Transcript antipsychotics- - Department of Psychiatric Nursing

DRUG TREATMENT OF
PSYCHOSIS
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Psychosis
Psychosis is a thought disorder characterized
by disturbances of reality and perception,
impaired cognitive functioning, and
inappropriate or diminished affect (mood).
Psychosis denotes many mental disorders.
Schizophrenia is a particular kind of psychosis
characterized mainly by a clear sensorium but a
marked
thinking disturbance.
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Psychosis Producing Drugs
1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine
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Schizophrenia
• Pathogenesis is unknown.
• Onset of schizophrenia is in the late teens early
twenties.
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• Afflicts 1% of the population worldwide.
• May or may not be present with anatomical
changes.
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Schizophrenia
• It is a thought disorder.
• The disorder is characterized by a divorcement
from reality in the mind of the person
(psychosis).
• It may involved visual and auditory
hallucinations, delusions, intense suspicion,
feelings of persecution or control by external
forces (paranoia), depersonalization, and there is
attachment of excessive personal significance to
daily events, called
“ideas of reference”.
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Schizophrenia
Positive Symptoms.
Hallucinations, delusions, paranoia, ideas of reference.
Negative Symptoms.
Apathy, social withdrawal, anhedonia, emotional blunting,
cognitive deficits, extreme inattentiveness or lack of
motivation to interact with the environment.
These symptoms are progressive and non-responsive to medication.
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Etiology of Schizophrenia
Idiopathic
Biological Correlates
1) Genetic Factors
2) Neurodevelopmental abnormalities.
3) Environmental stressors.
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Etiology of Schizophrenia
Schizophrenia is not characterized by any
reproducible neurochemical abnormality.
However, structural and functional
abnormalities have been observed in the
brains of schizophrenic patients:
1) Enlarge cerebral ventricles.
2) Atrophy of cortical layers.
3) Reduced volume of the basal ganglia.
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Dopamine Theory of Schizophrenia
Many lines of evidence point to the
aberrant increased activity of the
dopaminergic system as being critical in
the symptomatology of schizophrenia.
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Dopamine Theory of Schizophrenia
Dopamine Correlates:
• Antipsychotics reduce dopamine synaptic activity.
• These drugs produce Parkinson-like symptoms.
• Drugs that increase DA in the limbic system cause
psychosis.
• Drugs that reduce DA in the limbic system
(postsynaptic D2 antagonists) reduce psychosis.
• Increased DA receptor density (Post-mortem, PET).
• Changes in amount of homovanillic acid (HVA), a
DA metabolite, in plasma, urine, and CSF.
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Pharmacodynamics
Anatomic Correlates of Schizophrenia...
Areas Associated with Mood and Thought Processes:
Frontal cortex
Amygdala
Hippocampus
Nucleus accumbens
Limbic Cortex
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DA
DA
DA
DA
DA
Dopamine Theory of Schizophrenia
Evidence against the hypothesis
• Antipsychotics are only partially effective in most
(70%) and ineffective for some patients.
• Phencyclidine, an NMDA receptor antagonist,
produces more schizophrenia-like symptoms in nonschizophrenic subjects than DA agonists.
• Atypical antipsychotics have low affinity for D2
receptors.
• Focus is broader now and research is geared to
produce drugs with
less extrapyramidal effects.
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Dopamine System
There are four major pathways for the
dopaminergic system in the brain:
I.
II.
III.
IV.
The Nigro-Stiatal Pathway.
The Mesolimbic Pathway.
The Mesocortical Pathway.
The Tuberoinfundibular Pathway.
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THE DOPAMINERGIC SYSTEM
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Catecholamines
Tyrosine
 Tyrosine hydroxylase
L-Dopa
 Dopa decarboxylase
Dopamine (DA)
 Dopamine  hydroxylase
Norepinephrine (NE)
(Noradrenaline)
Phenylethanolamine-

-N-methyltransferase
Epinephrine (EPI)
(Adrenaline)
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Tyrosine
Tyrosine
L-DOPA
DA
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Dopamine Synapse
Dopamine System
•
DOPAMINE RECEPTORS
There are at least five subtypes of receptors:
Receptor
D1
D2
D3
D4
D5
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Dopamine System
•
DOPAMINE RECEPTORS
Receptor
D1
D2
D3
D4
D5
2o Messenger System
cAMP
cAMP,K+ ch.,Ca2+ch.
cAMP,K+ ch.,Ca2+ch.
cAMP
cAMP
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Dopamine Reuptake System
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Antipsychotic treatments
SCHIZOPHRENIA IS FOR LIFE
There is no remission
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Antipsychotic treatments
Schizophrenia has been around perhaps, since the
beginning of humankind, however, it was not until
the last century that it was established as a separate
entity amongst other mental disorders.
Many treatments have been devise:

Hydrotherapy:
“The pouring of cold water in a stream, from a height of
at least four feet onto the forehead, is one of the most
certain means of subsiding violent, maniacal excitement
that we have ever seen tried”... wrote an anonymous
physician in the
early 1800’s.
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Antipsychotic treatments

Lobotomies (Egaz Moniz received the Nobel Prize).

In 1940’s Phenothiazenes were isolated and were
used as pre-anesthetic medication, but quickly were
adopted by psychiatrists to calm down their mental
patients.

In 1955, chlorpromazine was developed as an
antihistaminic agent by Rhône-Pauline Laboratories
in France. In-patients at Mental Hospitals dropped
by 1/3.
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Antipsychotics treatment
Antipsychotics/Neuroleptics
•
•
Antipsychotics are the drugs currently used in
the prevention of psychosis.
They have also been termed neuroleptics,
because they suppress motor activity and
emotionality.
** These drugs are not a cure **
•
Schizophrenics must be treated with
medications indefinitely, in as much as the
disease in lifelong and it is preferable to
prevent the psychotic episodes than to treat
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Antipsychotics/Neuroleptics
Although the antipsychotic/neuroleptics are drugs
used mainly in the treatment of schizophrenia,
they are also used in the treatment of other
psychoses associated with depression and
manic-depressive illness, and psychosis
associated with Alzheimer’s disease. These
conditions are life-long and disabling.
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Antipsychotics/Neuroleptics
NON-compliance is the major reason for relapse.
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Antipsychotic/Neuroleptics
OLDER DRUGS
Three major groups :
1) Phenothiazines
2) Thioxanthines
3) Butyrophenones
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Antipsychotics/Neuroleptics
Tyrosine
Tyrosine
Dopamine Synapse
L-DOPA
DA
dopamine
receptor
antagonist
D2
• Old antiphsychotics
/neuroleptics are D2
dopamine receptor
antagonists.
Although they are
also effective
antagonists at ACh,
5-HT, NE receptors.
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Antipsychotics/Neuroleptics
•
It appears that the specific interaction of
antipsychotic drugs with D2 receptors is
important to their therapeutic action.
•
The affinities of most older “classical” agents
for the D2 receptors correlate with their
clinical potencies as antipsychotics.
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Antipsychotic/Neuroleptics
Correlations between therapeutic potency and
affinity for binding D2 receptors.
promazine
chlorpromazine
clozapine
thiothixene
haloperidol
spiroperidole
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Clinical
dosee.com
of drug [mg d ]
Antipsychotics/Neuroleptics
•
Both D1 and D2 receptors are found in high
concentrations in the striatum and the nucleus
accumbens.
•
Clozapine has a higher affinity for the D4 receptors
than for D2.
•
Recently it has been found that most antipsychotic
drugs may also bind D3 receptors (therefore, they
are non-selective).
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Antipsychotics/Neuroleptics
•
Antipsychotics produce catalepsy (reduce motor
activity).
–
•
BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
Antipsychotics reverse hyperkinetic behaviors
(increased locomotion and stereotyped behavior).
–
•
BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
Antipsychotics prevent the dopamine inhibition of
prolactin release from pituitary.
–
BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
 hyperprolactinemia
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Pharmacokinetics
Absorption and Distribution
• Most antipsychotics are readily but incompletely
absorbed.
• Significant first-pass metabolism.
• Bioavailability is 25-65%.
• Most are highly lipid soluble.
• Most are highly protein bound (92-98%).
• High volumes of distribution (>7 L/Kg).
• Slow elimination.
**Duration of action longer than expected, metabolites are present
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and relapse occurs, weeks aftere.com
discontinuation of drug.**
Pharmacokinetics
Metabolism
• Most antipsychotics are almost completely
metabolized.
• Most have active metabolites, although not
important in therapeutic effect, with one exception.
The metabolite of thioridazine, mesoridazine, is
more potent than the parent compound and
accounts for most of the therapeutic effect.
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Pharmacokinetics
Excretion
• Antipsychotics are almost completely metabolized
and thus, very little is eliminated unchanged.
• Elimination half-lives are 10-24 hrs.
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Antipsychotic/Neuroleptics
1)
Phenothiazines
• Aliphatic
Chlorpromazine
Trifluopromazine
Piperidine
Thioridazine
Piperacetazine
Mesoridazine
Piperazine*
Fluphenazine
Perfenazine
Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
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* Most likely to cause
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extrapyramidal effects.
Antipsychotic/Neuroleptics
Piperazine
Piperidine
Aliphatic
[Drug dose]
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Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene
Closely related to phenothiazines
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Antipsychotic/Neuroleptics
3) Butyrophenones
Haloperidol
Droperidol*
*Not marketed in the USA
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Antipsychotic/Neuroleptics
Butyrophenone d.
Phenothiazine d.
Thioxanthene d.
[Drug dose]
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Antipsychotics/Neuroleptics
•
Newer drugs have higher affinities for D1, 5HT or -AR receptors.
•
NE, GABA, Glycine and Glutamate have
also been implicated in schizophrenia.
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Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why
their therapeutic effects are not evident until 4-8
weeks of treatment.
Blockade of D2 receptors

Short term/Compensatory effects:

Firing rate and activity of nigrostriatal and
mesolimbic DA neurons.

DA synthesis, DA metabolism, DA release
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Antipsychotics/Neuroleptics
Presynaptic Effects
Blockade of D2 receptors

Compensatory Effects


Firing rate and activity of nigrostriatal and mesolimbic DA
neurons.
DA synthesis, DA metabolism, DA release.
Postsynaptic Effects
Depolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.

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Receptor
Supersensitivity
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Antipsychotic/Neuroleptics
Newer Drugs
Pimozide
Molindone
Loxapine
Clozapine
Olanzapine
Qetiapine
Risperidone
Sertindole
Ziprasidone
Olindone
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Antipsychotic/Neuroleptics
Drug
Chlorpromaz.
Haloperidol
Thiothixene
Clozapine
Ziprasidone
Risperidone
Olanzapine
Sertindole
Clinical
Potency
Low
High
High
Medium
Medium
High
High
High
Ex. Py.
toxicity
Sedation
Hypote.
Medium
Very High
Medium
Very low
Very Low
Low
Very Low
Very Low
Medium
Very High
Medium
Low
Low
Low
Medium
Very low
High
Low
Medium
Medium
Very low
Low
Very low
Very Low
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Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2
Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 >H1>M = 2
Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1 = 2 ; H1
Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1
Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1
Sertindole: 5-HT2 > D2 = 1
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Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1)
2)
Failure to control negative effect
Significant toxicity
a)
b)
c)
d)
e)
3)
Parkinson-like symptoms
Tardive Dyskinesia (10-30%)
Autonomic effects
Endocrine effects
Cardiac effects
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Poor Concentration
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The Nigro-Striatal Pathway
DA
neuron
Striatum
ACh
neuron
+
Substantia
Nigra
GABA
- neuron
-
Inhibition
of
Motor Activity
-
GABA
neuron
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Antipsychotic/Neuroleptics

Some antipsychotics have effects at
muscarinic acetylcholine receptors:
•
•
•
•
dry mouth
blurred vision
urinary retention
constipation
Clozapine
Chlorpromazine
Thioridazine
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Antipsychotic/Neuroleptics
Some antipsychotics have effects at adrenergic receptors:

•
orthostatic hypotension
Chlorpromazine
Thioridazine

Some antipsychotics have effects at H1histaminergic receptors:
•
sedation
Risperidone
Haloperidol
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Antipsychotic/Neuroleptics

Blockade of D2 receptors in lactotrophs
in breast increase prolactin concentration
and may produce breast engorgement
and galactorrhea.
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Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Is a rare but serious side effect of neuroleptic
(antipsychotic) therapy that can be lethal. It
can arise at any time in the course of treatment
and shows no predilection for age, duration of
treatment, antipsychotic medication, or dose.
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Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
•
•
•
•
•
•
Occurs in pts. hypersensitive to the Ex.Py. effects of
antipsychotics.
Due to excessively rapid blockade of postsynaptic
dopamine receptors.
The syndrome begins with marked muscle rigidity.
If sweating is impaired, a fever may ensue. The
stress leukocytosis and high fever associated with this
syndrome may be mistaken for an infection.
Autonomic instability with altered blood pressure and
heart rate is another midbrain manifestation.
Creatine kinase isozymes are usually elevated,
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reflecting muscle
damage.
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Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Treatment
Vigorous treatment with antiparkinsonian drugs is
recommended as soon as possible.
Muscle relaxants such as diazepam, dantrolene or
bromocriptine may be helpful.
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Antipsychotic/Neuroleptics
Drug Interactions
•
•
•
•
•
Additive effects with sedatives.
Additive effects with anticholinergics.
Additive effects with antihistaminergics.
Additive effects with -AR blocking drugs.
Additive effects with drugs with quinidine-like
action (thioridazine).
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