Antipsychotic Drugs "Typical and Atypical"

pathophysiology of Schizophrenia
first and second generation antipsychotics

1. Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University

2. The Antipsychotic drugs
= Major tranquilizers
= Neuroleptic drugs
used 1
ry
to treat schizophrenia
ةيسيئرلا تائدهملا

3. Antipsychotics
“Not curative”
Control Manifestations of
Psychosis

4. Psychosis
•Ineverydaylanguage,assomeonewhois
“crazyormad”
•Itisamentalstateinwhichthe
perceptionofrealityisdistorted.
•InPsychosis,therearechangesin
personality,impairedfunctioning.
Psychosis(psyche=mind/soul,and-osis=abnormal")refers
toanabnormalconditionofthemind.

5. Manifestations of Psychosis
1.Hallucinations
(perception without stimulus): e.g. auditory (most
frequent), visual, tactile….
2. Delusions (False fixed beliefs): e.g.
paranoid, persecution, grandeur.
3. Disorganized speech & behavior
(aggression, agitation ….).

6. Psychosis
•Schizophrenia
•Schizoaffective disorder
•Bipolar disorder
•Delusional disorder
•Psychotic Depression
•Personality disorders
•Psychosis NOS
⚫Dementia
⚫Drugs (Alcohol, Hashish..)
⚫Cushing S
⚫Epilepsy (M Temp. L)
⚫Infections (HIV)
⚫Tumor (brain)
⚫Trauma (Head injuries)
(Non-psychiatric)

7. What is schizophrenia?
Schizophreniaisachronicpsychoticmental
disorderch.bydisturbancesincognition,
emotion,perception,thinking,&behavior.(DSM)
Delusions
Hallucinations
Disorganized Thinking
Disorganized Behavior
Negative Symptoms

8. “Schizophrenia does NotMean
Split Personality”
•Dissociation or ‘loosening’ of thoughts and feelings
Schizophrenia
MindSplit
1910

9. Schizophrenia
ماصف
•Cognitive Abnormalities
•Positive Symptoms
•Negative Symptoms

10. Schizophrenia
•Hallucination
•Delusions
Positive Symptoms
•Disorganized behavior
•Disorganized Speech
•Agitation & Hostility

11. •Affect flattening,
•Alogia(↓speech)
•Avolition,
•Anhedonia,
•Asociality
Drug Resistant
Negative
Symptoms
5A

12. Cognitive Symptoms
•Attention
•Working memory (does not learn from mistakes)
•Executive function and problem solving
There is Lack or defect in:

13. Diagnosis of Schizophrenia
A) At least 2 of the following present for ≥ 1-month period
1.Delusions*
2.Hallucinations*
3.Disorganized speech*
4.Grossly disorganized or catatonic behavior
5.Negative symptoms
B) Social or occupational dysfunction
C) Ruling out other disorders e.gdrug Abuse , Manic bipolar …
American Psychiatric Association, 2013
Diagnostic and Statistical Manual of Mental Disorders.5th ed. (DSM-5) Washington, DC:
At least one of these

14. Epidemiology and Etiology
•Epidemiology
–1% of the population
–Prevalence
•Equal in males and females (middle age)…..
•Symptoms appear earlier in males (15-24)
compared to females(25-34).

15. Etiology
GABA
5-HT
Dopamine
NE NMDA
No single factor is considered causative
Biologic
Infectious theory
(e.g. perinatal complications)
Genetic
(Prevalence 10 -12 % in 1
st
degree relative)
Environmental
(e.g. stressors, drug abuse ….)

16. Does Cannabis “Hashish” Use Cause
Schizophrenia?
Daily Cannabis use increases the risk of schizophrenia .
(The New York times & LANCET 2019)
Teens and young adults who use cannabis are more likely to develop
schizophrenia 3-5 times than their peers “WHO”

17. GABA
5-HT
Dopamine
5-HTNE NMDA
NE NMDA
Pathophysiology
•Dopamine hypothesis (↑D
2, ↓D
1-R)
•Serotonin hypothesis (↑ 5-HT
2A&C-R)
•Glutamate hypothesis (↓NMDA-R)
•Other hypothesis

18. ↑↑↑ Dopamine
in Mesolimbic System
Dopamine Hypothesis
5-HT may also play a role
Psychotic Symptoms

19. D2
D1

20. ALL Antipsychotics
Block D2-R
Mesolimbic System
Improve
+veSymptoms

21. ↓↓Hallucination
Few Hours
Calm
2 Weeks
Antipsychotics
ALL Block D2
Mesolimbic System
Effect is delayed for several weeks patient compliance.
↓Delusions delayed

22. D1
Atypical
Antipsychotics
5HT
2
Blockade
Improve
-veSymptoms
D1

23. Typical
Antipsychotics
Atypical
DA
2
>>>5HT
2
Antagonists
5HT
2/DA
2
Antagonists
(FGA) (SGA)

24. Typical Antipsychotics
Chlorpromazine (prototype) -Thioridazine
Haloperidol-Fluphenazine

25. Action of Typical Antipsychotics
DA
2
>>>5HT
2 Antagonists
Block Autonomic M, α& H1 receptors
Cardiotoxicity & Convulsion& Corneal

26. Side effects of
Typical Antipsychotics

27. H
1
Sedation
M
Dry mouth, Urinary retention
Constipation, Blurred vision,
↑Glaucoma, Confusion …..
Be Cautious in Elderly
Hypotension
Autonomic Blockade


28. Cardiotoxic
Convulsions
-Arrhythmia (↑QT)
Be Cautious in Cardiac
& Epileptic patients
4 C
Thioridazine“black box warning,”

29. Corneal-lens deposits.
Cholestatic jaundice

30. Mid Brain
(Meso)

31. Mesolimbic
CTZ
Basal
Ganglia
Hypothalamus
& pituitary
Antipsychotic
Antiemetic
Extrapyramidal
side effects
Blockage of central
D2 receptors
↑ prolactin
↑Body Weight
Dystonia ,
Akathisia,
Parkinson-like
Tardive Dyskinesia
Anti-hiccup
Indication Side effect

32. Disorder Features Mechanism Management
1.Akathesia Motor
restlessness
Due to blockade of D
2
receptors in basal ganglia
Propranolol, a β-blocker is
the drug of choice in Akathesia
Anticholinergics, e.g.
benztropine may be given
routinely with
antipsychotics as
prophylaxis against EPS but
may exacerbate tardive
dyskinesia
2.Dystonia Muscle spasm,
e.g. neck
torticollis
3.ParkinsonismRigidity
Hypokinesia
Tremors
Blockade of D
2receptors
in basal ganglia
relativein cholinergic
activity
------------------
DA ACh
Relieved byanticholinergics
Extrapyramidal Side Effects (EPS)

33. Disorder Features Mechanism Management
4.Tardive
dyskinesia
(late, after > 6
months up to 2-5
years)
Abnormal
involuntary
movements:
-chewing
-suckling
-"fly –catching"
movement of
tongue
Supersensitivityof DA
receptors following chronic
blockade
-----------------
DA ACh
Exacerbated by
anticholinergics
Preventive:
1.Least possible dose of
antipsychotics
2. Minimal duration
3. Avoid routine use of
anticholinergics
Treatment : Switch to
atypical agents (SGA)
-ClozapineLow dose
Extrapyramidal Side Effects (EPS)

34. 5. Antipsychotic malignant syndrome
(Sudden Excess DA blockade)
Muscle rigidity, Hyperthermia, Tachycardia,
Hypertension & altered mental status
Treatment:
1.Discontinue the antipsychotic,
2.BZD, Muscle relaxant (diazepam),
3.Bromocriptine (DA ++).
4.Dantrolene

35. (Equal in efficacy but differ in potency & side effects)
(Equal in efficacy but differ in potency & side effects)Equal in efficacybut differ in potency& side effects
↑ CNS side effects (EPS)
↓ autonomic & Cardiac
& Convulsion
preferred in
elderly & cardiac
patients.
↓ CNS side effects (EPS)
↑ autonomic & Cardiac &
Convulsion
Contraindicated in
elderly & cardiac
patients.

36. Zuclopenthixol
Classification of FGA according to potency& side effects

37. Pharmacotherapy Handbook 10
th
ed.,2017 (+ Nortriptyline = Motival)
FDA approved 2012

38. Pharmacokinetics & Routes
➢Lipophilic Absorbed orally& Readily cross BBB
➢Agitation: IMI(Haloperidol 5mg, Clopixol-Acuphase50mg) Max. 3 amp/day
Oral inhalation (Loxapine10mg/day) FDA,2012
➢I.M depot injections for chronic use
➢Metabolized by liver (CYP450) “Drug interaction?!”
Antipsychotics
Haloperidol

39. Pharmacotherapy Handbook 10
th
ed.,2017 Modecate

40. Fluvoxamine
CYP1A2Intermediate
potency
As Clozapine

41. -Haloperidoldecanoate(Haldol50mg):
50-300mg/month,Dose=10-20timesoraldailydose.
Anoralhaloperidoloverlapisrecommendedforthe
firstmonth(Bridging).
-Fluphenazinedecanoate(Modecate25,50mg)
12.5-100mg/2-4weeks.NeedBridging2weeks.
-Zuclopenthixoldecanoate(Clopixol-depot)
200-600mg/2-3weeks.NeedoralBridgingfor
1weekorgivenwithclopixol-Acuphase(can
bemixedinsamesyringe).
Long-Acting I.M depot injections FGA

42. Advantage of Typical Antipsychotics
•Cheap
•Slow release IM Depot long acting
long-acting Injectable “Depot” formulations useful for patients with
difficulty adhering to therapy and less EPS & side effects
•Fast acting IM & inhalation for agitation

43. Atypical Antipsychotics

44. “↑QT”

45. Mechanism of action of Atypical Antipsychotics
•Block5-HT
2receptorsandD
2receptors.
•Possesscentral,autonomic&miscellaneousside
effects(seebefore).

46. Atypical Antipsychotics
Mesolimbic Basal Ganglia
LessMore
Less Extra-Pyramidal Side Effects &
hyperprolactinemia (Amenorrhea/Galactorrhea S)
EXCEPT Risperidone
Hypothalamic/pituitary

47. Atypical Antipsychotics have
Low potential for extrapyramidal effects
So, used in tttof Psychosis
induced by Dopaminergic
Drugs in parkinsonism
QuetiapineClozapine

48. More Effective
DA/5HT Antagonists
Negative
Symptoms
Resistant
Cases (20-30%)
So used in
Esp. Clozapine

49. Refractory patients:
➢20% of schizophrenics are resistant to all 1
st
& 2
nd
generation antipsychotics.
➢Clozapine is effective even in resistant cases (FDA, 1989)
with minimal risk of EPS. However, its use is limited
because of serious side effects.

50. Side effects of Clozapine
1-Insulinresistance(dyslipidemiaandhyperglycemia)
↑riskofDM&weightgain.
2-Seizures,Nocturnalsalivation,
3-Autonomic:hypotension,sedation,anticholinergicsymptoms
4-Agranulocytosis(Themostserious):→needmonitoringof
white-blood-cellcounts

51. Q:Precautionsduring the use of Clozapine.
1.Monitor white-blood-cellcounts for fatal
agranulocytosis (1-2% of patients)
2.Monitor Blood glucose & Lipid for insulin resistance
3.It is contraindicated in pts with seizure
4.Take drug-interaction cautiously …

52. (Current Psychiatry, 2016)

53. Risperidone:LessEPS(≤6mg),lessautonomic&lessweightgain.
But,mayinducegalactorrhea&gynecomastiaandQTinterval.
Quetiapine:Asclozapine,leastEPS→tttofpsychosisinParkinsonD.
Highlysedative(H
1-Blockade)→off-labelhypnoticuse.
Aripiprazole:-hasEPSesp.akathisia.
-Favorableeffectoncognitivefunction(preferredinchildren)
-Lessereffectonbodyweight&lipids(preferredinobesepatients).
Olanzapine:asclozapine,NOagranulocytosis,
↑Sedation,highestBodyweight.

54. Prolactin sparing : 1
st
6.
Prolactin elevating: Risperidone, Paliperidone, Ami-Sulpride& FGA “More”

55. -RisperidoneConsta25-50mg/2wks.
Need3wksBridging
-Olanzapinepamoate(ZypAdhera)/2-4wks.
BUT2%→post-injectionssed./deliriumS(boxedwarning).
-Aripiprazole(AbilifyMaintena)300-400mg/Month
Need2wksBridging.
-Paliperidonepalmitate(InvegaSustenna)/Month
&(InvegaTrinza)/3month
“atleast4monthswithInvegaSustennabeforeit”.
Long-Acting I.M depot injections SGA

56. Q: Therapeutic uses of Antipsychotics
1.Schizophrenia and psychosis.
2.Agitatione.g. Haloperidol IM, Loxapineoral inhalation
3.Anti-emetic. (sever vomiting) Chlorpromazine.
4.IntractableHiccups (Chlorpromazine)
5.Manic& mixed BipolarDisorders.
6.Autism(Risperidone, Aripiprazole)
7.Adjunctive in refractory depression (Aripiprazole, Quetiapine….)
8.Insomnia(Quetiapine, Clozapine, Chlorpromazine..)

57. Neuropathic
Neuroleptanalgesia & Anesthesia

58. Sulpiride, (Dogmatil50-200mg tab.) FGA off-label used for
1-Irritable bowel syndrome
(Anxiolytic &↓colon motility through DA-antagonistic activity)
2-Hypersexuality
(D2-antagonist →↑prolactin → ↓ testosterone in male & estrogen
in female→↓ Libido & other sexual functions)