1/24/2017

Drug Interactions in Cardiology

Medicine
How to asses its risk and benefit

Bambang S Zulkarnain, S.Si., Apt., M.Clin.Pharm (UQ)

Clinical Pharmacy Department
Faculty of Pharmacy Universitas Airlangga

Untreated
indication
Medication Improper
use without drug
indication selection

DRP
Subtherap
Drug
interaction
eutic
dosage

Adverse
drug Over dose
reaction
Failure to
receive
medication

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DRUG INTERACTIONS
Drug interactions (DI) - important cause of ADRs.
326% of all ADRs leading to admission are caused
by DDIs
DI increased length of stay, healthcare costs,
emergency department visits
NSAIDs were the most involved in DDI for hospital
admission
Warfarin was the most involved DDI in hospital visit
(Dechanont S et al, 2014)

Pharmacoepidemiol Drug Saf 2014 May;23(5):489-97

Cardiovascular
Pharmacotherapeutics
At A Glance

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HYPERTENSION
ACEi/ARBs captopril, ramipril/valsartan
Beta Blockers metoprolol, carvedilol,
bisoprolol
Calcium Channel Blockers
- Dihidropyridine: Amlodipin
- Non dihidropyridine: diltiazem, verapamil
Diuretics HCT, Aldosterone antagonists

CORONARY ARTERY DISEASE

Beta blockers cardioselective, non ISA
Calcium Channel Blockers
Nitrates
Antiplatelets
- COX2 inhibitors
- ADP antagonists
- Glycoprotein IIb/IIIa inhibitors

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CORONARY ARTERY DISEASE (Cont)

Anticoagulants
- warfarin, dabigatran
- Heparin, LMWH
Trombolytics
- Streptokinase
Lipid Lowering Agents

HEART FAILURE
Drugs to relieve symptoms
- Diuretics, Digoxin
Drug for survival
- ACEis/ARBs
- Beta Blockers
- Aldosterone Antagonist

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RHEUMATOID HEART DISEASE

Antibiotics
NSAIDs
Steroids
Heart Failure Therapy including Diuretics
Anticoagulants warfarin arrhytmia

Surgical Care

Drug Interactions In
Cardiovascular
Pharmacotherapeutics

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NSAIDs and Antihypertensives

Rationale
Some NSAIDs may use for analgesics or antiplatelet

NSAIDs may reduce effect of antihypertensive

agents
Beta blockers >> Vasodilators and Diuretics
Piroxicam >> sulindac and aspirin
(Johnson AG et al, 1994)
Ann Intern Med. 1994;121(4):289-300.

NSAIDs and Antihypertensives

Low dose ASA 75-100 mg vs ACEi
ASA blocks COX interfere prostaglandin
mediated hemodynamic effect of ACEi
Long term low dose ASA does not reduce
antihypertensive effect of ACEi
Higher dose ASA or patient with CHF may
produce significance interaction
(Nawarskas JJ, Sarah AP, 1998; Zanchetti et al, 2002)

Pharmacotherapy Vol 18 (5), 1998 pp 10411052

J Hypertension Vol 20 (5), 2002, pp 105-1022

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ACEi and Food

Food reduces bioavailability of captopril by
35%-40% (Singhvi et al, 1982)
But, food did not influence either acute or
chronic Blood Pressure (BP) of Captopril
(Salvetti A et al, 1985)

J Clin Pharmacol. 22(2-3),1982, pp. 135-40.

J Cardiovasc Pharmacol. 1985;7 Suppl 1:S25-9.

Triple Whammy
Rationale
CAD and HF or other commorbid

What?
Triple Drugs Combo related with pre renal
Acute Kidney Injury (AKI)
Concomittant use of NSAIDs, ACEIs/ARBs and
Diuretics
(Garcia LP et al, 2016)
Pharmacol Ther. 2016 ;167:132-145

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Triple Whammy
AKI
abrupt decline in renal excretory function
causing azotaemia, oliguria, or both
Cr increase, GFR decrease
(Garcia LP et al, 2016)

Pharmacol Ther. 2016 ;167:132-145

AKI
Incidence
1-2% hospital admission
2-7% hospitalized patients
30% in critically ill patients
Economical impact:
5% hospital impact (extended hospital stays, closer
monitoring and dialysis)
1% overall health expenditure
(Garcia LP et al, 2016)
Pharmacol Ther. 2016 ;167:132-145

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Mechanism of Triple Whammy

http://www.hps.com.au/knowledge-centre/clinical-articles/clinical-article-the-triple-
whammy/ accessed January 18, 2017

Antiplatelet PPI Interaction

Rationale
Long term combination of clopidogrel ASA is
used
Antiplatelet blockade of prostaglandin in
gastrointestinal tract GIT Bleeding
PPI is used to prevent GI Bleeding

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Antiplatelet PPI Interaction

Clopidogrel vs Omeprazole
Clopidogrel is pro drug; metabolize via CYP
2C19
Omeprazole strong inhibitor CYP 2C19
FDA Box Warning (2009)
significant reductions in clopidogrel's active
metabolite levels and antiplatelet activity.
increased risk of adverse cardiovascular outcome

Clopidogrel dan PPI

sama-sama
dimetabolisme pada
jalur CYP-450. PPI
bersifat inhibitor
kompetitif jika
digunakan bersamaan
dengan Clopidogrel
sehingga metabolit
aktif Clopidogrel yang
dihasilkan lebih sedikit
dan efektivitasnya
sebagai antipaltelet
menjadi lebih rendah

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Clopidogrel vs Omeprazole
Conflicting evidence
30 observational studies significant
4 RCTs no significant
COGENT (2010) no significant
(ORiordan M, 2015)

Clopidogrel-PPI Interaction Questioned in Metaanalysis.

Medscape. Jan 27, 2015

Clopidogrel vs Omeprazole
COGENT 2010 (Clopidogrel With or Without Omeprazole in
Coronary Artery Disease)

Omeprazole reduces GI Bleeding

No cardiovascular interaction between Clopidogrel and
Omeprazole;
Clinically difference cardiovascular events may be possible
(Bhatt DL et al, 2010)
N Engl J Med 2010; 363:1909-1917

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Clopidogrel vs Omeprazole
Clopidogrel is enantiomer (S-enantiomer
clopidogrel)

FDA Update Nov 1, 2016

- Continues to warn this interaction
- Not all PPIs; Only Omeprazole
- Pantoprazole as alternative
(http://www.fda.gov/Drugs/DrugSafety/ucm231161.htm accessed Jan
18, 2017)

Statin-Fibrate Combinations
Rationale
Complex dyslpidemias or severe hypertriglyceridemia

Risk of rhabdomyolisis
Statin-Fenofibrate is preferred than Statin-Gemfibrozil
If gemfibrozil must be used,
AVOID combination with lovastatin, pravastatin and simvastatin
USE LOW DOSE if combine with atorvastatin, pitavastatin or rosuvastatin
(AHA, 2016)
Circulation. 2016; 134

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Warfarin - Trombolytic
Rationale
Acute Myocardial Infarction with AF

Higher risk for intracranial haemorrhage

during thrombolytic therapy.
Previous history of taking warfarin

(Harder S and Klinkhardt U, 2000)

Warfarin - Thrombolytic
Monitoring INR
Monitoring aPTT
Monitoring Hb

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Digoxin - Frusemide
Rationale
Heart Failure with AF

Digoxin toxicity
Hyperkalemia
Hypokalemia

Digoxin - Frusemide
These are symptoms of digitalis toxicity:
Confusion.
Irregular pulse.
Loss of appetite.
Nausea, vomiting, diarrhea.
Fast heartbeat.
Vision changes (unusual), including blind spots, blurred vision,
changes in how colors look, or seeing spots)

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Clinical Pharmacist Intervention

Reduces clinically relevant drug-drug
interactions in patients with heart failure

(Roblek T et al, 2016)

Int J Cardiol. 2016 Jan 15;203:647-52

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