Second Gen Anti-psychotics

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Second-Generation or Atypical Antipsychotics
Espiritu, Neil F.
Talento, Aldrine

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Schizophrenia

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Dopamine Pathways

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ROLE OF SEROTONIN IN SCHIZOPHRENIA

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 Mode of Action
 Affinity to D2 receptors
 Side Effects

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EPS

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 The term atypical is used because these drugs differ in their
side effect profiles, most notably a lower risk of
extrapyramidal side effects (EPS)
 As of 20 1 3 , ten second-generation antipsychotic drugs were
approved by the Food and Drug Administration (FDA).
 These include the following: Risperidone (Risperdal), Olanzapine
(Zyprexa), Quetiapine (Seroquel), Ziprasidone (Geodon),
Aripiprazole (Abilify), Paliperidone (Invega), Asenapine (Saphris),
Lurasidone (Latuda), Iloperidone (Fanapt), and Clo zapine
(Clozaril).

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MECHAN ISMS OF ACTION
 The presumed antipsychotic effects of the SDAs are blockade
of D2 dopamine receptors. Where the SDAs differ from older
antipsychotic drugs is their higher ratio interactions with
serotonin receptor subtypes, most notably the 5-HT2A
subtype, as well as with other neurotransmitter systems.
 It is hypothesized that these properties account for the distinct
tolerability profiles associated with each of the SDAs. All SDAs
have different chemical structures, receptor affinities, and side
effect profiles.

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THERAPEUTIC INDICATIONS
 Schizophrenia
 Acute Mania
 Adjunctive therapy in major depressive disorder.
 Posttraumatic stress disorder
 Anxiety Disorders
 **All of these agents are considered first-line drugs for
Schizophrenia except Clozapine

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Risperidone (Risperdal)
 INDICATIONS:
 Acute and maintenance treatment of Schizophrenia in adults and
adolescents.
 Short-term treatment of acute manic - mixed with lithium or
valproate
 Irritability associated with autistic spectrum DO in 5-16 years of
age
On August 22, 2007, risperidone was approved as the ONLY drug agent available
for treatment of schizophrenia in youths, ages 13–17

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Pharmacology
 Extensive first pass hepatic metabolism to 9-hydroxy
risperidone
 Peak plasma level for the parent compound – 1hr
 Metabolite – 3hrs
 Half-life - 20hrs (implication?)
 If dose is below 6mg per day – less likely to cause EPS

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Dosages
 Availability – 0.25, 0.5, 1, 2, 3 and 4mg tablets and a 1mg/ml
oral solution.
 Initial dosage is usually 1 to 2mg at night which can be
increased to 4mg per day.

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Side Effects
 EPS – dosage dependent
 Weight gain
 Anxiety
 Nausea and vomiting
 Erectile dysfunction
 Elevated prolactin

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Drug Interaction
 Paroxetine and fluoxetine inhibits CYP2D6 – block formation
of risperidone’s active metabolite.
 SSRIs + Risperidone = significant elevation of prolactin >
leading to?

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PALIPERIDONE (INVEGA)
 Indications:
 Acute and maintenance treatment for
schizophrenia
 Acute treatment of schizoaffective disorder as
monotherapy
 Adjunct to mood stabilizers or antidepressants

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Pharmacology
 MAJOR active metabolite of risperidone
 No dose adjustment required in patients with hepatic impairment
 Peak plasma concentration – 24 hours after dosing
 Steady-state concentrations – 4 or 5 days.

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Dosage
 Available in 3,6, and 9 mg tablets
 Recommended dosage: 6mg OD in the morning.
 No more than 12mg per day
 (Invega Sustenna) – by IM once a month
 39mg, 78mg, 117mg (recommended), 156mg, 234mg paliperidone
palmitate.
 Half life = 25-49 days.

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Side Effects
 Orthostatic hypotension, tachycardia
 Somnolence
 EPS

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OLANZAPINE (Zyprexa)
 Indications:
 Schizophrenia
 Monotherapy for the ACUTE treatment of manic
or mixed episodes associated with bipolar I
disorder adjunct to lithium or valproate
 Adjunct to fluoxetine for the treatment of
depressive episodes associated with bipolar I

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Pharmacology
 85% absorbed in the GI
 40% inactivated by first pass hepatic metabolism
 Peak in 5 hours
 Half life averages 31 hours
 Once daily dosing

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Dosages
 2.5, 5, 7.5, 10, 15, and 20mg oral tablets.
 Initial dosage for psychosis – 5 or 10mg
 Acute mania – 10 or 15mg
 30 to 40mg – treatment-resistant patients.

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DRUG INTERACTIONS
 Cimetidine (Tagamet) – increases concentration of Olanzapine
 Carbamazepine and phenytoin – decreases serum
concentration of Olanzapine
 Ethanol increases olanzapine absorption by more than 25
percent

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SIDE EFFECT
 More frequent WEIGHT GAIN
 Somnolence, dry mouth, dizziness, constipation, dyspepsia,
increased appetite, akathisia, and tremor
 Dose related EPS

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Quetiapine (Seroquel)
 Indications:
 Schizophrenia
 Acute treatment of manic episodes associated with bipolar I disorder
(monotherapy or adjunct to lithium or divalproex)

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Pharmacology
 Structurally related to clozapine
 Rapidly absorbed in the GI tract, peak plasma concentrations
reached 1-2 hours
 Steady state half life 7 hours (dosing is two or three times a
day)
 Not associated with EPS

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Dosages
 25, 50, 100, 200, 300, and 400mg tablets
 Dosing should begin 25mg twice daily, with doses increased
by 25 to 50mg per dose every 2 to 3 days, up to a target of 300
to 400mg a day.
 More aggressive dosing is both tolerated and effective
 25 to 300mg at night – used for insomnia

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Drug Interactions
 Phenytoin increases quetiapine clearance fivefold
 Avoid drugs that prolong QT interval(quinidine, procainamide,
amiodarone, sotalol, ziprasidone, chlorpromazine, thioridazine,
gatifloxacin, moxifloxacin

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Side Effect
 Somnolence, postural hypotension, and dizziness – most
common
 Least likely to cause EPS
 Transient weight gain

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Ziprasidone (Geodon)
 Indications:
 Schizophrenia
 Monotherapy for the acute treatment of manic or mixed episodes
associated with bipolar I DO adjunct to lithium or valproate

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Pharmacology
 Peak 2-6 hours
 Recommended twice daily dosing
 Peak serum concentrations of IM ziprasidone occur
approximately 1 hour, with a half life of 2 to 5 hours.

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Dosages
 20, 40, 60 and 80mg capsules
 IM use – single use 20mg/ml vial.
 Oral ziprasidone dosing should be initiated at 40mg a day
divided into two daily doses.

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Side Effects
 Somnolence, headache, dizziness, nausea, and
lightheadedness are the most common adverse effects
 Prolongation of QTc complex

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Aripiprazole (Abilify)
 D2 antagonist, partial D2 agonist and potent 5-HT2A
antagonist
Indications:
 Schizophrenia and schizoaffective disorders
 Acute and maintenance treatment and adjunctive
therapy to either lithium or valproate for manic and
mixed episodes associated with bipolar I disorder.
 Treatment of irritability associated with autistic disorder.

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Aripiprazole (Abilify)
 Well absorbed, reaching peak plasma
concentrations after 3 to 5 hours.
 Absorption is not affected by food.
 Mean elimination half-life: 75 hours
 Clearance is reduced in elderly persons.
 minimal EPS and may cause orthostatic
hypotension.
 Primarily metabolized by CYP3A4 and CYP2D6
genes.

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Aripiprazole (Abilify)
Drug Interactions:
Carbamazepine and valproate reduce serum
concentrations
Ketoconazole, fluoxetine, paroxetine, and
quinidine increase serum concentrations
Combined with antihypertensives may cause
hypotension. Drugs that inhibit CYP2D6
activity reduce elimination.

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Aripiprazole (Abilify)
Dosage and guidelines
 Available as 5, 1 0, 1 5, 20, and 30 mg tablets.
 The effective dosage range is 10 to 30 mg per day. Starting dose
is 10 to 15 mg per day.
 Initial dose of 5 mg increases tolerability.
Side effects
 Headache, somnolence, agitation, dyspepsia, anxiety, and nausea
 Akathisia, Insomnia, weight gain or diabetes

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ASENAPINE (SAPHRIS)
 Acute treatment of adults with schizophrenia and of manic or
mixed episodes associated with bipolar I disorder with or
without psychotic features.
 Affinity for several receptors: serotonin, noradrenergic,
dopaminergic and histamine.
 Negligible affinity for muscarinic-1 cholinergic receptors

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ASENAPINE (SAPHRIS)
Dosage
 5 mg and 10 mg sublingual tablets
 Bioavailability is <2% when swallowed, but is 35% when
absorbed sublingually.
 Avoid drinking or eating for 10 minutes after because this may
lower the blood levels.
 Recommended starting and target dose for schizophrenia is
5mg BID and 5-10 mg BID for Bipolar disorder.

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ASENAPINE (SAPHRIS)
Side Effects
 somnolence, dizziness, EPS other than
akathisia, and increased weight.
 can elevate prolactin levels during chronic
administration
 Galactorrhea, amenorrhea, gynecomastia, and
impotence.

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CLOZAPINE (CLOZARIL)
 Most effective drug treatment for patients who have failed to
respond to standard therapies and also benefits patients with
severe tardive dyskinesia.
 treatment of psychotic patients who are intolerant of EPS caused
by other agents, treatment-resistant mania, severe psychotic
depression, idiopathic Parkinson's disease, Huntington's disease,
and suicidal patients with schizophrenia or schizoaffective disorder
 Pervasive developmental disorder, autism of childhood, and OCD

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CLOZAPINE (CLOZARIL)
 It is rapidly absorbed with peak plasma levels reached in about
2 hours.
 Steady state is achieved in less than 1 week if twice daily
dosing is used. Elimination half-life is about 12 hours
 An antagonist of 5-HT2A, D1, D3, D4, and adrenergic
receptors. It has relatively low potency as a D2 receptor
antagonist.

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CLOZAPINE (CLOZARIL)
Dosage and interactions
 Available in 25 mg and 100 mg tablets. Initial dose is usually 25
mg OD or BID.
 The dosage can then be increased gradually to 300 mg a day in
divided doses and up to 900 mg a day.
 Agranulocytosis or bone marrow suppression.
 Lithium may increase the risk of seizures, confusion, and
movement disorders. Clomipramine (Anafanil) can increase the
risk of seizure.
 Risperidone, fluoxetine, paroxetine, and fluvoxamine increase
serum concentrations. Paroxetine may precipitate clozapine-
associated neutropenia.

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CLOZAPINE (CLOZARIL)
Side effects
 Most common: sedation, dizziness, syncope, tachycardia,
hypotension, ECG changes, nausea, and vomiting.
 Fatigue, weight gain, various GI symptoms (most commonly
constipation), anticholinergic effects.
 Hypersalivation, is a side effect that begins early in treatment and is
most evident at night.
 Risk of seizures is about 4% in patients taking dosages >600 mg a
day
 Leukopenia, granulocytopenia, agranulocytosis, and fever
 Containdications: WBC count <3,500 cells per mm3; a
previous bone marow disorder; history of agranulocytosis; drugs that
suppress the bone marrow such as carbamazepine (Tegretol).

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ILOPERIDONE (FANAPT)
 For acute treatment of schizophrenia in adults.
 peak concentration of 2 to 4 hours and a half-life that is
dependent on hepatic metabolism (18 – 37 hrs)

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ILOPERIDONE (FANAPT)
Side Effects
 Prolongs the QT interval at12mg twice daily.
 dizziness, dry mouth, fatigue, sedation,
tachycardia, and orthostatic hypotension
Dosing
 Titrated slowly to avoid orthostatic hypotension
 Effective dose(12 mg) should be reached in
approximately 4 days based on a twice-a-day dosing.
The maximum recommended dose is 12 mg BID.

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LURASIDONE HCL (LATUDA)
 Oral, once-daily, atypical antipsychotic indicated for schizophrenia.
Side Effects
 somnolence, akathesia, nausea, parkinsonism, and agitation.
 Causes less weight gain and metabolic changes than asenapine and
iloperidone.
Drug Interactions
 should not be used in combination with a strong CYP3A4 inhibitor
(e.g., ketoconazole) or CYP3A4 inducer (e.g., rifampin).
 Dose should not exceed 40 mg per day with coadministration with a
moderate CYP3A4 inhibitor such as diltiazem.

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LURASIDONE HCL (LATUDA)
 20, 40, 80, and 120 mg tablets. Recommended starting dose is
40 mg OD and should be taken with food.
 Effective in a dose range of 40 to 120 mg per day.
 Dose adjustment for patients with renal impairment. <80 mg per
day for moderate and <40mg severe renal impairment.

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CLINICAL GUIDELINES FOR SDAS
 All SDAs are appropriate for the management of an initial
psychotic episode, but clozapine is reserved for persons who
are refractory to all other antipsychotic dugs.
 The choice of drug should be based on the patient's clinical
stats
and history of response to medication.
 Use of all SDAs must be initiated at low dosages and gradually
tapered upward to therapeutic dosages.
 Patient's history should include information about blood
disorders, epilepsy, cardiovascular disease, hepatic and renal
diseases, and drug abuse.

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CLINICAL GUIDELINES FOR
SDAS
 The physical examination should include supine and standing
blood pressure measurements to screen for orthostatic
hypotension.
 The laboratory examination should include an ECG and several
complete blood counts with WBC counts and liver and renal
function tests. Blood glucose, lipids, and body weight.
 Persons who developed agranulocytosis while taking clozapine
can safely switch to olanzapine.
 SDA use by pregnant women has not been studied, but
consideration should be given to the potential of risperidone to
raise prolactin concentrations, sometimes up to three to four times
the upper limit of the normal range. Because the drugs can be
excreted in breast milk, they should not be taken by nursing
mothers.