Exam 1 Antipsychotics Flashcards
What is Schizophrenia
neuro-developmental disorder with onset in late adolescence, early adulthood characterized by hallucinations, delusions, disorganized thinking and emotional abnormalities
First antipsychotic tx
chlorpromazine
Schizophrenics have increased activity in what pathway? Decreased in what?
increased in Limbic, decreased in frontal
Positive sx of Schizophrenia include
hallucinations (auditory and visual) and delusions
*disorganized speech and thinking
- due to over active DA pathways in limbic
Negative sx of Schizophrenia include
apathetic, withdrawn, anti-social, lack of motivation, depressed
- due to under active dopamine pathways in frontal cortex
What cognitive impairment do Schizophrenics have
distracted, disorganized thought, memory loss
Hypotheses of Schizo
DA and Serotonin hypotheses
- DA increased can induce psychosis, antipsych block DA R
- 5-HT mediates DA transmission
other = glutamate (PCP, KEtamine)
What are the 4 DA pathways
- Mesolimbic: VTA to limbic (emotion)
- Mesocortical: VTA to frontal cortex (cognition, emotion)
- Nigrostriatal: SN to striatum (motor control)
- Tuberoinfundibular: hypothalamus to pituitary (PRL)
What two major classes of antipsychotics are there and major actions?
Classical: “neuroleptics”, block DA D2 receptors to target mesolimbic system (+ sx)
Atypical: block 5-HT2a and DA D2 receptors to target mesocortical system (+/- sx)
D2 distributed where? D4?
D2 = limbic region
D4 = cortical
Prochlorperazine is
antipsychotic that is an antiemetic
What are general effects of antipsychotics? onset?
onset 6 wk
- decrease aggression, restlessness, anxiety
- slowed psychomotor function, decreased initiation/motivation
- Reduced spontaneous mvmt
- Sedation
- most also block M, alpha adrenergic and Histamine R in brain and periphery
In addition to DA D2 and 5-HT receptors, most (classical and atypical) antipsychotics also block…
M, alpha adrenergic and histamine receptors
Do antipsychotics have many SE
yes, SE are very common, generally not pleasant thus compliance is poor
SE of antipsychotics include
- decreased seizures threshold (dangerous bc seizures can trigger relapse)
- endocrine: wt gain, ^PRL
- Autonomic (antichol (dry mouth, blurred vision, tachy, constipation), alpha adrenergic (hypoTN), Histamine (sedation)
- dental (xerostomia, bruxism)
- EPS: PD sx
- Tardive dyskinesia
- neuroleptic malignant syndrome
Describe the EPS that are common with antipsychotics
Parkinsons like sx - tremor, akathisia (rocking), cogwheel rigiditiy, pacing, dyskinesias
- antipsychotics (DA receptor antag) also block DA receptors in nigrostriatal pathway –> imbalance of striatal DA & ACh
- *imbalance of striatal DA and ACh
EPS due to? degree based on? treat with?
imbalance of striatal DA & ACh
- degree of EPS based on anticholinergic activity of drug
- high antichol activity ie chlorpromazine = lower EPS
- low antichol activity ie haloperidol = higher deg EPS
*treat with anticholinergics = Benztropine (Congentin)
How do you treat EPS?
with anticholinergics such as Benztropine (Congentin)
Which have more EPS, classical or atypical antipsychotics
classical antipsychotics
Tardive dyskinesia is present in what percent of pt treated with antipsychotics and what sx does it entail
15-25%
- uncontrollable mouth and facial mvmts, occurs late in dz after LONG term TX
- difficult to treat, often irreversible; dc antipsychotic
what antipsychotics are least likely to cause TD
the atypicals CLOZAPINE and OLANZAPINE
What is neuroleptic malignant syndrome and what is it caused by?
life threatening condition char by muscle rigidity, hyperpyrexia, changes in BP and HR
- due to blockage of DA D2 R in striatum and hypothalamus by antipsychotic med
How do you treat neuroleptic malignant syndrome?
Dantrolene (dantrium)
- can also used DA agonists (bromocriptine) to stimulate DA receptors
- bromocriptine used to treat Parkinsons
What medications do Antipsychotics interact with?
Antichol: ^SE (dry mouth, urinary retention, constipation)
Sedative-hyp: ^sedation
TCA: ^seizures, cardiac effect
Drugs that induce CYP450s (carbamazepine, cimetidine)
Smoking (bc induces CYP450)
Unpredictable with antihypertensives due to alpha blockade (^hypoTN)
How do classical antipsychotics work and what receptor occupancy is required
block DA D2 receptors, require 60% R occupancy
PK of Classicals?
Oral admin, gut absorption
- high first pass, CYP 450 (2D6 and 3A4) metab
- 20-35 hr half life
- effects persists wks after last administration
Chlorpromazine (Thorazine).. class and use
Classical antipsychotic: block DA D2 Receptors
*psychosis associated w/ mania & drugs of abuse, pre-anesthetic
prochlorperazine = antiemetic
Risks of Chlorpromazine (classical Antipsych)
EPS, TD, Neuroleptic malignant syndrome may occur
*but high antichol effects thus lower incidence of EPS
SE of chlorpromazine include
sedation, postural hypoTN, blurred vision, constipation, decreased GI motility, inhibition of ejaculation, jaundice
DECREASED SEIZURE THRESHOLD
*may cause RETINAL DEPOSITS “browning of vision”
Fluphenazine (Prolixin).. what type of drug? is similar to? action?
classical antipsychotic
similar to Chlorpromazine
selective for DA DR R
less antichol thus more EPS
Haloperidol (Haldol) aka? MOA? use?
Vit H, potent DA DR r blocker
*also DA D1, 5HT2, a1 receptors
- used in acute situations, injected
half life and SE of Haldol
long half life
no anticholinergic activity thus increased EPS
Atypical antipsych include
Clozapine (Clozaril) Risperidone Olanzapine (Zyprexa) Quetiapine Ziprasidone Aripiprazole (Ability)
Clozapine (Clozaril) MOA, SE
blocks 5-HT2a and DA D4 receptors, some affinity DA D2
SE: hypersalivation, sedation, postural hypoTN, tachy, wt gain
*EPS and tardive dyskinesia rare
*rapid relapse if dc abruptly
Drug of LAST CHOICE due to AGRANULOCYTOSIS (monitor WBC)
Olanzapine (Zyprexa): class? is similar to? MOA, use?
Atypcial antipsychotic –>
Similar to clozapine, but NO agranulocytosis
Blocks 5-HT2a R and DA D4, D2
*improves +/- sx schizophrenia, also used for bipolar disorder
*some antichol activity, EPS rare
SE of Olanzapine (Zyprexa)
sedation, ortho hypoTN, wt gain, HYPERGLYCEMIA WITH T2DM
Olanzapine (zyprexa) use
improve +/- sx schizo w/o agranulocytosis SE
*also used for bipolar when comb with lithium
Risperidone (Risperdal) use, MOA
FIRST LINE drug for psychosis
- improves +/- sx
- blocks 5-HT2a and DA D2 rec
- no sig effect on DA neurotransmission in Nigrostriatal pathway (thus TD or EPS rare)
SE of Risperidone (Risperdal)
hypoTN, wt gain, insomnia, anxiety, some cardiac (lengthens QTI)
*EPS and TD rare bc little effect on DA neurotransmission in nigrostriatal pathway
Ziprasidone (Geodon) class? MOA?
atypical antipsychotic
*blocks DA D2 and 5HT2a r
activity and use of Ziprasidone (Geodon)
some antidepressant activity (5-HT1a R agonist, inhibition of 5-HT reuptake)
Use: TOURETTES, acute mania
PK of Ziprasidone (Geodon)
*atypical antipsych used for tourettes and acute mania
oral or IM
CYP3A4 metab
SE of Ziprasidone (Geodon)
PROLONGS QTI
SEDATION, impairs cog and motor skills
may cause hyperPRL (tubuloinfundibular pathway)
*decrease seizure threshold
Quetiapine (Seroquel) class? similar to? MOA?
atypical antipsychotic
similar to clozapine but no agranulocytosis (Olanzapine also no agranulocytosis)
MOA: blocks 5HT-2a and D2 rec
Use of Quetiapine (Seroquel)? SE?
promote sleep onset and maintenance
*SE: very sedating, dizzy, constipation, xerostomia, ortho hypoTN, wt gain, few EPS, does not elevate PRL (Ziprasidone elevates PRL)
Use of Aripiprazole (Abilify)?
Dopamine system stabilizer
- dopaminergic tone low, DA receptors activated
- dopaminergic tone high, DA receptors blocked
MOA of Aripiprazole (abilify)
Partial agonist for DA D2 and 5-HT1a; antagonist for 5-HT2a
*also blocks a1 and histamine r
SE, of Aripiprazole (ability)
SE: hypergly, seizures, sedation, orthostatic hypoTN, DECREASES ESOPHAGEAL MOTILITY
*no ^PRL, no ^QTI, low EPS :)
What is bipolar affective disorder
affects about 2% of the population, genetic component
- pt alternate bw manic and deep depression
- may be due to lack of GABAergic activity
How are bipolar pt normally treated
Lithium &anticonvulsants
*often treated with combinations of these drugs and antipsychotics such as OLANZAPINE (ZYPREXA)
How does lithium (Li) work
mood stabilizer works by suppression of 2nd messengers (IP3) - may increase ACh, NE, DA
PK of Lithium
gut absorption
body wide distribution
half life 24 hr
no metab, kidney excretion
effectiveness of Lithium (Li), compliance
calming effect in 60% of pt
- poor compliance bc feel sick
- extremely toxic in OD
How is Lithium reabsorbed and what influence does this have on Na?
Reabsorbed in PT of kidney
Competes w Na for reabs:
- high Na = increased Li abs = toxicity
- high Na = decreased Li abs = increased Li excretions
- increased Li = decreased Na absorption = hypoNa
Is lithium safe? Therapeutic window?
Small therapeutic window (optimal plasma concentrations 0.6-1.2 mEq/L)
- Plasma > 2mEq/L: N, diarrhea, anorexia, muscle weakness, HA, tremor, confusion, memory impairment
- Plasma > 2.5 mEq/L: confusion, seizures, renal failure, cardiac arrhythmia, coma, death
SE of Lithium
Hypothyroidism
Diabetes Insipidus (Li inhibits ADH, treat with amiloride)
*not recommended in pregnancy
how do you treat Diabetes insipidus due to Lithium
Amiloride
Drug interactions with Lithium include
- Antidep: mania may increase
- Diuretics (alter Na excretion), can alter Li clearance
- NSAIDs increase Li toxicity, decrease clearnace, increase Li uptake
- Na: high Na reduces Li concentration; high Li may lead to decreased Na reabsorption and hypoNa
BZ and antipsychotics are safe
Anticonvulsants that are alternatives to Lithium for tx of bipolar include
Valproic Acid (Depakene)
Gabapentin (Neurontin)
Carbamazepine (Tegretol)
Lamotrigine (Lamictal)
Valproic Acid (Depakene) MOA and use/efficacy
Unknown MOA
*used for Rapid cycling manic/depressive phases, efficacy in some pt who do not respond to lithium (just as or more effective than lithium), rapid onset
SE of Valproic Acid (Depakene)
*remember, used for rapid cycling in bipolar and is also an anticonvulsant
- GI, sedation, liver enzyme induction, wt gain, surgical bleeeding (dental)
- Teratogenic (anticonvulsants are generally not safe in pregnancy
Gabapentin (Neurontin) use specifically regarding mood disorders
anticonvulsant GABA analogue used for rapid cycling in bipolar disorder
*also neuropathic pain, partial seizures, generalized tonic clonic seizures
Preg Cat C
Carbamazepine (Tegretol) drug class and mood disorder use?
*used for REFRACTORY bipolar disorder when combined with Li
Anticonvulsant DOC for partial seizures, wide used for generalized seizures, trigeminal neuralgia inhibits Na channels thus inhibits Glutamate neurotransmission
Carbamazepine (Tegretol) SE?
GI, sedation, CNS toxicity, hematologic rxn, hypersensitivity rahss (risk SJS - toxic epidermal necrolysis, must test human antigen)
Lamotrigine (Lamictal) drug class and use?
Anticonvulsant that inhibits Na channels and thus Glutamate neurotransmission
*use: prevention of relapse, depressive state following mania and acute mania
just as a review, seizures are due to
underactive GABA neurotransmission, and/or over active glutamate
*thus anticonvulsants target increasing GABA Neurotransmission and inhibition Glutamate neurotransmission
