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Cardiac Medications

“The Essentials”

Kenneth Kenyon, PharmD, BCPSAssistant Clinical Professor

Cardiology Clinical PharmacistUniversity of Washington Medical Center

Hypertension

• Who should I initiate on antihypertensive therapy?

• What antihypertensive agents should I utilize?• Why would I choose one agent over another in

the same class (e.g. lisinopril vs. captopril)?• When should I reevaluate BP, adjust the dose and

monitor for potential ADRs?• Where do I need to get my patient’s blood

pressure to achieve adequate control?

The Who, What, Why, When and Where of Antihypertensive therapy

Hypertensive Crisis• Keys to success

– Ideal agents are short-acting, rapid onset/offset, easily titratable, and require little to no dose adjustment for hepatic or renal dysfunction

– Considerations prior to choosing an agent• Etiology of acute severe HTN (i.e. illicit drugs, non-compliance with

antihypertensives, reversible causes)• Treat the underlying cause if identifiable• Comorbidities (e.g. severe aortic stenosis)• Permissive HTN in stroke patients

– Evaluating “goals” of therapy• Unless otherwise known, assume that the patient has had long-

standing HTN and reduce BP gradually– Remember - cerebral autoregulation!!

– Initiate oral meds early in presentation if possible, along with IV meds

Hypertensive Agents

• Commonly utilized agents– Nitroprusside– Nitroglycerin– Esmolol– Labetalol– Hydralazine– Nicardipine or Clevidipine (new agent)

Antiplatelet and Anticoagulation Case• GT is a 72yo female awoke in the middle of the night with

sudden onset of chest pressure and pain, admitted to the Cardiology service to r/o MI.

• PMH: HTN, dyslipidemia, CAD s/p MI ‘88 w/stenting of the distal LAD , A-Fib

• Meds: amlodipine 10mg daily, atorvastatin 40mg qpm, aspirin EC 81mg daily, warfarin 3mg qpm, enalapril 10mg q12h, metoprolol SR 12.5mg daily

• Labs: Chem-7 WNL, WBC 16, Plts 296, Hct 36, INR 2.7, cardiac enzymes - pending

• Vitals: BP 150/90 HR 88

• Hospital course– Upon arrival patient’s chest pain had resolved with SL

NTG, morphine, and metoprolol 5mg IV. Presentation and findings were consistent with a NSTEMI

– Given patient’s prior cardiac history and presence of other risk factors, she was scheduled for a cardiac catheterization in the AM once her INR is reversed to < 1.8

– Patient underwent an uncomplicated cardiac catheterization and received DES to her mid-LAD and proximal circumflex. She was loaded with clopidogrel and continued on her aspirin.

– She was restarted on her warfarin and bridged with UF heparin until her INR ≥ 2

• The day prior to discharge the patient was started oral antibiotics for a positive UA concerning for UTI that was consistent with the patients complaint of dysuria and self-reported history of UTIs

• Medication changes/additions at discharge– Added clopidogrel 75mg daily– Increased metoprolol XL to 50mg daily– Increased enalapril to 15mg twice daily– Increased atorvastatin to 80mg qpm– Added Bactrim DS 1 tablet BID x 7 days

• Five days post-discharge the patient presents to her anticoagulation clinic for routine follow up and is referred to the ER due to an INR of 9.8 with no overt signs or symptoms of hemorrhage with the exception of increased bruising on her bilateral upper and lower extremities, but can remember injuring herself.

Case Discussion• What are the clinical issues that need to be

addressed in this case?• Clopidogrel (Plavix®) – duration of therapy?• Dual antiplatelet therapy + anticoagulation with warfarin, is

it really necessary? Which can I stop?• Does the patient have to stay in the hospital until her INR is

at goal?• Dealing with drug-drug interactions before they impact the

patient• Supratherapeutic INRs – when to watch, when to reverse

and how to reverse• What if this patient had presented with a STEMI rather than

NSTEMI or unstable angina?

• Clopidogrel and duration of therapy– Rx: Clopidogrel 75mg po daily, #30, PRN refills for

anyone with a new DES stent– Due to the risk of late in-stent thrombosis with DES,

current clinical practice and most guidelines recommend a minimum of one year following stent placement

• Dual antiplatelet therapy + anticoagulation with warfarin, are all three necessary?– If indicated, yes. It is necessary especially in patients

with an indication for anticoagulation with CAD recently having a stent placed within the last 12 months

– Clinical decision of risk vs. benefit in others

Low Molecular Weight Heparins• Agents: Enoxaparin, Dalteparin, Tinzaparin• Advantages

– Fairly consistent level of anticoagulation if dosed appropriately– Allows for decreased length of stay

• Drawbacks– Renally cleared

• Calculate CrCl, don’t just look at the SCr (especially in pts ≥ 75yrs of age) • Obesity

– $$$ - without Rx insurance coverage (and sometimes with)– Monitoring (anti-Xa levels) – not readily available at all clinical labs– Limited data in certain cardiac disease states (e.g. mechanical heart

valves)

What if this patient had a listed heparin allergy?What are the alternatives for anticoagulation?– Fonaparinux (Arixtra®)

• Factor Xa inhibitor (synthetic pentasaccharide)• Once daily SQ injection, renal clearance, 17 hr half-life• NO REVERSAL AGENT

– Direct Thrombin Inhibitors (DTIs)• Bivalirudin, Argatroban, Lepirudin• NO REVERSAL AGENT• Variable half-life depending on agent• All interfere with INR lab assay (falsely ↑ INR)• Check dosing, then recheck dosing – also important

consideration for how the drug is cleared

Drug-Drug Interactions with Warfarin

• Assume that 30% to 40% of all drugs you’ll be prescribing over the course of the next 2 to 3 years, and beyond may potentially interact with warfarin

• Antibiotics – most either via inhibition of metabolism or alteration in gut flora– Trimethoprim/sulfa, metronidazole, macrolides, fluoroquinolones– Rifampin – induces warfarin metabolism - ↓ INR

• Antifungals – any azole compound• Antiarrhythmics

– **Amiodarone, propafenone, flecainide, quinidine, diltiazem and verapamil

• Calcineurin inhibitors• Protease inhibitors• Antidepressants – fluoxetine, fluvoxamine• Statins – simvastatin, lovastatin, fluvastatin and rosuvastatin

Utilizing Vitamin K to Reverse INRsINR Clinical Setting Therapeutic Options

< 5 No bleeding Hold warfarin until INR in therapeutic range ± vitamin K 2.5mg po

Rapid reversal required Hold warfarin and give vitamin K 1mg IV infusion or 2.5mg po

5 – 8.9 No bleeding Hold warfarin until INR in therapeutic range ± vitamin K 2.5mg po

Rapid reversal required Hold warfarin and give vitamin K 1-2mg IV infusion or 2.5mg po

≥ 9 No bleeding Hold warfarin until INR in the therapeutic range and give vitamin K 2.5-5mg po or 1-2mg IV infusion and repeat q24h PRN

Rapid reversal required Hold warfarin and give vitamin K 1-10mg IV and may repeat q6-24h PRN

Any INR Serious or life threatening bleeding

Hold warfarin and give vitamin K 10mg IV infusion and supplement with FFP or PPC or recombinant factor VIIa and repeat as necessary guided by INR

How would your management of this patient differed if she presented with an STEMI?

• Immediate treatment is the same as NSTEMI– MONA, UF Heparin or LMWH, clopidogrel

• PCI: door-to-balloon within 90 minutes– GP IIb/IIIa therapy post-PCI at discretion of

interventionalist – what do you need to know?• Fibrinolytic therapy: door-to-needle w/in 30 minutes

of arrival if PCI not available– Streptokinase, Alteplase, Reteplase, Tenecteplase– Consideration for time from onset of chest pain and time

of patient presentation (risk vs. benefit)• Presentation > 24 hrs from onset of chest pain – likely no benefit

– What you need to know

• All patients receiving fibrinolytic therapy– Aspirin 162 to 325mg– UF Heparin 60 units/kg bolus (max 4000 units) followed by

continuous infusion of 12 units/kg/hr (max 1000 units/hr) adjusted to goal aPTT of 50-70 seconds

• Dosing differs for each agent– Streptokinase

• 1.5 MU IV over 60 minutes– Alteplase

• 15 mg IV bolus, then 0.75 mg/kg IV over 30 min (max 50 mg), then 0.5 mg/kg (max 35 mg) over 60 minutes (max total dose = 100mg)

– Reteplase• 10 units IV x 2, 30 minutes apart

– Tenecteplase• < 60 kg = 30 mg IV bolus• 60 to 69.9 kg = 35 mg IV bolus• 70 to 79.9 kg = 40 mg IV bolus• 80 to 89.9 kg = 45 mg IV bolus• ≥ 90 kg = 50 mg IV bolus

• Absolute Contraindications– Active internal bleeding (not including menses)– Previous intracranial hemorrhage at any time– Ischemic stroke within past 3 months– Known intracranial neoplasm– AVM or aneursym, or suspected aortic dissection

• Relative Contraindications– Severe, uncontrolled HTN (> 180/110 mmHg)– h/o ischemic stroke > 3 months– Concurrent use of anticoagulants– Known bleeding diathesis– Traumatic or prolonged CPR (> 10 minutes) or major

surgery (< 3 weeks), recent internal bleeding (< 4 weeks)– Pregnancy– Active peptic ulcer disease– History of severe, chronic poorly controlled hypertension

Heart Failure Case • 81yo male is admitted to the Cardiology service for increased SOB, fatigue and

malaise over the past 2 to 3 weeks. Of note his weight has increased 12 kg during this time. The patient reports he had been in his usual state of health, with the exception of a recent gout attack a few weeks ago, his pain was well controlled with colchicine and ibuprofen.

• PMH: HTN, DM, CAD, CHF (EF ~ 18%), paroxysmal AFib, gout

• Meds: lisinopril 10mg bid, carvedilol 6.25mg bid, torsemide 60mg daily, spironolactone 12.5mg daily, warfarin 2mg daily, digoxin 0.125mg, simvastatin 80mg qpm, allopurinol 150mg daily, pioglitazone 15mg daily, glipizide XL 10mg daily and colcichine 0.6mg PRN gout pain

• Pertinent Labs: K+ 4.6, BUN 45, SCr 2.3, Hct 8.2, Hct 25 (↓ 31), INR 5.2, Digoxin 1.0

• Vitals: BP 122/74 , HR 118, SaO2 • ECG: atrial fibrillation, QTc = 452 msec

• Hospital course: Patient was aggressively diuresed with IV diuretics, warfarin was held until INR within goal range, TEE-guided cardioversion failed, amiodarone was initiated and the patient remained in AF but achieved adequate rate control, patient’s HF symptoms improved significantly following 15-liter net negative diuresis and he was discharged home with clinic follow up in 2 weeks

• Medication changes at d/c: ↑ torsemide to 80 daily, amiodarone 400mg daily

Therapeutic Issues to Consider

• Drug-disease state interactions• Drug-drug interactions• Optimizing diuretic therapy• When to consider using intravenous

vasodilators or inotropes in ADHF

HF Drug-Disease State Interactions• Anti-inflammatory agents

– Non-steroidal anti-inflammatory agents (NSAIDs)• Inhibition of prostaglandin synthesis - ↓ renal blood flow,

compensatory Na+ and fluid retention, blunts diuretic response, and ↑ SVR

– Prednisone • Na+ and fluid retention• Often anti-inflammatory of choice in HF pts, secondary to lack of

prostaglandin effects• Anti-diabetic agents

– Thiazolidineldiones (TZDs)• Fluid retention. Contraindication in NYHA Class III and IV

– Metformin• Increased anaerobic glucose metabolism and subsequent elevated

lactate levels • Decreased renal function and pulmonary edema-induced hypoxia

increased this risk

HF Drug-Disease State Interactions• Antiarrhythmics

– Class I agents – contraindicated in HF patients• Negative inotropic effect and risk of proarrhythmia

– Class III agents – use with caution*• *Amiodarone has been well studied in this population• Others including sotalol and dofetilide use with caution

– Class IV agents • Non-dihydropyridine Ca++ channel blockers possesses significant

negative inotropic effect. Verapamil >> Diltiazem• Nifedipine (dihydropyridine class) also possesses negative

inotropic effects, albeit less than the non-dihydropyridines• Antihypertensives

– Avoid α1- adrenergic blockers (e.g. prazosin) and potent arterial dilating agents such as minoxidil

• Can lead to significant compensatory Na+ and fluid retention

HF Drug-Disease State Interactions• Vitamin K antagonists (warfarin)

– HF-related fluid retention and ↓ cardiac output can lead to hepatic congestion decreased warfarin metabolism (↑ INR).

• Additionally, patients with significant volume overload often have ↓ oral intake

– Monitor INRs more closely in those prone to HF exacerbations

• Spironolactone (also Eplerenone)– Class I recommendation in HF guidelines, can lead to

significant and potentially life-threatening hyperkalemia• Risk increases with renal dysfunction, concomitant ACE Inhibitor or

ARB therapy (also a class I indication in HF patients)– Should absolutely use in those for whom therapy is

indicated, but monitor K+ more closely

Drug-Drug Interactions

• Drug-Drug Interactions– Pharmacokinetic (PK)

• results in alteration in ADME characteristics of another agent

– Pharmacodynamic (PD) • results in synergistic or antagonistic effects of

an expected property of an agent

• In this particular case there are multitude of potential drug-drug interactions

Drug-Drug Interactions• Amiodarone

– Moderate inhibitor of CYP 2C9, 2D6, 3A4, 2A6– Weak inhibitor of CYP 1A2, 2B6, 2C19– P-glycoprotein inhibitor (PGP)

• Amiodarone + Warfarin– PK – inhibits warfarin metabolism via inhibition of 2C9, 3A4– On average, requires 20-50% warfarin dose reduction within 5 – 7

days, but due to long t ½, full effect may take weeks to be realized• Amiodarone + Digoxin

– PK – inhibits PGP, thus increasing digoxin serum levels– Empiric 50% dose reduction for digoxin– PD – enhanced effect on AV node – may lead to bradycardia

• Amiodarone + Simvastatin– PK – inhibition of CYP 3A4 metabolism, results in potentially 50-100%

increase in AUC of simvastatin– Maximum dose of simvastatin 20mg/day while on amiodarone

• Amiodarone + Carvedilol (as well as other B-blockers)– PD – Enhanced effect on sinus node – may lead to bradycardia

Optimizing Diuretics in HF

• Additional characteristics– Torsemide is absorbed faster and/or better than bumetanide or

furosemide– Furosemide – metabolized/excreted in the kidney– Torsemide/bumetanide – metabolized in liver

• Dosing– Double the home maintenance dose and give intravenously– If UOP has not increased within 2 to 4 hours, double previous dose– Increasing frequency will not work unless you’ve achieved diuretic

“threshold”

Equivalent dose

BioavailabilityT½

Bumetanide Furosemide Torsemide

1 mg 40 mg 20 mg

85% 60% 85%1-1.5hr 1.5-3hrs 3-6 hrs

IV:PO conversion 1:1 1:2 1:1

“Maximum” dose 10 mg 400 mg 200 mg

• When do you consider utilizing intravenous agents such as vasodilators and inotropes in heart failure patients?

• How do I know which agent to use?

Hemodynamic Profile AssessmentCongestion at Rest

LowPerfusionat Rest

No

No Yes

Yes

Warm & Dry Warm & Wet

Cold & WetCold & Dry

Signs/symptoms of congestion• Orthopnea/PND

• JVD

• Ascites

• Edema

• Rales

Possible evidence of low perfusion• Narrow pulse pressure• Sleepy/obtunded• Low serum sodium

• Cool extremities• Hypotension with ACE inhibitor• Renal dysfunction (one cause)

Reference: Stevenson LW. Eur J Heart Fail. 1999;1:251.

Patient Selection and TreatmentCongestion at Rest

YesNo

Warm & DryPCWP normal CI normal (compensated)

Cold & WetPCWP elevatedCI decreased

Cold & DryPCWP low/normalCI decreased

VasodilatorsNitroprussideNitroglycerin

Inotropic DrugsDobutamineMilrinone

Normal SVR

High SVR

LowPerfusionat Rest

No

Yes

Warm & WetPCWP elevatedCI normal

Natriuretic PeptideNesiritide or

Reference: Stevenson LW. Eur J Heart Fail. 1999;1:251.

Therapy CO PCWP BP HR ArrhythmiaShorter Onset

LongerOffset

Dopamine (ng/kg/min)

Low (<3)Mod (3–7)High (7–15)

+++++++++

000

Dobutamine +++ 0

Milrinone + ++

Nitroglycerin +++ 0

Nesiritide ++ ++

Nitroprusside ++++ 0

increase; decrease; + effect (number of and qualitatively associated with degree of effect); 0 no effect

Intravenous Agents for Heart Failure

Reference: Adapted from Young JB. Rev Cardiovasc Med .2001;2(suppl 2):S19.

Antiarrhythmics

• HV is a 37 yr old female admitted to the Cardiology service secondary to chest palpitations, SOB and lethargy which have been progressive for the past 4 to 5 days

• PMH: none• Meds: Alesse• Labs: WNL• ECG: atrial fibrillation with RVR (130 bpm)

• Hospital course– Patient was initially given 5mg IV metoprolol x 2 without

adequate rate control, then received diltiazem 25mg IV x1 followed by a continuous infusion at 5mg/min with adequate rate control. She was also initiated on heparin via continuous infusion.

– The following morning the patient underwent TEE-guided cardioversion, which was unsuccessful as a LAA thrombus could not be ruled out, so cardioversion was cancelled.

– The patient was converted from IV to oral diltiazem and later discharged home still in atrial fibrillation but with adequate rate control

• Clinical Decision Points– Rate vs. rhythm control vs. DCC vs. pharmacologic

cardioversion– If you chose rate control which agent would be

the most appropriate for this particular patient?– If you chose rhythm control which agent would be

the most appropriate for this particular patient?– This case doesn’t mention warfarin, does this

patient require anticoagulation?

• Approach to treating atrial fibrillation/flutter– How symptomatic is the patient and is there

sequela (ischemia, acute pulmonary edema)• Risk vs. benefit of immediate cardioversion

– Symptoms uncomfortable but immediately tolerable

• Initial therapy should be based on drugs that slow conduction and increase refractoriness of the AV node

• Consider etiology of atrial fibrillation/flutter– Precipitated by high states of adrenergic tone (e.g.

thyrotoxicosis

So which antiarrhythmic do I choose?

Class Specific Antiarrhythmic Agents Mechanism of Action† Role

Class I IA IB IC

Disopyramide, Procainamide, QuinidineLidocaine, MexilitinePropafenone, Flecainide, Moricizine

Na+ channel blockade Intermediate Fast on/off Slow on/off

A/VVA

Class II Metoprolol, Esmolol, etc. Beta-adrenergic blockade A/V

Class III Amiodarone, Sotalol, Dofetilide, IbutilideDronedarone (pending FDA approval)

Potassium channel blockade A/V

Class IV Diltiazem, Verapamil Ca++ channel blockade A

Misc. Adenosine, Digoxin, Magnesium Agent specific A/V

Depends – what is the goal of therapy? Rate or rhythm control?Depends – what type of patient are we talking about – age, cardiac history, acuity?

† - denotes predominate ion channel interaction, most agents have a multitude of effects responsible for their antiarrhythmic potential

Rate Control

• Considerations for immediate rate control– LVSD (EF < 40%) – use caution, may exacerbate HF– Blood pressure

• Long-term consideration for rate control

Class Specific Antiarrhythmic Agents Mechanism of Action†

Class II Metoprolol, Esmolol, etc. Beta-adrenergic blockade

Class IV Diltiazem, Verapamil Ca++ channel blockade

Misc. Adenosine (SVT), Digoxin (AF. AFL) Agent specific

Rhythm Control

• Considerations in atrial fibrillation/flutter– Select agents with proven role in atrial arrhythmias– Significant considerations for side-effects and

tolerability– Concurrent disease states

Class Specific Antiarrhythmic Agents Mechanism of Action† Role

Class I IA IB IC

Disopyramide, Procainamide, QuinidineLidocaine, MexilitinePropafenone, Flecainide, Moricizine

Na+ channel blockade Intermediate Fast on/off Slow on/off

A/VVA

Class III Amiodarone, Sotalol, Dofetilide, IbutilideDronedarone (pending FDA approval)

Potassium channel blockade A/V

Rhythm Control

• Via process of elimination – 5 remaining agents

• Structural heart disease present?– Excludes class I agents (3 remaining agents)

• Other patient characteristics• Consideration for drug-drug side-effects

Class Specific Antiarrhythmic Agents Mechanism of Action† Role

Class I IA IB IC

Side effects preclude long-term useNo efficacy in atrial arrhythmiasPropafenone, Flecainide

Na+ channel blockade Intermediate Fast on/off Slow on/off

A/VVA

Class III Amiodarone, Sotalol, DofetilideDronedarone (pending FDA approval)

Potassium channel blockade A/V

Intravenous Antiarrhythmic DosingDrug Clinical Situation Dose

Amiodarone Recurrent VT/VF

Cardiac Arrest

150 mg IVPB x 1 over 10 minutes, then 1 mg/min x 6 hrs, then 0.5 mg/min infusion x 18+ hours

150-300mg IV bolus repeated PRN

Diltiazem PSVT; rate control AF 0.25 mg/kg IV bolus (may repeat x 1 with 0.35 mg/kg bolus) then 5-15 mg/hr infusion

Ibutilide Termination AF 1 mg/10min IVPB, may repeat x 1

Lidocaine VT/VF 100 mg IV push (may repeat x 2), then 2-4 mg/min infusion (1-2 mg/min in HF or liver disease)

Magnesium Torsades, VT/VF 1-2 grams in 10ml NS IV push (MR x 2)

Procainamide AF (WPW), VT 15-18 mg/kg at 20-50 mg/min IV load, then 1-6 mg/min infusion

Verapamil PSVT; rate control AF 5mg IV push (may repeat up to 20mg), then 5-15 mg/hr infusion

Side Effects of Antiarrhythmic Drugs• Disopyramide

– Anticholinergic symptoms, GI, negative inotrope• Procainamide

– SLE, GI, negative inotrope, agranulocytosis• Quinidine

– Cinchonism, diarrhea, GI, hepatitis, thrombocytopenia, hemolytic anemia• Lidocaine

– CNS, seizures, psychosis (usually with supratherapeutic levels)• Propafenone

– Blurred vision, dizziness, headache, *bronchospasm (asthmatics)• Flecainide

– Blurred vision, dizziness, headaches, bitter taste• Amiodarone

– Corneal deposits, hepatitis, pulmonary fibrosis, hypo/hyperthyroidism – Photosensitivity, blue-grey skin discoloration, GI

• Sotalol– Fatigue, GI, depression, *bronchospasm (asthmatics)

• Dofetilide– Torsades de pointes

Top 10 Drug-Drug Interactions in Cardiology

Drugs Consequence/Suggested Action

1) Amiodarone - Warfarin Inhibits warfarin metabolism ↑INRs, 25-50% dose reduction of warfarin usually required

2) Amiodarone – Digoxin Inhibits digoxin clearance – empiric 50% digoxin dose reduction

3) Amiodarone – Simvastatin/Lovastatin Inhibits metabolism/elimination of agents-Maximum simvastatin dose 20mg/day- Maximum lovastatin dose 40mg/day

4) Nitrates – PDE inhibitors (e.g. Viagra) Synergistic reduction in venous tone resulting in significant hypotension. Avoid combination

5) Warfarin - Rifampin Induces warfarin metabolism – often requires significant increases in warfarin doses by 50-100% within 7-14 days

Top 10 Drug-Drug Interactions in CardiologyDrugs Consequence/Suggested Action

6) Amiodarone – Beta-blockers Potential for bradycardia (and arrhythmias) especially on initiation, monitor for bradycardia

7) Amiodarone – Diltiazem/Verapamil Additive reduction in heart rate and myocardial contraction – monitor for bradycardia or signs of CO

8) Diltiazem/Verapamil - Statins Similar to amiodarone-statin interaction, try to avoid simvastatin, and lovastatin

9) Spironolactone – ACE Inhibitors/ARBs & KCl supplements

Clinically indication concomitant therapy in HF, but carries high risk for hyperkalemia, especially with SCr – monitor closely, within 3 to 5 days of initiation or dose escalation

10) Propafenone - Warfarin Increased warfarin effect due to inhibition of metabolism – monitor INRs more closely x 2 weeks, dose reduce PRN