Antipsychotic Medications.

March 23,2024
 Presentation out line
• Introduction
• Classification of antipsychotic medication
• MOA
• Pharmacokinetic and pharmackdynamis
• Chlorpomazipine
• aripiprazole
 Presentational objectives
At the end of the presentation you will be
• define anti psychotic medications
• know the classification of antipsychotic med.
• state the MOA antipsychotic med.
• state the pharmacokinetics and dynamics
property of antipsychotic med.
• know pharmacological indication of
antipsychotic Med.
 Brain storming
What is psychosis?

Have you ever heard about psychosis

 Introduction
Antipsychotic medicines are primarily used to manage psychosis
(i.e., a loss of contact with reality that may include delusions or
hallucinations).
Psychosis can be a symptom of a physical condition (such as a
high fever, head injury, or substance intoxication) or a mental
disorder (such as schizophrenia, bipolar disorder, or severe
depression).
Antipsychotic medications may also be used in combination with
other medications to treat the symptoms of other mental health
conditions, including attention deficit hyperactivity disorder
(ADHD), eating disorders, post-traumatic stress disorder (PTSD),
obsessive-compulsive disorder (OCD), and generalized anxiety
disorder.
Classification
 Chemical classes of antipsychotics

• Typical antipsychotics
– Phenothiazines (chlorpromazine)
– Butyrophenones (haloperidol, droperidol)
• Atypical antipsychotics
– Phenylpiperaxines (aripiprazole)
– Dibenzodiazepine (clozapine, quetiapine)
– Thienobenzodiazepines (olanzapine)
– Benzisothiazoles and
benzisoxazoles (risperidone, lurasidone)
MOA
 CON’
First generation(typical)
block D2 receptors in brain
Second generation(atypical)
serotonin-1A (5-HT1A; aripiprazole)
serotonin-1C (5-HT1C; clozapine, olanzapine, risperidone)
histamine-1 (H1; olanzapine, quetiapine)
α1-(aripiprazole, clozapine, olanzapine, paliperidone,
quetiapine)
α2-adrenergic (clozapine, olanzapine, paliperidone,
quetiapine, risperidone) receptor blockers..
 Pharmacokinetics
• Administration and absorption the old ones They are usually
available in IV and IM formulations, whereas the newer agents are
usually only oral. Both groups have various conveniently long-acting
versions which can sit happily in a deltoid or a buttock as a depot,
slowly dissociating into the bloodstream over weeks.
• Bioavailability is pretty variable, but most of these drugs are subject
to a significant first pass effect. The range is from 10% to 70%.
• Protein-binding Most agents are 90-99% protein bound (for
example, haloperidol is92% protein-bound)
• Distribution is vast, as these highly lipophilic protein-loving drugs
tend to accumulate in tissues. For haloperidol, for example, the
volume of distribution is 18L/kg.
• Elimination is invariably by hepatic mechanisms, with inactive
metabolites escaping via the urine
 Mechanism of side effect
• Extrapyramidal side effects are the consequences of blocking striatal
D2 receptors:
– Dystonia: involuntary muscle spasm
– Oculogyric crisis is the extreme version of this,.
– Akathisia, a sort of motor restlessness,
– Rigidity and parkinsonism typically takes months to develop
– Tardive dyskinesia is only seen with prolonged treatment
• Hyperprolactinaemia: Dopamine is a normal regulator of prolactin
secretion, and dopamine receptor block in the tuberoinfundibular tract
leads to the suppression of this regulation. With the breaks disabled,
the pituitary gland pumps out gallons of prolactin. Galactorrhea and
breast enlargement occurs in women, and gynecomastia in men.
 Con..
• Postural hypotension and sexual dysfunction are both
the gifts of α-adrenergic receptor blockade. In overdose,
the block can be sufficiently deep to produce significant
vasodilation and hypotension.
• Anticholinergic side effects (xerostomia, urinary
retention, tachycardia, constipation, blurred vision,
tachycardia and delirium)
.
• QT interval prolongation occurs because antipsychotics
block the delayed rectifier currents (Ik), which are
responsible for Phase 3 of the action potential.
 Chlorpromazine

• It is one of the phenothizides group

• Trade name Thorazine and Largactil
MOA; a dopamine antagonist.
antiserotonergic
antihistaminergic
Indication: for schizophrenia.
bipolar disorder,
in children including those with
attention deficit hyperactivity disorder, nausea and
vomiting, anxiety
con
 con
Common advers effects; in movement problems

sleepiness, dry mouth, low blood pressure upon standing, and increased

weight.

Serious advese effects; may include the potentially permanent movement

disorder tardive dyskinesia, neuroleptic malignant syndrome, severe

lowering of the seizure threshold, and low white blood cell levels.In older

people with psychosis as a result as result of dementia it may cause death

 Cont..

Precaution: Avoid driving or hazardous activity

• Avoid getting up too fast from a sitting or
lying position.
• Avoid drinking alcohol .
• Avoid direct sunlight
Preparation oral preparation
Intravenous preparation
 Con…….
Contraindications
Absolute contraindications include:
• Circulatory depression
• CNS depression
• Coma
• Drug intoxication
• Bone marrow suppression
• Phaeochromocytoma
• Hepatic failure
• Active liver disease
• Previous hypersensitivity (including jaundice, agranulocytosis,
etc.) to phenothiazines, especially chlorpromazine, or any of the
excipients in the formulation being used.
 Con…
Relative contraindications include:
• Epilepsy
• Parkinson's disease
• Myasthenia gravis
• Hypoparathyroidism
• Prostatic hypertroph
Pharmacokinetics protein binding 90-99%
metabolize in liver by CYP2D6,CYP1A2
bio availability 10-80%
tmax 1-4 hr
excretion via urine
 CON.
Interaction(ADME) It reduce absorption by
food
benztropine .
Alcohol .
Antacids.
Lithium and chronic treatment with barbiturates can increase
chlorpromazine clearance significantly.[
Tricyclic antidepressants (TCAs) can decrease chlorpromazine
clearance and hence increase chlorpromazine exposure. [
Cotreatment with CYP1A2 inhibitors like ciprofloxacin,
fluvoxamine or vemurafenib can reduce chlorpromazine
clearance . 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
 Con
• Chlorprozamine is also a moderate inhibitor of CYP2D6 and a
substrate for CYP2D6, and hence can inhibit its own
metabolism..
• Other drugs like codeine and tamoxifen, which require CYP2D6
-mediated activation into their respective active metabolites, may
have their therapeutic effects attenuated. Likewise, CYP2D6
inhibitors such as paroxetine or fluoxetine can reduce
chlorpromazine clearance, increasing serum levels of
chlorpromazine and potentially its adverse effects.
• It also reduces propranolol clearance and antagonizes the
therapeutic effect of antidiabetic agents, levodopa (a Parkinson's
medication. This is likely due to the fact that chlorpromazine
antagonizes the D2 receptor which is one of the receptors
dopamine,alevodopametabolite,activates), amphetamines and
anticoagulants.
 CON..

Pharmacodanamics
Acts as an antagonist (blocking agent) on different postsynaptic and
presynaptic receptors:
• Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its
different antipsychotic properties on productive and unproductive symptoms,
• Serotonin receptors (5-HT2, 5-HT6 and 5-HT7), with anxiolytic, antidepressant
and ant aggressive properties.
• Histamine receptors (H1 receptors, accounting for sedation, antiemetic effect,
vertigo, and weight gain)
• α1- and α2-adrenergic receptors (accounting for sympatholytic properties,
lowering of blood pressure, reflex tachycardia, vertigo, sedation,
hypersalivation and incontinence as well as sexual dysfunction, but may also
attenuate pseudoparkinsonism – controversial. Also associated with weight gain
as a result of blockage of the adrenergic alpha 1 receptor as well as with
intraoperative floppy iris syndrome due to its effect on the iris dilator muscle. [40]
• M1 and M2 muscarinic acetylcholine receptors (causing anticholinergic
symptoms such as dry mouth, blurred vision, constipation, difficulty or inability
to urinate, sinus tachycardia, electrocardiographic changes and loss of memory,
 Aripiprazole

brand names Abilify and Aristada,

atypical antipsychotic.
Indication

• schizophrenia
• obsessive compulsive disorder (OCD)
• and bipolar disorder
• major depressive disorder
• tic disorders, and irritability associated with autism.
• Preparation; oral
• Injection
Chemical structure
 pharmacokinetics

• Aripiprazole displays linear kinetics and has an elimination half-life of

approximately 75 hours. Steady-state plasma concentrations are
achieved in about 14 days. Cmax (maximum plasma concentration) is
achieved 3–5 hours after oral dosing.
• Bioavailability of the oral tablets is about 90% and the drug undergoes
extensive hepatic metabolization (dehydrogenation, hydroxylation,
and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4
• . Its only known active metabolite is dehydro-aripiprazole, which
typically accumulates to approximately 40% of the aripiprazole
concentration.
• The parenteral drug is excreted only in traces, and its metabolites,
active or not, are excreted via feces and urine.
 pharmacodynamics
• Aripiprazole is a quinolinone antipsychotic that is a partial agonist at the
D2 and 5HT-1a receptors and an antagonist at the 5HT-2a receptor.
• It has a high affinity for D2, D3, 5HT-1a, and 5HT2a receptors and
moderate affinity for D4, 5HT-2c, 5-HT7, alpha-1 adrenergic, and H1
receptors.
• Aripiprazole has no affinity for muscarinic receptors at recommended
doses. It stabilizes dopamine and serotonin within the nucleus accumbens,
ventral tegmental area, and frontal cortex resulting in the management of
positive, negative, and cognitive symptoms in schizophrenia.
• Aripiprazole demonstrates functional selectivity in intracellular signaling
pathways by requiring a greater than 90% occupancy rate at D2 receptors
to be clinically active, thus not producing as many extra pyramidal
symptoms
 Summary
• The metabolic effects of antipsychotic drugs should be of
concern when planning a patient's treatment strategy. Baseline
screening and regular follow-up monitoring whose intervals
should depend on the individual predisposition are advised.
• Possible therapeutically strategies for the management of drug-
induced obesity include therapeutic approaches, such as life
style change and pharmaceutical intervention.
• Drugs with a weight reducing effect become more important
because of the lack of compliance with behavioural
intervention. Topiramate, histamine-antagonists, dopaminergic-
and serotoninergic agents have shown positive results in the
management of psychotropic medication induced weight gain.
 Reference
• Wijesinghe R. A review of pharmacokinetic
and pharmacodynamic interactions with
antipsychotics. Ment Health Clin. 2016 Mar
8;6(1):21-27. doi: 10.9740/mhc.2016.01.021.
PMID: 29955443; PMCID: PMC6009248.S