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

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

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)..

►► 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

►► 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

Treatment flowchart for status Treatment flowchart for status epilepticusepilepticus

Medications Medications

BarbituratBenzodiazepinAsam valproat

Gabapentin

Lamotrigin

FenitoinKarbamazepinAsam valproatEtosuksimid

FenitoinKarbamazepin

GABA

Glutamate

Ca

Na

STATUS EPILEPTICUS

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

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

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

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)

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

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

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

Anti cholinergicAmantadine

L-dopa+karbidopa

Dopamine agonists drugsMAO B inhibitors

Protocol of therapyProtocol of therapy

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

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

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

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.

Headache/Headache/CephalgiaCephalgia

►► MigraineMigraine►► Tension headacheTension headache►► Cluster headacheCluster headache

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) )

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

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.

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

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))

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

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