-Block Na+, K+, Cl- resorption in the kidneys -Decrease PVR and increase renal blood flow -Cause low potassium in the serum, but increase the Ca++ content of the urine -Work in the ascending loop of Henle—of all diuretics, they mobilize Na+ and Cl- from the body, producing large volumes of urine

Indications for Loop Diuretics

Prototype drug is Mannitol

-Given IV -ADEs—dehydration, extracellular water expansion [Mannitol in the extracellular fluid extracts water from the cells and causes hyponatremia until diuresis occurs]

How do Thiazide Diuretics cause Elevated Uric Acid [serum]?

How do Thiazide Diuretics case low potassium?

-Reduction in HR without a reduction in contractility, AV conduction, ventricular repolarization and BP -In those with HFrEF, a slower HR increases stroke volume and improves symptoms

Blocks the effects of both aldosterone and androgen— causing the retention of K+ and the excretion of Na+ and has some beneficial endocrine effects

DOC in HFrEF

How do Thiazide Diuretics cause Elevated Blood Sugar?

Therapeutic Strategies to Prescribe for HF

In HF, aldosterone levels are elevated, from angiotensin II stimulation and reduced liver clearance of the hormone. These drugs prevent Na+ retention, cardiac hypertrophy and low K+.

_______ has been shown to improve symptoms and survival in Aortic Aneurysm patients with HFrEF on standard HF therapy [BB + ACE or ARB]

Pharmacokinetics of Thiazide Diuretics

ADEs of Carbonic Anhydrase Inhibitors

Potassium Sparing Diuretics that are hormone blockers

K+ Sparing Diuretics work here

ADEs of Potassium Sparing Diuretics

Like in acne—blocking androgen receptors and inhibiting steroid synthesis at high doses, helps to lower elevated androgen levels seen in polycystic ovarian syndrome

These Loop Diuretics have better bioavailability and are more potent

Pharmacokinetics Angiotensin Receptor Neprilysin Inhibitors

Beta Blocker that is a substrate of p-glycoprotein

Pathology of Heart Failure (2nd Step)

-K+ sparing diuretics work here -Cells of this part of the kidney are impermeable to water -5-10% of the filtered NaCl is reabsorbed here

To get the best effect of these peptides—stimulation of the RAAS must be offset without any increase in bradykinin—therefore, and ARB is combined with this drug class (reduce risk of angioedema)

-These agents reduce preload—which decreases cardiac workload and O2 demand -They also decrease afterload by reducing plasma volume

Prototype drug is Furosemide

-Leads to natriuresis, diuresis, vasodilation and prevention of fibrosis -Decreases preload, afterload and myocardial fibrosis -Improve survival and signs/symptoms of HF—as compared to an ARB or ACEI

-They decrease HR -They inhibit release of renin from the kidneys -They prevent the negative effects of norepinephrine on the cardiac fibers -They decrease remodeling, hypertrophy and myocardial cell death

Is a enzyme responsible for breaking down he vasoactive peptides, such as angiotensin I, angiotensin II, bradykinin and natriuretic peptides—blocking this enzyme ugments the activity of these vasoactive peptides

-Pulls H2O from cells in the body transporting them to the kidnesy and increasing renal flow and preventing H20 reabsorption in the proximal tubule and thin desceding tubule causing increase in flow rate and less time for Na+ to be reabsorbed - little Na+ loss but +++H2O loss! -Not used for treating conditions in which Na+ retention occurs—used to maintain urine flow after acute toxic ingestion of substances that can cause renal failure -Also used to treat patients with increased ICP

DOC for pulmonary edema and acute/chronic peripheral edema from HF or renal impairment, and for HF

Thiazide-like but, MOA, indications, and ADEs are similar to HCTZ

Therapeutic Strategies to Prescribe for HFrEF

Thiazide Diuretics used for HF

If your patient is intolerant to an ACEI or an ARB, and more vasodilation is needed—a combination of __________ can be prescribed

ADEs of Loop Diuretics

-They have a K+ sparing effect, much like the aldosterone blockers, but their ability to block the Na+/K+ exchange site in the collecting tubule DOES NOT depend on aldosterone -Neither of these are potent diuretics -Are both used with other diuretics for the purpose of their K+ sparing effects

Has a lower bioavailability than other Thiazide Diuretics [15-30%]—and the only thiazide with an IV form

MOA of Loop Diuretics

Pharmacokinetics of Loop Diuretics

Thiazides cause ________

How can Thiazide Diuretics cause Elevated Calcium?

-Carbonic Anhydrase Inhibitors work here -65% of filtered Na+ and water is reabsorbed here -Diuretics working here display weak diuretic effects -This area of the kidney is also the site of the organic acid and base secretory systems

Triamterene is the prototype drug

Pathology of Heart Failure (1st Step)

Thiazide Diuretic preferred for HTN

A dose of loop diuretics must be prescribed to cross the response threshold [patient specific], reducing the dose below this threshold will result in _______

Pharmacokinetics of Potassium Sparing Diuretics

Is the only thiazide that is metabolized in the liver and excreted in the urine and feces

These drugs interact with Beta Blockers and slow AV conduction

How to loop diuretics increase urinary Ca++ excretion?

_______ are excreted into the tubular lumen at the proximal convoluted tubule to be effective

How can Thiazide Diuretics treat DI?

Pharmacokinetics of Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

How do Thiazide Diuretics treat Hypercalciuria?

Are standard of care in patients with symptomatic HFrEF or HFpEF and in those with a recent MI

-These drugs inhibit epithelial sodium transport at the distal and collecting duct -These agents reduce K+ loss in the urine and antagonize aldosterone—thus decreasing remodeling see in HF -These agents must be used with caution in those with moderate renal dysfunction— and avoided in those with severe CKD -Within the class there are drugs that antagonize aldosterone while the others are epithelial Na+ channel blockers

-Start at low dose and titrate to the maximally tolerated dose -Used in asymptomatic & symptomatic HFrEF -Indicated for patients with ALL stages of LV failure -Those who have had an MI or are at high risk for a CV event benefit from these drugs

Pathology of Heart Failure (3rd Step)

ADEs of Thiazide Diuretics

How do Loop Diuretics cause Venodilation?

With the exception of _______, all thiazides require a GFR of >30 cc/min in order to be effective

Carvedilol and Metoprolol succinate are metabolized

How do Thiazide Diuretics cause low sodium?

In high doses can be used in edema in those with secondary hyperaldosteronism—hepatic cirrhosis and nephrotic syndrome

ADEs Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

Is more selective for aldosterone receptors [and no endocrine effects—such as gynecomastia]

MOA of Thiazide Diuretics

______ inhibit renal prostaglandin synthesis and reduce the diuretic effect of thiazide and loop diuretics

Indications for Potassium Sparing Diuretics

Increasing the dose of loop diruetics may not result in more diuresis because of a ceiling effect—thus after the prescriber has determined an effective diuretic dose you modify the ________ to get more or less daily diuresis

-Three Beta Blockers that are considered DOC in HFrEF -One of these drugs should be Rx in stable HFrEF

MOA of Carbonic Anhydrase Inhibitors

Lower Ca++ in the plasma because cause Ca++ excretion

Pharmacokinetics of Carbonic Anhydrase Inhibitors

These Loop Diuretics are not often used due to their severe adverse drug effects

The prototype is Ivabradine [Corlanor]

-Loop Diuretics work here -Dilutes the tubular fluid and raises the osmolarity of the medullary interstitium -25-30% of the filtered NaCl is absorbed here -Drugs that work here have the greatest diuretic effects

Twice as potent as HCTZ

ADEs Angiotensin Receptor Neprilysin Inhibitors

Often given with thiazides or loops to prevent K+ loss

Reduce afterload and preload as does an ACEI; use in HF is mainly as a substitute in those who cannot take an ACEI

How do Beta Blockers help to slow progression of HF?

-Osmotic Diuretics work here -Remaining filtrate, which is isotonic, next enters the descending limb of the loop of Henle -The osmolarity increases along the descending portion—this causes a fluid with a 3 fold increase in Na+ and Cl- concentration

Are most commonly used in HF for symptom managment

Hydrochlorothiazide is the prototype drug

These drugs are synthetic steroids that block aldosterone receptors— this causes Na+ loss and K+ and H+ retention

Pathology of Heart Failure (4th Step)

Replaces and ACEI or ARB in those with HFrEF who are still symptomatic on maximum medical therapy with a BB + ACEI [or ARB]

What conditions do Carbonic Anhydrase Inhibitors treat?

To improve symptoms of HFrEF [on maximal medical therapy]— specifically those on maximum dose of a BB or have a contraindication to a BB

Decreases HR by slowing depolarizaiton without decreasing contractility or BP

Potassium Sparing Diuretics that block the epithelial sodium channels (ENaC)

Sacubitril/Valsartan is the prototype

Aldosterone blockers at low doses prevent the myocardial remodeling mediated by aldosterone, and decrease mortality in low EF HF

How do Loop Diuretics cause elevated uric acid?

-Hydralazine is the prototype drug -Dilating venous vessels leads to decreased cardiac preload -It reduces SVR and decreases afterload -ADEs—headache, dizziness, hypotension -Rarely, is has been associated with drug-induced lupus

Start these drugs at low dosages and gradually titrate up to a dose that is tolerable for the patient [or up to a resting HR of 50 – 60]