Pharmacology of Antipsychotics

Symptoms

Postive: hallucinations, delusions, disorganized speech, disorganized/agitated behavior

Negative: apathy, avolition, logia, anhedonia, sociality

Cognitive deficits: reduction in working memory, processing speech, social cognition, problem solving

Medical therapy: most drugs help positive symptoms, some 2nd gen can help the negative

Abnormalities in brain

Morphology

-decreases in grey matter
-dec in white matter
-inc in ventricular size

Cell

-dec in axonal and dendritic communication b/w neurons
-abnormal neuronal pruning

Neurotransmitter

Dopamine receptor abnormality

Dopamine hypothesis:
-D2 Dopamine receptor (DR) density is inc in certain regions of the schizo brain
-Antipsychotic drugs block D2 DR - good correlation b/w binding affinity/clinical potency
-dopamine agonists (used to treat PD) produce/exacerbate psychotic eps.

Dopamine pathways in the brain

Nigrostriatal:
-Substantia nigra to basal ganglia, fine
turning of movement

Mesolimbic:
-VTA --> nucleus accumbens
-regulates emotion/motivation and positive sxs

Mesocortical:
-VTA--> cortex
-rregulates attention/cognition and negative sxs

Tuberoinfundibular:
-hypothalamus --> anterior pituitary, controls
prolactin release

Multiple Receptor Systems

Pharmacological Actions:

Antipsychotic effects

-all drugs equal in efficacy
-all reduce positive sxs by blocking D2
-SGA can reduce negative sxs to some extent

Additional:
-many SGAs useful for bipolar disorder
-some SGAs may be useful for depression as adj
-most antipsychotics have antiemetic effects by blocking D2

Long-Acting Injection (LAI)

Use: pts unreliable in taking daily PO meds

-reduced 1st pass metabolism
-"flip-flop" kinetics AKA time to SS is a function of the absorption rate; conc. at SS is a func. of the elimination rate

Drugs:
-Fluphenazine
-Haloperidol
-Paliperidone
-Aripiprazole
-Olanzapine
-Risperidone

Haloperidol

Indication: Schizo/Tourette's

MOA/Metabolism:
-D2 R antagonism
-CYP3A4/2D6/UGT

ADEs:
-EPS
-Hyperprolactinemia
-Tachy/Hypo/HTN
-Neuroleptic Malignant Syndrome (NMS)*

Aripiprazole

MOA: unique
-partial D2/5HT1a agonist
-5HT2a antagonist
Metabolism:
-CYP3A4

Indication:
-schizo/manic phase of bipolar disorder
-major depressive disorder
-irritability assoc. w/ autistic disorder
-tourette's disorder

ADEs:
-somnolence/sedation/insomnia
-akathisia (fidgeting, restlessness)
-relatively low risk for weight gain

Similar drugs:

Olanzapine

Indication:
-schizo
-Manic/mixed eps of bipolar disorder
-Together w/ fluoxetine, treat depressive eps of bipolar disorder

PK/MOA:
-Antagonist: D2/5HT
-Metab CYP1A2 (smoking induces CYP1A2)

ADEs:
-Weight gain
-Somnolence/sedation
-EPS
-DRESS

Combo: Olanzapine-Samidorphan

Sami: opioid antagonist

Metabolism:
-CYP1A2/UGT/CYP3A4

ADEs:
-weight gain
-somnolence
-EPS

Clozapine

MOA:
-does NOT block D receptor
-blocks D1/4, a1, 5HT, muscarinic receptors

Indication:
-treat schizo who fail standard antipsychotic drugs (NOT 1ST LINE)
-reduce risk of suicidal behavior

DDI:
-metabolized by CYP1A2/3A4/2D6

ADEs:
-Agranulocytosis/severe neutropenia
-Weight gain (one of the worst)
-somnolence
-orthostatic hypoTN
-constipation/GI hypo motility (may be fatal)

Lumateperone

MOA:
-D2/5HT antagonist
Metabolism:
-CYP3A4/UGT

ADEs:
-Somnolence/dry mouth

Indication: treat schizo

-Movement disorder due to chronic exposure to dopaminergic receptor antagonists (essppp FGA)

Symptoms:
-grimacing
-tongue movements
-lip smacking/puckering/pursing
-excessive eye blink

MOA:
-inhibition of VMAT2 --> dec release of dopamine