Drug induced movement Drug induced movement disorderdisorder

Surat tanprawate, MD, FRCP(T)Surat tanprawate, MD, FRCP(T)

Neurological centerNeurological center

Chiangmai universityChiangmai university

Basal ganglia

+D1recepter

Indirect pathway

Direct pathway

-D2recepter

NeurotransmitterNeurotransmitter

Four classes of neurotransmitters:

1) Acetylcholine

2) Biogenic amines: serotonin, histamine, and the catecholamines - dopamine and norepinephrine

3) Excitatory amino acids - glutamate and aspartate, and

inhibitory amino acids - gamma-aminobutyric acid (GABA), glycine and taurine

4) Neuropeptides, over 50 are known. Amino acid neurotransmitters are the most numerous

NNeuroleptic euroleptic drugsdrugs

• Effects on cognition and behavior of antipsychotic drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses.

• 7 classes of drugs: – Phenothiazines, further divided into the aliphatics, piperidines, an

d piperazines – Thioxanthenes (eg, droperidol) – Butyrophenones (eg, haloperidol) – Dibenzoxazepines (eg, loxapine) – Dihydroindolone (eg, molindone) – Diphenylbutylpiperidine (eg, pimozide) – Benzisoxazole (eg, risperidone)

Pathophysiology:Pathophysiology:

Their therapeutic actionTheir therapeutic action

Antagonism of central dopaminergic (D-2 receptor) neurotransmission

Antagonist effects at muscarinic, serotonergic, alpha1-adrenergic, and H1-histaminergic receptors.

Drug induced movement disorderDrug induced movement disorder(DIMD)(DIMD)

• Excessive motor activity(hyperkinesia or dyskinesia)Excessive motor activity(hyperkinesia or dyskinesia)– TremorTremor– MyoclonusMyoclonus– ChoreaChorea– AtetosisAtetosis– BallismBallism– TicsTics– DystoniaDystonia

• Diminish spontaneous movement (bradykinesia)Diminish spontaneous movement (bradykinesia)– Parkinsonism Parkinsonism

Class of drugsClass of drugs

• Neuroleptic drugNeuroleptic drug– TypicalTypical– Atypical Atypical

• Non-neuroleptic drugNon-neuroleptic drug

Neuroleptic induced movement disorderNeuroleptic induced movement disorder

• Acute dystoniaAcute dystonia• Acute akathisiaAcute akathisia• ParkinsonismParkinsonism• Neuroleptic malignant syndromeNeuroleptic malignant syndrome• Tardive syndrome (tardive dyskinesia)Tardive syndrome (tardive dyskinesia)

– Buccolinguomastigatory syndromeBuccolinguomastigatory syndrome– Tardive stereotypeTardive stereotype– Tardive dystoniaTardive dystonia– Tardive tourettismTardive tourettism– Tardive tremorTardive tremor– Tardive myoclonusTardive myoclonus– Tardive akathisiaTardive akathisia

Neuroleptic induced acute dystoniaNeuroleptic induced acute dystonia

• OnsetOnset– First few dayFirst few day

• DrugDrug– Neuroleptic drug (high potency)Neuroleptic drug (high potency)– metoclopamidemetoclopamide

• RiskRisk– ChildrenChildren– Young adultYoung adult

• PathophysiologyPathophysiology– Sudden imbalance between striatal dopamine VS Sudden imbalance between striatal dopamine VS

cholinergic systemcholinergic system– Relative preponderance of AchRelative preponderance of Ach

• ClinicalClinical– Sustained involuntary muscle contractionSustained involuntary muscle contraction– Affect various body pathAffect various body path

• Face, jaw, tongue, neck, throatFace, jaw, tongue, neck, throat• Sustain deviation of the eye(oculogyric crisis)Sustain deviation of the eye(oculogyric crisis)• Limb dystoniaLimb dystonia• Air way and respiratory muscleAir way and respiratory muscle

• Treatment Treatment – Drug withdrawalDrug withdrawal– Parenteral anticholinergic: BenztropineParenteral anticholinergic: Benztropine– Anti histamine:DiphenhydramineAnti histamine:Diphenhydramine– Muscle relaxant (BZD) in some caseMuscle relaxant (BZD) in some case

Neuroleptic induced akathisiaNeuroleptic induced akathisia

• Very common, very early, dose related SEVery common, very early, dose related SE• Onset Onset

– Few dayFew day

• DrugDrug– Neuroleptic (typical and atypical)Neuroleptic (typical and atypical)– Non-neuroleptic medication (SSRIs anti depressant)Non-neuroleptic medication (SSRIs anti depressant)– Dopamine receptor blockling drugDopamine receptor blockling drug

• PathophysiologyPathophysiology– Not completely understoodNot completely understood– Complex interaction at the cortical-subcortical-Complex interaction at the cortical-subcortical-

spinal levelspinal level

ClinicalClinical• RestlessnessRestlessness

– Wingging legsWingging legs– Pacing or rocking from foot to footPacing or rocking from foot to foot– Stereotypies: involuntary movement that asr Stereotypies: involuntary movement that asr

coordinated patterned, repetitivecoordinated patterned, repetitive– Seemingly purposeful but actually purposelessSeemingly purposeful but actually purposeless

• Involve trunk, legs, lower face, tongueInvolve trunk, legs, lower face, tongue

• TreatmentTreatment– Lower dose or switching to a less potent Lower dose or switching to a less potent

neuroleptic drugsneuroleptic drugs– BZPBZP– B-blockerB-blocker– OpiateOpiate– clonidinesclonidines

Neuroleptic induced parkinsonismNeuroleptic induced parkinsonism

• Dopamine antagonists Dopamine antagonists (neuroleptic, antiemetics)(neuroleptic, antiemetics)– Phenothiazine(chlorpromazine)Phenothiazine(chlorpromazine)– Butyrophenone(haloperidol)Butyrophenone(haloperidol)– Thioxanthenes(thiothixine)Thioxanthenes(thiothixine)– Substituted Substituted

benzamides(metoclopramide)benzamides(metoclopramide)

• Dopamine depletorsDopamine depletors– ReserpineReserpine– TetrabenazineTetrabenazine– Alpha-methydopaAlpha-methydopa

• CCB with dopamine CCB with dopamine agonist activityagonist activity– Flunarizine, cinnarizineFlunarizine, cinnarizine

• OthersOthers– Diltiazem, captoprilDiltiazem, captopril– Amiodarone, procaneAmiodarone, procane– LithiumLithium– PhenytoinPhenytoin– Fluoxetine and SSRIsFluoxetine and SSRIs– Ara-CAra-C– Amphotericin BAmphotericin B

• Risk factorRisk factor– FemaleFemale– Older ageOlder age– Greater drug potencyGreater drug potency– Higher doseHigher dose– Genetic predispositionGenetic predisposition– Previous brain injuryPrevious brain injury

• ClinicalClinical– Identical to the idiopathic formIdentical to the idiopathic form– Clinical may diffClinical may diff

• Symmetrical S/SSymmetrical S/S• Associated with Rabbit syndrome or tremor of Associated with Rabbit syndrome or tremor of

the mouth and jaw giving rise to peculiar the mouth and jaw giving rise to peculiar chewing motionchewing motion

• Concurrent TDConcurrent TD

Tardive syndromeTardive syndrome

• OnsetOnset– Chronic(>3 Mo. of total cumulative neuroleptic Chronic(>3 Mo. of total cumulative neuroleptic

exposure)exposure)– Occur: Occur:

• during the course of Rxduring the course of Rx• after dose reduction (unmask TD)after dose reduction (unmask TD)• after the causative drug has been withdrawal(covert or after the causative drug has been withdrawal(covert or

withdrawal TD) withdrawal TD)

• DDx with “withdrawal dyskinesia”DDx with “withdrawal dyskinesia”– Choreotic type dyskinesiaChoreotic type dyskinesia– ChildrenChildren– Acute discontinuation of neurolepticAcute discontinuation of neuroleptic– Short live, spontaneous remittingShort live, spontaneous remitting

• characteristiccharacteristic– Persistent, sometime irriversible abnormal Persistent, sometime irriversible abnormal

movementmovement– Hyperkinetic type: chorea, dystonia, tics, Hyperkinetic type: chorea, dystonia, tics,

myoclonus, tremormyoclonus, tremor– Usually “choreic” in typeUsually “choreic” in type– Unaware of TDUnaware of TD

• RegionRegion– Orolinguomandibular, truncal, Limb regionOrolinguomandibular, truncal, Limb region

Pathophysiology Pathophysiology

Long term dopamine recepter

blockage

Increased number, affinity of post synaptic dopamine D2 recepter

Drug that may cause Tardive dyskinesiaDrug that may cause Tardive dyskinesia

Classification of Tardive dyskinesiaClassification of Tardive dyskinesia

• Tardive dyskinesiaTardive dyskinesia– Bucco-linguo-masticatory syndromeBucco-linguo-masticatory syndrome

(BLMS)(BLMS)

• Tardive dyskinesia varientsTardive dyskinesia varients– Tardive dystoniaTardive dystonia– Tardive akathisiaTardive akathisia– Tardive myoclonusTardive myoclonus– Tardive ticsTardive tics– Tardive tremorTardive tremor

Bucco-linguo-masticatory syndromeBucco-linguo-masticatory syndrome(BLMS)(BLMS)

• Repetitive stereotyped movement of oral and Repetitive stereotyped movement of oral and facial movementfacial movement– Twisting and protrusion of tongueTwisting and protrusion of tongue– lip smacking and puckering and chewinglip smacking and puckering and chewing

• Sometime spread to involve trunk and Sometime spread to involve trunk and extremityextremity

• Often uninvolved the upper faceOften uninvolved the upper face

Tardive dystoniaTardive dystonia

• Clinical same as idiopathic dystoniaClinical same as idiopathic dystonia• Suspected in Suspected in • Hx. Exposure to anti-psychotic drug or Hx. Exposure to anti-psychotic drug or

dopamine receptor blocking drugdopamine receptor blocking drug• Exclude secondary dystoniaExclude secondary dystonia• Focal, segmental, generalizedFocal, segmental, generalized

Tardive tourettismTardive tourettism

• Motor or vocal ticsMotor or vocal tics• Simple voclizationSimple voclization

– barking, clicking noisebarking, clicking noise

• Complex verbal ticsComplex verbal tics– Coprolalia, echolalia, palilaliaCoprolalia, echolalia, palilalia

Tardive akathisiaTardive akathisia

• Inability to sit still accompanied by an inner Inability to sit still accompanied by an inner sense of restlessnesssense of restlessness

• Fidgety, march in place Fidgety, march in place • Complex and stereotyped movementComplex and stereotyped movement

Tardive tremorTardive tremor

• Head, position, osillationHead, position, osillation• Rabbit syndrome- 4-6Hz rhythm involve jaw, Rabbit syndrome- 4-6Hz rhythm involve jaw,

perinasal, perioral musculature( like chewing perinasal, perioral musculature( like chewing move of rabbit)move of rabbit)

• PrognosisPrognosis– Persistent in most casePersistent in most case

• ManagementManagement– Early detectionEarly detection– Discontinue drugsDiscontinue drugs– Symptomatic treatment: dopamine depleting agentSymptomatic treatment: dopamine depleting agent

• Reserpine (Serpasil)Reserpine (Serpasil)

• Metyrosine (Demser)Metyrosine (Demser)

• Tetrabenasine (Nitoman)Tetrabenasine (Nitoman)

– Clonazepam may useful in some caseClonazepam may useful in some case

Others Others

• PhenytoinPhenytoin– chorea, atetosis, chorea, atetosis,

dystonia, tremor, dystonia, tremor, asterixisasterixis

• TCATCA– Choreoatetosis, tremor, Choreoatetosis, tremor,

myoclonusmyoclonus

• SSRIsSSRIs– Myoclonus, chorea, Myoclonus, chorea,

dystonia, stereotypedystonia, stereotype

• CNS stimulantCNS stimulant– Oropharyngeal Oropharyngeal

dyskinesiadyskinesia

• B-adrenergic agonistsB-adrenergic agonists– tremortremor

• OCOC– choreachorea