risperidone (Risperdal)

Introduction

Tradename: Risperdal.

Indications

• psychotic disorders with or without negative symptoms
• psychosis & agitation in the elderly
• non psychotic symptoms associated with dementia in the elderly
• manic symptoms associated with bipolar disorder
• depression
• autism

Contraindications

• not useful for agitation in severely demented patients

pregnancy category = c

safety in lactation = -

Dosage

• start 1 mg PO BID (lower initial dose in elderly)
• usual effective dose is 4-6 mg/day
• doses > 6 mg may not provide additional benefit, but do increase incidence of extrapyramidal symptoms
• max 16 mg/day
• injection 25-50 mg every 2 weeks
  • continue oral therapy for 3 weeks after 1st injection
• elderly 0.5-2 mg PO daily

Tabs: 0.25, 1, 2, 3, 4 mg.

Injection: (Risperdal Consta) 25, 37.5, 50 mg vials

Pharmacokinetics

• peak plasma levels within 1 hour
• metabolized by cyt P450 2D6 primarily to 9-hydroxy- risperidone (active metabolite*)
• 1/2life of the parent compound is 3 hours
• active metabolite* has a 1/2life of 24 hours
• 1/2life increases in patients with renal or hepatic impairment
• protein binding 90%
• injectable form has delayed onset of action (weeks)

elimination via liver

elimination via kidney

1/2life = 3-24 hours

protein binding = 90 %

Adverse effects

• not common (1-10%)
  • extrapyramidal reactions, headache, sedation, impaired concentration, blurred vision, dry mouth, palpitations, syncope, dizziness, nausea, anorexia, anxiety, hyperprolactinemia, sexual dysfunction, sedation
• uncommon (< 1%)
  • hypotension, bradycardia, seizures
• other
  • suppresses cough reflex
  • QT prolongation
  • agitation
  • insomnia
  • dyspepsia
  • rhinitis
  • orthostatic hypotension
  • weight gain, in adolescents 5.3 kg after 11 weeks of therapy
  • does NOT appear to cause agranulocytosis
  • sedation occurs at doses > 20 mg/day
  • MINIMAL extrapyramidal effects
    • rigidity is most common
    • frequency & severity is dose-dependent
  • anticholinergic effects NOT prominent
  • also see clozapine
  • parkinsonism in 20% of nursing home residents
    • increased risk of falls
  • stroke, transient ischemic attack (TIA)
    • risk increase (from 2% - 4%) {double} in demented patients prescribed risperidone for agitation
    • risk NOT observed for other indications
  • hyperglycemia; increased risk of diabetes mellitus
  • increased serum triglycerides
  • may carry small risk of congenital birth defects
  • does not appear to increase risk of osteoporosis
• black box warning
  • increased risk of hyperglycemia
  • increased risk of cerebrovascular events
  • increased risk of mortality in patients with dementia
    • see atypical antipsychotic agent for number needed to harm

• drug adverse effects of antipsychotic agents
• drug adverse effects of atypical antipsychotic agents
• drug adverse effects of psychotropic agents
• drug adverse effects of dopaminergic receptor antagonists
• drug adverse effects of antihypertensive agents

Drug interactions

• inhibitors of cyt P450 2D6 decrease metabolism (activation) of risperidone
  • cimetidine, haloperidol, perphenazine, propoxyphene, quinidine, ritonavir, paroxetine, sertraline, fluoxetine
• other agents that prolong the QT interval
• repsiridone may antagonize effects of L-dopa & dopamine agonists
• chronic administration of carbamazepine may increase risperidone clearance as much as 50%
• similar to clozapine

• drug interaction(s) of antipsychotics & dopamine receptor agonists
• drug interaction(s) of antipsycotics with benzodiazepines
• drug interaction(s) of risperidone with carbamazepine
• drug interaction(s) of NSAIDs & antihypertensives

Mechanism of action

• atypical antipsychotic
• combined dopamine & serotonin receptor blockade
  • potent 5HT-2 receptor antagonist
  • dopamine D2 receptor antagonist
• strong affinity for:
  • alpha adrenergic receptors
  • histamine H1 receptor
  • muscarinic receptors

More general terms

• atypical antipsychotic agent; second generation antipsychotic
• dopaminergic receptor antagonist
• serotonin antagonist

Additional terms

• clozapine (Clozaril)
• cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6)
• QT interval

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5073