. Diminution of glutaminergic function AMPA-R blockade NMDA-R blockade
Phenytoin Sodium
（苯妥英钠
, Dilantin,
大仑丁 ）
Mechanisms
1.inhibit diffusion in normal neuron by inhibiting post tetanic potentiation(PTP)
Post tetanic potentiation (PTP)
:
Increase in amplitude of EPSP after neuron has received tetanic stimulus, in neurons refers to any high frequency burst of stimulation
Mechanisms
2.Promote the stablization of the membrane a.block voltage-sensitive (use dependent effect) Na + channel b.block voltage-sensitive Ca 2+ channel c. inhibit K + out
Mechanisms
3.inhibit the activity of camudulin kinase 4. Potentiate GABA inhibiting function
Clinical uses
1.Epilepsy: generalized tonic-clonic seizures simple partial seizures complex partial seizures first choice except absence seizure Pay attention to children
Clinical uses
2. Central pain syndrome: neuralgias trigeminal neuralgia et al 3. Arrhythmia
（心律失常）
1.
Pharmacokinetics
Absorption pK a 8.3, slow and unpredictable after oral administration C ss 5-7d stimulation by oral and im(pH=10.4) 2. Distribution PPBR about 90%,Vd 0.6-0.7L/kg
Pharmacokinetics
3. Metabolism : by hepatomicroenzymes about 60%-70%, 5% unchanged
相互作用
4. Elimination : dose-dependent plasma concentration less than 10
g/ml, FOK, t 1/2 6-24hrs more than 10
g/ml, OOK, t 1/2 20-60hrs
Adverse Reactions
C max (E) 10
g/ml; C Tox 20
g/ml 1.
Gastrointestinal reaction 2.
Gingival hyperplasia by increasing the the induction of collagenase
Adverse Reactions
3. CNS symptoms
20
g/ml
：
drowsiness, dizziness, ataxia,
﹥
40
g/ml: psychotic,
﹥
50
g/ml: coma 4. Blood system: folic acid dysefficacy
Adverse Reactions
4. Allergy leukopenia
（白细胞减少）
, agranulocytosis
（粒细胞缺乏）
, thrombocytopenia
（血小板减少）
, aplastic anemia
（再生障碍性贫血）
5. Bone system hypocalcemia,osteomalacia, rachitis reason
：
vitamin D
Adverse Reactions
6.
心血管反
应 arrhythmia hypotension
Adverse Reactions
7.Others: a.Teratogenesis fetal hydantoin syndrome (
胎儿妥因
综合征） b.peripheral neuritis
芬兰 1980～1998年，研究人员追踪了 一家产科诊所中970位怀孕的癫痫妇女， 其中有740位在怀孕初期（前3个月）服 用抗癫痫药物，另外239位则无。结果在 这些服用抗癫痫药物的怀孕妇女中，共 产下28个严重畸形儿（3.8%），未服用 抗癫痫药物组仅产下2个严重畸形儿 （0.8%；P=0.02）
1.
Drug Interactions
Hepatomicrosomal enzyme inducer 2.
Hepatomicrosomal enzyme inhibiter 3.
PPBR
Carbamazepine
（卡
马西平
） • •
Broad–spectrum antiepileptic agent Mechanisms inhibit Na + channel potentiat GABA inhibitory function
Carbamazepine
1.
Actions and Uses Antiepileptic effects 2.
3.
4.
grad mal, partial seizures with complex symptomatology first choice Central algesia: trigeminal neuralgia more effective than phenytoin mania
（ 躁狂症）
and depression
尿崩症
1.
Pharmacokinetics
slow and unpredictable after oral administration 2. PPBR 80% 3. Active metabolite
：
cyclooxide 4. t 1/2 35 hrs at beginning, then may shorten by 50% due to enzyme induction
Adverse Reactions
1. Gastrointestinal reaction 2. CNS reactions: drowsness, vertigo, nausea, vomit, ataxia 3. Blood system: leukopenia
（白细胞减少）
, agranulocytosis
（粒细胞缺乏）
, thrombocytopenia
（血小板减少）
, aplastic anemia
（再生障碍性贫血）
4. Hepatic intoxication
Phenobarbital
Broad-spectrum and much effective in grad mal and partial seizures, but not drug choice for grad mal, alternative and iv in the treatment of status epilepticus
Mechanisms
1.
2.
3.
Potentiate the GABA inhibitory function: pre-synaptic GABA-R Ca 2+ Neurotransmitter Inhibitory of Na + and Ca 2+ channel
Primidone
（扑米
酮） Effective for all types of epilepsies Except absence mal, more effective than phenobarbital in complex partial seizures Mechanism similar to phenobarbital and
Na + in , K + out
Primidone
（扑米
酮） Primidone is metabolized to phenobarbital and phenylethylmalonamides(PEMA,
苯乙基丙二酰胺
) as active metabolites
Ethosuximide
（乙琥胺）
The only indication : absence epilepsy 1.
2.
Mechanisms: reducing the T-type Ca 2+ current inhibiting GABA aminotransferase
(转 氨酶)，
Na + -K + -ATP
Adverse Reactions(safe)
1.
2.
Gastric distress CNS distress Blood system
：
agranulocytosis, 3.
thrombocytopenia, aplastic anemia 4. SLE
Sodium Valproate
（丙戊酸
钠
）
Broad–spectrum antiepileptic agent
Mechanisms: 1.potentiate GABA function inhibit GABA-T increase the activity of GAD 2.inhibit Na + channel 3.inhibit L-Ca 2+ channel inhibit T-Ca 2+ channel
uses
Effective for all types of epilepsy, more effective than ethosuxide, less effective for grad mal and partial mal grad mal combine with absence seizures first choice
Adverse Reactions
1. Hepatic intoxication 2. CNS and blood system thrombocytopenia 3. Teratogenesis
Benzodiazepines
1. Diazepam : first choice for status epilepticus by iv 2. Nitrazepam
（硝西泮）
: myoclonic seizure, atypical absence seizure and infantile spasm 3. Clonazepam: absence seizure, atonic and akinetic seizures
1.
Other New Drugs
Flunarizine (
氟桂利嗪
) Nonselective calcium channel-blocking drugs 2.
Effective for all types of epilepsy, more effective for grad mal and partial mal 3. inhibit Na + channel inhibit L-Ca 2+ channel inhibit T-Ca 2+ channel
Antiepilepsirin
（抗
痫灵） 1.
2.
3.
Broad–spectrum antiepileptic agent 5-HT Safe
Lamotrigine
(拉莫三嗪）
1.
Used as an add-on therapy or monotherapy in the treatment of absence or myoclonic seizure 2. The mechanism may related to inhibit voltage-dependent Na + channel
Topiramate
（托吡
酯）
• • •
Used in the treatment of partial seizure with or without generalized tonic-clonic seizures inhibit Na + channel potentiat GABA inhibitory function Diminution of glutaminergic function
Therapy for Epilepsy
General Principles and Drug Choice for The Therapy of Epilepsy 1.
Accurate evaluation 2.
The drug choice for initial treatment of seizures
Therapy for Epilepsy
(1) grad mal and simple partial seizures: Carbamazepine, phenytoin Phenobarbital, primidone and valproic acid as alternative
Therapy for Epilepsy
(2)Absence seizure:
ethosuxide valproic acid, clonazepam (3)Complex partial seizures: Carbamazepine Phenytoin
，
primidone, valproic acid
Therapy for Epilepsy
（
4
）
Status epilepticus Diazepam iv , or clonazepam, phenytoin and phenobarbital (5)Tonic seizure: valproic acid (6)Myoclonic seizure: Glucocorticoids, clonazepam
Therapy for Epilepsy
3. Increase dose gradually 4. Withdrawn or discontinue --- gradually (half year) 5. Change drug or add a second drug and/or combination 6. Monitoring the serum drug level 7. Adverse reactions teratogenesis
Section 2 Anticonvulsants
Convulsion
Barbiturates
Benzodiazepines
Chloral hydrate
Magnesium Sulfate
1.
2.
3.
4.
5.
Magnesium Sulfate
给药途径不同，药理作用不同 Relaxant of skeletal muscle and CNS depression by iv or im Mechanism : calcium antagonism Used in convulsion caused by eclampsia
， 高血
压危象 respiratory inhibition and hypotension when overdose.