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Pharmacotherapy for Pharmacotherapy for Nervous System DisordersNervous System Disorders
M. M. BakhriansyahBakhriansyah, H., dr., , H., dr., M.KesM.Kes, , M.Med.EdM.Med.EdDepartment of PharmacologyDepartment of Pharmacology
Medical FacultyMedical FacultyLambungLambung MangkuratMangkurat UniversityUniversity
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Learning outcomesLearning outcomes
At the end of this course, students should be able At the end of this course, students should be able to:to:
1.1. To explain mechanism of action of drugs used in To explain mechanism of action of drugs used in nervous system disorders treatments. nervous system disorders treatments.
2.2. Choose the appropriate medications for status Choose the appropriate medications for status epilepticusepilepticus, , parkinsonparkinson disease, and disease, and cephalgiacephalgiatreatments treatments
3.3. Explain the chosen medications regarding Explain the chosen medications regarding patientspatients’’ condition.condition.
4.4. Explain the protocol of therapy of nervous Explain the protocol of therapy of nervous system disorderssystem disorders
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Status Status EpilepticusEpilepticus
►► SE : SE : Continues seizures Continues seizures occuringoccuring 30 minutes 30 minutes ((epilepsiepilepsi foundation)foundation)More than 30 minutes More than 30 minutes of continues seizures of continues seizures activity or 2 or more activity or 2 or more sequential seizures sequential seizures without full recovery of without full recovery of consciousness between consciousness between seizures (Dodson, seizures (Dodson, 1993)1993)..
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►► Systemic and primary brain changes Systemic and primary brain changes related to related to morbidity and mortality ratesmorbidity and mortality rates
Decreasing GABA inhibition. Decreasing GABA inhibition. Increasing blood pressure (early stage) Increasing blood pressure (early stage) decreasingdecreasingAcidosis (+)Acidosis (+)Pulmonary edemaPulmonary edemaHyperthermiaHyperthermiaMild Mild leukocytosisleukocytosisGABAergicGABAergic mechanism failsmechanism fails
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►► Goal of therapy: to treat the epilepsy and to Goal of therapy: to treat the epilepsy and to minimaliseminimalise the side effectsthe side effects
Principal therapy:Principal therapy:►► MonotherapyMonotherapy is better than is better than polypharmacypolypharmacy►► Dosage is increased until the therapeutic effect or Dosage is increased until the therapeutic effect or
toxicity effect are met. toxicity effect are met. ►► PolypharmacyPolypharmacy is introduced when is introduced when monotherapymonotherapy
does not workdoes not work►► Avoiding the sudden withdrawal Avoiding the sudden withdrawal
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Treatment flowchart for status Treatment flowchart for status epilepticusepilepticus
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Medications Medications
BarbituratBenzodiazepinAsam valproat
Gabapentin
Lamotrigin
FenitoinKarbamazepinAsam valproatEtosuksimid
FenitoinKarbamazepin
GABA
Glutamate
Ca
Na
STATUS EPILEPTICUS
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KarbamazepinKarbamazepin►► Stabilize neural Stabilize neural
membrane by membrane by decreasing Na, Ca and decreasing Na, Ca and K flows through it.K flows through it.
►► avoid to be given with avoid to be given with MAO inhibitor MAO inhibitor consecutivelyconsecutively
FenitoinFenitoin►► DifenilhidantoinDifenilhidantoin
derivatederivate►► Mechanism of actions Mechanism of actions
are similar to are similar to KarbamazepinKarbamazepin
►► Could be given orally, Could be given orally, intra venous and intra intra venous and intra muscularmuscular
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ValproicValproic AcidAcid►► Increasing GABA Increasing GABA
transmission transmission ►► Sedation effect is Sedation effect is
minimalminimal
EtosuksimidEtosuksimid►► Mechanism of action Mechanism of action is is
unknownunknown►► Probably by inhibiting Probably by inhibiting
Ca channelCa channel
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PhenobarbitalPhenobarbital►► Stimulating GABA Stimulating GABA
receptorreceptor►► SE: sedation, SE: sedation,
nistagmusnistagmus, ataxia and , ataxia and allergyallergy
►► Inducing Inducing enzymenzym P450 P450
PrimidonPrimidon►► Mechanism of actions Mechanism of actions
are unknownare unknown►► Its active Its active metabolitmetabolit
has long half lifehas long half life
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GabapentinGabapentin►► GABA agonist GABA agonist ►► Adjuvant therapyAdjuvant therapy
LamotriginLamotrigin►► Stabilizing neuron and Stabilizing neuron and
affecting glutamate affecting glutamate releaserelease
►► Adjuvant therapyAdjuvant therapy►► SE: rash (prominent)SE: rash (prominent)
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KlonazepamKlonazepam►► Stimulating GABA Stimulating GABA
receptor receptor
FelbamatFelbamat►► Stimulating GABA Stimulating GABA
receptor and inhibiting receptor and inhibiting NMDA receptorNMDA receptor
►► Used unUsed un--frequentlyfrequently
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Parkinson diseaseParkinson disease
►► A progressive A progressive neurodegenerative neurodegenerative disorder associated disorder associated with loss of with loss of dopaminergicdopaminergicnigrostriatalnigrostriatal neurons.neurons.
►► Distinctive features:Distinctive features:Resting tremor, rigidity, Resting tremor, rigidity, bradikinetiabradikinetia, and , and postural instability postural instability
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Principle therapyPrinciple therapy
►► Increasing the synthesis Increasing the synthesis and release of dopamine and release of dopamine (L(L--dopa+karbidopadopa+karbidopa, , amantadinamantadin))
►► Inhibiting Inhibiting dopamindopaminmetabolism metabolism ((selegilin/deprenilselegilin/deprenil))
►► Activating dopamine Activating dopamine receptor (receptor (bromocriptinebromocriptine, , pergolidepergolide))
►► Blocking Blocking muscarinicmuscarinic/ / cholinergic receptor cholinergic receptor ((trihexiphenidiletrihexiphenidile, , benzathropinebenzathropine, , diphenhidraminediphenhidramine))
To facilitate action of dopaminergic To suppress action of cholinergic
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Anti cholinergicAmantadine
L-dopa+karbidopa
Dopamine agonists drugsMAO B inhibitors
Protocol of therapyProtocol of therapy
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LL--dovadova ((levodopalevodopa))►► Dopamine precursor Dopamine precursor
inactive forminactive form►► Activated by Activated by
decarboxilasedecarboxilase enzyme;enzyme;Brain Brain Lever & kidneys Lever & kidneys can can not pass through BBB not pass through BBB
bioavailability bioavailability countered by countered by karbidopa/benserazidekarbidopa/benserazide..
►► Interaction: Interaction: piridoxinepiridoxineincreases increases decarboxilateddecarboxilatedreaction. reaction.
►► On/off phenomenon On/off phenomenon (+) after 3(+) after 3--5 years 5 years application application mechanism ??? mechanism ??? Desensitization of Desensitization of dopamine receptordopamine receptor
►► Not a first line therapy Not a first line therapy
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SelegilineSelegiline ((deprenildeprenil))►► Instead of inhibiting Instead of inhibiting
metabolism of dopamine:metabolism of dopamine:Stimulating dopamine Stimulating dopamine release.release.NeuroNeuro--protective effect protective effect
►► + MOA inhibitors + MOA inhibitors crisis crisis of hypertension. of hypertension.
BromociptineBromociptine & & PergolidePergolide►► Dopamine receptor Dopamine receptor
agonists agonists ►► Action: Lesser than LAction: Lesser than L--dopadopa►► As a single therapy at the As a single therapy at the
early stageearly stage►► Combination with LCombination with L--dopa dopa
at the moderate and late at the moderate and late stage. stage.
►► Tapering dose Tapering dose
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TrihexiphenidileTrihexiphenidile & & benzotropinebenzotropine
►► Action: less than LAction: less than L--dopadopa
►► Adjuvant therapyAdjuvant therapy►► Tapering doseTapering dose
DiphenhidramineDiphenhidramine►► Anti cholinergic effect Anti cholinergic effect
at central level at central level ►► Anti histamineAnti histamine
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AmantadineAmantadine►► Anti virusAnti virus►► Mechanism: ??? May be by Mechanism: ??? May be by
facilitating dopamine facilitating dopamine releaserelease
►► Action:Action:Less than LLess than L--dopadopaBetter than anti cholinergicBetter than anti cholinergic
►► Early stage:Early stage:Anti cholinergic orAnti cholinergic orAmantadineAmantadine
►► When early stage therapy When early stage therapy is not effective, Lis not effective, L--dopa+karbidopadopa+karbidopa are are started.started.
►► Final stage: dopamine Final stage: dopamine agonists medications and agonists medications and MAO inhibitors. MAO inhibitors.
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Headache/Headache/CephalgiaCephalgia
►► MigraineMigraine►► Tension headacheTension headache►► Cluster headacheCluster headache
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MigraineMigraine►► Mechanism: Mechanism:
GeneticGeneticVascularVascularNeural Neural Neurotransmitter serotoninNeurotransmitter serotoninNeurotransmitter dopamineNeurotransmitter dopamineActivation of Activation of symphaticsymphaticnervous systemnervous system
►► NSAIDsNSAIDs + caffeine + caffeine ((asetaminophenasetaminophen, acetic , acetic salicilicsalicilic acid, etc)acid, etc)
►► Serotonin receptor Serotonin receptor agonists (ergotamine, agonists (ergotamine, dihidroergotaminedihidroergotamine, , sumatriptanesumatriptane, , naratriptanenaratriptane, , rizatriptanerizatriptane, , zolmatriptanezolmatriptane))
►► Dopamine antagonist Dopamine antagonist ((metochlopramidemetochlopramide, CPZ, , CPZ, proCPZproCPZ) )
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Protocol of therapyProtocol of therapy
Serotonin receptor agonists (SC/IM/IV), orDopamine receptor antagonist (IM/IV)
Serotonin receptor agonists (oral/nasal/SC), orDopamine receptor antagonist (oral)
NSAIDs, orSerotonin receptor agonist (oral)
Heavy migraine
Moderate migraine
Mild migraine
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NSAIDsNSAIDs►► SE: SE: dispepsiadispepsia
Stimulator of serotonin (5Stimulator of serotonin (5--HTHT11) receptors: ) receptors: 1.1. ergotamine, ergotamine, dihidroergotaminedihidroergotamine►► Non selective 5Non selective 5--HTHT1 1 receptor agonistreceptor agonist►► Contra indication: CHD, pregnancy, peripheral Contra indication: CHD, pregnancy, peripheral
blood vessel constriction, level and kidney blood vessel constriction, level and kidney disorders.disorders.
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2. 2. triptantriptan►► Selective 5Selective 5--HTHT11 receptor agonistreceptor agonist►► RizatriptanRizatriptan: quickest onset, highest : quickest onset, highest
efficacyefficacy►► NaratriptanNaratriptan: in contrast: in contrast►► MonotherapyMonotherapy is unadvisableis unadvisable►► Contra indication: cardiovascular diseasesContra indication: cardiovascular diseases
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Dopamine antagonistsDopamine antagonists►► Adjuvant therapyAdjuvant therapy►► Increasing gut motilityIncreasing gut motility►► Also could treat: Nausea & Also could treat: Nausea &
vomit vomit
PreventionPrevention►► 3 times per month3 times per month►► Beta blockers (Beta blockers (propanololpropanolol, ,
timololtimolol))►► Anti convulsive agents Anti convulsive agents
((valproicvalproic acid)acid)►► MAO inhibitors MAO inhibitors
((phenelzinephenelzine, , isokarbosazideisokarbosazide))
►► SerotonergicSerotonergic agents agents ((metisergidemetisergide, , siproheptadinesiproheptadine))
►► Ca antagonist (Ca antagonist (verapamilverapamil))
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TensionTension headacheheadache
►►Usually bilateralUsually bilateral►►Usually following anxiety or depressionUsually following anxiety or depression►►Therapy:Therapy:
NSAIDsNSAIDs + + coffeinecoffeineMuscle relaxant agentsMuscle relaxant agents
►►Prevention: Prevention: amitriptilineamitriptiline a.na.n
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Cluster headacheCluster headache
►► PeriorbitalPeriorbital pain pain (temporal bone pain)(temporal bone pain)
►► Some signs and Some signs and symptoms related to symptoms related to eyeseyes
►► Mechanism: ??? May Mechanism: ??? May be be serotonergicserotonergictransmission disordertransmission disorder
►► Therapy:Therapy:PrednisonPrednisonLithiumLithiumMetisergidMetisergidErgotamineErgotamineNa Na valproicvalproicVerapamilVerapamil
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