1. 1
OH
N O
N
N
S
Clozapine Loxapine
CH3
N
N
H
S CH3
N
N
Cl
CH3
N
N
N
O
Cl
CH3
H
N
N
N
N
Olanzapine (Zyprexa) Atypical
O
F
CH3
N O
N
N
N
H
Cl
O
N
N
N
S
N
Risperidone (Risperdal) Atypical
Quetiapine (Seroquel) Atypical
Ziprasidone (Geodon) Atyical

2. Other names
• 2nd generation
• Serotonin Dopamine Antagonists
Features
• Higher ratio of serotonin : dopamine receptor
blockade
• Appear more specific for mesolimbic than striatal
dopamine system

3. Developments in Medical Treatments
for Psychotic Disorders
’30s ’40s ’50s ’60s ’70s ’80s ’90s ’00 ’02
ECT
Haloperidol
Fluphenazine
Thioridazine
Chlorpromazine
Loxapine
Perphenazine
Clozapine
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Next-generation
First-generation
antipsychotics Second-generation
antipsychotics
ECT = electroconvulsive therapy.
Kapur and Remington. Ann Rev Med. 2001;52:503.
Worrel et al. Am J Health Syst Pharm. 2000;57:238.

4. MARTA (multi acting receptor targeted agents)
 clozapine, olanzapine, quetiapine
SDA (serotonin-dopamine antagonists)
 risperidone, ziprasidone, sertindole
Selective D2/D3 antagonists
 sulpiride, amisulpiride

5. Atypical Antipsychotics In Vivo Binding Affinities
Low D2 receptor blocking effects
Reduced risk of extrapyramidal side
Healoffpeercidtsol. Clozapine Risperidone Olanzapine
Quetiapine Ziprasidone
5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonist)
Casey 1994

6. Schizophrenia and schizoaffective disorder
– acute and chronic psychoses
• Treatment of severe tardive dyskinesia (clozapine)
Mood disorder – acute mania
• OLANZAPINE – bipolar disorder
• Augments anti depressants in acute management
of depression.

7.  Other indications
• Exhibits outwardly aggressive and violent behaviour
• Autistic spectrum disorder
• Tourettes syndrome
• Huntington’s disease
• Lesch Nyhan Syndrome
• Along with methylphenidate/dextroamphetamine in
children with ADHD.
• Psychosis secondary to head trauma, dementia,
treatment resistant
• Decreases the risk of suicide and water intoxication in
patients with schizophrenia

8. Extra pyramidal side effects (EPS):
• Risperidone > Olanzapine = Ziprasidone >
Quetiapine > Aripiprazole = Clozapine
Anticholinergic:
• Clozapine > Olanzapine > others
Hypotension:
• Clozapine > > Quetiapine, Risperidone >
Ziprasidone, Olanzapine, Aripiprazole

9. Sedation
• Clozapine > > Olanzapine, Quetiapine >
Risperidone, Ziprasidone, Aripiprazole
Prolactin elevation
• Risperidone > others
Weight gain
• Clozapine = Olanzapine > Quetiapine, Risperidone
> Ziprasidone, Aripiprazole
Agranulocytosis: Clozapine

10.  Sexual dysfunction
• result from NE and SE blockade
• erectile dysfunction in 23-54% of men
• retrograde ejaculation
• loss of libido and anorgasmia in men and women
 Seizures - <1% for generalized grand mal

11. Adverse pharmacologic effects of antipsychotic drugs.
Type Manifestations Mechanism
Autonomic
nervous
system
Loss of accommodation, dry
mouth, difficulty urinating,
constipation
Muscarinic cholinoceptor blockade
Orthostatic hypotension,
impotence, failure to ejaculate
Alpha adrenoceptor blockade
Central
nervous
system
Parkinson's syndrome, akathisia,
dystonias
Dopamine receptor blockade
Tardive dyskinesia
Supersensitivity of dopamine
receptors
Toxic-confusional state Muscarinic blockade
Endocrine
system
Amenorrhea-galactorrhea,
infertility, impotence
Dopamine receptor blockade
resulting in hyperprolactinemia
Other Weight gain
Possibly combined H1 and 5-HT2
blockade

13. Benzisoxazole
Undergoes first pass metabolism
Peak plasma level levels – 1 hr (parent
compound) , 3 hrs for
metabolite
Combined half life 20 hrs (once daily
dosing)
Antagonist of serotonin 5HT2A, dopamine
D2, α1, α2 adrenergic histamine H1
receptors.

14. Side effects
• Weight gain
• Anxiety
• Nausea
• Dizziness, hyperkinesias, somnolence,
• Vomiting
• Rhinitis
• Erectile dysfunction

15.  Dosages – Initially 1-2 mg/day , raised to 4 mg/
day
 Only SDA available in depot formation IM injection
every 2 weeks (25mg,50mg or 75 mg)
 Drug interactions – Paroxetine and Fluoxetine
(blocks the formation of
RISPERIDONE’S active
metabolite)
RISPERIDONE + SSRI – significant elevation of
prolactin - galactorrohea and breast enlargement

17. 85% absorbed from the GI tract
40% is inactivated by first pass metabolism
Peak concentration - 5hrs
Half life - 31 hrs
5HT2A ,D1, D4, α1 ,5HT1A , muscarinic M1
through M5 and H1 receptors

18. Side effects
• Weight gain
• Somnolence
• Dry mouth
• Dizziness
• Constipation
• Dyspepsia
• Increased appetite
• Akathisia
• tremor

19.  Periodic assessment of “blood sugar” and
“transaminase”.
Increased stroke among patients with
dementia
DOSAGES – initial dose for treatment of
psychosis – 5-10 mg , acute mania- 10-15
mg.
• Start 5-10 mg , raise to 10 mg per day
• 30-40 mg in treatment resistant cases.

20. Drug interactions
• FLUVOXAMINE and CIMETIDINE – increases
• CARBAMAZEPINE and PHENYTOIN - decreases

21. DIBENZOTHIAZEPINE
Rapidly absorbed from GI tracts
Peak plasma concentration – 1-2 hrs
Steady half life – 7 hrs (2- 3 dosing per
day)
 lower-potency compound with relatively
similar antagonism of 5-HT2, D2, α1, and α2
receptors .

22. Side effects
• – somnolence, postural hypotension and
dizziness – most common side effect.
• Least likely to cause extra pyramidal side effects.
– used in Parkinsonism who develop DOPAMINE
AGONIST induced psychosis.
• Moderate weight gain
• Small rise in heart rate , constipation and transient
rise in liver transaminases can occur.

23. DOSAGES – available in 25, 50 and 200
mg.
Schizophrenia – target of 400 mg/ day
Mania & BPD – 800 & 300 mg respectively
Insomnia – 25- 300 mg at night

24. BENZOTHIAZOLYL PIPERAZINE
Peak plasma concentration- 2-6 hrs
Terminal half life at steady state – 5-10 hrs
Bioavailability doubles when taken along
with food.
Blocks 5HT2A and D2 receptors , antagonist
5HT1D, 5HT2C, D3,D4,α1 and H1 receptors.

25. Agonist activity at 5HT1A receptor
Serotonin reuptake inhibotor
Nor epinephrine reuptake inhibitor
Side effects –
• somnolence, headache, dizziness , nausea , light
headedness, prolongation of QTc interval.
• avoided in patients with cardiac arrythmias.

26. Dosages – 20,40, 60 ,80 mg.
IM comes single use daily 20mg/ml vial
Oral ziprasidone initiated at 40 mg a day.
Efficacy in the range of 80-160 mg/day.
High as much as 240 mg are being used.

28. DIBENZODIAZEPINE
Rapidly absorbed
Plasma level – 2 hrs
Steady state – less than one week if twice
daily dosing is used.
Half life – 12 hrs
Antagonist of 5HT2A , D1,D3,D4 and α
receptors.

29. Conventional antipsychotic:
90% of striatal D2 receptor
occupied
Clozapine occupies only 20-67% of D2
receptors

30.  Special indications –
• benefits patients with severe tardive dyskinesia.
• Treatment resistant mania
• Severe psychotic depression
• Idiopathic Parkinson’s disease
• Huntington’s disease
• Suicidal patients with schizophrenia and
schizoaffective disorder.
• Pervasive developmental disorder
• Autism of childhood
• OCD (rarely)

31.  Side effects –
• Sedation
• Dizziness
• Syncope
• Tachycardia
• Hypotension
• ECG changes
• Fatigue
• Weight gain
• constipation
• Anticholinergic effects
• SIALORROHEA
• AGRANULOCYTOSIS
• SEIZURES
• MYOCARDITIS

32.  Clozapine-associated seizures occur most often
at doses greater than 600 mg /day.

33. • AGRANULOCYTOSIS
 Leucocyte and differential blood count normal before
starting
 Monitor counts every week for 6 months, then at
least Q 2 weeks after 1 year
 At least Q 4 weeks after count stable for 1 year (for 4
more weeks after discontinuation)
 If leucocyte count < 3000/mm3, or if ANC <
1500/mm3, discontinue immediately and refer to
hematologist
 Patient should report immediately symptoms of
infection, esp. flu-like illness (fever, sore throat)

34. Dosages
• Initial dosage is 25 mg one or 2 times daily
although conservative initial dosage is 12,5 mg
daily.
• Raised gradually to 25 mg a day for every 2-3
days to 300 mg divided doses
• 900 mg can be used.
• Plasma conc greater than 350 ng/mL is likely hood
for better response.

35. Drug interactions
• Clozapine + (carbamazepine, phenytoin,
propulthiouracil, sulfonamides, captopril) causes
bone marrow suppression.
• Clozapine+ Lithium – increases the risk of
seizures, confusion and movement disorders.
• Clozapine+ Paroxetine – precipitate clozapine
associated neutropenia.

36. QUINOLONE DERIVATIVE
Well absorbed reaching peak levels of 3- 5
hrs
Half life is about 75 hrs

37. Therapeutic indications
• Schizophrenia - maintenance treatment for 15-30
mg
• Acute mania –
• Other uses – add on for SSRI in treatment of
mood disorder cases.
• Oppositional defiant disorder or conduct disorder.

38. CYP3A4
inducer
Increase in clearance and lower blood levels dose
must be increased (doubled).
e.g. carbamazepine
CYP3A4
inhibitor
Decrease in clearance and higher blood levels. dose
must be decreased (one-half).
e.g. ketoconazole
CYP2D6
inhibitor
Decrease in clearance and higher blood levels. dose
must be decreased (one-half).
e.g. quinidine, fluoxetine, paroxetine

39. Bifeprunox - partial dopamine agonist.
• Treatment of schizophrenia
• GI side effects are most common.
 Paliperidone – major active metabolite of
resperidone.
• Recommended dose of 6mg per day with 3-12
mg/day.