DRUG TREATMENT OF PSYCHOSIS презентация

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Слайд 1DRUG TREATMENT OF PSYCHOSIS

Слайд 2Psychiatric Nosology (Classification of disease)
Psychosis
Cognitive disorders: confusion, disorientation, memory disturbances and behavioral

disorganization (delirium and dementia)
Mood disorders
Anxiety disorders
Personality disorders

Слайд 3Psychosis
Psychosis is a thought disorder characterized by :
Disturbances of reality and

perception
Impaired cognitive functioning
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.

Слайд 4Schizophrenia
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.

Слайд 5Schizophrenia
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”.


Слайд 6Schizophrenia
Positive Symptoms.
Hallucinations, delusions, paranoia, ideas of reference.

Negative Symptoms.
Apathy, social

withdrawal, anhedonia (Loss of the capacity to experience pleasure), emotional blunting, cognitive deficits, extreme inattentiveness or lack of motivation to interact with the environment.
These symptoms are progressive and non-responsive to medication.

Слайд 8Etiology of Schizophrenia
Idiopathic

Biological Correlates
Genetic Factors
Neurodevelopmental abnormalities.
Environmental stressors.

Слайд 9Psychosis Producing Drugs
Levodopa
CNS stimulants
Cocaine
Amphetamines
Khat, cathinone, methcathinone
Apomorphine
Phencyclidine

Слайд 10Etiology 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:

Enlarge cerebral ventricles.
Atrophy of cortical layers.
Reduced volume of the basal ganglia.

Слайд 11Dopamine 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.

Слайд 12Dopamine 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.

Слайд 13Pharmacodynamics
Anatomic Correlates of Schizophrenia...
Frontal cortex
Amygdala
Hippocampus
Nucleus accumbens
Limbic Cortex
Areas Associated with Mood and

Thought Processes:

DA
DA
DA
DA
DA

Слайд 14Dopamine 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 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.

Слайд 15Dopamine System
There are four major pathways for the dopaminergic system in

the brain:

The Nigro-Stiatal Pathway: Voluntary movements
The Mesolimbic Pathway.: Behaviour
The Mesocortical Pathway: Behaviour
The Tuberoinfundibular Pathway: Prolactin release

Слайд 16THE DOPAMINERGIC SYSTEM










THE DOPAMINERGIC SYSTEM

Слайд 17Catecholamines
Tyrosine
⇓ Tyrosine hydroxylase
L-Dopa
⇓ Dopa decarboxylase
Dopamine (DA)
⇓ Dopamine β

hydroxylase
Norepinephrine (NE)
(Noradrenaline) Phenylethanolamine-
⇓ -N-methyltransferase
Epinephrine (EPI)
(Adrenaline)

Слайд 18
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine














Слайд 19Dopamine System
DOPAMINE RECEPTORS

There are at least five subtypes of receptors:
Receptor
D1
D2
D3
D4
D5

Слайд 21Dopamine System
DOPAMINE RECEPTORS

Receptor 2o Messenger System
D1 ⇑cAMP
D2 ⇓cAMP,⇑K+ ch.,⇓Ca2+ch.
D3 ⇓cAMP,⇑K+ ch.,⇑Ca2+ch.
D4 ⇓cAMP
D5 ⇑cAMP

Слайд 22Dopamine Reuptake System



Слайд 23Antipsychotic treatments


SCHIZOPHRENIA IS FOR LIFE

There is no remission

Слайд 24Antipsychotic 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.

Слайд 25Antipsychotic treatments
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.

Слайд 26Antipsychotics 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 is lifelong and it is preferable to prevent the psychotic episodes than to treat them.

Слайд 27Antipsychotics/Neuroleptics
Although the antipsychotic/neuroleptics are drugs used mainly in the treatment of

schizophrenia, they are also used in the treatment of :
Psychoses associated with depression
Manic-depressive illness
Psychosis associated with alzheimer’s disease.

These conditions are life-long and disabling.

Слайд 28Antipsychotics/Neuroleptics


NON-compliance is the major reason for relapse.

Слайд 29Antipsychotic/Neuroleptics

Three major groups :
Phenothiazines
Thioxanthine
Butyrophenones


OLDER DRUGS

Слайд 30Antipsychotic/Neuroleptics
Phenothiazines


Chlorpromazine Thioridazine Fluphenazine
Trifluopromazine Piperacetazine Perfenazine
Mesoridazine Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
Aliphatic Piperidine Piperazine*
* Most likely to

cause extrapyramidal effects.

Слайд 31Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene

Closely related to phenothiazines

Слайд 32Antipsychotic/Neuroleptics
3) Butyrophenones
Haloperidol
Droperidol*

*Not marketed in the USA


Слайд 34Atypical Antipsychotic


Pimozide
Atypical Antipsychoitcs
Loxapine
Clozapine
Olanzapine
Qetiapine


Indolones
Sertindole
Ziprasidone
Olindone
Molindone
Risperidone



Слайд 35Classification of antipsychotic drugs:

Слайд 36Antipsychotics/Neuroleptics
Old antipsychotics /neuroleptics are D2 dopamine receptor antagonists. Although they are

also effective antagonists at ACh, 5-HT, NE receptors.

dopamine
receptor
antagonist







D2

Слайд 37Antipsychotics/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.

Слайд 38Antipsychotics/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).

Слайд 39Antipsychotics/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

Слайд 40Pharmacokinetics
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.**


Слайд 41Pharmacokinetics
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.


Слайд 42Pharmacokinetics
Excretion
Antipsychotics are almost completely metabolized and thus, very little is eliminated

unchanged.
Elimination half-lives are 10-24 hrs.



Слайд 43Antipsychotic/Neuroleptics



[Drug dose]
Effect






Piperazine
Aliphatic
Piperidine

Слайд 44Antipsychotic/Neuroleptics



[Drug dose]
Effect






Phenothiazine d.
Thioxanthene d.
Butyrophenone d.

Слайд 45Antipsychotics/Neuroleptics
Newer drugs have higher affinities for D1, 5-HT or α-AR receptors.

NE,

GABA, Glycine and Glutamate have also been implicated in schizophrenia.

Слайд 46Antipsychotics/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

Слайд 49Antipsychotics/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.
?
Receptor Supersensitivity




Слайд 50Antipsychotic/Neuroleptics
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

Слайд 51Antipsychotic/Neuroleptics
Chlorpromazine: α1 = 5-HT2 = D2 > D1 > M >

α2
Haloperidol: D2 > D1 = D4 > α1 > 5-HT2 >H1>M = α2
Clozapine: D4 = α1 > 5-HT2 = M > D2 = D1 = α2 ; H1
Quetiapine: 5-HT2 = D2 = α1 = α2 ; H1
Risperidone: 5-HT2 >> α1 > H1 > D2 > α2 >> D1
Sertindole: 5-HT2 > D2 = α1

Слайд 52Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:

Failure to control negative effect
Significant toxicity
Neurological effects
Autonomic

effects
Endocrine effects
Cardiac effects
3) Poor Concentration

Слайд 53Neurological effects
Acute dystonia- Spasms of muscles of tongue, neck and face
Akasthisia

– Uncontrolled motor restlessness
Parkinsonism
Neuroleptic Mallignant Syndrome
Rabbit syndrome (perioral tremors)
Tardive dyskinesia
Piperazines
Butyrophenones

Слайд 54Acute dystonia

Слайд 55Tardive Dyskinesia (TD)
Repetitive involuntary movements, lips, jaw, and tongue
Choreiform quick movements

of the extremities
As with Parkinson’s, movements stop during sleep
No effective treatment

Слайд 57The Nigro-Striatal Pathway

Слайд 58Antipsychotic/Neuroleptics
Some antipsychotics have effects at muscarinic acetylcholine receptors:

Dry mouth
Blurred vision
Urinary retention
Constipation
Clozapine
Chlorpromazine

Thioridazine

Слайд 59Antipsychotic/Neuroleptics
Some antipsychotics have effects at α−adrenergic receptors:
orthostatic hypotension
Chlorpromazine
Thioridazine

Some antipsychotics have effects

at H1-histaminergic receptors:
sedation
Risperidone
Haloperidol

Слайд 60Antipsychotic/Neuroleptics
Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration

and may produce breast engorgement and galactorrhea.

Слайд 61Blood Dyscrasias
Clozapine 1-3 % incidence agranulocytosis
Monitor WBC weekly
WBC < 3,000 hold

tx, check for infection
Restart when reach 3,500
WBC < 2,000 discontinue treatment, do not rechallange

Слайд 62Antipsychotic/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.

Слайд 63Antipsychotic/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, reflecting muscle damage.

Слайд 64Antipsychotic/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.


Слайд 65Antipsychotic/Neuroleptics
Drug Interactions
Additive effects with sedatives.
Additive effects with anticholinergics.
Additive effects with antihistaminergics.
Additive

effects with α-AR blocking drugs.
Additive effects with drugs with quinidine-like action (thioridazine).

Слайд 66XVI. Anti-Manic Drugs
Lithium (Li+) remains the drug of choice for the

treatment and prophylaxis of mania.
Acute manic episodes are managed with lithium salts (carbonate or citrate) alone, or in combination with:
1) Antipsychotics (carbamazepine, similar in structure to TCAs but not effective in depression).
2) Valproic acid
3) Calcium-channel blockers (nifendipine, diltiazem, verapamil).

Слайд 67XVI. Anti-Manic Drugs
Li+
Small monovalent cation (between H+ and Na+).
Distributed in total

body water, similar to sodium.
May partially inhibit Na+-K+ ATPase.
Inhibits ADH => diuresis.
May decrease thyroid function.
Teratogenic (tricuspid valve malformation).
Excreted by kidney.



Слайд 68XVI. Anti-Manic Drugs
Li+
Not to be taken with thiazide diuretics (e.g. chlorthiazide).
Lithium

clearance is reduced by 25%.

All neuroleptics (with the exception of clozapine), produce more severe extrapyramidal syndromes when combined with lithium.

Слайд 69XVI. Anti-Manic Drugs
Li+
Helps alleviate the depressive phase of bipolar illness.

Useful in

refractory depression when added to SSRIs or TCAs, but not a good antidepressant alone.

Слайд 70XVI. Anti-Manic Drugs
Li+
Mechanism of action:
Does not alter receptor numbers but alters

the coupling of the receptors with their second messengers by reducing coupling of G-proteins.
Regulation of β-AR and DAR.
Can reduce release of NTs (5-HT) and affinity of binding to receptor.

Слайд 71XVI. Anti-Manic Drugs
Li+
Mechanism of action (Con’t):
Inhibits breakdown of IP2 to IP1

(during PIP hydrolysis) => depletion of DAG and IP3 and ↓ [Ca2+] in response to receptor activation (i.e. from 5-HT2R, α1-AR, muscarinic receptors and others).
Alterations in adenylate cyclase and phospholipase C.

Слайд 72XVI. Anti-Manic Drugs




PIP


PIP2


G



IP3
IP2
IP1
Inositol
PI





X
Li+







PLC

DAG

Ca 2+

Слайд 73XVI. Anti-Manic Drugs
Valproic Acid
A well known antiepileptic has been found to

have antimanic effects. Shows efficacy equivalent as that of lithium during the early weeks of treatment and is being evaluated for maintenance treatment. Titrated well, the sedation can be controlled. Nausea being the only limiting factor in some patients.
May be used as first line treatment for mania, although it may not be as effective in maintenance treatment as lithium for some patients.
Mechanism of action: ???

Слайд 74XVI. Anti-Manic Drugs
Carbamazepine
Effective as an antimania medication

Mechanism of action (Con’t):
May be

due to decrease overexcitability of neurons (anticonvulsive effect).

Слайд 75XVI. Anti-Manic Drugs
Ca2+ Channel blockers
Nifedeipine
Verapamil

Mechanism of action (Con’t):
NT Release?

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