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The Usual and Unusual

Suspects:Management of Interactions and Side

Effects of Psychotropic Medications

Virginia Fernandes, HonBSc, PharmD, RPhClinical Pharmacist, Psychiatry

Practice Leader, Department of Pharmacy

Adjunct Lecturer, University of Toronto

Leslie Dan Faculty of Pharmacy

CSHP, Ontario Branch AGM

November 18, 2017

Speaker Disclosure

Speaker: Virginia Fernandes

• I have no current relationships with commercial entities

• I have received no speaker’s fee for this learning activity

Commercial Support Disclosure

• This program has received no financial or in‐kind

support from any commercial or other

organization.

Objectives

• Define pharmacokinetic and pharmacodynamic drug–drug interactions and provide examples of each

• Review mechanism of common pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs) involving psychotropic medications

• Provide recommendations for management of clinically significant DDIs and ADEs encountered in practice

Quiz, Cases and Consults!

Management of Drug

Interactions

Drug Drug Interaction - Defined

Modification of the pharmacokinetic or

pharmacodynamic characteristics of a drug

due to the addition of a second drug/chemical

May result in:

– Decreased/Increased plasma drug concentrations

– Additive effects (usually adverse effects)

– Antagonistic effects (attenuation of efficacy)

English BA et al Curr Psychiatry Rep 2012;14(4):376-390

Types of Drug-Drug Interactions

PharmcoKINETIC

Modification of a drug’s kinetic

profile due to addition of a second

drug resulting in a change

(increase or decrease) in serum

drug concentration

Absorption

Distribution

Metabolism

Elimination

PharmacoDYNAMIC

TWO drugs share similar target

sites of action

Additive effects

(enhancing effects)

or

Opposite effects

(weakening effects)

English BA et al Curr Psychiatry Rep 2012;14(4):376-390

AbsorptionPharmacokinetic Interactions

Impact of Interactions which limit absorption:

Reduced absorption Decreased Bioavailability Binding:

• Cholestyramine resins with acetaminophen, furosemide, digoxin, methotrexate, atorvastatin,

vitamins, etc

• Polyvalent cations Mg, Al, Ca with Fluoroquinolones, ex

Changes in gastric pH

• Gastric acid suppression (PPIs, H2As) and drugs with pH-dependent absorption (ex:

keto/itraconazole, cephalosporins, quinolones, NSAIDS, iron)

Inhibition of transport in gut and brain

• P-glycoprotein (P-gp) inhibitor (ex: verapamil, rifampin) on substrates: TCAs, SSRIs (not

Fluoxetine), SNRIs (not Duloxetine), clozapine

Distribution and EliminationPharmacokinetic Interactions

• Distribution

- Plasma protein binding displacement Increased free fraction

- Not thought to be clinically significant as free fraction is more

readily eliminated

(ex: lamotrigine + valproic acid)

• Elimination

- Alteration in renal clearance

(ex: lithium + thiazide diuretics, digoxin + amiodarone)

Expert Opin Drug Metab Toxicol 2014;10(5):721-746

METABOLISMPharmacokinetic Interactions

• Metabolism – majority of PK DDIs- Alterations in Phase I Metabolism by inhibition or Induction of CYP450 enzymes

• Cytochrome P-450 enzymes

–Over 40 different CYP450 subtypes identified

–6 enzymes mediate ~ 90% of all activity phase I

metabolism of drugs

• CYP1A2

• CYP2B6

• CYP2C9

• CYP2C19

• CYP2D6

• CYP3A4

Curr Psychiatry Rep 2012;14(4):376-390

Clinical Significance of Metabolic DDIs

Drug-Related Factors

– Inhibitor, Inducer, or Substrate (or both!)

– Potency

– Concentration/dose

– Therapeutic index of the substrate

– Metabolite(s): Active or inactive?

– Parent drug: Active or Inactive?

• (ie: Prodrug, ex: codeine, tamoxifen, clopidogrel, tramadol)

– Extent of metabolism of the substrate

• (ie: other metabolic pathways)

Expert Opin Drug Metab Toxicol 2014;10(5):721-746

http://www.psychiatrictimes.com/articles/drug-drug-interactions-psychopharmacology/page/0/2

Flockhart Table: Indiana University, Cytochrom P450 Drug Interaction Table

Clinical Significance of Metabolic DDIs

Patient-related factors

– Age

– Genetic predisposition - pharmacogenomics

– Smoker

– Caffeine intake

Expert Opin Drug Metab Toxicol 2014;10(5):721-746

CYP450 Mediated Metabolism

MetaboliteCYP450

Potent

Inducer

Potent

Inhibitor

Case: KD

Part 1

Caffeine Intake

• Found in variable

quantities in:

– Coffee

– Tea

– Cola

– Chocolate

– Energy drinks

Caffeine - Pharmacokinetics

• Metabolized by CYP1A2 (> 90%)

• Most studies of pharmacokinetic profile support

inhibition of CYP1A2 activity

• Impact on drug metabolism is variable

• Impact on Clozapine therapy

Metabolic effects of Caffeine

Drug Effect of caffeine on object

drug concentration

Effect of caffeine

withdrawal

Clozapine Variable

Level increase by 20 – 94%

Correction factor 0.6

Variable

Levels decrease by

29 – 80%

Olanzapine Variable

N/A

Lithium Levels decreased

Monitor

Levels increase by

24%

Monitor

Mental Health October 2013 Vol 20 No.3 ISSN 1323–1251

Clin Pharm and Tox 2004;94:13-18

Psychiatr Serv 2004;55(5):491-493

Case: KD

Part 2

Smoking - Impact on

Pharmacokinetics

• Highly prevalent in patients with psychiatric

disorders

– Up to 90% patients with Schizophrenia smoke

heavily

• Smoking as little as 7 cigarettes per day

significant reductions in drug metabolism

• 7 – 12 cigarettes daily is likely sufficient for

maximum induction of CYP1A2 activity

Clin Pharm and Tox 2004;94:13-18

Eur J Clin Pharmacol 2006;62:1049-1053

Metabolic Effects of Smoking

• Tobacco smoke contains Polycyclic Aromatic

Hydrocarbons (PAHs) that induce CYP1A2

• Induction is NOT due to nicotine component of

tobacco

• NRT does not influence enzyme activity

Acute Cessation or NRT TOXICITY

Raaska K et al. Clin Pharm and Tox 2004;94:13-18

Metabolic effects of Smoking

Drug Effect of Smoking Smoking cessation

Clozapine Variable

Levels reduced by > 50%

Correction factor 1.5 – 2.5

Reduce dose by 25% within 24 – 48

hours

Anticipate further dose reductions

over 1 week. Monitor levels

Olanzapine Levels reduced by 40% Reduce dose by 25% within 1 week

Fluphenazine Levels reduced up to 50% Reduce dose by 25% within 24 – 48

hours

Haloperidol Levels reduced by 20% Reduce dose by 10% within 24 – 48

hours

Mirtazapine Levels reduced by 25% Monitor. Dose may need to be

reduced

Fluvoxamine Levels reduced by 33% Monitor. Dose may need to be

reduced

Duloxetine Levels reduced by 50% Monitor. Dose may need to be

reduced

Tricyclic

antidepressants

Levels reduced by 25 – 50% Consider reducing dose by 10 – 25%.

Monitor closely

Psychiatr Serv 2004;55(5):491-493

Mental Health October 2013 Vol 20 No.3 ISSN 1323–1251

CONSULT #1

Oral AnticoagulantsPharmacokinetic Interactions

• Warfarin

– racemic mixture of S-warfarin and R-warfarin, both inhibit the

synthesis of vitamin K–dependent clotting factors leading to an

anticoagulant effect.

– S isomer is 3 – 5 x more potent (considered ‘active’ moiety) and

is metabolized by CYP2C9

– R isomer is primarily metabolized by CYP1A2 and to a lesser

extent by CYP3A4 and CYP2C19

• Clopidogrel

– Prodrug requires CYP1A2 for activation

• DOACs

– Fewer clinically significant DDIs, but rivaroxiban should be

avoided with potent CYP3A4 inhibitors/inducers

Significant Metabolic Interactions

with Oral Anticoagulants

Drug Precipitant Drug Mechanism Clinical

Management

Warfarin

(s-isomer)

Carbamazepine CYP2C9 Induction Monitor INR

Fluoxetine

Fluvoxamine

Valproic acid

CYP2C9 Inhibition Monitor INR

Clopidogrel Fluvoxamine CYP1A2 Inhibition May weaken anti-

platelet effects

Monitor

Rivaroxiban Fluoxetine

Fluvoxamine

Paroxetine

Sertraline

CYP3A4 inhibition Consider citalopram,

escitalopram,

venlafaxine,

mirtazapine,

levomilnacipran

Carbamazepine CYP3A4 Induction Consider alternative

CONSULT #2

Antidepressants and TamoxifenPharmacokinetic Interactions

• Tamoxifen is a standard agent used in the management of

women with estrogen receptor-positive breast cancer

– Treatment

– Prevention

• 20 – 30% of women are also taking antidepressants for:

– Depression

– Anxiety

– Hot flashes

Tamoxifen is a prodrug endoxifen (active) via CYP2D6

High Risk for Drug-Drug Interactions

Tamoxifen – Antidepressant DDIs

Journal of Clinical Psychiatry 2009;70(2):1688-97

Drug Effect on CYP2D6 Clinical Management

Venlafaxine Minimal Safest Choice

Citalopram

Escitalopram

Mild Secondary choice

Sertraline

Duloxetine

Fluvoxamine

Moderate Avoid if possible

Paroxetine

Fluoxetine

Bupropion

Strong AVOID

PharmacoDYNAMIC Interactions

• Concomitant drugs with common site(s) of action

– Can result in additive effects (dry mouth, constipation, sedation, etc)

More serious risks include:

– Serotonin Syndrome:

• MAOI + SSRIs or meperidine, dextromethorphan

• SSRI + buspirone

• Triptan + SSRI?

– Bleeding

• SSRI/SNRI + NSAIDs

– QTc prolongation

• Antipsychotic + SSRI

Serotonin Syndrome• One of the first serious drug interactions described – still not

accurately diagnosed

• Sternbach and Hunter criteria developed to aid in diagnosis

Triptans + AntidepressantsPharmacodynamic Interaction?

Rarely cause by single agent, but confirmed reports with concomitant

MAOI + SSRI/SNRI

What about Triptans + SSRI/SNRIs?

2006 FDA issued alert: “Potential for life-threatening Serotonin Syndrome

with combined use of SSRIs or SNRIs and Triptan medications” based on

29 cases.

A) Reanalysis of same cases:

- None met Hunter Criteria

- 10 of 29 met Sternbach criteria

B) Questionable potential based on M of A:

- Triptans demonstrate weak affinity for 5-HT1A receptor and NO activity at 5-HT2 receptor

implicated in the development of Serotonin Syndrome

Headache 2012;52:198-203

Fake News?

• 2010 American Headache Society published a Position

Paper with recommendations that …

“..available evidence does not support limiting the use of

triptans with SSRIs or SNRIs due to concerns of serotonin

syndrome.”

• But should monitor for signs and symptoms given

seriousness of serotonin syndrome

Headache 2010;50;1089-1099

Headache 2012;52:198-203

Antidepressants and Bleeding Risk

Pharmacodynamic Interactions

SRIs inhibit uptake of serotonin into platelets

Impaired platelet aggregation

Increase risk of bleeding

Most cases of Upper GI bleeding associated with

concomitant use of NSAIDS

J Clin Psychiatry 2010;71(12):1565–1575

Gastroenterol 2014;147:784-792

SSRIs also

increase gastric

acidity

Gastroenterol 2014;147:784-792

Antidepressant and Bleeding RiskManagement strategies

• Avoid combination SSRI/SNRI + NSAIDS when

possible

• Consideration of alternative agents: – Bupropion or Mirtazapine previously considered safe

– 2017 Meta-analysis Ka et al. 2017 suggests no significant

difference in bleeding risk compared to SSRIs

– ?Levomilnacipran

• Consider administration of acid suppressants:

– elderly

– patients with history of GI ulceration or bleeds

• Counsel patient re: signs and symptoms of UGIB and

bleeding/bruising

J Affect Disord. 2018 Jan 1;225:221-226.

Management of

Adverse Drug Effects of

Psychotropic Drugs

Potential Side effects of Antipsychotics

• CNS effects

– Sedation, drowsiness, insomnia, agitation, seizures

• Extrapyramidal effects

– Tremor, abnormal movements, akathisia

• Anticholinergic effects

– Dry mouth, dry eyes, confusion

• Cardiovascular effects

– QT prolongation, ECG abnormalities, orthostatic hypotension

• Endocrine effects

– Increased prolactin levels, sexual dysfunction

• Blood dyscrasias

– Agranulocytosis

• Metabolic Syndrome

– Weight gain, increased blood glucose, increased lipids

Management of Cardiac and Neurologic Side Effects

Effect Drug Drug Management Notes

QTc

prolongation

Ziprasidone

Quetiapine

Citalopram

Escitalopram

n/a Monitor ECGs

Avoid combinations

Consider dose reduction

Orthostatic

hypotension

Clozapine

Risperidone

Quetiapine

Salt tablets

Fludrocortisone

Monitor Orthostatic vitals

Consider HS dosing

Risk for VTE Clozapine > other SGA VTE prophylaxis Consider other risk factors

Dystonia,

Parkinsonism

High potency FGAs >

SGAs

Benztropine, Procyclidine

Benzodiazepines

Diphenhydramine

Consider dose reduction

Tremor High potency FGAs >

SGAs

Propranolol Consider dose reduction

Akathisia High potency FGAs

Aripiprazole

Ziprasidone

Propranolol

Benzodiazepine (acute)

Consider dose reduction

Tardive

Dyskinesia

FGA > SGA Switch to Clozapine, or

other SGA

Early detection decreases

risk of permanent effects.

DOSE REDUCTION or

WITHDRAWAL may acutely

worsen TD

Management of METABOLIC and ENDOCRINE Side Effects

Effect Drug Management

Weight Gain Clozapine

Olanzapine

Quetiapine

Switch agents, diet, encourage physical activity

Consider: Topiramate, Metformin, Luraglutide

Combination therapy (lower dose of current agent and

addition of weight-neutral agent: Ziprasidone or

Aripiprazole)

Hyperglycemia Clozapine

Risperidone

Quetiapine

Reduce weight, increase physical activity

Consider: Metformin

Target Fasting blood glucose < 7

Dyslipidemia Clozapine > other

SGA

- Addition of lipid-lowering agent: Statin (Atorvastatin,

Pravastatin, etc) or Fibrates (Fenofibrate)

Risk of rhabdomyolysis (increase in CK)

Hypertenision High potency FGAs >

SGAs

Reduce weight, increase physical activity

Reduce dietary sodium

Consider: ACE Inhibitor, ARB

Target Blood pressure < 130/80 mmHg

Hyperprolactinemia Risperidone

Paliperidone

Reduce dose

Switch to other SGA if symptomatic

Hyperhidrosis(Excessive sweating)

SNRIs – Venlafaxine,

Desvenlafaxine

SSRIs

Consider dose reductions

Consider: Benztropine, Oxybutynin, Cyproheptadine

Principles of Medication Management

• CPA Guidelines: 7 general principles to guide

medication management:1. Medications are essential

2. Side effects vary

3. Tailor regimen to the individual

4. Keep it Simple

5. Dosing considerations: diet and lifestyle, DDIs, pharmacogenetics

6. Monitor for efficacy and side effects

7. Involve the patient