1

Review of antipsychotic drugs

.

Introduction : Dopaminergic system

Table 1 : Dopaminergic Tracts & Effects of Dopamine Antagonists

Dopamine Origin Innervation Function Dopamine
Tract Antagonist Effect
Nigrostriatal Substantia Caudate Extrapyramidal Movement disorders
nigra (A9 nucleus system,
area) Putamen movement

Mesolimbic Midbrain Limbic areas Arousal, Relief of psychosis

ventral (e.g., amygd memory,
tegmentum ala, olfactory stimulus
(A10 area) tubercle, processing,
septal motivational
nuclei), behavior
cingulate
gyrus
Mesocortical Midbrain Frontal & Cognition, Relief of psychosis
ventral prefrontal communication
tegmentum lobe cortex , social Akathisia
(A10 area) function,
response to
stress
Tuberoinfund Hypothalamus Pituitary Regulates prola Increased prolactin
ibular gland ctin release concentration

Figure 1 : Dopamine pathway

 2

Development in schizophrenia treatment

Receptor mediated in schizophrenia

 3

Effect of receptor blockage in treatment of schizophrenia

Table 2 : receptor blockage and effect

Receptors Possible benefits Possible side effects

() D1 / D4 Improve cognition
() D2 Antipsychotic (pos), EPS, akathisia, increased prolactin
Antimanic
(p+) 5HT1A Improve mood,
antidepressant
Improve cognition
() 5HT2A Antipsychotic (neg), Sexual dysfunction ??
AntiEPS, Improve REM
sleep
() 5HT2c Antidepressant Weight gain, increased appetite,
risk of diabetes
() 5HT7 Antipsychotic (neg)
() H1 Anxiolytic, AntiEPS Sedation, weight gain, risk of
diabetes
() AntiEPS Anticholinergic side effects
M1 (central) (memory, cognition, dry mouth,
M24 constipation, tachycardia,
Figure 2 : target symptom blurred
in schizophrenia
(peripheral) vision, urinary retention, sinus
tachycardia, tachyarrhythmia)
M3 antagonism: risk of diabetes
*M4 agonism of clozapine lead to
sialorrhea
() alpha1 Reduce stressful nasal congestion, postural
environment, Improve hypotension, reflex tachycardia,
REM sleep dizziness, syncope
()alpha2 Antidepressant, Alertness, increased BP/HR, insomnia
improve cognition
Typical antipsychotics
 4

Figure 3 : structure of typical antipsychotic drugs

Receptor binding of typical antipsychotic drugs

Table 3 : typical antipsychotic drugs

Figure 4: receptor binding of selected typical antipsychotic drugs

Class Agent Dose Usual D2 mAc H1 Alpha EPS Anti-

equi Oral h 1 cholin
vale Adult gic
nts Dosage
P Aliphati Chlorpromazi 100 50-2000 ++ ++ ++ ++ Moderate High
H c ne mg mg/d
E Piperidi Thioridazine 100 50-800 ++ +++ ++ +++ High High
N ne mg mg/d
O Piperazi Fluphenazine 2 mg 2-40 mg/d +++ + + ++ Low Low
T ne 12.5-7.5 +
H mg IM q2
I weeks
A Perphenazine 8 mg 8-64 mg/d +++ + ++ ++ Low Low
Trifluperazine 5 mg 5-80 +++ + + + Low Low
Z
mg/d +
I
N
E
S
Butyrophenone Haloperidol 2 mg 2-40 mg/d +++ + 0 ++ Very high Very lo
 5

50-300 +
mg IM q4
weeks
Dibenzoxazepin Loxapine 10 20-250 +++ + ++ ++ High Low
e mg mg/d +
Dihydroindolon Molindone 10 50-225 +++ + + ++ High Low
e mg mg/d
Thioxanthene Thiothixene 4 mg 5-60 mg/d +++ + ++ + High Low
 6

Atypical antipsychotic drugs

Figure 5 : classification of atypical antipsychotic drugs

Receptor binding

Table 4 : receptor binding of atypical antipsychotic drugs

Target Dosage Form Metabolic EPS Tardive Antichol

Dose Effects (Neuromu Dys- -inergic
(lipids, scular kinesia
BGs, Wt) Side
Effects)

Generic
(Brand)
 Table 4 : atypical antipsychotic drugs
7

Clozapine 300-400 Tablet ++++ Some: 0 ++++

(Clozaril) mg Max: = (Clozaril) akathisia,
900 (Blood Orally dystonia
Levels) disintegrating (Rare)

Olanzapine 20 mg Max IM IM Depot +++ Rare >30 <1% +++

(Zyprexa) = 40 Form (Relprevv) mg
Tablet SL
(Zyprexa Zydis)

Risperidon <6 mg Tablet Orally +++ Prominent <1% 0

e disintegrating with >6mg
(Risperdal) (Risperdal M-
Tabs) IM
(Risperdal
Consta) Oral
solution
Quetiapine 600-1200 Tablet ++ Rare >1500 <1% +
(Seroquel) mg QD- Extended mg
BID-TID release
(Seroquel XR)
Ziprasidon 160-320 Capsule +/- Rare <1% +
e (Geodon) mg QD-BID IM (20 mg IM = Akathisia
WITH 80 mg PO bid) more
FOOD common

Aripiprazol 10-20 mg Tablets + Rare <1% +

e (Abilify) </= 30 mg Orodisposible Akathisia
IM more
Oral solution common
 8

Pharmacokinetics of antipsychotic drugs

Table 5 : Pharmacokinetics of antipsychotic drugs

Drug Bioavailabili Half-Life (h) Major Active Metabolites

ty (%) Metabolic
Pathways
Selected first-generation antipsychotics (FGAs)
Chlorpromazine 1030 835 FMO3, CYP3A4 7-hydroxy, others
Fluphenazine 2050 1424 CYP2D6 ?
Fluphenazine 14.2 2.2a
decanoate days
Haloperidol 4070 1236 CYP1A2, Reduced haloperi
CYP2D6, dol
CYP3A4
Haloperidol 21 days
decanoate
Perphenazine 2025 8.112.3 CYP2D6 7-OH-
perphenazine
Selected second-generation antipsychotics (SGAs)
Aripiprazole 87 4868 CYP3A4, Dehydroaripiprazo
CYP2D6 le
Clozapine 1281 11105 CYP1A2, Desmethylclozapi
CYP3A4, ne
CYP2C19
Olanzapine 80 2070 CYP1A2, N-glucuronide; 2-
CYP3A4, FMO3 OH-methyl; 4-N-
oxide
Paliperidone ER 28 23 Renal None known
unchanged
(59%)
Multiple
pathways
Quetiapine 94 6.88 CYP3A4 7-OH-quetiapine
Risperidone 68 324 CYP2D6 9-OH-risperidone
Ziprasidone 59 410 Aldehyde None
oxidase,
CYP3A4

Drug interaction in antipsychotic therapy

Table 6 : Metabolism enzyme of antipsychotic drugs

Agents 1A2 2C9/2C 2D6 3A4

19
Convention +++ PIM: ++
al +
Aripiprazol ++ ++
e
Clozapine +++ +
norclozapi
 9

ne
Olanzapine +++ +/
Quetiapine +++
norqueti
apine
Risperidon +++ +
e
Ziprasidon ++
e

Side effect of antipsychotic drugs

Table 7 : side effect of antipsychotic drugs

Side First- Second-Generation Antipsychotics

Effects Generation
Antipsychotics
Halo Perph Molin Rispe Olanz Queti Aripip Zipras Paliperi Clozap
peri enazi done ridon apine apine razole idone done ine
dol ne e
Acute +++ +++ +++ +++ ++ - ++ ++ ++++ -
Parkinso +++ + + +
n
Syndrom
e
Akathisia +++ +++ +++ ++ ++ +++++ +++ ++ ++
+++ + + +
Diabetes ++ ++ + ++ +++ +++ + + ++ ++++
Mellitus +++ + +
Diabetes - - - - - - - - - +
Insipidus
Lipid + ++ + ++ +++ +++ + + ++ ++++
Levels +
Neutrope + + + + + + + + + ++++
nia
Orthosta + ++ ++ ++ +++ +++ + - ++ ++++
tic + + ++
hypotens
ion
+++ +++ +++ +++ +++ - - ++ ++++ -
Prolactin + + + +++ +
level
- - - - - - +++ - - -
Prolactin +
level
 10

QT + ++ ++ ++ + ++ + ++++++ ++
interval
Sedation + ++ ++ ++ +++ +++ + + ++ ++++
+ + ++
Seizures + + + + + + + + + ++++
Tardive +++ +++ +++ + + + + + + -
Dyskines + +
ia
Withdra +++ +++ +++ ++ + + +++ ++ ++ ++
wal + +
Dyskines
ia
Weight ++ +++ + +++ +++ +++ ++ ++ +++ ++++
Gain + + +++ + ++

Abbreviations: , decreased; , increased; -, none; + to ++++, mild to

severe.

Extrapyramidal System(EPS)

Table 8 : Extrapyramidal side effect of antipsychotics

Reaction features Maximum mechanism treatment

risk
Acute Acute Spasm of muscle 1-5 days unknown Antiparkins
dystonia of tongue, face, on agents
neck, back
Akathisia Motor 5-60 days unknown Reduce
restlessness dose,
change
drug,
propranolol
, BZDs
Parkinsoni Bradykinesia, 5-30 days Dopamine Antiparkins
sm rigidity, tremor, antagonist on agents
mask facies,
shuffking gait
Delay Tardive Oral-facial Months or Excess Treatment
dyskinesia dyskinesias, years dopaminer is
widespread gic unsatisfact
choreoathetosis functioning ory :
of dystonia ? prevention
is key
 11

Table 9 : drug for EPS

Neuroleptic malignant syndrome (NMS)

Table 10 : Management of NMS

 12

Hyperprolactinemia

Table 11: Effects of Antipsychotics on Prolactin Levels

Cardiovascular system
 13

- Orthostatic hypotension : Agents with alpha1receptor antagonist :

Thioridazine, clozapine, quetiapine, risperidone
- Myocarditis :Clozapine
- QTc prolongation-> Flag for risk of ventricular arrhythmia and/or sudden
Death, Prolongation associated with various antipsychotics :Thioridazine,
pimozide, ziprasidone

Figure 6 : antipsychotic drugs and QTc prolongation

Metabolic adverse effect

Table 12 : antipsychotics and metabolic effect

Medicatio Metabolic Weight Glucose Dyslipide

n syndrome gain metabolism mia
Aripiprazol Low Low Low Low
e
Clozapine High High High High
Olanzapine High High High High
Risperidon Mild Mild to Mild Mild
e moderate
Quetiapine Moderate Moderate Moderate High
Ziprasidone Low Low Low Low

Table 13 : Monitoring parameter for atypical antipsychotic drugs

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Hematologic system

Clozapine induce agranulocytosis

Strategies for management side effect in stable patients

 15

Reference

Journal

1. Byerly M; Suppes T; Tran QV; Baker RA: Clinical implications of

antipsychotic-induced hyperprolactinemia in patients with schizophrenia
spectrum or bipolar spectrum disorders: recent developments and current
perspectives. J Clin Psychopharmacol 2007; 27:639661
2. Carlisle L, McClellan J. Psychopharmacology of schizophrenia in children and
adolescents. Pediatr. Clin North Am 2011;58:205-18
3. Chandrasekaran PK . Agranulocytosis monitoring with Clozapine patients: To
follow guidelines or to attempt therapeutic controversies? Singapore Med J
2008;49(2):96-9.
4. Kim DH, Maneen MJ, Stahl SM. Building a better antipsychotic: receptor
targets for the treatment of multiple symptom dimensions of
schizophrenia. Neurotherapeutics. 2009;6:78-85.
5. Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J
Psychiatry 2007;164:870876

Textbook

1. Stahl SM. Stahls Essential Psychopharmacology. 3rd ed. New York, NY:
Cambridge University Press; 2008
2. Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds.
Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York:
McGraw-Hill; 2011.