-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

-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

-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

-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

K+ Sparing Diuretics work here

Hydrochlorothiazide is the prototype drug

Most widely used diuretics because of their diuretic effects reduce PVR with long term use They are sulfonamides—but do not usually cause a rash in those with known Sulfa allergies All drugs in the family work in the distal convoluted tubule and have equal diuretic effects—differ only in potency Low ceiling diuretics—increasing the dose above therapeutic dose does NOT cause more diuresis

Twice as potent as HCTZ

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

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

Thiazides cause ________

MOA of Thiazide Diuretics

Thiazide Diuretic preferred for HTN

Thiazide Diuretics used for HF

How do Thiazide Diuretics treat Hypercalciuria?

How can Thiazide Diuretics treat DI?

Pharmacokinetics of Thiazide Diuretics

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

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

How do Thiazide Diuretics case low potassium?

How do Thiazide Diuretics cause low sodium?

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

How can Thiazide Diuretics cause Elevated Calcium?

How do Thiazide Diuretics cause Elevated Blood Sugar?

Prototype drug is Furosemide

-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

These Loop Diuretics have better bioavailability and are more potent

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

MOA of Loop Diuretics

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

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

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

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

How to loop diuretics increase urinary Ca++ excretion?

How do Loop Diuretics cause Venodilation?

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

Indications for Loop Diuretics

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

Pharmacokinetics of Loop Diuretics

How do Loop Diuretics cause elevated uric acid?

ADEs of Loop Diuretics

ADEs of Thiazide Diuretics

Triamterene is the prototype drug

-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

Potassium Sparing Diuretics that are hormone blockers

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

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

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

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

Often given with thiazides or loops to prevent K+ loss

Indications for Potassium Sparing Diuretics

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

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

Pharmacokinetics of Potassium Sparing Diuretics

ADEs of Potassium Sparing Diuretics

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

-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

MOA of Carbonic Anhydrase Inhibitors

What conditions do Carbonic Anhydrase Inhibitors treat?

Pharmacokinetics of Carbonic Anhydrase Inhibitors

ADEs of Carbonic Anhydrase Inhibitors

Prototype drug is Mannitol

-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

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

Pathology of Heart Failure (1st Step)

Pathology of Heart Failure (2nd Step)

Pathology of Heart Failure (3rd Step)

Pathology of Heart Failure (4th Step)

Therapeutic Strategies to Prescribe for HF

Therapeutic Strategies to Prescribe for HFrEF

DOC in HFrEF

-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

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

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+.

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

How do Beta Blockers help to slow progression of HF?

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

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]

Carvedilol and Metoprolol succinate are metabolized

Beta Blocker that is a substrate of p-glycoprotein

These drugs interact with Beta Blockers and slow AV conduction

-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

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

Are most commonly used in HF for symptom managment

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

Sacubitril/Valsartan is the prototype

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)

-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

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

Pharmacokinetics Angiotensin Receptor Neprilysin Inhibitors

ADEs Angiotensin Receptor Neprilysin Inhibitors

The prototype is Ivabradine [Corlanor]

Decreases HR by slowing depolarizaiton without decreasing contractility or BP

-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

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

Pharmacokinetics of Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

ADEs Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

-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

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