ANTI-PSYCHOTIC DRUGS

Maria Soleil Tresmanio, MD

PSYCHOSIS acid (HVA), a metabolite of dopamine, in the cerebrospinal

fluid, plasma and urine.
• Pathophysiology PROBLEM
Actually, unknown but can be explained by the hypothesis • Antipsychotic drugs are only partially effective for
• Hypothesis most and ineffective for some patients
o Role of neurotransmitters • Extrapyramidal toxicity  traditional antipsychotics
o Dopamine Hypothesis & D2 receptors bind D2 50x more avidly than D1 or D3 receptors
o Four dopaminergic pathways SOLUTION
• New drugs to target non-dopamine receptors
(serotonin receptors)  synergistic effect and
protection against EPS of D2 antagonism  greater
efficacy  fewer S/E

Many antipsychotic drugs strongly block postsynaptic D2 receptors in

the central nervous system, especially in the mesolimbic-frontal
system; A drug’s potency is parallel to its AFFINITY for the D2
receptors. The higher the affinity for D2 receptor, the higher the
potency, the higher risks of developing extrapyramidal effects (e.g Nowadays, atypical antipsychotics are given to minimize the
Parkinsonian syndrome/ pseudo-parkinson’s). debilitating EPS associated with the 1st generation antipsychotics

DOPAMINE HYPOTHESIS (!!) Dopaminergic Typical Atypical

Pathways (!!) Antipsychotics Antipsychotics
EVIDENCES (more attracted to Dopa (Prefers to target
• Many antipsychotic drugs strongly block postsynaptic receptors) other receptors)
D2 receptors of the CNS (Mesolimbic-frontal) Mesolimbic
Assoc. with (+) Reduced (+) symptoms
• Drugs that increase dopaminergic activity, such as
symptoms of
levodopa (a precursor), amphetamines (releasers of schizophrenia
dopamine), and apomorphine (a direct dopamine receptor Mesocortical Improved (-)
agonist), either aggravate schizophrenia or produce Assoc. with (-) Worsen (-) symptoms cognitive
psychosis de novo in some patients. symptoms of (!!) symptoms
schizophrenia
• Dopamine receptor density has been found
Nigrostriatal EPS, Akathisia, Little or none
postmortem to be increased in the brains of Assoc. wth EPS Tardive dyskinesia
schizophrenics who have not been treated with Tuberoinfundibular Hyperprolactinemia Some or none
antipsychotic drugs Assoc. with Prolactin
• PET scan has shown increased dopamine receptor Memorize this table by hart.
density in both treated and untreated schizophrenics Mesolimbic  (+) symptoms  Hallucination, Delusion,
Disorganized behavior, Disorganized speech
when compared with such scans of non-schizophrenic
Mesocortical  (-) symptoms  Anhedonia (no happiness),
persons
Amutism, Akinesia, Asocial (social withdrawal)
• Successful treatment of schizophrenic patients has (All letter A’s are negative symptoms)
been reported to change the amount of homovanillic Nigrostriatal  EPS  Parkinsonism, Dystonia, Akathesia,
Dyskinesia, Neuroleptic malignant syndrome
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Tuberoinfundibular  Prolactin  speculated to increase the risk of CLASSIFICATION OF ANTI-PSYCHOTICS
carcinoma of the breast, however, studies were not able to prove a
1ST GENERATION/ 2ND GENERATION/ NEWER/
significant connection
CLASSICAL/ TYPICAL ATYPICAL
Chlorpromazine* Clopazine
Prochlorperazine* Olanzapine
Thioridazine* Ziprasidone
Trifluopherazine Quetiapine
Fluphenazine Aripiprazole
Haloperidol Risperidone
Pimozide Lurasidone
Thiotexene
Doc’s Mnemonics: COZQAR-L
Classification does not indicate clinical effectiveness of the drugs,
but rather, specifies AFFINITY for the specific receptors (dopamine
and/or serotonin receptors)
TYPICAL  blocks dopamine receptor; all are considered to be
equivalent in efficacy but not in potency (!!)
Legend: “*”  Low potency typical antipsychotics

PHARMACODYNAMICS
Affinity Very high for selected neurotransmitter
receptors in the CNS
Typical: High affinity for Dopamine receptors
Atypical: High affinity for Serotonin receptors
Prolonged occupancy of D2 receptors in the
brain
Half life Longer clinical duration of action than the
estimated plasma half-lives
SCHIZOPHRENIA
Biological effects of single dose of most
POSITIVE SYMPTOMS NEGATIVE SYMPTOMS antipsychotics usually persist for 24 hours,
Hallucination Anhedonia – inability to permitting once-daily dosing.
Delusion experience pleasure
Disorganized Behavior Alogia – inability to speak Absorption Oral administration
Disorganized Speech Akinesia – muscle rigidity • Most are rapidly, but incompletely
Asocial – Social withdrawal absorbed from GIT
Parenteral route
• Long Acting Injectable (LAI)
Mesolimbic Mesocortical o For non-compliant patients
e.g those who can’t swallow a tablet
NIGROSTRIATAL PATHWAY o Risperidone/ Haloperidol
• Short Acting Injectable
o Emergency cases
e.g in cases of sudden aggression & there’s no way
you can administer a tablet
o Olanzapine/ Ziprasidone
Distribution Highly lipid-soluble & protein bound
Large volumes of distribution (depending on
their potency)
May accumulate in the brain, lungs & tissues
rich in blood supply
May enter fetal circulation and breast milk
Mothers who are taking anti-psychotics, are not
Nigrostriatal  EPS  Parkinsonism, Dystonia, Akathesia, allowed to breastfeed their bebes.
Dyskinesia, Neuroleptic malignant syndrome Metabolism Most undergo significant first-pass
metabolism

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 Cytochrome P450 system COMPARATIVE PHARMACOLOGIC EFFECTS OF PROTOTYPE
Excretion Urine (slow removal) ANTIPSYCHOTICS
May be seen in the urine several months Sedation EPS ↓BP Wt. Hyper-
after last dose gain prolactinemia
A/E (!!) Typical EPS, neurologic toxicities
Atypical Cardiometabolic effects Chlorpromazine +++ ++ +++ + ++

Haloperidol + ++++ + + ++
GENERALIZATIONS
Suffix A/E
Clozapine + (-) ++ +++ (-)
“-pines” Increased risk of
Risperidone + + + + ++
(Clozapine, Olanzapine, • Weight gain
In the case of Chlorpromazine & Haloperidol. Despite both having
Quetiapine) • Metabolic syndrome
high affinity for the dopamine receptors, Chlorpromazine has less
• Diabetes chances of causing EPS compared to Haloperidol due to the high
Don’t give these drugs to patients
potency it needs to exert the maximal effect.
who are obese, on the other hand
for anorexics this can be an
advantage. ADVERSE EFFECTS DUE TO DOPAMINE BLOCKADE
“-dones” Increased risk of • Dyskinesia (Extrapyramidal Syndrome)
(Risperidone, • Movement disorders • Dysphoria
Lurasidone, Ziprasidone) • Cardiac conduction
• Neuroleptic Malignant Syndrome
problems
• Endocrine dysfunction
ACUTE EPS
• Facial grimacing,
ACUTE DYSTONIC REACTIONS torticollis
• Oculogyric crisis
• Abnormal contractions
of spinal muscles and
respiratory muscles
• Occurs within first 24-48
hours of treatment
• Potentially fatal (!!)

COMPARATIVE AFFINITY OF ANTIPSYCHOTICS ON • Strong subjective

RECEPTORS feelings of anxious
𝐷2 5𝐻𝑇2 Muscarinic ∝1 𝐻1 distress or a discomfort
TYPICAL • Compelling need to be in
AKATHISIA

Chlorpromazine +++ + ++ ++ +++ constant movement

Haloperidol +++ + ± + + • May be mistaken for
ATYPICAL agitation in psychotic
Clozapine + +++ ++ +++ +++ patients
Risperidone ++ +++ - +++ ++
Implication: Higher affinity for dopamine  more chances of EPS
Atypical: have less chances.
• Cannot be distinguished
from idiopathic PD
PARKINSONIAN SYNDROME

• Bradykinesia or Akinesia
• Masked facies
• Reduced arm movements
during walking
Due to blocking of D2
receptors

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MANAGEMENT: Hema Agranulocytosis
• Benzotropine  muscarinic cholinergic antagonist Patient will be more prone to infections so advise to
• Trihexyphenidyl  muscarinic antagonist wear a mask.
• Diphenhydramine  histamine antagonist  can Derma Photosensitivity
be given with administration of antipsychotics Allergic reaction
Ophtha Opacities
Doc’s Mnemonics
“Let’s use a Mercedes BENZ to visit the Pyramids” DRUG PROTOTYPES
BENZtropine is used for ExtraPYRAMIDAL symptoms Anti-Psychotic Prototype
Typical / 1st gen Chlorpromazine
CHRONIC EPS Atypical/ 2nd gen Clozapine
• Late appearing (>6 mos.)
• Greater risk in older patients TYPICAL ANTIPSYCHOTICS
• Involuntary movements
• Facial signs
TARDIVE DYSKINESIA

o Lip smacking
o Licking of lips
o Chewing
o Rolling/ tongue
protrusions
Management:
Discontinue the drug or switch to
Atypical
Perioral tremor (Rabbit syndrome) –
very prominent when you interview
patients with schizophrenia.

NEUROEPILEPTIC MALIGNANT SYNDROME (NMS) Piperazine (ex: Fluphenazine)

F  Fever Piperidine (ex. Thioridazine)
E  Encephalopathy Aliphatic (ex. Chlorpromazine)
V  Vital unstable Chlorpromazine compared to other typical antipsychotics has a lower
E  Elevated CPK potency so administer at higher doses. What’s good about this drug
R  Rigidity is that like the other drugs, it can reach the maximal effect.
Management:
• Discontinue the drug
• Dantrolene  post synaptic muscle relaxant
Note we don’t have Dantrolene in the Philippines.

DYSPHORIA
• Feeling of dissatisfaction with life
• Blockade of dopamine in the mesolimbic pathway

ENDOCRINE DYSFUNCTION
• Weight gain
• Inhibited prolactin release (tubero-infundibular
Butyrophenone (ex. Haloperidol)
pathway) Phenothiazine (ex. Chlorpromazine)
o Gynecomastia & infertility in males Thioxanthene (ex. Thiothixene)
o Amenorrhea / Galactorrhea in females
Doc’s Mnemonics
OTHER SYSTEMS Chlorpromazine  Low potency
CVS Prolongation of QT & PR intervals
Haloperidol  High Potency
Risk of life-threatening myocardial depression
ChLOWpromazine
 High doses of chlorpromazine
HIGHloperidol
ANS Orthostatic hypotension
GIT Constipation; cholestatic jaundice

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CHLORPROMAZINE Derma Photosensitivity
Class Aliphatic phenothiazine; Typical antipsychotic Allergic reaction
D2 receptor blockade Ophtha Opacities (cornea & lens deposits)
• Mesolimbic  antipsychotic effect
MOA

• Nigrostriatal  EPS MUST KNOWS

• Tuberoinfundibular  ↑ prolactin Typical Antipsychotics (!!)
secretion Chlorpromazine Blocks D2 & 5-HT2 receptors
Psychosis S/E: EPS, Cornea & Lens deposits
• Acute idiopathic psychoses Thioridazine Blocks D2- 5HT2 receptors
• Acute & chronic phases of schizophrenia S/E: EPS, Retinal deposits, cardiotoxic
• Mania  mostly adjunctive benefits Blocks D2 and 5-HT2 receptors
Nausea & vomiting Haloperidol Weakest autonomic effects
Uses

Intractable hiccough Least sedating typical antipsychotic

Anti-psychotic effects: S/E: EPS, neuroleptic malignant
• Less agitated syndrome
• More responsive & communicative
• Diminished impulsive & aggressive behavior
CLOZAPINE
• Amelioration of hallucinations, delusions &
Class Dibenzodiazepine; Atypical antipsychotic
disorganized or incoherent thinking
Blocks 𝐷2 and 5𝐻𝑇2𝐴 receptors
Readily absorbed from GIT
 𝐷2 receptor (40-50%)

MOA
Onset:
Pharmacokinetics

 5𝐻𝑇2𝐴 receptor (70-90%)

• IM  15-30 mins
Also interact with A1 & A2 adrenergic, muscarinic
• Oral  30-60 mins
& histaminergic receptors
Widely distributed (BBB, placenta & breast milk)
• Treatment of resistant schizophrenia
Half-life: 30 mins
o Severely ill px with Schizophrenia who fail to
Excretion: urine show acceptable response to adequate courses of
Drug can still be seen in the urine despite discontinuation standard antipsychotic drug
of the drug.
Uses

• Levodopa-induced psychosis in patients with

Low potency; High efficacy
PD
Notes

Generally non-addicting
• Reduction in the risk of recurrent suicidal
behavior in schizophrenia or schizoaffective
Latency to beneficial effects  4-6 weeks delay d/o (!!)
Advise patients about delay to avoid noncompliance Well absorbed from GIT
30% patients remain psychotic
Disadvantage

Food does not affect bioavailability

Minimal improvement of:
PK

Half-life: 12 hours.
• Negative symptoms Still given once a day since clinical effect exceeds half life
• Cognitive symptoms Excretion: Urine > Feces
• Overall function • Improves cognitive function in psychotic
EPS noted in 20-50% of patients patients
Relapse: 50% in two years • Minimal / transient effects on prolactin
Notes

CNS Sedation secretion

Beneficial for caregivers who are taking care • Less risk for EPS
of patients in their aggressive state.
• Never used as first-line treatment due to its
Neuroleptic syndrome
side effect profile
• Indifference to surroundings
CNS Neuroepileptic malignant syndrome
• Paucity of thought
Adverse Effects

• Psychomotor slowing Low seizure threshold level

Extrapyramidal symptoms Endo WEIGHT GAIN
Adverse effects

ANS Orthostatic hypotension Hyperlipidemia

CVS Prolongation of QT & PR intervals Hypertension
Risk of life-threatening myocardial New onset or worsening of Type 2 DM
depression (high doses) Transient fever (first 3 weeks)
GIT Constipation; cholestatic jaundice Hema Bone marrow depression (agranulocytosis)
Hema Agranulocytosis (first 8-12 weeks) CVS Orthostatic hypotension
** note CBC monitoring is needed on regular GIT Impairment of intestinal peristalsis
basis for agranulocytosis Sialorrhea

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 MUST KNOWS
Atypical Antipsychotics (COZQAR-L) 7. True/False: Clozapine can be given right away to a
Clozapine Reduces risk for suicide; for Suicidal 20-year-old patient who suddenly developed
schizophrenia. delusions, hallucinations, and disorganized
Note: Not 1st line of treatment behavior.
S/E: wt. gain, DM, MetS, ↓WBC ✓ False
Olanzapine S/E: weight gain, DM, MetS
8. Give one Clozapine Adverse effect
Ziprasidone S/E: QT prolongation
✓ See trans
Quetiapine Most sedating among Atypical antipsychotic
9. Give an example of a typical antipsychotic with
S/E: Priapism, Cataract
“Quet” kaya most sedating. HIGH potency
Aripiprazole Least sedating atypical antipsychotic ✓ Trifluopherazine
Risperidone Only approved antipsychotic for the youth ✓ Fluphenazine
S/E: Hyperprolactinemia ✓ Haloperidol
Lurasidone Only antipsychotic approved in Preg Cat B ✓ Pimozide
Safe for use in pregnant patients ✓ Thiotexene
All block 5-HT2 receptors more than D2 receptors ✓ Increased release of prolactin/
Hyperprolactinemia
QUIZ
1. Give one example of a 1st generation/ Typical
Antipsychotic END OF TRANSCRIPTION
✓ Chlorpromazine
✓ Prochlorperazine
✓ Thioridazine
✓ Trifluopherazine
✓ Fluphenazine
✓ Haloperidol
✓ Pimozide
✓ Thiotexene
2. Give one example of a 2nd generation/ Atypical
antipsychotic
✓ Clozapine
✓ Olanzapine
✓ Ziprasidone Transcription Team 2019
Transcribed by: Breanne Clea Miranda
✓ Quetiapine
Edited by: Rudyle Carlo Cadiz
✓ Aripiprazole
References: PPT 2017
✓ Risperidone Doc’s notes
✓ Lurasidone Recordings
3. What is the basis for much of the rationale of drug Remarks: Remember the 4
therapy in psychosis Dopaminergic pathways
✓ Dopamine Hypothesis & all with (!!)
4. What dopaminergic pathway is associated with the indicated.
development of extrapyramidal symptoms
Sorry if it’s wordy. I try
✓ Nigrostriatal Pathway
including all the
5. Give one drug used to target EPS situational notes she
✓ Benztropine mentioned so we know
✓ Diphenhydramine what’s the best drug to
✓ Trihexyphenidyl give. GO BESHIE 😉
6. What diagnostic modality that should be requested
for a schizophrenic patient who developed fever
and colds?
✓ Complete blood count/ Differential WBC count

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