Download Important side effects to be considered when choosing antipsychotic

Neuroleptics
prof Dr Elham Aljammas
2016
Antipsychotics used to treat schizophrenia.
 Schizophrenia is a severe chronic disorder
 Positive symptoms: hallucinations, and delusions
 Negative symptoms: amotivation, poverty of speech, flat affect
 Disorganized symptoms: speech, thought, and behavior
 Now being used to treat Bipolar as well
Antipsychotics
 Indications for use:
 schizophrenia, schizoaffective disorder, bipoalar disorder- for mood stabilization
and/or when psychotic features are present, delirium,
 psychotic depression,
 dementia,
 trichotillomania, augmenting agent in treatment resistant anxiety disorders.
Pathways affected by DA in the Brain
Antagonize dopamine – block a specific
receptor
Atypical
Typical
Chlorpromazine Risperdal Trifluperazine Risperidone
Olanzepine - Zyprexia
Thorazine
Quetiapine - Seroquel
Haloperidol – Ziprasidone –
(Haldol)
Geodon
Aripiprazole – Abilify
Paliperidone – Invega
The Atypical Antipsychotics
atypical agents are serotonindopamine 2 antagonists (SDAs)
They are considered atypical in
the way they affect dopamine and
serotonin neurotransmission in
the four key dopamine pathways
in the brain.
-
Antipsychot
ics drugs
(typical)
group
drug
Usual dose
phenothiazines
chlorpromazine
100-1500mg daily
butyrophenones
haloperidol
5-30mg daily
50-100mg IMI
monthly
5mg IMI orIVI on
need
thioxanthenes
flupentixol
40-200mg
fortnight
Short & long
acting
Diphenylbutylpiperidines Pimozide
Trifluperazine
stelazine
Substituated benzamides Sulpiride
4-30mg daily
1,5,10mg orally
600-1800mg daily
Neuroleptics
. The traditional or typicalneuroleptic drugs (also called conventional
or first-generation antipsychotics) are competitive inhibitors at a
variety of receptors, but their antipsychotic effects reflect
competitive blocking of dopamine receptors. These drugs vary in
potency. For example, chlorpromazine is a low-potency drug, and
fluphenazine is a high-potency agent No one drug is clinically
more effective than another.
Atypical group
antipsych dibenzodiazepine
otic agent
Bezisoxazole
Quetiapine -
drugs
clozapine
Usual dose
25-900mg
daily
Risperidone
Seroquel
2-16mg daily
100-200mg/d
thienobenzodiazepi olanzapine
ne
5-20mg daily
Atypical
atypical agents are serotonindopamine 2 antagonists (SDAs)
They are considered atypical in
the way they affect dopamine and
serotonin neurotransmission in the
four key dopamine pathways in the
brain.
Mechanism of action
 Dopamine receptor blocking activity in the brain:. D1 and D5 receptors activate adenylyl
cyclase, often exciting neurons, whereas D2, D3 and D4 receptors inhibit adenylyl
cyclase, or mediate membrane K+ channel opening leading to neuronal
hyperpolarization. The neuroleptic drugs bind to these receptors to varying degrees.
However, the clinical efficacy of the typical neuroleptic drugs correlates closely
with their relative ability to block D2 receptors in the mesolimbic system of the
brain. atypical drug clozapine has higher affinity for the D4 receptor and lower
affinity for the D2 receptor, which may partially explain its minimal ability to
cause extrapyramidal side effects (EPS).
 Serotonin receptor blocking activity in the brain: Most of the newer atypical agents
appear to exert part of their unique action through inhibition of serotonin receptors (5HT), particularly 5-HT2A receptors. (clozapine ,olanzapine,aripiprazole , Quetiapine ).
however, are often a result of actions at these
other receptors.
 Antipsychotic actions: All of the neuroleptic drugs can reduce the
hallucinations and delusions associated with schizophrenia
by blocking dopamine receptors in the mesolimbic system of the
brain. The antipsychotic effects usually take several days to
weeks to occur, suggesting that the therapeutic effects are related
to secondary changes in the corticostriatal pathways.

 Extrapyramidal effects: Dystonias (sustained contraction of
muscles leading to twisting distorted postures), parkinson-like
symptoms, akathisia (motor restlessness), and tardive dyskinesia
(involuntary movements of the tongue, lips, neck, trunk, and
limbs) occur with chronic treatment. Blocking of dopamine
receptors in the nigrostriatal pathway probably causes these
unwanted movement symptoms. The atypical neuroleptics exhibit
a lower incidence of these symptoms.
 Antiemetic effects: With the exceptions of aripiprazole and
thioridazine , most of the neuroleptic drugs have antiemetic
effects that are mediated by blocking D2-dopaminergic receptors
of the chemoreceptor trigger zone of the medulla.
 Antimuscarinic effects: Some of the neuroleptics, particularly
thioridazine, chlorpromazine, clozapine, and olanzapine
,produce anticholinergic effects, including
blurred vision dry mouth (exception: clozapine increase
salivation), confusion, and inhibition of gastrointestinal and
urinary tract smooth muscle, leading to constipation and urinary
retention. This anticholinergic property may actually assist in
reducing the risk of EPS with these agents.
Important side effects to be
considered when choosing
antipsychotic drugs
 1-Extrapyramidial side effects:
 Atypical antipsychotic has less extrapyramidal effect.
Lead to menstrual
disturbances,increased risk of malignancy,increased
galactorrhea,& increased osteoporosis.
Prolactine sparingis aripiprazole
2-hyperprolactinaemia:
 3-sedationIncreased sedation with high affinity to histamine& muscarinic
receptors
CPZ,olanzapine,clozapine
Helpful in acute state
4-weight gain:
Histamine & 5HT R block
(>olanzapine)less with resperidone,amisulpride,&aripipraz 5.Type 11 DM
>clozapine &olanzapine
Should be monitored by Bd sugar,lipid profile& weight.
6-CV& cerbrovascular events ,
through their effect on the
lipid profile ,Wt,& insulin
resistance. Some produce prolonge QT interval.
olanzapine& resperidone
7-postural hypotension
 8-sexual dysfunction
 9-photosensitivity
10-agranulocytosis
11-constipation
12-reduction of fit threshold
 Other effects: Blockade of -adrenergic receptors causes
orthostatic hypotension and light-headedness. The neuroleptics
also alter temperature-regulating mechanisms and can produce
poikilothermia (body temperature varies with the environment).
In the pituitary, neuroleptics block D2 receptors, leading to an
increase in prolactin release. Atypical neuroleptics are less likely
to produce prolactin elevations. Sedation occurs with those
drugs that are potent antagonists of the H1-histamine receptor,
including chlorpromazine, olanzapine, quetiapine, and
clozapine. Sexual dysfunction may also occur with the
antipsychotics due to various receptor-binding characteristics.
Therapeutic uses
 Treatment of schizophrenia:
 The neuroleptics are considered to be the only efficacious
treatment for schizophrenia.
 Prevention of severe nausea and vomiting: The older neuroleptics
(most commonly prochlorperazine) are useful in the treatment of
drug-induced nausea

 Other uses: The neuroleptic drugs can be used as tranquilizers to
manage agitated and disruptive behavior secondary to other
disorders.
 Neuroleptics are used in combination with narcotic analgesics for
treatment of chronic pain with severe anxiety
 . Chlorpromazine is used to treat intractable hiccups.
 Promethazine, this agent is used in treating pruritus .
 Pimozide is primarily indicated for treatment of the motor and phonic tics of
Tourette's disorder. risperidone and haloperidol are also commonly prescribed for
this tic disorder.
 Also, risperidone is now approved for the management of disruptive behavior and
irritability secondary to autism
Antipsychotic adverse effect
 Tardive Dyskinesia (TD)-involuntary muscle movements that may not resolve with
drug discontinuation- risk approx. 5% per year
 Neuroleptic Malignant Syndrome (NMS): Characterized by severe muscle rigidity,
fever, altered mental status, autonomic instability, elevated WBC, CPK and lfts.
Potentially fatal.
 Extrapyramidal side effects (EPS): Acute dystonia, Parkinson syndrome, Akathisia
Adverse effects
. Parkinson-like symptoms of
bradykinesia, rigidity, and tremor
usually occur within weeks to months
of initiating treatment. Clozapine can
produce bone marrow suppression,
seizures, and cardiovascular side
effects. The risk of severe
agranulocytosis necessitates
frequent monitoring of white-bloodcell counts
. The neuroleptics depress the
hypothalamus, affecting
thermoregulation, and causing
amenorrhea, galactorrhea,
gynecomastia, infertility, and
impotence. Significant weight gain is
often a reason for noncompliance. It
is also recommended that glucose
and lipid profiles be monitored in
patients taking antipsychotics
The choice of medication &dose
depend on :
 1-sevirety of the problems.
 2-degree of sedation required.
 3-side effect profile.
 4-preferance of individual clinician.
Study Questions
 Choose the ONE best answer.
 13.1 An adolescent male is newly diagnosed with schizophrenia. Which of the
following neuroleptic agents may improve his apathy and blunted affect?
 A. Chlorpromazine.
 B. Fluphenazine.
 C. Haloperidol.
 D. Risperidone.
 E. Thioridazine
Correct answer = D. Risperidone is the only neuroleptic on the list that has
some benefit in improving the negative symptoms of schizophrenia. All the
agents have the potential to diminish the hallucinations and delusional
thought processes.
 Which one of the following neuroleptics has been shown to be
a partial agonist at the D2 receptor?
 A. Aripiprazole.
 B. Clozapine.
 C. Haloperidol.
 D. Risperidone.
 E. Thioridazine.
 Correct answer = A. Aripiprazole is the agent that acts as a partial agonist at
D2 receptors. Theoretically, the drug would enhance action at these receptors
when there is a low concentration of dopamine and would block the actions
of high concentrations of dopamine. All the other drugs are only antagonistic
at D2 receptors, with haloperidol being particularly potent.
 A 21-year-old male has recently begun pimozide therapy for
Tourette's disorder. He is brought to the emergency department
by his parents. They describe that he has been having
“different-appearing tics―than before, such as prolonged
contraction of the facial muscles. While being examined, he
experiences opisthotonus (spasm of the body where the head
and heels are bent backward and the body is bowed forward. A
type of extrapyramidal effect). Which of the following drugs would
be beneficial in reducing these symptoms?
 A. Benztropine.
 B. Bromocriptine.
 C. Lithium.
 D. Prochlorperazine.
 E. Risperidone
Correct answer = A. The patient is experiencing
extrapyramidal symptoms due to pimozide, and a
muscarinic antagonist such as benztropine would be
effective in reducing the symptoms. The other drugs
would have no effect or, in the case of prochlorperazine,
might increase the symptoms.
 A 28-year-old woman with schizoid affective disorder and
difficulty sleeping would be most benefited by which of the
following drugs?
 A. Aripiprazole.
 B. Chlorpromazine.
 C. Haloperidol.
 D. Risperidone.
 E. Ziprasidone.
Correct answer = B. Chlorpromazine has significant sedative activity as well as
antipsychotic properties. Of the choices, it is the drug most likely to alleviate
this patient's major complaints, including her insomnia
Anxiolytic
Prof. Dr Elham Aljammas
Anxiolytic
 Treat anxiety disorders
 Generalized Anxiety Disorder
 Panic Disorder
 PTSD
 OCD
 Social Anxiety Disorder (SAD)
Anxiolytic
 Used to treat many diagnoses including panic disorder,
 generalized Anxiety disorder,
 substance-related disorders and their withdrawal,
 insomnias and parasomnias.
In anxiety disorders often use anxiolytics in combination with SSRIS or SNRIs for
treatment.
Benzodiazepines
 Used to treat insomnia, parasomnias and anxiety disorders.
 Often used for CNS depressant withdrawal protocols ex. ETOH withdrawal.
 Side effects/cons
 Somnolence
 Cognitive deficits
 Amnesia
 Disinhibition
 Tolerance
 Dependence
Dose Equivalency
(mg)
Drug
Alprazolam (Xanax)
0.5
Peak Blood
Level
(hours)
Elimination HalfLife1 (hours)
1-2
12-15
Rapid oral absorption
2-4
15-40
Active metabolites; erratic
bioavailability from IM
injection
1-4
18-50
Can have layering effect
1-2
20-80
Active metabolites; erratic
bioavailability from IM
injection
1-2
40-100
Active metabolites with long
half-lives
1-6
10-20
No active metabolites
2-4
10-20
No active metabolites
2-3
10-40
Slow oral absorption
Comments
10.0
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
0.25
5.0
Diazepam (Valium)
30.0
Flurazepam (Dalmane)
Lorazepam (Ativan)
Oxazepam (Serax)
Temazepam (Restoril)
1.0
15.0
30.0
0.25
Triazolam (Halcion)
1
2-3
Rapid onset; short duration of
action
Monitor for efficacy and tolerance and
adjust as indicated.
If the patient does not improve step back,
rethink your diagnosis and treatment plan!
Keep an eye on drug-drug interactions
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Benzodiazepines
Facilitate GABA neurotransmission
Bind to a particular site on the GABA receptor
Xanax, Ativan, Valium, Serax, Librium
Beta-Blockers
Antagonize NE by blocking Beta receptor subtype
SSRIs
PTSD, OCD, SAD, and to some degree GAD
Others
Buspar
Non-sedating
Does not interact with alcohol
Not highly effective
ADD
 Methylphenidate – Ritalin
 DA reuptake inhibitor
 So slowly it enters the brain that it is not addictive like cocaine even though they have
the same mechanism
 Concerta (Immediate release combined with time release)
 Adderal (mixed amphetamine salts)
 Has extended release
 Modafinil – Provigil
 Vyvanse
 An amphetamine pro-drug
 Less abusable
 Straterra
Mixing Med.
 Although classified as a certain type of drug most psych meds used for many
different disorders.
 Antipsychotics in Bipolar Disorder
 Abilify
 Zyprexa
 Mood stabilizers in alcoholism
 Topiramate
 Prescribing a medication for a disorder when it is known to work, but there is no
formal FDA indication is called “off-label prescribing”
 It’s perfectly legal and quite common
Thank You