Renal Pathophysiology and Diuretics Flashcards
Define diuretics
Agents that induce natriuresis (sodium excretion) and diuresis (water excretion)
Diuretics indications
- edematous states
- HTN
- heart failure
- acute renal failure
Common active ingredient in OTC diuretics
caffeine
Diuretic key principles
- osmosis: water follows salt
- when NA is excreted more than Na intake, BW and ECF decrease
- When Na excretion is equal to na intake, BW and ECF stabilize at lower level due to braking effect
- When Na excretion is less than Na intake, BW and ECF rise
Diuretic Braking Effect
The activation of the renin-angiotension-aldosterone system (RAAS) and symptomatic nervous system (SNS) when a new steady state is formed after Na excretion exceeds intake. There is a subsequent new steady state achieved where Na and excretion are equal but at a lower ECFV and body weight.
Classifications of diuretics (site of action, efficacy, structure, effect K+ excretion)
- site of action = loop diuretics
- efficacy = high-ceiling diuretics
- structure = thiazides
- effect K+ excretion = potassium-sparing
Site of diuretic drug action
in tubule
most diuretics have ____ protein binding —-> don’t filter through bowman’s capsule
high
most diuretics require transport/secretion in the _______ tubule
proximal
- drug interactions with renal transporters
- contrast many other drug classes (P450s)
T/F: Pharmacodynamic action doesn’t track with serum concentrations
TRUE
-correlates with renal excretion rates
Inhibitors of Carbonic anhydrase facts
- CA-I inhibit both cytoplasmic CA and membrane-bound CA
- CA-I essentially block reabsorption of NaHCO3
- H2O chases Na
Carbonic anhydrase catalyzes
OH- + CO2 –> HCO3-
Since H2O –> OH- + H+, and HCO3- + H+ –> H2CO3, the net reaction is H2O + CO2 —> H2CO3
Sulfanilamide shown to produce mild _____
diuresis
inhibitors of carbonic anhydrase causes urine to become more
basic, acid is blocked from being formed. The antiporter is blocked
Carbonic anhydrase inhibitors POTENCY
dichlorphenamide (30) >
Methazolamide (>1, <10) >
acetazolamide (1)
Carbonic anhydrase inhibitor inhibitors ORAL BIOAVAILABILITY
acetazolamide = methazolamide = 100% bioavailability
dichlorphenamide = ID
Carbonic anhydrase inhibitor inhibitors HALF-LIFE
acetazolamide = 6 - 9 hours
methazolamide = ~14 hours
dichlorphenamide = ID
Carbonic anhydrase inhibitor inhibitors ROUTE OF ELIMINATION
acetazolamide = R
methazolamide = ~25%, ~75% M
dichlorphenamide = ID
Carbonic anhydrase inhibitor inhibitors CLINICAL USES
- low efficacy
- acute mountain sickness
- metabolic alkalosis
- glaucoma
- urinary alkalinization
Carbonic anhydrase inhibitor inhibitors TOXICITIES
***hyperchloremic metabolic acidosis
- renal stones
- renal potassium wasting
- drowsiness / paresthesia
Cross sensitivity with diuretics and sulfonamide antimicrobials
- possibility but not contraindicated
- most patients with purported drug allergy do not react upon exposure
- rash is super rare
- no study confirmed cross-sensitivity
Osmotic diuretics facts
- pharmacologically inert
- non-reabsorbable substances that shift osmotic gradient/flow
- major site = loop of henle + PCT
- alternating renal medullary blood flow contributes to diuresis
Osmotic diuretics: Mannitol can cause
- loss of water
- reduced intracellular volume
- hypernatremia risk
IV delivered osmotic diuretics
Mannitol, urea
Orally active osmotic diuretics
isosorbide, glycerin, glucose
Osomotic diuretics act in regions of _____ water permeability
high
Thick ascending limb =
high ceiling diuretics
Inhibitors of Na+, -K+, -2Cl- Symport =
loop diuretics, high-ceiling diuretics
Inhibitors of Na+, -K+, -2Cl- Symport (loop diuretics) facts
- act on luminal surface symport –> must be in lumen for diuretic activity
- rapid response after IV admin
- most POTENT class (useful for edema)
- some possess weak CA inhibitory activity (e.g. furosemide)
- chronically reduce uric acid secretion
- problems with K, Ca, Mg reuptake
Most potent diuretic
inhibitors of Na+ -K+ -2Cl- Symport (loop diuretics)
Inhibitors of Na+, -K+, -2Cl- Symport (loop diuretics) Problems with
K, Ca, Mg reuptake
Inhibitors of Na+-K+-2Cl- Symport RELATIVE POTENCY
Bumetanide (40) > Torsemide (3) > Furosemide (1) > Ethacrynic Acid (0.7)
Inhibitors of Na+-K+-2Cl- Symport ORAL BIOAVAILABILITY
Bumetanide = 80%
Torsemide = 80%
Furosemide = 60%
Ethacrynic Acid = 100%
Inhibitors of Na+-K+-2Cl- Symport HALF-LIFE
Bumetanide = 0.8 hrs
Torsemide = 3.5 hrs
Furosemide = 1.5 hrs
Ethacrynic Acid = 3.5 hr
Inhibitors of Na+-K+-2Cl- Symport ROUTE OF ELIMINATION
Bumetanide = 62% r, 38% m
Torsemide = 20% R, 80% M
Furosemide = 65% R, 35% m
Ethacrynic Acid = 67% R, 33% M
Inhibitors of Na+-K+-2Cl- Symport CLINICAL USES
- edematous conditions
- acute pulmonary edema
- acute hypercalcemia
- hyperkalemia
- acute renal failure
- anion overdose
Inhibitors of Na+-K+-2Cl- Symport TOXICITIES
- dehydration (fluid intake important)
- hypokalemic metabolic alkalosis
- ototoxicity (rate of admin impt)
- hyperuricemia (gout)
- hypomagnesemia
Inhibitors of Na+-Cl- Symport (thiazide) facts
- predominantly increase NaCl excretion independent of CA
- Act primarily on DCT, proximal tubule secondary
- affects K+ reuptake
Thiazides originally CA inhibitors
-optimization for diuretic efficacy revealed alternate target
(-Na-K+-2Cl- Symport –> Na+Cl- Symport)
- work well but for the wrong reason
- two subclasses: Thiazide + hydrothiazide
Thiazide potency
Most potent = Polythiazide, Trichlormethiazide, Indapamide
Least potent = hydrochlorothiazide, hydroflumethiazide, chlorothiazide
Thiazide Clinical uses
- HTN
- Heart failure
- Nephrolithiasis due to idiopathic hypercalciuria
- nephrogenic diabetes insipidus
Thiazide Toxicities
- hypokalemic metabolic alkalosis
- hyperuricemia (secretion)
- impaired carbohydrate tolerance
- hyperlipidemia
- hyponatremia
Inhibitors of Renal Epithelial Na+ channels (aka K-sparing diuretics)
- act at late distal tubule and collecting duct
- agents are relatively weak diuretics
***primarily used in combination with other diuretics
-K sparing
Inhibitors of Renal Epithelial Na+ channels (aka K-sparing diuretics) RELATIVE POTENCY
Amiloride (1) > triamterene (0.1)
Inhibitors of Renal Epithelial Na+ channels (aka K-sparing diuretics) ORAL BIOAVAILABILITY
Amiloride = 15 - 25%
triamterene = 50%
Inhibitors of Renal Epithelial Na+ channels (aka K-sparing diuretics) HALF LIFE
Amiloride = 21 hours
triamterene = 4 hours
Inhibitors of Renal Epithelial Na+ channels (aka K-sparing diuretics) ROUTE OF ELIMINATION
Amiloride = r
triamterene = m (transformed into an active metabolite that is excreted in the urine)
Inhibitors of Renal Epithelial Na+ channels (aka K-sparing diuretics) CLINICAL USES
adjunctive treatment with thiazide or loop diuretic in heart failure or HTN
Inhibitors of Renal Epithelial Na+ channels (aka K-sparing diuretics) TOXICITIES
- hyperkalemia
- hyperchloremic metabolic acidosis
Inhibitors of Renal Epithelial Na+ channels (aka K-sparing diuretics) CONTRAINDICATIONS
- k+ supplements
- ACE inhibitors
Mineralocorticoid Receptor Antagonists (MRA) - (aka aldosterone antagonists, K-sparing diuretics) FACTS
- MRA bind to MR and block AIP production
- only diuretics that do not act within the tubular lumen
- Drugs need to be lipophillic to enter cells
- DRUGS LOOK LIKE STEROIDS!!!
Mineralocorticoid Receptor Antagonists (MRA) - (aka aldosterone antagonists, K-sparing diuretics) ORAL BIOAVAILABILITY
Spironolactone = 65%
other 3, ID
Mineralocorticoid Receptor Antagonists (MRA) - (aka aldosterone antagonists, K-sparing diuretics) HALF LIFE
- Spironolactone = 1.6 hrs
- Canrenone = 16.5 hrs
- Potassium = ID
- Eplerenone = 5 hrs
Mineralocorticoid Receptor Antagonists (MRA) - (aka aldosterone antagonists, K-sparing diuretics)
- Spironolactone = M
- Canrenone = M
- Potassium = M
- Eplerenone = M
Mineralocorticoid Receptor Antagonists (MRA) CLINICAL USES
- HTN
- Mineralocorticoid excess
- Aldosteronism (primary or secondary from HF, hepatic cirrhosis or nephrotic syndrome)
Mineralocorticoid Receptor Antagonists (MRA) TOXICITIES
- hyperkalemia
- hyperchloremic metabolic acidosis
- gynecomastia (due to blocking P450, blocks androgen)
- impotence
- BPH
Mineralocorticoid Receptor Antagonists (MRA) CONTRAINDICATIONS
- k+ supplements, ACE inhibitors
- chronic renal insufficiency
Non-specific Cation Channel Inhibitors (Nesiritide Natrecor)
- recombinant form of the 32 AA human B-type natriuretic peptide
- inhibits cGMP-gated cation channel
- therapeutic role in HF debated
(large peptide that interferes with ion channels)
Vasopressin Antagonists Facts
V1 = blood vessels constrict = increased systemic vascular resistance = increased arterial pressure
V2 = kidneys cause fluid reabsorption = increased blood bolume = increased arterial pressure
H2O REABSORPTION IS STOPPED
Vasopressin Antagonists are ______ potent diuretics
not very
Diuretic response: Action ______ correlate with serum/plasma concentrations
does not
Diuretic response: site of action is __________
luminal
CA inhibitors, furosemide and thiazide diuretics highly bound to plasma protein —> _________ not __________
secreted not filtered
Secretion (transporters) is saturable —> _________
Increased doses will not ______ urine
Consider changing ________ to increase response
Secretion of diuretics decreases with progressive renal failure —> _______ their effectiveness (drug doesn’t reach site of action)
DOSE DEPENDENT
increase
frequency
reduces
Sensitivity to diuretics is _______ due to homeostatic responses in CRF (including hyperaldosteronism)
reduced