1. Dr. Karrar Husain
Moderator :Dr. Piyush P. Singh
Pharmacology of 2nd generation
antipsychotics

2. HISTORY
 Before 1952 –lobotomy, convulsive therapy, physical restrain, seclusion
,sedation.
 Chlorpromazine – first antipsychotic drug
 Discovered by chance
 After 2 yrs- side effects
 This is followed by development of subsequent antipsychotic agent.

3.  Drawbacks- dystonia, akathisia, tardive dyskinesia and negligible
effects on negative symptoms.
 Clozapine  1958 bern Switzerland
 Low chance of EPS and also ameliorate negative symptoms
 Released in european market in 1972
 Becoz of hematological toxicity 50 patient had died worldwide ….it
was withdrawn

4.  However, when studies demonstrated that clozapine was more effective
against treatment-resistant schizophrenia than other antipsychotics,
 the FDA and health authorities in most other countries approved its use
only for treatment-resistant schizophrenia.
 In December 2002, clozapine was approved in the US for reducing the
risk of suicide in schizophrenic or schizoaffective patients.

5. Classification of Antipsychotic drugs
 Main categories are:
 Typical antipsychotics
Phenothiazines (chlorpromazine, perphenazine,
fluphenazine, thioridazine )
Thioxanthenes (flupenthixol, clopenthixol)
Butyrophenones (haloperidol, droperidol)
 Atypical antipsychotics (e.g. clozapine, risperidone,
sulpiride, olanzapine)

6. What makes an antipsychotic
atypical
 clinical perspective, it is “low EPS” and “good for negative symptoms.
 From a pharmacological perspective,the atypical antipsychotics as a
class may be defined in at least four ways: as “serotonin dopamine
antagonists” as
 “D2 antagonists with rapid dissociation” ,as
 “D2 partial agonists (DPA)”
 or as “serotonin partial agonists (SPA)”at 5HT1A receptors.

7. Classification of atypical
antipsychotics
 Benzisoheterazoles
 Resperidone
 Ziprasidone
 Dibenzazepines
 Clozapine
 Quetiapine fumarate
 Thiobenzodiazepenes
 Olanzapine

8. MECHANISM OF ACTION
 Dopamaine pathways
1. Mesolimbic,
2. Mesocortical,
3. Nigrostriatal, and
4. tuberoinfundibular dopamine pathways

10. Mesolimbic dopamine pathway
 Projects from the ventral tegmental area of the brainstem to nucleus
accumbens in the ventral striatum.
 Hyperactivity of the mesolimbic dopamine pathway hypothetically
accounts for positive psychotic symptoms.
 The mesolimbic dopamine pathway is also thought to be the site of the
brain’s reward system or pleasure center.

12. Mesocortical dopamine
pathways
 Project ventral tegmental area to areas of the prefrontal cortex
 cognitive and some negative symptoms  deficit of dopamine activity
in mesocortical projections to dorsolateral prefrontal cortex.
 affective and other negative  deficit of dopamine activity in
mesocortical projections to ventromedial prefrontal cortex.

15. Nigrostriatal dopamine
pathway
 Deficiencies in dopamine in this pathway cause movement disorders,
including Parkinson’s disease.
 Dopamine deficiency in the basal ganglia can also produce akathisia
and dystonia .
 These movement disorders can be replicated by drugs that block
dopamine-2 receptors in this pathway
 Chronic blockade of dopamine-2 receptors in this pathway may result
in a hyperkinetic movement disorder known as neuroleptic-induced
tardive dyskinesia

16. Tuberoinfundibular dopamine
pathway
 Project from the hypothalamus to the anterior pituitary.
 Normally, these neurons are active and inhibit prolactin release.
 Blockage of dopamine in this pathway would result in
hyperprolactinemia.

19. Serotonin
 Serotonin is also known as 5-hydroxytryptamine.
 Synthesis of 5HT begins with the amino acid tryptophan

20. Serotonin receptors
 presynaptic (5HT1A and 5HT1B/D)
 postsynaptic (5HT1A, 5HT1B/D as well as 5HT2A, 5HT2C, 5HT3,
5HT4, 5HT5, 5HT6, and 5HT7).
 Presynaptic 5HT receptors are autoreceptors
 5HT1A receptors act as an accelerator for dopamine release, whereas
5HT2A receptors act as a brake on dopamine release

22. 5HT2A antagonism makes an
antipsychotic atypical
 5HT2A antagonism reduces EPS
 5HT2A antagonism stimulate dopamine relaese in striatum
 Increased dopamine competes with drug at D2 receptors and reduces
binding of drug there enough to eliminate EPS.

24.  5HT2A antagonism reduces negative symptoms
 5HT2A antagonism increase DA release in prefrontal cortex.
 The increased availability of dopamine to these areas may lead to
improvement in the negative, cognitive, and affective symptoms.

26.  5HT2A antagonism may improve positive symptoms
 Activation of 5HT2A receptors in the prefrontal cortex may contribute
to positive symptoms of hallucinations by enhancing the excitation of
glutamate neuron
 5HT2A antagonists block glutamate release thus reducing
hallucinations and other positive symptoms.

28.  5HT2A antagonist actions reduce hyperprolactinemia
 Dopamine inhibits prolactin whereas serotonin promotes prolactin
release by stimulating 5HT2A receptors.
 Thus 5HT2A antagonism reduce prolactin release and chance of
hyperprolactinemia

31. Rapid dissociation from D2
receptors makes an antipsychotic
atypical
 atypical antipsychotics also have the ability to rapidly dissociate from
D2 receptors.
 Theoretically, such an agent is able to stay at D2 receptors long enough
to exert an antipsychotic action
 but then leaves prior to producing an extrapyramidal side effect,
elevation of prolactin, or worsening of negative symptoms.

32.  clozapine and quetiapine have faster dissociation from the D2 receptor
than risperidone with olanzapine in the middle.
 This roughly correlates with the abilities of these drugs to cause motor
side effects..
 Sulpiride and amisulpride also dissociate rapidly from D2 receptor
…this explain the atypical clinical properties of these drugs even in
absence of serotonin antagonism

33. D2 partial agonism (DPA) makes
an antipsychotic atypical
 DPAs theoretically bind to the D2 receptor in a manner that is neither
too antagonizing, like a conventional antipsychotic
 nor too stimulating, like a stimulant or dopamine itself.
 DPAs reduce D2 hyperactivity in mesolimbic dopamine neurons to a
degree that is sufficient to exert an antipsychotic action on positive
symptoms, even though they do not completely shut down the D2
receptor.
 At the same time, DPAs reduce dopamine activity in the nigrostriatal
system to a degree that is insufficient to cause EPS

35. 5HT1A partial agonist (SPA)
actions make an antipsychotic
atypical
 5HT1A  increase dopamine release and reduce glutamate release.
 Enhanced dopamine release in the striatum improve extrapyramidal
actions;
 in the pituitary would reduce the risk of hyperprolactinemia;
 in the prefrontal cortex would improve negative, cognitive, and
affective symptoms of schizophrenia
 Reduced glutamate release in prefrontal cortex could reduce positive
symptoms.

37. Pharmacology of individual
antipsychotics(common)

38. CLOZAPINE
 Pharmacokinetics
 only available as an oral preparation
 peak plasma levels 2 hours after oral administration
 half-life is approximately 12 hours(dosing should be twice daily)
 steady-state plasma concentrations reach in less than 1 week
 Demethylation and oxidation of the terminal nitrogen of the piperazine
side chain form the two main metabolites(N-demethyl and N-oxide
metabolites )

39.  Receptor binding
 D2 receptor activity < traditional antipsychotic agents
 5-HT2 receptor activity is among the highest for antipsychotic agents.
 Blood concentration
 Women and older adults have higher plasma levels.
 smokers slightly lower plasma levels
 Patients are more likely to respond when their clozapine plasma
concentrations are greater than 350 ng/mL.

40.  Therapeutic indication
 Treatment-Resistant Patients
 Severe Tardive Dyskinesia : clozapine can suppress abnormal
movements in tardive dyskinesia
 Patients with a Low Extra pyramidal Side Effect Threshold
 Treatment-Resistant Mania
 Severe Psychotic Depression

41.  Suicidal Patients with Schizophrenia or Schizoaffective Disorder
 Treatment Resistance in Other Disorders:Autism of childhood, or
obsessive-compulsive disorder (OCD.
 Neurological Illnesses : secondary psychotic symptoms of Idiopathic
Parkinson's disease (doses of 25 to 75 mg).

42.  Precautions and Adverse Reactions
 Agranulocytosis: contraindications a WBC count below 3,500 cells per
mm3,
 a previous bone marrow disorder,
 a history of agranulocytosis during clozapine treatment,
 or the concomitant use of another bone marrow suppressant drug such
as carbamazepine
 The risk is greatest during the first 3 months of treatment,

43.  The risk increases with age and is higher in women
 Monitoring : weekly for the first 6 months, then every 2 weeek and
continued for at least 1 month after it is discontinued.
 If the patient has a WBC count below 2,000 cells per mm3 or a
granulocyte count below 1,000 cells per mm3, clozapine must be
discontinued
 Others : leukocytosis (0.6 percent), eosinophilia (1 percent), and
leukopenia, neutropenia, decreased WBC count (3 percent), and,
rarely, thrombocytopenia

44.  Sialorrhea
 CVS: most frequent are tachycardia and postural hypotension
 Orthostatic hypotension is more likely to occur during initial titration of
clozapine in association with rapid dose escalation but may occur after
the first dose.
 Hypertension.
 Myocarditis

45.  Peripheral Anti cholinergic Effects
 Weight Gain
 Diabetes Mellitus
 Extra pyramidal Side Effects : lower incidence of extra pyramidal side
effects than do other antipsychotics.
 Lowering of Seizure Threshold

46.  Drug Interactions
 CYP isoenzyme 1A2
 fluvoxamine and Risperidone Erythromycin and ketoconazole will elevate
clozapine concentrations,
 Cimetidine, SSRIs, tricyclic drugs, and divalproic acid decrease clearance.
 Phenytoin and carbamazepine may decrease concentrations of clozapine
 Benzodiazepines a few case reports of delirium, increased somnolence,
and acute respiratory suppression have appeared.

47. RISPERIDONE
 PHARMACOKINETICS
 Food does not affect the rate or extent of absorption in the gut.
 Risperdal Consta  long-acting (IM) preparation of risperdone
 Aqueous suspension  minimizes pain and inflammation at the
injection
 twice-per-week
 It has a lower incidence of side effects such as extrapyramidal
symptoms, insomnia, orthostatic hypotension, sexual dysfunction (<2
percent), and weight gain.

48.  BLOOD CONCENTRATIONS AND CLINICALACTIVITY
 No relationship exists between clinical efficacy and plasma
concentrations of risperidone.
 Dose response curve is an inverted U with two optimal dosages.
 Most patients will require the lower of the two dosages (4 mg per day),
experiencing some loss of efficacy with higher doses, whereas others
will do best with 6 to 8 mg per day.
 RECEPTOR BINDING
 Potent central antagonism of both serotonin (particularly 5-HT2A) and
D2 receptors

49.  Treatment Indications
 Acute Psychosis
 Maintenance Treatment in Schizophrenia and Schizoaffective Disorder
 Tardive Dyskinesia : tardive dyskinesia is significantly less severe in
risperidone (vs haloperidol).
 Case reports also suggest that tardive dyskinesia may improve with
risperidone

50.  Patients with a Low Extrapyramidal Side Effect Threshold
 Other : acute mania, Children with severe disruptive behavioral
disorders and conduct disorders, Behavioral and psychological
symptoms of dementia.

51.  Precautions and Adverse Reactions
 Extra pyramidal side effects: usually occur at higher dose.
 rise in plasma prolactin concentration
 Other common side effects : sedation, dizziness, constipation,
tachycardia, and weight gain.
 Interactions : not significant.

52. OLANZAPINE
 pharmacokinetics
 Food does not affect absorption of olanzapine
 Peak plasma levels of olanzapine are reached in 5 hours.
 The half-life is 31 hours (range 21 to 54 hours), ie once-daily dosing
 Age, gender, and ethnicity effects on olanzapine concentration are
small.
 Olanzapine has a very weak affinity for hepatic P450 cytochromes , Ie
it has little effect on the metabolism of other drugs and that other drugs
minimally affect its concentration in blood.

53.  Receptor binding
 Olanzapine specifically blocks 5-HT2A and D2 receptors and
additionally blocks muscarinic (M1), H1, 5-HT2C, 5-HT3, 5-HT6, α1, D1,
and D4 receptors.
 5-HT: dopamine blockade is approximately 8:1
 Also has 5-HT1A agonist properties  antianxiety and antidepressant
effects.

54.  BLOOD CONCENTRATIONS AND CLINICALACTIVITY
 Side effects do not appear to be dose dependent.
 Women tend to have higher olanzapine levels than men.

55.  Treatment Indications
 Acute Psychosis
 Tardive Dyskinesia: risk during 1 year of treatment is less than one-
tenth that associated with haloperidol
 Patients with Low Extra pyramidal Side Effect Threshold
 acute mania and bipolar mania
 Other diagnosis: schizoaffective disorder, psychosis in dementia,
Tourette's syndrome, and as an adjunct to SSRIs for PTSD, weight gain
in patients with anorexia nervosa

56.  Precautions and Adverse Reactions
 Main side effects are transient sedation, orthostatic hypotension,
excessive weight gain, and its metabolic and cardiovascular
consequences
 Extra pyramidal side effects: significantly lower than with haloperidol.
 Hyperlipidemia and Weight Gain: significant, Compared with clozapine
its lower.
 Diabetes Mellitus: significantly increased risk of developing diabetes.

57.  Dosage: effective at dosages between 7.5 and 30.0 mg per day.
 Treatment-resistant patients or chronic patients with poor response may
need higher dosages (30 to 40 mg).
 Drug Interactions
 The small effects on hepatic metabolism suggest that interactions with
other drugs are not significant.
 Ethanol increases olanzapine absorption (>25 percent)  increased
somnolence and orthostatic hypotension
 Smokers may require higher dosages.

58. QUETIAPINE
 Pharmacokinetics
 Food doesn’t affect absorption
 half-life of 6.9 hours
 But No difference was found between twice- and thrice-daily dosing.

59.  RECEPTOR BINDING
 Quetiapine has a high affinity for 5-HT2, H1, 5-HT6, α1, and α2
receptors
 It has a transiently high D2 occupancy, which decreases to low levels by
the end of the dosing interval (faster dissociation), suggesting that
transient D2 occupancy may be sufficient to induce antipsychotic
response while minimizing side effects.

60.  BLOOD CONCENTRATIONS AND CLINICALACTIVITY
 Quetiapine response is independent of dosage.
 In elderly people the dosage may need to be reduced, with 300 mg
generally the optimum dosage.
 Patients with impaired renal or hepatic clearance need to receive 30 to
50 percent lower dosages.
 There is no evidence of gender or ethnic differences in terms of clinical
activity or plasma concentration.

61.  Treatment Indications
 acutely exacerbated schizophrenic and schizoaffective patients
 functional and organic psychoses in the elderly
 levodopa-induced psychosis in Parkinson's disease patients
 acute and long-term treatment of bipolar mania and bipolar relapse
prevention.

62.  Precautions and Adverse Reactions
 most frequent are somnolence, postural hypotension, and dizziness
,tolerance quickly develops to these side effects
 Rarely diabetic coma, and ketoacidosis
 Extrapyramidal side effects were generally not observed(low chance)
 wt gain
 Inclusion body in eye
 cataract

63.  Dosage
 dosage range of 500 to 750 mg daily
 must be titrated to avoid postural hypotension and syncope. 25 mg per
day be given initially, with increments of 25 to 50 mg twice to three
times daily.
 Drug Interactions
 Only phenytoin caused a fivefold increase in quetiapine clearance
through CYP 3A4 induction
 others have minimal effect

64. ZIPRASIDONE
 Benzisothiazolyl piperazine
 Pharmacokinetics
 Bioavailability doubles when ziprasidone is administered with food
 plasma half-life ranges from 5 to 10 hours
 Age, gender, or mild to moderate renal or hepatic impairment has no
significant effect.

65.  RECEPTOR BINDING
 very potent antagonist at the 5-HT2A receptor, with a very high 5-HT2A
to D2 ratio of 11.
 Ziprasidone is an agonist at the 5-HT1A receptor and a potent antagonist
at 5-HT2C and 5-HT1D receptors

66.  Treatment Indications
 positive, negative, and depressive symptoms in patients with
schizophrenia and schizoaffective disorder
 Tourette's syndrome
 The IM formulation for acutely agitated and psychotic patients

67.  Precautions and Adverse Reactions
 Extra pyramidal side effects : infrequent and mild
 Akathisia has been notably absent
 The major side effects include somnolence, dizziness, nausea, and
light-headedness
 incidence of clinically significant weight gain (>7 percent) was low.

68.  Dosage
 20 – 80 mg twice a day with food
 IM dosage is 10 to 20 mg administered every 2 hours for the 10-mg
dose and every 4 hours for the 20-mg dose, up to a maximum dosage of
40 mg per day.
 Drug Interactions
 low potential for clinically significant drug interactions

69. ARIPIPRAZOLE
 Aripiprazole is a highly lipid-soluble quinolinone derivative. Its
chemical structure does not resemble any of the available
antipsychotics
 Pharmacokinetics
 Aripiprazole's absorption is not affected by administration with food.
 half-life of aripiprazole is approximately 75 hours
 Aripiprazole is extensively metabolized in the liver by
dehydrogenation, hydroxylation, and N-alkylation. Metabolism is
primarily by CYP 3A4 and CYP 2D6 enzymes

70.  RECEPTOR BINDING
 D2 partial agonism
 partial agonist at 5-HT1A receptors - decrease anxiety
 binds with high affinity to D3, 5-HT2A, 5-HT2C, and H1 receptors

71.  Treatment Indications
 Acute Psychosis:Its effectiveness similar to that of haloperidol and
risperidone
 May be effective in acute mania
 Acute Agitation: Short-acting intramuscular aripiprazole has been
approved for acute agitation..
 Maintenance Treatment in Schizophrenia and Schizoaffective Disorder
 Bipolar disorder

72.  Precautions and Adverse Reactions
 low rate of extrapyramidal side effects
 least sedating of available antipsychotics
 only minimal weight gain
 DOSAGE
 10-30 mg

73.  Drug Interactions
 metabolized by CYP 3A4 and CYP 2D6.
 carbamazepine induces CYP 3A4 and may reduce aripiprazole
concentrations.
 CYP 3A4 inhibitor, such as ketoconazole, may increase the
concentrations.
 CYP 2D6 inhibitors such as quinidine, may raise aripiprazole
concentration.

74. Amisulpride
 amisulpride is unusual in that it lacks the combined antagonism of
5HT2/D2 receptors.
 At low doses, amisulpride enhances dopaminergic neurotransmission
by preferentially blocking pre-synaptic D2/D3 dopamine receptors.
 At higher doses, amisulpride antagonises post-synaptic D2/D3
dopamine receptors, reducing dopaminergic transmission.
 It is selective for dopamine receptors in the limbic system rather than
the striatum, which should reduce its tendency to produce EPS.

75.  Pharmacokinetics
 Amisulpride is absorbed rapidly
 Amisulpride undergoes minimal metabolism
 Excretion is primarily via urine (mainly as unchanged drug).
 The elimination half life is approximately 12 hours.( twice daily dosing)

76.  Adverse effects
 dose-related EPS and hyperprolactinemia.
 insomnia, anxiety, agitation and weight gain.
 sedation and hypotension are not prominent

77.  Dosage and administration
 The recommended dose varies according to which symptoms
predominate.
 Acute positive symptoms: 400-800mg/day
 May be increased to 1200mg/day in individual cases
 Predominantly negative symptoms: 50- 300mg/day given once daily.

78.  Interactions : via the CYP450 system are unlikely as amisulpride is
not significantly metabolised by the liver.
 Caution is advised when used with other renally cleared drugs eg.
lithium, which may interfere with clearance of amisulpride.
 Use with Class IA and III antiarrhythmic agents eg. flecainide and
amiodarone respectively, is contraindicated

79. Antipsychotic in special patient group
 Hepatic impairment:
 Recommended drugs:
 low dose haloperidol
 Sulpride and amisulpride
 Renal impairment
 Recommended drugs: haloperidol and olanzapine
 Sulpride, amisulpride and highly anticholinergic drugs are avoided

80.  Breast feeding
 Recommended drugs : sulpride and olanzapine
 Resperidone, quetiapine and aripiprazole can also be used
 Pregnancy
 1st generation can be used, most experience is with
chlorpromazine,trifluperazine and haloperidol
 Olanzapine and clozapine can be used but metabolic side effects should
be monitored

81.  Epilepsy
 Good choices: trifluperazine, haloperidol and sulpride
 Resperidone, olanzapine, quetiapine, amisulpride and aripiprazole
should be used with care.
 Clozapine, chlorpromazine, loxapine, and depot antipsychotic should
be avoided.

82. CATIE and CUtLASS
 The US Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) was a double-blind trial to compare the effectiveness of
perphenazine with several second-generation antipsychotics.
 CATIE included a subsequent trial for those participants who
discontinued the first phase because of a lack of efficacy.
 They were invited to be re-randomised to a comparison of open-label
clozapine v. other second-generation antipsychotics.

83.  The UK Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia Study (CUtLASS) comprised a pair of smaller, open
randomised trials comparing classes of drug
 first-generation v. second-generation drug other than clozapine
(CUtLASS 1),
 and other second-generation drug v. clozapine.

84.  The trials were designed wholly separately of each other and conducted
in different healthcare systems.
 Both trials were government funded and both were designed to reflect
routine clinical practice as much as possible, with broad inclusion
criteria intended to enroll representative patients.
 The participants were very similar clinically and demographically in the
two trials.

85.  In both trials, the second-generation antipsychotics were not found to
be more effective (with the exception of olanzapine in CATIE).
 Moreover, they did not produce measurably fewer extrapyramidal side-
effects overall.
 In both trials, clozapine was the most effective for treatment-resistant
patients.

86. Thank you