Pharmacology of common Second-Generation Anti-Psychotics

2. INTRODUCTION
• Also known as “second-generation” anti-psychotics.
• Most widely used type of antipsychotic drugs – minimal EPSE and broader spectra of action
than typical anti-psychotics.
• However, these drugs are expensive and are not frequently used in our set up
• Their pharmacology is complex - individual drugs in this group have multiple NT effects.

3. EXAMPLES
• Clozapine (Clozaril)
• Asenapine (Saphris)
• Olanzapine (Zyprexa; Zyprexa Relprevv - olanzapine for extended-release injectable) suspension
• Quetiapine (Seroquel; Seroquel XR – Quetiapine XR)
• Paliperidone (Invega)
• Risperidone (Risperdal; Consta – IM long acting)
• Ziprasidone (Geodon)
• Aripiprazole (Abilify)

4. CLOZAPINE
• Indication - Refractory schizophrenia; Severe tardive dyskinesia.
• Mechanism of action - Blocks serotonin and dopamine (especially, D1 and D4) receptors, with
a greater effect on serotonin receptor 5-HT2A.
• Pharmacokinetics – peak plasma levels reached 2hrs after absorption; metabolized by hepatic
CYP enzymes; elimination half life – 12 hrs.
• Dosages – initial dosing; 25 mg OD or BD; increased gradually to 300mg BD or TDS a day at a
rate of 25mg OD every two or three days; Dosages up to 900 mg a day can be used.
• Drug interactions – Not to be used with drugs that induce agranulocytosis or BM suppression
e.g. phenytoin; Lithium + clozapine may increase the risk of seizures, confusion, and movement
disorders; Risperidone, fluoxetine, paroxetine, and fluvoxamine increase serum concentrations
of clozapine.

5. •Common Side Effects - sedation, dizziness, syncope, tachycardia, hypotension,
electrocardiography (ECG) changes, nausea, and vomiting.
•Other common adverse effects include fatigue, weight gain, various GI symptoms
(most commonly constipation), anticholinergic effects, subjective muscle weakness
and hypersalivation.
•Major limitation - agranulocytosis (0.8%) and other blood dyscrasia and as such it
should be discontinued if the WBC count is <3,000 cells/mm3 or the granulocyte
count is < 1 ,500 per mm3.
•Contraindications; WBC count < 3,500 cells/mm3; a previous bone marrow disorder;
a history of agranulocytosis during clozapine treatment; or the use of another drug
that is known to suppress the bone marrow, such as carbamazepine (Tegretol).

6. OLANZAPINE
• Indications – Schizophrenia; Manic or mixed episodes associated with bipolar I disorder
either as monotherapy or in combination with lithium; Depressive episodes associated
with bipolar I disorder and treatment-resistant depression in combination with fluoxetine.
• Pharmacokinetics – 85% absorbed from GI tract; 40% inactivated by 1st pass
metabolism; peak plasma concentration reached in 5 hours; elimination half life averages
31 hrs.
• Mechanism of action – resembles clozapine in blocking multiple monoaminergic (D2, 5-
HT2, α1, α2) as well as muscarinic (M1 –M5) and H1 receptors.
• Dosages - 5 to 10 mg (starting daily dose) recommended for psychosis; After 1 week,
the dosage can be raised to 10 mg a day; Dosages in clinical use ranges vary, with 5 to
20 mg a day being most commonly used, but 30 to 40 mg a day being needed in
treatment-resistant patients.

7. • The parenteral form (Relprevv) is indicated for treatment of acute agitation associated
with schizophrenia and bipolar disorder, and the IM dosage is 10 mg.
• This injection ONLY ADMINISTERED GLUTEALLY carries increased risk of Post
injection delirium sedation syndrome (PDSS) – requires observation for 3 hrs post
injection.
• The injection can be given every 2 or 4 weeks depending on the dosing guidelines.
• Drug Interactions – concentrations raised by fluvoxamine and cimetidine and reduced
by phenytoin; Absorption increased by ethanol; Little effect on metabolism of other
drugs.
• Side Effects – weight gain, somnolence, dry mouth, dizziness, constipation, dyspepsia,
increased appetite, akathisia, tremor, dose-related EPSE, and transaminase elevation.

8. DRUG-INDUCED DIABETES
MELLITUS AND WEIGHT GAIN
• Mainly mediated by olanzapine and clozapine.
• The following factors be considered for all patients prescribed second-generation antipsychotics.
• Personal and family history of obesity, diabetes, dyslipidemia, hypertension, and cardiovascular disease
• Weight and height (so that body mass index can be calculated)
• Waist circumference (at the level of the umbilicus)
• Blood pressure
• Fasting plasma glucose level
• Fasting lipid profile
• Patients with preexisting diabetes should have regular monitoring, including HbA1C and in some
cases insulin levels.

9. RISPERIDONE
• Indications – Schizophrenia; Short-term treatment of acute manic or mixed episodes associated
with bipolar I disorder either as monotherapy or in combination with lithium or valproate; treatment
of irritability associated with ASD in children and adolescents age 5 to 16 years.
• Pharmacokinetics - undergoes extensive first-pass hepatic metabolism to 9-hydroxyrisperidone;
Peak plasma levels of risperidone occur within 1 hour and 3 hours for the metabolite; The
combined half-life of risperidone and 9-hydroxy risperidone averages 20 hours.
• Mechanism of Action – in addition to D2 + 5-HT2 receptor blockade, it has high affinity for α1, α2
and H1 receptors.
• Dosages - Initial dosage is usually 1-2 mg at night, which can then be increased to 4 mg per day;
Higher dosages are associated with more adverse effects. Children require lower starting
dosages.

10. • Risperdal Consta (depot formulation) given as IM injection every 2 weeks. The dose may
be 25, 50, or 75 mg.
• Oral risperidone should be co-administered with Risperdal Consta for the first 3 weeks
before being discontinued.
• Drug Interactions - paroxetine and fluoxetine can block the formation of risperidone's
active metabolite; Risperidone in combo with SSRIs may result in significant elevation of
prolactin, with associated galactorrhea and breast enlargement.
• Side Effects – EPSE (dose dependent), weight gain (more common in children), anxiety,
nausea and vomiting, rhinitis, erectile dysfunction, orgasmic dysfunction, and increased
pigmentation.
• The most common drug-related reasons for discontinuation of risperidone use are EPS,
dizziness, hyperkinesias, somnolence, and nausea.

11. PALIPERIDONE
• Indications – Schizophrenia; Acute treatment of schizoaffective disorder as monotherapy, or as an
adjunct to mood stabilizers or antidepressants.
• Pharmacokinetics – Major active metabolite of risperidone; Peak plasma concentrations reached in
24 hrs; Steady state concentrations reached in 4-5 days.
• Dosages - The recommended dosage is 6 mg once daily administered in the morning. It can be taken
with or without food; No more than 12 mg should be administered per day;
• Invega Sustenna - A long-acting formulation of paliperidone is given by injection once a month; a dose
of 117mg is recommended with alterations dependent on clinical situation; t1/2 of 25-49 days; The first
two injections should be in the deltoid muscle (plasma conc are 28% higher with deltoid administration)
with subsequent injections alternating between gluteal and deltoid sites.
• Precautions – Reduced doses in renal impairment
• Side Effects – Increased sensitivity to temperature extremes, QT prolongation, orthostatic
hypotension, tachycardia, somnolence, akathisia, dystonia, EPS, and parkinsonism.

12. QUETIAPINE
• Indications – Schizophrenia; Acute treatment of manic episodes associated with bipolar I disorder,
both as monotherapy and as an adjunct to lithium or divalproex; Monotherapy for acute treatment of
depressive episodes associated with bipolar disorder; Maintenance treatment of bipolar I disorder
as an adjunct to lithium or divalproex.
• Pharmacokinetics – Rapidly absorbed from GIT; Peak plasma concentrations reached in 1-2 hrs;
steady-state half-life is about 7 hours.
• Mechanism of Action – It blocks 5-HT1A, 5-HT2, D2, α1, α2 and H1 receptors in the brain, but D2
blocking activity is low.
• Dosages – initial dosing (25 mg twice daily), with doses then increased by 25 to 50 mg per dose
every 2 to 3 days, up to a target of 300 to 400 mg a day. Quetiapine in doses of 25 to 300 mg at
night has been used for insomnia

13. • Other formulations – Quetiapine XR; has more bioavailability than quetiapine; given once daily,
preferably in the evening 3 to 4 hours before bedtime without food or a light meal to prevent an
increase in plasma concentration· The usual starting dose is 300 mg, and it may be increased to
400 to 800 mg.
• Drug Interactions/Precautions – Clearance is increased x5 by phenytoin; Use should be
avoided with drugs that cause QT prolongation e.g. class A I or III antiarrhythmics; Quetiapine
should also be avoided in circumstances that may increase the risk of occurrence of torsade de
pointes and/or sudden death.
• Side Effects - Somnolence, postural hypotension, and dizziness are most common. Prolactin
elevation is rare. Modest transient weight gain in some persons, but some patients occasionally
gain a considerable amount of weight. Small increases in heart rate, constipation, and a transient
increase in liver transaminases may also occur.

14. ZIPRASIDONE
• Indications – Schizophrenia; Monotherapy for the acute treatment of manic or mixed episodes
associated with bipolar I disorder; Adjunct to lithium or valproate for the maintenance treatment of
bipolar I disorder.
• Pharmacology - Peak plasma concentrations are reached in 2-6 hrs; The mean terminal half-life
ranges from 5 to 10 hours; Bioavailability doubles when ziprasidone is taken with food; Peak
serum concentrations of IM ziprasidone occur after approximately 1 hour, with a half-life of 2 to 5
hours.
• Mechanism of Action - blocks 5-HT2A and D2 receptors. It is also an antagonist of 5-HT1D, 5-HT2c,
D3, D4, ai, and H1 receptors. It has very low affinity for Di, Mi, and a2 receptors. In addition,
ziprasidone has agonist activity at the serotonin 5-HT IA receptors and is an SSRI and a
norepinephrine reuptake inhibitor.

15. •Dosages - Oral ziprasidone dosing should be initiated at 40 mg a day divided into
two daily doses. In clinical practice, doses as high as 240 mg a day are being
used. The recommended IM dosage is 10 to 20 mg every 2 hours for the 10 mg
dose and every 4 hours for the 40 mg dose. The maximum total daily dose of IM
ziprasidone is 40 mg.
•Drug Interactions - Use should be avoided with drugs that cause QT
prolongation.
•Side Effects – Somnolence, headache, dizziness, nausea, and lightheadedness
are the most common adverse effects

16. ARIPRIPAZOLE
• Indications – Schizophrenia; Acute mania associated with bipolar I disorder; Adjunctive therapy to
antidepressants for the treatment of MDD; Treatment of irritability associated with ASD.
• Pharmacology – Peak plasma concentrations reached in 3-5 hrs; Absorption not affected by food; half
life is about 75 hrs; It has a weakly active metabolite with a half-life of 96 hours; Clearance is reduced in
elderly persons.
• Mechanism of Action – Partial agonist at D2 and 5-HT1A receptor, but antagonist at 5-HT2 receptor.
• Dosages - The effective dosage range is 10 to 30 mg per day. Although the starting dosage is 10 to 15
mg per day. Many clinicians find that an initial dose of 5 mg increases tolerability.
• Side Effects – Headache, somnolence, agitation, dyspepsia, anxiety, and nausea. It also causes
akathisia-like activation.
• Drug Interactions - Carbamazepine and valproate reduce concentrations; Ketoconazole, fluoxetine,
paroxetine, and quinidine increase concentrations. Combined use with antihypertensives may cause
hypotension.

17. CARBAMAZEPINE
• Indications – Acute mania in bipolar disorder; Preventing relapses, particularly among patients
with bipolar II disorder and schizoaffective disorder, and dysphoric mania; Refractory acute
depression; Controlling nonacute agitation and aggressive behavior in patients with schizophrenia
and schizoaffective disorder.
• Pharmacokinetics – Absorption is slow and unpredictable; Food enhances absorption; Peak
plasma concentrations are reached 2 to 8 hours after a single dose, and steady-state levels are
reached after 2 to 4 days on a steady dosage; The half-life of carbamazepine averages of 26
hours.
• Mechanism of Action - Carbamazepine exerts a lithium-like therapeutic effect in mania and
bipolar mood disorder.

18. • Drug Interactions – Can reduce efficacy of haloperidol, oral contraceptives, lamotrigine,
valproate and topiramate. Metabolism of carbamazepine is induced by phenobarbitone, phenytoin,
and vice versa. Erythromycin, fluoxetine, isoniazid inhibit metabolism of carbamazepine.
• Side Effects - Carbamazepine produces dose-related neurotoxicity—sedation, dizziness, vertigo,
diplopia and ataxia. Vomiting, diarrhoea, worsening of seizures are also seen with higher doses.
Acute intoxication causes coma, convulsions and cardiovascular collapse.
• Hypersensitivity reactions are rashes, photosensitivity, hepatitis, lupus like syndrome, rarely
agranulocytosis and aplastic anaemia. Some degree of leucopenia due to hypersensitivity is more
common.
• Water retention and hyponatremia can occur in the elderly because it enhances ADH action.
• Increased incidence of minor foetal malformations has been reported. Its combination with
valproate doubles teratogenic frequency.

19. THE END
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