Diuretics Flashcards
How kidneys control ECF volume
Adjusting NaCl and H2O excretion
Diuretics
Increase urine volume and increase Na excretion and Cl excretion
Acetazolamide
Acts on PCT
CA inhibtor
Inhibits 85% of NaHCO3 reabsorption
Mannitol
Osmotic diuretic
Limits water reabsorption in water-permeable segments of nephron (PCT, thin descending limb, and CT with ADH)
Furosemide
Loop diuretic
Inhibits Na/K/2Cl cotransport in thick ascending limb
Thiazides
Inhibit NaCl co-transport in DCT
K sparing diuretics
Act on CT
Inhibition aldosterone actions or directly blocking Na channels
ADH antagonist
Prevent ADH-stimulated reabsorption of H2O in collecting tubulue
Diuretic Pharmacology
Primarily preventing Na entry into tubule cell
Diuretics enter tubule fluid, site of action determines which electrolyes will be affected
EXCEPT for spironolactone and some ADH antagonists, diuretics generally exert effects on luminal side of nephron
Entry into tubule
Mannitol: filtration at the glomerulus
Most other diuretics are tightly protein bound- get secreted across proximal tubulue (organic acid or base secretory pathway)
Tubule epithelial cells
Have Na/K ATPase on basolateral (blood) side
Pumps 3 Na out and 2 K in
Keeps Na concentration down so Na will leave lumen
Luminal side has pathways for passive movement of Na down its electrochemical gradient (Na/H exchangers)
Acetazolamide
MoA
Reversible inhibition of CA
Inhibits reabsorption of HCO3 in proximal tubule (more is peed out, less HCO3 in blood, blood more acidic)
Na accompanies HCO3 as it is excreted, and water goes with
Acetazolamide
Pharmacokinetics
Well absorbed PO
Effect begins within 30 minutes, max at 2 hours, duration 12 hours
Renally secreted via organic acid transporter
Acetazolamide
Adverse Effects
Metabolic acidosis
Hypokalemia
Ca phosphate stones
Drowsiness, paresthesia, hypersensitivity rxns
Acetazolamide
Contraindications
Cirrhosis (increased urine pH reduces NH3 secretion and increases serum NH3)
Tubular fluid is more alkaline (from the extra bicarb), NH3 is less likely to be protonated to NH4 and trapped/excreted. Goes back into blood
Acetazolamide
Clinical Indications
Weak diuretic agent, good as backup
Glaucoma
Urinary alkalinazation: drug overdose/stone removal
Acute mountain sickness: this drug can buy some time by acidifying the blood and reducing hemoglobin’s affinity to O2, releasing it to tissues. Also acidifying blood increases ventilation
Other CA inhibitors
Dichlorphenamide (30x more potent than acetazolamide)
Methazolamide (5x more potent)
Dorzolamide (topical for ocular use, reduces pressure)
Mannitol
MoA
Osmotic diuretic
Proximal tubulue and descending loop of Henle, collecting ducts (with ADH present)
IV causes expansion of IV volume
Powerful diuretic once it reaches the kideny
Mannitol
Pharmacokinetics
NOT ORALLY ABSORBED
Must be injected IV to reach kidney
1/2 life is 1.5 hours
Mannitol
Adverse Effects
If kidney filtration is impaired
More mannitol stays in blood, increases blood volume, capillary filtration, more fluid in ECS, hyponutremia, edema
Acute pulmonary edmea, dehydration, headache, nausea, vomiting
Mannitol
Contraindications
Congestive heart failure
Renal failure
Pulmonary edema
Mannitol
Clinical Indications
Maintain or increase urine volume Used in acute renal failure May promote renal excretion of toxic substances (dyes, drugs) Reduce intracranial pressure Reduce intraocular pressure
Thick Ascending Limb of Loop of Henle
Impermeable to H2O
Na/K/2Cl cotransporter
Na gradient from Na/K ATPase drives the gradient
Influx of K from both sides raises the intracellular [K]
K diffuses back into the lumen creating a (+) charge in lumen
(+) charge in lumen causes Mg2+ and Ca2+ to leave lumen via paracellular diffusion
Loop Diuretics
MoA
Big one: Furosemide (LASIX)
Block Na/K/2Cl transporter in apical membrane
More Na and K in lumen, urine is more diluted (more fluid stays in lumen)
Increases excretion of Na, K, Ca, Mg, and water
MOST EFFECTIVE CLASS
Also, something with prostaglandin production, causes renal venodilation
Loop Diuretics
Pharmacokinetics
Rapid oral absorption
Short half life
Renally secreted via organic acid transporter
Loop Diuretics - Furosemide
Adverse Effects
Lasix Hyponatremia, hypokalemia, hypomagnesemia Dehydration metabolic alkalosis Mild hyperglycemia Ototoxicity Hypersensitivity rxns
Loop Diuretics - Furosemide
Clinical Indications
Acute pulmonary edema, CHF edema, acute hypercalcemia, acute hyperkalemia, hypertension
Additional Loop Diuretics
Bumetanide
40x more potent
Shorter half-life
50% metabolized by the liver
Additional Loop Diuretics
Torsemide
Longer half life than lasix
Longer duration of action
Better oral absorption
80% metabolized by the liver
Additional Loop Diuretics
Ethacrynic Acid
Last resort, only used when hypersensitive to others
No CA inhibition
Nephrotoxic and ototoxic
Worse side effects
Distal Convoluted Tubule
Na/Cl contransporter
Na gradient drives this
Ca reabsorption is controlled by PTH (regulates production of Ca channels in luminal border)
Basolateral Na/Ca pump (Ca pumped into blood)
Thiazide Diuretics - Hydrochlorothiazide
MoA
Inhibits apical Na/Cl cotransporter (into cell) in distal tubule
Produces mild diuresis
Results in increased Ca reabsorption
Thiazide Diuretics - Hydrochlorothiazide
Pharmacokinetics
Good oral absorption and renal elimination
Half life of 2.5
Thiazide Diuretics - Hydrocholorothiazide
Hypercalcemic Effects of Thiazide Diuretics
Inhibition of apical Na/Cl cotransporter decreases intracellular Ca
Na/Ca pump will compensate by increases Na pumped into cell and Ca pumped out of cell into blood
Thiazide Diuretics - Hydrochlorothiazide
Adverse Effects
Hyponatremia and **hypokalemia
Dehydration
**Metabolic alkalosis
Hyperuricemia (competes with organic acid transporter that also transports uric acid)
Hyperglycemia (thought to be secondary to hyperkalemia)
Hyperlipidemia (increased LDL)
Weakness, fatigue, parathesias and hypersensitivity
Thiazide Diuretics - Hydrochlorothiazide
Clinical Indications
Hypertension
Congestive heart failure
Reduce Ca excretion to prevent kidney stones
Collecting Tubule
Principal Cells
Na and K Channels
Na gradient in lumen drives Na back into cell
K effluxes out of cells into lumen
More Na in than K out, (-) lumen, drives paracellular K secretion
Aldosterone regulates expression of basolateral Na/K ATPase and channels
ADH regulates water channels and water absorption (segment is usually impermeable to water until ADH acts on it)
Collecting Tubule
Intercalated Cells
Luminal: proton pumps transport H into lumen, the H ATPase is regulated by aldosterone
Basolateral: HCO3/Cl is passive countertransporter
Hypokalemia
CA inhibitors
Acetazolamide
Proximally increases HCO3 (in proximal convoluted tubule)
Increase in luminal HCO3 increases (-) charge of lumen
More K is effluxed into lumen to counteract the (-) charge
Less K in the blood
Hypokalemia
Loop and Thiazide Diuretics
Inhibition of apical Na/Cl cotransporter in distal convoluted tubule decreases Na/Cl going into cell, more hangs out in the lumen, lumen is more (-)
More (-) lumen encourages more K effluxed from cell into lumen. Less K in blood.
Metabolic Alkalosis
Loop and Thiazide Diuretics
Increased Na and Cl from inhibition of cotransporter in distal convoluted tubule makes lumen more (-)
More H will be pumped from intercalated cells into lumen
Concurrently HCO3 will go into the blood, blood is alkalotic
K Sparing Diuretics
Given to avoid hypokalemia
NEVER BE GIVEN IN HYPERKALEMIA or if pts are on drugs/have disease states that can cause hyperkalemia:
Diabetes mellitus, multiple myeloma, tubulointerstitial renal disease, and renal insufficiency
K supplements and ACEi
Spironolactone
MoA
Competetive inhibition of aldosterone receptor
Anti-androgenic effects (decrease testosterone synthesis, competitive inhibition of DHT receptor)
Mild diuresis from decreased Na reabsorption (secondary to aldosterone inhibition)
“Sparing” of K and H also secondary
Spironolactone
Pharmacokinetics
Slow onset of action, takes DAYS
Liver metabolism to several active metabolites
Spironolactone
Adverse Effects
Hyperkalemia
Metabolic acidosis
Gynecomastia, amenorrhea, impotence, decreased libido
Gi upset, peptic ulcers
CNS effects: headache, fatigue, confusion, etc
Eplerenone
More expensive than spironolactone
Competitive antagonist of aldosterone binding to MR
Does not inhibit testosterone binding
Does not induce gynecomastia or other anti-androgenic side effects
Spironolactone
Primary hyperaldosteronism
Secondary hyperaldosteronism (renin-angiotensin system activated)
Liver cirrhosis
Hypertesion
Amiloride
MoA
Blocks Na channels in principal cells
Blocking Na influx decreases the driving force for K efflux so K IS SPARED
Amiloride
Pharmacokinetics
1/2 life of 21 hours
Secreted into tubule via organic base transporter
Excreted unchanged by the kidney
Amiloride
Adverse Effects
Hyperkalemia (NSAIDs can exacerbate this)
GI upset: nausea, vomiting, diarrhea
Muscle cramps
CNS effects: headache, dizziness, etc
Amiloride
Clinical Indications
Edema
Hypertension
Usually used in combination with other diuretics to reduce K loss
Not very efficacious by themselves
Triamterene
MoA
Blocks Na channels in principal cells
Blocking Na influx decreases driving force for K efflux so K is “spared”
Traimteren
Pharmacokinetics
1/2 life of 4 hours
10X less potent than AMILORIDE
Liver metabolizes the drug to it active form
Active metabolite secreted into proximal tubule using the organic base transporter
ADH Antagonists
Antagonize ADH, decrease water channel insertion, decreases water reabsorption in collecting tubule
ADH Antagonists
Demeclocycline
Tetracycline antibiotic
Nephrotoxic
ADH Antagonists
Litium
Psych drug used for mania
Nephrotoxic
ADH Antagonists
Tolvaptan
Selective antagonist of vasopressin V2 receptor
Induces increased, dose-dependent production of dilute urine
Does not alter serum electrolyte balance
Orally available
1/2 life 6 hours
V2 receptor antagonists
Tolvaptan
Mozavaptan
Lixivaptan
V1 and V2 receptor antagonist
Conivaptan
Diuretics and Edema
Diuretics tend to decrease capillary hydrostatic pressure and increase plasma oncotic pressure
Favor absorption over filtration
Kidney Diseases
Most cause retention of Na and H2O
Renal insufficiency reduces efficacy of most diuretics (reduced glomerular filtration)
Diabetic nephropathy (associated with hyperkalemia) can be treated with THIAZIDES or LOOP DIURETICS
Hepatic Cirrhosis
Portal hypertension, hypoalbuminemia
Reduction in plasma volume
Activates renin-angiotensin-aldosterone system
Secondary hyperaldosteronism results in Na retention in kidney
Associated with edema and acites
RESISTANT to loop diuretics
Spironolactone is effective
Diuretics and Congestive Heart Failure
Renin-angiotensin-aldosterone system activated, Na retention and edema
Thiazide or loop diuretics can cause K loss if aldosterone is high
Hypokalemia can lead to coronary events/stroke/death
Spironolactone may be effective adjunct/alternative to prevent hypokalemia-induced cardiac dysfunction
ACEi may be combined with thiazide or loop diuretics, but NOT WITH SPIRONOLACTONE
RHF (chronic)
ECFV redistributes from arterial to venous circulation
Venous, hepatic, splenic congestion
Peripheral tissue edema
ORAL LOOP DIURETICS
LHF (acute)
Increased hydrostatic pressure in lung capillaries
Pulmonary edema
Life-threatening, need rapid, aggressive therapy
I.V. LOOP DIURETIC
Hyponatremia
Serum Na below 136 mEq/L
Symptoms: Headache, fatigue, hallucinations, respiratory arrest, seizures, coma, death
Associated with hypovolemia, euvolemia, hypervolemia
ADH receptor antagonists can increase serum [Na]
Tolvaptan, mozavaptan, lixivaptan, conivaptan
Uncomplicated Hypertension
THIAZIDE diuretic
Patients with BP that is more than 20 over systolic goal or 10 diastolic goal
Use two agents
Usually one is a THIAZIDE diuretic
Nephrogenic Diabetes Insipidus
Loss of ADH effects
ADH binds to V2 vasopressin receptors on principal cells
AC -> cAMP -> PKA -> Aquaporin 2 channels and H2O reabsorption
In insipidus this does not work, we cannot concentrate the urine and end up peeing a ton
THIAZIDE use, don’t know MoA
Kidney stones
Contain Ca, usually occur in hypercalciuria
THIAZIDE diuretics decrease [Ca] in urine by promoting Ca reabsorption in distal convoluted tubule
Hypercalcemia
Serum calcium > 14 mg/dL
Nausea, vomiting, AMS, abdominal pain, constipation, lethargy, depression, weakness and vague muscle/joint aches, polyuria, headache, coma
LOOP DIURETIC
Avoid thiazides because they INCREASE reabsorption of Ca
Diuretic Resistance
NSAIDs
NSAIDs increase expression of Na/K/2Cl
Compete for organic acid transporter
Diuretic Resistance
CHF or Renal failure
Decreases delivery of diuretics to tubule
Also build-up of organic acids competes for secretory transport into tubule
Diuretic Resistance
Nephrotic Syndrome
Protein in tubule bind to diuretic drugs and limits their actions
Diuretic Resistance
Hepatic Cirrhosis
Decreased GFR causes increased PCT absorption of Na
Decreased delivery of Na to distal nephron decreases effect of drugs that target Na transporters or channels in these segments
Combination Therapy
Loop + Thiazide Diuretics
Only in patients refractory to one or the other
May be too robust -> K wasting
Combination Therapy
K sparing + Loop or Thiazide
Prevents hypokalemia
Avoid in renal insufficiency
