Cardiology Exam 2

Hydrochlorothiazide

Microzide

Amlodipine

Norvasc

Nifedipine ER

Adalat CC, Procardia XL

Diltiazem SR/ER

Cardizem LA, Cardizem CD

Verapamil IR/SR

Calan, Calan SR, Verelan

Benazepril

Lotensin

Captopril

Capoten

Enalapril

Vasotec

Fosinopril

Monopril

Lisinopril

Prinivil, Zestril

Quinapril

Accupril

Ramipril

Altace

Candesartan

Atacand

Irbesartan

Avapro

Losartan

Cozaar

Olmesartan

Benicar

Telmisartan

Micardis

Valsartan

Diovan

Bumetanide

Bumex

Furosemide

Lasix

Torsemide

Demadex

Eplerenone

Inspra

Spironolactone

Aldactone

Atenolol

Tenormin

Bisoprolol

Zebeta

Metoprolol Tartrate

Lopressor

Metoprolol Succinate

Toprol XL

Nebivolol

Bystolic

Propranolol IR/LA

Inderal, Inderal LA

Carvedilol

Coreg, Coreg CR

Labetalol

Normodyne, Trandate

Aliskiren

Tekturna

Doxazosin

Cardura

Clonidine

Catapres, Catapres-TTS

Hydralazine

Apresoline

Sacubitril/Valsartan

Entresto

Diuresis

An increase in urine production by the kidneys, which leads to a greater output of urine

• Key substance lost = H₂O

Diuretics are useful for treating diseases associated with _____

Edema

• Excess watery fluid collection → “swelling”

• Abnormal retention of Na⁺ and H₂O in the extracellular components of the body

How do diuretics treat hypertension?

Reduce blood volume via increase in urination

How do diuretics increase urine excretion by the kidneys?

Decrease tubular reabsorption of Na⁺ and its osmotic equivalent H₂O from the urine back into the blood

• Na⁺ leads and H₂O follows

Nephrons are responsible for _____

Filtering the blood and regulating blood and urine levels of chemical species such as H₂O, Na⁺, K⁺, Ca²⁺, and Cl^-

Direction of Filtration

Blood to tubule

Direction of Reabsorption

Tubule to blood

Direction of Secretion

Blood to tubule

Direction of Excretion

Tubule to external environment

Natriuresis

Increased Na⁺ excretion from the blood into the urine

• Key substance lose = Na⁺

Potential causes of diuresis

Excess fluid intake, osmotic effects, or diuretics

IV fluids, high blood sugar

Potential causes of natriuresis

Drugs or hormones that block Na⁺ reabsorption from the urine back into the blood

Loop diuretics, thiazide diuretics, Atrial Natriuretic Peptide (ANP)

Clinical Importance of Diuresis vs. Natriuresis

Diuresis

• Used to reduce fluid overload

Natriuresis

• Important for lowering blood pressure and reducing fluid volume since Na⁺ retention in the blood drives H₂O retention

How are diuresis and natriuresis linked?

ALL natriuresis cause SOME diuresis, but NOT ALL diuresis involves natriuresis

Significant concern with the most commonly used diuretics

Potassium blood levels

Potassium blood levels must be tightly regulated because _____

Even small deviations can be life threatening

• < 3.5 mEq/L = Hypokalemia

• > 5.0 mEq/L = Hyperkalemia

Hypertension Medications that can cause hypokalemia

Loop diuretics

Thiazide diuretics

Hypertension Medications that can cause hyperkalemia

Potassium-sparing diuretics

ACE Inhibitors

ARBs

Main dangers of hypokalemia

Muscle weakness

Cramps

Paralysis (loss or impairment of voluntary movement)

Life-threatening cardiac arrhythmias

Main dangers of hyperkalemia

Cardiac conduction disturbances

Risk of sudden cardiac arrest

• A sudden and unexpected cessation of the heart’s pumping action leading to a lack of blood flow to the body

Sodium Potassium Chloride Cotransporter 2 (NKCC2)

Active transporter protein in the ascending limb of the Loop of Henle that reabsorbs Na⁺, K⁺, and Cl^- from the urine into the blood in a ratio of 1:1:2

Function of the ascending limb of the Loop of Henle

Reabsorbs ~25% of filter sodium (and water) from the urine into the blood

Reabsorbs most, if not all, of the potassium from the urine into the blood by the time the urine reaches the distal end

Mechanism of Loop Diuretics

Bind to and inhibit the function of NKCC2, leading to desired diuresis but also potentially dangerous hypokalemia

Blocks the reabsorption/promotes the excretion of Na⁺, K⁺, and H₂O

How do different loop diuretics compare in terms of absorption?

Furosemide, the most widely prescribed, has unreliable oral absorption

Torsemide exhibits more reliable oral absorption

The structures of furosemide, bumetanide, and torsemide contain an aryl sulfonamide, which means _____

They can trigger a “sulfa” drug allergy

• Can cause an IgE or T-cell mediated immune reaction, which can range from a mild rash to anaphylaxis

• Not as likely to trigger this reaction as sulfonamide antibiotics

Main benefit of ethacrynic acid

Does not contain an aryl sulfonamide, so it is the loop diuretic of choice for sulfa-allergic patients

Why is ethacrynic acid rarely used outside of sulfa drug allergies?

It is very expensive and has the highest ototoxicity (ear) risk

Effect of Loop Diuretics on blood calcium levels

Increased excretion of calcium from the blood into the urine, which leads to hypocalcemia

• Undesired in patients with osteoporosis

Effect of Thiazide Diuretics on blood calcium levels

Decreased excretion of calcium from the blood into the urine, which leads to hypercalcemia

• Potentially beneficial in patients with osteoporosis

Of the 3 major classes of diuretics, loop diuretics produce _____

The strongest natriuresis and diuresis

Boxed warning for loop diuretics

High ceiling/efficacy diuretics which can cause profound diuresis (working too well) → fluid and electrolyte depletion

Thiazide diuretics are considered low to moderate ceiling/efficacy diuretics, which means _____

Increasing the dose leads to a plateau effect

Noteworthy adverse effects of loop diuretics

Hypokalemia

Ototoxicity

Hypokalemia with a loop diuretics can potentially be avoided with _____

Regular intake of potassium-rich foods, potassium supplements, or concurrent use with a potassium-sparing diuretic

Ototoxicity caused by loop diuretics may present itself as _____

Hearing loss, tinnitis, and/or vertigo

Why can loop diuretics cause ototoxicity?

Similar drug target in the kidney (NKCC2, desired) and the ear (NKCC1, undesired)

• NKCC1 is found in the stria vascularis of the inner ear and drives normal healing

Risk factors for ototoxicity caused by loop diuretics

High doses and/or rapid IV administration

• Reach the inner ear rapidly and can concentrate there

Additive risk via concurrent use with other ototoxic drugs

• Ex. Aminoglycoside antibiotics and cisplatin

Ototoxicity is usually reversible after stopping the loop diuretic, but it can be irreversible at _____

Very high doses or when used with other ototoxic drugs

Onset and duration of action for loop diuretics

Rapid onset of action

• IV emergency use = ~5 minutes; Oral = 30-60 minutes

Short duration of action

• 4-6 hours, which limits use to some extent

Uses for loop diuretics outside of treatment of hypertension

Acute pulmonary edema or peripheral edema

• Provides potent, profound acute diuresis

Heart failure

• Decreases fluid volume

How does decreasing fluid volume with a loop diuretic benefit heart failure patients?

Decreases preload (the amount of stretch places of the heart muscle before the heart contracts)

Reduces congestive heart failure symptoms

Makes it easier for the heart to pump blood

Restores euvolemia (the state of having a normal amount of body fluids)

Chronic use of a loop diuretic may lead to _____

Drug resistance, where increasing the dose does not prove helpful

• More Na⁺ is forced downstream to the DCT and collecting duct, which adapt by hypertrophy (increased kidney size or volume) and upregulation of NCC and ENAC. This allows these segments of the nephron to reclaim much of the Na⁺ that was lost in the urine

Function of the distal convoluted tubule (DCT)

Reabsorbs 5-8% of filtered Na⁺ and H₂O from the urine into the blood

Diuretics that work in the DCT

Thiazide diuretics and thiazide-like diuretics

Benefits of Thiazide and Thiazide-like Diuretics

Effective, cheap, mild side effects

Increased duration of action vs. loop diuretics

Compared to agressive diuresis (from loop diuretics), these are effective for long-term blood pressure lowering

Mechanism of Thiazide and Thiazide-like Diuretics

Bind to and inhibit the function of NCC (Na⁺ Cl^- Cotransporter), which leads to desired diuresis but also hypokalemia

Blocks the reabsorption/promotes the excretion of Na⁺

How do Thiazide and Thiazide-like Diuretics cause hypokalemia?

These diuretics inhibit NCC, increasing the amount of sodium and water delivered to the collecting duct, where a compensatory reabsorption of sodium occurs via ENaC. To balance the electrical gradient, more potassium is pumped from the blood into the urine via ROMK channels

• NOT by directly blocking potassium reabsorption

How does aldosterone amplify hypokalemia caused by thiazide and thizide-like diuretics?

Thiazide-diuretic induced volume loss leads to activation of RAAS. Aldosterone further boosts:

• Na⁺ reabsorption by increasing activity of ENaC

• K⁺ secretion by increasing activity of Na⁺/K⁺-ATPase

Similar to loop diuretics, thiazide and thiazide-like diuretics should not be used in patients with _____

Sulfa drug allergies

• Contain an aryl sulfonamide

• No alternatives in this class

How do thiazide and thiazide-like diuretics compare in terms of duration of action?

Thiazides

• Shorter (6-12 hours)

Thiazide-likes

• Longer (24-72 hours)

How do thiazide and thiazide-like diuretics compare in terms of potency?

Thiazides have moderate potency, while thiazide-likes have higher potency

How do thiazide and thiazide-like diuretics compare in terms of uses/indications?

Thiazides

• Routine HTN, mild edema

Thiazide-likes

• Resistant HTN, resistant edema

Hydrochlorothiazide is the most commonly prescribed thiazide diuretic and is commonly used in combination with _____

ARBs and ACEIs

Chlorothiazide is the only thiazide diuretic that is _____

Available IV

Why does chlorthalidone have a higher risk of hypokalemia and hyponatremia?

Long acting

• Half life of 40-60 hours

First line/preferred diuretic for hypertension

Chlorthalidone

How do thiazide diuretics affect blood calcium levels?

Increases calcium reabsorption from urine into the blood

What is the purpose of combining a loop diuretic with metolazone?

Synergistic drug combination

• Sequential nephron blocking

Powerful diuresis in resistant edema

What is the purpose of combining a thiazide diuretic with an ACEI or an ARB?

Counteracts thiazide hypokalemia

• ACEIs and ARBs cause hyperkalemia

Enhanced anti-HTN effects via multiple MOAs

What is the function of the final 1/3-1/2 of the DCT?

Final chance for Na⁺ and H₂O to be reabsorbed from the urine into the blood

Reabsorbs 2-3% of filtered Na⁺ and H₂O from the urine into the blood

Primarily executes Na⁺ exchange with K⁺

Dictates the final amount of K⁺ in the urine

How does aldosterone control electrolyte movement at the end of the DCT?

Binds to mineralocorticoid receptors to:

• Increase Na⁺ and H₂O retention in the blood

• Increase K⁺ secretion from the blood into the urine

What class of diuretics acts on the last 1/3-1/2 of the DCT

Potassium-sparing diuretics

Drug targets of potassium-sparing diuretics

Triamterene

• Blocks ENaC in the collecting duct

Spironolactone

• Mineralocorticoid Receptor Antagonist, but also binds to the Androgen Receptor and the Progesterone Receptor

Eplerenone

• Selective Mineralocorticoid Receptor Antagonist

How do potassium-sparing diuretics compare to other diuretics in terms of efficacy?

Lowest efficacy