Cardiology Pharmacology Review

Dhiren Patel, PharmD, CDE

Assistant Professor of Pharmacy Practice Massachusetts College of Pharmacy and Health Sciences - Boston Clinical Pharmacy Specialist / Certified Diabetes Educator VA Boston Healthcare System E-mail: dhiren.patel1@mcphs.edu

Patient Case

A 50 yo man with diabetes receives the results of a FLP that reveals hypercholesterolemia. His physician recommends lifestyle changes and initiates therapy with a statin. Which of the following mechanisms describes the action of statins in reducing serum levels of LDL cholesterol? A. Inactivation of 3-hydroxy-3-methlyglutaryl coenzyme A synthase B. Competitive inhibition of 3-hydroxy-3methlyglutaryl coenzyme A reductase C. Positive feedback to increase 3-hydroxy-3methlyglutaryl coenzyme A lyase activity

HMG-CoA Reductase Inhibitors

Drug (Trade Name)

Atorvastatin (Lipitor) Fluvastatin (Lescol)

Lovastatin (Mevacor) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor)

Board worthy!

MOA: Inhibits HMG-CoA reductase, which prevents the conversion to mevalonate preventing cholesterol synthesis Adverse effects: Hepatotoxicity, myalgias, myopathy, rhabdomyolysis Special Considerations: New patients cant be started on simvastatin 80mg Do not combine with fibrates

Clinical Pearls for Rotations

Clinical uses: Dyslipidemia, s/p MI, diabetic patients First line agent (mortality data, pleotropic effects) Initial recommended starting dose of any statin will provide ~30% reduction in LDL Subsequent dose increases will only provide an additional 67% reduction in LDL, however, will increase risk of adverse effects by 50% Consider metabolism pathway when selecting statins CYP3A4 atorvastatin, simvastatin, lovastatin Sulfation pravastatin (DOC if concerned about DDIs or AEs) CYP2C19, CYP2C9 rosuvastatin

Statin dose conversion table

LDL Reduction lovastatin (Mevacor) pravastatin (Pravachol) simvastatin fluvastatin (Zocor) (Lescol) atorvastatin (Lipitor) rosuvastatin (Crestor)
25-32% 31-39% 37-45% 48-52% 55-60% 20mg 40mg 80mg --20mg 40mg 80mg --10mg 20mg 40mg 80mg -40mg 80mg ----10mg 20mg 40mg 80mg --5mg 10mg 20mg

60-63%

--

--

--

--

--

40mg

Patient Case

A 50 yo man with moderate familial hypertriglyceridemia is treated with gemfibrozil. Which of the following is the primary mechanism of action? A. Binding of bile acids in the intestine B. Inhibition of hepatic VLDL secretion C. Inhibition of HMG-CoA reductase D. Stimulation of HDL production E. Stimulation of lipoprotein lipase

Fibrates
Drug (Trade Name)

Gemfibrozil (Lopid) Fenofibrate (Tricor)

Fenofibric acid (Trilipix)

Board worthy!

MOA: Decreases TGs by up-regulating lipoprotein lipase Adverse effects: Increased LFTs, abdominal pain, HA, dyspepsia, fatigue Special Considerations: Do not use in combination with statin (risk>benefit) Could use fibrate over statin if TGs > 500 due to risk of pancreatitis

Clinical Pearls for Rotations

Clinical uses: (limited) Hypertriglyceridemia Treating triglycerides is not associated with positive clinical outcomes! Dosing Fenofibrate is dosed once daily Gemfibrozil is dosed twice daily (30 mins before food) Consider lifestyle modifications, weight loss, and omega 3 fatty acids for management of TGs

Patient Case

Drugs such as cholestyramine and colestipol have been shown to decrease circulating serum LDL cholesterol and to slightly elevated TGs. These drugs work by which of the following mechanisms? A. Decreased peripheral lipolysis B. Increased lipoprotein lipase activity C. Inhibition of cholesterol absorption at the small intestine brush border D. Binding and excretion of bile-soluble lipids E. Inhibition of the rate-limiting enzyme of cholesterol formation

Bile Acid Resins

Drug (Trade Name)

Colestipol (Colestid) Colesevelam (Welchol)* Cholestyramine (Questran) *Has approved indication for diabetes mellitus

Board worthy!

MOA: Prevents intestinal reabsorption of bile acids Bile acids needed to make cholesterol Adverse effects: GI side effects (constipation, abdominal pain, flatulence, nausea)

Special Considerations: Decrease absorption of fat soluble vitamins

Clinical Pearls for Rotations

Clinical uses: Dyslipidemia (Decreases LDL) Off label uses: diarrhea and pruritus Dosing Colesevelam: Give other oral drugs >4h before Colestipol: Give other oral drugs >1h before or 4h after Cholestyramine: Give other oral drugs >1h before or >4-6 after

Board worthy!
Ezetimibe (Zetia) MOA:

Inhibits the intestinal absorption of exogenous cholesterol Diarrhea, Fatigue, Cholelithiasis Does not effect cholesterol made by liver

Adverse effects: (minimal)

Special Considerations:

Clinical Pearls for Rotations

Clinical uses: (limited) Dyslipidemia (lower LDL) Has not been demonstrated to improve clinical outcomes in combination with statin therapy! ENHANCE trial (used surrogate endpoints) Vytorin did not result in a significant difference in changes in intimamedia thickness, as compared with simvastatin alone ARBITER-6-HALTS trial Compared with ezetimibe, niacin had greater efficacy regarding the change in mean carotid intimamedia thickness Dosing (10mg daily not any more effective than 5mg)

Board worthy!
Niacin (Niaspan) MOA: Inhibits lipolysis in adipose tissue Reduces hepatic VLDL secretion into circulation Adverse effects: Flushing, itching, headache, hepatotoxicity Special Considerations: Use with caution in patients with history of diabetes and gout Contraindicated in patients with PUD and severe hepatic impairment

Clinical Pearls for Rotations

Clinical uses: Dyslipidemia (Increases HDL) AIM-HIGH Study Adding Niacin to a statin dose NOT improve cardiovascular outcomes and might increase strokes Dosing Start with 500mg and increase by 500mg every 4 weeks Flushing can be minimized if aspirin dose is given hour before

Patient Case

Class I antiarrhythmics are Na+ channel blockers that slow or block cardiac conduction, especially in depolarized cells. Which of the following class I antiarrhythmics will increase both the action potential and the effective refractory period? A. Mexiletine B. Procainamide C. Flecanide D. Propafenone E. Tocainide

Patient Case

An elderly man presents with complaints of ringing in his ears, blurred vision, and upset stomach. He is taking multiple medications. His wife states that he has had a few episodes of confused, delirious behavior over the past few weeks. Which of the following agents might be responsible for this mans syndrome? A. Allopurinol B. Hydralazine C. Niacin D. Quinidine E. Spironolactone

Anti-arrhythmics

Class 1 (Na+ Channel blockers)

Drug (trade name) 1A Quinidine Procainamide Disopyramide (Norpace) 1B Lidocaine (Xylocaine) Tocainide (Tonocard) Mexiletine (Mexitil) Phenytoin (Dilantin) 1C Flecainide (Tambocor) Propafenone (Rythmol)

Board worthy!

MOA: Na+ channel blockers

Slow or block conduction especially in depolarized cells Decrease slope of phase 0 depolarization

Class IA:

Increases AP duration, ERP and QT interval Decreases AP duration No effect on AP duration

Class IB:

Class IC:

Board worthy!
Adverse effects: Class IA
Quinidine cinchonism, thrombocytopenia, torsades de pointes Procainamide reversible SLE-like syndrome

Class IB

Cardiovascular depression and CNS related AEs Proarrhythmic

Class IC

Clinical Pearls

Class IA

Affect both atrial and ventricular arrhythmias

Useful in acute ventricular arrhythmias (especially post-MI) and in digitalis-induced arrhythmias

Class IB

Class IC
Useful in V-tachs that progress to VF and in intractable SVT Usually used only as last resort Contraindicated post MI

Patient Case

A 57 old smoker with a long history of chronic obstructive lung disease presents to the physician with a BP of 150/90 mm Hg. Which of the following anti-hypertensives is contraindicated in this patient? A. Acebutolol B. Atenolol C. Esmolol D. Metoprolol E. Nadolol

Patient Case

A 45 yo woman is brought to the hospital after collapsing on the sidewalk in front of the hospital. Her friend reports that the patient has no known medical conditions. Initial evaluation reveals severe hypotension, and she is given IV norepinephrine. Which of the following drugs antagonize both the vascular and cardiac actions of the given medication? A. Atenolol B. Esmolol C. Carvedilol D. Metaproterenol E. Bisoprolol

Class II Beta blockers (Selective)

Drug (Trade Name)

Acebutolol (Sectral) Atenolol (Tenormin) Betaxolol (Kerlone) Bisoprolol (Zebeta) Metoprolol Tartrate (Lopressor) Metorolol Succinate (Toprol XL) Esmolol (Brevibloc)*only available as IV formulation

Board worthy!

MOA: Selectively blocks beta1-adrenergic receptors in the heart and vascular smooth muscle Adverse effects: Dizziness, fatigue, impotence Bradycardia

Special Considerations: Up regulation of receptors is seen in chronic use so it is important to not abruptly discontinue medication

Clinical Pearls for Rotations

Clinical uses:

Tachycardia Angina Arrhythmias Hypertension

Decreases post MI mortality Proven to decrease mortality in heart failure

Bisoprolol, metoprolol succinate, carvedilol

May mask symptoms of hypoglycemia

Class II Beta blockers (Non-Selective)

Drug (Trade Name)

Nadolol (Corgard) Pindolol (Visken)

Propranolol (Inderal) Sotalol (Betapace)

Timolol

Board worthy!

MOA: Blocks the beta-1 and beta-2 receptors in the heart and vascular smooth muscle Adverse effects: Dizziness, fatigue, sleep disturbances Special Considerations: Causes increase airway resistance contraindicated in asthmatics Use with caution in patients with diabetes receiving hypoglycemic drugs

Clinical Pearls for Rotations

Clinical uses: Arrhythmias Angina Other indications: pheochromocytoma, tremor, migraine prophylaxis, portal hypertension Carvedilol (Coreg) and Labetolol (Normodyne) Antagonists at beta-1, beta-2 and alpha-1 receptors Added benefit of vasodilatation

Class III K+ channel blockers

Drug (Trade Name) Amiodarone (Cordarone, Pacerone) Ibutilide (Corvert) Dofetilide (Tikosyn) Sotalol (Betaspace, Sorine) Bretylium

Board worthy!

MOA: Block the potassium channels, prolonging repolarization Increases AP duration, ERP and QT interval Adverse effects: Sotalol torsades de pointes Ibutilide torsades Bretylium new arrhythmias, hypotension Amiodarone pulmonary fibrosis, hepatotoxicity, hypo/hyperthyroidism (check PFTs, LFTs, TFTs)

Clinical Pearls for Rotations

Clinical uses: Ventricular arrhythmias Atrial fibrillation and flutter Sotalol also has Class II activity Amiodarone has Class I, II, III, and IV activity Amiodarone does not have any negative inotropic effects and lowest incidence of Torsades de pointes

Patient Case

A physician decides to place a pt on CCB for treatment of her angina. CCBs can relax the smooth muscle of blood vessels and can also have various effects on cardiac contractility, conduction, and HR. Which of the following CCBs would be most effective in reducing HR and contractility? A. Diltiazem B. Nifedipine C. Nimodipine D. Verapamil

Patient Case

A 56 yo woman arrives in the ED complaining of dizziness and headache. Her BP is 210/140. She is currently not taking any medications and has not seen a doctor for several years. The physician decides to address her HTN urgently. Which of the following drugs is contraindicated? A. IV diltiazem B. IV labetaolol C. IV metoprolol D. Oral captopril E. SL nifedipine

Class IV Calcium Channel Blockers

Drug (Trade Name)

Dihydropyridines

Amlodipine (Norvasc)
Felodipine (Plendil) Nifedipine (Adalat CC, Procardia XL) Isradipine (Dynacirc) Nisoldipine (Sular) Non-dihydropyridines Verapamil (Calan) Diltiazem (Cardizem)

Board worthy!

Dihydropyridines MOA: Selectively binds to L-type voltage-gated calcium channels in vascular smooth muscle Non-dihydropyridines MOA: Binds to L-type voltage-gated calcium channels in sinoatrial node, atrialventricular node, and vascular smooth muscle Adverse effects: Peripheral edema, constipation, flushing, headache AV block, bradycardia, CHF (Non-DHPs)

Clinical Pearls for Rotations

Clinical uses: Hypertension Arrhythmias: afib, aflutter, PSVT Angina: vasospastic, Prinzmetal, exertional Verapamil is a stronger negative inotrope than diltiazem DHPs drug of choice for HTN

Patient Case

A 25 yo white woman with no PMH presents to the ED for a racing heartbeat. It is determined that she has paroxysmal supraventricular tachycardia. Which of the following is the drug of choice used for diagnosing and abolishing AV nodal arrhythmias by virtue of its effectiveness and its low toxicity? A. Adenosine B. Bretylium C. Lidocaine D. Sotalol

Other anti-arrhythmics

Adenosine Slows down AV node conduction time and interrupts AV node re-entry pathways DOC in diagnosing/abolishing supraventricular tachycardia Short acting (15 secs) Magnesium Effective in torsades de pointes and digoxin toxicity

Board worthy!
Digoxin MOA:
Direct inhibition of Na+/K+ ATPase Stimulates vagus nerve

Adverse effects:

Cholinergic side effects, blurry yellow vision Increased risk of digoxin toxicity if pt is hypokalemic and impaired renal function

Special considerations:

Clinical Pearls for Rotations

Clinical uses:
CHF (increases contractility) Afib (decreases conduction at AV node and depression of SA node)

Monitor levels of digoxin

CHF: 0.5-0.8 ng/mL Afib: 0.8-2 ng/mL

Digoxin toxicity

DigiFab

Patient Case

A patient who is being treated for a hypertensive crisis that occurred 2 hours ago is medicated with IV nitroprusside. Which of the following is the expected action of this drug? A. Constriction of arterioles alone B. Constriction of both arterioles and venules C. Constriction of venules alone D. Dilation of arterioles alone E. Dilatation of arterioles and venules

Nitrates
Drug (Trade Name) Nitroglycerin (available in various forms) Isosorbide dinitrate (Isordil) Isosorbide mononitrate (Imdur)

Board Worthy!

MOA: Vasodilates by releasing nitric oxide in smooth muscle Increases cGMP and smooth muscle relexation Decreases preload Adverse effects: Reflex tachycardia, hypotension, HA, flushing Special considerations: Contraindicated with PDE-5 inhibitors (severe hypotension)

Clinical Pearls

Clinical uses: Angina Various formulations available such as oral, IV, topical ointment, transdermal, sublingual, Onset: nitroglycerin > isosorbide dinitrate > isosorbide mononitrate Dilate veins > arteries Can develop tolerance (drug free periods to avoid tolerance)

Board Worthy!
Hydralazine (Apresolin) MOA: Peripheral vasodilator Increases cGMP and causes smooth muscle relaxation Adverse effects: Compensatory tachycardia, headache, nausea Lupus like syndrome Special considerations: Contraindicated in angina/CAD

Clinical Pearls for Rotations

Clinical Uses: Severe hypertension CHF Vasodilates arterioles > veins (afterload reduction) First line therapy for HTN in pregnancy with methyldopa Combination hydralazine and isosorbide dinitrate when added to standard heart failure medications improved symptoms and reduced risk of death and hospitalizations in African Americans

Board worthy!
Ranolazine (Ranexa) MOA
Unknown Inhibits late sodium current, reducing sodiuminduced calcium overload in myocytes

Adverse effects:

Constipation, nausea, prolonged QT interval, syncope Use with caution in renal impairment

Special considerations

Clinical Pearls for Rotations

Clinical use

Chronic angina (not indicated for acute angina)

Counsel patients on orthostatic hypotension Contraindicated in liver cirrhosis Should avoid grapefruit juice

Anti-platelets

Patient Case

A 65 yo patient has experienced several TIAs over the past few months. Because his general health is poor, he is not considered an appropriate candidate for carotid endarterectomy. The decision is made to treat him medically. Which of the following agents would be most appropriate for this therapy? A. Aspirin B. Coumadin C. Dipyridamole D. Heparin

Board worthy!
Aspirin MOA: Acetylates and irreversibly inhibits cyclooxygenase (COX-1 and COX-2) Adverse Effects: Gastric ulceration, bleeding, tinnitus Special Considerations: Reyes syndrome (use with caution in children)

Clinical Pearls for Rotations

Clinical uses: Antipyretic Analgesic Anti-platelet drug (ACS, MI prevention, TIA/thromboembolic stroke prevention) Use with caution in patients with asthma Increases bleeding time but does not effect PT or PTT

Patient Case

A patient admitted to the ED with CP is diagnosed with MI. On discharge, the pt is prescribed aspirin but develops an allergic hypersenitivity reaction. Ticlopidine is prescribed instead as a maintenance anticoagulant. Which of the following is the MOA? A. It binds to the active site of cyclo-oxygenase via acetylation B. It blocks the binding of plasmin to fibrin C. It hinders the production of thromboxane A2 D. It prevents fibrinogen from binding to platelets E. It stimulates platelet adenylyl cyclase

Thienopyridines
Drug (Trade Name)
Ticlopidine (Ticlid) Clopidogrel (Plavix) Prasugrel (Effient)

Board worthy!

MOA: Inhibit platelet aggregation by irreversibly blocking ADP receptors Inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa expression Adverse Effects: Ticlopidine- neutropenia Bleeding clopidogrel and prasugrel Special Considerations: Use with caution in patients that are poor metabolizers of 2C19 (Black Box Warning)

Clinical Pearls for Rotations

Clinical uses: Acute coronary syndrome Coronary stenting Thrombotic event prevention Use of PPIs and Plavix controversial Prasugrel is not recommended in patients 75 years of age and older, except for high-risk situations (diabetes, history of prior myocardial infarction) May be a good option for poor metabolizers of 2C19 and chronic PPI users as it isnt significantly affected

Glycoprotein IIb/IIIa inhibitor

Drug (Trade Name) Tirofiban (Aggrastat) Eptifibatide (Integrilin) Abciximab (Reopro)

Board worthy!

MOA: Inhibits aggregation of platelets by reversibly antagonizing fibrinogen binding to the GP IIb/IIIa receptor Adverse Effects: Bleeding, bradyarrythmia, dizziness (tirofiban) CP, hypotension, nausea, backache (abciximab) Hypotension, bleeding (eptifibatide) Special considerations: Tirofiban can not be used in patients allergic to aspirin

Clinical Pearls for Rotations

Clinical use
Acute coronary syndrome PCI Myocardial ischemia

Abciximab has the most potential to cause allergic reactions Tirofiban and eptifibatide requires renal dosing

Anti-thrombins

Patient Case

A 62 yo white man complains of left thigh and leg pain and swelling that are exacerbated by walking. One week earlier, the patient underwent cardiac catheterization. The patient is currently vacationing and has spent 28 hours in a car. Which of the following drugs, which might be prescribed in this instance, works by inhibiting the enzyme epoxide reductase? A. Acetylsalicylic acid B. Dipyridamole C. Heparin D. Streptokinase E. Warfarin

Heparin vs. Warfarin

Heparin Activates antithrombin (decreases action of IIa and Xa) Monitored by PTT Warfarin Interferes with synthesis of vitamin K clotting factors (II, VII, IX, X) Monitored by PT/INR

Given IV or SQ
Toxicity treated with protamine sulfate

Given orally
Toxiciity treated with vitamin K and fresh frozen plasma

Rapid anticoagulation
Can be used in pregnancy

2-3 days before anticoagulation

Cant be used in pregnancy

Direct Thrombin Inhibitors

Drug (Trade Name)

Argatroban Dabigatran (Pradaxa) Desirudin(Iprivask) Lepirudin (Refludan) Bivalirudin (Angiomax)

Board worthy!

MOA: Reversibly binds and inhibits the active site on thrombin Adverse effects: Bleeding, hemorrhage Special Considerations: Dabigatran, lepirudin, bivalirudin, desirudin: renal elimination Argatroban: hepatic elimination Predictable dose-response

Clinical Pearls for Rotations

Clinical uses:

HIT VTE DVT PE Afib PCI

Monitory therapy with PTT None have antidotes for reversal All are continuous IV infusions except dabigatran Expensive: $800-$1000/day

Low Molecular Weight Heparins

Drug (Trade Name)

Dalteparin (Fragmin)

Tinzaparin (Inohep) Exoxaparin (Lovenox)

Board worthy!

MOA: Inhibits thrombin and Factor Xa Adverse effects: (lesser degree than heparin) Bleeding, hemorrhage HIT, osteoporosis (chronic) Special Considerations: Use with caution in renal impairment and obese patients

Clinical Pearls for Rotations

Clinical uses:

DVT PCI N/STEMI

No therapeutic monitoring Can be dosed subcutaneously as an outpatient Weight-based dosing

Thank you!
Dhiren Patel, PharmD, CDE
Assistant Professor of Pharmacy Practice Massachusetts College of Pharmacy and Health Sciences-Boston Clinical Pharmacy Specialist / Certified Diabetes Educator VA Boston Healthcare System

E-mail: dhiren.patel1@mcphs.edu