HTN Lapinsky 1

What is diuresis?

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

• AKA process of increased urine formation & excretion from body

What are the thiazide-type diuretics?

• Chlorthalidone

• Hydrochlorothiazide

• Chlorothiazide (Diuril)

• Indapamide

• Matolazone

What are the potassium-sparing diuretics?

• Spironolactone (Aldactone, CaroSpir)

• Triamterene (Dyrenium)

  • & Hydrochlorothiazide (Maxzide, Maxzide-25)

• Amiloride

• Eplerenone (Inspra)

What are the loop diuretics?

• Furosemide (Lasix, Furoscix)

• Bumetanide (Bumex)

• Torsemide (Soaanz)

• Ethacrynic Acid (Edecrin)

What does a kidney contain?

Approximately 2 million nephrons, which are responsible for filtering blood & regulating blood & urine levels of multiple chemical species (H2O, K+, Na+, Ca2+, Cl-)

What is filtration?

Blood to tubule

What is reabsorption?

Tubule to blood

What is secretion?

Blood to tubule

What is excretion?

Tubule to external environment

What is hypokalemia?

• Caused by losses (GI, diuretics) or intracellular shift

• Causes ventricular arrhythmias

• Loop & thiazide diuretics, beta2 agonists cause

What is hyperkalemia?

• Caused by reduced renal excretion or potassium-retaining drugs

• Causes conduction block → cardiac arrest

• Ace-I/ARBs, potassium-sparing diuretics (spironolactone, eplerenone, amiloride, triamterene) cause

What do loop diuretics act on?

Ascending limb of nephron loop to block reabsorption of sodium, chloride, & water

• Excretion of potassium is increased

What do thiazide diuretics act on?

Early DCT to block reabsorption of sodium, chloride, & water

• Excretion of potassium is increased

What do potassium-sparing diuretics act on?

Late DCT & collecting ducts to block reabsorption of sodium & reduce secretion of potassium (sodium-potassium exchange)

• Excretion of potassium is not increased

What can a pt w/ acute heart failure not do?

Breath b/c their lungs are filling w/ fluid

• Heart suddenly cannot pump enough blood effectively, causing fluid to rapidly back up into the lungs

What can IV furosemide dramatically improve breathing w/in?

Minutes

What is the 1 job of a loop diuretics?

Remove excess Na+ from body

→ no reabsorption of Na+ from urine back into blood in kidneys

→ MASSIVE Na+ & H2O excretion from body

→ Decreases blood volume

→ Reduced preload (amount of blood returning to heart before it pumps)

→ Less pulmonary edema

→ Patient breathes easier

What is the key concept about Na+ & H2O?

Na+ leads, H2O follows

What does everything start w/ for ALL diuretics (“water pill”)?

Na+

• Diuretics do not “remove water”

• Rather, diuretics remove Na+ & H2O simply follows!

Where does a loop diuretics work w/in nephron of a kidney?

Thick ascending limb of Loop of Henle

What protein does a loop diuretic bind to & inhibit w/in nephron of a kidney?

Na+/K+/2Cl- co-transporter = NKCC2

Compared to all classes of diuretics, why do loop diuretics produce the most powerful (greatest amount) diuresis?

B/c noted transporter protein normally reabsorbs ~25 of filtered Na+ from urine back into blood at this anatomical location, which is greatest amount of Na+ (H2O) reabsorbed by ANY diuretic drug target w/in kidney

What are 2 most common uses of loop diuretics?

1. Addressing acute pulmonary or peripheral edema

• Compared to thiazide & potassium-sparing diuretics, loop diuretics

  • Have a rapid onset of onset (IV emergency use= ~5 minutes; oral= 30-60 mins)

  • Produce a massive acute rescue diuresis

2. Treatment of chronic HTN (HTN; increased BP)

• Loop diuretics have relatively short duration of actions (~4-6 hours), which can limits their use to some extent for clinical indication (too short to provide reliable 24-hour BP control)

What are the loop diuretics known as?

“Emergency” diuretic

What are the thiazide diuretics known as?

“Maintenance” diuretics

What happens w/ less reabsorption of Na+ & H2O from urine back into blood in kidneys?

Decreased blood volume

→ Decreased cardiac preload

→ Lower BP

What drugs would be avoided w/ a “sulfa” drug allergy?

• Furosemide

• Bumetanide

• Torsemide

What may ethacrynic acid be preferred in?

Pts w/ a history of a severe aryl sulfonamide drug allergy

What does “sulfa” drug allergy refer to?

Immune system reaction to certain medications that contain an acyl sulfonamide

• Allergy can range from mild rashes to severe, life-threatening reactions

What are the most common offenders of immune system reactions to aryl sulfonamide-containing drugs?

Sulfonamide antibiotics (Sulfamethoxazole w/in Bactrim/Septra)

What may other sulfonamide-containing drugs (loop & thiazide diuretics, sulfonylureas, Celecoxib (COX2 (-)) usually?

NOT cross-reactive BUT severe allergy → many clinicians choose ethacrynic acid

What rare but serious adverse effect is uniquely associated w/ loop diuetics?

Ototoxicity (ear)

What loop diuretic is highest risk/most notorious for this?

Ethacrynic acid

What may ototoxicity present itself as?

• Hearing loss, tinnitus (a perception of ringing, buzzing, hissing, or clicking sound in ears/head w/o an external sound source)

• &/or vertigo (a medical condition that causes a sensation of spinning/whirling, as if environment/oneself is moving due to an imbalance in inner ear’s vestibular system, which is responsible for maintaining balance)

What is the mechanism for ototoxicity?

Loop diuretics share a similar drug target in kidney/nephron vs. ear

• Desired loop diuretic drug target in thick ascending limb of LoH= NKCC2

• Undesired loop diuretic drug target present in stria vascularis of inner ear that drives normal hearing= NKCC1

What risk factors should clinicians & pharmacists by concerned about here?

• High doses &/or rapid IV administration (IV furosemide; >4mg/min= increased risk of ototoxicity)

  • Loop diuretics reach inner rapidly & can concentration there

• Additive risk via concurrent use alongside other ototoxic drugs

  • Most notoriously in pharmacy/medicine= aminoglycoside antibiotic, Cisplatin

What usually happens to ototoxicity after stopping the loop diuretic?

Reversible but can be irreversible at very high doses or w/ additive risks

Where does a thiazide diuretics work w/in the nephron of a kidney?

Distal Convoluted Tubule (DCT)

What is the drug target for a thiazide diuretic?

Na+/Cl- co-transporter (NCC)

How do thiazide diuretics compare to loop diuretics in terms of diuretic efficacy (aka ceiling)?

Amount of Na+ (& H2O) reabsorbed from urine back into blood

• Loop: 20-25%

• Thiazide: only 5-8%

What is responsible for this difference in diuretic efficacy w/ thiazide diuretics vs. loop diuretics?

• Loop diuretics’ drug target: NKCC2

  • High diuretic efficacy

  • Max urine output: massive

• Thiazide diuretics’ drug target: NCC

  • Low-moderate efficacy

  • Max urine output: moderate

What are the uses for loop diuretics?

• Heart failure

• Pulmonary edema

• Severe edema

What is the use for thiazide/thiazide-like diuretics?

Chronic uncomplicated HTN

What is a stronger diuretic (loop) NOT necessarily than thiazide diuretics?

Better hypertensive!

What are heart failure, pulmonary edema, & severe edema primarily a problem of?

Fluid

What is chronic uncomplicated HTN primarily a problem of?

Vascular (blood vessels) resistance

Why are thiazide diuretics better for treating chronic uncomplicated HTN than loop diuretics?

• First, it is important to recognize that blood volume depletion via a diuretic is continuously opposed by a number of compensatory mechanisms to raise BP & normalize blood volume (RAAS, SNS, ADH)

• Second, key difference b/w loop & thiazide diuretics in treatment of chronic uncomplicated HTN is what happens over weeks-months(!) (not acute) of treatment w/ a given diuretic

What can thiazide diuretics develop in sharp contrast to loop diuretics?

Additional BP-lowering effects(!) over weeks-months of treatment, such as:

1. Decreased peripheral vascular resistance

2. Improved vascular smooth muscle relaxation

3. Reduced responsiveness to a variety of vasoconstrictors

How do thiazide diuretics lower BP by?

Reducing peripheral vascular resistance over long-term via **chronic vascular remodeling**

What do loop diuretics mainly produce?

Short-lived blood volume loss via massive natriuresis (& diuresis)

• Do NOT consistently produce chronic vascular remodeling like thiazide diuretics!

What is the best clinical use in loop vs. thiazide diuretics?

• Loop: heart failure, pulmonary edema, severe edema

• Thiazide: chronic uncomplicated HTN

What is the primary problem solved in loop vs. thiazide diuretics?

• Loop: too much fluid!

• Thiazide: too much vascular resistance!

What is the “type of drug” in loop vs. thiazide diuretics?

• Loop: “kidney drugs”

• Thiazide: “kidney & blood vessels drugs”

What is the initial effect (days) in loop vs. thiazide diuretics?

• Loop: decreased blood volume → decreased BP

• Thiazide: decreased blood volume → decreased BP

What is the long-term effect (weeks) in loop vs. thiazide diuretics?

• Loop: mainly continued natriuresis

• Thiazide: **decreased peripheral vascular resistance**

What is the effect on blood vessel over time in loop vs. thiazide diuretics?

• Loop: minimal chronic change

• Thiazide: arteries become less constricted (but mechanism incompletely understood)

What is the major determinant of long-term BP lowering in loop vs. thiazide diuretics?

• Loop: fluid removal

• Thiazide: **vasodilation!**

What is the duration of action in loop vs. thiazide diuretics?

• Loop: usually shorter

• Thiazide: typically longer (helps, but does not fully explain difference concerning BP management)

What is the mental model in loop vs. thiazide diuretics?

• Loop: “empties the tank”

• Thiazide: “widens the pipes”

What is the key point to remember in loop vs. thiazide diuretics?

• Loop: “removes fluid”

• Thiazide: “lowers vascular resistance”

What is the key point to calcium in loop vs. thiazide diuretics?

• Loop: “lose calcium”

• Thiazide: “save/spare calcium”

What is the effect on Ca2+ reabsorption from urine back into blood in loop vs. thiazide diuretics?

• Loop: decreased

• Thiazide: increased

What is the effect on amount of Ca+ in urine in loop vs. thiazide diuretics?

• Loop: increased

• Thiazide: decreased

What is the calcium kidney stones in loop vs. thiazide diuretics?

• Loop: may increase urinary calcium kidney stone risk

• Thiazide: helps prevent recurrent urinary calcium kidney stones

What is the bone health in loop vs. thiazide diuretics?

• Loop: chronic use may lead to bone loss & fractures

• Thiazide: can increase bone mineral density & decreased fracture risk

What is the diuretic choice if pt has hypercalcemia?

Loop

What is the diuretic choice if pt has recurrent calcium kidney stones?

Thiazide

What is the diuretic choice if pt has osteoporosis or fracture risk?

Thiazide