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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.Ed

Department of PharmacologyDepartment of Pharmacology

Medical FacultyMedical Faculty

LambungLambung 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

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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)..

►► 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) �� decreasingdecreasing

�� Acidosis (+)Acidosis (+)

�� Pulmonary edemaPulmonary edema

�� HyperthermiaHyperthermia

�� Mild Mild leukocytosisleukocytosis

�� GABAergicGABAergic 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 monotherapymonotherapydoes not workdoes not work

►► Avoiding the sudden withdrawal Avoiding the sudden withdrawal

Treatment flowchart for status Treatment flowchart for status

epilepticusepilepticus

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Medications Medications

BarbituratBenzodiazepinAsam valproatGabapentin

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

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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

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)

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

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

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

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--dopadopa

�� Better than anti cholinergicBetter than anti cholinergic

►► Early stage:Early stage:

�� Anti cholinergic orAnti cholinergic or

�� AmantadineAmantadine

►► 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

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MigraineMigraine

►► Mechanism: Mechanism: �� GeneticGenetic

�� VascularVascular

�� Neural Neural

�� Neurotransmitter serotoninNeurotransmitter serotonin

�� Neurotransmitter dopamineNeurotransmitter dopamine

�� Activation 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

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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.

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))

TensionTension headacheheadache

►►Usually bilateralUsually bilateral

►►Usually following anxiety or depressionUsually following anxiety or depression

►►Therapy:Therapy:

�� NSAIDsNSAIDs + + coffeinecoffeine

�� Muscle 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 serotonergicserotonergic

transmission disordertransmission disorder

►► Therapy:Therapy:

�� PrednisonPrednison

�� LithiumLithium

�� MetisergidMetisergid

�� ErgotamineErgotamine

�� Na Na valproicvalproic

�� VerapamilVerapamil