Cardiology pharm – Mixed HY drugs

a) Amlodipine, Nifedipine

b) Verapamil, Diltiazem

c)

MOA of dihydropyridine CCBs (i.e., amlodipine, nifedipine, etc.)?

• Vascular-selective (i.e., block calcium channels on arteries/arterioles only).
• Cause arterial vasodilation → ↓ BP + afterload on the left heart  → HR increases to compensate (baroreceptor reflex).

MOA of non-dihydropyridine calcium channel blockers (i.e., verapamil, diltiazem)?

• Cardiac-selective (blocks calcium channels on myocardial and nodal tissue only).
• Verapamil is pure non-dihydropyridine.
• Diltiazem is a mixed agent, with effects on both cardiac and arterial calcium channels.

When do we use dihydropyridine CCBs?

• To treat hypertension in patients without pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease.
  • If patient has any of the above, use an ACEi or ARB first to manage the HTN.
  • If patient doesn’t have any of the above, dihydropyridine CCB or a thiazide diuretic is chosen.
  • Sounds weirdly specific, but this is HY notably for the 2CK FM component.
  • 45M + increased fasting sugars with 1+ protein on dipstick + BP of 142/90; which agent should we commence? –> answer = ACEi or ARB.
  • 45M + repeated HTN measurements despite lifestyle modifications + no other issues; which agent should we commence? –> answer = nifedipine or HCTZ.
  • That’s the over-simplified version of it, but that’s the gist you need to take away: if the patient has pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease –> use an ACEi or ARB; if the patient doesn’t, use a dCCB or a thiazide.

When do we use dihydropyridine CCBs?

• To treat hypertension in patients without pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease.
  • If patient has any of the above, use an ACEi or ARB first to manage the HTN.
  • If patient doesn’t have any of the above, dihydropyridine CCB or a thiazide diuretic is chosen.
  • Sounds weirdly specific, but this is HY notably for the 2CK FM component.
  • 45M + increased fasting sugars with 1+ protein on dipstick + BP of 142/90; which agent should we commence? –> answer = ACEi or ARB.
  • 45M + repeated HTN measurements despite lifestyle modifications + no other issues; which agent should we commence? –> answer = nifedipine or HCTZ.
  • That’s the over-simplified version of it, but that’s the gist you need to take away: if the patient has pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease –> use an ACEi or ARB; if the patient doesn’t, use a dCCB or a thiazide.

Nifedipine or amlodipine (dihydropyridine CCB)

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When do we use dihydropyridine CCBs?

• To treat hypertension in patients without pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease.
  • If patient has any of the above, use an ACEi or ARB first to manage the HTN.
  • If patient doesn’t have any of the above, dihydropyridine CCB or a thiazide diuretic is chosen.
  • Sounds weirdly specific, but this is HY notably for the 2CK FM component.
  • 45M + increased fasting sugars with 1+ protein on dipstick + BP of 142/90; which agent should we commence? –> answer = ACEi or ARB.
  • 45M + repeated HTN measurements despite lifestyle modifications + no other issues; which agent should we commence? –> answer = nifedipine or HCTZ.
  • That’s the over-simplified version of it, but that’s the gist you need to take away: if the patient has pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease –> use an ACEi or ARB; if the patient doesn’t, use a dCCB or a thiazide.

IV nicardipine is a hard-hitting dCCB often used as part of hypertensive emergencies with sodium nitroprusside and fenoldopam (D1 agonist).

—

When do we use dihydropyridine CCBs?

• To treat hypertension in patients without pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease.
  • If patient has any of the above, use an ACEi or ARB first to manage the HTN.
  • If patient doesn’t have any of the above, dihydropyridine CCB or a thiazide diuretic is chosen.
  • Sounds weirdly specific, but this is HY notably for the 2CK FM component.
  • 45M + increased fasting sugars with 1+ protein on dipstick + BP of 142/90; which agent should we commence? –> answer = ACEi or ARB.
  • 45M + repeated HTN measurements despite lifestyle modifications + no other issues; which agent should we commence? –> answer = nifedipine or HCTZ.
  • That’s the over-simplified version of it, but that’s the gist you need to take away: if the patient has pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease –> use an ACEi or ARB; if the patient doesn’t, use a dCCB or a thiazide.
• IV nicardipine is a hard-hitting dCCB often used as part of hypertensive emergencies with sodium nitroprusside and fenoldopam (D1 agonist).
• Nimodipine is a dCCB used post-subarachnoid hemorrhage to prevent vasospasm and ischemic stroke.

Nimodipine is a dCCB used post-subarachnoid hemorrhage to prevent vasospasm and ischemic stroke.

—

When do we use dihydropyridine CCBs?

• To treat hypertension in patients without pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease.
  • If patient has any of the above, use an ACEi or ARB first to manage the HTN.
  • If patient doesn’t have any of the above, dihydropyridine CCB or a thiazide diuretic is chosen.
  • Sounds weirdly specific, but this is HY notably for the 2CK FM component.
  • 45M + increased fasting sugars with 1+ protein on dipstick + BP of 142/90; which agent should we commence? –> answer = ACEi or ARB.
  • 45M + repeated HTN measurements despite lifestyle modifications + no other issues; which agent should we commence? –> answer = nifedipine or HCTZ.
  • That’s the over-simplified version of it, but that’s the gist you need to take away: if the patient has pre-diabetes, diabetes, proteinuria, cardiovascular/cerebrovascular disease –> use an ACEi or ARB; if the patient doesn’t, use a dCCB or a thiazide.
• IV nicardipine is a hard-hitting dCCB often used as part of hypertensive emergencies with sodium nitroprusside and fenoldopam (D1 agonist).
• Nimodipine is a dCCB used post-subarachnoid hemorrhage to prevent vasospasm and ischemic stroke.

Major side-effect of dihydropyridine CCBs?

• Peripheral edema (fluid retention).
• This is one of the highest yield side-effects for pharmacology on all USMLE Steps. Do not confuse with verapamil, which causes constipation.
• 35F + recently started on amlodipine + has puffy limbs + massive paragraph of a vignette with other extraneous info; Q asks the cause of her edema; answer  = “side-effect of medication” (amlodipine).

When do we use non-dihydropyridine CCBs?

• Verapamil is used for rate-control for atrial fibrillation when beta-blockers are contraindicated or not effective, prior to attempting rhythm-control.
• Diltiazem is not assessed on USMLE beyond just needing to know it’s a calcium channel blocker. It can be used for HTN and arrhythmias.

Constipation.

This is one of the highest yield side-effects for pharmacology on all USMLE Steps.

Do not confuse with the nifedipine/amlodipine, which cause peripheral edema (fluid retention).

Hydralazine

MOA of hydralazine?

• Causes disruption of arterial smooth muscle calcium currents, resulting in vasodilation and decreased BP. Used for hypertensive emergency in pregnancy.
• Arterial vasodilation → ↓ BP + afterload on the left heart  → heart rate increases to compensate (baroreceptor reflex).
• In other words, USMLE will ask you where hydralazine acts (arteries/arterioles) or what will happen to HR when you give it (↑).

ACE inhibitors act in the lung (ACE is in the lung).

Dipyridamole is a phosphodiesterase inhibitor that acts on arteries –> vasodilation –> drop in BP –> heart rate increases as part of baroreceptor reflex –> increased cardiac workload –> can reveal areas of ischemia using an uptake-radioisotope such as thallium.

Cilostazol is a phosphodiesterase inhibitor used for intermittent claudication. It works on arterial smooth muscle.

It is almost always the wrong answer when listed on the USMLE for the management of arterial disease on 2CK Surg shelves.

Choose “commence a walking program,” or “commence an exercise program” as the first management for intermittent claudication.

If the exercise program fails, cilostazol can be commenced.

Causes disruption of arterial smooth muscle calcium currents, resulting in vasodilation and decreased BP.

Used for hypertensive emergency in pregnancy.

Arterial vasodilation → ↓ BP + afterload on the left heart  → heart rate increases to compensate (baroreceptor reflex).

In other words, USMLE will ask you where hydralazine acts (arteries/arterioles) or what will happen to HR when you give it (↑).

Angiotensin II receptor blockers (e.g., valsartan) act on arteries.

In contrast, ACE inhibitors (e.g., lisinopril) act in the lungs (where ACE is located).

An ACEi or ARB is commenced in diabetics who have any evidence of creatinine elevation, proteinuria, or a BP > 130/80.

HTN in diabetes is considered >130/80 (either number). This is in contrast to the non-diabetic population (>140/90).

Sodium nitroprusside, unlike other nitrates, acts on arteries > veins.

It is used for hypertensive emergencies.

Verapamil (non-dihydropyridine calcium channel blocker) is cardiac-selective.

In contrast, dihydropyridines (e.g., nifedipine, amlodipine) are vascular-selective and act on arteries (choice D).

Adenosine

MOA of adenosine?

• Increases potassium release from cells, resulting in hyperpolarization.

When is adenosine used?

• To treat supraventricular tachycardia (SVT) if carotid massage (vagal maneuvers) or ice pack to the face (in young kids) fails to re-establish sinus rhythm.

Side-effect of adenosine?

• Causes severe chest pain for a few seconds, then the patient is fine.

Miscellaneous important info about adenosine:

• Produced endogenously by muscles as a result of cellular metabolism.
• Adenosine is the molecule responsible for cardiac pain with angina and MI. USMLE likes this. Essentially: myocardium becomes ischemic, where ATP is metabolized maximally and adenosine builds up –> increased pain in the setting of ischemia.

Ivabradine

MOA of ivabradine?

• Inhibits mixed Na/K “funny currents” at the sinoatrial node, resulting in decreased heart rate.
• Reduces chronotropy (HR) without reducing inotropy (contractility).
  • This is in contrast to beta-blockers and verapamil, which reduce both HR and contractility.

When is ivabradine used?

• Can be used to manage angina in patients who cannot take beta-blockers (BB contraindicated in: diabetes, depression, sexual dysfunction, asthma, 2nd/3rd degree heart block, unstable heart failure).

Side-effect of ivabradine?

• “Luminous phenomena” –> sensations described by patients as enhanced brightness despite a fully maintained visual field.

Inhibits myocardial Na/K ATPase pumps by binding to the extracellular K+ binding site –> causes buildup of sodium in the cell –> creates a less favorable gradient for sodium to move into the cell via the Ca/Na ATPase pump –> leads to indirect inhibition of the Ca/Na ATPase –> calcium stays in the cell –> increased myocardial contractility.

Slows heart rate due to increasing parasympathetic potentiation at nodal tissue.

In other words: digoxin ↑ inotropy but ↓ chronotropy.

For heart failure in patients failing other management.

ACEi or ARB.

Students often choose beta-blocker, which is the wrong answer.

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Hierarchy for drugs in heart failure (simplified but HY for USMLE):

• Start with ACE inhibitor or an angiotensin II receptor blocker (ARB) to improve ejection fraction (normal is 55-70%).
• If the patient is fluid overloaded (i.e., peripheral edema or pulmonary edema), attempt to achieve euvolemia by adding furosemide (loop diuretic).
• If insufficient ejection fraction with the ACEi or ARB, add a beta-blocker (metoprolol XR, bisoprolol, carvedilol, or nebivolol).
• If insufficient ejection fraction with ACEi/ARB + beta-blocker, add spironolactone (aldosterone receptor antagonist).
• If insufficient ejection fraction, add the combination of hydralazine + nitrates. Only the combo decreases mortality in HF. It is especially efficacious in African Americans (tend to have stiffer vessels).
• If insufficient ejection fraction when already on ACEi/ARB + beta-blocker + spironolactone + hydralazine + nitrates, add digoxin.
• If pharmacologic therapy insufficient, use implantable device.

A nitrate (e.g., isosorbide dinitrate).

Metoprolol XR, Bisoprolol, Carvedilol, Nebivolol

Yellow, wavy “Vincent van Gogh” vision.

Hyperkalemia (prevents K+ from entering the cell).

Hypokalemia (since K+ and digoxin compete for the extracellular K+ binding site on the Na/K ATPase pump, if less K+ is floating around, then more digoxin binds per unit time).

Quinidine (displaces digoxin from bilirubin –> less protein-bound digoxin –> more digoxin available to bind to Na/K ATPases).

Treatment for digoxin toxicity?

• Normalize serum potassium.
• Give anti-digoxin immunoglobulin Fab fragment.
• Give Mg2+.

a) Blocks sodium channels.

b) Angina refractory to other therapies (i.e., nitrates, beta-blockers).

Sacubitril

MOA of sacubitril?

• Neprilysin inhibitor.
• Neprilysin is an enzyme that breaks down atrial and brain natriuretic peptides (i.e., ANP and BNP).
• ANP and BNP act as natural diuretics that are secreted by atria and ventricles, respectively, in response to increased chamber stretch. They function to decrease sodium retention at the distal kidney.

When is sacubitril used?

• Sacubitril is combined with valsartan (an angiotensin II receptor blocker) as sacubitril/valsartan for treatment of heart failure.

Sacubitril

MOA of sacubitril?

• Neprilysin inhibitor.
• Neprilysin is an enzyme that breaks down atrial and brain natriuretic peptides (i.e., ANP and BNP).
• ANP and BNP act as natural diuretics that are secreted by atria and ventricles, respectively, in response to increased chamber stretch. They function to decrease sodium retention at the distal kidney.

When is sacubitril used?

• Sacubitril is combined with valsartan (an angiotensin II receptor blocker) as sacubitril/valsartan for treatment of heart failure.

Ranolazine

MOA of ranolazine?

• Blocks sodium channels.

When is ranolazine used?

• Angina refractory to other therapies (i.e., nitrates, beta-blockers).

Treatment for digoxin toxicity?

• Normalize serum potassium.
• Give anti-digoxin immunoglobulin Fab fragment.
• Give Mg2+.

What causes digoxin toxicity?

• Hypokalemia (since K+ and digoxin compete for the extracellular K+ binding site on the Na/K ATPase pump, if less K+ is floating around, then more digoxin binds per unit time).
• Quinidine (displaces digoxin from bilirubin –> less protein-bound digoxin –> more digoxin available to bind to Na/K ATPases).

Side-effects of digoxin?

• Yellow, wavy “Vincent van Gogh” vision.
• Hyperkalemia (prevents K+ from entering the cell).

Hierarchy for drugs in heart failure (simplified but HY for USMLE):

• Start with ACE inhibitor or an angiotensin II receptor blocker (ARB) to improve ejection fraction (normal is 55-70%).
• If the patient is fluid overloaded (i.e., peripheral edema or pulmonary edema), attempt to achieve euvolemia by adding furosemide (loop diuretic).
• If insufficient ejection fraction with the ACEi or ARB, add a beta-blocker (metoprolol XR, bisoprolol, carvedilol, and nebivolol decrease mortality in heart failure; propranolol does not).
• If insufficient ejection fraction with ACEi/ARB + beta-blocker, add spironolactone (aldosterone receptor antagonist).
• If insufficient ejection fraction, add the combination of hydralazine + nitrates. Only the combo decreases mortality in HF. It is especially efficacious in African Americans (tend to have stiffer vessels).
• If insufficient ejection fraction when already on ACEi/ARB + beta-blocker + spironolactone + hydralazine + nitrates, add digoxin.
• If pharmacologic therapy insufficient, use implantable device.

Digoxin competes with K+ for the extracellular binding site on the Na/K ATPase pump. Digoxin directly inhibits this pump. This results in indirect inhibition of the Na/Ca ATPase pump due to effects on the Na gradient.

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MOA of digoxin?

• Inhibits myocardial Na/K ATPase pumps by binding to the extracellular K+ binding site –> causes buildup of sodium in the cell –> creates a less favorable gradient for sodium to move into the cell via the Ca/Na ATPase pump –> leads to indirect inhibition of the Ca/Na ATPase –> calcium stays in the cell –> increased myocardial contractility.
• Slows heart rate due to increasing parasympathetic potentiation at nodal tissue.
• In other words: digoxin ↑ inotropy but ↓ chronotropy.

Ivabradine

MOA of ivabradine?

• Inhibits mixed Na/K “funny currents” at the sinoatrial node, resulting in decreased heart rate.
• Reduces chronotropy (HR) without reducing inotropy (contractility).
  • This is in contrast to beta-blockers and verapamil, which reduce both HR and contractility.

When is ivabradine used?

• Can be used to manage angina in patients who cannot take beta-blockers (BB contraindicated in: diabetes, depression, sexual dysfunction, asthma, 2nd/3rd degree heart block, unstable heart failure).

Side-effect of ivabradine?

• “Luminous phenomena” –> sensations described by patients as enhanced brightness despite a fully maintained visual field.

Ivabradine

MOA of ivabradine?

• Inhibits mixed Na/K “funny currents” at the sinoatrial node, resulting in decreased heart rate.
• Reduces chronotropy (HR) without reducing inotropy (contractility).
  • This is in contrast to beta-blockers and verapamil, which reduce both HR and contractility.

When is ivabradine used?

• Can be used to manage angina in patients who cannot take beta-blockers (BB contraindicated in: diabetes, depression, sexual dysfunction, asthma, 2nd/3rd degree heart block, unstable heart failure).

Side-effect of ivabradine?

• “Luminous phenomena” –> sensations described by patients as enhanced brightness despite a fully maintained visual field.

Adenosine

—

Produced endogenously by muscles as a result of cellular metabolism.

Adenosine is the molecule responsible for cardiac pain with angina and MI. USMLE likes this. Essentially: myocardium becomes ischemic, where ATP is metabolized maximally and adenosine builds up –> increased pain in the setting of ischemia.