Atypical antipsychotic pharmacology
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Atypical Antipsychotic Pharmacology. Stephanie Nichols, Pharm.D., BCPS, BCPP Associate Professor of Pharmacy Practice [email protected] Using Receptor Binding Profiles to Predict Adverse Effects. Objectives. Recognize atypical antipsychotics by brand and generic name

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Atypical Antipsychotic Pharmacology

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Atypical Antipsychotic Pharmacology

Stephanie Nichols, Pharm.D., BCPS, BCPP

Associate Professor of Pharmacy Practice

[email protected]

Using Receptor Binding Profiles to Predict Adverse Effects


Objectives

  • Recognize atypical antipsychotics by brand and generic name

  • Understand how key pharmacological properties of antipsychotics translate into side effects

  • Compare and contrast the pharmacology of the atypical antipsychotics

  • Predict which antipsychotics may be more, or less, desirable in various patient scenarios


1950

1960

1970

1980

1990

2000

2010

FDA Approval of Antipsychotics

Thioridazine

Perphenazine

Aripiprazole

Trifluoperazine

Risperidone

Mesoridazine

Iloperidone

Chlorpromazine

Pimozide

Clozapine

Asenapine

Quetiapine

Haloperidol

Droperidol

Ziprasidone

Prochlorperazine

Lurasidone

Fluphenazine

Paliperidone

Loxapine

Olanzapine

Thiothixene

Stephanie Nichols, PharmD BCPS BCPP

2014


What defines an Antipsychotic?

  • Dopamine2 post synaptic antagonism

  • Reduce DA in the mesolimbic tract

    • Nucleus accumbens

  • Positive Symptoms

  • EPS


Antagonism

Partial Agonism


Mesolimbic

– VTA to NA, HC, amygdala

Mesocortical

– VTA to PFC

Nigrostriatal

– SN to BG

Tuberoinfundibular

– Hypothalamus to Pituitary Gland

http://psychopharmacologyinstitute.com/antipsychotics-videos/dopamine-pathways-antipsychotics-pharmacology/


What defines an Atypical Antipsychotic?

  • Serotonin2a post-synaptic antagonism

  • 5HT2a puts the brakes on DA in PFC

    • Disinhibiting the inhibitor – increased mesocortical DA

  • ? Improved negative and cognitive symptoms

  • Reduced EPS – at what cost?


Typicals vs. Atypicals


Recognize atypical antipsychotics by brand and generic name


Atypical Antipsychotics in the US

Generic Availability

Brand Name Only

Aripiprazole (Abilify)

Paliperidone (Invega)

Iloperidone (Fanapt)

Asenapine (Saphris)

Lurasidone (Latuda)

  • Clozapine (Clozaril)

  • Olanzapine (Zyprexa)

  • Quetiapine (Seroquel)

  • Risperidone (Risperdal)

  • Ziprasidone (Geodon)


Understand how key pharmacological properties of antipsychotics translate into side effects


Receptor Antagonism & Clinical Effect


Compare and contrast the pharmacology of the atypical antipsychotics


Addressing Negative Symptoms in Schizophrenia. CPNP University 2013


NIMH Psychoactive Drug Screening Program (PDSP) Ki Database: http://pdsp.med.unc.edu/pdsp.php


What do you think?

  • Based upon Quetiapine’s binding profile, which of the following adverse effects is most likely to occur?

    • Parkinsonism

    • Antimuscarinic Effects

    • Sedation


↑ BDNF


5HT2c

and H1

Metabolic Changes

  • Dyslipidemia and hypertriglyceridemia

    • pancreatitis

  • Hyperglycemia and insulin resistance

    • diabetic ketoacidosis

  • Increased body weight

  • Increased adiposity


Quetiapine Metabolic Effects

  • Even low dose (<200mg/day) quetiapine causes significant weight gain and increase in BMI after 52 weeks

Cates ME et al. Metabolic Consequences of Using Low Dose Quetiapine for Insomnia in Psychiatric Patients. Community Ment Health J. 2009;45:251-4.


Olanzapine in Healthy Volunteers

  • 10mg nightly x3 days

Albaugh VL, Singareddy R, Mauger D, Lynch CJ (2011) A Double Blind, Placebo-Controlled, Randomized Crossover Study of the Acute Metabolic Effects of Olanzapine in Healthy Volunteers. PLoS ONE 6(8): e22662.


  • 15 healthy subjects given 10mg po olanzapine or placebo (self-control)

  • Results:

    • decrease in glucose effectiveness, free fatty acids, and serum cortisol

    • increase in fasting glucose and prolactin

After a

single

dose!!

Hahn MK. et al. J Clin Psychopharmacol 2013; 33(6):740-6.


Newer Agents: Metabolic Profiles

CNS Drugs 2012. 26(9):733-59.


*

Partial 5HT2cAgonist

Data from: Nguyen CT et al. Prim Care Comp CNS Disord 2012;12(5).


Metabolic Changes

  • iloperidone

  • quetiapine

  • risperidone


Weight Gain /

Metabolic Effects


Extra Pyramidal Symptoms (EPS)

  • Dystonia

  • Parkinsonism

  • Tardive Dyskinesia

    _______________________________________________

  • Akathisia


Parkinsonism


Akathisia

  • ziprasidone

  • lurasidone

  • asenapine

  • aripiprazole

Poyurovsky M. BJP 2010;196:89-91.


Decreased EPS


D2

Hyperprolactinemia

  • Gynecomastia

  • Amenorrhea

  • Breast tenderness

  • Sexual dysfunction

  • Galactorrhea


Hyperprolactinemia

Peuskens J et al. CNS Drugs 2014. PMID 24677189


EPS and

Hyperprolactinemia


H1 and

alpha1

Sedation

  • iloperidone

  • risperidone

  • paliperidone

  • lurasidone


Sedation


What do you think?

  • Based upon receptor binding, which agent may be expected to be associated with constipation, urinary retention, and blurred vision?

    • Clozapine

    • Asenapine

    • Ziprasidone

    • Iloperidone


Anticholinergic Effects

M1

  • Blind as a bat

  • Dry as a bone

  • Red as a beet

  • Mad as a hatter

  • Urinary retention

  • Constipation

  • Tachycardia

  • Blurred vision

  • Dry mucous membranes

  • Flushing

  • Confusion and delirium


Anticholinergic Effects

  • risperidone

  • paliperidone

  • asenapine

  • lurasidone

  • iloperidone

  • ziprasidone

  • aripiprazole


alpha1

Orthostasis and Dizziness

  • Reduces sympathetic tone and decreases peripheral vascular resistance

  • Especially in elderly patients and those on diuretics


Orthostatic Hypotension and Dizziness


All antipsychotics

can cause this

to varying degrees

QTc Prolongation

Torsades de Pointes


Beach et al. Psychosomatics 2013:54:1–13


Neilsen et al. CNS Drugs 2011;25(6):473-90.


monotherapy

w/ paroxetine

w/ parox & keto

Potkin et al. J Clin Psychopharmacol2013;33: 3Y10


Paliperidone?

Watanabe et al. J Clin Psychopharmacol2012;32: 18Y22


P>0.05

r=0.361;

p=0.004


QTc Prolongation

  • asenapine

  • clozapine

  • olanzapine

  • lurasidone

  • quetiapine

  • risperidone


Predict which antipsychotics may be more, or less, desirable in various patient scenarios


Diabetes, Obesity or Metabolic Syndrome

Usually Weight Neutral

Most Weight Gain

Clozapine

Olanzapine

Quetiapine

  • Aripiprazole

    (except with 5HT antidepressants)

  • Lurasidone

  • Ziprasidone

5HT2c

H1


Parkinson’s Disease or History of Extra Pyramidal Symptoms (EPS)

Less likely to cause EPS

More EPS

Parkinsonism and Dystonia

Risperidone

Paliperidone

Akathisia

Aripiprazole

Lurasidone

Asenapine

Ziprasidone

  • Clozapine

  • Quetiapine

D2


Orthostatic Hypotension, Dizziness, or Recurrent Falls

Highest Risk

Lower Risk

Aripiprazole

Lurasidone

Ziprasidone

  • Clozapine

  • Risperidone

  • Iloperidone

  • Quetiapine

α1

Titrate


Insomnia

More Sedating

Less Sedating

Aripiprazole

Ziprasidone

  • Quetiapine

  • Clozapine

H1

5HT2a

α1


History of Hyperprolactinemia or Concerns About it’s Occurrence

More Hyperprolactinemia

Less Hyperprolactinemia

Clozapine

Aripiprazole

Iloperidone

Asenapine

Quetiapine

  • Risperidone

  • Paliperidone

D2


History of Ventricular Arrhythmias

More likely to prolong QTc

Less likely to prolong QTc

Aripiprazole

?Lurasidone

  • Ziprasidone

  • Iloperidone

K+ channel blockade


Will adjusting the dose fix the problem?

Dose related effects

Non-dose related effects

Weight gain

Metabolic changes

  • EPS

  • Sedation

  • Amenorrhea

  • Agitation

  • Activation

Aripiprazole – somnolence at higher doses

Ziprasidone – activating at lower doses (5HT2c)

Quetiapine – less sedating at higher doses


Take Home Points

  • D2 antagonism = ↓ positive symptoms

    • EPS (ex. parkinsonism, dystonia) = high D2 antagonism

      • Risperidone, paliperidone

  • 5HT2a antagonism = ↓ EPS

    • may help with (or not exacerbate) negative and cognitive symptoms

  • Histamine1, alpha1, and muscarinic antagonism = side effects

    • Quetiapine, clozapine, and olanzapine

  • 5HT2c + H1 antagonism = metabolic dysregulation & weight gain

    • Olanzapine, clozapine

  • Effects of binding 5HT1a, 5HT7, alpha2a, and alpha2c are still not fully understood but felt to contribute to efficacy


Thank you!!

[email protected]


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