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ANTIPSYCHOTICS

EDALYN RAMOS CAPILI


Metropolitan Medical Center
College of Medicine
Dopamine Receptor Antagonists
(First-Generation Antipsychotics)
• first group of effective agents for schizophrenia and other
psychotic illnesses.
• phenothiazine chlorpromazine (Thorazine)- introduced in early
1950s
• Other DRAs:
-phenothiazines -dibenzoxazepines
-butyrophenones -dihydroindoles
-thioxanthenes -diphenylbutylpiperidines
• associated with extrapyramidal syndromes
• newer antipsychotic drugs: serotonin-dopamine antagonists
• SDA - lower liability to cause EPS but can cause weight gain, lipid
elevations and diabetes
• perphenazine (Trilafon)- as effective and well tolerated as SDAs
PHARMACOLOGICAL ACTIONS
• well absorbed after oral administration
• liquid preparations absorbed more efficiently than tablets or
capsules
• Peak Plasma Concentrations: 1-4 hours (oral) and 30-60
minutes (parenteral)
• Smoking, coffee, antacids and food interfere with absorption
• Steady-state levels reached in 3-5 days
• t1/2 = 24 hours
• 1 daily oral dose, if tolerated, after patient is in stable condition.
• Most are highly protein bound
• Most are metabolized by cytochrome P450 (CYP) CYP2D6 and
3A isozymes. There are differences among the specific agents.
• MOA: inhibition of dopaminergic neurotransmission
PHARMACOLOGICAL ACTIONS
• Effective when 72% of dopamine D2
receptors in the brain are occupied.
• DRAs also block noradrenergic,
cholinergic, and histaminergic
receptors, with different drugs having
different effects on these receptor
systems.
• Low-potency drugs (chlorpromazine
and thioridazine) given in doses of
100 mg/day, produce more weight
gain and sedation.
• High-potency drugs (haloperidol
and fluphenazine) given in doses of
<10 mg/day are more likely to cause
EPS.
PHARMACOLOGICAL ACTIONS

Table 1. Factors Influencing the Pharmacokinetics of Antipsychotics


Age Elderly patients may demonstrate reduced
clearance rates.
Medical condition Decreased hepatic blood flow can reduce
clearance.
Hepatic disease can decrease clearance.
Enzyme inducers Carbamazepine, phenytoin, ethambutol,
barbiturates.
Clearance inhibitors SSRls, TCAs, cimetidine, -blockers
isoniazid, methylphenidate, erythromycin
triazolobenzodiazepines, ciprofloxacin, and
ketoconazole.
Changes in binding Hypoalbuminemia can occur with malnutrition
protein or hepatic failure.
THERAPEUTIC INDICATIONS

Table 2. Indications for Dopamine Receptor Antagonists


Acute psychotic episodes in schizophrenia and schizoaffective disorder
Maintenance treatment in schizophrenia and schizoaffective disorders
Mania
Depression with psychotic symptoms
Delusional disorder
Borderline personality disorder
Substance-induced psychotic disorder
Delirium and dementia
Mental disorders caused by a medical condition
Childhood schizophrenia
Pervasive developmental disorder
Tourette's disorder
Huntington's disease
THERAPEUTIC INDICATIONS
SCHIZOPHRENIA AND SCHIZOAFFECTIVE DISORDER
• DRAs are effective in short-term and long-term management
of schizophrenia and schizoaffective disorder.
• reduce acute symptoms and prevent future exacerbations
• against (+) symptoms of schizophrenia (e.g., hallucinations,
delusions, and agitation)
• (-) symptoms (e.g., emotional withdrawal and ambivalence) less
likely to improve and may worsen because the drugs produce
constriction of facial expression and akinesia, S/E that mimic (-)
symptoms
• DRAs decrease the risk of reemergence of psychosis in patients
who have recovered while on medication.
• After first episode of psychosis, patients should be maintained on
medication for 1-2 years; after multiple episodes, for 2-5 years.
THERAPEUTIC INDICATIONS
MANIA
• DRAs are effective for treating psychotic symptoms of acute
mania. Antimanic agents (e.g., lithium) have slower onset of
action than antipsychotics in the treatment of acute symptoms.
• STANDARD PRACTICE: combine DRA or SDA with lithium
(Eskalith), divalproex (Depakote), lamotrigine (Lamictal), or
carbamazepine (Tegretol), then gradually withdraw antipsychotic.
DEPRESSION WITH PSYCHOTIC SYMPTOMS
• antipsychotic + antidepressant  treatment of choice for major
depressive disorder with psychotic features
DELUSIONAL DISORDER
• Patients with delusional disorder respond to treatment with DRAs.
Some persons with borderline personality disorder who have
paranoid thinking may also respond to antipsychotics.
THERAPEUTIC INDICATIONS
SEVERE AGITATION AND VIOLENT BEHAVIOR
• Symptoms (e.g., extreme irritability, lack of impulse control,
severe hostility, gross hyperactivity, and agitation) respond to
short-term treatment.
• Children with mental disabilities often have associated episodes
of violence, aggression, and agitation that respond to treatment
with antipsychotics.
TOURETTE'S DISORDER
• Haloperidol and pimozide (Orap) are most frequently used, but
other DRAs are also effective. Some clinicians prefer to use
clonidine (Catapres) because of its lower risk of neurological S/E.
BORDERLINE PERSONALITY DISORDER
• Patients who experience transient psychotic symptoms may need
to be treated with DRA.
THERAPEUTIC INDICATIONS
DEMENTIA AND DELIRIUM
• 2/3 of agitated, elderly patients with various forms of dementia
improve when given DRA. Low doses of high potency drugs (e.g.,
0.5-1 mg/day haloperidol) are recommended.
• DRAs are also used to treat psychotic symptoms and agitation
associated with delirium.
• Orthostasis, Parkinsonism, and worsened cognition are the most
problematic side effects in this elderly population.
SUBSTANCE-INDUCED PSYCHOTIC DISORDER
• Intoxication with cocaine, amphetamines, alcohol, phencyclidine,
or other drugs can cause psychotic symptoms.
• It is preferable to avoid use of DRA unless patient is severely
agitated and aggressive. Benzodiazepines can be used to calm
the patient.
THERAPEUTIC INDICATIONS
CHILDHOOD SCHIZOPHRENIA
• Studies to determine if intervention with medication at the very
earliest signs of disturbance in children genetically at risk for
schizophrenia can prevent emergence of more florid symptoms.
Careful consideration needs to be given to S/E, especially those
involving cognition and alertness.
OTHER PSYCHIATRIC & NONPSYCHIATRIC INDICATIONS
• DRAs reduce the chorea in early stages of Huntington's disease.
Patients may develop hallucinations, delusions, mania, or
hypomania.
• Clinicians should be aware that patients with the rigid form of this
disorder may experience acute EPS. DRAs to treat impulse
control disorders should be reserved for patients in whom other
interventions have failed.
PRECAUTIONS AND ADVERSE
REACTIONS
Table 3. Dopamine Receptor Antagonists: Potency and Adverse Effects
Drug Name Chemical Therapeutically Side Effects
Classification Equivalent Oral Sedation Autonomic Extrapyramidal
Reactions
Pimozidec Diphenylbutyl-piperidine 1.5 + + +++

Fluphenazine Phenothiazine: 2 + + +++


piperazine compound
Haloperidol Butyrophenone 2 + + +++
Thiothixene Thioxanthene 4 + + +++
Trifluoperazine Phenothiazine: 5 ++ + +++
piperazine compound
Perphenazine Phenothiazine: 8 ++ + ++/+++
piperazine compound
Molindone Dihydroindolone 10 ++ + +
Loxapine Dibenzoxazepine 10 ++ +/++ ++/+++

Prochlorperazine Phenothiazine: 15 ++ + +++


piperazine compound
PRECAUTIONS AND ADVERSE
REACTIONS
Table 3. Dopamine Receptor Antagonists: Potency and Adverse Effects
Drug Name Chemical Therapeutically Side Effects
Classification Equivalent Oral Sedation Autonomic Extrapyramidal
Reactions
Acetophenazine Phenothiazine: 20 ++ + ++/+++
piperazine compound
Triflupromazine Phenothiazine: 25 +++ ++/+++ ++
aliphatic compound
Mesoridazine Phenothiazine: 50 +++ ++ +
piperidine compound
Chlorpromazine Phenothiazine: 100 +++ +++ ++
aliphatic compound
Chlorprothixene Thioxanthene 100 +++ +++ +/++

Thioridazine Phenothiazine: 100 +++ +++ +


piperidine compound
PRECAUTIONS AND ADVERSE
REACTIONS
NEUROLEPTIC MALIGNANT SYNDROME
• Potentially fatal S/E of DRA, can occur at any time
during the course of treatment.
• Symptoms: extreme hyperthermia, severe muscular
rigidity, dystonia, akinesia, mutism, confusion,
agitation, and increased pulse rate and blood
pressure.
• Laboratory findings: increased WBC count, creatinine
phosphokinase, liver enzymes, plasma myoglobin,
and myoglobinuria, occasionally associated with renal
failure.
• Symptoms evolve over 24-72 hours and untreated
syndrome lasts 10-14 days. Diagnosis is often missed
in early stages, and the withdrawal or agitation may
mistakenly to reflect increased psychosis.
PRECAUTIONS AND ADVERSE
REACTIONS
NEUROLEPTIC MALIGNANT SYNDROME
• Men>Women and Young>Elderly
• If NMS is suspected, DRA should be stopped immediately and the
following done: medical support to cool the person; monitoring of
VS, electrolytes, fluid balance, and renal output; and treatment of
fever.
• Antiparkinsonian medications may reduce muscle rigidity.
• Dantrolene (Dantrium), skeletal muscle relaxant (0.8-2.5 mg/kg
every 6 hours, up to a total dosage of 10 mg/day)
• When the person can take oral medications, dantrolene can be
given in doses of 100-200 mg/day.
• Bromocriptine (20-30 mg/day in four divided doses) or
amantadine can be added to the regimen. Treatment should be
continued for 5-10 days.
PRECAUTIONS AND ADVERSE
REACTIONS
SEIZURE THRESHOLD
• DRAs may lower the seizure threshold. Chlorpromazine and
thioridazine are more epileptogenic than high-potency drugs.
SEDATION
• Blockade of histamine H1 receptors- usual cause of sedation
associated with DRAs.
• Chlorpromazine- most sedating typical antipsychotic
CENTRAL ANTICHOLINERGIC EFFECTS
• Symptoms: severe agitation; disorientation to time, person, and
place; hallucinations; seizures; high fever; and dilated pupils.
Stupor and coma may ensue.
• Treatment of anticholinergic toxicity: discontinuing the causal
agents, close medical supervision, and physostigmine (Antilirium,
Eserine), 2 mg by slow IV infusion, repeated within 1 hour.
PRECAUTIONS AND ADVERSE
REACTIONS
CARDIAC EFFECTS
• DRAs decrease cardiac contractility, disrupt enzyme contractility
in cardiac cells, increase circulating levels of catecholamines,
and prolong atrial and ventricular conduction time and refractory
periods.
• Phenothiazines are more cardiotoxic than highpotency drugs.
• Exception is haloperidol, which has been linked to abnormal
heart rhythm, ventricular arrhythmias, torsades de pointes, and
sudden death when injected IV.
• Chlorpromazine- causes prolongation of QT and PR intervals,
blunting of T waves and depression of ST segment.
SUDDEN DEATH
• Occasional reports of sudden cardiac death during treatment with
DRAs may be the result of cardiac arrhythmias.
PRECAUTIONS AND ADVERSE
REACTIONS
ORTHOSTATIC (POSTURAL) HYPOTENSION
• most common with lowpotency drugs
• When using IM low-potency DRAs, clinician should measure patient's
BP (lying and standing) before and after the first dose and during
the first few days of treatment.
• Fainting or falls may lead to injury. Patients should be instructed to
rise slowly after sitting and reclining. Patients should avoid all
caffeine and alcohol; should drink at least 2 L of fluid/day; if not under
treatment for hypertension, should add liberal amounts of salt to their
diet.
• Hypotension can be managed by having patients lie down with their
feet higher than their heads and pump their legs as if bicycling.
• Pure -adrenergic pressor agents (e.g., metaraminol and
norepinephrine) are the DOC in the treatment of the disorder.
PRECAUTIONS AND ADVERSE
REACTIONS
HEMATOLOGIC EFFECTS
• Temporary leukopenia with WBC count of 3,500 is a common but
not serious problem.
• Agranulocytosis occurs in 1 in 10,000 persons treated with DRAs.
• Thrombocytopenic or nonthrombocytopenic purpura, hemolytic
anemias, and pancytopenia occur rarely in persons treated with
DRAs.
• If a person reports a sore throat and fever, CBC should be done
immediately to check for the possibility of serious blood dyscrasia.
• If blood index values are low, administration of DRAs should be
stopped, and the patient should be transferred to medical facility.
The mortality rate for the complication may be as high as 30%.
PRECAUTIONS AND ADVERSE
REACTIONS
PERIPHERAL ANTICHOLINERGIC EFFECTS
• dry mouth and nose, blurred vision, constipation, urinary
retention, and mydriasis, with low-potency DRAs
• Some may also have nausea and vomiting.
• Constipation should be treated with laxatives, but severe
constipation can progress to paralytic ileus.
• Pilocarpine (Salagen) may be used to treat paralytic ileus.
• Bethanechol (Urecholine) (20-40 mg/day) in persons with urinary
retention.
• Low-potency DRAs may cause significant weight gain but not as
much as is seen with SDAs olanzapine (Zyprexa) and clozapine
(Clozaril).
• Molindone and loxapine (Loxitane) - least likely to cause weight
gain.
PRECAUTIONS AND ADVERSE
REACTIONS
ENDOCRINE EFFECTS
• Blockade of dopamine receptors in tuberoinfundibular tract results
in increased secretion of prolactin, which result in breast
enlargement, galactorrhea, amenorrhea, and inhibited orgasm
(W) and impotence (M).
• SDA with exception of risperidone (Risperdal), are not associated
with an increase in prolactin levels.
SEXUAL ADVERSE EFFECTS
• M and W can experience anorgasmia and decreased libido.
• Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are
used to treat psychotropic-induced orgasmic dysfunction.
• Thoridazine is associated with decreased libido and retrograde
ejaculation in M. Priapism and painful orgasms possibly from 1-
adrenergic antagonist activity.
PRECAUTIONS AND ADVERSE
REACTIONS
SKIN AND EYE EFFECTS
• Allergic dermatitis and photosensitivity in low-potency agents.
• Urticarial, maculopapular petechial, and edematous eruptions
occur early in treatment, and remit spontaneously.
• Photosensitivity reaction resembles severe sunburn in persons
taking chlorpromazine.
• Persons should be warned of this, should spend no more than
30-60 minutes in the sun, and should use sunscreens.
• Long-term chlorpromazine use is associated with blue-gray
discoloration of skin areas exposed to sunlight.
• Irreversible retinal pigmentation is associated with thioridazine at
dosages >1,000 mg/day. Early symptom - nocturnal confusion
related to difficulty with night vision.
PRECAUTIONS AND ADVERSE
REACTIONS
JAUNDICE
• Elevations of liver enzymes tend to be transient and not clinically
significant.
• When chlorpromazine first came into use, cases of obstructive or
cholestatic jaundice were reported, in the first month of treatment
and heralded by symptoms of upper abdominal pain, nausea, and
vomiting. Followed by fever; rash; eosinophilia; bilirubin in the
urine; and increases in levels of serum bilirubin, alkaline
phosphatase, and hepatic transaminases.
• Medication should be discontinued.
OVERDOSES
• S/S: CNS depression, EPS, mydriasis, rigidity,
restlessness, decreased deep tendon reflexes,
tachycardia, hypotension
• Severe symptoms: delirium, coma, respiratory
depression, seizures
• Haloperidol - safest typical antipsychotics in overdose.
• After an overdose, electroencephalography shows
diffuse slowing and low voltage.
• Activated charcoal and gastric lavage should be
administered if the overdose is recent.
• Emetics are not indicated because the antiemetic
actions of DRAs inhibit their efficacy.
• Seizures can be treated w/ IV diazepam (Valium) or
phenytoin (Dilantin).
• Hypotension can be treated w/ norepinephrine or
dopamine.
PREGNANCY AND LACTATION
• Low correlation between the use of antipsychotics during pregnancy
and congenital malformations.
• Antipsychotics should be avoided during pregnancy, particularly in the
first trimester unless the benefit outweighs the risk.
• Highpotency drugs are preferable because low-potency drugs are
associated with hypotension.
• DRAs are secreted in the breast milk, although concentrations are low.
W taking these agents should be advised against breastfeeding.
DRUG INTERACTIONS
Table 4. Antipsychotic Drug Interactions: Drug interactions assessed to have major severity
Interacting Mechanism Clinical Effect
Medication
B-Adrenergic receptor Synergistic pharmacologic effect; antipsychotic Severe hypotension
antagonists inhibits metabolism of propranolol; antipsychotic
increases plasma concentrations
Anticholinergics Pharmacodynamic effects Decreased antipsychotic effect
Additive anticholinergic effect Anticholinergic toxicity
Barbiturates Phenobarbital induces antipsychotic metabolism Decreased antipsychotic concentrations
Carbamazepine Induces antipsychotic metabolism Up to 50% reduction in antipsychotic
concentrations
Charcoal Reduces GI absorption of antipsychotic and adsorbs May reduce antipsychotic effect or cause
drug during enterohepatic circulation toxicity when used to treat overdose or for
GI disturbances
Cigarette smoking Induction of microsomal enzymes Reduced plasma concentrations of
antipsychotic agents
Epinephrine, Antipsychotic antagonizes pressor effect Hypotension
norepinephrine
Ethanol Additive CNS depression Impaired psychomotor status
Fluvoxamine Inhibits metabolism of haloperidol and Increased concentrations of haloperidol and
clozapine clozapine
Guanethidine Antipsychotic antagonizes guanethidine reuptake Impaired antihypertensive effect
Lithium Unknown Rare reports of neurotoxicity
Meperidine Additive CNS depression Hypotension and sedation
DRUG INTERACTIONS
Table 5. Antipsychotic Drug Interactions: Drug interactions assessed to have minor or moderate severity
Interacting Mechanism Clinical Effect
Medication
Amphetamines, Decreased pharmacologic effect of amphetamine Diminished weight loss effect; amphetamines
anorexiants may
exacerbate psychosis
Angiotensin-converting Additive hypotensive crisis Hypotension, postural intolerance
enzyme inhibitor
Antacids containing Insoluble complex formed in GI tract Possible reduced antipsychotic effect
aluminum
Antidepressant Decreased metabolism of antidepressant through Increased antidepressant concentration
nonspecific competitive inhibition
Benzodiazepines Increased pharmacologic effect of the benzodiazepine Respiratory depression, stupor, hypotension
Bromocriptine Antipsychotic antagonizes dopamine receptor stimulation Increased prolactin
Caffeinated beverages Form precipitate with antipsychotic solutions Possible diminished antipsychotic effect
Cimetidine Reduced antipsychotic absorption and clearance Decreased antipsychotic effect
Clonidine Antipsychotic potentiates A-adrenergic hypotensive effect Hypotension or hypertension
Disulfiram Impairs antipsychotic metabolism Increased antipsychotic concentrations
Methyldopa Unknown Blood pressure elevations
Phenytoin Induction of antipsychotic metabolism; decreased Decreased antipsychotic concentrations:
phenytoin metabolism increased phenytoin levels
SSRls Impair antipsychotic metabolism; pharmacodynamic Sudden onset of extrapyramidal symptoms
interaction
Valproic acid Antipsychotic inhibits valproic acid metabolism Increased valproic acid half-life and levels
DRUG INTERACTIONS
• CYP2D6 is the most common hepatic isozyme involved in DRA
pharmacokinetic interactions.
• Antacids, activated charcoal, cholestyramine (Questran), kaolin,
pectin, and cimetidine (Tagamet) taken w/in 2 hours of
antipsychotic administration can reduce absorption of these
drugs.
• Anticholinergics may decrease absorption of DRAs.
• Digoxin (Lanoxin) and steroids, decrease gastric motility and
increase DRA absorption.
• Phenothiazines (esp. thioridazine) may decrease metabolism of
and cause toxic concentrations of phenytoin.
• Barbiturates may increase metabolism of DRAs.
• Cigarette smoking may decrease plasma levels of typical
antipsychotics.
DRUG INTERACTIONS
• Tricyclic drugs and SSRIs that inhibit CYP2D6---paroxetine
(Paxil), fluoxetine (Prozac), and fluvoxamine (Luvox}-interact with
DRAs, resulting in increased plasma concentrations of both drugs.
• Typical antipsychotics may inhibit the hypotensive effects of -
methyldopa (Aldomet). Antipsychotics have variable effect on the
hypotensive effects of clonidine. Propranolol (Inderal)
coadministration increases blood concentrations of both drugs.
• DRAs potentiate CNS-depressant effects of sedatives,
antihistamines, opiates, opioids, and alcohol, particularly in
persons with impaired respiratory status.
• Epinephrine has paradoxical hypotensive effect in persons taking
typical antipsychotics.
• May decrease blood concentration of warfarin (Coumadin),
resulting in decreased bleeding time.
DRUG INTERACTIONS
• Chlorpromazine and perphenazine (Trilafon) may cause both
false-positive and false-negative results in immunological
pregnancy tests and falsely elevated bilirubin (with reagent
test strips) and urobilinogen (with Ehrlich's reagent test)
values.
• Associated with an abnormal shift in results of the glucose
tolerance test, although shift may reflect the effects of the drugs
on the glucose-regulating system.
• Phenothiazines interfere with the measurement of 17-ketosteroids
and 17-hydroxycorticosteroids and produce false-positive results
in tests for phenylketonuria.
DOSAGE AND CLINICAL
GUIDELINES
Contraindications to the use of DRAs include the following:
1) history of serious allergic response
2) possible ingestion of substance that will interact with
antipsychotic to induce CNS depression (e.g., alcohol, opioids,
barbiturates, and benzodiazepines) or anticholinergic delirium
(e.g., scopolamine and phencyclidine)
3) presence of severe cardiac abnormality
4) high risk for seizures
5) presence of narrow-angle glaucoma or prostatic hypertrophy if a
drug with high anticholinergic activity is to be used
6) presence or a history of tardive dyskinesia
• Antipsychotics should be administered with caution in persons
with hepatic disease, because impaired hepatic metabolism may
result in high plasma concentrations.
DOSAGE AND CLINICAL
GUIDELINES
Table 6. Dopamine Receptor Antagonists
SHORT-TERM TREATMENT
• 5-20 mg of haloperidol - reasonable dose for adult in acute state
• Elderly person may benefit from 1 mg of haloperidol.
• Administration of >25 mg of chlorpromazine in one injection may
result in serious hypotension. IM administration results in peak
plasma levels in 30 minutes versus 90 minutes using oral route.
• Doses of drugs for IM administration are about half those given
by the oral route.
• In a short-term treatment setting, person should be observed for 1
hour after the first dose of medication. After that time, most
clinicians administer a second dose or a sedative agent (e.g.,
benzodiazepine) to achieve effective behavioral control.
• Possible sedatives include lorazepam (Ativan) (2 mg IM) and
amobarbital (50-250 mg IM).
RAPID NEUROLEPTIZATION
• Also called PSYCHOTOLYSIS
• the practice of administering hourly IM doses of antipsychotic
medications until marked sedation is achieved.
• Several research studies have shown that merely waiting several
more hours after one dose yields the same clinical improvement
as is seen with repeated doses.
• Clinicians must be careful to keep patients from becoming violent
while they are psychotic.
• Help prevent violent episodes by using adjuvant sedatives or by
temporarily using physical restraints until the persons can control
their behavior.
EARLY TREATMENT
• A full 6 weeks may be necessary to evaluate extent of the
improvement in psychotic symptoms. Agitation and excitement
usually improve quickly with antipsychotic treatment. Psychotic
symptoms, both positive and negative, usually continue to
improve 3-12 months after the initiation of treatment.
• 5 mg haloperidol or 300 mg chlorpromazine is a usual effective
daily dose. A single daily dose is given at bedtime to help induce
sleep and to reduce incidence of adverse effects.
• Bedtime dosing for elderly persons may increase their risk of
falling if they get out of bed during the night.
• Sedative effects of typical antipsychotics last a few hours, in
contrast to the antipsychotic effects, which last for 1-3 days.
LONG-ACTING DEPOT
MEDICATIONS
• needed to overcome problems with compliance
• IM preparations are given once every 1-4 weeks
• decanoate and enanthate of fluphenazine
• decanoate of haloperidol
• Preparations are injected IM into an area of large muscle
tissue, from which they are absorbed slowly into the blood.
• It is good practice to give at least one oral dose of specific
drugs to assess the possibility of an adverse effect, such as
severe EPS or an allergic reaction.
• Initiate depot treatment with low doses so that the absorption
of the preparations may be faster than usual at onset of
treatment, resulting in frightening episodes of dystonia that
discourage compliance with the medication.
PLASMA CONCENTRATIONS
• Genetic differences among persons and pharmacokinetic
interactions with other drugs influence the metabolism of the
antipsychotics.
• If a person has not improved after 4-6 weeks of treatment, the
plasma concentration of the drug should be determined if
feasible. After a patient has been on a particular dosage for at
least 5X the half -life of the drug and thus approaches steady-
state concentrations, blood levels may be helpful.
• Obtain plasma samples at trough levels-just before the daily
dose is given, usually at least 12 hours after the previous dose
and most commonly 20-24 hours after the previous dose.
TREATMENT-RESISTANT PERSONS
• Treatment resistance is a failure on at least two adequate trials of
antipsychotics from two pharmacological classes.
• Determine plasma concentrations for such persons because it is
possible that they are slow or rapid metabolizers or are not taking
their medication.
• Clozapine has been conclusively shown to be effective when
given to patients who have failed multiple trials of DRAs.
ADJUNCTIVE MEDICATIONS
• Use of lithium or other mood-stabilizing agents, SSRIs, or
benzodiazepines.
• It was once held that antidepressant drugs exacerbated psychosis
in patients with schizophrenia.
• In some cases, amphetamines can be added to DRAs if patients
remain withdrawn and apathetic.
SECOND GENERATION
ANTIPSYCHOTIC
• Also known as serotonin-dopamine antagonists (SDAs) or
Atypical Antipsychotics
• differ in their side effect profiles, most notably lower risk of
extrapyramidal side effects, and have spectra of action that are
broader than DRAs
• have significant effects on both the dopamine and serotonin
systems
• individual drugs in this group has multiple neurotransmitter effects
SECOND GENERATION
ANTIPSYCHOTIC

• risperidone (Risperdal) • ziprasidone (Geodon)


• risperidone IM • aripiprazole (Abilify)
• long acting (Consta), • paliperidone (Invega)
• olanzapine (Zyprexa), • paliperidone palmitate
• olanzapine for extended (Invega, InvegaSustenna)
release injectable • asenapine (Saphris)
suspension (Zyprexa, • lurasidone (Latuda)
Relprevv), • iloperidone (Fanapt)
• quetiapine (Seroquel), • clozapine (Clozaril)
• quetiapine XR
(Seroquel XR),
Table 7. Comparison of Usual Dosing for Some Available
Second-generation Antipsychotics in Schizophrenia
PRECAUTION
Consider the following when prescribing this kinds of
medication:
1. Personal and family history of obesity, diabetes, dyslipidemia,
hypertension, and cardiovascular disease
2. Weight and height (so that BMI can be calculated)
3. Waist circumference (at the level of the umbilicus)
4. Blood pressure
5. Fasting plasma glucose level
6. Fasting lipid profile
• Drugs has lower risk of EPS but produce other S/E. Substantial
weight gain is evident and poses risk for development of Diabetes
Mellitus (Olanzapine and Clozapine).
• Patients with preexisting diabetes should have regular monitoring,
including hemoglobinAlC and in some cases insulin levels.
MECHANISM OF ACTION
• blockade of D2 dopamine receptors
• higher ratio interactions with serotonin receptor subtypes, most
notably the 5-HT2A subtype
• All SDAs have different chemical structures, receptor affinities,
and side effect profiles. No SDA is identical in its combination of
receptor affinities, and the relative contribution of each receptor
interaction to the clinical effects is unknown.
INDICATIONS
• treatment of schizophrenia (except clozapine
because of hematologic side effect)
• Effective in addressing (+) symptoms and superior in
(-) symptoms compared to DRA’s.
• improve depressive symptoms and decreases risk
of suicide and water intoxication in patients with
schizophrenia
Clozapine can be used if:
1. Resistant to all other antipsychotics.
2. Severe tardive dyskinesia which can be reversed
with high dosages
3. Has low threshold for EPS.
Used with Risperidone = more effective (raises
clozapine concentrations)
INDICATIONS
MOOD DISORDERS
• All of the SDAs (except clozapine) are
FDA approved for treatment of acute
mania.
Quetiapine+quetiapine XR=
Bipolar Depression
Olanzapine+Fluoxetine=
Treatment- Resistant Depression (TRD)
Olanzapine+Fluoxetine (Symbyax)=
Bipolar Depression
Aripiprazole+quetiapine XR=
Major Depression (Adjunctive Treatment to
Anti-Depressant)
INDICATIONS
• Acquired Immunodeficiency Syndrome
• Dementia
• Autistic spectrum disorders
• Tourette's disorder
• Huntington's disease
• Lesch-Nyhan syndrome
• Aggression (Risperidone and Olanzapine)
• ADHD (Coadministered with Ritalin/ Dexedrine)
• Psychotic depression
• Psychosis secondary to head trauma
• OCD’s and Borderline Personality Disorder
RISPERIDONE (RISPERDAL)
Indications:
• Acute and maintenance treatment of schizophrenia in adults
and in adolescents age 13-17 years
• Short-term treatment of acute manic or mixed episodes
associated with bipolar I disorder in adults and in children
and adolescents age 10-17 years (combined with
lithium/valproate)
• Treatment of irritability associated with autistic spectrum
disorder in children and adolescents age 5-16 years
(aggression toward others, deliberate self-injuriousness,
temper tantrums, and quickly changing moods)
RISPERIDONE (RISPERDAL)
Pharmacology
• Benzisoxazole
• Undergoes extensive first-pass hepatic metabolism to 9-
hydroxy risperidone
• Peak plasma levels of the parent compound occur within 1
hour for the parent compound and 3 hours for the
metabolite.
• bioactivity of 70%
• risperidone and 9-hydroxyrisperidone averages 20 hours
• Antagonist of serotonin 5-HT2A, dopamine D2, 1- and 2-
adrenergics, and histamine H1 receptors
• less likely than haloperidol to cause EPS (antagonist of
D2) in humans when risperidone is <6 mg/day.
RISPERIDONE (RISPERDAL)
Dosage
• Initial dosage is usually 1-2 mg at night, which can be increased to
4 mg per day
• Dosages >6 mg/day are associated with a higher incidence of
adverse effects, particularly EPS.
• Depot formulation (Risperdal Consta) IM injection formulation
every 2 weeks. The dose may be 25, 50, or 75 mg.
Side Effects
• Weight gain (common in children)
• Anxiety
• Nausea and Vomiting
• Rhinitis
• Erectile dysfunction and orgasmic dysfunction
• Increased pigmentation
RISPERIDONE (RISPERDAL)
Oral risperidone should be coadministered with Risperdal
Consta for the first 3 weeks before being discontinued.

Withdrawal Symptoms
• EPS, dizziness, hyperkinesias, somnolence, and nausea.
Marked elevation of prolactin may occur
Drug Interactions
• Inhibition of CYP2D6 by paroxetine and fluoxetine can block
formation of risperidone's active metabolite
• Risperidone + SSRI’s= Inc. in prolactin, galactorrehea and
breast enlargement
PALIPERIDONE (INVEGA)
Indications:
• acute and maintenance treatment of schizophrenia
• acute treatment of schizoaffective disorder (monotherapy)
• adjunct to mood stabilizers or antidepressants
Pharmacology:
• benzisoxazole derivative
• major active metabolite of risperidone
• Peak plasma concentrations = approximately 24 hours
after dosing
• steady-state concentrations = 4 or 5 days
• hepatic isoenzymes CYP2D6 and CYP3A4 has limited role in
the metabolism and elimination
PALIPERIDONE (INVEGA)
Dosage:
• recommended dosage is 6 mg once daily administered in the
morning with or without food
• available as extendedrelease tablets
• available in 3, 6, and 9 mg tablets administered once daily
• It is recommended that no >12 mg should be administered
per day.
• long-acting formulation (InvegaSustenna) is given by IM injection
once a month.
• Invega Sustenna is available as a white to off-white sterile
aqueous extended-release suspension in dose strengths of 39
mg, 78 mg, 117 mg, 156 mg, and 234 mg paliperidone palmitate.
PALIPERIDONE (INVEGA)
• hydrolyzes to active
moiety, paliperidone,
resulting in dose
strengths of 25 mg,
50 mg, 75 mg, 100
mg, and 150 mg of
paliperidone
• Invega Sustenna is
provided in a
prefilled syringe with
plunger stopper and
tip cap.
PALIPERIDONE (INVEGA)
• The kit contains two safety needles (1 inch 22 gauge and 1 inch
23 gauge safety needles).
• half-life of 25-49 days
• Monthly injections of 117 mg are recommended
• The first two injections should be in the deltoid muscle
because plasma concentrations are 28 % higher with deltoid
versus gluteal administration.
Side Effects
• more sensitivity to temperature extremes such as very hot or cold
conditions
• Dosage should be reduce for patient with renal impairment
• Increase in QT (QTc) interval
• Orthostatic hypotension, tachycardia, somnolence, akathisia, dystonia,
EPS, and parkinsonism.
OLANZAPINE (ZYPREXA)
Indications:
• treatment of schizophrenia
• Acute treatment of manic or mixed episodes associated with
bipolar I disorder and maintenance treatment of bipolar I disorder
(Monotherapy)
• manic or mixed episodes associated with bipolar I disorder
(Adjunct Lithium/Valproate)
• Depressive episodes associated with bipolar I disorder
(Olanzapine+Fluoxetine (Symbyax))
Pharmacology:
• 85% absorbed from GI tract, 40% of the dosage is inactivated by
first-pass hepatic metabolism
• Peak concentrations= 5 hours
• Half life= averages 31 hours (range 21-54 hours)
OLANZAPINE (ZYPREXA)
Pharmacology:
• 5-HT 2A and D2 antagonism
• an antagonist of Di, D4, 5-HT1A, M1-M5, and H1 receptors.
Dosage:
• available in 2.5, 5, 7.5, 10, 15, and 20 mg oral Zydis form
(orally disintegrating) tablets.
• initial dosage for treatment of psychosis is 5-10 mg, and for
treatment of acute mania is 10-15 mg given once daily.
• higher dosages are associated with increased EPS and other
adverse effects, and dosages >20 mg/day were not studied in
the pivotal trials that led to the approval of olanzapine
OLANZAPINE (ZYPREXA)
• Parenteral form for acute agitation associated with
schizophrenia and bipolar disorder and IM dosage (10 mg).
• Coadministration with benzodiazepines is not approved.
Drug Interactions
• Fluvoxamine (Luvox) and cimetidine (Tagamet) INCREASE
concentration
• Carbamazepine and phenytoin DECREASE serum
concentrations
• Ethanol increases olanzapine absorption by >25%, leading to
increased sedation
Side Effects
• weight gain
• Somnolence, dry mouth, dizziness, constipation, dyspepsia,
increased appetite, akathisia, and tremor
QUETIAPINE (SEROQUEL)

Indications:
• treatment of schizophrenia, as well as acute treatment of
manic episodes associated with bipolar I disorder
(Monotherapy)
Pharmacology:
• dibenzothiazepine
• rapidly absorbed from the GI tract
• peak plasma concentrations= 1-2 hours
• half-life= 7 hours (optimal dosing 2X-3X/day)
• antagonist of D2 and 5-HT2, also blocks 5-HT6, D1 and Hi,
and 1 and 2 receptors.
• Does not block muscarinic or benzodiazepine receptors
QUETIAPINE (SEROQUEL)
Drug Interaction:
• Phenytoin increases quetiapine clearance fivefold
• Avoid use with drugs that increase QT interval and in patients
with risk factors for prolonged QT interval.
1) history of cardiac arrhythmias such as bradycardia;
2) hypokalemia or hypomagnesemia;
3) concomitant use of other drugs that prolong QTc interval;
4) presence of congenital prolongation of QT interval.
Side Effects
• Somnolence, postural hypotension, and dizziness
• Modest transient weight gain
• Small increases in heart rate, constipation, and transient increase
in liver transaminases
ZIPRASIDONE (GEODON)
Indications:
• Schizophrenia
• acute treatment of manic or mixed episodes associated with
bipolar I disorder (monotherapy)
• maintenance treatment of bipolar I disorder (adjunct to
lithium/valproate)
Pharmacology:
• benzisothiazole piperazine
• Peak plasma concentrations= 2-6 hours
• Steadystate levels from 5-10 hours are reached between the
first and the third days of treatment
• twice-daily dosing is necessary
ZIPRASIDONE (GEODON)
• Bioavailability doubles when taken with food
• Peak serum concentrations of IM= 1 hour
• half -life of 2-5 hours
• blocks 5-HT2A and D2 receptors
• antagonist of 5-HT1n, 5-HT2c, D3, D4, and H1 receptors
• has very low affinity for Di, Mi, and 2 receptor
• agonist activity at the serotonin 5-HT IA receptors and an SSRI
and a norepinephrine reuptake inhibitors
Dosages:
• Oral dosing should be initiated at 40 mg/day divided into two daily
doses.
• IM dosage is 10-20 mg every 2 hours for the 10 mg dose and
every 4 hours for the 40 mg dose.
ZIPRASIDONE (GEODON)

Side Effects
• Somnolence, headache, dizziness,
nausea, and lightheadedness
• Concerns about prolongation of
QTc complex have deterred some
clinicians from this as first choice.
• Should be avoided in patients with
congenital long QT syndrome and
those with history of cardiac
arrhythmias.
CLOZAPINE (CLOZARIL)
Indications:
• benefit patients with severe tardive dyskinesia. Other clinical
situations in which clozapine may be
• treatment of psychotic patients who are intolerant of EPS
• treatment-resistant disorders
Pharmacology
• Dibenzothiazepine
• rapidly absorbed, peak plasma levels reached in 2 hours
• Steady state achieved <1 week if twice daily dosing is used.
• half -life is 12 hours
• occupy 40-50% striatal D2 receptors - this is probably why
clozapine does not cause EPS
CLOZAPINE (CLOZARIL)
Dosage:
• The initial dose is 25 mg one or two times daily.
• Conservative initial dosage is 12.5 mg twice daily.
Drug Interactions
• Should not be used with any other drug associated with
agranulocytosis or bone marrow suppression.
• Lithium with clozapine may increase risk of seizures, confusion,
and movement disorders.
• Clomipramine (Anafranil) can increase risk of seizure by
lowering the seizure threshold and by increasing plasma
concentrations.
• Paroxetine may precipitate clozapine-associated neutropenia.
CLOZAPINE (CLOZARIL)
Side Effects
• Most Common: sedation, dizziness, syncope, tachycardia,
hypotension, ECG changes, nausea, and vomiting
• Others: fatigue, weight gain, constipation, anticholinergic
effects, and subjective muscle weakness
• Sialorrhea or hypersalivation - S/E that begins early in
treatment and is most evident at night.
• Impairment of swallowing
Contraindications
• WBC count <3,500 cells/mm3
• previous bone marrow disorder
• history of agranulocytosis during clozapine treatment
• use of another drug known to suppress the bone marrow
ARIPIPRAZOLE (ABILIFY)
Indications
• Schizophrenia and acute mania
• Augmentation of antidepressant agents in MDD
• Maintenance treatment of manic and mixed episodes
associated with bipolar I disorder
• Adjunctive therapy to either lithium or valproate
• Treatment of irritability associated with autistic disorder
• Oppositional defiant disorder or conduct disorder
• D2 antagonist, but can also act as a partial D2 agonist
• Partial D2 agonists compete at D2 receptors for endogenous
dopamine, thereby producing a functional reduction of
dopamine activity.
ARIPIPRAZOLE (ABILIFY)
Pharmacology
• well absorbed, peak plasma concentrations after 3-5 hours
• Absorption not affected by food.
• half-life of is 75 hours (once-daily dosing)
• exhibits linear pharmacokinetics and is primarily metabolized by
CYP3A4 and CYP2D6 enzymes
• 99% protein bound
• excreted in breast milk in lactating rats
• acts as a modulator, rather than a blocker, and acts on both
postsynaptic D2 receptors and presynaptic autoreceptors
• 1-adrenergic receptor antagonist, may cause some patients to
experience orthostatic hypotension
• 5-HT 2A antagonist
ARIPIPRAZOLE (ABILIFY)
Drug Interactions
• Carbamazepine and valproate reduce serum concentrations;
ketoconazole, fluoxetine, paroxetine, and quinidine increase
aripiprazole serum concentrations.
• Lithium and valproic acid do not affect the steady-state
concentrations of aripiprazole.
• Combined use with antihypertensives may cause hypotension.
• Drugs that inhibit CYP2D6 activity reduce aripiprazole
elimination.
Dosage and Clinical Guidelines
• Effective dosage range 10-30 mg/day.
• Clinicians find that an initial dose of 5 mg increases tolerability.
ARIPIPRAZOLE (ABILIFY)
Side effects
• Most common: headache, somnolence, agitation, dyspepsia,
anxiety, nausea
• Can cause akathisia-like activation
• Insomnia
• Data so far do not indicate that weight gain or diabetes mellitus
have an increased incidence with aripiprazole.
• Does not cause significant QTc interval changes
• Reports of seizures
REFERENCE
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