dr. womble
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Antipsychotics. Dr. Womble. Psychosis. Psychosis is defined as a state in which a person’s mental capacity to recognize reality, communicate, and relate to others is impaired, thus interfering with the capacity to deal with life’s normal everyday demands - PowerPoint PPT PresentationTRANSCRIPT
Dr. Womble
Antipsychotics
Psychosis Psychosis is defined as a state in which a
person’s mental capacity to recognize reality, communicate, and relate to others is impaired, thus interfering with the capacity to deal with life’s normal everyday demands
most common mental disorder in which psychotic sx may be present is schizophrenia.
Schizophrenia a general term for a mental disorder
characterized by delusions, loosening of associations, decrease
speech content, auditory hallucinations, disturbed sense of self, and withdrawal from the external world.
Onset early adulthood prior to normal function
Antipsychotics (Neuroleptics)
Referred to as antischizophrenic, antipsychotic or major tranquilizers
Typical properties due to dopamine receptor antagonism 1950’s, first generation, D2
High EPS Atypical properties due to Serotonin and DA receptor
antagonism Second generation
Not curative, does not eliminate thinking disorder, but allow patient to function in supportive environment
Pathogenesis of schizophrenia is unknown
Schizophrenia Characterized by delusions, hallucinations (hearing
voices), thinking and speech disturbances Often affected during adolescence, strong genetic
component Characterized by 2 components;
breakdown of personalityloss of contact with reality
Antianxiety agents not useful for psychotic disorders Considered neurodevelopmental disorder
Structural and functional changes present in utero
Schizophrenia Positive symptoms - symptoms that most
individuals do not normally experience but are present in schizophrenia. Delusions, auditory hallucinations, thought
disorder, regarded as manifestations of psychosis Negative symptoms - symptoms that reflect
the loss or absence of normal traits or abilities.Blunted affect and emotion, poverty of speech,
inability to experience pleasure, lack of desire to form relationships, and lack of motivation
Schizophrenia Etiology Serotonin Hypothesis
5-HT stimulation responsible for hallucinations Atypical antipsychotics - MOA
Dopamine Hypothesis Firtst NT based MOA, no longer considered to cover all
aspects of schizophrenia Important in uderstanding pos./neg. symptoms
Glutamate Hypothesis Hypofunction of NMDAr - decreased GABAergic inhibitory
activity
Antipsychotics Reserpine and chlorpromazine were first drugs used
for schizophrenia / psychosis Divided into five major classifications based on
structure. Side chains have significant effect on potencies1. Phenothiazines2. Benzisoxazoles3. Dibenzodiazepines4. Butyrophenones5. Thioxanthenes
Management of psychotic disorder can be determined by familiarity of effects drugs in each class
Typical Antipsychotics(1. Phenothiazine)
3 subclasses
1. Aliphatic – least potent Chlorpromazine –intermediate extrapyramidal side effects and intermediate
anticholinergic action, high incidence of sedative action
2. Piperazine – most potent, selective and effective, increased incidence of Tardive dyskinesia Fluphenazine (Prolixin) Prochlorperazine (Compazine) Perphenazine (Trilafon)
3. Piperidine – least potent, lower incidence of extrapyramidal side effects, high incidence of anticholinergic action Thioridazine (Mellaril) Mesoridazine (Serentil)
Action of Phenothiazine CNS – reduces anxiety, response to external stimuli,
intelligence is not diminished, reflexes not suppressed, mild sedation Limbic system Da receptors involved in mood/feeling
○ 5 subclasses of DA receptors (D1-D5) D1/5 activate, D2/3 inhibit adenyl cyclase D2 involved in psychotic disorders
- Blockade of D2 receptor is antipsychotic action
Autonomic effects – antimuscarinic action (piperidines – strongest, piperizines – weakest) urinary retention, ortho hypo, dry mouth, sedation, inh of GI smooth muscle - constipation
Alpha-antagonist – ortho hypo, poikilothermia, inc. prolactin release Basal Ganglia – blockade of D1 or D2 results in EPS Cardiovascular – depressed by antipsychotics – hypotension Chemoreceptor trigger zone (CTZ) - (anti-emetic action) Hypothalmus – DA receptors inhibit release of prolactin, phenothiazines block DA
receptors - stimulate release of prolactin – hormonal side effects Misc. – no physical dependence, mild CNS depressant (toxic dose), decrease
seizure threshold
Side effects of Phenothiazine
Side effects Orthostatic hypotension – due to alpha blockade,
dose/effect response Extrapyramidal Syndrome – increased cholinergic
activity (Piperazine – highest, Piperidines – lowest) Parkinson-like Syndrome Akathesia – uncontrollable restlessness, distress, anxiety Tardive Dyskinesia – develops late in antipsychotic
therapy, usually at high doses x 6 months, rhythmic motions of head, face and shoulders, may be irreversible
Do not use DA or Levo-Dopa, use diphenhydramine (Benadryl), benztropine (Cogentin) or trihexephenidyl (Artane).
Therapeutic use of Phenothiazines Tx psychotic disorders
Schizophrenia, senile dementia, extreme paranoia, manic phase of manic depressive syndrome,
Anti-emetics – radiation toxicity, anticancer meds, opioids, gastroenteritis
Phenothiazines control ○ positive symptoms – Hallucinations, delusions,
hostility, hyperactivity○ Not negative symptoms – social withdrawal, lack
of expression, decrease in speech patterns
Douglas L. Geenens, D.O. 2000
Dopamine Pathways Nigrostriatal
Mesocortical – Mesolimbic
Tuberoinfundibular
Incertohypothalamic
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysNigrostriatal Projects from the substantia niagra to
the basal gangliapart of extrapyramidal systemThus side effects are called “extrapyramidal”
Chronic blockade can cause Potentially irreversible movement disorder
○ “Tardive Dyskinesia
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysNigrostriatal Controls movements
Types of movement disorders caused by this pathway include:Akathisia
Dystonia
Tremor, rigidity, bradykinesia ○ Drug-induced Parkinsonism
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysMesolimbic - Mesocortical
Blockade may help reduce negative symptoms of schizophrenia
May be involved in the cognitive side effects of antipsychotics “mind dulling”
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysTuberoinfundibular
DA released at this site regulates the secretion of prolactin from the anterior pituitary gland.
Blockade produces galactorrhea
Dopamine=PIF
Douglas L. Geenens, D.O. 2000
Dopamine PathwaysIncertohypothalamic
Connects the hypothalamus and the limbic system
Regulates sexual desire
Classes of Antipsychotics1. Phenothiazines2. Benzisoxazoles3. Butyrophenones4. Thioxanthenes 5. Dibenzodiazepines
Atypical Antipsychotics In the last decade new "atypical" antipsychotics
have been introduced, >effective, <s/e typical antipsychotics appear to be equally
effective for helping reduce the positive symptoms like hallucinations and delusions but may be better than the older medications at relieving
the negative symptoms of the illness, such as withdrawal, thinking problems, and lack of energy.
Mechanism of Action of Atypical Antipsychotics
Blockade of DA (D1 and D4) and / or 5-HT receptors. Many also block cholinergic, adrenergic, and histamine receptors – variety of side effects (low D2)
DA receptor antagonism in brain (typical and atypical antipsychotics) Neuroleptics are antagonized by agents that increase DA
concentration (L-dopa and amphetamines) Serotonin receptor antagonism in brain (atypical)
NEUROBIOLOGY OF CLOZAPINE
Here you can see that Clozapine will not bind to any Dopamine receptor, it is selective, it has an affinity for the D4 receptor subtype.
Atypical Antipsychotics Low or no EPS
5-HT2A antagonist
Control both positive and neg. symptoms
Aripiprazole (Abilify),Risperidone (Risperdal), Clozapine (Clozaril), Olanzapine (Zyprexa), Quetiapine (Seroquel), and Ziprasidone (Geodon).
Atypical Antipsychotics(second generation)
Clozapine (prototype)Little to no EPS, high incidence of agranulocytosis
(regular CBC’s), High incidence of siezures Olanzapine (Zyprexa)
Sedation, weight gain, no agranulocytosis, low incidence of siezures
Quetiapine (Seroquel)Sedation, low incidence of all side effects
Action of Atypical Antipsychotics
Antipsychotic – reduce hallucinations, agitation, require several weeks to occur
EPS – Parkinsonian symptoms, akathisia, tardive dyskinesia.(clozapine, risperidone show low incidence)
Antiemetic – D2 receptor antagonist in CMZ of medulla (except thioridazine)
Antimuscarinic – blurred vision,dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscle – constipation, urinary retention. (all esp. thioridazine and chlorpromazine)
α-blockade – orthostatic hypotension, lightheadedness, alter temperature regulating mechanisms, block D2 receptors in pituitary – prolactin release
Therapeutic application of antiemetic agents
Vertigo – meclizine, dimenhydrinate Motion sickness – scoopolamine,
promethazine Cancer chemo – droperidol, haloperidol,
metoclopramide, prochloperazine Radiation therapy – thiethylperazine,
domperidone