anti psychotics

Question 1

Psychosis

Answer 1

Derangement of personality, loss of contact with reality, delusions, hallucinations

Question 2

Schizophrenia spectrum and other psychotic disorders

Answer 2

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)

Question 3

Dopamine hypothesis

Answer 3

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

Question 4

Mesolimbic tract vs mesocortical tract

Answer 4

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

Question 5

dopaminergic synapse

Answer 5

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)

Question 6

atypical antipsychotics

Answer 6

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

Question 7

pharmacokinetics of antipsychotics

Answer 7

Oral absorption- variable, lipid soluble, protein binding, large volumes of distribution, complex metabolism

LONG half lives

Question 8

Actions of antipsychotic drugs

Answer 8

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

Question 9

extrapyramidal symptoms

Answer 9

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)

Question 10

Actions of antipsychotic drugs

Answer 10

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

Question 11

Nueroleptic malignant syndrome

Answer 11

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

Question 12

Phenothiazines

Answer 12

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

Question 13

butyrophenone, and pimozide

Answer 13

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

Question 14

Atypical drugs

Answer 14

more acceptable side effects, better to treat the negative symptoms of schizophrenia

Question 15

clozapine

Answer 15

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

Question 16

Olanzapine

Answer 16

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

Question 17

risperidone

Answer 17

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

Question 18

Quetiapine

Answer 18

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

Question 19

aripiprazole

Answer 19

parital D2 and 5HT2 antagonist

also approved in depression for bipolar 1 and tourettes syndrome

Associated with increased impulsive behavior

Long acting forms available

Question 20

other atypical antipsychotics

Answer 20

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

Question 21

uses of antipsychotic drugs

Answer 21

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

Question 22

bipolar and related disorders

Answer 22

strong genetic disorder

reasonably rare,

Question 23

bipolar 1 vs 2 vs cyclothymic disorder

Answer 23

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

Question 24

lithium

Answer 24

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

Question 25

Se and toxic reactions of lithium

Answer 25

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

Question 26

clinical uses of lithium

Answer 26

treats mania, prevents recurrences of bipolar disease

schizoaffectic and cluster headaches

Question 27

Alternatives to lithiume

Answer 27

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