Clinical Pharmacology Study Guide (Antiplatelet Drugs)

Antiplatelet Drugs *Aspirin, (oral) common medical abbreviation, “ASA” acetylsalicylic acid • Mechanism of Action: Irreversibly inhibits the enzyme, cyclooxygenase • Therapeutic effects last for the life of the platelet (7 – 10 days) • Aspirin is taken daily at doses of 81mg (baby aspirin) to 325mg. Costs ~ $3/month • Adverse effects: upset stomach and GI discomfort, GI ulcers • Aspirin withdrawal has been associated with an increased risk of clots • Drug Interaction: Ibuprofen may block the antiplatelet benefits of aspirin. Administer aspirin at least 2 hours before or 4 hours after an ibuprofen dose to maximize the antiplatelet benefits of aspirin *Clopidogrel (Plavix  ) (kloh· PID· oh·grel) , Prasugrel (Effient) (PRA soo grel) and Ticagrelor (Brilinta®) (tye· ka· grel) • Mechanism of Action: Inhibits the binding of platelets to each other by interfering with adenosine diphosphate (ADP). Blocks ADP receptors, preventing ADP-stimulated aggregation. 3 – 7 day lag time for onset of action • Dosed once daily with food • Adverse Effects: Most common adverse effects are GI disturbance, diarrhea, & abdominal pain (take with food). May cause dizziness or headache. Excessive bleeding. *Extended Release Dipyridamole 200mg + Aspirin 25mg (Aggrenox ) oral (dye peer ID a mole) • • • Mechanism of Action: The exact mechanism is complex: dipyridamole inhibits phosphodiesterase, which leads to accumulation of cAMP & cGMP & enhances the antithrombotic potential of the vascular wall. Aspirin – previously discussed Dosed twice daily. Much more expensive than plain aspirin alone. ~$250/month Adverse Effects: Obviously it contains aspirin so carries all the aspirin related adverse effects. Other side effects include headache, N/V, diarrhea, dizziness & excessive bleeding Therapeutic Uses of Antiplatelet Drugs Primary Prevention (Aspirin 75 – 162 mg daily) • Primary prevention is for patients who have not yet experienced a clotting event, but who are at risk. Exactly who will benefit the most from daily aspirin therapy is highly debatable. Daily aspirin therapy for primary prevention is considered appropriate for men age 45 – 79 years old and women age 55 – 79 years old who have cardiac risk factors (diabetes, hypertension, high cholesterol, smoker) and are at a low risk of GI hemorrhage. For men & women over the age of 79 years old, there isn’t enough evidence to make a specific recommendation. The risk of stroke & MI are high in the elderly, but the risk of GI hemorrhage is also higher. The decision regarding daily aspirin in primary prevention is made on a case-by-case basis by the prescriber. Secondary Prevention • • • Secondary prevention is for patients who have already experience clotting issues (ischemic stroke, TIA, MI, angina, stent placement, etc) Some sort of antiplatelet drug will be prescribed. The best choice depends upon the type of clot the patient suffered. Some patients will receive aspirin (325mg/day); others clopidogrel or Aggrenox; and others may receive clopidogrel plus aspirin. Following cardiac-related clots (MI, angina, stent placement, etc) Other Therapeutic Uses of Antiplatelet Drugs • • Acute Coronary Syndrome (ACS) – Chew & swallow 325mg aspirin – this is one of the most important interventions a person can do; sometimes clopidogrel is also administered. Combinations of antiplatelet drugs may be used right after ACS or ischemic stroke for 3 to 9 months. Then, usually the patient will take just one antiplatelet drug lifelong thereafter. A common combination is clopidogrel + aspirin. 32 Anticoagulants These medications inhibit parts of the coagulation cascade. They prevent clots from forming. By preventing clot formation, they allow the body time to naturally dissolve any already formed clots. *Heparin (unfractionated heparin) (IV, SC) Mechanism of Action: binds to antithrombin III to inhibit fibrin formation. Liver metabolized. Quick onset of action and fairly short duration of action. Therapeutic Uses • Drug of choice in situations requiring rapid onset of anticoagulant effects o acute stroke, acute MI, DVT, PE • Prevent DVT & PE following surgeries known to increase clot potential (e.g. hip, knee) and bedridden/immobile patients. • Prevent clotting during renal dialysis & open-heart surgery. • Central line IV flushes to prevent clotting. Adverse effects • Major and minor bleeding – i.e. cerebral, GI tract, urinary tract, nosebleeds • Heparin induced thrombocytopenia (HIT) – immune mediated destruction of platelets Contraindications/Precautions • Pre-existing thrombocytopenia, uncontrollable bleeding • Avoid after surgeries/procedures with a high risk of bleeding (e.g. eye, brain, spinal cord, lumbar puncture, & spinal epidural) Monitoring, Dosing, Antidote • Heparin is prescribed in “units” rather than “mg.” • Monitoring: activated partial thromboplastin time (APTT) – measures the length of time it takes a clot to form. Normal = 30-40 seconds. Therapeutic = 1.5 – 2 times normal. • Continuous, infusion, weight-based regimens are commonly used in acute treatment of DVT, PE, & MI. During these situations, aPTT monitoring generally occurs every 4-6 hours. • Antidote: infrequently used, protamine sulfate (binds to & inactivates heparin molecules) Low Molecular Weight Heparins (LMWH) SC *Enoxaparin (Lovenox ) Dalteparin (Fragmin) Tinzaparin (Innohep) • Composed of molecules that are shorter than those found in standard heparin. Considered as effective as heparin. Longer half-life. More selective in their activity on the coagulation cascade. Cleared primarily by the kidneys. Cost 4x more than heparin. Therapeutic Uses • Similar to unfractionated heparin Adverse effects • Similar to unfractionated heparin except less thrombocytopenia Monitoring, Dosing: • Fixed dosing in “mg,” and dosing is based on patient weight. Given once or twice daily. • Routine use does not require monitoring. aPTT is NOT monitored with the LMWHs. 33 Selective Factor Xa inhibitors Fondaparinux (Arixtra ) (inj) Similar in structure to heparin and LMWH’s—much smaller Mechanism of action • Selectively inhibits Factor Xa by enhancing antithrombin activity No affect on bleeding time, APTT, prothrombin time Therapeutic uses • Similar to unfractionated heparin Given once daily, dosed in mg/kg basis *Warfarin (Coumadin ) Oral Anticoagulants Mechanism of Action: Vitamin K is required for the liver to synthesize four of the clotting factors involved in the coagulation cascade (factors VII, IX, X & prothrombin). Warfarin blocks formation of active vitamin K needed for synthesis of these factors. • Onset of clinical effectiveness is delayed (3-5 days). Why? Warfarin inhibits synthesis of new clotting factors only. It takes 3-5 days for existing clotting factors to be depleted. • Very narrow therapeutic window Therapeutic Uses • Treatment and prevention of a DVT or PE • Prevention of DVT in patients undergoing hip or knee surgeries • Prevention of thromboembolism in patients with atrial fib. • Prevention of thromboembolism in patients with prosthetic heart valves Adverse effects • Bleeding: Minor bleeding is fairly common, major bleeding (hemorrhage) i • Loss of appetite, nausea, vomiting, stomach cramps, diarrhea, hair loss Contraindications • Uncontrolled bleeding • Recent surgery where risk of bleeding is high • Alcoholism, liver disease, vitamin K deficiency • Pregnancy- it will cross the placenta Drug Interactions • Metabolism: CYP2C9 inhibitors/inducers • Protein binding: Highly protein bound (99%) • Drugs that promote bleeding Monitoring Warfarin Therapy • As with heparin, actual serum levels are not monitored. • The pharmacological effectiveness or the anticoagulant effect is monitored using the prothrombin time (PT) which is mathematically converted to the International Normalized Ratio (INR). PT measures the amount of time (in seconds) required to produce a clot. INR standardizes the PT value to avoid influence of variations in-lab reagents. • Although we expect a lag time in the onset of clinical effectiveness – shown in the INR, we still monitor daily initially. • Typical INR in someone not taking warfarin is 1.0. Therapeutic INR is usually 2.0 – 3.0 depending on what is being treated. Elevated INR is associated with increased risk of bleeding. Low INR is associated with increased risk of clots. 34 Dosing • Once daily, start at 2-5mg/day. • Adjusted based on INR • Genetic variations: VKORC1, CYP2CP variants requires dose reduction Antidote (reversal agent) • Vitamin K oral: phytonadione (Mephyton) Vitamin K injection (phytonadione) • This is is a slow acting antidote because it won’t work until the body uses the vitamin K to make more clotting factors – this takes several hours • If immediate reversal is needed, fresh frozen plasma which contains clotting factors will need to be administered Dietary restrictions • Dietary vitamin K, like medicinal vitamin K will reduce the anticoagulant effect of warfarin. • Foods rich in vitamin K include: green leafy vegetables (spinach, broccoli, Brussels sprouts, kale, collard greens, cabbage,) • Should foods high in vitamin K be avoided? No, consistency is key. Avoid binging on foods high in vitamin K or completely avoiding vitamin K. Warfarin Patient Education is Essential • Provide a brief mechanism of action but do not be overly technical. Just explain why the patient is taking it and for how long. • Explain the importance of having the INR checked to monitor safety and adjust dosages. Explain that doses may change from time to time. • Suggest wearing a medical alert bracelet. • Signs & symptoms of bleeding: blood in urine or stools, bloody nose, bruising, bleeding gums, cuts that will not stop bleeding. Patient should be told to contact his/her prescriber if any of these symptoms occur. • Signs & symptoms of clots: shortness of breath, chest pain, swelling in legs. Patient should be told to contact his/her prescriber if any of these symptoms occur. • Vitamin K in diet: Educate patients on consistency • Patient should make all heath care providers aware he/she is taking warfarin. This includes all prescribers, dentists, pharmacists, etc. • Patient should not use aspirin or other NSAIDs. Many cough & cold products contain aspirin and/or NSAIDs so patients should check the labels of all over-the-counter products carefully before use. Rarely, a patient may be told by his prescriber to take low dose daily aspirin WITH the warfarin. As long as the prescriber is aware of the warfarin, it is OK. But even in these cases patients should not take any more than 81 mg aspirin per day. • Patient should be advised to always double check refills for the correct dose & tablet color. This may help avoid medication errors. • Patients should take the medication at the same time each day. • Patient should not skip doses. • If a patient does accidentally forget a dose, they should not double up on doses to get “caught up.” If a dose is missed, the patient should write it down and tell their prescriber at the next INR check. • Alcohol: some prescribers tell patients no alcohol at all; others will allow some alcohol depending on the patient. If alcohol is allowed, generally no more than one “serving” per day (1 can of beer, 1 ounce of hard liquor, 1 glass of wine) and no more than once or twice per week. • Patient should avoid pregnancy. 35 *Dabigatran (Pradaxa®) Mechanism of Action: • Direct thrombin Inhibitor: binds to thrombin preventing conversion of fibrinogen to fibrin. Therapeutic Uses: • Stroke prevention in Atrial Fib • Treatment and prevention of DVT/PE Dosing: • 150mg twice daily Adverse effects: • Minor bleeding (17%), major bleeding (hemorrhage) (3%) • GI Disturbances: Abdominal pain, bloating, N/V, GERD, (Take with food) Antidote: Idarucizumab (Praxbind®) Monitoring: None required *RivaroXAban (Xarelto®) Mechanism of Action: • Direct Factor Xa inhibitor: binds to Factor Xa inhibiting production of thrombin Therapeutic Uses: • Stroke prevention in Atrial Fib • Prevention of DVT/PE post hip or knee replacement • Treatment and prevention of DVT/PE Dosing: • 10, 15, 20mg once daily Adverse effects: • Minor and major bleeding Antidote: None Monitoring: None required *ApiXAban (Eliquis®) Mechanism of Action: • Direct Factor Xa inhibitor: binds to Factor Xa inhibiting production of thrombin Therapeutic Uses: • Stroke prevention in Atrial Fib • Prevention of DVT/PE post hip or knee replacement • Treatment and prevention of DVT/PE Dosing: • 2.5, 5mg twice daily Adverse effects: • Minor and major bleeding Antidote: None Monitoring: None required Thrombolytics (IV) fibrinolytics, clot busters “Lytic” means to lyse…These drugs actually help to lyse, or break-up, an already formed clot Alteplase (Activase ), tissue plasminogen activator (tPA); Streptokinase (Streptase ); Tenecteplase (TNKase); Reteplase (Retavase ) Mechanism of Action: Converts plasminogen to plasmin. Plasmin dissolves clots.Therapeutic Uses: Treatment of acute DVT, massive PE, MI, and acute ischemic stroke. Also used to clear clotted IV catheters. Adverse effects: Severe hemorrhage; Re-thrombosis after initial lysis – sometimes busting up the clot causes little chunks of the clot to travel throughout the body to lodge in smaller vessels & activate more platelets. (Always follow up a clot-buster with heparin to prevent more clots form forming.) Absolute Contraindications: Active bleeding, Aortic dissection, cerebral neoplasm (cancer) or aneurysm, history of recent intracranial hemorrhage, surgery, or trauma and others. 36 Treatment of Angina Chest Pain is the most frequent reason for ED visits. The consequences of misdiagnosis are significant (clinically for false-negative diagnoses and economically for false-positives). Angina is substernal chest pain caused by coronary blood flow that is insufficient to meet the oxygen demands of the heart. When the myocardial tissue is low on oxygen, cells will die (ischemia) & pain occurs. The majority of angina is due to obstruction of the coronary vessels by atherosclerotic plaques. A small percentage is due to spasms of the vascular smooth muscles leading to the heart, which temporarily narrow the artery. This type usually does not progress to MI. Classification of Angina (3 classes) 1) Chronic Stable Angina (exertional angina): Exertion related, predictable pattern. 2) Variant Angina (Prinzmetal’s or vasospastic angina): Associated with more severe pain. Usually occurs at rest rather than with exertion: early morning/awakening from sleep. It tends to involve the right coronary artery, and is apt to be associated with arrhythmias or conduction defects. It is due to vasospasms of the coronary artery. 3) Unstable angina: Medical emergency Determinants of Myocardial Oxygen Demand • Heart rate – faster rate requires more O 2 . • Heart muscle contractility – Stronger contractions require more O2 . • Preload – Increased blood volume in ventricle just prior to contraction. (venous) • Afterload – Increased resistance the ventricles must pump against. (arterial) Drug Therapy Options: β-blockers, Calcium Channel Blockers, Nitrates, and Ranolazine β -blockers • Increased sympathetic activity is a common feature in exertional anginal attacks. • β-blockers reduce the O 2 demands of the heart by decreasing myocardial oxygen requirements during exertion and stress. Reduced heart rate & contractility = ↓ myocardial O2 demand. • β-blockers have the strongest evidence supporting their ability to reduce morbidity & mortality. • β-blockers are used prophylactically to reduce the frequency of attacks and decrease sublingual nitroglycerin use. Calcium Channel Blockers • CCBs reduce arteriolar tone = ↓ afterload by ↓ peripheral resistance = ↓ myocardial O 2 demand. • Beneficial effects on coronary arteries may also increase myocardial oxygenation • Diltiazem & verapamil also mimic the β-blockers’ effects of reduced heart rate & contractility. • CCBs are used prophylactically to reduce the frequency of attacks and decrease sublingual nitroglycerin use. 37 Nitrates • Mechanism of Action: Nitrates are venous dilators. • Nitrates are converted to nitric oxide (NO) which acts at a cellular level through a chain of chemical reactions to ultimately relax the vascular smooth muscle. • They decrease the release of Ca++ from storage sites along the vascular endothelium. • Sulfhydryl groups are required both for the conversion to nitric oxide and the stimulation of cells to activate the chemical reactions. • Reduced arteriolar and venous tone = ↓ preload & ↓ afterload = ↓ myocardial O 2 demand. • Also promote increased blood flow to deep myocardial muscle Adverse effects • Very common vasodilatory adverse effects: venous pooling (edema), headache (acute and transient with the SL products; usually goes away after several days or weeks of chronic use), orthostatic hypotension (light-headedness, dizziness), hypotension, & flushing. Nitrate Tolerance • Partial or complete nitrate tolerance will occur to some degree in most patients upon multiple dosing or use of long-acting formulations. This is due to the depletion of sulfhydryl groups. • Avoid tolerance by allowing a drug-free interval of 8 – 12 hours per day. • Some clinicians are concerned with reports of some rebound ischemia during the nitrate-free interval and therefore may not initiate a nitrate-free interval Nitrate Formulations (nye-troe-GLI-ser-in) *Nitroglycerin Sublingual Tablets (Nitrostat ) or Spray • Used to treat acute anginal attacks or taken prior to exercise to prevent attacks. Rapid onset of action (1 – 3 minutes) • Patient Instructions: Dissolve 1 tablet under tongue; if pain is not relieved in 5 minutes call 911 or report of emergency room. While waiting for emergency care, 1 more tablet may be taken and a third tablet may be taken in 5 min. Nitroglycerin Topical Ointment • Dosed in inches; applied every 6 – 8 hours. Quick onset of action (15-30 minutes) • Can easily titrate dose based on response. Can be removed quickly if adverse effects occur. • Very messy to use. Makes it somewhat difficult for outpatient use. Nitroglycerin Transdermal Patches (Nitro-Dur , Minitran ) • Are NOT effective for acute attacks; used prophylactically to reduce frequency of exertional or variant angina attacks. They provide a steady constant release of drug over 24 hours. Patches are applied once daily. Nitroglycerin Sustained Release Capsules (Nitro-Bid ) • Are NOT effective for acute attacks; used prophylactically to reduce frequency of exertional or variant angina attacks. Isosorbide dinitrate (Isordil®) & Isosorbide mononitrate (Ismo®, Monoket®, Imdu®r) (eye-soe-SORE-bide dye-NYE-trate) (eye-soe-SORE-bide mon-oh-NYE-trate) • Are NOT effective for acute attacks; used prophylactically to reduce frequency of exertional or variant angina attacks. 38 Ranolazine (Ranexa®) (ran-OH-laa-zeen) (oral) • First new antianginal agent in more than 25 years • Exact mechanism unknown --reduces sodium and calcium accumulation in myocardial cells….. • Can cause QT prolongation (dysrhythmia) • Not used as first-line treatment Management of Angina Drug Therapy for Unstable Angina Medical Emergency / Hospital setting • Goal: Reduce risk of MI & death. • IV Nitrates: increase O 2 supply & decrease O 2 demand • β-blockers: reduce O 2 demand • CCBs: if nitrates & β-blockers are inadequate • IV morphine if pain persists. ECG is obtained & monitored. Coronary catheterization – view the vessels near and around the heart for blood flow, blockage, or damage. • Supplemental oxygen as needed • Heparin: prevent clots & maintain O2 supply • Aspirin/clopidogrel: block platelet aggregation Drug Therapy for Chronic Stable Angina • Goal: Reduce intensity & frequency of anginal attacks. • Agents that decrease oxygen demands by decreasing heart rate, contractility, preload, or afterload may be used to treat chronic stable angina. All 3 classes of drugs increase exercise tolerance & aerobic capacity. • Prophylaxis with nitrates, CCB, or β-blockers. Acute attacks: SL nitro Drug Therapy for Variant Angina • Goal: Reduce intensity & frequency of anginal attacks. • Nitrates & CCB’s relax smooth muscle of the vessels & are effective treatments. • Variant angina is due to reduced O 2 supply rather than increased O 2 demand. • β-blockers are not vasodilators and thus are ineffective for this type of angina. • Prophylaxis with nitrates or CCB. Acute attacks: SL nitro 39 Heart Failure (HF) Heart failure (formerly known as congestive heart failure) is a condition where the heart is unable to pump enough blood to meet the needs of the body. Inadequate tissue perfusion leads to fatigue, shortness of breath, exercise intolerance, & volume overload. About 5 million people in the US have HF. HF accounts for huge amounts of health care expenditure each year & is the leading cause of hospitalizations. About 40% of deaths from HF are sudden; the rest are slow and may require palliative care. Oral medications are used to manage symptoms of HF & to slow the progression of the disease. Some patients will have exacerbations of their chronic heart failure (called “acute heart failure” or “acute decompensated heart failure, ADHF) and usually require hospitalization and treatment with IV medications. Common Risk Factors (Causes) • Coronary heart disease (angina, plaques, hardened arteries = ischemia) • Myocardial infarction (cause ischemic damage to the heart) • Uncontrolled hypertension (over-exertion of the heart to pump against high blood pressure) • Renal failure (over-exertion of the heart to pump against increased blood volume) • Arrhythmias (including bradycardia & tachycardia) • Age > 65 years Heart Failure is a Vicious Cycle of Compensatory Responses!!! Heart failure = decreased cardiac output (↓ CO) ↓ Body kicks in its compensatory mechanisms to try to increase CO ↓ Ultimately leads to more heart damage & worsening of heart failure What the body tries to do to fix the problem ends up making it worse in the long run. • Compensatory Mechanisms Increased sympathetic activity – ↑ catacholamine release (epinephrine, norepi, & dopamine) -This increases heart rate & force of contraction. (Good) -But this also increases heart workload, stress, & oxygen demand. (BAD) • Decreased cardiac output means decreased blood flow to the kidney. This is interpreted as dehydration and the kidney attempts to compensate with fluid retention. -Kidney releases renin which will cause fluid & Na+ retention & vasoconstriction. -This fluid overload & ↑ BP further strains the heart & leads to edema & pulmonary congestion. • Myocardial hypertrophy (enlargement of the heart) -Heart stretches, dilates, & increases in size to create stronger contractions. (Good) -But, if the muscle fibers are stretched too far, which they eventually will, contractions are weakened. (BAD) 40 Cardiac Glycosides (Digoxin) *Digoxin (Lanoxin / Lanoxicaps) (inj, oral) Mechanism of Action • Inhibits the Na+/K+ pumps of the cardiac cell membranes. This increases intracellular Na+ levels. • High intracellular Na+ levels facilitates Ca++ influx into cells. • Increased intracellular Ca++ equals stronger muscle contractions. Pharmacokinetics of Digoxin • Half-life = 1 – 2 days; much longer if severely renally impaired • Excreted by kidney & metabolized by liver • Distributed widely in body tissues = large Vd • Therapeutic serum levels = 0.5 – 0.8 ng/ml Dose / Monitoring Information • Loading doses are sometimes due to the large Vd & rapidly achieve adequate serum levels. This is only done when an immediate effect is desired and in a hospital setting. • Serum levels should be obtained only for the following reasons: Questionable compliance, Lack of improvement, Lack of ventricular control in A-fib, Changing renal function, Interacting medications, Abnormal ECG, or other suspected toxicity. • Correlation between plasma levels and clinical affect is not reliable. Digoxin toxicity is common (estimated as occurring in 5 – 25% of patients receiving it) • • • • Narrow therapeutic window / index Patient variable pharmacokinetics Multiple drug interactions -Hypokalemia will predispose patients to digoxin toxicity. Low serum potassium (K+) levels will strengthen the effects of digoxin on cardiac membranes. Example: Normally a serum digoxin level of 1.7 ng/ml would not cause toxicity. If that same patient had a decreased K+ level we may see toxicities & heart arrhythmias Elderly are at increased risk of toxicity due to decreased renal function, increased myocardial sensitivity, & frequent use of diuretics, laxatives, & other interacting medications. Signs & Symptoms of Digoxin Toxicity • • • It is important to discuss these signs & symptoms with patients taking digoxin! Nausea & vomiting, loss of appetite. Fatigue, confusion, mental disturbances, dizziness, blurred vision, haloes on dark objects, yellow or green tinted vision. • Pulse less than 60 beats/minute. • Any type of cardiac arrhythmia (AV heart block, asystole, atrial tachycardia with block, AV dissociation, accelerated junctional rhythm, ventricular tachycardia, ventricular fibrillation, PR prolongation, ST segment depression) Treatment of Digoxin Toxicity • Give K+ supplements (↑ K+ to high/normal will have a protective effect on the heart.) • Treat any arrhythmias with the appropriate antidysrhythmic • Digoxin Immune Fab (Digibind) – binds with molecules of digoxin in the blood, inactivating it. The molecules are then excreted by the kidney. 41 o Do not expect digoxin levels to go down after Digibind is administered. Although inactivated, the drug is still present in the blood stream & will be detected by serum assay. Levels may even be reported as higher than before Digibind. Monitor patient response as an indication of Digibind effectiveness rather than repeat serum levels. Pharmacological Treatment of Heart Failure Goals of Therapy: ↑ Survival, ↓ Symptoms, ↓ Damaging Compensatory Mechanisms, Prevent Disease Progression & Improve Quality of Life 1. ACE-Inhibitors / ARBs ¾ Cornerstone of therapy for HF; proven to decrease mortality rate by close to 50%. ¾ Prevent harmful compensatory activation of the renin-angiotensin system. ¾ All patients who can tolerate an ACE-inhibitor should receive one. ¾ For patients allergic or intolerant to ACE-I, ARB may be more appropriate. Some patients may take both an ACE-I and ARB. 2. Loop Diuretics ¾ Relieve many symptoms of HF (peripheral & pulmonary edema). ¾ Decrease preload & circulatory congestion. ¾ Thiazide diuretics may be adequate in patients with only mild symptoms. Loop diuretics are generally preferred. Synergistic combinations of thiazides & loop diuretics can be helpful in patients who do not respond to maximal doses of a loop diuretic alone. 3. Aldosterone antagonists (spironolactone, eplerenone) ¾ Prevent harmful compensatory activation of aldosterone in the renin-angiotensin system. 4. β -Blockers ¾ Prevent harmful compensatory activation of sympathetic nervous system, increase ejection fraction, and reduce left ventricular hypertrophy. ¾ Proven beneficial in patients with mild to moderate HF in reducing mortality & hospitalizations. ¾ Carvedilol (Coreg®) is an α1, β1, β2 blocker with possible antioxidant properties specifically FDA approved for HF, but other beta-blockers can also be used. ¾ Proven beneficial in patients with mild to moderate HF in reducing mortality & hospitalizations. ¾ Start low & go slow! May cause fatigue & worsen heart failure & fluid accumulation initially in some patients. Benefits are generally seen in 2-3 months. 5. Digoxin ¾ Reduces symptoms, decreases hospitalizations, & improves quality of life for patients with severe heart failure [low ejection fraction heart failure, EF < 20% ]. ¾ Has not been shown to reduce mortality. 6. Other Measures ¾ Annual influenza vaccine & a one-time pneumococcal vaccine are recommended. ¾ Aggressively control hypertension, hypercholesterolemia, & diabetes if present. ¾ Recommend smoking cessation, low-intensity aerobic exercise; discourage alcohol intake. ¾ Dietary salt restrictions for later stages of HF, and have patients monitor weight daily for early signs of fluid accumulation. ¾ Appropriate end of life measures and decisions regarding appropriate level of care must be considered for end-stage HF. 42