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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

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
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
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
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?




Atypical antipsychotics in the us
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
Understand how key pharmacological properties of antipsychotics translate into side effects


Receptor antagonism clinical effect
Receptor Antagonism & Clinical Effect antipsychotics translate into side effects




NIMH Psychoactive Drug Screening Program (PDSP) K University 2013i Database: http://pdsp.med.unc.edu/pdsp.php


What do you think
What do you think? University 2013

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

    • Parkinsonism

    • Antimuscarinic Effects

    • Sedation


University 2013BDNF


Metabolic changes

5HT2c University 2013

and H1

Metabolic Changes

  • Dyslipidemia and hypertriglyceridemia

    • pancreatitis

  • Hyperglycemia and insulin resistance

    • diabetic ketoacidosis

  • Increased body weight

  • Increased adiposity


Quetiapine metabolic effects
Quetiapine Metabolic Effects University 2013

  • 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
Olanzapine in Healthy Volunteers University 2013

  • 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 University 2013healthy 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
Newer Agents: Metabolic Profiles University 2013

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


* University 2013

Partial 5HT2cAgonist

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


Metabolic changes1
Metabolic Changes University 2013

  • iloperidone

  • quetiapine

  • risperidone


Weight Gain / University 2013

Metabolic Effects


Extra pyramidal symptoms eps
Extra Pyramidal Symptoms (EPS) University 2013

  • Dystonia

  • Parkinsonism

  • Tardive Dyskinesia

    _______________________________________________

  • Akathisia


Parkinsonism
Parkinsonism University 2013


Akathisia
Akathisia University 2013

  • ziprasidone

  • lurasidone

  • asenapine

  • aripiprazole

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


Decreased EPS University 2013


Hyperprolactinemia

D2 University 2013

Hyperprolactinemia

  • Gynecomastia

  • Amenorrhea

  • Breast tenderness

  • Sexual dysfunction

  • Galactorrhea


Hyperprolactinemia1
Hyperprolactinemia University 2013

Peuskens J et al. CNS Drugs 2014. PMID 24677189


EPS and University 2013

Hyperprolactinemia


Sedation

H1 and University 2013

alpha1

Sedation

  • iloperidone

  • risperidone

  • paliperidone

  • lurasidone


Sedation University 2013


What do you think1
What do you think? University 2013

  • 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
Anticholinergic Effects University 2013

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 effects1
Anticholinergic Effects University 2013

  • risperidone

  • paliperidone

  • asenapine

  • lurasidone

  • iloperidone

  • ziprasidone

  • aripiprazole


Orthostasis and dizziness

alpha1 University 2013

Orthostasis and Dizziness

  • Reduces sympathetic tone and decreases peripheral vascular resistance

  • Especially in elderly patients and those on diuretics



Qtc prolongation

All antipsychotics University 2013

can cause this

to varying degrees

QTc Prolongation

Torsades de Pointes


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


Neilsen University 2013 et al. CNS Drugs 2011;25(6):473-90.


monotherapy University 2013

w/ paroxetine

w/ parox & keto

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


Paliperidone? University 2013

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


P>0.05 University 2013

r=0.361;

p=0.004


Qtc prolongation1
QTc Prolongation University 2013

  • asenapine

  • clozapine

  • olanzapine

  • lurasidone

  • quetiapine

  • risperidone



Diabetes obesity or metabolic syndrome
Diabetes, Obesity or Metabolic Syndrome in various patient

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
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
Orthostatic Hypotension, Dizziness, or Recurrent Falls (EPS)

Highest Risk

Lower Risk

Aripiprazole

Lurasidone

Ziprasidone

  • Clozapine

  • Risperidone

  • Iloperidone

  • Quetiapine

α1

Titrate


Insomnia
Insomnia (EPS)

More Sedating

Less Sedating

Aripiprazole

Ziprasidone

  • Quetiapine

  • Clozapine

H1

5HT2a

α1


History of hyperprolactinemia or concerns about it s occurrence
History of Hyperprolactinemia or Concerns About it’s Occurrence

More Hyperprolactinemia

Less Hyperprolactinemia

Clozapine

Aripiprazole

Iloperidone

Asenapine

Quetiapine

  • Risperidone

  • Paliperidone

D2


History of ventricular a rrhythmias
History of Ventricular OccurrenceArrhythmias

More likely to prolong QTc

Less likely to prolong QTc

Aripiprazole

?Lurasidone

  • Ziprasidone

  • Iloperidone

K+ channel blockade


Will adjusting the dose fix the problem
Will adjusting the dose fix the problem? Occurrence

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
Take Home Points Occurrence

  • 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
Thank you Occurrence!!

[email protected]


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