1. Antipsychotic drugs

2. Phenothiazines
Aliphatic side chain:
-Chlorpromazine
-Triflupromazine
Piperidine side chain:
-Thioridazine
Piperazine side chain:
-Trifluoperazine
-Fluphenazine

3. Butyrophenones
-Haloperidol
-Trifluperidol
-Penfluridol
Thioxanthenes
-Flupenthixol
Other heterocyclics
-Pimozide, Loxapine

4. Atypical antipsychotics
-Clozapine
-Risperidone
-Olanzapine
-Quetiapine
-Aripiprazole
-Ziprasidone

5. Schizophrenia - symptoms
Positive Symptoms(↑↑DA)
Hallucinations
Delusions (bizarre, persecutory)
Disorganized Thought
Perception disturbances
Inappropriate emotions
Negative Symptoms(↓↓NMDA)
Blunted emotions
Anhedonia
Lack of feeling
FUNCTION
Mood Symptoms
Loss of motivation
Social withdrawal
Insight
Demoralization
Suicide
Cognition
New Learning
Memory

6. Positive/active symptoms include thought disturbances, delusions, hallucinations
Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene

7. Prognosis of Schizophrenia
10% continuous hospitalization
< 30% recovery = symptom-free for 5 years
60% continued problems in living/episodic periods

8. Etiology
A gene encodes for neuregulin-1 has been associated with schizophrenia.
Hereditary Influences may account for 10% of schizophrenia cases
Prenatal Biological Trauma 5-10% cases of schizophrenia
Perinatal biological trauma

9. Schizophrenia Pathophysiology
Schizophrenia Pharmacologic Pathophysiology Profile of APDs
Past Excess dopaminergic Dopamine D2-receptor activity antagonists
Present
-Renewed interest in the Combined 5-HT2/D2 role of serotonin (5-HT) antagonists
Future
-NMDA NMDA agonists
Imbalance in cortical More selective antagonists communication and Mixed agonist/antagonists cortical-midbrain Neuropeptide analogs integration, involving multiple neurotransmitters

10. Dopaminergic Pathways and Innervation

12. Schizophrenia - Dopamine Hypothesis
Repeated administration of stimulants like amphetamines and cocaine, which enhance central dopaminergic neurotransmission, can cause a psychosis that resembles the positive symptoms of schizophrenia.
Low doses of amphetamine can induce a psychotic reaction in schizophrenics in remission.
Some early studies with postmortem tissue revealed increased numbers of DA receptors (in particular D2-like) in schizophrenic patients

13. Serotonin Hypothesis of Schizophrenia
Hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists
5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine.
5-HT2A-receptor modulate the release of dopamine in the cortex, limbic region, and striatum.

14. Schizophrenia - Glutamate Hypothesis
Preclinical as well as clinical studies provide evidence of hypofunction of NMDA receptors as a primary, or at least, a contributory process in the pathophysiology of schizophrenia
Several clinical trials with agents that act at the glycine modulatory site on the NMDA receptor have revealed consistent reductions in negative symptoms and variable effects of cognitive and positive symptoms
These studies also provide evidence that suggests the effects of clozapine on negative symptoms and cognition may be through activation of the glycine modulatory site on the NMDA receptor.

15. ANTIPSYCHOTICS Pre-90’s
“Typical”, conventional, traditional neuroleptics, major tranquilizors
Modeled on D2 antagonism
EPS/TD
Post-90’s
“Atypical”, novel, 2nd generation
Modeled on 5-HT2/D2 antagonism
Less EPS, prolactin effects
Weight gain, sedation, diabetes

16. Adverse Effects
Sedation ‑ initially considerable; tolerance usually develops after a few weeks of therapy; dysphoria
Postural hypotension ‑ results primarily from adrenergic blockade; tolerance can develop
Anticholinergic effects ‑ include blurred vision, dry mouth, constipation, urinary retention; results from muscarinic cholinergic blockade
Endocrine effects ‑ increased prolactin secretion can cause galactorhea; results from antidopamine effect
Hypersensitivity reactions ‑ jaundice, photosensitivity, rashes, agranulocytosis can occur
Idiosyncratic reactions ‑ malignant neuroleptic syndrome
Weight gain
Neurological side effects -

17. Neurological Side Effects of antipsychotics
REACTION
FEATURES
TIME OF MAXIMAL RISK
PROPOSED MECHANISM
TREATMENT
Acute dystonia
Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria
1 to 5 days
Unknown
Diphenhydramine, promethazine
Akathisia
Motor restlessness; not anxiety or "agitation"
5 to 60 days
Reduce dose or change drug: antiparkinsonian agents, benzodiazepines or propranololc may help
Parkinsonism
Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait
5 to 30 days
Antagonism of dopamine
Antiparkinsonian agents helpful- trihexyphenidyl, procyclidine, benztropines
a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).

18. Neuroleptic malignant syndrome
REACTION
FEATURES
TIME OF MAXIMAL RISK
PROPOSED MECHANISM
TREATMENT
Neuroleptic malignant syndrome
Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal
Weeks; can persist for days after stopping neuroleptic
Antagonism of dopamine may contribute
Stop neuroleptic immediately: dantrolene or bromocriptine may help: antiparkinsonian agents not effective
Perioral tremor ("rabbit" syndrome)
Perioral tremor (may be a late variant of parkinsonism)
After months or years of treatment
Unknown
Antiparkinsonian agents often help
Tardive dyskinesia
Oral-facial dyskinesia; widespread choreoathetosis or dystonia
After months or years of treatment (worse on withdrawal)
Excess function of dopamine hypothesized
Stop neuroleptics, then Diazepam, Change to clozapine/olanzapine,

19. Adverse Effects - EPS Parkinson-like symptoms Tardive dyskinesia
Details on two main extrapyramidal disturbances (EPS):
Parkinson-like symptoms
tremor, rigidity
direct consequence of block of nigrostriatal DA2 R
reversible upon cessation of antipsychotics
Tardive dyskinesia
involuntary movement of face and limbs
less likely with atypical antipsychotics (AP)
appears months or years after start of AP
? result of proliferation of DA R in striatum
presynaptic?
treatment is generally unsuccessful

20. Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; possibly also histamine (for newer antipsychotics anyway)
Sexual dysfunction
result from NE and SE blockade
erectile dysfunction in 23-54% of men
retrograde ejaculation in
loss of libido and anorgasmia in men and women
Seizures - <1% for generalized grand mal

21. Neuroleptic malignant syndrome (1-2% early in trt)
combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up)
can be fatal in 5-20% of cases if untreated
treatment – discontinue meds; give trts for fever and cardiac problems

22. Sensitivity to sun
some phenothiazines collect in skin (chlorpromazine)
sunlight causes pigmentation changes – grayish-purple (look bruised)
in eye, brown cornea, brownish cloud to vision and possibly permanent impairment
Agranulocytosis - <1% (with clozapine)
reduced white blood cell count
lowered resistance to infection
can be fatal
Jaundice – elevated bilirubin in liver - < ½%

23. Limitations Of Conventional Antipsychotics
Approximately one-third of patients with schizophrenia fail to respond
Limited efficacy against
Negative symptoms
Affective symptoms
Cognitive deficits
High proportion of patients relapse
Side effects and compliance issues

24. Antipsychotic Drugs – New Generations “atypical”
About 40-60% do not respond to phenothiazines or cannot handle side effects
Questions remain about the efficacy of phenothiazines and haloperidole for negative symptoms
Drugs needed that are low in extrapyramidal side effects and at least equal in efficacy for positive symptoms, perhaps better for negative

25. Antipsychotic Drugs – New Generations “atypical”
clozapine
risperidone
olanzapine
sertindole
Quetiapine
Aripiprazole
Ziprasidone

26. Clozapine (1989)
Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathway
α-blockade
Also blocks H1
More strongly blocks 5-HT2 receptors in cortex which then acts to modulate some dopamine activity
Among non-responders to first generation meds or those who cannot tolerate side effects, about 30% do respond to Clozapine

27. Clozapine Extrapyramidal side effects are minimal
May help treat tarditive dyskinesia
S/E- orthostatic hypotension effects, sedation, weight gain, increased heart rate
Increased risk for seizures (2-3%)
Agranulocytosis in 1%
Agranulocytosis risks increase when co-administered with carbamazepine

28. Risperidone (1994) Fewer side effects than Clozapine
Marketed as first line approach to treatment
Blocks selective D2, norepinephrine, and 5-HT2
effective for positive and negative symptoms
Extrapyramidal side effects low (but are shown at high doses)
Shares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactin
No agranulocytosis risks
Increased risk of stroke in elderly
May cause anxiety/agitation (possible OCD)

29. Olanzipine – 1996 Improved negative symptom reduction
Argued to be better than risperidone in extrapyramidal issues
Does not cause prolactin elevation
reduced agranulocytosis risks

30. Sertindole – 1995 Improved negative symptom reduction
Low risk for extrapyramidal side effects – major advantage
No sedation and very mild prolactin elevation– major advantages
Shares orthostatic hypotension, tachycardia, and weight gain
Common side effects are rhinitis and reduced ejaculatory volume (not associated with disturbed function)
concern about sudden cardiac death or episodes due to cardiac arrhythmia led to its voluntary removal in 1998

31. Quetiapine - 1997 Ziprasidone - 2001
No increased risks for extrapyramidal symptoms
Shares sedation (sleepiness), orthostatic hypotension, weight gain
Does cause anticholinergic side effects (like older and Clozapine) – dry mouth, constipation
Does not elevate prolactin
Ziprasidone
Similar to advantages of others, but argued not to cause weight gain
May induce cardiac arrhythmias
Also has anxiolytic and antidepressant activity

32. Non- psychiatric Indications
As Antiemetics
-chlorpromazine, prochlorperazine, haloperidol
Anaesthesia
-droperidol (with fentanyl)
Intractable Hiccups
-chlorpromazine
-haloperidol

33. MCQs
Q1. A female suffering from psychosis, taking fluphenazine now complains of sudden onset of high grade fever, muscle rigidity and altered sensorium. The diagnosis is:
A. Malignant hyperthermia
B. Tardive dyskinesia
C. Akathisia
D. Neuroleptic malignant syndrome
Ans- D - Neuroleptic malignant syndrome

34. Q2. Antipsychotic drug induced parkinsonism is treated by:
Levodopa
Selegiline
Amantadine
Central anticholinergic drugs
Ans- D (Trihexyphenidyl
Procyclidine
Biperiden )

35. Q3. Least extrapyramidal side effects are seen with:
Clozapine
Haloperidol     
Trifluoperazine
Chlorpromazine
Ans- A- Clozapine

36. Q4. Risperidone is associated with the risk of:
Cerebrovascular accidents
Agranulocytosis
Diabetes Insipidus       
 Gout
Ans- A - Cerebrovascular accidents

37. Q5. The antipsychotic drug that can also be used as antiemetics:
chlorpromazine
Clozapine
Aripiprazole
Loxapine
Ans- A - chlorpromazine

38. Q6. The antipsychotics that can also be used as anaesthetic drug:
Chlorpromazine
Penfluridol
Clozapine
Droperidol
Ans- D - Droperidol

39. Q7. The antipsychotic drug that can also be used to treat Intractable Hiccups:
Clozapine
Chlorpromazine
Haloperidol
Ziprasidone
Ans- B, C - Chlorpromazine, Haloperidol

40. Thank you

41. Bibliography
Essentials of Medical Pharmacology -7th edition by KD Tripathi
Goodman & Gilman's the Pharmacological Basis of Therapeutics  12th edition by Laurence Brunton (Editor)
Lippincott's Illustrated Reviews: Pharmacology  - 6th edition by Richard A. Harvey
Basic and Clinical pharmacology 11th edition by Bertram G Katzung
Rang & Dale's Pharmacology -7th edition  by Humphrey P. Rang
Clinical Pharmacology 11th edition By Bennett and Brown, Churchill Livingstone
Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
Review of Pharmacology by Gobind Sparsh