Antipsychotics Drug Treatmen

DRUG TREATMENT OF
PSYCHOSIS
Martha I. Dvila-Garca, Ph.D.
Howard University
Department of Pharmacology
Spring 2002
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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.
Psychosis Producing Drugs
1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine
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.
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.
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.
Etiology of Schizophrenia
I diopathic
Biological Correlates
1) Genetic Factors
2) Neurodevelopmental abnormalities.
3) Environmental stressors.
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.
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.
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.
Pharmacodynamics
Anatomic Correlates of Schizophrenia...
Frontal cortex
Amygdala
Hippocampus
Nucleus accumbens
Limbic Cortex
Areas Associated with Mood and Thought Processes:
DA
DA
DA
DA
DA
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 non-
schizophrenic 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.
Dopamine System
There are four major pathways for the
dopaminergic system in the brain:
I. The Nigro-Stiatal Pathway.
II. The Mesolimbic Pathway.
III. The Mesocortical Pathway.
IV. The Tuberoinfundibular Pathway.
THE DOPAMINERGIC SYSTEM
Catecholamines
Tyrosine
Tyrosine hydroxylase
L-Dopa
Dopa decarboxylase
Dopamine (DA)
Dopamine hydroxylase
Norepinephrine (NE)
(Noradrenaline) Phenylethanolamine-
-N-methyltransferase
Epinephrine (EPI)
(Adrenaline)
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
Dopamine System
DOPAMINE RECEPTORS
There are at least five subtypes of receptors:
Receptor
D1
D2
D3
D4
D5
Dopamine System
DOPAMINE RECEPTORS
Receptor 2
o
Messenger System
D1 cAMP
D2 cAMP,K
+
ch.,Ca
2+
ch.
D3 cAMP,K
+
ch.,Ca
2+
ch.
D4 cAMP
D5 cAMP
Dopamine Reuptake System
Antipsychotic treatments
SCHIZOPHRENIA IS FOR LIFE
There is no remission
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:
v 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 1800s.
v Lobotomies (Egaz Moniz received the Nobel Prize).
v In 1940s Phenothiazenes were isolated and were
used as pre-anesthetic medication, but quickly were
adopted by psychiatrists to calm down their mental
patients.
v In 1955, chlorpromazine was developed as an
antihistaminic agent by Rhne-Pauline Laboratories
in France. In-patients at Mental Hospitals dropped
by 1/3.
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
them.
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 Alzheimers disease. These
conditions are life-long and disabling.
NON-compliance is the major reason for relapse.
Antipsychotic/Neuroleptics
Three major groups :
1) Phenothiazines
2) Thioxanthines
3) Butyrophenones
OLDER DRUGS
Old antiphsychotics
/neuroleptics are D
2
dopamine receptor
antagonists.
Although they are
also effective
antagonists at ACh,
5-HT, NE receptors.
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
dopamine
receptor
antagonist
D
2
It appears that the specific interaction of
antipsychotic drugs with D
2
receptors is
important to their therapeutic action.
The affinities of most older classical agents
for the D
2
receptors correlate with their
clinical potencies as antipsychotics.
Correlations between therapeutic potency and
affinity for binding D2 receptors.
[
3
H
]
H
a
l
o
p
e
r
i
d
o
l
b
i
n
d
i
n
g
I
C
5
0
(
m
o
l
/
L
)
Clinical dose of drug [mg d
-1
]
haloperidol
clozapine
thiothixene
chlorpromazine
promazine
spiroperidole
Both D1 and D2 receptors are found in high
concentrations in the striatum and the nucleus
accumbens.
Clozapine has a higher affinity for the D
4
receptors
than for D
2
.
Recently it has been found that most antipsychotic
drugs may also bind D
3
receptors (therefore, they
are non-selective).
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
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
and relapse occurs, weeks after 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.
Pharmacokinetics
Excretion
Antipsychotics are almost completely metabolized
and thus, very little is eliminated unchanged.
Elimination half-lives are 10-24 hrs.
1) Phenothiazines
Chlorpromazine Thioridazine Fluphenazine
Trifluopromazine Piperacetazine Perfenazine
Mesoridazine Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
Aliphatic Piperidine Piperazine*
* Most likely to cause extrapyramidal effects.
[Drug dose]
E
f
f
e
c
t
Piperazine
Aliphatic
Piperidine
2) Thioxanthines
Thiothixene
Chlorprothixene
Closely related to phenothiazines
3) Butyrophenones
Haloperidol
Droperidol*
*Not marketed in the USA
[Drug dose]
E
f
f
e
c
t
Phenothiazine d.
Thioxanthene d.
Butyrophenone d.
Newer drugs have higher affinities for D1, 5-
HT or -AR receptors.
NE, GABA, Glycine and Glutamate have
also been implicated in schizophrenia.
The acute effects of antipsychotics do not explain why
their therapeutic effects are not evident until 4-8
weeks of treatment.
Blockade of D
2
receptors
Short term/Compensatory effects:

Firing rate and activity of nigrostriatal and
mesolimbic DA neurons.
DA synthesis, DA metabolism, DA release
Presynaptic Effects
Blockade of D
2
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.
Receptor Supersensitivity
Pimozide
Molindone
Loxapine
Clozapine
Olanzapine
Qetiapine
Risperidone
Sertindole
Ziprasidone
Olindone
Newer Drugs
Clinical Ex. Py.
Drug Potency toxicity Sedation Hypote.
Chlorpromaz. Low Medium Medium High
Haloperidol High Very High Very High Low
Thiothixene High Medium Medium Medium
Clozapine Medium Very low Low Medium
Ziprasidone Medium Very Low Low Very low
Risperidone High Low Low Low
Olanzapine High Very Low Medium Very low
Sertindole High Very Low Very low Very Low
Chlorpromazine:
1
= 5-HT
2
= D
2
> D
1
> M>
2
Haloperidol: D
2
> D
1
= D
4
>
1
> 5-HT
2
>H
1
>M=
2
Clozapine: D
4
=
1
> 5-HT
2
= M> D
2
= D
1
=
2
; H
1
Quetiapine: 5-HT
2
= D
2
=
1
=
2
; H
1
Risperidone: 5-HT
2
>>
1
> H
1
> D
2
>
2
>> D
1
Sertindole: 5-HT
2
> D
2
=
1
Clinical Problems with antipsychotic drugs
include:
1) Failure to control negative effect
2) Significant toxicity
a) Parkinson-like symptoms
b) Tardive Dyskinesia (10-30%)
c) Autonomic effects
d) Endocrine effects
e) Cardiac effects
3) Poor Concentration
The Nigro-Striatal Pathway
Inhibition
of
Motor Activity
DA
neuron
ACh
neuron
GABA
neuron
GABA
neuron
Substantia
Nigra
+
-
-
-
-
Striatum
v Some antipsychotics have effects at
muscarinic acetylcholine receptors:
dry mouth
blurred vision
urinary retention
constipation
Clozapine
Chlorpromazine
Thioridazine
v Some antipsychotics have effects at
adrenergic receptors:
orthostatic hypotension
Chlorpromazine
Thioridazine
v Some antipsychotics have effects at H1-
histaminergic receptors:
sedation
Risperidone
Haloperidol
v Blockade of D2 receptors in lactotrophs
in breast increase prolactin concentration
and may produce breast engorgement
and galactorrhea.
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.
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,
reflecting muscle damage.
Treatment
Vigorous treatment with antiparkinsonian drugs is
recommended as soon as possible.
Muscle relaxants such as diazepam, dantrolene or
bromocriptine may be helpful.
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).
REFERENCES
1. Katzung, B.G. (2001) Basic and Clinical
Pharmacology, Chapter 29, 8
th
Ed. Lange. 478-
497pp.
2. Kandell, E.R. and Schwartz, J.H. (1981).
Principles of Neuroscience. Elsvier/North
Holland. N.Y.
3. Wingard et al., (1991) Human Pharmacology.
Molecular to Clinical. Mosby Year Book.

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