I presented this topic on the very beginning of 2019 at the dept. of psychiatry, SOMCH

1. Welcome to topic presentation

2. DR. MD. AZIZUL HAKIM
MD RESIDENT PHASE-A
DEPT. OF PSYCHIATRY
SOMC
Typical Antipsychotics

3. Content
 Psychosis- definition, classification, belongingness,
symptoms, neurobiology & treatment.
 Dopamine- synthesis, pathways, receptor
 Antipsychotics- definition, types, neuroleptics,
neurolepsis
 Typical antipsychotics- classifications & names,
history, therapeutic actions, other biniding
properties, pharmacokinetics, pharmacodynamics,
undesired drug actions, overdose.
 More about chlorpromazine, haloperidol &
flupenthixol

4. What is psychosis?
 Psychosis is a syndrome.
 A set of symptoms in which a person’s mental
capacity, affective response and capacity to recognize
reality, communicate and relate others is impaired.
 At a minimum, psychosis means delusions &
hallucinations
 It generally also includes symptoms such as
disorganized speech, disorganized behavior & gross
reality distortions.
-Stahl’s

5. Types of psychosis
 Paranoid psychosis
 Disorganized/excited psychosis
 Depressive psychosis
Perceptual distortions & motor disturbances can be
associated with any type of psychosis.
-Stahl’s

6. Psychosis is a defining feature in
 Schizophrenia
 Substance induced (i.e. drug induced) psychotic
disorder
 Schizophreniform disorder
 Delusional disorder
 Brief psychotic disorder
 Psychotic disorder due to a general medical
condition
Schizophrenia is more than a psychosis. Not
synonymous
-Stahl’s

7. Psychosis is an associated feature in
 Mania
 Depression
 Cognitive disorder
 Alzheimer’s dementia
-Stahl’s

8. Positive symptoms of psychosis
 Delusions
 Hallucinations
 Distortions or exaggerations in language and
communications
 Disorganized speech
 Disorganized behavior
 Catatonic behavior
 Agitation
-Stahl’s

9. Negative symptoms
 Blunted affect
 Emotional withdrawal
 Poor rapport
 Passivity
 Apathetic social
withdrawal
 Difficulty in abstract
thinking
 Lack of spontaneity
 Stereotyped thinking
 Alogia
 Avolition
 Anhedonia
 Attentional impairment
-Stahl’s

10. Brain circuits
-Stahl’s

11. Neurotransmitters in psychosis
 Dopamine
 Glutamate
 Serotonin
 GABA

12. More about dopamine
Dopamine
Dihydroxy-phenylalamine (DOPA)
(Amino acid decarboxylase)
Tyrosin
(Tyrosine hydroxylase)
Ganong’s

13. Dopamine synthesis
-Stahl’s

14. Dopamine pathways
 Mesolimbic pathway
 Nigrostriatal pathway
 Mesocortical pathway
 Tuberoinfundibular pathway
 Pathway arises from multiple sites; periacquiductal
gray, ventral mesencephalon, hypothalamic neucleua
& lateral parabrachial neucli.
-Stahl’s

15. -Stahl’s

16. Receptors of Dopamine
 5 dopamine receptors have been cloned. They fall
into 2 major catagories- D1 like (D1 & D5) & D2 like
(D2, D3 & D4)
• All dopamine receptors are metabotropic GPCR.
• Activation of D1 type causes increase in cAMP
• Activation of D2 like causes reduce in cAMP
• D2 receptor overstimulaion is the main
pathophysiology schizophrenia
• D3 highly localized in nucleus accumbens, D4 has
greater affinity to atypical antipsychotics- clozapine.
Ganong’s

17. Treatment of psychosis?
 Psycho-bio-social approach
Non pharmacological
Pharmacological
 Antipsychotics

18. What is antipsychotic drug?
 The term is applied to drugs that reduce
psychomotor agitation and control symptoms of
psychosis.
 Alternate terms for these agents are neuroleptics or
major tranquilizers.
 The term ‘antipsychotic’ is used in BNF
Shorter oxford

19. Neuroleptics & neurolepsis
 Neuroleptics: The drugs that cause neurolepsis are
called neuroleptics. The original antipsychotics were
first discovered largely by their ability to produce
this effect in experimental animals & are thus
sometimes called neuroleptics.
 Neurolepsis: knowns as an extreme form of slowness
or absence of motor movements as well as behavioral
indifference in experimental animals.
-Stahl’s

20. Types of antipsychotics
 According to receptor binding properties-
 Typical (chlorpromazine, haloperidol etc.)
 Atypical (olanzapine, risperidon etc)
• According to potency-
 High potency (haloperidol, fluphenazine etc.)
 Low potency (chlorpromazine, olanzapine etc.)
-Stahl’s

21. Types of antipsychotics
 According to chemical structure-
- Phenothiazines; chlorpromazine, trifluoperazine
- Thioxanthenes; flupenthixol, clopenthixol
- Butyrophenons; haloperidole
- Dibenzodiazepines; clozapine, olanzapine
- Dibenzothiazepines; quetiapine
- Substituted benzamides; sulpiride, amisulpiride
- Benzisoxazole; risperidone
- Quinolinone ; aripiprazole
Shorter oxford

22. Types of antipsychotics
 According to preparation-
Enteral preparations
Parenteral preparations
Depot preparations
- Flupenthixol decanoate
- Fluphenazine decanoate
- Haloperidol decanoate
- Olanzapine pamoate
- Risperidon microspheres
- Aripiprazole
Kaplan & Sadock’s

23. A JOURNEY TOWARDS THE
SUCCESS IN PSYCHIATRIC
TREATMENT
Typical Antipsychotics

24. Types of typical antipsychotics
 Group 1: Aliphatic
phenothiazines
 Chlorpromazine
 Promazine
 Group 2: piperidine
phenothiazines
 Pericyazine
 Piperazine
phenothiazines & others
 Trifluoperazine
 Fluphenazine
 Perphenazine
 Flupenthixol
 Zuclopenthixol
 Haloperidol
 Pimozide
 Sulpiride
Oxford handbook

25. Typical/classical/conventional/FGA
Generic name Trade name Comment
Chlorpromazine Tab. Opsonil 25,5o,100 mg LP
Cyamemazine Tab. Tercian Atypical at low doses
Flupenthixol Tab. Fluanxol 0.5,1 mg Depot
Fluphenazine Inj. Fenazine 25mg/ml HP, depot
Haloperidol Tab./inj. Halop 5 mg HP, depot
Loxapine Tab. Loxitane Atypical at low doses
Mesoridazine Tab. Serentil LP
Perphenazine Inj. Trilafon HP
-Stahl’s

26. Typical/Classical/Conventional/FGA
Generic name Trade name Comment
Pimozide Tab. Orap HP, Tourette’s
syndrome
Pipothiazine Inj. Piportil Depot
Sulpiride Tab. Dolmatil Atypical properties
Thioridazine Tab. Melleril 10, 25 mg LP
Thiothixene Tab. Navane HP
Trifluoperazine Tab. Telazine 1, 5 mg HP
Zuclopenthixol Tab./inj. Clopixol 10
mg, 50 mg/ml
Depot
-Stahl’s

27. History of new arena
 The earliest treatment of schizophrenia & psychosis
were based on serendipitous clinical observations.
 First antipsychotic drug is discovered in 1952, the
chlorpromazine.
 In 1970s, it was widely recognized that the key
pharmacologic properties of all neuroleptic
withantipsychotic properties was their ability to
block D2 receptor
-Stahl’s

28. Why typical?
 For sharing the
primary
pharmacological
property of D2
antagonism.
-Stahl’s

29. Therapeutic action for D2 antagonism
 Due to blockade of D2 receptor in mesolimbic area
mainly reduces positive symptoms.
 But to achieve this desired effect, one must
simultaneously block the same number of D2
receptors throughout the brain.
-Stahl’s

30. High cost business?
 Nigrostriatal DA pathway; EPSE, tardive dyskinesia
 Mesocortical DA pathway; psychomotor retardation
 Tuberoinfundibular DA pathway; hyperprolacinemia
-Stahl’s

31. Binding properties of FGAs
 Dopamine D2 receptor
 Muscarinic M1 receptor
 Histamin H1 receptor
 α1 adrenergic receptor
-Stahl’s

32. Review of receptors
NT Receptor G protein Agonist Antagonist
Ach Nm, Nn,
M1,3,5
M2,4
+ IP3, DAG
Nicotine
Muscarine
Tubocurarin
e
Atropine
Tropicamide
NA α1
α2
β1
β2
+IP3
-cAMP
+cAMP
+cAMP
Phenylepheri
n
Clonidine
Dobutamine
albuterol
Prazosin
Atenolol
Histamin H1
H2
H3, H4
+PLPC
+cAMP
Loratadine
Renitidine
Ganong’s

33. Autonomic activation of receptors
Organ Sympatheti
c
Receptor
Sympatheti
c
action
Parasympa
thetic
receptor
Parasympa
thetic
action
Vascular
smooth
muscle
α1 Constricts
blood vessels
GIT α1 Constricts
sphnicters
M1 Dry mouth.
constipation
Male sex
organ
α1 Erection M1 Erection
Bladder α1 Constricts
sphnicters
Eye α1 Mydriasis M Miosis,
contracts of
CM
Ganong’s

34. Pharmacokinetics
 Absorption: well absorbed from gut, mainly from
jejunum. Not affected by food in stomach.
 Metabolism: when taken by mouth extensive first pass
metabolism by the liver to produce various range of
metabolites. i.e 75 metabolites of chlorpromazine.
 Distribution: highly protein bound drugs. Large volume
of distributions. Readily cross BBB. Half life of most
antipsychotics are around 20-24 hours. Steady state
reach in 3-5 days, When depot administered it may be 8-
12 weeks long.
 Elimination: by urine, bile & feces
Shorter oxford

35. Pharmacokinetics of depot drugs
Depot Peak
plasma
level (days)
Steady
state
(weeks)
Dosing
interval
(weeks)
Typical
clinical
dose (mg)
Flupenthixol
decanoate
3-7 8 2-4 60
Fluphenazin
e decanoate
1-2 8 2-5 50
Haloperidol
decanoate
7 8-12 4 100
Piptiazine
palmitate
7-14 8 4 50
Zuclopenthix
ol decanoate
7 8 2-4 300
Shorter oxford

36. Factor influencing pharmacokinetics
 Age
 Medical conditions
 Enzyme inducers
 Clearance inhibitiors
 Changes in binding
proteins
-Stahl’s

37. Pharmacodynamics
Drugs Interactions Effects
Antihypertensive;
propanolol, ACEi
Synergistic effect, -
metabolism, + plasma
conc.
Severe hypotension
Anticholinergics Additive anticholinergic
effect
Anticholinergic toxicity
- Antipsychotics effect
Antiepileptics;
carbamazepine,
barbiturates
enhance antipsychotic
metabolism, viceversa
-Antipsychotic effect
+ antiepileptic effect
Central sedatives Potentiate their actions + sedation, respiratory
depression
TCAs Delay TCAs metabolism + QT prolongation
SSRIs Impair metabolism of
antipsychotics
Sudden onset of EPSE
Cigerrate smoking Induce microsomal
enzymes
- Antipsychotic effect
Kaplan & Sadock’s

38. Undesired drug actions
 Extrapyramidal side effects due to D2 antagonism
- Acute dystonia
- Akathisia
- Parkinsonism
- Tardive dyskinesia
• Antiadrenergic effects
- Sedation
- Postural hypotension
- Inhibition of ejaculation
Shorter oxford

39. Continue …
 Anticholinergic effects
- Dry mouth
- Reduced sweating
- Urinary hesitation & retention
- Constipation
- Blurred vision
- Precipitation of glaucoma
• Antihistaminic effects
- Sedation
- Weight gain
Shorter oxford

40. Continue…
 Side effects due to prolactin elevation
- Galactorrhea
- Sexual dysfuction
- Amenorrhea
- Infertility
- Osteoporesis
- weight gain
• Cardio-pulmonary side effects
- Cardiac arrhythmias
- Sudden death
- Pulmonary emboli
Shorter oxford

41. Continue…
 Endocrine side effects
- Metabolic syndrome
- DM
• Hematological
- Leucopenia
- Thrombocytopenia
- Purpura & hemolytic anemia
• Dermatological
- Allergic dermatitis, photosensitivity, urticaria
• Others; cholestatic jaundice, hypothermia, lower seizure
threshold
Kaplan & Sadock’s

42. Therapeutic indications
 Schizophrenia
 Schizoaffective disorder
 Mania
 Depression with psychotic feature
 Delusional disorder
 Severe agitation & violent behavior
 Tourette’s syndrome
 Borderline personality disorder
 Dementia & delirium
 Substance induced psychotic disorder
Kaplan & Sadock’s

43. Continue …
 Pervasive developmental disorder
 Childhood schizophrenia
 Mental disorder caused by another medical
condition
 Neurological diseases
- Huntington’s disease, parkinson’s disease
- Ballismus & hemiballismus
• Others; treatment of nausea, vomiting, hiccup,
pruritus etc.
Kaplan & Sadock’s

44. Contraindication
 Myasthenia gravis
 Addison’s disease
 Glaucoma
 Liver disease
Kaplan & Sadock’s

45. With great cautions
 Cardiovascular disease
 Epilepsy
 Severe infection
 Parkinson’s disease
 Dementia; LBD
 Cerebrovascular disease
 In the elderly
Kaplan & Sadock’s

46. General principles of prescribing
 The lowest possible dose should be used. The dose
should be titrated.
 Dose increases should then take place only after 2
weeks of assessment.
 With depot medication, plasma level rises at least 6-
12 weeks after starting.
 The use of single antipsychotic at a time is
recommeded. Combination only can be used with
clozapine as augmentation & during cross tapering.
 Should not be used as ‘pro re nata’ sedative.
The Maudsley

47. General principles of prescribing
 Response to antopsychotic drugs should be assessed
by recognized rating scales.
 Close monitoring of physical health including BP,
pulse, ECG, plasma glucose & plasma lipids.
The Maudsley

48. Dosage of FGAs
Drug Minimum effective
dose (mg/day)
Maximum licensed
dose (mg/day)
Chlorpromazine 200 1000
Trifluoperazine 10 30
Haloperidol 2 20
Flupenthixol 1 18
Sulpiride 200-400 2400
Zuclopenthixol 20-30 150
Pimozide 2 20
Perphenazine 12 24
Pericyazine - 300
The Maudsley

49. Equivalent dose of FGAs
Drug Equivalent dose (mg)
Chlorpromazine 100
Haloperidol 3
Benperidol 2
Flupenthixol 2
Pericyazine 24
Perphenazine 8
Pimozide 2
Promazine 100
Sulpiride 200
Trifluoperazine 5
Zuclopenthxiol 25
Oxford handbook

50. Metabolic monitoring & interventions
 Monitoring
1. BMI; once every 4 weeks for 3 months then at least
2 yearly
2. Blood glucose; 3 months, 6 months, then 1 yearly
3. Lipid profile; same as above schedule
4. BP; ( ,, )
5. Enquire about tobacco & alcohol at every visit.
Shorter oxford

51. Continue …
 Possible interventions
1. Lifestyle interventions; diet, exercise, smoking,
alcohol
2. Switch to antipsychotics less likely to cause weight
gain
3. Adjunctive metformin for weight gain
4. Medical management of diabetes, dyslipidemia,
HTN according to NICE guidelines.
Shorter oxford

52. Drug overdose
 Overdoses typically consist of exaggerated DRA side
effects.
 Symptoms and signs include central nervous system
(CNS) depression, EPS, mydriasis, rigidity, restlessness,
decreased deep tendon reflexes, tachycardia, and
hypotension.
 The severe symptoms of overdose include delirium,
coma, respiratory depression, and seizures. Haloperidol
may be among the safest typical antipsychotics in
overdose.
 After an overdose, electroencephalography (EEG) shows
diffuse slowing and low voltage.
Kaplan & Sadock’s

53. Continue…
 Extreme overdose may lead to delirium and coma,
with respiratory depression and hypotension.
 Life threatening overdose usually involves ingestion
of other CNS depressants, such as alcohol or
benzodiazepines.
 Activated charcoal, if possible, and gastric lavage
should be administered if the overdose is recent.
Emetics are not indicated because the antiemetic
actions of the DRAs inhibit their efficacy. Seizures
can be treated with IV diazepam or phenytoin.
Kaplan & Sadock’s

54. Neuroleptic malignant syndrome
 A potentially fatal side effect of DRA treatment,
neuroleptic malignant syndrome, can occur at any time
during the course of DRA treatment.
 Symptoms include extreme hyperthermia, severe
muscular rigidity and dystonia, akinesia, mutism,
confusion, agitation, and increased pulse rate and blood
pressure.
 Laboratory findings include increased white blood cell
(WBC) count, and levels of CPK, liver enzymes, plasma
myoglobin, and myoglobinuria, occasionally associated
with renal failure.
 The symptoms usually evolve over 24 to 72 hours, and
the untreated syndrome lasts 10 to 14 days.
Kaplan & Sadock’s

55. Chlorpromazine
 Chlorpromazine is a prototypic phenothiazine.
 It antagonizes D2 receptor widely, α1 adrenoceptors, H1
receptor, M1 receptor
 Low potency
 more than 75 active metabolites is detected in blood &
urine.
 Bioavailability: 10–80% (Oral)
 Elimination half-life: 30 hours
 Metabolism: Liver, mostly CYP2D6-mediated
 Long term use causes photosensitivity
 Causes cholestatic jaundice

56. Continue …
 Consuming food prior to taking chlorpromazine
orally limits its absorption, likewise co-treatment
with benztropine can also reduce absorption.
 Alcohol can also reduce absorption. Antacids slow
absorption.
 Lithium and chronic treatment with barbiturates can
increase chlorpromazine clearance significantly.
TCAs can decrease clearance and hence increase
exposure.

57. Continue …
 Co-treatment with CYP1A2 inhibitors
like ciprofloxacin, fluvoxamine or vemurafenib can
reduce clearance and hence increase exposure and
potentially also adverse effects.
 Chlorpromazine can also potentiate the CNS
depressant effects of drugs
like barbiturates, benzodiazepines, opioids, lithium
and anesthetics and hence increase the potential for
adverse effects such as respiratory
depression and sedation.

58. Contraindication of CPZ
 Circulatory failure
 CNS depression
 Coma
 Drug intoxication
 Bone marrow suppression
 Phaeochromocytoma
 Hepatic failure
 Active liver disease

59. Haloperidol
 Haloperidol was discovered in 1958 by Paul
Janssen. It was made from pethidine (meperidine).
 Haloperidol is a typical butyrophenone type
antipsychotic
 Excretion: Biliary (hence in feces) and in urine
 Bioavailability: 60–70% (Oral)
 Elimination half-life: 14–26 hours (IV), 20.7 hours
(IM), 14–37 hours (oral).
 Relatively safer in pregnancy. Secrets through breast
milk.

60. Continue…
 Amiodarone: Q-Tc interval prolongation (potentially
dangerous change in heart rhythm).
 Amphetamine and methylphenidate: counteracts
increased action of norepinephrine and dopamine in
patients with narcolepsy or ODD/ADHD
 Epinephrine: action antagonized, paradoxical decrease in
blood pressure may result
 Guanethidine: antihypertensive action antagonized
 Levodopa: decreased action of levodopa
 Methyldopa: increased risk of extrapyramidal side effects

61. Contraindication to haloperidol
 Pre-existing coma, acute stroke
 Severe intoxication with alcohol or other central
depressant drugs
 Known allergy against haloperidol

62. Flupenthixol
 It was introduced in 1965 by Lundbeck.
 Depot formulation available
 Acts as antidepressant, also used in DSH
 Elimination half-life: 35 hours
 Metabolism: Gut wall, hepatic
 It should not be used concomitantly with
medications known to prolong the Q-Tc interval
 Neither should it be given concurrently with lithium
(medication) as it may increase the risk of lithium
toxicity and neuroleptic malignant syndrome.

63. Contraindication of flupenthixol
 Pheochromocytoma
 Prolactin-dependent tumors such as
pituitary prolactinomas and breast cancer
 Long QT syndrome
 Coma
 Circulatory collapse
 Subcortical brain damage
 Blood dyscrasia
 Parkinson's disease
 Dementia with Lewy bodies

64. At a glance
 Psychosis is a syndrome & schizophrenia is more
than a psychosis.
 Psychosis include delusion & hallucination at
minimum.
 Psychosis has neurobiological basis.Dopamine
pathways & brain circuits are involved there.
 Psychosis can effectively be treated with
antipsychotics.
 Antipsychotics are classified as typical & atypical
 Typical due to D2 receptor antagonism.

65. At a glance
 These drugs has other receptor binding properties
also. Like- M1, H1 & α1 receptor.
 Therapeutic actions mainly are done by D2 receptor
antagonism in meso-limbic pathway of dopamine.
 Drug interactions with antihypertensive, sedative,
antiepileptic, TCAs, lithium should be kept in mind.
 During prescribing start with minimum effective
dose. Avoid poly-pharmacy. Care about side effects.
 Metabolic & physical health monitoring is essential.
 Don’t use in patient with glaucoma, liver disease.

66. References
 Shorter oxford textbook of psychiatry; 17th ed.
 Kaplan & Sadock’s synopsis of psychiatry; 11th ed.
 Stahl’s essential psychopharmacology; 4th ed.
 The Maudsley prescribing guidelines in psychiatry;
13th ed.
 Oxford handbook of psychiatry; 3rd ed.
 Lippincott’s illustrated reviews Pharmacology; 6th ed.
 Ganong’s review of medical physiology; 24th ed.
 Wikipedia