Diuretics Flashcards
Diuretics
-agents that help the body get rid of sodium and water
-natriuresis (sodium excretion)
-diuresis (water excretion)
Diuretics and blood pressure
-dec blood pressure by decreasing plasma volume
-less burden on cardiovasc disease
Diuretic indications
-edematous states
-HTN
-Heart failure
-Acute renal failure
Is caffeine a diuretic?
-doses in drinks don’t have diuretic action
Membrane transporters
-convective flow
-simple diffusion
-channel-mediated diffusion
-carrier-mediated diffusion
-ATP-mediated transport (active)
-Symport (active)
-Antiport (active)
-which are likely tarets of diuretics
Classification of Diuretics
-sites of action
-efficacy
-structure
-effect on potassium excretion
-MOA
Classification of diuretics based on MOA
- inhibitors of carbonic anhydrase
- Osmotic Diuretics
- Inhibitors of Na-K-2Cl symport
- Inhibitors of NaCl symport
- INhibitors of renal Na channels
5b. Mineralcorticoid receptor antagonists
Transport of diuretics into proximal tubule
-high protein binding
-not filtered through Bowman’s (only unbound is filtered)
-transport/secretion into proximal tube
Active secretion in Proximal Tubule
-Organic Anion Transporter (OAT)
-Organic Cation Transporter (OCT)
Drugs secreted by Organic Anion Transport in proximal tubule
-Furosemide
-thiazides
-penicillin
-cephalosporin
-probenecid
-NSAIDs
Drugs secreted by Organic Cation Transport in proximal tubule
-Amiloride
-Cimetidine
-Digoxin
-Metformin
-Morphine
-Procainamide
-Quinidine
-Ranitidine
-Triamterene
-Trimethoprim
-Vancomycin
Active secretion in Prox tube mech (OAT and OCT)
- Diffusion out of capillary space into interstitial space
- Transport across basolateral membrane
- secretion across luminal membrane
-non-selective = competition
Active secretion depends on
-plasma protein binding
-rate of delivery of drug
-transporter saturation
-competing drugs
Probenecid
-secreted by OAT
-treats gout
-inc uric acid secretion
-competes w penicilin = slow excretion = prolong PCN activity (doubles blood concentration and exposure)
Penicillin
-secreted by OAT
-inhibit transpeptidase
-block crosslinking of peptidoglycans
-dec cell wall synthesis
-mostly cleared by kidneys unchanged
-was extracted and reused during WWII
-competition by probenecid at OAT to slow penicillin excretion and prolong activity
Inhibitors of Carbonic Anyhydrase
-inhibit cytoplasmic and membrane bound CA
-inhibit NaHCO3 reabsorption
=inc NaHCO3 excretion
Carbonic Anhydrase INhibitors SAR
-sulfanilamide derivatives
-high partition coefficient and lowest pKa have greater potency
-Sulfamoyl group essential
-sulfamoyl N unsubstituted to reatin activity
Carbonic Anhydrase Inhibitor Drugs
-Acetazolamide
-Dichlorphenamide
-Methazolamide
Carbonic Anhydrase Inhibitor Drug Uses
-low diuretic efficacy
-acute mountain sickness
-metabolic alkalosis
-glaucoma
-urinary alkalinization
Carbonic Anhydrase Inhibitor Drug Toxicities
-hypercloremic metabolic acidosis
-renal stones
-renal potassium wasting
-drowsiness/paresthesia
Acute Mountain sickness tx
-acetazolamide prophylactically several days before ascent above 10,000 feet
-metabolic acidosis produced by the drug counteracts the respiratory alkalosis that can result from hyperventilation
diuretic and sulfonaimde antimicrobials cross-sensitivity
-most pt do with drug allergy don’t react
-Sulfa rash in 5-10% of pt (rare in diuretics)
-withholding sulfamoyl containing diuretics from pt with hx of sulfonamide allergy is not justified
Osmotic Diuretics
-inc H2O excretion
-renal prox tubule
-descending limb of loop of henle
-pharmacologically inert
-non-reabsorbable substances shifting osmotic flow
-alter renal blood flow
Osmotic diuretic drugs
-Mannitol (IV)
-Urea (IV)
-Glucose
-Isosorbide
-Glycerine
Mannitol side effects?
-loss of water
-reduced intracellular volume
-hypernatremia risk
Osmotic SAR and MOA
Na-K-2Cl symport Inhibitors
-inc Na, K, Cl
-loop diuretics and high ceiling diuretics
-thick ascending limb
Na-K-2Cl inhibitors
-act on luminal surface symport = must be in lumen for diuretic activity
-rapid response after IV admin
-most potent class (useful for edema)
-some have weak CA inhibitory activity
-Chronically reduce uric acid secretion
-problems w K, Ca, Mg reuptake
Na-K-2Cl symport inhibitor SAR
-1 position must have acidic substitent (carboxyl best, tetrazole)
-sulfamoyl group at 5 is essential
-activating group at 4 (Cl, CF3, phenoxy, alkoxy, anilino, benzyl, benzoyl group
Na-K-2Cl symport inhibitor drugs
-Furosemide
-Bumetanide
-Ethacrynic acid
-Torsemide
Na-K-2Cl symport inhibitor drug use
-edema
-acute pulmonary edema
-HTN, HF
-acute hypercalcemia
-hyperkalemia
-acute renal failure
-anion overdose
Na-K-2Cl symport inhibitor drug toxicities
-dehydration
-hypokalemic metabolic alkalosis*
-Ototoxicity*
-hyperuricemia
-hypomagnesmia
Ethacrynic Acid (Edecrin)
-Na-K-2Cl symport inhibitor
=not derived from sulfonamides
-alkylates thiols to give the sulfhydryl-containing conjugates that are diuretics
-prodrug?
-structure?
NaCl symport inhibitors
-inc NaCl excretion
-thiazides
-DCT, PCT secondary
-enhance potency of CA-I
-reduce K reuptake
SAR of thiazides (NaCl inhibitor)
-slide 30
-sulfaniliamide to acetazolamide to dichlorphenamide to chlorothiazide
-2 rings
NaCl inhibitor drug classes
-Thiazide (acylating agent)
-Hydrothiazide (aldehyde or ketones)
NaCl inhibitor drugs
-Chlorothiazide
-Hydrochlorothiazide
-Chlorothalidone
-Metolazone
NaCl inhibitor drug use
-HTN
-HF
-nephrolithiasis due to hypercalciuria
-nephrogenic diabetes insipidus
NaCl inhibitor drug toxicities
-Hypokalemic metabolic acidosis
-hyperuricemia
-hyperglycemia
-impaired carbohydrate tolerance
-hyperlipidemia
-hyponatremia
The post-discharge therapy included a substitution of hydrochlorothiazide
with furosemide. Which of the following statements best explains why loop
diuretics are far more effective than thiazide diuretics?
More sodium is physiologically reabsorbed at the loop of Henle than at the
distal convolute tubule.
Renal Epithelial Na channel inhibitors
-potassium-sparing diuretics
-late DCT and collecting duct
-weak diuretics
-used in combo w other diuretics
Renal Epithelial Na channel inhibitor drugs
-Amiloride
-Triamterene
Renal Epithelial Na channel inhibitor drug use
-adjunctive tx w thiazide or loop diuretic in HF or HTN
Renal Epithelial Na channel inhibitor drug toxicities
-Hyperkalemia*
-Hyperchloremic metabolic acidosis
Renal Epithelial Na channel inhibitor drug contraindications
-K+ supplements
-ACE inhibitors
Mineralcorticoid Receptor Antagonists (MRA)
-aldosterone antagonists
-potassium-sparing diuretics
-inc Na excretion
-inc K retention
-bind to MR but don’t stimulate AIP production
-only diuretics that do not act within the tubular lumen!
MRA drugs
-spironolactone
-canrenone
-potassium canrenoate
-eplerenone
MRA toxicities
-Hyperkalemia
-Hyperchloremic metabolic acidosis
-Gynecomastia
-impotence
-benign prostatic hyperplasia
MRA drug use
-HTN or HF w other diuretics
-excess mineralcorticoids
-Aldosteronism
MRA drug contraindications
-K supplements
-ACE inhibitors
-Chronic renal insufficiency
PK and PD determinants of diuretic response
-luminal (not MRAs)
-CA-I, furosemide and thiazide are highly bound to plasma protein (secreted not filtered)
-secretion is saturable (dose-dependent)
-secretion decreases with renal failure (reduced efficacy)
-sensitivity to diuretics reduced bc homeostatic responses in CRF (inc hyperaldosteronism)
Diuretic site of action
-luminal
-except MRAs
Diuretic secretion
-CA-I, furosemide, thiazide (not filtered bc bound to plasma protein)
-saturable (dose-dependent)
-dec with renal failure
Braking Phenomenon
-Osmosis (water follows salts)
-when Na excretion > Na intake, BW and ECF decrease
-activation of RAAS and SNS
-BW and ECF stabilize at output=input
-BW and ECF rise when output<input
Diuretic responsiveness in HF
-reduced
-diuretics can;t manage pt well as HF progresses
Diuretic responsiveness in CRF
-potency shifts
-efficacy can be obtained w increased dose
Combining diuretics w different MOAs
-more effective than dose inc of single agent
Slide 44
Slide 44
CA I Drugs to know
Acetazolamide
Osmotic diuretics to know
Mannitol
Loop diuretics to know
-Furosemide
-Bumetanide
-Torsemide
-Ethacrynic acid
Distal tubule diuretics to know
-Hydrochlorothiazide
-chlorthalidone
-metolazone
K-sparing diuretics to know
-NaCl I: amiloride and triamterine
-Aldosterone Antagonists (MRA): spirinolactone and eplerenone
chart on slide 45
chart on slife 45
A 55-year-old male with kidney stones has been placed on a
diuretic to decrease calcium excretion. However, after a few weeks,
he develops an attack of gout. Which diuretic was he taking?
-thiazides associated w elevated SUA levels
Question: An 83-year-old man has been effectively treated with
hydrochlorothiazide to control his elevated blood pressure. He has
had a recent onset of weakness. Blood chemistry analysis reveals
hypokalemia. Another drug is added, and 1 month later his serum
K+ is normal. Which of the following drugs most likely helped
normalize his serum potassium levels?
Amiloride
Question: A patient taking an oral diuretic for about 6 months
presents with elevated fasting and postprandial blood glucose
levels. You suspect the glycemic problems are diuretic-induced.
Which of the following was the most likely cause?
Hydrochlorothiazide
Question: A patient with severe infectious disease is being treated
with an aminoglycoside antibiotic. Which of the following diuretics
should be avoided, if possible, because of the risk of a serious
common and additive adverse effect?
-Furosemide
aminoglycoside antibiotic
-gentamicin
-protein synthesis inhibitor
-avoid with loop diuretics
-ototoxic and nephrotoxic
