anti psychotics Flashcards
Psychosis
Derangement of personality, loss of contact with reality, delusions, hallucinations
Schizophrenia spectrum and other psychotic disorders
All disorders in this class share some form of the syndrome psychosis with abnormalities in one or more domains: delusions, hallucinations, disorganized thinking, abnormal motor behavior and negative symptoms
Central criteria: 2 or more symptoms during a 1 month period, at least one must be a Core postive
Core postive: delusions, hallucinations, disorganized speech
Others- grossly disorganizsed or catatonic behavior, Negative symptoms (Blunted affect, lack of spontaneity, poor abstract thinking, pverty of thought, social withdrawal)
Dopamine hypothesis
Schizophrenia results from hyperactivity of dopaminergic neurons or their receptors, particularly those with terminals in limbic areas of the brain
Abnormal dopamine neurotransmission in frontal cortical areas may be responsible for negative symptoms
MOA: all effective antipsychotics interact with dopamine systems
Mesolimbic tract vs mesocortical tract
MEsolimbic tract: Arousal memory, stimulus processing, locomotor activity, motivational behavior, dopamine hyperactivty–>positive symtpoms
MEsocortical tract: cognition, communication, social activity, altered dopaminergic activty–>negative symptoms
Nigrostriatal pathway- dopamine blockade–> increase in extrapyramidal symptoms, Blockade of 5HT2a–> decrease extrapyramidal symptoms, parkinsonism
Tuberoinfundibular tract: dopamine blockade–> increased prolactin release
dopaminergic synapse
dopaime from tyrosine (and tyrosine hydroxylase and DOPA) gets in the vesicles
binds to Dopamine receptors
Metabotropic G proteins coupled receptors
D1- like family: includes subtypes D1 and D5, Activation is coupled to Gas: activates adenylyl Cyclase which leads to increase in concentration of cAMP
D2-like family: includes D2, D3 and D4: activation is coupled to Gai, inhibits adenylyl cyclase leading to decrease in concentration of cAMP
Dopamine autoreceptors are like D2 (and inhibit DA release)
atypical antipsychotics
most of the newer drugs such as clozapine, risperidone have an additional neurochemical effect in additional to DA receptor blockade
Block 5HT2 receptors in the forebrain, often with greater potency than for DA receptors
pharmacokinetics of antipsychotics
Oral absorption- variable, lipid soluble, protein binding, large volumes of distribution, complex metabolism
LONG half lives
Actions of antipsychotic drugs
Decrease in psychotic behavior: typical drugs differ only in potency, the negative symptoms of schizophrenia are not well treated by the older typical agents, atypical drugs, in addition to treating positive symptoms, may be more effective in treating negative symptoms
Sedation
Extrapyramidal effects: dystonias, parkinsonism- early reacions with more typicals, akathisia, tardive dyskinesia- late reaction may be less frequent with atypicals
extrapyramidal symptoms
Early reactions: Acute dystonia (1-5 days, spasm of muscles in head and neack, opisthotonus), parkinsonism (5-30 days, bradykinesia, mask like facies, tremor, rigidity, shuffling gait, drooling, cogwheel, stooped), Akathisia (5 days to 2 months- compulsice, restless movement, symptoms of anxiety and agitation)
Late reaction: tardive dyskinesia- month to years- oral facial dyskinesias, choreoathetoid movements
TARDIVE DYSKINESIA treatmentL valbenazine)
Actions of antipsychotic drugs
Anticholinergics- dry mouth, blurred vision, urinary retention
Orthostatic hypotension
Neuroendocrine effects- result of dopamine receptor blockade
Cardiac effects- thioridazine
Decreased seizure threshold- particularly clozapine
Weight gain- diabetes related events are more common with atypicals, particularly olanzipine, resperidone, clozapine, and quetiapine, ziprasidone, and aripiprazole have less
Nueroleptic malignant syndrome
life threatening hypo- dopaminergic side effect of antipsychotic drugs
Hyperthermia, parkinson-like symptoms (muscular rigidity and tremor), mutism, and death
a medical emergenecy
Treatment includes cooling and hydration, dopamine agonist (bromocriptine) and dantrolene
Phenothiazines
Original typical antipsychotic drugs
Phenothiazines- Original antipsychotics currently less commonly used
Aiphatic side chains- Chlorpromazine- Low to medium potency, sedative, pronounced anti cholinergic actions
Piperazines: fluphenazine, prochlorperazine: high potency, less sedative, more extrapyramidal reactions, less anticholinergics
butyrophenone, and pimozide
HAloperidol: pharmacologically related to the phenothiazines but is pharmacologically similar to the high potency piperazine derivatives, also indicated for tourettes
Pimozide: potent neuroleptic, many side effects, approved for only tourettes
Atypical drugs
more acceptable side effects, better to treat the negative symptoms of schizophrenia
clozapine
Blocks D4 and 5HT2 receptors, little effect on D2, muscarinic antagonist, improves positive symptoms even in patients not helped by other drugs, improves negative symptoms, lowers seizure thresholds more than other antipsychotics
CAN CAUSE FATAL AGRANULOCYTOSIS- requires monitoring
Olanzapine
related to clozapine, potent 5HT2 antagonist, D1 and 2 antagonist some D4
Few EPS (5HT>D)
Less seizure incidence than clozapine
No agranulocyctosis, weight gain, and diabetes related adverse events, reports of olanzapine abuse
risperidone
Combined D2 and 5HT2 antagonist
Greater reduction in negative symptoms and less extrapyramidal symptoms than traditional antipsychotics, less seizure activity and less antimuscarinic than clozapine, paliperidone is the active metabolite, both are available as intramuscular depot preps
Quetiapine
similar to risperidone and olanzapine, but shorter half life good for older people because they have less ability to metabolize drugs
Augmentationin depression
Reports of abuse
aripiprazole
parital D2 and 5HT2 antagonist
also approved in depression for bipolar 1 and tourettes syndrome
Associated with increased impulsive behavior
Long acting forms available
other atypical antipsychotics
ziprasidone and lurasidone- 5ht2 and D2 antagonists
zip may have 5HT1a agonists activty (anxiolytic) , little weight gain
Lura- also approved for schizophrenia and bipolar 1, Acute dpression
uses of antipsychotic drugs
acute psychotic episodes, chronic schizophrenia, manic episodes, bipolar disorder- aripiprazole, olanzapine, quetiapine, ziprasidone, risperidone, asenapine, lursidone, cariprazine
Schizoaffective disorder- paliperidone
Augmentation in depression- aripiprazole, olanzapine, quetiapine, brexpiprazole
Tourettes syndrome- haloperidol, aripiprazole and pimozide
Antiemesis- not thioridazine
bipolar and related disorders
strong genetic disorder
reasonably rare,
bipolar 1 vs 2 vs cyclothymic disorder
Bipolar 1: one or more manic episodes
Bipolar 2: at least one hypomanic episode and one MDD
Cyclothymic disorder- 2 years periods with hypomanic and depressive symptoms not meeting criteria for hypomania or major depressive episode
lithium
Monovalent cation of the lightest alkali metal
no behavioral effects in normals
Blocks manic behavior
MOA- blocsk phospholipase C IP3 phosphorylation and glycogen synthase kinase
Half life 18 to 24 hours, not bound to plasma proteins, in total body water, narrow therapeutic window, sodium levels affect Li levels, increased Na excretion causes increase in Li
ACes and Arbs also inccrease Li levels
Se and toxic reactions of lithium
Fatigue and muscular weakness, tremor- may be treated with beta blockers
GI symptoms
Slurred speech and ataxia
Serious toxicity at plasma levels about 2-3 times levels (impaired consciousness, rigidity and hyperactive deep reflexes, Coma)
lithium levels are
clinical uses of lithium
treats mania, prevents recurrences of bipolar disease
schizoaffectic and cluster headaches
Alternatives to lithiume
Carbamezpine (acts at sodium channel, CNS side effects sedation and delerium)
Valproate and divalproex sodium- first line drug in bipolar, sedating
Lamotrigine- antiseizure agents that also act at sodium channels r glutamate receptors- SuICID
For initial control of manic symptoms- haloperidol or other parenteral antipsychotic
