Cardiac/Renal Pharm 2

100問 • 1年前

問題一覧

-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

Proximal Convoluted Tubule

-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

Descending Loop of Henle

-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

Ascending Loop of Henle

-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

Distal Convoluted Tubule

K+ Sparing Diuretics work here

Distal Tubule and Collecting Duct

Hydrochlorothiazide is the prototype drug

Thiazide Diuretics

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

Thiazide Diuretics

Twice as potent as HCTZ

Chlorthalidone

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

Indapamide and Metolazone

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

Metolazone

Thiazides cause ________

low K+, Low Na+, elevate the uric acid and can elevate BS

MOA of Thiazide Diuretics

-Act in the distal convoluted tubule to decrease resorption of Na+ -Cause diuresis with an increased Na+ and Cl- excretion, which causes a concentrated urine -Decrease Ca++ in the urine by promoting its reabsorption in the distal convoluted tubule

Thiazide Diuretic preferred for HTN

Chlorthalidone

Thiazide Diuretics used for HF

Metolazone or HCTZ (in combo with Loop Diuretics)

How do Thiazide Diuretics treat Hypercalciuria?

Inhibiting urinary Ca++ excretion

How can Thiazide Diuretics treat DI?

Because they can produce a hyperosmolar urine

Pharmacokinetics of Thiazide Diuretics

-Effective orally, with 60-70% bioavailabilty -Long 1⁄2 life [10- 15 hours] -Excreted in the urine

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

Chlorthalidone

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

Indapamide

How do Thiazide Diuretics case low potassium?

Thiazides increase Na+ in the filtrate, more K+ is also exchanged for Na+ resulting in a continual loss of K+ with prolonged use

How do Thiazide Diuretics cause low sodium?

Low Na+ develops from elevated ADH, and diminished diluting capacity of the kidney and increased thirst

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

Serum uric acid is increased by decreasing the amount of acid secreted through competition in the organic acid secretory system—use in caution in those with a history of gout or at risk for gout

How can Thiazide Diuretics cause Elevated Calcium?

They increase calcium reabsorpiton

How do Thiazide Diuretics cause Elevated Blood Sugar?

Due to impaired release of insulin from low K+

Prototype drug is Furosemide

Loop Diuretics

-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

Loop Diuretics

These Loop Diuretics have better bioavailability and are more potent

Bumetanide and Torsemide

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

Ethacrynic acid

MOA of Loop Diuretics

-Act on Loop of Henle (thick ascending limb) which is impermeable to water, and inhibit Na+/CL-,K+ transporter preventing Na+, Cl-, and K+ resporption and they are instead excreted in the urine -They also act on prostaglandins which dilate afferrent arterioles and increase renal plasma flow and GFR

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

Loop diuretics

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

NSAIDs

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

no duresis

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

frequency

How to loop diuretics increase urinary Ca++ excretion?

Loop diuretics increase Ca++ in the urine

How do Loop Diuretics cause Venodilation?

Before they cause diuresis, loop diuretics cause acute venodilation and reduce LVH filling pressures via enhanced prostaglandin synthesis

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

Loop Diuretics

Indications for Loop Diuretics

Edema, Hypercalcemia, and Hyperkalemia

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

Loop Diuretics

Pharmacokinetics of Loop Diuretics

-Given orally or IV -Furosemide has unpredictable bioavailability [10- 90%] when given PO, while Torsemide and Bumetanide have reliable 80-100% bioavailability when given PO -Duration of action for Lasix and Bumex is 6 hours—and moderately longer for Demadex

How do Loop Diuretics cause elevated uric acid?

Loops compete with uric acid and block it secretion

ADEs of Loop Diuretics

Acute hypovolemia, Low Potassium, Low Magnesium, Ototoxicity, and Elevated Uric Acid

ADEs of Thiazide Diuretics

Low Potassium, Magnesium, and Sodium, Elevated Uric Acid, Hypovolemia, Elevated Calcium and Blood Sugar

Triamterene is the prototype drug

Potassium Sparing Diuretics

-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

Potassium Sparing Diuretics that are hormone blockers

Spironolactone and Eplerenone

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

Spironolactone and Eplerenone

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

Eplerenone

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

Spironolactone

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

Spironolactone and Eplerenone

Often given with thiazides or loops to prevent K+ loss

Spironolactone and Eplerenone

Indications for Potassium Sparing Diuretics

Edema, Hypokalemia, HF, Resistant HTN, Acne, and Polycystic Ovarian Syndrome

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

Spironolactone and Eplerenone

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

Spironolactone and Eplerenone

Pharmacokinetics of Potassium Sparing Diuretics

-Well absorbed orally -Spironolactone extensively metabolized and converted to several active metabolites, which are part of its therapeutic effects -Eplerenone is metabolized by CYP 450 3A4

ADEs of Potassium Sparing Diuretics

-Hyperkalemia -Gynecomastia—Spironolactone

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

Triamterene and Amiloride

-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

Triamterene and Amiloride

MOA of Carbonic Anhydrase Inhibitors

-Acetazolamide inhibits carbonic anhydrase intracellularly and the apical membrane of the proximal tubular epithelium, ciliary body of the eyes, adn choroid plexus in brain ventricles -The decrease in exchange of Na+ for H+ in the presence of Acetazolamide results in a mild diuresis

What conditions do Carbonic Anhydrase Inhibitors treat?

Glaucoma, Gout, CSF leak, and Altitude Sickness

Pharmacokinetics of Carbonic Anhydrase Inhibitors

-Can be given orally or IV -90% protein bound and eliminated renally by both active tubular secretion and passive reabsorption

ADEs of Carbonic Anhydrase Inhibitors

-Mild metabolic acidosis -K+ depletion -Renal stones -Drowsiness -Paresthesias -Avoid in those with cirrhosis [it can cause decreased release of NH4+]

Prototype drug is Mannitol

Osmotic Diuretics

-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

Osmotic Diuretics

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

Osmotic Diuretics

Pathology of Heart Failure (1st Step)

increase in sympathetic activity begins

Pathology of Heart Failure (2nd Step)

activation of the RAAS

Pathology of Heart Failure (3rd Step)

activation of natriuretic peptides (atrial, B-type, C-type)

Pathology of Heart Failure (4th Step)

myocardial hypertrophy (HFrEF or HFpEF)

Therapeutic Strategies to Prescribe for HF

-Limit fluids [less than 1500 – 2000 cc/day] -Low salt diet [less than 2000 mg/day] -Treat comorbid conditions -Judicious use of diuretics -Avoid drugs that can precipitate HF—NSAIDs, ETOH, nondihydropyridine CCBs

Therapeutic Strategies to Prescribe for HFrEF

-Inhibition of RAAS inhibits the SNS which enhances the effects of natriuretic peptides that alleviate symptoms and improve outcomes -In some cases inotropes can be used for inpatients

DOC in HFrEF

ACE Inhibitors [Lisinopril—prototype]

-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

ACE Inhibitors [Lisinopril—prototype]

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

ARBs [Losartan—prototype]

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+.

Aldosterone Receptor Antagonists (Spironolactone and Eplerenone)

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

Aldosterone Receptor Antagonists (Spironolactone and Eplerenone)

How do Beta Blockers help to slow progression of HF?

They prevent changes that occur from chronic activation of the SNS

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

Bisoprolol, Carvedilol, Metoprolol Succinate ER

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]

Beta Blockers

Carvedilol and Metoprolol succinate are metabolized

CYP 450 2D6

Beta Blocker that is a substrate of p-glycoprotein

Carvedilol

These drugs interact with Beta Blockers and slow AV conduction

-Amiodarone -Verapamil -Diltiazem

-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

Beta Blockers

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

Diuretics

Are most commonly used in HF for symptom managment

Loop diuretics

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

Neprilysin

Sacubitril/Valsartan is the prototype

Angiotensin Receptor Neprilysin Inhibitors

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)

Neprilysin blocker

-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

Angiotensin Receptor Neprilysin Inhibitors

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

Angiotensin Receptor Neprilysin Inhibitors

Pharmacokinetics Angiotensin Receptor Neprilysin Inhibitors

-Orally active -Both components have a high Vd and are highly protein bound -Sacubitril is renally excreted, with a 1⁄2 life of 10°; drug is given BID

ADEs Angiotensin Receptor Neprilysin Inhibitors

-Similar to those see with the use of an ACEI or an ARB, but hypotension is more common -Angioedema; contraindicated in hereditary angioedema & previous angioedema from ACEI -ACEI must be stopped for at least 36° before starting the drug

The prototype is Ivabradine [Corlanor]

Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

Decreases HR by slowing depolarizaiton without decreasing contractility or BP

Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

-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

Actions of Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

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

Uses for Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

Pharmacokinetics of Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

-Taken with food to increase absorption -Extensive 1st pass metabolism by CYP P450 3A4 to an active metabolite, which is also a 3A4 substrate -High Vd and is 70% protein bound -1⁄2 life is 6 hours [requires BID dosing]

ADEs Hyperpolarization Activated Cyclic Nucleotide-Gated Channel Blockade

-Bradycardia -Not effective for rate control in AF—and has shown to increase the risk of AF -Vision changes -CI in pregnancy or breast-feeding -Avoid in advanced heart block or with potent 3A4 inhibitors

-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

Vaso and Veno Dilators

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

Hydralazine + Isosorbide dinitrate [BiDil]

100

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

BiDil

Patho Renal

Two Clean Queens · 100問 · 2年前

Patho Renal