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Thread: Therapeutic goals and options of cardiovascular diseases

  1. #1

    Default Therapeutic goals and options of cardiovascular diseases

    ACS includes unstable angina (UA) and myocardial infarction (MI). ACSs are classified according to EKG changes into STE MI or NSTE ACS (NSTE MI and UA).

    AN STE MI typically results in an injury that transects the thickness of the myocardial wall. NSTE MI is limited to the subendocardial myocardium. NSTE MI differs from UA in that ischemia is severe enough to produce myocardial necrosis resulting in the release of a detectable about of biomarkers, mainly troponin T or I, but also creatine kinase (CK) myocardial band (MB), from the necrotic myocytes in the bloodstream.

    Time Course of Cardiac Biochemical Markers
    Marker Molecular weight (daltons) Range of time to initial elevations (hr) Mean time to peak elevations (non-thrombolysis) Time return to normal range
    Troponin I 23,500 3-12 24 hr 5-10 days
    Troponin T 33,000 3-12 12 hr - 2 days 5-14 days
    CK-MB 86,000 3-12 24 hr 2-3 days
    Myoglobin 17,800 1-4 6-7 hr 24 hr

    1.NSTE MI

    The predominant cause of ACS in more than 90% of patients is atheromatous plaque rupture, fissuring, or erosion of an unstable atherosclerotic plaque that occludes less than 50% of the coronary lumen prior to the event, rather than a more stable 70% to 90% stenosis of the coronary artery. Stable stenoses are characteristic of stable angina.


    #Short-term goal: Early restoration of blood flow to the infarct-related artery to prevent infarct expansion; prevention of death and otherMI complications; prevention of coronary artery reocclusion and as evidence of restoration of coronary artery blood flow; relief ofischemic chest discomfort; resolution of ST-segment and T-wave changes on the ECG

    #Long-term goal: Control of CV risk factors; prevention of additional CV events, including reinfarction, stroke, and HF, and improvementin quality of life.

    Risk Stratification
    TIMI Score (NSTE MI)
    High-risk 5-7 points
    Medium-risk 3-4 points
    Low-risk 0-2 points

    List of options

    #Nonpharmacologic therapy
    *PCI or CABG surgery

    The most recent PCI ACCF/AHA/SCAI clinical practice guidelines recommend coronary angiography with either PCI or coronary artery by pass graft (CABG) surgery revascularization as an early treatment (early invasive strategy) for patients with NSTE ACS at an elevated risk for death or MI, including those with a high risk score (TIMI Score for NSTE MI) or patients with refractory angina, acute HF, other symptoms of cardiogenic shock, or arrhythmias.

    All patients undergoing PCI should receive low-dose aspirin (ASA) therapy indefinitely. A P2Y12 inhibitor antiplatelet (clopidogrel, prasugrel, or ticagrelor) should be administered concomitantly with ASA for at least 12 months following PCI for a patient with ACS. Earlier discontinuation of the P2Y12 inhibitor should be considered if the risk of bleeding outweighs the anticipated benefit in reduction in risk of death, MI, or stroke as well as stent thrombosis. A longer duration of P2Y12 inhibitor therapy may be considered for patients receiving a drug-eluting stent because the risk of stent thrombosis is greater upon cessation of dual antiplatelet therapy. Drug-eluting stents reduce the rate of smooth muscle cell growth causing stent restenosis. However, there is a delay in endothelial cell regrowth at the site of the stent that places the patient at higher risk of thrombotic events following PCI. Therefore, dual antiplatelet therapy is indicated for a longer period of time following PCI with a drug-eluting stent. Trials are ongoing evaluating the need for an extended duration (greater than 12 months) of P2Y12 inhibitor therapy following PCI. Regardless of whether or not a patient with NSTE ACS receives a stent, the preferred duration P2Y12 therapy is at least a year.

    #Pharmacologic therapy
    In general, early pharmacotherapy of NSTE ACS is similar to that of STE MI. In the absence of contraindications, all patients with NSTE ACS should be treated in the emergency department with intranasal oxygen (if oxygen saturation is low), SL NTG, ASA, and an anticoagulant: UFH, enoxaparin, fondaparinux, or bivalirudin. High risk patients should proceed to early angiography and may receive a GP IIb/IIIa inhibitor. A P2Y12 inhibitor should be administered to all patients. IV beta-blockers and IV NTG should be given in selected patients. Oral beta-blockers should be initiated within the first day in patients without cardiogenic shock. Morphine is also administered to patients with refractory angina as described previously. These agent should be administered early while the patient is still in the emergency department. Fibrinolytic therapy is never administered.

    #Antiplatelet agents
    *Systemic, NSAIDs (ASA)
    *Systemic, P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel)
    *Systemic, GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)

    ASA reduces the risk of death or developing MI by about 50% (compared with no antiplatelet therapy) in patients with NSTE ACS. Therefore, ASA remains the cornerstone of early treatment for all ACS. Dosing of ASA for NSTE ACS is the same as that for STE MI. Low-dose ASA is continued indefinitely.

    P2Y12 Inhibitors
    For patients with NSTE ACS where an initial invasive management strategy is selected, two initial options for dual antiplatelet therapy are described by practice guidelines depending on choice of P2Y12 inhibitor. In addition to ASA administered either prehospital or in the emergency department, either

    1.Early use of clopidogrel or ticagrelor (in the emergency department), or
    2.Double bolus dose eptifibatide or high-dose tirofiban administered at the time of PCI (bivalirudin should not be administered as the anticoagulant in this option)

    Subsequent antiplatelet therapy following PCI is selected based on the coronary anatomy at the time of angiography. For patients undergoing PCI initially treated with regimen 1 above, a GP IIb/IIIa inhibitor (abciximab, eptifibatide, or tirofiban) can be added and then clopidogrel continued with low-dose aspirin. For patients undergoing PCI initially treated with option 2, clopidogrel, prasugrel, or ticagrelor can be selected following PCI (within 1 hour following PCI) and the P2Y12 inhibitor continued with low-dose ASA. Following PCI in ACS, dual oral antiplatelet therapy is continued for at least 12 months.

    For patients receiving an initial conservative treatment strategy, the 2011 ACCF/AHA NSTE ACS guidelines recommended early administration of clopidogrel in addition to ASA. Dual antiplatelet therapy is continued for at least 1 month and ideally for 1 year.

    Glycoprotein IIb/IIIa Receptor Inhibitors
    The role of GP IIb/IIIa inhibitors in NSTE ACS is diminishing as P2Y12 inhibitors are used earlier in therapy, and bivalirudin is selected more commonly as the anticoagulant in patients receiving an early intervention approach. Routine administration of eptifibatide (added to aspirin and clopidogrel) prior to angiography and PCI (i.e., "upstream" use) in NSTE ACS does not reduce ischemic events and increases bleeding risk. Therefore, the two antiplatelet initial therapy options described in the previous section, are preferred.

    For low-risk patients where a conservative management strategy is selected, there is no role for routine GP IIb/IIIa inhibitors because the bleeding risk exceeds the benefit.


    The choice of anticoagulant for a patient with NSTE ACS is guided by risk stratification and initial treatment strategy, either an early invasive approach with early coronary angiography and PCI or an early conservative strategy with angiography in selected patients guided by relief of symptoms and stress testing. For patients treated by an early invasive strategy, UFH, enoxaparin, or bivalirudin should be administered.

    In patients in whom an initial conservative strategy is planned (i.e., they are not anticipated to receive angiography and revascularization), enoxaparin, UFH, or low-dose fondaparinux is recommended.

    Therapy should be continued for at least 48 hours for UFH, until the patient is discharged from the hospital (or 8 days, whichever is shorter) for either enoxaparin or fondaparinux, and until the end of PCI or angiography procedure (or up to 72 hours following PCI) for bivalirudin.

    *Sublingual (NTG)
    *Systemic (NTG)

    SL NTG followed by IV NTG should be administered to patients with NSTE ACS and ongoing ischemia, HF, or uncontrolled high BP. IV NTG is typically continued for approximately 24 hours following ischemia relief.

    One SL NTG tablet should be administered every 5 minutes for up to three doses to relieve myocardial ischemia. If patients have been previously prescribed SL NTG and ischemic chest discomfort persists for more than 5 minutes after the first dose, the patient should be instructed to contact emergency medical services before self-administering subsequent doses to activate emergency care sooner.

    IV NTG should then be initiated in all patients with an ACS who have persistent ischemia, HF, or uncontrolled high blood pressure in the absence of contraindications. IV NTG should be continued for approximately 24 hours after ischemia is relieved.

    Nitrates promote the release of nitric oxide from the endothelium, which results in venous and arterial vasodilation. Venodilation lowers preload and myocardial oxygen demand. Arterial vasodilation may lower BP, thus reducing myocardial oxygen demand. Arterial vasodilation also relieves coronary artery vasospasm, dialing coronary arteries to improve myocardial blood flow and oxygenation.

    Although used to treat ACS, nitrates have been suggested to play a limited role in the treatment of ACS patients because two large randomized clinical trials failed to show a mortality benefit for IV nitrate therapy followed by oral nitrate therapy in acute MI.

    Nitrate administration is contraindicated in patients who have received oral phosphodiesterase-5 inhibitors, such as sildenafil and vardenafil, within the past 24 hours, and tadalafil within the past 48 hours.

    *Systemic, beta-1 selective (metoprolol, esmolol, atenolol)

    The use of beta-blockers in NSTE ACS is similar to STE MI in that oral beta-blockers should be initiated within 24 hours of hospital admission to all patients in the absence of contraindications. Benefits of beta-blockers in this patient group are assumed to be similar to those seen in patients with STE MI. beta-Blockers are continued indefinitely.

    Beta-blockers produce a reduction in heart rate, myocardial contractility, and BP, decreasing myocardial oxygen demand. In addition, the reduction in heart rate increases diastolic time, thus improving ventricular filling and coronary artery perfusion. As a result of these effects, beta-blockers reduce the risk for recurrent ischemia, infarct size, risk of reinfarction, and occurrence of ventricular arrhythmias in the hours and days following MI.

    Landmark clinical trials have established the role of early beta-blocker therapy in reducing MI mortality.

    *Systemic, non-dihydropyridine (diltiazem, verapamil)
    *Systemic, dihydropyridine (amlodipine)

    Calcium channel blockers should not be administered to most patients with ACS. Their role is a second-line treatment for patients with certain contraindications to beta-blockers and those with continued ischemia despite beta-blocker and nitrate therapy. Administration of amlodipine, diltiazem, or verapamil is preferred.

    *Systemic (captopril, enalapril, lisinopril, ramlpril, trandolapril)

    *Systemic (candesartan, valsartan, losartan)

    #Mineralocorticoid receptor antagonists
    *Systemic (eplerenone, spironolactone)
    Last edited by TomHsiung; Wed 24th August '16 at 2:46pm.
    Clinical Pharmacy Specialist - Infectious Diseases

  2. #2
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    Default Dyslipidemia



    #Short-term goal: LDL-C less than 130 mg/dL (optional goal of less than 100 mg/dL)
    #Long-term goal: Prevent long-term cardiovascular events

    List of options

    #Nonpharmacologic therapy
    *Therapeutic lifestyle changes/TLC

    *Systemic (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin)

    #Bile acid sequestrants
    *Systemic (cholestyramine, colesnvelam, colestipol)

    #Cholesterol absorption inhibitor
    *Systemic (ezetimibe)

    #Nicotinic acid
    *Systemic (Niacin)

    #Fibric acid derivatives
    *Systemic (fenofibrate, gemfibrozil)

    #Omega-3-fatty acids
    *Systemic (lovaza)
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease. Chengdu, Sichuan, China.

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  3. #3
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    Default Ihd/chd/cad

    Ischemic heart disease (IHD) is also called coronary heart disease (CHD) or coronary artery disease (CAD). The term ischemic refers to a decreased supply of oxygenated blood, in this case to the heart muscle. IHD is caused by the narrowing of one or more of the major coronary arteries that supply blood to the heart, most commonly by atherosclerotic plaques. Atherosclerotic plaques may impede coronary blood flow to the extent that cardiac tissue distal to the site of the coronary artery narrowing is deprived of sufficient oxygen in the face of increased oxygen demand. Ischemic heart disease results from an imbalance between myocardial oxygen supply and oxygen demand. Common clinical manifestations of IHD include chronic stable angina and the acute coronary syndromes.

    Risk Factors

    Therapeutic goals and options of cardiovascular diseases-screen-shot-2016-08-23-at-9-59-37-am-png

    Desired Outcomes

    The major goals for the management of IHD are to:
    • Prevent acute coronary syndrome and death
    • Alleviate acute symptoms of myocardial ischemia
    • Prevent recurrent symptoms of myocardial ischemia
    • Prevent progression of the disease
    • Reduce complications of IHD
    • Avoid or minimize adverse treatment effects


    Lifestyle Modifications
    Lifestyle modifications reduce cardiovascular risk factors, slow the progression of IHD, and decrease the risk for IHD-related complications.

    Specific dietary recommendations for patients with IHD should include the following:
    • Limit fat intake to less than 30% of total caloric consumption
    • Limit cholesterol intake to less than 200 mg/day
    • Limit consumption of saturated fat and trans unsaturated fat found in fatty meats, full-fat dairy products, and hydrogenated vegetable oils to less than 7% of total calories.
    • Consume approximately 1 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day in the form of fatty fish or fish oil capsules.
    • Consume at least six servings of grains, five servings of fruits and vegetables, and two servings of nonfat or low-fat dairy products per day.
    • Consider plant stanol/sterols (2 g/day) and/or viscous fiber (over 10 g/day) to lower LDL cholesterol. It is recommended that patients with diabetes consume 14 g of fiber for every 1,000 kcal consumed.
    • Limit daily sodium intake to 2.4 g (6 g of salt) for blood pressure control.

    Interventional Approaches

    Percutaneous Coronary Intervention

    There is no reduction in major adverse cardiac events or mortality with PCI compared with optimal medical therapy alone in patients with stable IHD. Thus optimal medical therapy is the preferred initial strategy for patients with stable IHD. Proceeding to PCI is appropriate for patients with one or more critical coronary stenoses (i.e., greater than 70% occlusion of the coronary lumen) detected during coronary angiography whose symptoms are unstable and/or persist despite optimal medical therapy.

    Drug-eluting stents are impregnated with low concentrations of an anti proliferative drug (paclitaxel, everolimus, sirolimus, or zotarolimus), which is released locally over a period of weeks to inhibit restenosis or re-narrowing of the coronary artery after PCI.

    An observational study demonstrated a significant reduction in all-cause mortality over a 4.5-year interval among patients who received a drug-eluting stent compared to those with a bare metal stent.

    Stents are thrombogenic, especially until the become endothelialized (covered in endothelial cells like a normal coronary artery). Dual antiplatelet therapy is required until the stent becomes endothelialized, generally a period of 6 to 12 months, and, in some cases indefinitely following stent placement to reduce the risk for stent thrombosis, MI, or death.

    Coronary Artery Bypass Graft Surgery

    As an alternative to PCI, CABG surgery, or open-heart surgery, may be performed if the patient is found to have extensive coronary atherosclerosis (generally greater than 70% occlusion of three or more coronary arteries) or is refractory to optimal medical treatment. In the former case, CABG surgery has been shown to reduce the need for revascularization, but not death, compared with PCI.

    Because of the extremely invasive nature of this surgery, CABG surgery is generally reserved for patients with extensive coronary disease or as a treatment of last resort in patients with symptoms refractory to medical therapy.

    Pharmacologic Therapy

    Pharmacotherapy to Prevent Acute Coronary Syndromes and Death

    #Control of risk factors
    Control of dyslipidemia
    Control of hypertension
    Control of diabetes

    #Antiplatelet agents

    Antiplatelet therapy with aspirin should be considered for all patients without contraindications, particularly in patients with a history of myocardial infarction. Aspirin doses of 75 to 162 mg daily are recommended in patients with or at risk for IHD. If aspirin is contraindicated or is not tolerated by the patient, and alternative antiplatelet agent such as clopidogrel should be considered.

    P2Y12 receptor antagonist
    Inhibition of the P2Y12 receptor with either a thienopyridine or ticagrelor prevents platelet aggregation and is indicated in combination with aspirin in selected patients with IHD. Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is recommended following hospitalization for ACS and/or PCI with stent placement to prevent ischemic events, although indications for specific drugs differ slightly. Following stent placement, prolonged treatment with dual antiplatelet therapy (often greater than or equal to 12 months) is often necessary to prevent in-stent thrombosis prior to stent endothelialization.

    #Control of dyslipidemia

    Statins are the preferred drugs to achieve LDL cholesterol goals based on their potency in lowering LDL cholesterol and efficacy in preventing cardiac events. Specifically, over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol with statin is effective for both primary and secondary prevention of IHD-related events. Statins were shown to decrease morbidity and mortality associated with IHD.

    Statins have been shown to modulate the following characteristics thought to stabilize atherosclerotic plaques and contribute to the cardiovascular risk reduction seen with these drugs:

    • Shift LDL cholesterol particle size from predominantly small, dense, highly atherogenic particles to larger, less atherogenic particles.
    • Improve endothelial function leading to more effective vasoactive response of the coronary arteries.
    • Prevent or inhibit inflammation by lowering C-reactive protein and other inflammatory mediators thought to be involved in atherosclerosis.
    • Possibly improve atherosclerotic plaque stability.

    In summary, to control risk factors and prevent major adverse cardiac events, statin therapy should be considered in all patients with ischemic heart disease, particularly in those with elevated low-density lipoprotein cholesterol or diabetes.

    Moreover, based on evidence that statins improve outcomes in patients with IHD and "normal" LDL cholesterol concentration, statins should be considered in all patients with IHD at high risk of major adverse cardiac events, regardless of baseline LDL cholesterol.

    #ACE Inhibitors and Angiotensin Receptor Blockers

    Angiotensin II, a neurohormone produced primarily in the kidney, is a potent vasoconstrictor and stimulates the production of aldosterone. Together, angiotensin II and aldosterone increase blood pressure and sodium and water retention (increasing ventricular wall tension), cause endothelial dysfunction, promote blood clot formation, and cause myocardial fibrosis.

    ACE inhibitors decrease angiotensin II production and have consistently been shown to decrease morbidity and mortality in patients with heart failure or a history of MI. In addition, there is evidence that ACE inhibitors reduce the risk of vascular events in patients with chronic stable angina or risk factors for IHD. Specifically, in nearly 10,000 patients with vascular disease (including IHD) or risk factors for vascular disease, such as diabetes, ramipril reduced the risk of death, acute MI, and stroke by 22% compared with placebo after an average of 5 years of treatment. Similar results have been demonstrated with perindopril in patients with IHD.

    In the absence of contraindications, ACE inhibitors should be considered in all patients with IHD, particularly those individuals who also have hypertension, diabetes mellitus, chronic kidney disease, left ventricular dysfunction, history of myocardial infarction, or any combination of these. Additionally, ACE inhibitors should be considered in patients at high risk for developing IHD based on findings from studies summarized above.

    ARBs may be used in patients with indications for ACE inhibitors but who cannot tolerate them due to side effects. In one large trial, valsartan was as effective as captopril at reducing morbidity and mortality in post-MI patients. However, there are far more data supporting the use of ACE inhibitors in IHD. Therefore, ACE inhibitors should remain first line in patients with a history of MI, diabetes, chronic kidney disease, or left ventricular dysfunction.

    #Nitroglycerin to relieve acute symptoms

    Short-acting nitrates are first-line treatment to terminate acute episodes of angina. All patients with a history of angina should have sublingual nitroglycerin tablets or spray to relieve acute ischemic symptoms. Nitrates undergo biotransformation to nitric oxide. Nitric oxide activates smooth muscle guanylate cyclase, leading to increased intracellular concentrations of cyclic guanosine monophosphate, release of calcium from the muscle cells, and ultimately, to smooth muscle relaxation. Nitrates primarily cause ventilation, leading to reductions in preload. The resultant decrease in ventricular volume and wall tension leads to a reduction in myocardial oxygen demand. In higher doses, nitrates cause arterial dilation and reduce oxygen demand, nitrates increase myocardial oxygen supply by dilating the epicardial coronary arteries and collateral vessels, as well as relieving vasospasm.

    At the onset of an angina attack, a 0.3 to 0.4 mg dose of nitroglycerin should be administered sublingually, and repeated every 5 minutes up to three times or until symptoms resolve.

    Pharmacotherapy to Prevent Recurrent Ischemic Symptoms

    The drugs traditionally used to prevent ischemic symptoms are beta-blockers, CCBs, and nitrates. These drugs exert their antianginal effects by improving the balance between myocardial oxygen supply and demand (Table 7-6). beta-Blockers, CCBs and nitrates decrease the frequency of angina and delay the onset of angina during exercise. However, there is no evidence that any of these agents prevent ACS or improve survival in patients with chronic stable angina.

    Therapeutic goals and options of cardiovascular diseases-screen-shot-2016-08-23-at-9-59-37-am-png

    beta-Blockers are first-line therapy for preventing ischemic symptoms, particularly in patients with a history of myocardial infarction. In the absence of contraindications, beta-blockers are the preferred abtianginal therapy because of their potential cardioprotective effects.

    Stimulation of beta1- and beta2-adrenergic receptors in the heart increases heart rate and cardiac contractility. beta-Blockers antagonize beta1- and beta2-adrenergic receptors, reducing heart rate and cardiac contractility, and decreasing myocardial oxygen demand. beta-Blockers may also reduce oxygen demand by lowering blood pressure and ventricular wall tension through inhibition of renin release from juxtaglomerular cells. By slowing heart rate beta-Blockers prolong diastole, thus increasing coronary blood flow. However, with marked reductions in heart rate, beta-Blockers may actually increase ventricular wall tension. This is because slower heart rates allow the ventricle more time to fill during diastole, leading to increased left ventricular volume, end diastolic pressure, and wall tension. However, the net effect of beta-blockade is usually a reduction in myocardial oxygen demand. beta-Blockers do not improve myocardial oxygen supply.

    Specifically, beta-Blockers possessing membrane stabilizing properties may prevent cardiac arrhythmias by decreasing the rate of spontaneous depolarization of ectopic pacemakers. Secondly, although the long-term effects of beta-blockers on morbidity and mortality in patients with chronic stable angina are largely unknown, certain beta-blockers have been shown to decrease the risk of reinfarction and improve survival in patients who have suffered an MI.

    beta-Blockers with intrinsic sympathomimetic activity have partial beta-agonist effects and cause lesser reductions in heart rate at rest. As a result, beta-blockers with intrinsic sympathomimetic activity may produce lesser reductions in myocardial oxygen demand and should be avoided in patients with IHD. The beta-blocker dose is commonly titrated to achieve the following:
    • Resting heart rate between 55 and 60 beats/min
    • Maximum heart rate with exercise of 100 beats/min or less or 20 beats/min above the resting heart rate

    Calcium Channel Blockers
    Calcium channel blockers inhibit calcium entry into vascular smooth muscle and cardiac cells, resulting in the inhibition of the calcium-dependent process leading to muscle contraction. Inhibition of calcium entry into the vascular smooth muscle cells leads to systemic vasodilation and reductions in after load. Inhibition of calcium entry into the cardiac cells leads to reductions in cardiac contractility. Thus CCBs reduce myocardial oxygen demand by lowering both wall tension (through reductions in afterload) and cardiac contractility. The nondihdropyridine CCBs, verapamil and diltiazem, further decrease myocardial oxygen demand by slowing cardiac sinoatrial and atrioventricular (AV) nodal conduction and lowering heart rate. Because of their negative chronotropic effects, verapamil and diltiazem are generally more effective abtianginal agents than the dihydropyridine CCBs. In addition to decreasing myocardial oxygen demand, all CCBs increase myocardial oxygen supply by dilating coronary arteries, thus increasing coronary blood flow and relieving vasospasm.

    In randomized controlled clinical trials, CCBs were as effective as beta-blockers at preventing ischemic symptoms. Calcium channel blockers are recommended as alternative treatment in IHD when beta-blockers are contraindicated or not tolerated. In addition, CCBs may be used in combination with beta-blockers when initial treatment is unsuccessful.

    Long-Acting Nitrates
    The major limitation of nitrate therapy is the development of tolerance with continuous use. The loss of abtianginal effects may occur within the first 24 hours of continuous nitrate therapy. The most effective method to avoid tolerance and maintain the abtianginal efficacy of nitrates is to allow a daily nitrate-free interval of at least 8 to 12 hours. Nitrates do not provide protection from ischemia during the nitrate-free period. Therefore, the nitrate-free interval should occur when the patient is least likely to experience angina. Generally, angina is less common during the nighttime hours when the patient is sleeping and myocardial oxygen demand is reduced.

    Monotherapy with nitrates for the prevention of ischemia should generally be avoided for a couple of reasons. First, reflex increases in sympathetic activity and heart rate, with resultant increases in myocardial oxygen demand, may occur secondary to nitrate-induced venodilation. Patients are unprotected from ischemia during the nitrate-free interval. Treatment with long-acting nitrates should be added to baseline therapy with either a beta-blocker or CCB or a combination of the two. Monotherapy with nitrates may be appropriate in patients who have low blood pressure at baseline or who experience symptomatic hypotension with low doses of beta-blockers or CCBs.
    Last edited by admin; Tue 23rd August '16 at 2:56pm.
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease. Chengdu, Sichuan, China.

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  4. #4
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    Default Heart Failure

    Heart failure (HF) is defined as the inadequate ability of the heart to pump enough blood to meet the blood flow and metabolic demands of the body. Hight-output HF is characterized by an inordinate, increase in the body's metabolic demands that outpaces an increase in cardiac output (CO) of a generally normally functioning heart. More commonly, HF is a result of low CO secondary to impaired cardiac function.

    HF is a clinical syndrome characterized by a history of specific signs and symptoms related to congestion and hypoperfusion. HF results from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.

    The term acute heart failure is used to signify either an acute decompensation of a patient with a history of chronic HF or to refer to a patient presenting with new-onset HF symptoms.

    Physiology: Renal Regulation of Excretion of Sodium

    Sodium determines the volume of ECF.

    1) Sympathetic stimulation would reduce the RBF and GFR which results in decreased renal sodium excretion

    2) Renin-angiotensin system reduces the RBF and GFR, increases the sodium tubular sodium reabsorption, stimulates salt appetite, thirst, and sympathetic drive

    3) Dopamine inhibits sodium reabsorption

    4) ADH increases the uptake of sodium

    5) Glomerulotubular balance

    6) Pressure natriuresis and diuresis. Because the kidneys are responsive to arterial pressure, there are situations in which elevated blood pressure can lead directly to increased excretion of sodium. This phenomenon is called pressure diuresis.

    7) Natriuretic peptides relax the afferent arteriole, thereby promoting increased filtration. They act at several sites in the tubule. Anyway, natriuretic peptides increases the renal excretion of sodium.

    Physiology: Control of the Circulating RAAS

    1) The first controller is sympathetic input, which stimulates the secretion of renin

    2) The second controller of renin secretion is pressure in the afferent arteriole. The fall of this pressure stimulates the secretion of renin

    3) The third controller of renin secretion is the sense of flow of salt content passing the macula densa, where renin secretion of renin is reduced when the flow and of sodium content is high

    The most common causes of HF are CAD, hypertension, and dilated cardiomyopathy.

    Therapeutic goals and options of cardiovascular diseases-screen-shot-2016-08-24-at-8-49-34-pm-png

    Risk Factors of HF
    • High blood pressure
    • Coronary artery disease
    • MI
    • Diabetes
    • Drugs
    • Sleep apnea
    • Congenital heart defects
    • Valvular heart disease
    • Viruses
    • Alcohol use
    • Tobacco use
    • Obesity
    • Arrhythmias

    Exacerbating or Precipitating Factors in HF
    Therapeutic goals and options of cardiovascular diseases-screen-shot-2016-08-26-at-10-19-41-am-png

    Drugs That May Precipitate or Exacerbate Heart Failure
    Therapeutic goals and options of cardiovascular diseases-screen-shot-2016-08-26-at-10-20-46-am-png

    Stages of HF
    Stage A
    : At high risk for HF but without structural heart disease or symptoms of HF
    Stage B: Structural heart disease but without signs or symptoms of HF
    Stage C: Structural heart disease with prior or current symptoms of HF
    Stage D: Refractory HF requiring specialized interventions

    Desired Therapeutic Outcomes

    There is no cure for HF.

    The general therapeutic management goals for chronic HF include preventing the onset of clinical symptoms or reducing symptoms, preventing or reducing hospitalizations, slowing progression of the disease, improving quality of life, and prolonging survival.

    Stage A: Risk factor management is the primary goal
    Stage B: Addition of pharmacologic therapies known to slow the progression of the disease in an attempt to prevent the onset of clinical symptoms
    Stage C: Use of additional therapies aimed at controlling symptoms and decreasing morbidity
    Stage D: Improve quality-of-life

    Control and Treatment of Contributing Disorders
    All causes of HF must be investigated to determine the etiology of cardiac dysfunction in a given patient. Because the most common etiology of HF in the United States is ischemic heart disease, coronary angiography is warranted in most patients with a history suggestive of underlying CAD. Revascularization of those with significant CAD may help restore some cardiac function in patients with reversible ischemic defects. Aggressive control of hypertension, diabetes, and obesity is also essential because each of these conditions can cause further cardiac damage. Surgical repair of valvular disease or congenital malformations may be warranted if detected. Clinical HF partly depends on metabolic processes, so correction of imbalances such as thyroid disease, anemia, and nutritional deficiencies is required. Other more rare causes such as autoimmune disorders or acquired illnesses may have specific treatments. Identifying and discontinuing medications that can exacerbate HF is also an important intervention.

    Nonpharmacologic Interventions
    Nonpharmacologic treatment involves dietary modifications such as sodium and fluid restriction, risk factor reduction including smoking cessation, timely immunizations, and supervised regular physical activity. Patient education regarding monitoring symptoms, dietary and medication adherence, exercise and physical fitness, risk factor reduction, and immunizations are important for the prevention of AHF exacerbations.

    Home monitoring should include daily assessment of weight and exercise tolerance. Daily weights should be done first thing in the morning upon arising and before any food intake to maintain consistency. Patients should record their weight daily in a journal and bring this log to each clinic or office visit. Changes in weight can indicate fluid retention and congestion prior to onset of peripheral or pulmonary symptoms. Individuals who have an increase of 2 to 3 pounds (0.91 to 1.36 kg) in a single day or 5 pounds (2.27 kg) over 5 days should alert their HF care provider. In addition to weight changes, a marked decline in exercise tolerance should also be reported to the HF care provider.

    Nonadherence is an important issue because it relates to acute exacerbations of HF. Ensuring an understanding of the importance of each medication used to treat HF, proper administration, and potential adverse effects may improve adherence.

    Pharmacologic Treatment

    Diuretics have been the mainstay for HF symptom management for many years. Diuretics are used for relief of acute symptoms of congestion and maintenance of euvolemia. These agents interfere with sodium retention by increasing urinary sodium and free water excretion. No prospective data exist on the effects of diuretics on patient outcomes. Therefore, the primary rationale for the use of diuretic therapy is to maintain euvolemia in symptomatic or stage C and D HF. Diuretic therapy is recommended for all patients with clinical evidence of fluid overload. In more mild HF, diuretics may be used on an as-needed basis. However, once the development of edema is persistent, regularly scheduled doses will be required.

    ACE Inhibitors
    ACE inhibitors are the cornerstone of treatment for HF. ACE inhibitors decrease neurohormonal activation by blocking the conversion of angiotensin I to angiotensin II, a potent mediator of vasoconstriction and cardiac remodeling. The breakdown of bradykinin is also reduced. Bradykinin enhances the release of vasodilatory prostaglandins and histamines. These effects result in arterial and venous dilatation, and a decrease in myocardial workload through reduction of both preload and after load. ACE inhibitors demonstrate favorable effects on cardiac hemodynamics, such as long-term increases in cardiac index, stroke work index, and SV index, as well as significant reductions in LV filling pressure, SVR, mean arterial pressure, and HR.

    There is extensive clinical experience with ACE inhibitors in systolic HF. Numerous clinical studies show ACE inhibitor therapy is associated with improvements in clinical symptoms, exercise tolerance, NYHA FC, LV size and function, and quality of life as compared with placebo. ACE inhibitors significantly reduce hospitalization rates and mortality regardless of underlying disease severity or etiology. ACE inhibitors are also effective in preventing HF development in high-risk patients. Studies in acute MI patients show a reduction in new-onset HF and death with ACEI inhibitors whether they are initiated early (within 36 hours) or started later. In addition, ACE inhibition decreases the risk of HF hospitalization and death in patients with asymptomatic LV dysfunction. The exact mechanisms for decreased HF progression and mortality are postulated to involve both the hemodynamic improvement and the inhibition of angiotensin II's growth promoting and remodeling effects. All patients with documented LV systolic dysfunction, regardless of existing HF symptoms, should receive ACE inhibitors unless a contraindication or intolerance is present.

    Angiotensin receptor blockers (ARBs) selectively antagonize the effects of angiotensin II directly at the AT1 receptor. AT1 receptor stimulation is associated with vasoconstriction, release of aldosterone, and cellular growth promoting effects, whereas AT2 stimulation causes vasodilation. By selectively blocking AT1 but leaving AT2 unaffected, ARBs block the detrimental AT1 effects on cardiac function while allowing AT2-mediated vasodilation and inhibition of ventricular remodeling. Angiotensin receptor blockers are considered an equally effective replacement for ACE inhibitors in patients who are intolerant or have a contraindication to an ACE inhibitor.

    It was hoped that the more complete blockade of angiotensin II's AT1 effects would confer greater long-term efficacy with ARBs compared with ACE inhibitors. However, prospective randomized trials suggest that the clinical efficacy of ARBs is similar to that of ACE inhibitors for reduction of hospitalizations for HF, sudden cardiac death, and all-cause mortality. Despite poorer suppression of AT2, comparable efficacy of ACE inhibitors may be due to the additional effects on the kvllikrein-kinin system. Although ARBs produce hemodynamic and neurohormonal effects similar to those of ACE inhibitors, they are considered second-line therapy due to the overwhelming clinical trial experience with ACE inhibitors.

    Because the mechanism for long-term benefit appears different for ACE inhibitors and ARBs, the combination has been studied for additive benefits. One study evaluated the addition of the ARB candesartan versus placebo in HF patients with systolic dysfunction intolerant to an ACE inhibitor, or systolic dysfunction currently on ACE inhibitor therapy, or patients with preserved systolic function. Candesartan reduced the combined incidence of cardiovascular death and hospitalization for HF in all three groups; the greatest benefit was noted in those not on an ACE inhibitor. Candesartan significantly decreased mortality compared with placebo when all three groups were combined. Based on this study, the addition of an ARB to ACE inhibitor therapy can be considered in patients with evidence of disease progression despite optimal ACE inhibitor therapy, although this strategy is still undergoing investigation. This study also demonstrates the importance of having some form of angiotensin II antagonism as part of a treatment regimen.

    Hydralazine and Isosorbide Dinitrate
    Complementary hemodynamic actions originally led to the combination of nitrates with hydralazine. Nitrates reduce preload by causing primarily venous vasodilation through activating guanylate cyclase and a subsequent increase in cGMP in vascular smooth muscle. Hydralazine reduces afterload through direct arterial smooth muscle relaxation via an unknown mechanism. More recently, nitric oxide has been implicated in modulating numerous pathophysiological processes in the failing heart including inflammation, cardiac remodeling, and oxidative damage. Supplementaton of nitric oxide via administration of nitrates has also been proposed as a mechanism for benefit from this combination therapy. The beneficial effect of an external nitric oxide source may be more apparent in the African American population, which appears to be predisposed to having an imbalance in nitric oxide production. In addition, hydralazine may reduce the development of nitrate tolerance when nitrates are given chronically.

    The combination of hydralazine and isosorbide dinitrate was the first therapy shown to improve long-term survival in patients with systolic HF, but it has largely been supplanted by angiotensin II antagonist therapy (ACE inhibitors and ARBs). Therefore, until recently, this combination therapy was reserved for patients intolerant to ACE inhibitors or ARBs secondary to some conditions.

    beta-Adrenergic Antagonists
    beta-Adrenergic antagonists, or beta-blockers, competitively block the influence of the SNS at beta-adrenergic receptors. Chronic beta-Blockers also exhibit antiarrhythmic effects, slow or reverse catecholamine-induced ventricular remodeling, decrease myocyte death from catecholamine-induced necrosis or apoptosis, and prevent myocardial fetal gene expression. Consequently, beta-blockers improve EF, reduce all-cause and HF-related hospitalizations, and decrease all-cause mortality in patients with systolic HF.

    The ACC/AHA recommends that beta-blockers be initiated in all patients with ACC/AHA stages B through D HF if clinical stable. To date, only three beta-blockers have been shown to reduce mortality in systolic HF including the selective beta1-antagonists bisoprolol and metoprolol succinate, and the nonselective beta1-, beta2-, and alpha1-antagonist carvedilol. The positive findings of beta-blockers are not a class effect because bucindolol did not exhibit a beneficial effect on mortality when studied for HF, and there is limited information with propranolol and atenolol.

    The key to utilizing beta-blockers in systolic HF is initiation with low doses and slow titration to target doses over weeks to months. It is important that the beta-blocker be initiated when a patient is clinically stable and euvolemic. Volume overload at the time of beta-blocker initiation increases the risk for worsening symptoms. beta-Blockade should begin with the lowest possible dose, after which the dose may be doubled every 2 to 4 weeks depending on patient tolerability.
    Last edited by admin; Fri 26th August '16 at 12:25pm.
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease. Chengdu, Sichuan, China.

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  5. #5
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    Default Re: Therapeutic goals and options of cardiovascular diseases

    Heart Sounds

    Therapeutic goals and options of cardiovascular diseases-screen-shot-2016-08-25-at-1-27-21-pm-png
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease. Chengdu, Sichuan, China.

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    Default Re: Therapeutic goals and options of cardiovascular diseases

    Jugular Venous Pressure and Pulsations

    The jugular veins provide an important index of right heart pressures and cardiac function. Jugular venous pressure (JVP) reflects right atrial pressure, which in turn equals central venous pressure and right ventricular end-diastolic pressure. The JVP is best estimated from the right internal jugular vein, which has the most direct channel into the right atrium.

    Therapeutic goals and options of cardiovascular diseases-screen-shot-2016-08-25-at-1-37-29-pm-png

    Changing pressures in the right atrium during diastole and systole produce oscillations of filling and emptying in the jugular veins, or jugular venous pulsations. Atrial contraction produces an a wave in the jugular veins just before S1 and systole, followed by the x descent of atrial relaxation. As right atrial pressure begins to rise with inflow from the vena cava during right ventricular systole, there is a second elevation, the v wave, followed by the y descent as blood passively empties into the RV during early and middiastole.
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease. Chengdu, Sichuan, China.

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