7.7 psychotic drugs Flashcards
Psychoses (major and obvious)
are disorders in which pateints exhibits fals beliefs (delusions) and false perceptions (ahllucinations). There is detachment from reality
Affective disorders
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
Neuroses (not detached from reality)
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
psychotropic or psychoactive drugs
durgs which affect mental processes eg cognition or affect
classes of psychotropic drugs
antipsychotics, antianxiety, antidepressants, antimanic, psychotomimetic
antipsychotics
(neuroleptics or major tranquilizers) –useful in all types of psychoses, particulary schizophrenia
antianxiety
(anxiolytic-sedative, minor tranquilizer) used for anxiety and phobic states
antidepressants
used for minor as well as major depressive illness, phobic states, obsessive compulsive behavior and certain anxiety disorders
antimanic (mood stabilizers)
used to control mania and break into cyclic affective disorders
Drugs for affective disorders
antidepressants and antimaniac drugs are sometimes collectively referred as drugs for affective disorders
Psychotomimetic (psychedelic, hallucinogens)
seldom used in therapy, however produces psychosis ike states, majority are drugs of abuse
Schizophrenia
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,
Schizophrenia biochemical nature
biochemical abnormality, possibly an overactivty of the mesolimbic, mesocortical dopaminergic neurons, inc in D2 receptors in Nucleus Accumbens - PET (Dopamine hypothesis) –> positive symptoms
dopamine hypothesis
functional excess of cerebral dopamine leads to schizophrneia
drugs that block dopamine receptors or deplete monoamines (reserpine)
ameliorate schizophrenic systems (+ve)
drugs that activate dopamine receptors or release amines (amphetamines)
exacerbate symptoms or cause psychoses
Antipsychotic effects is related to
antidopaminergic drug potency drug potency (IC50–dose required to block 50% of receptors)
Dopamine hypothesis of schizophrenia
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
Positive symptoms of schizophrenia
disorer of Perception and inferences delusions, hallucinations, thought disorder
delusions
fixed false beliefs (invulnerable to logical contradictory evidcnes) “flat earth society”
Hallucinations
auditory “running commentary voices” and others
thought disorder
thougth insertion, thougth broadcast, illogicla decisions
Negative symptoms
abnormal relationships, expressions or speech –affective flattening, alogia, anhedonia, apathy
Affective flattening
lack of or inappropriate emotional expression
Alogia
absence of words
Anhedonia
inability to derive pleasure from any activity
Apathy
withdrawal from the social contact
Cognitive dysfucntions in schizophrenia
impaired attention, impaired working memory, impaired executive function
Dopamine agonists cause
psychosis ex. Amphetamines, levodopa, ampmorphine
Dopamine antagonists have
antipsychotic actions
Serotonin abnormality in schizophrenia
dec in 5H2/5H1A receptors in prefrontal cortex of pts
glutamatergic dysfunction in schizophrenia
a deficiency of glutamatergic activity – decrease hipocampal NMDA (glutamate) receptors
Dopamine paths
slide 20, 21–take pictures
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
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
slide 24
take a picure
what accounts for negative symptoms of schizophrenia
dec mesocortical dopaminergic account for the negative symptoms
what accounts for the positive symptoms of schizophrenia
increased meoslimbic dopamine neurotransmission results in positive and cognitive symptoms
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
DA agonists my cause
dyskinesias
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
increased prolactin secretion form DA antagonists results in
gynecomastia, infertility, amenorrhea
Dopamine paths in the brain - medullary0periventricular
consists of neurons in the motor nucleus of the vagus, may be involved in eating behaviour
Dopamine paths in the brain - incertohypothalamic
forms connections from the medial zona incerta to the hypothalamus and amygdala, regulate sexual behaviour
nigrostriatal origin
substantia nigra
nigrostriatal innervation
caudate nuc, putamen
nigrostiratal fn
extra pyramidal motor control
mesolimbic origin
midbrain ventral tegmentum
mesolimbic innervation
limbic system
mesolimbic fn
arousal memory motivation
mesocortical origin
MVT
mesocortical innervation
frontal and prefrontal cortex
mesocortical fn
cognition communication
tuberoinfundibular origin
hypothalamus
tuberoinfundibular innervation
pituitary
tuberoinfundibular fn
regulates prolactin secretion
Dopamine receptors
5 types D1 to D5, Fall in 2 categories D1like, D2 like
D1 like receptors
Gs - inc cAMP
D2 like
Gi - dec cAMP —these ones are what we are worried about in schizophrenia
D2a
nigrostriatal
D2c
mesolimbic
classes of neuroleptic drugs
typical conventional first generation, atypical second generation
typical first generation antipsychotics
phenothiazines, butyrophenes, thiotixines
phenothiazines
chlorpromazine, fluphenazine, thioridazine
butyrophenones
haloperidol
thiotixines
thiotixine
atypical second generation antipsychotics
Dopamine/serotonin blockers, Dopamine partial agonists
Dopamine/Serotonin blockers
Clozapine, Olanzapine, Risperidone, Asenapine, Quetiapine, Ziprasidone, Iloperidone, Paliperidone
Dopamine partial agonists
Aripriprazole
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
Mechanism of action –serotonin receptor blocking activity in the brain
atypical antispychotics (second generation) exhibit their action primaryly through inhibition of serotonin receptors 5HT2
Mechanism of action – Other
also block cholinergic (muscarinic), adrenergic (alpha) and histaminergic (H1) receptors
Mechanism of action
dopamine receptor blockers, serotonin receptors blcokers, others
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)
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)
Atypical in nigrostriatal path
increased dopamine release counteracts the extrapyramidal side effects caused by D2 receptor block
therapuetic effects
take several weeks to develop
most of these drugs show
little correlation btw plasma levels and therapeutic action (not good for TDM -therapeutic drug monitoring)
Actions of Antipsychotics
Antipsychotic actions, extrapyramidal effects, Antiemetic effects, antimuscuranic effects, CNS effects, CVS effects, other effects
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),
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)
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
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
CNS effects
hyperprotactinemia, poikilothermic effect
hyperprolactinemia
inc the secretion of prolactin (by blocking D2 receptors in pituitary), atypical antipsychotics are less likely to produce prolactin elevations
Poikilothermic effect
on the bodytemperatur (body tem varies with environment) bc DA blocage affects temperature regulation areas
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
Other effects
H1 antagonists–increases appetite and produces sedation (chlorpormazine, clozapine, olanzapine, quetiapine)
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
Chlorpromazine as D2 antagonists
aleeviation of positive s/s and presence of extrapyramidal s/s
chlorpromazine as an alpha 1 antagonist
hypotension
chlorpromazine as an H1 antagonist
increased appetite and produce sedation
Chlorpromazine anticholinergic action
urinary retention, dry mouth
chlorpormazine on CVS
hypotension, QT interval prolongation and ventricular arrhythmia
Thioridazine
pharmacological properties similar to Chlorpromazine
compared to chlorpromazine, thioridazine produces
greater antimuscarinic effects (probably the reason to cause fewer extrapyramidal side effects)
high doses of thioridazine may cause
pigmentary retinopayt (retinitis pigmentosa) and cardiac arrhythmia, and sexual dysfunction –retrograde ejaculation
Fluphenazine and Trifluoperazine
potent pehnothiazines, produce fewer autonomic side effects but more EP side effects than do low-potency penothiazines
Haloperidol
highly potent, properties similar to fluphenazine and may cause significant EPS
EPS sypmptms
fluphenazine=haloperidol>CPZ>thioridaine
Sedative
CPZ=Thio>Fluphenazine= Haloperidol
Hypotension (alpha blockade)
CPZ=Thio>Fluphenazine= Haloperidol
antimuscarinic effects
Thio>CPZ>Fluphenazine= Haloperidol (opposite to EPS)
sturcture of typical antipschotics
lipophillic, orally effectve
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
tolerance to antipsychotics
tolerance to the sedative and hyptensive action but not for antipsychotic and extra pyramidal effects. No physical dependence.
Adverse effects of typical antispychotics
extrapyramidal symptoms, CNS, ANS, endocrine, weight gain, neuroleptic malignant syndrome, Retinopathy
Acute EPS
Acute muscular dystonia, Akinesia, Pseudo-parkinsonism, Akathisea
acute muscular dystonia
4hrs (irregular spasms of the facial, neck and trunk muscles torticollis, locked jaw, jerky movements, trouble speaking
akinesia
4 days – can’t initiate movements
pseudo-parkinsonism
1-4 weeks – rigiditiy, tremor, hypokinesia, mask like face, shuffling gait, pillrolling
akathisia
4 weeks – restlessness, irresistible compulsion to be in motion
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
Management of EPS
lower the dose of typical andtipsychotics and swithc over to atypical ones, antimuscarinic drugs like benztropine or dipehnhydramine, TD is irreversible
Adverse CNS effects of typicals
sedation (central H1 block), mental confusion (central muscarinic blck), aggravation of seizures in epileptics
Adverse ANS effects of typicals
alpha blocker – postural hypotension, reflex tachycardia, anticholinergic – dry mouth, constipation, urinary retention, blurred vision
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
Adverse weight gain of typicals
5HT2 block and H1 block
Neuroleptic malignant syndrome is most common with
haloperidol
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
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
Retinopathy of typicals
retinal diposits
Cardiotoxicity with typicals
torsades–“quinidine-like” effects,
retinopathy and cardiotoxicity is especially seen with
thioridazine at high dose
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)
Limitation of Clozapine
agranulocytosis (requires weekly WBC monitoring) and Seizures (even in non-epileptics)
Clozapine and EPS
lower incidence of EPS and no tardive dyskinesia
Clozapine effects
inc salivation (wet pillow syndrome, bed wetting and other autonomic side effects like weight gain, orthostatic hypotension, hyperglycemia (diabetes)
Clozapine and prolactin
does not cause a rise in prolactin level
Clozapine is reserved for
drug resistant shizophrnia due to its side-effect profile
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
most common adverse effects of olanzapine
sedation and weight gaint (more than clozapine) and can cause hyperglycemia (diabetes)
Olanzapine vs Haloperidol
as effective as haloperidol in alleviating the positive symptoms of schizophrenia and is superior to haloperidol in alleviating the negative symptoms
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)
Risperidone vs. Olanzapine
causes less sedation, but more EPS than Olanzapine
Risperidone on QT
prolongs the QT interval and may predispose pts to cardiac arrhythmias (including torsades de pointes)
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
Quetiapine
distinct in having a weak D2 effect, also 5HT2 antagonsit effect, also potent alpha1 and histamine blocker
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
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
Parenteral (IM) atypical antipsychotics
Aripiprazole, ziprasidone, Long acting – olanzapine, paliperidone, resperidone
chart on slide
77
antipsychotics on schizophrnia
antipsychotics – the mainstay of treatmetn, many pts show little response and virtually none show a complete response
use of antipsychotics
nausea and vomiting (drug induced or radiation induced) , EXCEPT Thioridazine and Aripiprazole
use of antipsychotics on tourette syndrome
vocal and motor tics —pimozide, haloperidol, fluphenazine/risperidone, olanzapine, ziprasidone
Use of antipsychotics on neuroleptanalgesia
droperidol
for hiccups
cholpromazine
for behavior and irritability secondary to autism
risperidone
