RISPERIDONE

DR. SARANG PANDITJUNIOR RESIDENT

LATA MANGESHKAR HOSPITAL NAGPUR

HISTORY

• Developed by Janssen Clag, subsidy of Johnson and Johnson 1988-1992

• First approved by FDA in 1994• Present in WHO list of most important

medications needed in basic health system

Timeline of Major Antipsychotic Therapies

Ziprasidone

1950 1960 1970 1980 1990 2001 2003 2007

ECT, etc.

Chlorpromazine

Fluphenazine

ThioridazineHaloperidol Clozapine

Risperidone

OlanzapineQuetiapine

Aripiprazole Consta

Paliperidone

Consta = Long-acting injectable risperidone

Antipsychotic drugs are not curative and do not eliminate the fundamental thinking disorder, but they often:

1.Decrease the intensity of hallucinations and delusions.

2.Permit the psychotic patient to function in a supportive environment.

Chemistry and Preparations• It is Benzisoxizole derivative.• C23-H27-FN4-O2.

• Trade names :- Risnia, Risdone, Sizodon.Formulation Strength

Tablet (Including mouth dissolving)

0.25/0.5/1/2/3/4

Solution 1mg/mL

Injection (Powder for suspension, ER)

12.5/25/37.5/50

PHARMACOKINETICSAbsorption

o PO• Absolute oral bioavailability is 70%.• Tmax is 1 hr for Risperidone (parent compound), 3 h (9-

hydroxyrisperidone extensive metabolizers), or 17 h (9-hydroxyrisperidone poor metabolizers).

• Steady state is approximately 1 day(extensive metabolizers) or approximately 5 days (poor metabolizers).

• Food - DOES NOT affect absorption.

o IM• Release of the drug-3rd wk after injection. Maintained from 4-6 wk. Subsides by 7th wk.• Steady state is reached after 4 injections.

Distribution• Rapidly distributed.• Vd :– 1-2 L/kg.• Protein binding is approximately 90% (parent compound)

and approximately 77% (9-hydrox yrisperidone).

Metabolism• Extensively metabolized in liver - CYP2D6 to major active

metabolite 9-hydroxyrisperidone.• 9-hydroxyrisperidone has similar activity to risperidone.

Elimination• Eliminated in urine (70%) and feces (14%).

o PO• The half-life is 20 h (overall mean half-life) for

combined risperidone and 9-hydroxyrisperidone.o IM

• The half-life of risperidone plus 9-hydroxyrisperidone is 3 to 6 days.

MECHANISM OF ACTION Receptor (NT) Action

D1,D2,D3, D4, D5 (Dopamine)

Blocks mesolimbic pathway, prefrontal cortex, limbic pathway, tubero-infudibular pathway

5HT2A, 5HT2C (Serotonin)

2A – ↓ EPS, improvement of –ve symptoms as compared to typical

2C – Weight gain

α1 High affinity. Orthostatic hypotension, sedation.

α2 Greater +ve, -ve, affective, cognitive symptom control.

H1 Sedation, ↓ in vigilance, drowsiness & weight gain.

•It blocks 65% of D2 receptors (lowest threshold for antipsychotic efficacy)•At 6mg/day - 80% of D2 receptors are blocked and EPS can occur.

INDICATIONS AND DOSAGES

ACUTE PSYCHOSIS AND SCHIZOPHRENIA

o ADULTS• INITIAL DOSE SHOULD NOT BE GREATER THAN 2

MG/DAY, • DOSE INCREASE OF 1-2 MG/DAY ACCEPTABLE BUT

SHOULD BE SPACED 24 HRS APART• TARGET DOSE IS 2-8 MG/DAY IN OD/DIVIDED

DOSAGE

INDICATIONS AND DOSAGES

o ADOLESCENTS (13 TO 17 Y OF AGE )• PO INITIATE TREATMENT WITH 0.5 MG ONCE DAILY

AS A SINGLE DOSE IN THE MORNING OR EVENING. IF INDICATED, DOSAGE ADJUSTMENTS SHOULD BE AT INTERVALS OF NO LESS THAN 24 H, IN INCREMENTS OF 0.5 TO 1 MG/DAY, AS TOLERATED, TO A RECOMMENDED DOSAGE OF 3 MG/DAY (DOSE RANGE, 1 TO 6 MG/DAY).

• PATIENTS EXPERIENCING PERSISTENT SOMNOLENCE MAY BENEFIT FROM ADMINISTERING HALF THE DOSE TWICE DAILY.

INDICATIONS AND DOSAGES

BIPOLAR MANIAo ADULTS

• 2 TO 3 MG/DAY ONCE DAILY INITIALLY. ADJUST DOSE AT INTERVALS OF NO LESS THAN 24 H, IN INCREMENTS/DECREMENTS OF 1 MG/DAY (USUAL DOSAGE, 1 TO 6 MG/DAY). NO DATA TO SUPPORT SHORT-TERM TREATMENT BEYOND 3 W K.

INDICATIONS AND DOSAGES

o ADOLESCENTS (13 TO 17 Y OF AGE )• START WITH 0.5 MG ONCE DAILY. IF INDICATED,

DOSAGE ADJUSTMENTS SHOULD OCCUR AT INTERVALS OF NO LESS THAN 24 H AND IN INCREMENTS OF 0.5 OR 1 MG/DAY, AS TOLERATED, TO A RECOMMENDED DOSAGE OF 2.5 MG/DAY (DOSE RANGE, 0.5 TO 6 MG/DAY).

INDICATIONS AND DOSAGES

IRRITABILITY ASSOCIATED WITH AUTISTIC DISORDER• CAN BE ADMINISTERED ONCE DAILY OR HALF THE TOTAL

DAILY DOSE TWICE DAILY. USE CAUTION WITH DOSAGE FOR CHILDREN WEIGHING LESS THAN 15 KG. FOR PATIENTS LESS THAN 20 KG, THE INITIAL DOSAGE IS 0.25 MG/DAY. AFTER A MINIMUM OF 4 DAYS, THE DOSAGE MAY BE INCREASED TO 0.5 MG/DAY. MAINTAIN THIS DOSE FOR A MINIMUM OF 14 DAYS. I F SUFFICIENT CLINICAL RESPONSE IS NOT OBTAINED, THE DOSAGE MAY BE INCREASED IN INCREMENTS OF 0.25MG/DAY AT INTERVALS OF NO LESS THAN 14 DAYS.

• FOR PATIENTS 20 KG OR MORE, THE INITIAL DOSAGE IS 0.5 MG/DAY. AFTER A MINIMUM OF 4 DAYS, THE DOSAGE MAY BE INCREASED TO 1 MG/DAY. MAINTAIN THIS DOSE FOR A MINIMUM OF 14 DAYS. I F SUFFICIENT CLINICAL RESPONSE IS NOT OBTAINED, THE DOSAGE MAY BE INCREASED IN INCREMENTS OF 0.5 MG/DAY AT INTERVALS OF NO LESS THAN 14 DAYS.

INDICATIONS AND DOSAGES

OTHER OFF LABEL USES – TOURETTE SYNDROME – PTSD– PSYCHOSIS RELATED TO ALZHEIMERS– BEHAVIOUR DISTURBANCES RELATED TO MENTAL

RETARDATION– TREATMENT RESISTANT OCD– BIPOLAR DEPRESSION

Adverse effectsCNS :- EPS (Including Parkinsonism, dystonia,

tremors, akathasia & dyskinesia); tardive dyskinesia; automatism (m/c in Paeds.); drowsiness

CVS :- Tachycardia, palpitations, postural hypotension (d/t α-blockade), QTc prolongation (mild), AV bundle branch blockade (rare)

RS :- Dyspnea, cough, rhinitis and URTI (Paeds.)GIT :- Abdominal pain & hypersalivation (m/c), dyspepsia,

dry mouth, nausea and diarrhea.

Haematological :- Anemia, epistaxis (rare)Genito-Urinary :- Ejaculatory disorder,

priapism, sexual dysfunction (men), non purpural lactation and menstrual irregularities (women) [d/t hyperprolactinemia]

Dermatological :- Rash, giant urticaria & angioedema

Black Box warning• Increased Mortality in Elderly Patients with Dementia-Related

Psychosis :- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis :- Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. Risperidone is not approved for the treatment of patients with dementia-related psychosis.

• Neuroleptic Malignant Syndrome• Clinical manifestations 1. Hyperpyrexia, muscle

rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and

cardiac dysrhythmia). 2. Additional signs may

include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure.

• Management

1. Immediate discontinuation of antipsychotic drugs

2. Intensive symptomatic treatment and medical monitoring

3. Treatment of any concomitant serious medical problems for which specific treatments are available.

Tardive Dyskinesia

• A syndrome of potentially irreversible, involuntary, hyperkinetic movements.It causes facial movements like constant chewing,tongue protrusion&facial grimacing.

• Caused D/t chronic blokage of nigrostriatal pathway.

• T/t- non-specific pharmachotherapy, but discontinuation of drug may help

• Hypercholesterolemia,Hyperglycemia & Diabeties Mellitus :- less risk than other anti psychotics.

• Orthostatic Hypotension & Syncope :- due to α- receptor antagonist properties

• Hyperprolactinemia :-– ↑ prolactin levels [mean of 15.4 ng/dL].– ↓ reproductive functioning - galactorrhea, amenorrhea,

anorgasmia. If left untreated, leads to decreased bone mineral density in both sexes, with hypogonadism.

– F/H/O Breast cancer s/b enquired before T/t.

Special population

• Pregnancy :- Category C drug.• Lactation :- Excreted in breast milk. Milk : plasma conc. < 0.5• Geriatric :- Use cautiously as prone for

orthostatic hypotension. Concomitant administration with Furosemide increases risk of mortality in elderly patients.

Overdosage

• No mortality reported even upto 360 mg of Risperidone.

DRUG INTERACTIONS

• Inhibition of CYP2D6 by drugs such as paroxetine & Fluoxetine blocks formation of active metabolite.

• Combined use of risperidone with SSRI can result in significant hyperprolactnemia.

THANK YOU

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