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TRANSCRIPT
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