Cardiovascular disease

Heart failure

Heart failure (HF) is caused by the heart’s inability to pump enough blood to meet the body’s needs. In response, the body activates compensatory mechanisms, such as the sympathetic nervous system which leads to tachycardia, sodium and water retention, vasoconstriction, and over time, ventricular hypertrophy, all geared towards increasing cardiac output. Leading causes of HF are coronary artery disease and hypertension.

Neurohormonal signaling by angiotensin II, norepinephrine, aldosterone, and others drive cardiac remodeling. These hormones promote disease progression, making them ideal targets for pharmacologic therapy. On the other hand, some other medications may exacerbate HF through negative inotropic effects, direct cardiotoxicity, or increased sodium and water retention.

Heart failure with reduced ejection fraction (HFrEF) (Systolic heart failure) is characterized by a reduced (≤40%) left ventricular ejection fraction (LVEF). It is caused by the heart’s impaired ability to contract. Myocardial infarction, dilated cardiomyopathies, and ventricular hypertrophy can lead to HFrEF. Heart failure with reduced ejection fraction is amenable to the medical therapies described below.

Heart failure with preserved ejection fraction (HFpEF) (Diastolic heart failure) is characterized by impaired ventricular relaxation and increased diastolic stiffness. In HFpEF, the LVEF is preserved (≥50%). Ventricular stiffness, ventricular hypertrophy, myocardial ischemia and myocardial infarction, mitral or tricuspid valve stenosis, and pericardial disease can lead to HFpEF. There is no standard treatment regimen for patients with HFpEF. Management consists of optimal treatment of the underlying diseases, such as hypertension, diabetes, and obesity.

 

The following classes of drugs have been shown to reduce mortality in patients with HFrEF:

1) Angiotensin Converting Enzyme Inhibitors (ACEIs) decrease angiotensin II and aldosterone, reducing ventricular remodeling, vasoconstriction, and sodium and water retention. These drugs inhibited the conversion of angiotensin I to angiotensin II by inhibiting ACE. All patients with HFrEF should receive an ACEI unless contraindicated. Patients who do not yet have HF symptoms but already have structural heart disease should receive an ACEI to prevent HF development. Drugs in this class include captopril, lisinopril, enalapril and others. ACEIs also inhibit the inactivation of bradykinin which contributes to dry cough in patients taking an ACEI.

2) Angiotensin Receptor Blockers (ARBs) such as valsartan are similar to ACEIs in their blockade of the harmful effects of angiotensin II. Drugs in this class are highly selective, competitive receptor antagonists at the AT1 receptor, which mediates the effects of angiotensin II. They are recommended for patients unable to tolerate ACEIs, usually due to dry cough. ARBs should not be initiated in patients with a history of angioedema, hypotension, hyperkalemia, or renal insufficiency with ACEIs.

Doses of ACEIs/ARBs should start low and be titrated to the target dose every 2 weeks as tolerated. Monitor renal function and potassium at baseline and 1 to 2 weeks after initiation.

3) Angiotensin Receptor/Neprilysin Inhibitors (ARNI) include the combination valsartan and sacubitril. Natriuretic peptides may produce beneficial effects in patients with heart failure including promotion of diuresis and natriuresis, vasodilation, and inhibition of sympathetic nervous system by reduced catecholamine secretion and inhibition of renin-angiotensin-aldosterone system. Natriuretic peptides are catabolized and inactivated by the enzyme neprilysin. Sacubitril inhibits neprilysin thereby maintaining levels of natriuretic peptides. Neprilysin also breaks down angiotensin II, necessitating the combination of the sacubitril with valsartan.

Patients with HFrEF that remain symptomatic while taking an ACEI or ARB can be transitioned to an ARNI. Patients taking an ARB can switch immediately; however, patients taking an ACEI require a 36-hour washout period due to the risk of angioedema.

4) Aldosterone Receptor Antagonists (ARAs) such as spironolactone block the aldosterone (mineralocorticoid) receptor, thereby inhibiting oxidative stress, sodium reabsorption, potassium excretion, and cardiac remodeling.

ARAs are recommended for patients with a LVEF <35%. HF patients with mild symptoms should only be considered for ARAs if they have a history of prior cardiovascular hospitalization or elevated BNP levels. ARAs are also recommended in patients who develop symptoms of HF or with a history of diabetes mellitus following an acute-MI and a LVEF <40%. ARAs are contraindicated in patients with an eGFR <30 mL/min/1.73 m2 or a potassium level >5 mEq/L.

5) Beta-blockers reduce heart rate, cardiac oxygen consumption, remodeling due to cardiac hypertrophy, and stimulation of the renin-angiotensin-aldosterone system by antagonizing the sympathetic nervous system.

Only bisoprolol, carvedilol, and metoprolol succinate have shown mortality benefits and are recommended for all patients with HFrEF. Doses should start low and be titrated to the target dose every two weeks as tolerated. Beta-blockers can be initiated while optimizing the dose of ACEI/ARBs but should not be started in patients with volume overload.

The following classes of drugs decrease symptoms associated with HFrEF and improve quality of life. However, they have not been shown to reduce mortality.

6) Diuretics, in addition to dietary sodium restriction, are recommended for patients with clinical signs of volume overload. Loop diuretics such as furosemide are typically required. However, patients with mild fluid retention may benefit from a less potent thiazide class diuretic like hydrochlorothiazide.

7) Nitrates and hydralazine: The combination of hydralazine and nitrates (isosorbide dinitrate) decreases cardiac remodeling by promoting vasodilation. The combination is recommended to reduce morbidity and mortality in symptomatic patients self-described as African American already receiving ACEI/ARB, an ARA, and evidence-based beta blockers. They are also recommended in patients who cannot tolerate an ACEI or an ARB.

8) Ivabradine inhibits the “funny” current in the SA node, decreasing heart rate. The funny current is responsible for a steady increase in resting membrane potential through sodium and potassium ionic currents. Inhibition of this current prolongs diastolic depolarization, slowing firing in the SA node, and ultimately reducing heart rate. Ivabradine reduces hospitalizations in HF patients on a target dose of ACEI/ARB and beta-blocker. Patients must be in sinus rhythm and have a heart rate over 70 bpm.

9) Digoxin inhibits the Na/K ATPase pump, resulting in increased intracellular sodium. This promotes an influx of calcium via the Na/Ca exchange pump which increases contractility of the heart. Because the heart can pump with greater contractility, sympathetic tone is reduced and vagal tone predominates, suppressing AV node conduction and slowing the heart rate. It is recommended in patients experiencing symptoms despite taking the target doses of ACEI/ARBs and beta-blockers.

Abigail Elmes, Kelly Karpa

This 15-minute narrated, animated video describes the principal types of heart failure, including systolic and diastolic. The associated changes in hemodynamics, pathophysiology, and symptomatology are discussed along with treatments for each. Suitable for beginners.

Average: 5 (1 vote)

Heart failure (HF) is caused by the heart’s inability to pump enough blood to meet the body’s needs. In response, the body activates compensatory mechanisms, such as the sympathetic nervous system which leads to tachycardia, sodium and water retention, vasoconstriction, and over time, ventricular hypertrophy, all geared towards increasing cardiac output. Leading causes of HF are coronary artery disease and hypertension.

Neurohormonal signaling by angiotensin II, norepinephrine, aldosterone, and others drive cardiac remodeling. These hormones promote disease progression, making them ideal targets for pharmacologic therapy. On the other hand, some other medications may exacerbate HF through negative inotropic effects, direct cardiotoxicity, or increased sodium and water retention.

Heart failure with reduced ejection fraction (HFrEF) (Systolic heart failure) is characterized by a reduced (≤40%) left ventricular ejection fraction (LVEF). It is caused by the heart’s impaired ability to contract. Myocardial infarction, dilated cardiomyopathies, and ventricular hypertrophy can lead to HFrEF. Heart failure with reduced ejection fraction is amenable to the medical therapies described below.

Heart failure with preserved ejection fraction (HFpEF) (Diastolic heart failure) is characterized by impaired ventricular relaxation and increased diastolic stiffness. In HFpEF, the LVEF is preserved (≥50%). Ventricular stiffness, ventricular hypertrophy, myocardial ischemia and myocardial infarction, mitral or tricuspid valve stenosis, and pericardial disease can lead to HFpEF. There is no standard treatment regimen for patients with HFpEF. Management consists of optimal treatment of the underlying diseases, such as hypertension, diabetes, and obesity.

 

The following classes of drugs have been shown to reduce mortality in patients with HFrEF:

1) Angiotensin Converting Enzyme Inhibitors (ACEIs) decrease angiotensin II and aldosterone, reducing ventricular remodeling, vasoconstriction, and sodium and water retention. These drugs inhibited the conversion of angiotensin I to angiotensin II by inhibiting ACE. All patients with HFrEF should receive an ACEI unless contraindicated. Patients who do not yet have HF symptoms but already have structural heart disease should receive an ACEI to prevent HF development. Drugs in this class include captopril, lisinopril, enalapril and others. ACEIs also inhibit the inactivation of bradykinin which contributes to dry cough in patients taking an ACEI.

2) Angiotensin Receptor Blockers (ARBs) such as valsartan are similar to ACEIs in their blockade of the harmful effects of angiotensin II. Drugs in this class are highly selective, competitive receptor antagonists at the AT1 receptor, which mediates the effects of angiotensin II. They are recommended for patients unable to tolerate ACEIs, usually due to dry cough. ARBs should not be initiated in patients with a history of angioedema, hypotension, hyperkalemia, or renal insufficiency with ACEIs.

Doses of ACEIs/ARBs should start low and be titrated to the target dose every 2 weeks as tolerated. Monitor renal function and potassium at baseline and 1 to 2 weeks after initiation.

3) Angiotensin Receptor/Neprilysin Inhibitors (ARNI) include the combination valsartan and sacubitril. Natriuretic peptides may produce beneficial effects in patients with heart failure including promotion of diuresis and natriuresis, vasodilation, and inhibition of sympathetic nervous system by reduced catecholamine secretion and inhibition of renin-angiotensin-aldosterone system. Natriuretic peptides are catabolized and inactivated by the enzyme neprilysin. Sacubitril inhibits neprilysin thereby maintaining levels of natriuretic peptides. Neprilysin also breaks down angiotensin II, necessitating the combination of the sacubitril with valsartan.

Patients with HFrEF that remain symptomatic while taking an ACEI or ARB can be transitioned to an ARNI. Patients taking an ARB can switch immediately; however, patients taking an ACEI require a 36-hour washout period due to the risk of angioedema.

4) Aldosterone Receptor Antagonists (ARAs) such as spironolactone block the aldosterone (mineralocorticoid) receptor, thereby inhibiting oxidative stress, sodium reabsorption, potassium excretion, and cardiac remodeling.

ARAs are recommended for patients with a LVEF <35%. HF patients with mild symptoms should only be considered for ARAs if they have a history of prior cardiovascular hospitalization or elevated BNP levels. ARAs are also recommended in patients who develop symptoms of HF or with a history of diabetes mellitus following an acute-MI and a LVEF <40%. ARAs are contraindicated in patients with an eGFR <30 mL/min/1.73 m2 or a potassium level >5 mEq/L.

5) Beta-blockers reduce heart rate, cardiac oxygen consumption, remodeling due to cardiac hypertrophy, and stimulation of the renin-angiotensin-aldosterone system by antagonizing the sympathetic nervous system.

Only bisoprolol, carvedilol, and metoprolol succinate have shown mortality benefits and are recommended for all patients with HFrEF. Doses should start low and be titrated to the target dose every two weeks as tolerated. Beta-blockers can be initiated while optimizing the dose of ACEI/ARBs but should not be started in patients with volume overload.

The following classes of drugs decrease symptoms associated with HFrEF and improve quality of life. However, they have not been shown to reduce mortality.

6) Diuretics, in addition to dietary sodium restriction, are recommended for patients with clinical signs of volume overload. Loop diuretics such as furosemide are typically required. However, patients with mild fluid retention may benefit from a less potent thiazide class diuretic like hydrochlorothiazide.

7) Nitrates and hydralazine: The combination of hydralazine and nitrates (isosorbide dinitrate) decreases cardiac remodeling by promoting vasodilation. The combination is recommended to reduce morbidity and mortality in symptomatic patients self-described as African American already receiving ACEI/ARB, an ARA, and evidence-based beta blockers. They are also recommended in patients who cannot tolerate an ACEI or an ARB.

8) Ivabradine inhibits the “funny” current in the SA node, decreasing heart rate. The funny current is responsible for a steady increase in resting membrane potential through sodium and potassium ionic currents. Inhibition of this current prolongs diastolic depolarization, slowing firing in the SA node, and ultimately reducing heart rate. Ivabradine reduces hospitalizations in HF patients on a target dose of ACEI/ARB and beta-blocker. Patients must be in sinus rhythm and have a heart rate over 70 bpm.

9) Digoxin inhibits the Na/K ATPase pump, resulting in increased intracellular sodium. This promotes an influx of calcium via the Na/Ca exchange pump which increases contractility of the heart. Because the heart can pump with greater contractility, sympathetic tone is reduced and vagal tone predominates, suppressing AV node conduction and slowing the heart rate. It is recommended in patients experiencing symptoms despite taking the target doses of ACEI/ARBs and beta-blockers.

Abigail Elmes, Kelly Karpa

This 5-minute narrated, animated video describes the treatment of heart failure in the early stages, including dietary changes, ACEIs, ARBs, hydralazine and nitrates, and beta blockers. Suitable for beginners.

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Hypertension

Elevated blood pressure (BP) is the product of increased cardiac output (CO) and peripheral vascular resistance (PVR). Increased CO may result from increased fluid volume from excess sodium intake or renal sodium retention, stimulation of the renin-angiotensin-aldosterone system (RAAS), or activation of the sympathetic nervous system (SNS). Functional constriction or structural hypertrophy of the vasculature increases PVR. Both result from excess stimulation of the RAAS, SNS overactivity, genetic alterations of cell membranes, or endothelial-derived factors.

Recommendations for treating hypertension are based on the 2017 American College of Cardiology /American Heart Association (ACC/AHA) Hypertension Guidelines. Hypertension is diagnosed from the average of two or more BP measurements. Normal BP is less than 120/80 mmHg. Elevated BP is 120-129/<80 mmHg. Stage 1 hypertension is classified as 130-139/80-89 mmHg. Stage 2 hypertension is considered at pressures greater than 140/90 mmHg. The BP goal for most patients with hypertension is less than 130/80 mmHg.

Patients with elevated and Stage 1 hypertension with an atherosclerotic cardiovascular disease (ASCVD) 10-year risk less than 10% should be managed through nonpharmacologic regulation of BP which includes weight loss with a heart-healthy diet, dietary sodium restriction and potassium supplementation, increased physical activity, and limited alcohol consumption. If these patients have an ASCVD 10-year risk greater than 10% or clinical CVD, antihypertensive drug therapy should also be initiated. Patients with Stage 2 hypertension will most likely require two or more medications to reach the target BP.

Angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazides reduce mortality in patients with hypertension and are considered first-line therapies. As a group, African American patients show a smaller response in BP reduction to ACEIs or ARBs than Caucasian patients. Therefore, patients that self-identify as Black or African American should be preferentially placed on a CCB or thiazide. If microalbuminuria is present (urine albumin:creatinine ≥300 mg/g), an ACEI or ARB should be considered.

1. ACEIs (lisinopril, enalapril, captopril, etc.) decrease angiotensin II formation and subsequent aldosterone synthesis, thereby reducing vasoconstriction and sodium and water retention. ARBs (losartan, valsartan, telmisartan, etc.) are similar to ACEIs.  While ACEI’s block formation of angiotensin II, ARBs block the effects of angiotensin II by antagonizing AT1 receptors. ARBs are recommended for patients that are unable to tolerate ACEIs, usually due to dry cough or rare incidences of angioedema. ARBs should not be initiated in patients with a history of angioedema, hypotension, hyperkalemia, or renal insufficiency with ACEIs

2. CCBs reduce calcium ion influx during depolarization of cardiac and/or vascular smooth muscle leading to muscle relaxation.  Non-dihydropyridine CCBs (diltiazem, verapamil) are more cardioselective, have negative inotropic effects, and decrease CO.  On the other hand, the dihydropyridine CCBs (amlodipine, nicardipine, nifedipine, etc.) act mostly on vascular smooth muscle to decrease PVR.

3. Thiazides (hydrochlorothiazide, chlorthalidone, etc.) inhibit sodium reabsorption in the renal distal tubules causing increased excretion of sodium, water, potassium and hydrogen ions. While their diuretic effect is not as potent as loop diuretics, thiazides exhibit significant antihypertensive activity and have a longer duration of action. Loop diuretics, however, should replace thiazides in patients with impaired kidney function and a reduced estimated glomerular filtration rate.

 

Comorbidities drive therapeutic decision-making. Beta-blockers are not recommended as monotherapy for the treatment of hypertension and should only be considered if heart failure or other comorbidities are also present. Dihydropyridine CCBs should be avoided in patients with heart failure. Alpha-blockers are not recommended due to orthostasis risk unless the patient has benign prostatic hyperplasia.

1. Resistant hypertension

This occurs when BP is not at goal while taking a 3-drug complementary regimen which typically includes a longer-acting thiazide like chlorthalidone, ACEI or ARB, and a CCB. Mineralocorticoid (aldosterone) receptor antagonists like spironolactone are advantageous additions in this setting and have shown evidence of greater BP reduction than beta or alpha blockers. Vasodilators like hydralazine or minoxidil have also shown significant reductions in BP in these patients. Direct renin inhibitors like aliskiren show similar reductions in BP to ACEIs or ARBs but should not be used in combination with them due to increased likelihood of angioedema and hyperkalemia. Central alpha-2 agonists like clonidine are generally reserved as last line therapy due to adverse effects in the central nervous system, particularly in elderly populations.

2. Pregnancy

Women with hypertension who become pregnant or are planning to become pregnant, should be transitioned to methyldopa, nifedipine, and/or labetalol during pregnancy. Hydralazine is a reasonable addition to these medications if BP remains above goal, however, it should not be used as monotherapy. ACEIs, ARBs, and direct renin inhibitors are contraindicated in pregnancy.

Abigail Elmes, Kelly Karpa

This 15-minute animated, narrated video describes the components and pathways involved with the renin-angiotensin-aldosterone system. The role of the RAAS and its regulation of blood pressure is also discussed. Suitable for beginners.

 Author: Rishi Desai, Khan Academy

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Elevated blood pressure (BP) is the product of increased cardiac output (CO) and peripheral vascular resistance (PVR). Increased CO may result from increased fluid volume from excess sodium intake or renal sodium retention, stimulation of the renin-angiotensin-aldosterone system (RAAS), or activation of the sympathetic nervous system (SNS). Functional constriction or structural hypertrophy of the vasculature increases PVR. Both result from excess stimulation of the RAAS, SNS overactivity, genetic alterations of cell membranes, or endothelial-derived factors.

Recommendations for treating hypertension are based on the 2017 American College of Cardiology /American Heart Association (ACC/AHA) Hypertension Guidelines. Hypertension is diagnosed from the average of two or more BP measurements. Normal BP is less than 120/80 mmHg. Elevated BP is 120-129/<80 mmHg. Stage 1 hypertension is classified as 130-139/80-89 mmHg. Stage 2 hypertension is considered at pressures greater than 140/90 mmHg. The BP goal for most patients with hypertension is less than 130/80 mmHg.

Patients with elevated and Stage 1 hypertension with an atherosclerotic cardiovascular disease (ASCVD) 10-year risk less than 10% should be managed through nonpharmacologic regulation of BP which includes weight loss with a heart-healthy diet, dietary sodium restriction and potassium supplementation, increased physical activity, and limited alcohol consumption. If these patients have an ASCVD 10-year risk greater than 10% or clinical CVD, antihypertensive drug therapy should also be initiated. Patients with Stage 2 hypertension will most likely require two or more medications to reach the target BP.

Angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazides reduce mortality in patients with hypertension and are considered first-line therapies. As a group, African American patients show a smaller response in BP reduction to ACEIs or ARBs than Caucasian patients. Therefore, patients that self-identify as Black or African American should be preferentially placed on a CCB or thiazide. If microalbuminuria is present (urine albumin:creatinine ≥300 mg/g), an ACEI or ARB should be considered.

1. ACEIs (lisinopril, enalapril, captopril, etc.) decrease angiotensin II formation and subsequent aldosterone synthesis, thereby reducing vasoconstriction and sodium and water retention. ARBs (losartan, valsartan, telmisartan, etc.) are similar to ACEIs.  While ACEI’s block formation of angiotensin II, ARBs block the effects of angiotensin II by antagonizing AT1 receptors. ARBs are recommended for patients that are unable to tolerate ACEIs, usually due to dry cough or rare incidences of angioedema. ARBs should not be initiated in patients with a history of angioedema, hypotension, hyperkalemia, or renal insufficiency with ACEIs

2. CCBs reduce calcium ion influx during depolarization of cardiac and/or vascular smooth muscle leading to muscle relaxation.  Non-dihydropyridine CCBs (diltiazem, verapamil) are more cardioselective, have negative inotropic effects, and decrease CO.  On the other hand, the dihydropyridine CCBs (amlodipine, nicardipine, nifedipine, etc.) act mostly on vascular smooth muscle to decrease PVR.

3. Thiazides (hydrochlorothiazide, chlorthalidone, etc.) inhibit sodium reabsorption in the renal distal tubules causing increased excretion of sodium, water, potassium and hydrogen ions. While their diuretic effect is not as potent as loop diuretics, thiazides exhibit significant antihypertensive activity and have a longer duration of action. Loop diuretics, however, should replace thiazides in patients with impaired kidney function and a reduced estimated glomerular filtration rate.

 

Comorbidities drive therapeutic decision-making. Beta-blockers are not recommended as monotherapy for the treatment of hypertension and should only be considered if heart failure or other comorbidities are also present. Dihydropyridine CCBs should be avoided in patients with heart failure. Alpha-blockers are not recommended due to orthostasis risk unless the patient has benign prostatic hyperplasia.

1. Resistant hypertension

This occurs when BP is not at goal while taking a 3-drug complementary regimen which typically includes a longer-acting thiazide like chlorthalidone, ACEI or ARB, and a CCB. Mineralocorticoid (aldosterone) receptor antagonists like spironolactone are advantageous additions in this setting and have shown evidence of greater BP reduction than beta or alpha blockers. Vasodilators like hydralazine or minoxidil have also shown significant reductions in BP in these patients. Direct renin inhibitors like aliskiren show similar reductions in BP to ACEIs or ARBs but should not be used in combination with them due to increased likelihood of angioedema and hyperkalemia. Central alpha-2 agonists like clonidine are generally reserved as last line therapy due to adverse effects in the central nervous system, particularly in elderly populations.

2. Pregnancy

Women with hypertension who become pregnant or are planning to become pregnant, should be transitioned to methyldopa, nifedipine, and/or labetalol during pregnancy. Hydralazine is a reasonable addition to these medications if BP remains above goal, however, it should not be used as monotherapy. ACEIs, ARBs, and direct renin inhibitors are contraindicated in pregnancy.

Abigail Elmes, Kelly Karpa

This 7-minute animated, narrated video describes the factors affecting blood pressure such as cardiac output, blood volume, and vascular resistance. Methods of blood pressure measurement, long term consequences of elevated blood pressure, and treatments of hypertension are also briefly discussed. Suitable for beginners.

Author: Covenant Health

No votes yet

Elevated blood pressure (BP) is the product of increased cardiac output (CO) and peripheral vascular resistance (PVR). Increased CO may result from increased fluid volume from excess sodium intake or renal sodium retention, stimulation of the renin-angiotensin-aldosterone system (RAAS), or activation of the sympathetic nervous system (SNS). Functional constriction or structural hypertrophy of the vasculature increases PVR. Both result from excess stimulation of the RAAS, SNS overactivity, genetic alterations of cell membranes, or endothelial-derived factors.

Recommendations for treating hypertension are based on the 2017 American College of Cardiology /American Heart Association (ACC/AHA) Hypertension Guidelines. Hypertension is diagnosed from the average of two or more BP measurements. Normal BP is less than 120/80 mmHg. Elevated BP is 120-129/<80 mmHg. Stage 1 hypertension is classified as 130-139/80-89 mmHg. Stage 2 hypertension is considered at pressures greater than 140/90 mmHg. The BP goal for most patients with hypertension is less than 130/80 mmHg.

Patients with elevated and Stage 1 hypertension with an atherosclerotic cardiovascular disease (ASCVD) 10-year risk less than 10% should be managed through nonpharmacologic regulation of BP which includes weight loss with a heart-healthy diet, dietary sodium restriction and potassium supplementation, increased physical activity, and limited alcohol consumption. If these patients have an ASCVD 10-year risk greater than 10% or clinical CVD, antihypertensive drug therapy should also be initiated. Patients with Stage 2 hypertension will most likely require two or more medications to reach the target BP.

Angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazides reduce mortality in patients with hypertension and are considered first-line therapies. As a group, African American patients show a smaller response in BP reduction to ACEIs or ARBs than Caucasian patients. Therefore, patients that self-identify as Black or African American should be preferentially placed on a CCB or thiazide. If microalbuminuria is present (urine albumin:creatinine ≥300 mg/g), an ACEI or ARB should be considered.

1. ACEIs (lisinopril, enalapril, captopril, etc.) decrease angiotensin II formation and subsequent aldosterone synthesis, thereby reducing vasoconstriction and sodium and water retention. ARBs (losartan, valsartan, telmisartan, etc.) are similar to ACEIs.  While ACEI’s block formation of angiotensin II, ARBs block the effects of angiotensin II by antagonizing AT1 receptors. ARBs are recommended for patients that are unable to tolerate ACEIs, usually due to dry cough or rare incidences of angioedema. ARBs should not be initiated in patients with a history of angioedema, hypotension, hyperkalemia, or renal insufficiency with ACEIs

2. CCBs reduce calcium ion influx during depolarization of cardiac and/or vascular smooth muscle leading to muscle relaxation.  Non-dihydropyridine CCBs (diltiazem, verapamil) are more cardioselective, have negative inotropic effects, and decrease CO.  On the other hand, the dihydropyridine CCBs (amlodipine, nicardipine, nifedipine, etc.) act mostly on vascular smooth muscle to decrease PVR.

3. Thiazides (hydrochlorothiazide, chlorthalidone, etc.) inhibit sodium reabsorption in the renal distal tubules causing increased excretion of sodium, water, potassium and hydrogen ions. While their diuretic effect is not as potent as loop diuretics, thiazides exhibit significant antihypertensive activity and have a longer duration of action. Loop diuretics, however, should replace thiazides in patients with impaired kidney function and a reduced estimated glomerular filtration rate.

 

Comorbidities drive therapeutic decision-making. Beta-blockers are not recommended as monotherapy for the treatment of hypertension and should only be considered if heart failure or other comorbidities are also present. Dihydropyridine CCBs should be avoided in patients with heart failure. Alpha-blockers are not recommended due to orthostasis risk unless the patient has benign prostatic hyperplasia.

1. Resistant hypertension

This occurs when BP is not at goal while taking a 3-drug complementary regimen which typically includes a longer-acting thiazide like chlorthalidone, ACEI or ARB, and a CCB. Mineralocorticoid (aldosterone) receptor antagonists like spironolactone are advantageous additions in this setting and have shown evidence of greater BP reduction than beta or alpha blockers. Vasodilators like hydralazine or minoxidil have also shown significant reductions in BP in these patients. Direct renin inhibitors like aliskiren show similar reductions in BP to ACEIs or ARBs but should not be used in combination with them due to increased likelihood of angioedema and hyperkalemia. Central alpha-2 agonists like clonidine are generally reserved as last line therapy due to adverse effects in the central nervous system, particularly in elderly populations.

2. Pregnancy

Women with hypertension who become pregnant or are planning to become pregnant, should be transitioned to methyldopa, nifedipine, and/or labetalol during pregnancy. Hydralazine is a reasonable addition to these medications if BP remains above goal, however, it should not be used as monotherapy. ACEIs, ARBs, and direct renin inhibitors are contraindicated in pregnancy.

Abigail Elmes, Kelly Karpa

This 15-minute animated, narrated video describes the pharmacology of major classes of antihypertensive medications. The role of other medications such as bosentan, fenoldopam, hydralazine, and minoxidil is also discussed. Suitable for beginners.

Author: Speed Pharmacology

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Ischemic heart disease

Oxygen demand of the heart dynamically changes, and the coronary artery can adjust its blood flow to fulfill the myocardial oxygen demand (coronary blood flow reserve). Normally, the oxygen supply and the oxygen demand are well balanced in healthy subjects. When the oxygen supply to the heart becomes inadequate for the needs of the heart, myocardial ischemia occurs. That is, ischemic heart disease (IHD) is caused by an imbalance between the oxygen supply (coronary blood flow) and the oxygen demand of the heart. Depending on myocardial damage caused by ischemia, IHD is categorized into two groups: angina pectoris and myocardial infarction. However, from the therapeutic point of view, IHD is divided into chronic coronary artery disease (CAD) and acute coronary syndrome (ACS).

Chronic CAD is characterized by atherosclerosis that results in reduction of blood supply to the heart. Stable atherosclerotic plaques cause narrowing of coronary arteries in most chronic CAD (stable angina), while functional spasm narrows coronary arteries in some cases (variant angina). When mechanical coronary stenosis is present, the downstream coronary artery maximally dilates by metabolic responses. Therefore, drugs that dilate coronary arteries aiming at increasing blood supply are not effective for stable angina. In that case, oxygen demand should be decreased. In contrast, if coronary artery spasm is the underlying cause of CAD, coronary vasodilators are effective.

ACS is characterized by unstable atherosclerotic plaques that are prone to rupture. Atherosclerotic plaque rupture is followed by dysregulated platelet aggregation and thrombus formation, which causes coronary artery narrowing and occlusion. There are three subtypes of ACS: unstable angina, non-ST elevated myocardial infarction, and ST elevated myocardial infarction. Drugs that affect arterial thrombosis are used to treat ACS.

1. Chronic CAD

Chronic CAD is treated with nitrates, β-adrenergic blockers and calcium channel blockers depending on the pathologies: anti-ischemic therapy.

(1) Nitrates

Organic nitrates are metabolized in the body to release nitric oxide (NO). NO activates soluble guanylyl cyclase to produce cyclic guanosine 3', 5'-monophosphate (cGMP) that relaxes vascular smooth muscle. Nitrates decrease preload to the heart by dilating capacitance veins, which is their primary therapeutic effect. Decrease of the preload reduces myocardial oxygen demand. Nitrates also decrease afterload of the heart by dilating resistance arterioles, which also reduces myocardial oxygen demand. In addition, nitrates increase myocardial blood flow by dilating large coronary arteries. Adverse effects include headache, postural hypotension, and tachycardia. Nitrates cannot be used in combination with phosphodiesterase 5 (PDE5) inhibitors such as sildenafil, because it may cause severe hypotension. Tolerance to nitrates can easily develop, which should be considered in clinical settings.

(2) β-blockers

β-blockers reduce myocardial oxygen demand by decreasing myocardial contractility and heart rate via acting on cardiac β1-adrenoceptors. It is their primary therapeutic effect for CAD. β-adrenergic blockers are used to treat stable angina. Blocking of vascular β2-adrenoceptor inhibits vascular relaxation, which may worsen myocardial ischemia. Therefore, β-blockers cannot be used to treat CAD when coronary artery spasm is the underlying mechanism.

(3) Calcium channel blockers (CCBs)

CCBs block Ca2+ entry into cells via L-type Ca2+ channels that play an important role in cardiac muscle and vascular smooth muscle. Each CCB has a different profile in terms of tissue selectivity: dihydropyridines (DHPs) such as nifedipine have a high selectivity to vascular L-type Ca2+ channels, whereas verapamil and diltiazem have a relatively high selectivity to cardiac L-type Ca2+ channels. CCBs can increase oxygen supply by dilating coronary arteries. CCBs can also reduce myocardial oxygen demand by dilating resistance arterioles to decrease afterload. In addition, CCBs that act on the heart at therapeutic concentrations, such as verapamil and diltiazem, reduce myocardial oxygen demand by decreasing cardiac contractility and heart rate. Although increase of oxygen supply and decrease of oxygen demand are therapeutic effects of CCBs, each CCB has differential effect on the supply and demand. For example, nifedipine (a short acting DHP) strongly dilates arterioles to cause hypotension that leads to reflex tachycardia. Therefore, nifedipine rather increases myocardial oxygen demand, which may worsen CAD. Adverse effects include flushing, dizziness, pedal edema, constipation, and gingival hyperplasia. Unlike β-blockers, CCBs are the first-line drug for vasospastic angina.

 

2. ACS

In addition to anti-ischemic therapy, antithrombotic therapy is indicated for the treatment of ACS, since ACS is caused by dysregulated platelet aggregation and thrombus formation.

(1) Antiplatelet drugs

As antiplatelet drugs, aspirin, a nonsteroidal-antiinflammatory drug (NSAID), is most frequently prescribed to treat ACS. Aspirin inhibits cyclooxygenase (COX), reducing the synthesis of thromboxane A2 (TXA2) that potently stimulates platelet aggregation. Since aspirin irreversibly inhibits COX and de novo protein synthesis does not occur in platelets, antiplatelet effects of aspirin continue until new platelets are produced. Other antiplatelets used include ADP receptor inhibitors, such as clopidogrel and ticlopidine, and inhibitors of phosphodiesterase 3 (PDE3), such as cilostazol and dipyridamole.

(2) Anticoagulants

Heparin is indicated in most ACS patients. Heparin acts on the endogenous anticoagulant antithrombin III (AT III) that inhibits coagulation factor proteases including thrombin and factor X. Heparin shows its anticoagulation activity via accelerating binding of AT III to the coagulation factors by 1,000-fold. Besides heparin, direct and indirect inhibitors of Factor Xa are used. Fondaparinux, an indirect inhibitor of factor Xa, also binds to AT III and selectively inhibits factor Xa.

(3) Thrombolytics

Cross-linked fibrin that is digested by plasmin is a major component of a thrombus. Therefore, tissue plasminogen activator (t-PA) and pro-urokinase that activates plasminogen, the plasmin precursor, are used to lyse thrombus. They are administered intravenously or intra-coronary.

Kuniaki Ishii

A 3-minute video summarizing the pathophysiology of coronary artery disease (CAD). This video briefly describes causes (atherosclerotic plaque formation, plaque rupture and clot formation), types (stable angina and acute coronary syndrome) and therapy (thrombolysis, angioplasty and thrombectomy) of CAD.

Learner level: Beginner

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Oxygen demand of the heart dynamically changes, and the coronary artery can adjust its blood flow to fulfill the myocardial oxygen demand (coronary blood flow reserve). Normally, the oxygen supply and the oxygen demand are well balanced in healthy subjects. When the oxygen supply to the heart becomes inadequate for the needs of the heart, myocardial ischemia occurs. That is, ischemic heart disease (IHD) is caused by an imbalance between the oxygen supply (coronary blood flow) and the oxygen demand of the heart. Depending on myocardial damage caused by ischemia, IHD is categorized into two groups: angina pectoris and myocardial infarction. However, from the therapeutic point of view, IHD is divided into chronic coronary artery disease (CAD) and acute coronary syndrome (ACS).

Chronic CAD is characterized by atherosclerosis that results in reduction of blood supply to the heart. Stable atherosclerotic plaques cause narrowing of coronary arteries in most chronic CAD (stable angina), while functional spasm narrows coronary arteries in some cases (variant angina). When mechanical coronary stenosis is present, the downstream coronary artery maximally dilates by metabolic responses. Therefore, drugs that dilate coronary arteries aiming at increasing blood supply are not effective for stable angina. In that case, oxygen demand should be decreased. In contrast, if coronary artery spasm is the underlying cause of CAD, coronary vasodilators are effective.

ACS is characterized by unstable atherosclerotic plaques that are prone to rupture. Atherosclerotic plaque rupture is followed by dysregulated platelet aggregation and thrombus formation, which causes coronary artery narrowing and occlusion. There are three subtypes of ACS: unstable angina, non-ST elevated myocardial infarction, and ST elevated myocardial infarction. Drugs that affect arterial thrombosis are used to treat ACS.

1. Chronic CAD

Chronic CAD is treated with nitrates, β-adrenergic blockers and calcium channel blockers depending on the pathologies: anti-ischemic therapy.

(1) Nitrates

Organic nitrates are metabolized in the body to release nitric oxide (NO). NO activates soluble guanylyl cyclase to produce cyclic guanosine 3', 5'-monophosphate (cGMP) that relaxes vascular smooth muscle. Nitrates decrease preload to the heart by dilating capacitance veins, which is their primary therapeutic effect. Decrease of the preload reduces myocardial oxygen demand. Nitrates also decrease afterload of the heart by dilating resistance arterioles, which also reduces myocardial oxygen demand. In addition, nitrates increase myocardial blood flow by dilating large coronary arteries. Adverse effects include headache, postural hypotension, and tachycardia. Nitrates cannot be used in combination with phosphodiesterase 5 (PDE5) inhibitors such as sildenafil, because it may cause severe hypotension. Tolerance to nitrates can easily develop, which should be considered in clinical settings.

(2) β-blockers

β-blockers reduce myocardial oxygen demand by decreasing myocardial contractility and heart rate via acting on cardiac β1-adrenoceptors. It is their primary therapeutic effect for CAD. β-adrenergic blockers are used to treat stable angina. Blocking of vascular β2-adrenoceptor inhibits vascular relaxation, which may worsen myocardial ischemia. Therefore, β-blockers cannot be used to treat CAD when coronary artery spasm is the underlying mechanism.

(3) Calcium channel blockers (CCBs)

CCBs block Ca2+ entry into cells via L-type Ca2+ channels that play an important role in cardiac muscle and vascular smooth muscle. Each CCB has a different profile in terms of tissue selectivity: dihydropyridines (DHPs) such as nifedipine have a high selectivity to vascular L-type Ca2+ channels, whereas verapamil and diltiazem have a relatively high selectivity to cardiac L-type Ca2+ channels. CCBs can increase oxygen supply by dilating coronary arteries. CCBs can also reduce myocardial oxygen demand by dilating resistance arterioles to decrease afterload. In addition, CCBs that act on the heart at therapeutic concentrations, such as verapamil and diltiazem, reduce myocardial oxygen demand by decreasing cardiac contractility and heart rate. Although increase of oxygen supply and decrease of oxygen demand are therapeutic effects of CCBs, each CCB has differential effect on the supply and demand. For example, nifedipine (a short acting DHP) strongly dilates arterioles to cause hypotension that leads to reflex tachycardia. Therefore, nifedipine rather increases myocardial oxygen demand, which may worsen CAD. Adverse effects include flushing, dizziness, pedal edema, constipation, and gingival hyperplasia. Unlike β-blockers, CCBs are the first-line drug for vasospastic angina.

 

2. ACS

In addition to anti-ischemic therapy, antithrombotic therapy is indicated for the treatment of ACS, since ACS is caused by dysregulated platelet aggregation and thrombus formation.

(1) Antiplatelet drugs

As antiplatelet drugs, aspirin, a nonsteroidal-antiinflammatory drug (NSAID), is most frequently prescribed to treat ACS. Aspirin inhibits cyclooxygenase (COX), reducing the synthesis of thromboxane A2 (TXA2) that potently stimulates platelet aggregation. Since aspirin irreversibly inhibits COX and de novo protein synthesis does not occur in platelets, antiplatelet effects of aspirin continue until new platelets are produced. Other antiplatelets used include ADP receptor inhibitors, such as clopidogrel and ticlopidine, and inhibitors of phosphodiesterase 3 (PDE3), such as cilostazol and dipyridamole.

(2) Anticoagulants

Heparin is indicated in most ACS patients. Heparin acts on the endogenous anticoagulant antithrombin III (AT III) that inhibits coagulation factor proteases including thrombin and factor X. Heparin shows its anticoagulation activity via accelerating binding of AT III to the coagulation factors by 1,000-fold. Besides heparin, direct and indirect inhibitors of Factor Xa are used. Fondaparinux, an indirect inhibitor of factor Xa, also binds to AT III and selectively inhibits factor Xa.

(3) Thrombolytics

Cross-linked fibrin that is digested by plasmin is a major component of a thrombus. Therefore, tissue plasminogen activator (t-PA) and pro-urokinase that activates plasminogen, the plasmin precursor, are used to lyse thrombus. They are administered intravenously or intra-coronary.

Kuniaki Ishii

This 12-minute narrated animated video summarizes the pathophysiology and treatment of acute myocardial infarction. The causes (endothelial dysfunction, atherosclerosis, clot formation and others), types (subendocardial and transmural infarction), symptoms (direct and indirect), diagnosis (ECG changes and time course of changes in biomarkers), and complications (changes over the time course) of acute myocardial infarction are described. Additionally, the therapy (medications and others) of acute myocardial infarction is summarized.

Learner level: Beginner

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Oxygen demand of the heart dynamically changes, and the coronary artery can adjust its blood flow to fulfill the myocardial oxygen demand (coronary blood flow reserve). Normally, the oxygen supply and the oxygen demand are well balanced in healthy subjects. When the oxygen supply to the heart becomes inadequate for the needs of the heart, myocardial ischemia occurs. That is, ischemic heart disease (IHD) is caused by an imbalance between the oxygen supply (coronary blood flow) and the oxygen demand of the heart. Depending on myocardial damage caused by ischemia, IHD is categorized into two groups: angina pectoris and myocardial infarction. However, from the therapeutic point of view, IHD is divided into chronic coronary artery disease (CAD) and acute coronary syndrome (ACS).

Chronic CAD is characterized by atherosclerosis that results in reduction of blood supply to the heart. Stable atherosclerotic plaques cause narrowing of coronary arteries in most chronic CAD (stable angina), while functional spasm narrows coronary arteries in some cases (variant angina). When mechanical coronary stenosis is present, the downstream coronary artery maximally dilates by metabolic responses. Therefore, drugs that dilate coronary arteries aiming at increasing blood supply are not effective for stable angina. In that case, oxygen demand should be decreased. In contrast, if coronary artery spasm is the underlying cause of CAD, coronary vasodilators are effective.

ACS is characterized by unstable atherosclerotic plaques that are prone to rupture. Atherosclerotic plaque rupture is followed by dysregulated platelet aggregation and thrombus formation, which causes coronary artery narrowing and occlusion. There are three subtypes of ACS: unstable angina, non-ST elevated myocardial infarction, and ST elevated myocardial infarction. Drugs that affect arterial thrombosis are used to treat ACS.

1. Chronic CAD

Chronic CAD is treated with nitrates, β-adrenergic blockers and calcium channel blockers depending on the pathologies: anti-ischemic therapy.

(1) Nitrates

Organic nitrates are metabolized in the body to release nitric oxide (NO). NO activates soluble guanylyl cyclase to produce cyclic guanosine 3', 5'-monophosphate (cGMP) that relaxes vascular smooth muscle. Nitrates decrease preload to the heart by dilating capacitance veins, which is their primary therapeutic effect. Decrease of the preload reduces myocardial oxygen demand. Nitrates also decrease afterload of the heart by dilating resistance arterioles, which also reduces myocardial oxygen demand. In addition, nitrates increase myocardial blood flow by dilating large coronary arteries. Adverse effects include headache, postural hypotension, and tachycardia. Nitrates cannot be used in combination with phosphodiesterase 5 (PDE5) inhibitors such as sildenafil, because it may cause severe hypotension. Tolerance to nitrates can easily develop, which should be considered in clinical settings.

(2) β-blockers

β-blockers reduce myocardial oxygen demand by decreasing myocardial contractility and heart rate via acting on cardiac β1-adrenoceptors. It is their primary therapeutic effect for CAD. β-adrenergic blockers are used to treat stable angina. Blocking of vascular β2-adrenoceptor inhibits vascular relaxation, which may worsen myocardial ischemia. Therefore, β-blockers cannot be used to treat CAD when coronary artery spasm is the underlying mechanism.

(3) Calcium channel blockers (CCBs)

CCBs block Ca2+ entry into cells via L-type Ca2+ channels that play an important role in cardiac muscle and vascular smooth muscle. Each CCB has a different profile in terms of tissue selectivity: dihydropyridines (DHPs) such as nifedipine have a high selectivity to vascular L-type Ca2+ channels, whereas verapamil and diltiazem have a relatively high selectivity to cardiac L-type Ca2+ channels. CCBs can increase oxygen supply by dilating coronary arteries. CCBs can also reduce myocardial oxygen demand by dilating resistance arterioles to decrease afterload. In addition, CCBs that act on the heart at therapeutic concentrations, such as verapamil and diltiazem, reduce myocardial oxygen demand by decreasing cardiac contractility and heart rate. Although increase of oxygen supply and decrease of oxygen demand are therapeutic effects of CCBs, each CCB has differential effect on the supply and demand. For example, nifedipine (a short acting DHP) strongly dilates arterioles to cause hypotension that leads to reflex tachycardia. Therefore, nifedipine rather increases myocardial oxygen demand, which may worsen CAD. Adverse effects include flushing, dizziness, pedal edema, constipation, and gingival hyperplasia. Unlike β-blockers, CCBs are the first-line drug for vasospastic angina.

 

2. ACS

In addition to anti-ischemic therapy, antithrombotic therapy is indicated for the treatment of ACS, since ACS is caused by dysregulated platelet aggregation and thrombus formation.

(1) Antiplatelet drugs

As antiplatelet drugs, aspirin, a nonsteroidal-antiinflammatory drug (NSAID), is most frequently prescribed to treat ACS. Aspirin inhibits cyclooxygenase (COX), reducing the synthesis of thromboxane A2 (TXA2) that potently stimulates platelet aggregation. Since aspirin irreversibly inhibits COX and de novo protein synthesis does not occur in platelets, antiplatelet effects of aspirin continue until new platelets are produced. Other antiplatelets used include ADP receptor inhibitors, such as clopidogrel and ticlopidine, and inhibitors of phosphodiesterase 3 (PDE3), such as cilostazol and dipyridamole.

(2) Anticoagulants

Heparin is indicated in most ACS patients. Heparin acts on the endogenous anticoagulant antithrombin III (AT III) that inhibits coagulation factor proteases including thrombin and factor X. Heparin shows its anticoagulation activity via accelerating binding of AT III to the coagulation factors by 1,000-fold. Besides heparin, direct and indirect inhibitors of Factor Xa are used. Fondaparinux, an indirect inhibitor of factor Xa, also binds to AT III and selectively inhibits factor Xa.

(3) Thrombolytics

Cross-linked fibrin that is digested by plasmin is a major component of a thrombus. Therefore, tissue plasminogen activator (t-PA) and pro-urokinase that activates plasminogen, the plasmin precursor, are used to lyse thrombus. They are administered intravenously or intra-coronary.

Kuniaki Ishii

This 6-minute narrated animated video describes the principal types of angina pectoris including stable, unstable and vasospastic angina. The associated symptoms, ECG changes and pathophysiology (atherosclerosis, thrombosis and others) of each are discussed together with treatments (indication of nitroglycerin and calcium channel blockers) of angina pectoris.

Learner level: Beginner

No votes yet

Oxygen demand of the heart dynamically changes, and the coronary artery can adjust its blood flow to fulfill the myocardial oxygen demand (coronary blood flow reserve). Normally, the oxygen supply and the oxygen demand are well balanced in healthy subjects. When the oxygen supply to the heart becomes inadequate for the needs of the heart, myocardial ischemia occurs. That is, ischemic heart disease (IHD) is caused by an imbalance between the oxygen supply (coronary blood flow) and the oxygen demand of the heart. Depending on myocardial damage caused by ischemia, IHD is categorized into two groups: angina pectoris and myocardial infarction. However, from the therapeutic point of view, IHD is divided into chronic coronary artery disease (CAD) and acute coronary syndrome (ACS).

Chronic CAD is characterized by atherosclerosis that results in reduction of blood supply to the heart. Stable atherosclerotic plaques cause narrowing of coronary arteries in most chronic CAD (stable angina), while functional spasm narrows coronary arteries in some cases (variant angina). When mechanical coronary stenosis is present, the downstream coronary artery maximally dilates by metabolic responses. Therefore, drugs that dilate coronary arteries aiming at increasing blood supply are not effective for stable angina. In that case, oxygen demand should be decreased. In contrast, if coronary artery spasm is the underlying cause of CAD, coronary vasodilators are effective.

ACS is characterized by unstable atherosclerotic plaques that are prone to rupture. Atherosclerotic plaque rupture is followed by dysregulated platelet aggregation and thrombus formation, which causes coronary artery narrowing and occlusion. There are three subtypes of ACS: unstable angina, non-ST elevated myocardial infarction, and ST elevated myocardial infarction. Drugs that affect arterial thrombosis are used to treat ACS.

1. Chronic CAD

Chronic CAD is treated with nitrates, β-adrenergic blockers and calcium channel blockers depending on the pathologies: anti-ischemic therapy.

(1) Nitrates

Organic nitrates are metabolized in the body to release nitric oxide (NO). NO activates soluble guanylyl cyclase to produce cyclic guanosine 3', 5'-monophosphate (cGMP) that relaxes vascular smooth muscle. Nitrates decrease preload to the heart by dilating capacitance veins, which is their primary therapeutic effect. Decrease of the preload reduces myocardial oxygen demand. Nitrates also decrease afterload of the heart by dilating resistance arterioles, which also reduces myocardial oxygen demand. In addition, nitrates increase myocardial blood flow by dilating large coronary arteries. Adverse effects include headache, postural hypotension, and tachycardia. Nitrates cannot be used in combination with phosphodiesterase 5 (PDE5) inhibitors such as sildenafil, because it may cause severe hypotension. Tolerance to nitrates can easily develop, which should be considered in clinical settings.

(2) β-blockers

β-blockers reduce myocardial oxygen demand by decreasing myocardial contractility and heart rate via acting on cardiac β1-adrenoceptors. It is their primary therapeutic effect for CAD. β-adrenergic blockers are used to treat stable angina. Blocking of vascular β2-adrenoceptor inhibits vascular relaxation, which may worsen myocardial ischemia. Therefore, β-blockers cannot be used to treat CAD when coronary artery spasm is the underlying mechanism.

(3) Calcium channel blockers (CCBs)

CCBs block Ca2+ entry into cells via L-type Ca2+ channels that play an important role in cardiac muscle and vascular smooth muscle. Each CCB has a different profile in terms of tissue selectivity: dihydropyridines (DHPs) such as nifedipine have a high selectivity to vascular L-type Ca2+ channels, whereas verapamil and diltiazem have a relatively high selectivity to cardiac L-type Ca2+ channels. CCBs can increase oxygen supply by dilating coronary arteries. CCBs can also reduce myocardial oxygen demand by dilating resistance arterioles to decrease afterload. In addition, CCBs that act on the heart at therapeutic concentrations, such as verapamil and diltiazem, reduce myocardial oxygen demand by decreasing cardiac contractility and heart rate. Although increase of oxygen supply and decrease of oxygen demand are therapeutic effects of CCBs, each CCB has differential effect on the supply and demand. For example, nifedipine (a short acting DHP) strongly dilates arterioles to cause hypotension that leads to reflex tachycardia. Therefore, nifedipine rather increases myocardial oxygen demand, which may worsen CAD. Adverse effects include flushing, dizziness, pedal edema, constipation, and gingival hyperplasia. Unlike β-blockers, CCBs are the first-line drug for vasospastic angina.

 

2. ACS

In addition to anti-ischemic therapy, antithrombotic therapy is indicated for the treatment of ACS, since ACS is caused by dysregulated platelet aggregation and thrombus formation.

(1) Antiplatelet drugs

As antiplatelet drugs, aspirin, a nonsteroidal-antiinflammatory drug (NSAID), is most frequently prescribed to treat ACS. Aspirin inhibits cyclooxygenase (COX), reducing the synthesis of thromboxane A2 (TXA2) that potently stimulates platelet aggregation. Since aspirin irreversibly inhibits COX and de novo protein synthesis does not occur in platelets, antiplatelet effects of aspirin continue until new platelets are produced. Other antiplatelets used include ADP receptor inhibitors, such as clopidogrel and ticlopidine, and inhibitors of phosphodiesterase 3 (PDE3), such as cilostazol and dipyridamole.

(2) Anticoagulants

Heparin is indicated in most ACS patients. Heparin acts on the endogenous anticoagulant antithrombin III (AT III) that inhibits coagulation factor proteases including thrombin and factor X. Heparin shows its anticoagulation activity via accelerating binding of AT III to the coagulation factors by 1,000-fold. Besides heparin, direct and indirect inhibitors of Factor Xa are used. Fondaparinux, an indirect inhibitor of factor Xa, also binds to AT III and selectively inhibits factor Xa.

(3) Thrombolytics

Cross-linked fibrin that is digested by plasmin is a major component of a thrombus. Therefore, tissue plasminogen activator (t-PA) and pro-urokinase that activates plasminogen, the plasmin precursor, are used to lyse thrombus. They are administered intravenously or intra-coronary.

Kuniaki Ishii

This 11-slide slide set created with PowerPoint describes the pharmacology of organic nitrates: mechanisms of action; routes of administration; common unwanted effects; mechanisms of tolerance and the interaction between organic nitrates and phosphodiesterase 5 inhibitors. This is an introduction to the topic of organic nitrates which would be appropriate for beginners. Contributed by Christopher Fowler, Umeå University, Sweden.

Learner level: Beginner

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