Disclosure. Learning Objectives. Development of DIMD DIMD 12/10/2017. How to apply drug-induced movement disorder monitoring to your pharmacy practice

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1 Presenter Disclosure Presenters: Claudine Lang-Hodge and Heidi Van Hee How to apply drug-induced movement disorder monitoring to your pharmacy practice We have no current or past relationships with commercial entities We have no relationships with commercial interests Speaking Fees for current program: We have received no speaker s fee for this learning activity We received complimentary registration and accommodation for Saturday s sessions This program has received no financial or in-kind support from any commercial or other organization Disclosure Many of the medications we will be discussing in the treatment of EPS are being used offlabel Learning Objectives Review impact of Drug-Induced Movement Disorders (DIMD) on patient outcomes Identify medication classes and risk factors involved in DIMD Describe how physical assessment skills for DIMD can and should be integrated into medication monitoring in the clinical pharmacy practice setting Discuss risk reduction and treatment options for DIMD DIMD Drug-induced movement disorders (DIMD) also referred to as extrapyramidal symptoms (EPS) EPS caused by dopamine blockade in nigrostriatal pathway (if over 80%) or depletion in the basal ganglia mimic idiopathic pathologies of extrapyramidal system Dopamine receptor blocking agents commonly implicated Antipsychotics, antiemetics Also many other psychotropics and non-psychotropics SSRIs, stimulants, TCAs, antiepileptics, sympathomimetics Development of DIMD May occur at various times during drug therapy Hours to days vs. weeks vs. months to years after drug exposure Includes: Akathisia, dystonia, parkinsonism, tardive dyskinesia, withdrawal dyskinesia, tremor Patients may develop two or more co-existing DIMDs 1

2 Why monitor for DIMD? Impact of DIMD on patients Impede social functioning and interpersonal communication Interfere with performance of motor tasks and activities of daily living Reduce quality of life Contribute to stigma, need for adjunct medications, associated with suicidality, abnormal posturing may be painful Why monitor for DIMD? Impact of DIMD on patients Often lead to non-adherence with drug therapy Results in disease relapse and re-hospitalization Create potential for misdiagnosis May be mild and distressing or permanent and disfiguring May become irreversible even with drug discontinuation Increased use of health system Expanding Pharmacists Role With training, pharmacists can play a role in identifying and managing patients experiencing EPS Pharmacists are part of the multidisciplinary team with regular, direct patient access In both hospital and community setting They have a responsibility to identify and resolve drug therapy problems including evaluation and management of adverse effects Primary Prevention of DIMD Identify medications and risk factors Obtain detailed hx of med use in past 3 months Inquire specifically about commonly overlooked causes anti-nauseants antidepressants adrenergic agents Consider role of drug interactions P450 inhibitors: exposure to implicated medication Additive dopaminergic effects Ensure treatment clinically appropriate Titrate dose slowly to avoid excessive dose escalation Medications associated with DIMD Acute and Tardive Akathisia Antiemetics: Droperidol Metoclopramide Prochlorperazine Promethazine Antiepileptics: Carbamazepine Psychotropics: Conventional antipsychotics Atypical antipsychotics (clozapine and quetiapine considered low risk) Reserpine SSRIs Lithium TCAs Medications associated with DIMD Acute and Tardive Dyskinesia Antiemetics: Metoclopramide Prochlorperazine Antiepileptics: Phenytoin Psychotropics: Conventional antipsychotics Atypical antipsychotics (clozapine and quetiapine considered low risk) Lithium Adapted From: US Pharm. 32(11)HS16-HS32, Ment Health Clin (internet) 2012; 1(7) Adapted From: US Pharm. 32(11)HS16-HS32, Ment Health Clin (internet) 2012; 1(7)

3 Medications associated with DIMD Acute and Tardive Dystonia Antiemetics: Droperidol Metoclopramide Prochlorperazine Promethazine Psychotropics: Conventional antipsychotics Atypical antipsychotics (clozapine and quetiapine considered low risk) Medications associated with DIMD Parkinsonism Antiemetics: Droperidol Metoclopramide Prochlorperazine Promethazine Antiepileptics: Valproate Cardiovascular Agents: Alpha-methyldopa Reserpine Psychotropics: Conventional antipsychotics Atypical antipsychotics (clozapine and quetiapine considered low risk) Other: Flunarizine Tetrabenazine Adapted From: US Pharm. 32(11)HS16-HS32 Ment Health Clin (internet) 2012; 1(7) Adapted From: US Pharm. 32(11)HS16-HS32 Ment Health Clin (internet) 2012; 1(7) Risk Factors for Drug-Induced Movement Disorders Dystonia Akathisia Parkinsonism Tardive Dyskinesias Acute Dystonia -High-potency neuroleptics -History of electroconvulsive therapy -Male sex -Young age Tardive Dystonia -Male sex -Presence of tardive dyskinesia -Young age -Advanced age -Acquired immune -Affective disorder deficiency syndrome -Cognitive impairment -Advanced age -Female sex -Dementia -High-potency -Female sex neuroleptics -High neuroleptic dosage -History of akathisia -Iron deficiency -Negative symptoms of schizophrenia -Rapid neuroleptic dosage escalation -Advanced age -Affective disorder -Alcoholism -Diabetes mellitus -Duration of treatment -Electroconvulsive treatment -Female sex -History of extrapyramidal reaction -Intermittent neuroleptic treatment -Iron deficiency -Organic brain disorder -Total daily drug dosage Risk Factors for Drug-Induced Movement Disorders Dystonia Akathisia Parkinsonism Tardive Dyskinesias Acute Dystonia -High-potency neuroleptics -History of electroconvulsive therapy -Male sex -Young age Tardive Dystonia -Male sex -Presence of tardive dyskinesia -Young age -Advanced age -Acquired immune -Affective disorder deficiency syndrome -Cognitive impairment -Advanced age -Female sex -Dementia -High-potency -Female sex neuroleptics -High neuroleptic dosage -History of akathisia -Iron deficiency -Negative symptoms of schizophrenia -Rapid neuroleptic dosage escalation -Advanced age -Affective disorder -Alcoholism -Diabetes mellitus -Duration of treatment -Electroconvulsive treatment -Female sex -History of extrapyramidal reaction -Intermittent neuroleptic treatment -Iron deficiency -Organic brain disorder -Total daily drug dosage Adapted from US Pharm. 32(11)HS16-HS32 Potential modifiable risk factors Adapted from US Pharm. 32(11)HS16-HS32 Secondary Prevention of DIMD Ensure baseline neurological assessment performed Ensure recommended monitoring schedule followed Ex. antipsychotics Designated team member to perform assessment and quantify findings using standardized rating scale Specific DIMD identified on assessment should be communicated with health care team and documented! Seek patient/caregiver input regarding adverse effects Process to capture pt awareness of EPS and distress from same in rating scales Document! Initial Patient Assessment Ideally, patients should be examined for movement disorders BEFORE the initiation of medication! Recognize role of medication in distinguishing between idiopathic movement disorder/other medical condition Early detection key factor in probability of eventual remission Treatment of DIMD is inconsistent in providing benefit, primary prevention is essential 3

4 Patient Assessment DIMD often under-recognized: EPS may resemble sx associated with psychotic illness Ex. Bradykinesia and facial mask resemble blunted affect and psychomotor retardation (vs. negative symptoms of schizophrenia/depression) Ex. Akathisia vs. substance withdrawal EPS may be worsened with misdiagnosis Ex. Akathisia treated as agitation with antipsychotics Ex. TD treated with anticholinergic Monitoring for DIMD Patients should play a role in identifying emergence of EPS Health care team including pharmacists to educate patients and caregivers to facilitate early detection of DIMD Caregivers/family members play a significant role in identification of DIMD since some movements may go unnoticed by patients Monitoring for DIMD AHS Antipsychotic Adult Monitoring Form Often not formally monitored and/or documented Failure to follow clinical guidelines regarding assessment and documentation of EPS may pose significant medico-legal challenges Pharmacists can advocate, encourage and assist in the use of monitoring tools Ex. AHS Adult Monitoring, CAMESA Guidelines AHS Antipsychotic Adult Monitoring Form CAMESA Guidelines The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children 4

5 CAMESA Guidelines The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children Tertiary Prevention of DIMD Restrict dopamine receptor blocking agents to patients for whom no alternative is available Keep dopamine receptor blocking agent at lowest effective dose Switch to medication without EPS side effects or reduced EPS incidence Switchrx.ca Monitor patient on drugs with potential for DIMD every 3 months Antipsychotic guidelines: qmonthly x 3 months, then q3 months Reassess need for continued treatment 4. Tools available for monitoring extrapyramidal symptoms include: Abnormal Involuntary Movement Scale (AIMS), Simpson Angus Scale, Extrapyramidal Symptom Rating Scale, & Barnes Akathisia Rating Scale. Switching Antipsychotics Due to EPS Relative risk of EPS among antipsychotics: Switching Antipsychotics: an example High Potency FGA Mid-potency FGA= risperidone Paliperidone Low-potency FGA Lurasidone=Asenapine=Ziprasidone Aripiprazole Olanzapine Quetiapine Clozapine Switching Antipsychotics: an example ESRS Reveals DIMD.Now What? Management of Specific DIMD 5

6 Acute Dystonia Acute dystonic reactions are seen within days of starting or increasing the dose of an antipsychotic Administer diphenhydramine 1,lorazepam 1 or an anticholinergic (benztropine 1, procyclidine 2, trihexyphenidyl 2 ) Symptoms resolve within minutes of parenteral therapy (diphenhydramine, lorazepam, benztropine available as IV/IM) If ongoing antipsychotic treatment is required, dose of medication Co-administration of antipsychotic with an anticholinergic may be considered Clinical Handbook of Psychotropic Drugs, 19 th edition: 1 Good effect (>50% response) 2 Moderate effect (20-50% response) Neuroleptic-Induced Akathisia or Parkinsonism Dose-dependent adverse effect of antipsychotic therapy Switch to SGA if on FGA and use lowest effective dose Consider switching the current SGA to quetiapine or clozapine If on valproic acid, lithium or SSRI, consider discontinuation since these medications can cause symptoms of akathisia or parkinsonism If SGA must be continued, consider adding a beta blocker (propranolol), mirtazapine, anticholinergic, benzodiazepine, amantadine, or clonidine Can take months to resolve after withdrawal of the offending agent Tardive Dyskinesia (TD) Remission is more likely with prompt discontinuation of antipsychotic therapy If D/C not possible, consider dosage D/C anticholinergic medication if patient taking concurrently anticholinergics may exacerbate TD Consider switching antipsychotic to clozapine Small studies suggest: Consider treatment of TD with tetrabenazine Others: (Off-label use) Vitamin E, levetiracetam, branched chain amino acids, pyridoxine, clonazepam Tardive Dyskinesia (TD) Neurol Clin February ; 29(1): 127 viii. Withdrawal Dyskinesias Occurs when antipsychotics are discontinued abruptly Can occur when switching from one antipsychotic to another with less D2-affinity Self-limiting and tends to resolve over weeks Re-introduce withdrawn antipsychotic to suppress the movements and taper over a longer time period Use slow cross-taper if switching from one antipsychotic to another Switchrx.ca : Anticholinergics Anticholinergics: by reducing cholinergic activity, restores the functional balance between acetylcholine and dopamine in the basal ganglia of patients with EPS Diphenhydramine (Off-label use) Oral: 25 to 50 mg 3 or 4 times daily IM, IV: 10 to 50 mg per dose; single doses up to 100 mg may be used if needed; maximum: 400 mg daily Benztropine: Oral/IM/IV: 1-2mg BID (max 6mg/day) Procyclidine: Oral: 2.5mg BID to TID, by 2.5mg/day as required (max 30mg/day) Trihexyphenidyl: Oral: 4-15mg/day in 3-4 divided doses (up to 30mg tolerated in younger patients) 6

7 : Correcting the Imbalance Anticholinergic side effects Central Acetylcholine Cognitive Impairment Delirium Hyperthermia Peripheral Dopamine Dry Mouth Blurred Vision, Glaucoma Constipation, Ileus Urinary Retention Central Monoamine-Depleting Agent; Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor: presynaptic dopamine and serotonin storage and antagonizes postsynaptic dopamine receptors Tetrabenazine: Oral: 12.5 mg 2 to 3 times a day to start. by 12.5 mg a day weekly until the maximal tolerated and effective dose is reached In most cases the maximal tolerated dose will be 25 mg TID VMATs not available in Canada: Valbenazine Received breakthrough therapy designation by FDA fall 2014 Highly-selective, vesicular monoamine transporter 2 (VMAT2) inhibitor that modulates dopamine release. In Phase III studies in Canada for tardive dyskinesia Deutetrabenazine FDA approved for Huntington s Chorea, currently in trials for TD VMATs monitor: parkinsonism, orthostatic hypotension, NMS, depression/si/psychiatric status, prolactin, sedation May QTc; caution when used with a strong CYP2D6 or in poor CYP2D6 metabolizers with other drugs that QTc Beta blockers (Off-label use): exact mechanism of action in EPS unclear thought to block noradrenergic and serotonergic inputs into the dopamine pathways of the brain Choose a lipophilic, non-selective beta-blocker such as propranolol β1 receptor blockers less effective, but may be considered if β2 blockade undesirable Hydrophilic beta blockers do not appear to be effective Propranolol Oral: 10mg TID to 120mg daily Monitor: HR, BP, titrate slowly, consider drug interactions/contraindications diabetes mellitus, cardiac conductance impairment, asthma Others (Off label use) Amantadine: NMDA receptor blocker exerts its activity by dopamine at the receptor Oral: mg/day divided BID Cyproheptadine: antihistamine with anticholinergic effects, 5HT2a receptor antagonist Oral: 4mg TID, up to 24mg/day Botulinum Toxin: paralytic, improves spasticity Injection: units/site (multiple sites used) Levetiracetam: inhibits neuronal hypersynchronization which may help neuronal firing and thus dyskinesias Oral: mg/day in divided doses 7

8 Others (Off label use) Vitamin E: antioxidant which may protect against further oxidative damage from antipsychotic treatment Oral: units/day Pyridoxine: oxidative reactions in pathways involving dopamine, serotonin, GABA and scavenging of free radicals Oral: mg/day Branched-chain amino acids: thought to neurotoxic effects of free radicals created as a byproduct of catecholamine metabolism Oral: 222mg/kg TID using ratio of Valine: Isoleucine: Leucine of 3:3:4 Pharmacists Role Summary Identify medications and risk factors involved in DIMD Incorporate physical assessment skills for DIMD into medication monitoring using tools provided (ESRS, CAMESA guidelines and AHS antipsychotic monitoring forms) Communicate any neurological findings to treatment team, and document in patient chart Discuss risk reduction with patients and treatment team (including drug dose or switching medications) Provide and monitor treatment options for specific DIMD Reassess need for continued treatment References Caroff et al. Movement Disorders Induced by Antipsychotic Drugs:Implications of the CATIE Schizophrenia Trial Neurol Clin February ; 29(1): 127 viii. doi: /j.ncl Chen JJ. Drug-Induced Movement Disorders: A Primer US Pharm. 2007; 32(11)HS16-HS32 Chen JJ. Drug-induced movement disorders. Ment Health Clin. 2012;1(7): Chouinard G, Margolese H.C. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophrenia Research. 2005;76: Claxton K et al. Drug-induced Movement disorders. Journal of Pharmacy Practice 2007; 20(6) Cortese L, Jog M, McAuley TJ, Kotteda V, Costa G. Assessing and monitoring antipsychotic-induced movement disorders in hospitalized patients: a cautionary study. Can J Psychiatry. 2004;49(1):31-6. Kalachnik JE. Applied monitoring for tardive dyskinesia and other extrapyramidal side effects. Mental Health Clinician Jan 2012; 1 (7) Pringsheim T, Doja A, Belanger S, Patten S. Treatment recommendations for extrapyramidal side effects associated with second-generation antipsychotic use in children and youth. Paediatr Child Health. 2011:16(9): Spadaro A, Kellar J, Remington G, Sproule B, Al-Sukhni M, Chaiet A. Evaluation of an educational program for clinical pharmacists to conduct standardized assessments for medication-induced movement-related disorders. Canadian Journal of Hospital Pharmacy. 2015;68(3): Stoner SC, Worrell JA, Jones MT, Farrar CA, Ramlatchman LV. Pharmacist-designed and implemented pharmaceutical care plan for antipsychotic-induced movement disorders. Pharmacotherapy. 2000;20(5): Zagaria MA. Recognizing Antipsychotic induced movement disorders. US Pharm 2015; 40 (11)