PDA III Antipsychotics

Types of antipsychotics

-Typical: first gen

-Atypical: second gen

-Third gen

3 types of typical antipsychotics

-Phenothiazines: 3 subtypes

-Thioxanthenes

-Butyrophenones

3 types of phenothiazines

-Aliphatic: low potency

-Piperidine: low potency

-Piperazine: high potency

Atypical drugs

-Clozapine

-Risperidone

-Olanzapine

-Quetiapine

-Ziprasidone

Third gen drugs

-Aripiprazole

-Brexpiprazole

-Cariprazine

MOA of typical antipsychotics

-All are competitive D2 antagonists

-Vary in potency, but are all equally efficacious for treating schizophrenia when adjusted

-Main therapeutic effect is to relieve hallucinations, delusions, and disordered thought (positive symptoms)

-Not effective on negative symptoms (may make them worse)

D2 antagonists in the mesolimbic pathway

-Untreated symptoms on the top

-Treated symptoms on the bottom

-Decreases positive symptoms (good)

D2 antagonists in the mesocortical pathway

-Left: DLPFC (worsens motivation and cognitive function)

-Right: VMPFC (worsens motivation and increases social withdrawal)

-Worsens negative symptoms (bad)

Side effects of typical antipsychotics (D2 antagonism)

-Extrapyramidal motor symptoms

-Thermoregulatory effects

-Endocrine changes (prolactin)

-Tardive dyskinesia

Extrapyramidal motor symptoms

-Describes symptoms in the N. Striatal motor tract

-Acute dystonia

-Akinesia, parkinsonism, pseudo-parkinsonism

Acute dystonia

-Twisting contractions of trunk, limbs, and face

-Abnormal posture

-Pt thinks they're having a seizure

-Hypothesis: rapid decrease in D2 causes rapid increase in ACh

-First 1-5 days of treatment

-Seen when dose and/or potency is high

Akinesia, parkinsonism, pseudo-parkinsonism

-Akinesia: lack of movement

-(Pseudo) parkinsonism: pill rolling tremor, poor posture, shuffling gait

-Losing DA binding to receptors in the nigrostriatal tract

-Imbalance between DA and ACh

-"Dirty drugs" that also bind other receptors in the brain

-Occurs after around 5-30 days of treatment

Dirty drugs

-Nonspecific drugs

-These antipsychotics may also bind a few other receptors

-High potency group have higher affinity for DA receptors (more specific)

-Antipsychotics that bind muscarinic receptors are less likely to cause parkinsonism

Akathisia

-Uncontrolled restlessness, fidgeting

-Occurs after 5-60 days of treatment

D2 antagonists in the nigrostriatal pathway

-Cause of parkinsonism

-Low DA, high ACh

Cholinergic circuit review

-Muscarinic antagonists can combat the adverse effects from increased ACh

-Benztropine is a common muscarinic antagonist

Thermoregulatory effects

-Problems for elderly pts in the summer

-Body can't regulate its temperature

Endocrine changes

-DA in the hypothalamus inhibits the release of prolactin

-Removal of inhibition allows for excessive release of PRL

-Result is gynecomastia and milk production (galactorrhea): both men and women

-Decreased libido

-Causes adherence issues

D2 antagonism in the tuberoinfundibular pathway

-Leads to hyperprolactinemia

Tardive dyskinesia

-Involuntary, repetitive movements of face, tongue, lips

-Thought to be caused by DA receptor supersensitivity due to long term use

-Most cases preceded by drug-induced parkinsonism

-Occurs in the nigrostriatal tract

-Abrupt removal of antipsychotic makes it worse

-Increased dose only temporarily delays TD

-Anticholinergics worsen TD

-Pretty bad side effect

Tardive dyskinesia treatment

-VMAT2 inhibitors: valbenazine (ingrezza)

VMAT 1 vs VMAT2

-1: in the periphery and brain

-2: only in the brain

Reserpine

-Irreversibly blocks VMAT1 in the periphery

-Prevents the storage of DA, and therefore the storage of NE

-Causes depression, not used anymore

VMAT2 MOA

-Normally transports DA from the cytoplasm into synaptic vesicles for storage and release

-VMAT2 inhibitors prevent this storage: decreased DA stimulation overall

VMAT2 inhibitors drugs

-Tetrabenazine

-Deutetrabenazine

-Valbenazine

Tetrabenazine

-All four of these are reversible inhibitors of VMAT2

-Tetrabenazine converted to 4 enantiomers via carbonyl reductase

-4 enantiomers are metabolized by 2D6

-Approved for Huntington's disease, not TD

Deutetrabenazine

-Longer half life

-Less drug interactions w/ 2D6

-Approved for HD and TD

Valbenazine

-Prodrug

-End with an agent that inhibits VMAT2

-Drug goes inside DA neurons, inhibiting VMAt2 preventing VMAT from breaking down DA vesicles,

Typical antipsychotic side effects

-Sedation

-Anti-sludge

-Decreased BP and orthostatic hypotension

Sedation

-Low potency group is more sedating than high potency group

-Can be an advantage in aggressive or violent pts

-Sedative effects subside in 1-2 weeks

Anti-sludge

-Anticholinergic effects (tachycardia, dry mouth, constipation)

-Due to muscarinic antagonism

-Most common in low potency group

Decreased BP and orthostatic hypotension

-Due to alpha blockade

-Most common in low potency group

Elements of low potency group

-Sedation

-Anticholinergic effects (muscarinic antagonism)

-Decreased BP and orthostatic hypotension (alpha blockade)

Elements of high potency group

-More dopaminergic effects

Chlorpromazine

-Low potency

-Dirty drug: binds a lot of receptors

-Boxes on the bottom: furthest to the left has highest affinity, bigger box has higher affinity

Fluphenazine

-High potency

Haloperidol

-High potency

Characteristics of atypical antipsychotics

-Distinguished by side effect and efficacy profile

-Lower incidence of motor side effects and TD

-Effective at treating negative symptoms

Atypical antipsychotic MOA

-5HT2A antagonists

-Block 5HT2A receptors in addition to D2

-Benefits of 5HT2A appear to include decreased EPS, TD, and treating negative symptoms

-Work on 3 pathways in the brain

EPS

-Extrapyramidal symptoms: motor symptoms

3 pathways effected by 5HT2A antagonists

-Mesolimbic

-Nigrostriatal

-Mesocortical

Mesolimbic pathway and its therapy in atypical antipsychotics

-Glutical neurons in cortex release glutamate at the VTA

-VTA: where cell body is in mesolimbic pathway

-Emotional striatum: where axons release DA in mesolimbic pathway

-When there is too much DA in emotional striatum, causes positive symptoms

-So excitement of glutical neurons in cortex cause positive symptoms

-Glutical neurons are regulated by 5HT2A (excites glutical neurons)

-5HT2A antagonist inhibit glutical neurons, causing less DA release in emotional striatum, decreasing positive symptoms

Nigrostriatal tract and its therapy in atypical antipsychotics

-5HT2A excites glutamate's effect on GABA

-GABA causes less DA to be released in the motor striatum

-5HT2A antagonists will decrease excitement on GABA, less GABA gives more activity in the motor striatum, decreasing motor side effects (parkinsonism): drug recruits its own endogenous DA competitor

Mesocortical pathway and its therapy in atypical antipsychotics

-5HT2A excites glutamate's effect on GABA (low DA)

-GABA inhibits mesocortical pathway: causes negative symptoms

-5HT2A antagonist decrease excitement on GABA, less GABA gives more activity in mesocortical pathway, resulting in increased DA and a reduction in negative symptoms

Ratio of binding D2 to 5HT2A

-5HT2A : D2

-Higher in atypicals than typicals

Clozapine

-Granddaddy

-5HT2A > D4 > D2

-Fewer EPS side effects (no parkinsonism), few cases of TD, no effect on PRL secretion

-Strong antimuscarinic action (but hypersalivation), rapid/dramatic weight gain, increased blood sugar, QTc prolongation, dose related seizure risk

-Agranulocytosis

Pines/dones on weight gain / blood sugar

-Both pines and dones cause rapid weight gain and increased blood sugar

-Effect is more dramatic in pines (based on high 5HT2A to D2 ratio receptor binding)

Olanzapine

-Very similar to clozapine, but without agranulocytosis

-Sedating: H1

-Increased body weight (H1), DM, increased cholesterol

-EPS effects at high end of dise range

Quetiapine

-Just as effective on positive symptoms, but not as effective on negative symptoms as other atypicals

-Increased body weight, cataracts (eye exam before tx and q6months thereafter)

-Stars indicate norquetiapine metabolite

-H1: good for sleep in depression related insomnia

-NET binding is good for depression

-5HT2C and H1 may contribute to weight gain

Ziprasidone

-Contraindicated in pts w/ hx of prolonged QT, MI, or arrhythmias

-Causes QT prolongation, ventricular arrhythmias and sudden death

-No effect on body weight and blood glucose

-Doesn't act at sedating receptors

Risperidone

-Most typical of the atypicals

-Low to moderate doses, no EPS side effects

-Moderate to high doses can produce EPS side effects

-Minimal anticholinergic effects and orthostatic hypotension on the first dose

-Insomnia, agitation, anxiety

-Less weight gain than clozapine

Aripiprazole

-Partial DA agonist for D2 and D3 receptors (decrease DA where its too high, increase DA where its too low)

-5HT2A antagonist

-May decrease DA activity where it is too high and increase where it is too low

-Minor side effects: headache, agitation, insomnia, anxiety

Label each curve: DA, abilify, DA+abilify, DA+haloperidol

-A: DA

-B: abilify

-C: DA + haloperidol

-D: DA + abilify

Aripiprazole receptor profile

Brexipiprazole

-Rexulti

-D2 and D3 partial agonist

-5HT2A antagonist

-Weight gain, akathisia

Cariprazine

-Vraylar

-D2 and D3 partial agonist, selective for D3

-Weight gain, akathisia, insomnia

Other antipsychotics

-Pimavanserin

-Lumateperone

-Cobenfy

Pimavanserin

-Treat psychosis and PD

-5HT2A and C inverse agonist (decreases 5HT activity)

-Not a D2 antagonist

Inverse agonist

-The opposite effect of whatever the agonist does

-Decreases basal activity in receptors with basal activity

-Decrease signaling

Basal activity

-Level of the biological response in the

absence of added drug

-Receptor has an effect even when ligand isn't attached

Pimavanserin receptor profile

Lumateperone

-Caplyta

-Schizophrenia, Bipolar, depression adjunct

-D2 antagonist, 5HT2A antagonist, SERT inhibitor

-2nd gen MOA, 1st gen structure

Cobenfy

-Xanomeline and trospium

-Xanomeline: M1 and M4 agonist (decreases mesolimbic DA)

-Trospium: peripheral muscarinic antagonist (prevents peripheral cholinergic side effects)

Choosing an antipsychotic

-Determined mainly by risk of adverse effects

-1st and 2nd gen have about equal efficacy for positive symptoms

-2nd gen are more efficacious for negative and cognitive symptoms

-Typicals are limited by EPS and endocrine SEs

-Atypicals are limited by metabolic effects (weight gain, DM)

-First line: atypicals other than clozapine