Antipsychotics

Rowan AlEjielat, PhD

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 Introduction
 Psychosis: a variety of mental disorders:
 The presence of delusions (false beliefs),
 Various types of hallucinations, usually auditory or visual, but sometimes tactile or
olfactory
 Antipsychotic (sometimes called neuroleptic) drugs are able to reduce psychotic
symptoms in a wide variety of conditions, including schizophrenia, bipolar
disorder, and drug-induced psychoses.

 Some produce extrapyramidal side effects (EPS) at clinically effective doses

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 What do we mean by extrapyramidal side effects
(EPS)?
 Extrapyramidal pathway: These are motor pathways that lie outside the
corticospinal tract and involuntary. Their main function is to support voluntary
movement and help control posture and muscle tone.
 ExtraPyramidal Side Effects: a number of atypical involuntary muscle contractions
that influence gait, movement, and posture.
 Ex.: akinesia (inability to initiate movement) and akathisia (inability to remain
motionless).

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 SCHIZOPHRENIA
 Schizophrenia is a group of severe brain disorders in which people interpret reality
abnormally.

 Schizophrenia may result in some combination of hallucinations, delusions, and

disordered thinking and behavior.

 Schizophrenia isn't split personality or multiple personality.

 The word "schizophrenia" does mean "split mind," but it refers to a disruption of the
usual balance of emotions and thinking.

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 SCHIZOPHRENIA

 Schizophrenia is a chronic condition, requiring lifelong treatment.

 Schizophrenia has a strong genetic component and probably reflects some

fundamental biochemical abnormality

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 SCHIZOPHRENIA
 Signs and symptoms of schizophrenia generally are divided into three categories:

 Positive
 Negative
 Cognitive

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 Positive symptoms
 An excess or distortion of normal functions

 Delusions.
 These beliefs are not based in reality and usually involve misinterpretation of
perception or experience.
 They are the most common of schizophrenic symptoms.
 Hallucinations.
 Seeing or hearing things that don't exist
 Hearing voices is the most common

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 Positive symptoms
 Thought disorder.
 Difficulty speaking and organizing thoughts may result in stopping speech midsentence
or putting together meaningless words, sometimes known as word salad.
 Disorganized behavior.
 This may show in a number of ways, ranging from childlike silliness to unpredictable
agitation.

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 Negative symptoms
 Refer to a diminishment or absence of characteristics of normal function.
 They may appear with or without positive symptoms.

 They include:
 Loss of interest in everyday activities
 Appearing to lack emotion
 Reduced ability to plan or carry out activities
 Neglect of personal hygiene
 Social withdrawal
 Loss of motivation

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 Cognitive symptoms
 Problems with making sense of information
 Difficulty paying attention
 Memory problems

 To be diagnosed with schizophrenia, a person must meet the criteria spelled out in
the Diagnostic and Statistical Manual of Mental Disorders (DSM).

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 Antipsychotics
ATYPICAL ANTIPSYCHOTICS (second
First Generation - Typical generation)
 PHENOTHIAZINES  Aripiprazole
 Chlorpromazine
 Fluphenazine  Clozapine
 Thioridazine  Olanzapine
 Promethazine  Quetiapine
 THIOXANTHENE  Risperidone
 Thiothixene  Ziprasidone

 BUTYROPHENONE
 Haloperidol

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 Lumateperone
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 Antipsychotics
 The antipsychotic drugs are divided into first generation (typical) and second-
generation agents (atypical)
 The first-generation drugs are further classified as “low-potency” or “high-potency

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 First-generation antipsychotics
 Antipsychotic effects reflect competitive blocking of D2 dopamine receptors

 First-generation antipsychotics are more likely to be associated with

movement disorders

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 Second-generation antipsychotic drugs
 The second generation antipsychotic drugs (also referred to as “atypical”
antipsychotics) have fewer extrapyramidal symptoms (EPS) than the first-
generation agents, but are associated with a higher risk of metabolic side effects,
such as diabetes, hypercholesterolemia, and weight gain.

 The second-generation drugs appear to owe their unique activity to blockade of

both serotonin and dopamine (and, perhaps, other) receptors.

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 Drug selection
 First line therapy is Atypical or second generation drugs.
 This is to reduce movement side effects of the first generation.

 All of the second-generation antipsychotics exhibit an efficacy that is equivalent

to, and occasionally exceeds, that of the first-generation antipsychotic agents.

 Second-generation antipsychotics should not be considered interchangeable

because patients may respond differently to each drug in this class.

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 Refractory patients
 Approximately 20% of patients with schizophrenia will have an insufficient response
to all first- and second generation antipsychotics.

 For these patients, clozapine has shown to be an effective antipsychotic with minimal risk
of EPS.

 However, its clinical use is limited to refractory patients because of serious side effects.
 Clozapine can produce bone marrow suppression, seizures, and cardiovascular side
effects.
 The risk of severe agranulocytosis necessitates frequent monitoring of white blood cell
counts.

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 Mechanism of action
 Dopamine receptor–blocking activity in the brain
 All of the first generation and most of the second-generation antipsychotic drugs block
dopamine receptors in the brain and the periphery

 Serotonin receptor–blocking activity in the brain

 Most of the second-generation agents appear to exert part of their unique action
through inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors

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 Mechanism of action
 Clozapine has high affinity for D1, D4, 5-HT2, muscarinic, and α-adrenergic
receptors, but it is also a weak dopamine D2-receptor antagonist.

 Olanzapine, Risperidone block 5-HT2A receptors to a greater extent than D2

receptors
 Aripiprazole, brexipiprazole and cariprazine are partial agonists at D2 and 5-HT1A
receptors as well as antagonists of 5-HT2A recepors
 Quetiapine blocks D2 receptors more potently than 5HT2A receptors but is relatively
weak at blocking either receptor

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 Actions of antipsychotics
 1- antipsychotics
 All of the antipsychotic drugs can reduce the “positive” symptoms by
blocking dopamine receptors in the mesolimbic system of the brain.

 The “negative” symptoms, blunted affect, apathy, impaired attention, as well as

cognitive impairment, are not as responsive to therapy, particularly with the first-
generation antipsychotics

 Clozapine reduces the negative symptoms to some extent

 The antipsychotic effects usually take several days to weeks to occur

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 Extrapyramidal effects
 →occur with chronic treatment
 The inhibitory effects of dopaminergic neurons are normally balanced by the
excitatory actions of cholinergic neurons in the striatum.
 Blocking dopamine receptors alters this balance, causing a relative excess of
cholinergic influence, which results in extrapyramidal motor effects.

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 Extrapyramidal effects
 Dystonias (sustained contraction of muscles leading to twisting, distorted
postures), within few hours to days

 Akathisia (motor restlessness), within days to weeks

 Parkinson-like symptoms, within weeks to months

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 Extrapyramidal effects

 If cholinergic activity is also blocked, a new, more nearly normal balance is

restored, and extrapyramidal effects are minimized.

 This can be achieved by administration of an anticholinergic drug, such as

benztropine

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 Tardive dyskinesia
 Tardive dyskinesia (involuntary movements of the tongue, lips, neck, trunk, and limbs)
→ can be irreversible, may occur after months or years of treatment.

 Tardive dyskinesia is postulated to result from an increased number of dopamine receptors

that are synthesized as a compensatory response to long-term dopamine-receptor
blockade.

 This makes the neuron supersensitive to the actions of dopamine, and it allows the
dopaminergic input to this structure to overpower the cholinergic input, causing excess
movement in the patient.

 Traditional anti-EPS medications do not generally improve tardive dyskinesia and may
actually worsen this condition.

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 Other actions
 Antiemetic effects:

 Most of the antipsychotic drugs have antiemetic effects that are mediated by
blocking D2-dopaminergic receptors of the chemoreceptor trigger zone of the
medulla.
 The older antipsychotics (prochlorperazine, useful in drug induced nausea)
 Olanzapine, SGA→ prevention of both acute and delayed nausea and vomiting due to
chemotherapy

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 Other actions
 Anticholinergic effects:
 Anticholinergic properties may assist in reducing the risk of EPS with these agents.

 Side Effects:
 Blurred vision
 Dry mouth (the exception is clozapine, which increases salivation)
 Confusion
 Constipation and urinary retention

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 Other actions
 Drugs with anticholinergic effects:
 Thioridazine
 Chlorpromazine
 Clozapine
 Olanzapine

 Haloperidol and fluphenazine, have low anticholinergic activity and produce EPS
more frequently because of the preferential blocking of dopaminergic transmission
without the blocking of cholinergic activity.

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 Other uses
 Can be used as tranquillizers to manage agitated and disruptive behavior secondary
to other disorders.
 Risperidone, aripiprazole→ approved for the management of disruptive behavior
and irritability secondary to autism
 Pimozide→ motor and phonic tics of Tourette disorder.
 Risperidone, haloperidol also
 Chlorpromazine → intractable hiccups, baclofen, gabapentin preferred now
 Although promethazine is not an effective antipsychotic drug, this agent is
used in treating pruritus because of its antihistaminic properties.

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 Side effects
 Orthostatic Hypotension: as a result of the blockade of α-adrenergic receptors
 Affects Thermoregulation: alter temperature-regulating mechanisms and can produce
poikilothermia (condition in which body temperature varies with the environment
 Hyperprolactinemia: In the pituitary, antipsychotics block D2 receptors, leading to an
increase in prolactin release
 Sedation : occurs with those drugs that are potent antagonists of the H1-histamine
receptor, including chlorpromazine, olanzapine, quetiapine,and clozapine.
 Neuroleptic malignant syndrome: rare, potentially fatal: muscle rigidity, fever, altered
mental status, stupor, autonomic instability ( unstable blood pressure, tachcaredia,
myoglobinemia)

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 Absorption and metabolism
 After oral administration, the antipsychotics show variable absorption that is
unaffected by food

 These agents readily pass into the brain, have a large volume of distribution, bind
well to plasma proteins, and are metabolized to many different substances, usually
by the cytochrome P450 system in the liver

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 Antipsychotics
 The antipsychotic drugs produce some tolerance but little physical
dependence.

 long-acting injectable(LAI) formulations of antipsychotics that are administered via

deep gluteal intramuscular injection or deltoid injection have a therapeutic
duration of action of up to 2 to 4 weeks and, therefore, are often used to treat
outpatients and individuals who are noncompliant with oral medications.

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 Antipsychotics
 Drowsiness occurs due to CNS depression and antihistaminic effects, usually
during the first few weeks of treatment.

 Significant weight gain is often a reason for noncompliance.

 Some antipsychotics have been associated with QT prolongation.

 It is also recommended that glucose and lipid profiles be monitored in patients

taking antipsychotics due to the potential for the second-generation agents to
increase these laboratory parameters and the possible exacerbation of
preexisting diabetes mellitus or hyperlipidemia.

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 Antipsychotics
 All antipsychotics may lower the seizure threshold and should be used cautiously in
patients with seizure disorders.

 Antipsychotics used in patients with mood disorders should also be monitored for
worsening of mood and suicidal ideation or behaviors

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 Maintenance treatment for SZ
 Patients who have had two or more psychotic episodes, secondary to
schizophrenia, should receive maintenance therapy for at least 5 years, and some
experts prefer indefinite therapy.

 The rate of relapse may be lower with second generation drugs

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  Dosage equivalents (expressed as chlorpromazine [CPZ]-equivalent dosages—the
equipotent dosage of an FGA compared with 100 mg of CPZ) may be useful when
switching from one FGA to another FGA drug

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