7.7 psychotic drugs Flashcards
(148 cards)
1
Q
Psychoses (major and obvious)
A
are disorders in which pateints exhibits fals beliefs (delusions) and false perceptions (ahllucinations). There is detachment from reality
2
Q
Affective disorders
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emotional distrubances in which the mood is excessively low (depression) or high (mania), may be bipolar (manic depressive) with cyclically alternating manic depressive phases or unipolar (mania or depression) with waxing and waning course
3
Q
Neuroses (not detached from reality)
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less severe, unlike psychoses, ability to comprehend reality is not lost, though pt may undergo extreme suffereing, anxiety, phobic states (panic disorder), obsessive compulsive disorders, reactive depression, post raumatic stress disorder, hysterical conversion, personality disorders
4
Q
psychotropic or psychoactive drugs
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durgs which affect mental processes eg cognition or affect
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Q
classes of psychotropic drugs
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antipsychotics, antianxiety, antidepressants, antimanic, psychotomimetic
6
Q
antipsychotics
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(neuroleptics or major tranquilizers) –useful in all types of psychoses, particulary schizophrenia
7
Q
antianxiety
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(anxiolytic-sedative, minor tranquilizer) used for anxiety and phobic states
8
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antidepressants
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used for minor as well as major depressive illness, phobic states, obsessive compulsive behavior and certain anxiety disorders
9
Q
antimanic (mood stabilizers)
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used to control mania and break into cyclic affective disorders
10
Q
Drugs for affective disorders
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antidepressants and antimaniac drugs are sometimes collectively referred as drugs for affective disorders
11
Q
Psychotomimetic (psychedelic, hallucinogens)
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seldom used in therapy, however produces psychosis ike states, majority are drugs of abuse
12
Q
Schizophrenia
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a debilitating psychosis characterized by delusion, hallucinations (often in the form of voices, auditory) and thinking or speech disturbances, affects 1% of the world population, heredofamilial, prenatal abnormal cerebrum (MRI) and neurotransmitters,
13
Q
Schizophrenia biochemical nature
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biochemical abnormality, possibly an overactivty of the mesolimbic, mesocortical dopaminergic neurons, inc in D2 receptors in Nucleus Accumbens - PET (Dopamine hypothesis) –> positive symptoms
14
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dopamine hypothesis
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functional excess of cerebral dopamine leads to schizophrneia
15
Q
drugs that block dopamine receptors or deplete monoamines (reserpine)
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ameliorate schizophrenic systems (+ve)
16
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drugs that activate dopamine receptors or release amines (amphetamines)
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exacerbate symptoms or cause psychoses
17
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Antipsychotic effects is related to
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antidopaminergic drug potency drug potency (IC50–dose required to block 50% of receptors)
18
Q
Dopamine hypothesis of schizophrenia
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incomplete (explains positive symptoms, antipsychotic drugs are only partially effective for most and ineffective for some pts –indicates dopamine physicology not completely responsible for the pathogenesis of Schizophrenia, involvement of (glutamate) NMDA, cholinergic 5HT receptors likely
19
Q
Positive symptoms of schizophrenia
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disorer of Perception and inferences delusions, hallucinations, thought disorder
20
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delusions
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fixed false beliefs (invulnerable to logical contradictory evidcnes) “flat earth society”
21
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Hallucinations
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auditory “running commentary voices” and others
22
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thought disorder
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thougth insertion, thougth broadcast, illogicla decisions
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Q
Negative symptoms
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abnormal relationships, expressions or speech –affective flattening, alogia, anhedonia, apathy
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Affective flattening
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lack of or inappropriate emotional expression
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Alogia
absence of words
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Anhedonia
inability to derive pleasure from any activity
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Apathy
withdrawal from the social contact
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Cognitive dysfucntions in schizophrenia
impaired attention, impaired working memory, impaired executive function
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Dopamine agonists cause
psychosis ex. Amphetamines, levodopa, ampmorphine
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Dopamine antagonists have
antipsychotic actions
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Serotonin abnormality in schizophrenia
dec in 5H2/5H1A receptors in prefrontal cortex of pts
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glutamatergic dysfunction in schizophrenia
a deficiency of glutamatergic activity -- decrease hipocampal NMDA (glutamate) receptors
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Dopamine paths
slide 20, 21--take pictures
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Dopamine paths in the brain - mesolimbic
dopamine travels from the midbrain tegmental area to the nucleus acumbens. Increased activity in this pathway may cause delusions, ahllucinations, and other so-called positive symptoms and cognitive symptoms of schizophrenia
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Dopamine paths in the brain - mesocortical
decreased activity in pathway that goes from the midbrain to the prefrontal lobe cortex may caue apathy, withdrawal, lack of motivation and pleasure, and other so-called negative symptoms of schizophrenia, mesocortical dysfunction also disinhibits mesolimbic pathway
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slide 24
take a picure
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what accounts for negative symptoms of schizophrenia
dec mesocortical dopaminergic account for the negative symptoms
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what accounts for the positive symptoms of schizophrenia
increased meoslimbic dopamine neurotransmission results in positive and cognitive symptoms
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Dopamine paths in the brain - nigrostriatal
the pathway from substantia nigra to striatum, involved in the coordination of the body movements, inhibition of this pathways (DA antagonsits) results in extra pyramidal side effects of anti-psychotics
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DA agonists my cause
dyskinesias
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Dopamine paths in the brain - tuberoinfundibular
it is from hypthalamus to pituitary and inhibits prolactin secretion -- block of this pathways results in increase prolactin secretion
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increased prolactin secretion form DA antagonists results in
gynecomastia, infertility, amenorrhea
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Dopamine paths in the brain - medullary0periventricular
consists of neurons in the motor nucleus of the vagus, may be involved in eating behaviour
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Dopamine paths in the brain - incertohypothalamic
forms connections from the medial zona incerta to the hypothalamus and amygdala, regulate sexual behaviour
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nigrostriatal origin
substantia nigra
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nigrostriatal innervation
caudate nuc, putamen
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nigrostiratal fn
extra pyramidal motor control
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mesolimbic origin
midbrain ventral tegmentum
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mesolimbic innervation
limbic system
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mesolimbic fn
arousal memory motivation
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mesocortical origin
MVT
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mesocortical innervation
frontal and prefrontal cortex
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mesocortical fn
cognition communication
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tuberoinfundibular origin
hypothalamus
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tuberoinfundibular innervation
pituitary
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tuberoinfundibular fn
regulates prolactin secretion
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Dopamine receptors
5 types D1 to D5, Fall in 2 categories D1like, D2 like
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D1 like receptors
Gs - inc cAMP
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D2 like
Gi - dec cAMP ---these ones are what we are worried about in schizophrenia
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D2a
nigrostriatal
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D2c
mesolimbic
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classes of neuroleptic drugs
typical conventional first generation, atypical second generation
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typical first generation antipsychotics
phenothiazines, butyrophenes, thiotixines
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phenothiazines
chlorpromazine, fluphenazine, thioridazine
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butyrophenones
haloperidol
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thiotixines
thiotixine
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atypical second generation antipsychotics
Dopamine/serotonin blockers, Dopamine partial agonists
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Dopamine/Serotonin blockers
Clozapine, Olanzapine, Risperidone, Asenapine, Quetiapine, Ziprasidone, Iloperidone, Paliperidone
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Dopamine partial agonists
Aripriprazole
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Mechanism of action -- dopamine receptor blocking activity in the brain
all antipsychotic drugs (primarily first generation) block dopamine receptors in the brain and the periphery, antipsychotic drugs bind to dopamine receptors in varying degrees
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Mechanism of action --serotonin receptor blocking activity in the brain
atypical antispychotics (second generation) exhibit their action primaryly through inhibition of serotonin receptors 5HT2
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Mechanism of action -- Other
also block cholinergic (muscarinic), adrenergic (alpha) and histaminergic (H1) receptors
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Mechanism of action
dopamine receptor blockers, serotonin receptors blcokers, others
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Typical first generation work by
primarily block the D2 receptor in the mesolimbic pathways, decrease the dopaminergic transmission in the mesolimbic pathways to nucleus accumbens, alleviates positive symptoms, more extrapyramidal features (due to binding of D2 receptors in nigrostriatal pathway as well)
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Atypical second generation work by
block the 5HT2 preferentially and D2 receptrs faster dissociation from D2R, increase the release of dopamine in mesocortical pathways to prefrontal lobe, inc 5HT1A receptors --> alleviates negative symptoms more than typical, less extrapyramidal adverse effects (dec D2)
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Atypical in nigrostriatal path
increased dopamine release counteracts the extrapyramidal side effects caused by D2 receptor block
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therapuetic effects
take several weeks to develop
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most of these drugs show
little correlation btw plasma levels and therapeutic action (not good for TDM -therapeutic drug monitoring)
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Actions of Antipsychotics
Antipsychotic actions, extrapyramidal effects, Antiemetic effects, antimuscuranic effects, CNS effects, CVS effects, other effects
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antipsychotic actions
atypical agens such as clozapine-like drugs, ameliorate the negative symptoms, all altipsychotics have a calming effect and reduce spontaneous physical movement (neurolepsis),
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Extrapyramidal effects
dystonias, parkinson-like symptoms (pseudoparkinsonism; reversible), 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 CAUSE of these symptoms, atypical antipsychotics exhibit low incidence of these symptoms (bc in the nigrostriatal pathway, increased dopamine release counteracts the extrapyramidal side effects caused by D2 receptor blockade)
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Antiemetic effects
excpet tioridazine and aripiprazole, moste of the antipsychotics have antiemetic effects, they block D2 receptors of the CTZ (floor of the 4th ventricle) of medulla, atypical antipsychotics are not effective antiemetics
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antimuscarinic effects
some of the antipsychotics (particularly thioridazine, chlorpromazine, clozapine) produce antimuscarinic effects, cause blurring of vision, dryness of mouth, inhibition of GI and urinary muscles--leading to constipation and urinary retention
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CNS effects
hyperprotactinemia, poikilothermic effect
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hyperprolactinemia
inc the secretion of prolactin (by blocking D2 receptors in pituitary), atypical antipsychotics are less likely to produce prolactin elevations
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Poikilothermic effect
on the bodytemperatur (body tem varies with environment) bc DA blocage affects temperature regulation areas
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CVS effects
orthostatic hypotension (alpha 1 antagonist), relex tachycardia, inc QTc , ventricular arrhythmia, both typical and atypical agents show does dependent inc of torsade de pointes VT and sudden cardiac death
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Other effects
H1 antagonists--increases appetite and produces sedation (chlorpormazine, clozapine, olanzapine, quetiapine)
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Chlorpromazine on CNS
motor activity is decreased, sleep pattern is set normal (however not used as sedative-hypnotics), emesis is blocked, improve cognitive abilities, no impairment of intellectual functions, decrease the seizure threshold, inc the secretion of the prolactin, poikiolothermic effect on body temperature (body temp varies with environment), minimal respiratory depression compared to barbiturates
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Chlorpromazine as D2 antagonists
aleeviation of positive s/s and presence of extrapyramidal s/s
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chlorpromazine as an alpha 1 antagonist
hypotension
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chlorpromazine as an H1 antagonist
increased appetite and produce sedation
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Chlorpromazine anticholinergic action
urinary retention, dry mouth
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chlorpormazine on CVS
hypotension, QT interval prolongation and ventricular arrhythmia
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Thioridazine
pharmacological properties similar to Chlorpromazine
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compared to chlorpromazine, thioridazine produces
greater antimuscarinic effects (probably the reason to cause fewer extrapyramidal side effects)
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high doses of thioridazine may cause
pigmentary retinopayt (retinitis pigmentosa) and cardiac arrhythmia, and sexual dysfunction --retrograde ejaculation
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Fluphenazine and Trifluoperazine
potent pehnothiazines, produce fewer autonomic side effects but more EP side effects than do low-potency penothiazines
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Haloperidol
highly potent, properties similar to fluphenazine and may cause significant EPS
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EPS sypmptms
fluphenazine=haloperidol>CPZ>thioridaine
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Sedative
CPZ=Thio>Fluphenazine= Haloperidol
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Hypotension (alpha blockade)
CPZ=Thio>Fluphenazine= Haloperidol
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antimuscarinic effects
Thio>CPZ>Fluphenazine= Haloperidol (opposite to EPS)
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sturcture of typical antipschotics
lipophillic, orally effectve
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good drugs for noncompliant pts
haloperidol and fluphenazine are available as IM long acting (depot) preparations (2-4 weeks), hence rapid initiation of treatment and maintenance is possible in noncompliant pts -->administerd by a deep Z-track IM method
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tolerance to antipsychotics
tolerance to the sedative and hyptensive action but not for antipsychotic and extra pyramidal effects. No physical dependence.
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Adverse effects of typical antispychotics
extrapyramidal symptoms, CNS, ANS, endocrine, weight gain, neuroleptic malignant syndrome, Retinopathy
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Acute EPS
Acute muscular dystonia, Akinesia, Pseudo-parkinsonism, Akathisea
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acute muscular dystonia
4hrs (irregular spasms of the facial, neck and trunk muscles torticollis, locked jaw, jerky movements, trouble speaking
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akinesia
4 days -- can't initiate movements
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pseudo-parkinsonism
1-4 weeks -- rigiditiy, tremor, hypokinesia, mask like face, shuffling gait, pillrolling
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akathisia
4 weeks -- restlessness, irresistible compulsion to be in motion
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Chronic EPS
tardive dyskinesia --4 monts to years -- facial and limb movements choreathetosis (tics) like chewing, putting, puffing of cheeks, lip licking, tongue protrusion, chroeoathetoid-like movemens, caused by supersensitivity of dopamine receptros due to chronic blockade (months or years) of dopamine receptors in caudate, putamen); Tarditive dyskinesia is induced by all antipsychotics (except clozapine and more seen with Haloperidol) and is often irreversible
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Management of EPS
lower the dose of typical andtipsychotics and swithc over to atypical ones, antimuscarinic drugs like benztropine or dipehnhydramine, TD is irreversible
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Adverse CNS effects of typicals
sedation (central H1 block), mental confusion (central muscarinic blck), aggravation of seizures in epileptics
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Adverse ANS effects of typicals
alpha blocker -- postural hypotension, reflex tachycardia, anticholinergic -- dry mouth, constipation, urinary retention, blurred vision
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Adverse endocrine effects of typicals
amenorrhea -- galactorrhea, infertility, impotence (due to hyperprolactinemia) D2 blockade, in male -- decreased libido, gynecomastia, inhibition of ejactulation/retrograde ejaculation, in female --Amenorrhea--galactorrhea, infertility
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Adverse weight gain of typicals
5HT2 block and H1 block
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Neuroleptic malignant syndrome is most common with
haloperidol
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neuroleptic malignant syndrome
lifethreatening extreme muslce rigidity, fever, autonomic dysfunction (tachycardia, diaphoresis, and urinary and fecal incontinence), altered level of consciousness, myoglobinemia, associated with 20% mortality rate, occurs due to excessive rapid blockade of psotsynaptic dopamine receptors
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Treatment of Neuroleptic malignant syndrome
immediately stop offending antipsychotic drug and start bromocriptine/Pergolide (dopamine receptor agonist)/ Amantadien/Dantrolene and Diazepam, along with symptomatic management
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Retinopathy of typicals
retinal diposits
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Cardiotoxicity with typicals
torsades--"quinidine-like" effects,
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retinopathy and cardiotoxicity is especially seen with
thioridazine at high dose
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clozapine
potent 5HT2 blocker, weak D2 blcoking, most effective antipsychotic agent (superior over other antipsychotics), reduce both positive and negative symptoms (but more negative symptoms)
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Limitation of Clozapine
agranulocytosis (requires weekly WBC monitoring) and Seizures (even in non-epileptics)
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Clozapine and EPS
lower incidence of EPS and no tardive dyskinesia
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Clozapine effects
inc salivation (wet pillow syndrome, bed wetting and other autonomic side effects like weight gain, orthostatic hypotension, hyperglycemia (diabetes)
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Clozapine and prolactin
does not cause a rise in prolactin level
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Clozapine is reserved for
drug resistant shizophrnia due to its side-effect profile
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Olanzapine vs Clozapine
similar in that it causes minimal EPS BUT does NOT cause agranulocytosis, fewer autonomc side effects (due to less blcokade of histamine, muscarinic and alpha adrenergic receptors), less incidence of seizures compared to clozapine
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most common adverse effects of olanzapine
sedation and weight gaint (more than clozapine) and can cause hyperglycemia (diabetes)
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Olanzapine vs Haloperidol
as effective as haloperidol in alleviating the positive symptoms of schizophrenia and is superior to haloperidol in alleviating the negative symptoms
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Risperidone
blocks 5HT2 receptors and improves negative symptoms primarily, pharmacologically similar to olanzapine, nowadays used as first line antipsychotics drugs, not as effective as clozapine in treatment-resistant cases but does not carry a resk of blood dyscrasias (agranulocytosis) and has a low incidence of EPS (dose-dependent)
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Risperidone vs. Olanzapine
causes less sedation, but more EPS than Olanzapine
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Risperidone on QT
prolongs the QT interval and may predispose pts to cardiac arrhythmias (including torsades de pointes)
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Aripiprazole
blocks 5HT2 receptors, partial agonists of D2 receptors, hence less chance of tardive dyskinesia, also has little risk of weight gain or prolactin increase but amy increase anxiety, nausea, and insomnia as a result of its partial agonist properties, low potential for EPS, not good for severe psychosis due to its partial agonistic effects
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Quetiapine
distinct in having a weak D2 effect, also 5HT2 antagonsit effect, also potent alpha1 and histamine blocker
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Quetiapine causes
sedation, dizziness, drymouth and weight gain and hyperglycemia (diabetes), cataract formation (although mentioned in drug's package, not seen during clinical trials), Excellent EPS profile
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Ziprasidone
seldom causes minimal weight gain and is unlikely to increase prolactin, but may cause QT prolongation and somnolence, low potential for EPS, C/I--history of cardiac arrhythmias
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Parenteral (IM) atypical antipsychotics
Aripiprazole, ziprasidone, Long acting -- olanzapine, paliperidone, resperidone
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chart on slide
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antipsychotics on schizophrnia
antipsychotics -- the mainstay of treatmetn, many pts show little response and virtually none show a complete response
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use of antipsychotics
nausea and vomiting (drug induced or radiation induced) , EXCEPT Thioridazine and Aripiprazole
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use of antipsychotics on tourette syndrome
vocal and motor tics ---pimozide, haloperidol, fluphenazine/risperidone, olanzapine, ziprasidone
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Use of antipsychotics on neuroleptanalgesia
droperidol
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for hiccups
cholpromazine
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for behavior and irritability secondary to autism
risperidone
