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.
• 3–26% 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 1041–1052

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
(O’Riordan M, 2015)

Clopidogrel-PPI Interaction Questioned in Meta–analysis.

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

THANK YOU

Thanks You

Terima Kasih

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