Diuretics Flashcards
PCT
glucose
sodium bicarbonate (85%)
sodium chloride (40-50%)
amino acids
PCT features
water is reabsorbed passively (60%)
site of action of the diuretic acetazolamide
site of the organic acid and base secretory systems
acids: diuretics, antibiotics, uric acid
bases: creatinine, procainamide, choline
PCT diuretics
Na+ is exchanged for H + H + can combine with HCO3- to form H2CO3 H2CO3 is not reabsorbed but H2O and CO2 readily diffuse Na+ reabsorbed via basolateral Na+/ K+ ATPase HCO3- is reabsorbed Dissociation of H2CO3 results in H + for the Na+/ H+ pump
Thin descending and thin ascending limb
of loop of henle
does not participate in salt reabsorption
does contribute to water reabsorption
impermeant solutes such as mannitol or glucose will oppose water extraction
Thick ascending limb
actively reabsorbs NaCl (35-40%)
impermeable to water
“diluting segment” due to reabsorption of salt but not water
NaCl is transported by a Na+ /K+ /2Cl- cotransporter which is inhibited by the loop diuretics
the action of the cotransporter causes K+ accumulation in the cell and is the driving force for reabsorption of Mg++ and Ca++
thick ascending limb diuretics
Na+ transport by Na+K+2Cl- cotransporter pump is electrically neutral but excess K+ builds up causing K+ diffusion into the lumen Na+ reabsorbed via Na+K+ ATPase K+ diffusion reabsorption of Mg + + and Ca + + via the paracellular pathway
DCT
- Active reabsorption of NaCl (10%) by a Na+ /Cl- cotransporter
- Impermeable to water (also diluting)
- Site of action of the thiazide diuretics
- No intracellular K+ accumulation so no paracellular
reabsorption of Mg++ and Ca++ - Ca++ is actively reabsorbed via an apical Ca++ channel and basolateral Na+ /Ca++ exchanger; this process is affected by PTH
DCT diuretics
Na+ transport by Na+Cl- cotransporter pump is electrically neutral but no excess K+ builds up Na+ reabsorbed via Na+K+ ATPase Ca + + actively reabsorbed by apical Ca + channels and basolateral Na + /Ca + + exchanger
Collecting Tubule
- Active reabsorption of NaCl (2-5%)
a. Na+ and K+ are transported by ion channels
b. a Na+ /K+ ATPase pumps Na+ into the blood (principal cells) - Primary site of proton secretion (intercalated cells)
- Primary site of mineralocorticoids (aldosterone) which
regulate urine volume
Collecting tubule more
- Major site of K+ secretion
a. diuretics that act upstream of the collecting duct will increase
Na+ delivery to the collecting duct and increase K+ secretion
(diuretic-induced K+ wasting)
b. if Na+ is delivered to the collecting duct along with an anion
like bicarbonate (which is not readily absorbed like Cl-), the
lumen-negative potential is increased and K+ excretion is even
further enhanced
c. reabsorption of Na+ and its coupled secretion of K+ is
regulated by aldosterone (enhances apical ion channel activity
and basolateral Na+ /K+ ATPase activity)
Site of action of ADH; ADH causes intracellular vesicles
containing preformed water channels to fuse with the apical
membrane of the principal cells to increase water permeability
Collecting tubule diuretics
Na+ transport is by a Na+channel K+ secretion Na+ transport in >> K+ transport out; this drives Cl- transport via the paracellular pathway Na+ is reabsorbed by the Na+/K+ ATPase regulates reabsorption of Na+ and the secretion of K + regulates the permeability of water and causes water channels to form
secretion
loops and thiazides are weak acids; to reach their target they must be secreted into the tubule; site of interactions between diuretics and uric acid
Carbonic anhydrase inhibitors drugs
Acetazolamide
Brinzolamide (sol.), Dorzolamide (sol.), Methazolamide
Acetazolamide effects
inhibition of carbonic anhydrase results in a decreased ability to exchange Na+ for H+ and causes a mild diuresis; HCO3- is retained in the lumen and excreted which causes a marked elevation in urinary pH and hyperchloremic metabolic acidosis; also inhibits carbonic anhydrase in the ciliary body of the eye where it decreases the rate of aqueous humor formation (and decreases intraocular pressure)
Acetazolamide uses
glaucoma: acetazolamide is most commonly used for glaucoma treatment; it is effective in the chronic treatment of glaucoma but not acute attacks
acute mountain sickness: used prophylactically to treat acute mountain sickness in healthy individuals who rapidly ascend above 10,000 feet; the drug is given nightly for 5 days prior to the ascent to prevent weakness, breathlessness, dizziness, nausea, and cerebral and pulmonary edema
seizures: used as an adjuvant in the treatment of seizures
Acetazolamide adverse effects
metabolic acidosis (occurs in 2-3 days of use), potassium depletion, renal stones (form due to calcium and phosphate salts not being absorbed at alkaline pH), sulfonamide allergy
Brinzolamide (sol.), Dorzolamide (sol.), Methazolamide use & MOA
mechanism of action: inhibit carbonic anhydrase
in the eye to reduce intraocular pressure
b. therapeutic use: open-angle glaucoma
loop uses
a. acute pulmonary edema; rapid onset and powerful effect; given IV
b. CHF
c. hypertension (short t ½ makes them less desirable than thiazides)
d. edema: nephrotic syndrome accompanied by edema is initially treated with loop diuretics; chronic kidney disease, acute renal failure
e. hypercalcemia (+ saline)
loop pharmokinetics
oral or parenteral; duration of action is 1-4 hours; work well even at low GFRs
loop adverse
ototoxicity: tinnitus, hearing impairment, deafness, vertigo, a sense of fullness in the ears (particularly when used together with the aminoglycoside antibiotics); most common with ethacrynic acid
hyperuricemia: loops are weak acids and compete with uric acid for the renal secretory systems which can cause a build-up of uric acid leading to gout attacks
acute hypovolemia: can cause a severe and rapid
reduction in blood volume which could cause hypotension, shock, and cardiac arrhythmias
hypokalemic alkalosis
orthostatic hypotension
sulfonamide allergy (not with ethacrynic acid)
thiazide info
The thiazides are the most widely used of the diuretic drugs. These drugs are sulfonamide derivatives and are related in structure to the carbonic anhydrase inhibitors. Thiazides have significantly greater diuretic activity than acetazolamide, and their action is mainly on the distal tubule. The thiazides have equal efficacy but differ in potency.
thiazide info
Chlorothiazide is the prototype of this group and was the first modern diuretic that was active orally and used to treat edema associated with cirrhosis or CHF with minimum side effects. Its properties are representative of the thiazide group and we will discuss this drug in greater detail than the others. Newer derivatives such as hydrochlorothiazide and chlorthalidone are now used more commonly.
thiazide drugs
Hydrochlorothiazide, Chlorthalidone, Chlorothiazide
Thiazide analogs= metolazone, indapamide
thiazide MOA
acts mainly on the distal tubule to
decrease the reabsorption of Na+ by inhibiting a Na+/Cl-
cotransporter on the luminal membrane; like acetazolamide,
it has some actions on carbonic anhydrase in the proximal
tubule
neumonic
loops lose Ca, thiazides absorb Ca
thiazides action
i. increased excretion of Na+and Cl-
ii. loss of K+: prolonged use of the thiazides results in
continual loss of K+ from the body and serum levels of K+
should be measured once a month to assure that
hypokalemia does not develop; dietary (citrus fruits,
bananas, prunes) or K+ salt supplementation may be
necessary
iii. decreased urinary calcium excretion
iv. reduced peripheral vascular resistance: an initial reduction in blood pressure results from a decrease in blood volume and therefore a decrease in cardiac output; with continued therapy the volume recovers but there are continued hypotensive effects, resulting from relaxation of arteriolar smooth muscle
thiazide uses
hypertension: popular as antihypertensives since they are inexpensive, convenient to administer, and well tolerated; after 3-7 days of treatment, the blood pressure stabilizes at a lower level and can be maintained indefinitely by a daily dosage level of the drug which causes lower peripheral resistance without having a major diuretic effect; many patients can continue for years on the thiazides alone, but others may require the addition of a second drug such as a -blocker
ii. congestive heart failure: thiazides can be the diuretic of choice in reducing extracellular fluid volume in mild to moderate CHF; if the thiazide fails, loop diuretics may be useful
iii. edema: good for various causes of edema including heart (CHF), liver (cirrhosis), and kidney (nephrotic syndrome, chronic renal failure, acute glomerulonephritis)
iv. hypercalciuria: thiazides can be useful in treating idiopathic hypercalciuria because they inhibit calcium excretion; useful for patients with calcium oxalate stones in the urinary tract
v. nephrogenic diabetes insipidus: thiazides produce a hyperosmolar urine and act like antidiuretic hormone in the treatment of nephrogenic diabetes insipidus; these drugs may reduce daily urine volume from 11 L/day to about 3 L/day
central DI
desmopressin
nephrogenic DI
uncoupled V2 receptors tx with HCTZ
(proximal tubule compensation for sodium and
fluid loss)
thiazide adverse
i. hypokalemic alkalosis
ii. hyperuricemia: thiazides are weak acids and compete
with uric acid for the renal secretory system which can
cause a build-up of uric acid leading to gout attacks;
for this reason periodic blood tests for uric acid are
done on patients taking thiazides
iii. orthostatic hypotension
iv. hypercalcemia
v. hyperglycemia: most likely due to K+ loss; patients with diabetes mellitus who are taking thiazides for hypertension may become hyperglycemic and have difficulty in maintaining appropriate blood sugar levels (affect insulin release)
vi. sexual dysfunction: more likely cause than any other antihypertensives
vi. hyperlipidemia: increased LDLs and TGs
vii. sulfonamide allergy
metolazone, indapamide info
use is similar to thiazides
both work at low GFRs (most thiazides are ineffective when GFR is <40)
POTASSIUM-SPARING DIURETICS
These drugs act on the collecting tubule to inhibit Na+
reabsorption, K+ secretion, and H+ secretion. They are the
weakest of the diuretics. These agents are used in combination
with thiazides or loops to offset the loss of potassium caused
by those agents. It is extremely important that patients treated
with any potassium-sparing diuretic be monitored closely for
potassium levels. Exogenous potassium supplementation is
usually discontinued when potassium-sparing diuretic therapy
is initiated.
POTASSIUM-SPARING DIURETICS
Sodium channel is distinct from voltage-gated sodium channels Metabolic acidosis on overdose
potassium sparing drugs
Amiloride
Triamterene
Spironolactone
Eplerenone
Spironolactone, Eplerenone
MOA
counteract high blood levels of aldosterone resulting in excretion of Na+ and retention of K+; spironolactone can also block androgen receptors while eplerenone only blocks aldosterone receptors
Spironolactone, Eplerenone uses
i. diuretic: have low efficacy in mobilizing sodium from the body compared to other diuretics, but have the useful property of causing retention of K+
ii. secondary hyperaldosteronism: particularly effective in clinical situations associated with primary (adrenal adenomas) or secondary (cardiac failure, hepatic cirrhosis, nephrotic syndrome) hyperaldosteronism
iii. heart failure: decrease remodeling
iv. female hirsutism: spironolactone only due to androgen receptor block
Spironolactone, Eplerenone
pharmokinetics
spironolactone is highly bound to plasma proteins; it is rapidly converted to an active metabolite, canrenone, which has a much longer half-life than the parent drug and is responsible for much of the therapeutic effect; spironolactone induces hepatic cytochrome P450 activity
Spironolactone, Eplerenone
adverse
due to androgen receptor block spironolactone may cause gynecomastia in males and irregular menstrual cycles in females; because of this, the drug should not be given in high doses on a chronic basis; low doses may be used chronically with few side effects; hyperkalemia, nausea, lethargy, and mental confusion can occur
Triamterene and Amiloride
MOA
not very efficacious diuretics but frequently used in combination with other diuretics to maintain normal potassium levels
Triamterene and Amiloride adverse
hyperkalemia, leg cramps (triamterene)
Mannitol MOA
simple, hydrophilic substance filtered at the glomerulus (not reabsorbed) and causes diuresis by osmotic attraction in the tubular lumen; thus, it effects water rather than Na+ excretion; their main site of action appears to be the loop of Henle but may also be in the proximal tubule and in the collecting duct
Mannitol use
Therapeutic use: maintain urine flow following acute toxic ingestion of substances capable of producing acute renal failure; used to treat patients with increased intracranial pressure, or acute renal failure due to shock, drug toxicities, and trauma; occasionally used to lower IOP in glaucoma; rhabdomyolysis (severe muscle injury to eliminate myoglobin)
Pharmacokinetics: given IV
