• Information
  1. Thrombolytic Agents
  2. ACE Inhibitors
  3. Angiotensin II Receptor Blockers
  4. ß-Adrenergic Receptor Blockers
  5. Calcium Channel Blockers
  6. Summary of Properties of Calcium Channel Antagonists
  7. alpha1 Adrenergic Receptor Blocking Agents
  8. alpha-2 Adrenergic Agonists
  9. Nitrates
  10. Diuretics
  11. Endothelin Receptor Blockers
  12. Other Antianginals
  13. Hydralazine
  14. Inotropic Agents
  15. Comparison Of Commonly Used Sympathomimetic Agents

A. Thrombolytic Agents [36,70,73]

1. Utility [65]
   1. Myocardial Infarction, within 12 hours
   2. Generally not indicated for unstable angina
   3. Massive Pulmonary Embolism
   4. Stroke (Cerebrovascular Accident), within 3-4 hours
2. First Generation Thrombolytics
   1. Not fibrin specific (also degrade fibrinogen)
   2. Streptokinase (SK; Kabikinase®, Streptase®) - antigenic
   3. Anistreplase (APSAC; Eminase®)
   4. Urokinase
3. Second Generation
   1. Fibrin selective, short half-life requires continuous infusion over 90 minutes
   2. Tissue Plasminogen Activator (TPA, Alteplase®)
   3. Single-chain uorkinase-type plasminogen activator
4. Third Generation [70]
   1. Longer half-life allowing bolus administration, improved fibrin selectivity
   2. Plasma levels of plasminogen and fibrinogen are altered only slightly
   3. Tenecteplace (Metalyse®)
   4. Reteplase (Retavase®) - recombinant mutant derivative of TPA
   5. Monteplase
   6. Lanoplase
   7. Pamiteplase
   8. Staphylokinase
5. TPA (Alteplase®) [37]
   1. Recombinant 527 residue, 70K protein processed by plasmin
   2. Binds specifically to fibrin
   3. Selective second generation agent with 4-8 minute serum half-life
   4. Dose is 100mg IV total infusion (cost is 5-8 fold higher than SK)
   5. Usually given "front-loaded" with 15mg bolus, 35mg over 30min, 50mg over 30 min.
   6. Good early (90 minute) vessel patency of >50% (TIMI Grade 3 Flow)
   7. Mortality decrease with TPA is equal to or slightly greater than SK
   8. Double bolus infusion is less safe than accelerated infusion and less effective [43]
   9. Must be given with heparin to prevent early reclosure
6. Streptokinase (SK, Anistreplase®)
   1. Reduces mortality ~20%, similar to TPA
   2. Dose: 1.5 million units over one hour, fairly low incidence of bleeds
   3. Early (90 minute) vessel patency 30-35%, less than that seen with TPA
   4. Benefit seen especially in older patients [26]
   5. Specific contraindications: allergy, previous SK therapy
   6. Thus, SK may only be given once to any particular patient
   7. TPA is generally recommended over SK for patients with large anterior MI
   8. Side effects include hypotension, anaphylactic reactions
7. TPA versus SK [36,37]
   1. All protocols used heparin (GUSTO Trial; >40,000 patients)
   2. 1 month: "front-loaded" TPA (6.3% mortality) versus Streptokinase (7.3% mortality)
8. Reteplase (Retavase®) [70]
   1. Reteplase is a derivative of TPA missing finger, kringle-1 and EGF domains
   2. Produced in E. coli and so lacks carbohydrate side chains
   3. This 355 residue (39K) protein has a clearance rate slower than alteplase
   4. Given as two 10U IV boluses 30 minutes apart
   5. In a trial of reteplase versus SK, the 35d and 6 month morality rates were similar [41]
   6. Reteplase was indistinguishable from alteplase in GUSTO III [42]
   7. Reteplase appears at least as effective as alteplase, may work more quickly
   8. Less fibrin specificity than alteplase or tenecteplase
9. Tenecteplase (TNKase®, Metalyse®) [70,71]
   1. Derivative of of TPA where mutations T103N, N117Q and 296KHRR to AAAA introduced
   2. High fibrin selectivity and increased serum half-life (11-20 min)
   3. Increased resistance to plasminogen activator inhibitor (PAI)
   4. Single IV bolus tenectaplase (0.5mg/kg) versus front-loaded TPA in ASSENT-II trial [6]
   5. In ASSENT II, mortality similar, some reduction in bleeding with tenecteplase
   6. Tenecteplase required less blood transfusion than TPA as well [6]
   7. Tenecteplase has similar efficacy, is easier to give, and causes less bleeding than TPA
10. Pamiteplase (Solinase®) [70]
    1. Modified TPA with deleted kringle 1 and Arg274 to Glu substitution
    2. Thus, pamiteplase is resistant to cleavage by plasmin
    3. Serum half-life 30-47 minutes after single dose
    4. Comparisons with standard dose TPA have not yet been done
11. Lanoteplase [70]
    1. Mutant of TPA with fingerlike and EGF domains deleted; Asn117 mutated to Gln
    2. Prevents clearance by mannose receptor; half-life is 37 minutes
12. Staphylokinase [70]
    1. Recombinant form derived from lysogenic Staphylococcus aureus
    2. Preferentially reacts with plasmin on clot surface forming complex
    3. This staphylokinase-plasmin complex activates plasminogen trapped in the thrombus only
    4. alpha-2 antiplasmin rapidly inhibits any released or free staphylokinase-plasmin
    5. Half-life (ß phase) 37 minutes in serum and has good thrombolytic efficacy
    6. Patients develop neutralizing antibodies, however
13. Heparin should be started post-infusion of thrombolytic (clear benefit only with TPA)
14. Contraindications
    1. Uncontrolled hypertension (HTN)
    2. Recent Major Surgery
    3. Recent Cerebrovascular Accident
    4. Prolonged CPR
    5. Bleeding Diathesis
    6. Cerebral Metastases
    7. Menstruation is not a contraindication (benefits outweigh risks)
15. Major complication is bleeding
    1. Rates are variable but generally <10%
    2. Risk of cerebral hemorrhage with thrombolytics is 0.6% for standard, 0.8% for bolus [67]
16. Addition of glycoprotein IIb/IIIa inhibitors to thrombolytics improves vessel opening [65]
17. Tenecteplase and reteplase comparable with accellerated TPA and easier to give [73]

B. ACE Inhibitors (ACE I) [1,11,63,72]

1. Inhibition of angiotensin converting enzyme (ACE)
   1. Leads to decrease in angiotensin II levels, which causes vasodilation
   2. Aldosterone reduction decreases sodium fluid retention but may lead to hyperkalemia
   3. ACE also destroys bradykinin (BK) and Substance P (SP)
   4. Thus, ACE inhibition can lead to increased levels of BK and SP can occur
   5. BK may play a significant role in blood pressure lowering effects of ACE I
   6. In some patients, these high BK/SP levels lead to a cough (may have to stop drug)
   7. Proved mortality and morbidity benefits in HTN [62], post-MI, and in CHF
   8. Also provide renal protection in diabetes, sickle cell disease, and other diseases
   9. May exacerbate renal artery stenosis, precipitating renal failure [53]
   10. All patients initiating ACE I therapy should have renal functioning monitoring
2. Captopril (Capoten®) [62]
3. Enalapril (Vasotec®)
4. Lisinopril (Prinivil®, Zestril®)
5. Fosinopril (Monopril®)
6. Benazepril (Lotensin®)
7. Quinapril (Accupril®)
8. Ramipril (Altace®)
9. Moexipril (Univasc®) [18]
10. Trandolapril (Mavik®) [32]
11. Side Effects
    1. Cough
    2. Renal Insufficiency - elevation in BUN, Creatinine, and potassium
    3. Acute renal failure may be precipitated in patients with renal artery stenosis [53]
    4. Presence of single functioning kidney is major contraindication
    5. ACE inhibitors may be cautiously increased in patients with CrCl<30cc/min
    6. Hyperkalemia - due to renal insufficiency and decreased aldosterone production
    7. Severe hyperkalemia is rare in persons <70 years old with normal renal function [45]
    8. Angioedema - related to cough
    9. Hypotension - especially in patients with renal insufficiency

C. Angiotensin II Receptor Blockers [24,63,72]

1. Agents which directly block vasoconstrictive effects of angiotensin II (AT-II)
2. May also block development of ventricular hypertrophy in patients with HTN
3. Pathophysiology
   1. AT-II Receptor Type 1 blocking agents
   2. Block AT-II function without affecting Angiotensin Converting Enzyme
   3. Do not have effects on bradykinin (BK) and substance P (SP) metabolism
   4. BK and SP may play a role in renal and cardioprotective effects
4. Utility
   1. Appear to be as effective as ACE inhibitors for HTN reduction
   2. Do not cause angioedema or cough (probably related to bradykinin)
   3. Should be used in patients intolerant of ACE inhibitors
   4. Some Benefits in CHF in several trials (but probably less effective than ACE inhibitors)
   5. Unclear efficacy in diabetic nephropathy (ACE inhibitors first line)
5. Losartan (Cozaar®) [12]
6. Valsartan (Diovan®) [38]
7. Irbesartan (Avapro®) [46]
8. Tasosartan (Verdia®)
9. Candesartan (Atacand®)

D. ß-Adrenergic Receptor Blockers [11,19,22,49]

1. Mechanisms of Action [16]
   1. Slow heart rate and contractility, with good anti-ischemic properties
   2. Reduce cardiac oxygen demand
   3. Reduce rate of atheroma formation
   4. Reduce ventricular ectopy with stabilization of normal and injured cardiac muscle
2. Therapeutic Benefits [25]
   1. ß-blockers should be used in ALL patients peri- and post-MI who tolerate them [54]
   2. Excellent and safe anti-arrhythmics, with good PVC suppression
   3. Most effective therapy in prevention of sudden cardiac death [16]
   4. Very effective and well tolerated in patients with chronic stable angina [64]
   5. Proved reduction in morbidity and moratility in many long term studies
   6. Very effective in rate control of atrial fibrillation
   7. Low doses may improve exercise in moderate to severe systolic heart failure
   8. Improve exercise tolerance in hypertrophic cardiomyopathy of any cause
3. Side effects of Standard Agents
   1. Bradycardia
   2. Anti-inotropic activity which can lead to worsened systolic function
   3. Impotence
   4. Mental Slowing
   5. Possible worsening of peripheral vascular disease symptoms (via ß2-blockade)
   6. Worsening cholesterol and glucose profiles (especially with diuretics)
   7. Depression NOT a side effect
   8. May also suppress symptoms of hypoglycemia and cause hyperinsulinemia
4. Non-Selective Agents
   1. Propranolol (Inderal®, Inderal LA®): t1/2 6-7 hr. 80-240mg bid or qd for LA form
   2. Naldolol (Corgard®): nonselective ß-blocker, t1/2 ~22hrs. Dosing 20-240qd
   3. Esmolol (iv agent): t1/2 ~9 minutes (broken down by RBCs), some use in intensive care
5. ß1-Selective Agents
   1. Atenolol (Tenoramin®): t1/2 ~18hr. Dosing 25-100mg po qd to bid
   2. Metoprolol (Lopressor®; Toprol®, Toprol XL®): t1/2 ~3-7hr (XL ~18-24hrs). 50-200mg qd
   3. betaxolol (Kerlone®): t1/2 ~18hr. Dosing 5-40mg po qd
   4. Bisoprolol (Zebeta®): t1/2 ~18 hours. Dosing 5-20mg/day. Highly ß1-selective
6. ß-Blockers with Intrinsic Sympathomimetic Activity (ISA) [72]
   1. May be useful in patients with bradycardias who cannot tolerate usual ß-blockers
   2. Note that sympathomimetic agents have not been shown to improve survival post-MI
   3. Acebutolol (Sectral®): excellent PVC control. Initiate dose 200mg po bid
   4. Pindolol (Visken®): 10-60mg po in divided doses
7. Carvidilol (Coreg®) [7,55]
   1. Non-selective ß-blocker, alpha-1 blocker (vasodilator), antioxidant effects
   2. FDA approved for CHF and HTN; also effective in ischemic heart disease
   3. Agent is safe and effective in systolic congestive heart failure (CHF) [23]
   4. In CHF, improves LV EF, exercise tolerance, mortality as adjunct to ACE I
   5. Dose must be increased very slowly in CHF, particularly in NYHA Class IV CHF
   6. Improves glucose and lipid metabolism in type II diabetics [39]
   7. In CHF, initial dose is 3.125mg po bid with slow escalation to 50mg po bid as tolerated [7]
8. Bucindolol [55]
   1. ß-adrenergic blocking and direct vasodilator activities
   2. Ongoing evaluations in CHF, MI, other ischemic disease
9. Labetolol (Normodyne®, Trandate®)
   1. Non-specific ß blocker with anti-alpha1 activity
   2. Excellent for step 2 or step 3 therapy, in unresponsive or poorly controlled patients
   3. Excellent for hypertensive crisis
10. Combination Agents
    1. Bisopropol (ß1 selective, Zebeta®) 2.5-10mg and HCTZ 6.25mg (combination = Ziac®)
    2. Low dose of each agent may have fewer side effects [3]

E. Calcium Channel Blockers (CCB) [4,7,11,44,49,63,72]

1. Calcium Channels
   1. There are three types of voltage sensitive Ca Channels: L, N, and T
   2. Division of types based on conductances and sensitivities to voltages
   3. Majority of currently available agents act on L-type channels
   4. Mibefradil binds to T-type channels (no longer available)
2. Verapamil (Calan®, Isoptin SR®)
   1. Anti-inotropic, anti-chronotropic. Good Anti-ischemic.
   2. Especially useful for diastolic dysfunction
   3. Avoid in low EF states; do not use with ß-blockers except under observation
   4. Dose initially with low dose, long acting forms
   5. Short acting CCB should no longer be used
   6. Verapamil (controlled onset) neither superior nor inferior to diuretics or ß-blockers for initial treatment of HTN [77]
3. Diltiazem (Cardizem®, Dilacor®, Tiazac®)
   1. Some anti-inotropic and peripheral dilating activity; anti-ischemic
   2. Major activity is AV (and SA) nodal blockade, with mild anti-inotropic effects
   3. Effective and well tolerated in treatment of HTN
   4. As good as ß-blockers and diuretics for reducing vascular complications of HTN [69]
   5. May be useful in diastolic dysfunction (but verapamil or ß-blockers usually preferred)
   6. May have Improved survival post-MI for Non-Q wave infarctions with EF>40% only
   7. Diltiazem is safe in patients treated with thrombolytics and may reduce complications [66]
   8. Dose is 120-360mg po qd
4. Nifedipine (Procardia®, Adalat®) [69]
   1. Potent peripheral vasodilator with good afterload reduction (anti-HTN)
   2. Causes reflex tachycardia which may require ß-blockade
   3. Some mild clinically relevant anti-inotropic activity so avoid in patients with EF<20%
   4. Long acting nifedipine was as good as combination diuretic for reducing blood pressure and overall vascular mortality [69]
   5. Particularly effective in renal failure (usually combined with ACE inhibitor)
   6. Short acting forms of difedipine should not be used
   7. Nifedipine may subtly impair learning and memory in some elderly patients with HTN
   8. Other side effects include peripheral edema, headache, reflex tachycardia
   9. Sublingual nifedipine should not be used for hypertensive crisis [31]
   10. Dose 10mg - 40mg po tid (avoid in most patients); long acting daily forms preferable
5. Nicardipine (Cardene®)
   1. Little reflex tachycardia compared with nifedipine and good HTN therapy
   2. 60-120mg per day in 3 (2 with SR form) divided doses
6. Felodipine (Plendil®)
   1. Peripheral vasodilation; modest reflex tachycardia
   2. Apparently decreased incidence peripheral edema and HA compared with other agents
   3. Dose 5-10mg qd.
7. Isradipine (DynaCirc®)
   1. Peripheral vasodilation; mild reflex tachycardia
   2. Increased incidence of major vascular events versus HCTZ in MIDAS study [30]
   3. Dose: 2.5-5mg bid or qd
8. Amlodipine (Norvasc®)
   1. Good peripheral vasodilation, no reflex tachycardia, qd dosing (t1/2 30-50 hours)
   2. Excellent HTN and anginal control
   3. Proven benefit on survival in recent trials of mild HTN (TOHMS)
   4. May be effective in CHF with systolic dysfunction (unlike older calcium blocking agents)
   5. Benefits for patients with idiopathic dilated cardiomyopathy has been demonstrated
   6. Appears to have sympatholytic properties as well as calcium blocking activity
   7. Amlodipine (Norvasc®) 10mg qd reduced cardiac events by 30% and atherosclerosis progression in patients with CAD and normal blood pressure [81]
   8. Dose is 2.5-10mg po qd (may increase to bid)
   9. Available as combination with Benazepril (Lotrel®)
9. Nisoldipine (Sular®) [21]
   1. Dihydropyridine with peripheral vasodilatation
   2. Little or no anti-inotropic activity
   3. Dose is 20-60mg po qd
10. Bepridil
    1. Indicated only for patients with angina refractory to other drugs
    2. Dose is 200-400mg po qd
11. Nitrendipine
    1. L-type calcium blocker
    2. Reduces indicence of stroke in elderly patients with HTN
    3. Not yet available in the USA
12. Grapefruit juice prolongs duration of action and increases drug concentrations [14]
13. Safety Issues [35]
    1. Concern for increased sudden death with short acting nifedipine, particularly post-MI
    2. No increase in overall death in CAD patients on verapamil, diltiazem, or nifedipine [34]
    3. Dose related increase in cancer incidence with verapamil, diltiazem, or nifedipine [29]
    4. Hazard ratio for cancer was 1.72 for CCB use (no difference between agents)
    5. Risk ratio for all cancers with CCB was insignificant (1.1X) [51]
    6. Increase in major vascular events in isradipine group versus HCTZ in MIDAS study [30]
    7. No difference with controlled onset verapamil and other agents for HTN therapy [77]
    8. All short acting CCB should be avoided when possible
    9. Overall, no consistent data to avoid long acting CCB in HTN [5,51,77]

F. Summary of Properties of Calcium Channel Antagonists (NC=no change)

1. Block peripheral sympathetic vasoconstriction mediated through alpha1-receptors
2. Utility
   1. Highly effective blood pressure lowering agents
   2. Must be started at low doses and titrated upwards to prevent orthostasis
   3. Once daily newer agents (doxazosin, terazosin) well tolerated
   4. Improve lipid profile and reduce insulin resistance
3. Agents
   1. Prazosin HCl (Minipress®) - 1mg qhs initially, then 2-20mg po in 2 divided doses
   2. Terazosin (Hytrin®) - 1mg qhs initially, titrate to 1-20mg po qhs
   3. Doxazocin (Cardura®) - 1mg qhs initially, titrate to 1-16mg po qhs
4. Avoid initial high doses in elderly, who easily develop syncope
5. These agents also relax prostatic urethral muscle leads to improve symptoms of BPH

H. alpha-2 Adrenergic Agonists

1. Clonidine is the only currently available centrally acting alpha-2-adrenergic agonist
   1. Stimulates alpha-2 adrenergic receptors in vasomotor center of medulla
   2. This inhibits central sympathetic outflow
   3. Result is fall in total Peripheral vascular resistance
   4. Cardiac output is reduced initially, but returns to normal eventually
   5. May be useful in opiate withdrawal
   6. alpha2-adrenergic agonists have shown some benefit for prevention of perioperative cardiovascular events and should be considered in patients intolerant to ß-blockers [78]
2. Step 2 medication for any chronic HTN when BP not controlled by first line agent alone
3. Dosing
   1. Oral: 0.2mg loading dose, then 0.1mg. tid-qid po
   2. Clonodine patches available for long term HTN control
4. This agent cannot be discontinued abruptly, or (severe) rebound HTN may occur

I. Nitrates [48,49]

1. Characteristics of Nitrates
   1. Increase nitric oxide production
   2. At low doses, effects more prominant on veins than on arterioles
   3. Dilate epicardial cardiac arteries, but not coronary resistance vessels
   4. Therefore, have reduced risk of inducing coronary "steal" syndromes
   5. Clearly improve anginal symptoms but little data support major changes in outcomes in patients with acute coronary syndromes
2. Nitroglycerin
   1. Direct acting vasodilator, venous > arterial
   2. Dilates large epicardial arteries with little effect on intramyocardial vessels
   3. Treatment of angina in patients with coronary artery disease
   4. Tolerance to IV (Nitro-Bid®, Nitrostat®, Tridil®) nitroglycerin develops within 24 hours
   5. Often used transdermally (Nitro-Dur®, Transderm-Nitro®) as patches
   6. Paste preparation is available, dosed in inches q4-6 hours
   7. Sublingual (Nitrostat®, Nitroglycerin®)
3. Oral Nitrates [8]
   1. Isosorbide Dinitrate (Isordil®) and Isosorbide Mononitrate (Ismo®)
   2. Usual dose ~20 mg bid-tid for dinitrate, 10-40mg po qd for mononitrate
   3. Relaxes primarily venous smooth muscle
4. Hydralazine/isosorbide dinitrate (20mg/37.5mg) fixed dose single pill (BiDil®) is approved (1-2 tabs tid) as adjunctive treatment for black patients with CHF [82]

J. Diuretics [49,63]

1. Excellent first or second line for HTN treatment
   1. Thiazide Diuretics
   2. Thiazide-Like Diuretics - metalozone, indapamide
2. Loop Diuretics - mainly for CHF, other causes of edema
3. Potassium Sparing Diuretics
   1. Often used in combination therapy for HTN
   2. Spironolactone is effective in CHF with ACE inhibitors (caution: hypokalemia risk)
4. Adenosine Antagonists - experimental agents
5. Often available in combination with other agents

K. Endothelin Receptor Blockers [61]

1. Endothelin 1, 2 and 3 have mainly potent vasoconstricting activities
2. Produced by endothelium, lung, brain, kidney and some circulating cells
3. Receptors
   1. ETa and ETb found in vascular smooth muscle
   2. ETa mediates pure vasoconstriction
   3. ETb may mediate some vasodilation, but can mediate constriction
4. Bosentan for Systemic HTN [50]
   1. Orally active, mixed ETa/ETb receptor antagonist
   2. Administration of 100-2000mg/day reduces blood pressure (~12mm max)
   3. Bosentan increased plasma endothelin, mild reduction in angiotensin II
   4. As effective as enalapril
   5. Bosentan caused headache, flushing, leg edema, some transaminase
5. Bosentan (Tracleer®) for Pulmonary HTN [74,75]
   1. Evaluated in primary and secondary (scleroderma associated) pulmonary HTN
   2. Bosentan 62.5-125mg po bid reduced pulmonary pressures and improved functional class in patients with severe, symptomatic pulmonary HTN
   3. Initial dose is 62.5mg po bid, then increase to 125mg bid or 250mg bid (preferred)
   4. 250mg bid is associated with abnormal transaminases in 14% of cases
   5. Now FDA approved for P-HTN with Class III or IV symptoms
   6. Monthly hepatic monitoring is required
   7. Preferred initial agent due to good efficacy and oral dosing
6. Additional endothelin blockers in development for HTN and renal protection [61]

L. Other Antianginals

1. Nicorandil [76]
   1. Nicotinamide ester with dual actions: nitrate and K+ channel activities
   2. Reduced combination of CHD death, non-fatal MI, and unplanned hospitalization for cardiac chest pain 17% versus placebo in stable angina patients
2. Ranolazine (Ranexa®)
   1. Inhibitor of fatty acid oxidation, reduces angina and possibly infarct size [79]
   2. In severe chronic angina, ranolazine improved exercise capacity and reduced symptoms in combination with atenolol, amlodipine, or diltiazem [80]
   3. Reduces anginal pain but no benefits on cardiac events in ACS [2]
   4. Dose 1000mg po bid; monitor QTc interval
   5. May reduce dose to 500-750 mg bid

M. Hydralazine [72]

1. Not currently primary or secondary agent
2. Direct arteriolar vasodilator, stimulates sympathetic nervous system
3. Reflex tachycardia often occurs; can be controlled by adding ß-blocker
4. Useful in pregnancy
5. Useful for afterload reduction in CHF when ACE inhibitors not tolerated

N. Inotropic Agents

1. Digoxin (Lanoxin®)
   1. Digitalis glycoside with half-life ~ 1.5-2 days
   2. Reversible inhibition of cardiac Na+K+ ATPase
   3. Inotropic activity without increased ATP utilization
   4. Incease in Na inside cells, which leads to Ca flux into cells through Na/Ca exchange
   5. Improves symptoms of CHF and may reduce rates in atrial fibrillation
   6. Side effects include life-threatening arrhythmias: VT, VF, high grade AV block
   7. Also causes mental status changes, hallucinations, nausea and vomiting
   8. Unclear that benefits outweigh increased risks [10,58]
   9. Digitalis toxicity can be fatal and must be monitored carefully
2. Dopamine (Intropin®)
   1. Acts on D1, ß1, and alpha-receptors depending on the concentration used
   2. Low dose increases renal and mesenteric blood flow
   3. Moderate "cardiac" doses are inotropic, with increased heart rate and cardiac output
   4. At high doses (>10-15µg/kg/min), alpha-adrenergic vasoconstrictor effect predominates
   5. Excellent first line agent for hypotension
   6. Primary agent for severe refractory CHF
3. Dobutamine (Dobutrex®)
   1. Synthetic catecholamine with non-selective ß-adrenergic activity
   2. Increased myocardial contractility via ß1-agonist activity
   3. Afterload reduction due to ß2-agonist activity
   4. This afterload reduction can prevail leading to hypotension
4. Amrinone [56]
   1. Strongly inotropic agent with vasodilator activity
   2. cAMP phosphodiesterase inhibitor, given parenterally
   3. Increases mortality in CHF trials
   4. However, used for short term "tune-up" of inpatients with severe CHF
5. Milrinone [57]
   1. More potent inotropic activity than amrinone
   2. Similar vasodilator effects to amrinone
   3. Reduced pro-arrhythmic activity compared with amrinone
   4. Increased mortality in CHF trials when used chronically (oral)
6. Vesnarinone [58]
   1. Oral phosphodiesterase inhibitor
   2. First Phase III study showed improved function and reduced mortality with 60mg qd [59]
   3. Second larger Phase III showed increased mortality but improved function (at 6 and 16 weeks but not at end of trial which was 26 weeks) [60]
   4. Improved symptoms must be weighed against ~4% increase in 6 month mortality
   5. Unclear whether this agent will be submitted for regulatory approval (Otsuka America)

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