Diuretics Flashcards
what is the function of the kidney?
Maintain homeostasis through:
- Excretion of drugs and waste products
Filtration - autoregulated via blood flow
Secretion – saturable, blockable
Reabsorption - altered by diuretics
- Regulation of plasma volume and electrolyte balance by the juxtaglomerular apparatus:
Granule cells on afferent arterioles produce renin in response to Sympathetic (ß1 receptor) stimulation or sodium deficit.
Macula densa cells on distal convoluted tubule sense sodium levels.
- Regulation of acid/base balance by regulating HCO3- and H+ excretion
what is the basic functional unit of the kidney? What is the filtrate in bowman capsule? Where does the regulation of the ionic and water composition of the filtrate which becomes urine occur?
The basic functional unit of the kidney: ~1.2 million nephrons per kidney.
20% of blood plasma entering the kidneys is filtered into the Bowman capsule.
Filtrate: Glucose, bicarbonate, amino acids & electrolytes.
Regulation of the ionic & water composition of the filtrate which becomes urine – occurs in the nephron.
What occurs in the glomerulus?
function - formation of glomerular filtrate H20 permeabiltiy - very high Primary Drug targets - none Diuretic Class - none
What occurs in the proximal convoluted tubule?
function - 65% filtrate reabsorbed, 40% Na reabsorbed
H20 permeabiltiy - high
Primary Drug targets - carbonic anhydrase
Diuretic Class - carbonic anhydrase inhibitors
What occurs in the thin descending limb?
function - passive reabsorption of h20
H20 permeabiltiy - a little bit
Primary Drug targets - none
Diuretic Class - mannitol
What occurs is the thick ascending limb?
function - 15% of filtrate reabsorbed, 35% reabsorbed
H20 permeabiltiy - low
Primary Drug targets - Na-K-2Cl
Diuretic Class - Loop Diuretics
What occurs in the distal convoluted tubule?
function - 10% filtrate reabsorbed, 10% sodium reabsorbed
H20 permeabiltiy - low
Primary Drug targets - Na - Cl
Diuretic Class - Thiazides
What occurs in the Cortical collecting tubules?
function - 2-5% sodium reabsorption; K + & H + secretion H20 permeabiltiy - none Primary Drug targets - Na channels Diuretic Class - K+ sparing diuretics
what happens in the medullary collecting tubules?
function - h20 reabsorption under ADH control
H20 permeabiltiy - depends on ADH
Primary Drug targets - aquaporins
Diuretic Class - ADH antagonists
What are diuretics and what is the principle therapeutic uses?
Increase urine volume by inhibiting reabsorption of salt and water
Getting rid of sodium = natriuresis
Getting rid of water = diuresis
Principal Therapeutic Uses
Treatment of Edema
Treatment of Hypertension
In the proximal convoluted tubule, what occurs and why is carbonic anhydrase important?
Major site of reabsorption of glucose, amino acids, bicarbonate, sodium chloride & water
Bicarbonate absorbed as carbon dioxide through the action of carbonic anhydrase
On the cell membrane there is a sodium - hydrogen exchanger. In the lumen the bicarbonate combines with hydrogen to form carbonic acid. Carbonic anhydrase will convert the carbonic acid to water and carbon dioxide. The carbon dioxide will diffuse back into the proximal convoluted tubule cell to then be converted with water by carbonic anhydrase to carbonic acid which can disassociate again to hydrogen and bicarbonate to do the cycle again.
What are two carbonic anhydrase inhibitors? what are the actions and what does it cause? what are the therapeutic uses? what are the adverse effects?
- Carbonic Anhydrase Inhibitors: Acetazolamide Methazolamide - Actions: Excretion of alkaline urine (limited by body bicarbonate load). Increased excretion of NaHCO3 & K+. Retention of hydrogen ion. - Therapeutic Uses: Glaucoma Acute Mountain Sickness
Edema w/severe metabolic alkalosis.
Adverse Effects: Metabolic Acidosis, Hypokalemia, Hypersensitivity Reactions.
what occurs in the thin descending loop of loop of henle?
Water reabsorption into hypertonic medulla through osmotic forces
- Osmolarity increases along the descending portion of the loop
- End result: tubular fluid with 3 x Na+ than left the PCT.
what is the osmotic diuretic for the thin deschending loop of henle?
- Osmotic Diuretics : Mannitol
- Actions:
Potent diuretic causing minimal loss of electrolytes (little natriuresis). - Therapeutic Uses:
Cerebral edema – decrease ICP
Acute renal failure – maintain high urine flow. - Adverse Effects: Dehydration
what is happening in the thick ascending loop of henle?
- Impermeable to H2O
- Na+/K+/2Cl- Co-Transport
35% of NaCl returns to the interstitial fluid – major site of salt reabsorption.
Diluting segment of the nephron – dilutes the tubular fluid.
what are loop diuretics?
occur in the thick ascending loop of henle
Loop Diuretics: Sulphonamide Derivatives Furosemide (Lasix) Bumetanide Torsemide - Phenoxyacetic Acid Derivative Ethacrynic Acid
Actions:
- Inhibit Na+/K+/2Cl- co-transport system.
- Potent (high ceiling) diuretics.
- Increased excretion of Na+, K+, H+ and Ca2+.
Therapeutic Uses:
- Edema due to cardiac failure, liver disease or kidney disease.
- Hypercalcemia.
Adverse Effects: Hypokalemia, Alkalosis, Ototoxicity, Hypotension, Hyperuricemia.
what occurs in the distal convoluted tubule?
Na+/Cl- transporter
- Reabsorption of ~10% of NaCl.
Ca2+ Reabsorption
- Ca2+ actively reabsorbed by the cell via a Ca2+ channel.
- Na+/Ca2+ exchanger moves Ca2+ into the interstitial fluid.
- Regulated by PTH
what are thiazide diuretics?
act in the distal convoluted tubule
Thiazides:
- Hydrochlorothiazide (HCTZ)
- Chlorthalidone
- Indapamide
Actions:
- Inhibit Na+/Cl- Co-Transport
- Increased excretion of Na+, Cl-, K+ and H+
- Ca2+ reabsorption
Therapeutic Uses:
- Hypertension – first line
Adverse Effects: Hypokalemia, Alkalosis, Hyperuricemia, Hyperlipidemia, Impaired glucose tolerance.
what happens int he cortical collecting tubule?
Final site of NaCl reabsorption (2-5%)
- Responsible for final Na+ concentration in the urine
Most important site of K+ secretion by the kidney
Principal Cells: Na+, K+ & H2O Transport
Intercalated cells: H+ secretion
Regulated by: Aldosterone
what are potassium sparing diuertics?
act on the cortical collecting tubule
K+ Sparing Diuretics - Aldosterone Antagonists Spironolactone - Exchange Inhibitors Triamterene Amiloride
Action:
- Spironolactone – competitive antagonist at intracellular aldosterone receptors.
- Triamterene & Amiloride – block Na+ channels to inhibit exchange with K+ and H+.
Therapeutic Uses:
Hypertension – treat K+ wasting in patients taking Loop or Thiazide Diuretics.
Adverse Effects: Hyperkalemia, Acidosis,
Spironolactone: gynecomastia and menstrual
Irregularities (is an androgen receptor blocker).
what happens int he medullary collecting tubule?
Site of final urine concentration
- Responsible for tight regulation of body fluid volume
- Anti-diuretic hormone (ADH) facilitates water movement by insertion of preformed H2O channels into the membrane (aquaporins)
Mediated by V2 receptors and cAMP.
what is ADH and what is an ADH antagonist?
occurs in the medullary collecting tubule
ADH Antagonists:
- Conivaptan (Lixivaptan & Tolvaptan)
Actions:
- Competitive ADH antagonists at the V2
receptor
Therapeutic Uses:
- SIADH (The syndrome of inappropriate antidiuretic hormone secretion )/ (Schwartz-Bartter syndrome)
- Congestive Heart Failure
Adverse Effects:
- Demyelination if hyponatremia is corrected too quickly
- Severe hypernatremia
what is meant by diuretic potency?
LD = OD > THIAZ > CAI = K-SPARING
LD – Loop Diuretics (Thick Ascending Loop of Henle)
OD – Osmotic Diuretics (Thin Descending Loop of Henle)
THIAZ – Thiazides (Distal Convoluted Tubule)
CAI – Carbonic Anhydrase Inhibitors (Proximal Convoluted Tubule)
K-SPARING – Potassium sparing Diuretics (Cortical Collecting Duct)
SHOULD I LOOK AT THE TABLE IN THE NOTES THAT SUMMARIZES THE DIURETICS AND BLOOD ELECTROLYTES?
YES
what is meant by tolerance to diuretics?
First diuretic dose – Negative sodium balance is produced:
- Excretion of Na+ > Intake of Na+
- Blood volume is reduced & Edema disappears.
After a few days – Sodium balance is restored
- Blood volume increases & edema may return.
Factors causing the loss of the desired effects of diuretics:
- Segments of the nephron that are not affected by the drug, increase their reabsorption of Na+ .
- Macula dense cells sense reduction in total body Na+ & stimulate renin release.
- Baroreceptors sense reduction in total blood volume & stimulate the Sympathetic Nervous System to act on β1 receptors to release renin.
- In both cases – renin ends up as aldosterone – activates the Na+-K+ exchange pump in the distal tubule which increases the reabsorption of sodium, and restores sodium balance.
how can the development of tolerance to diuretics be overcome?
The development of tolerance to diuretics can be over-come by,
- Increasing the dose
- Reducing the intake of sodium and water
- Adding a second, or third, diuretic.
what are the combinations for diuretics for the potassium factor?
THIAZIDES/LOOP DIURETICS + K+ SPARING DIURETIC
- Hydrochlorothiazide + Spironolactone
- Hydrochlorothiazide + Triamterene
- Hydrochlorothiazide + Amiloride
- Furosemide + Spironolactone
Rationale: To reduce the hypokalemia and the alkalosis caused by the thiazide or loop diuretic.
what are combinations for the angiotensin factor and renin factor?
THIAZIDES + ACE INHIBITOR/β BLOCKER
- Hydrochlorothiazide + Enalapril
- Hydrocholothiazide + Propranolol
Rationale:
- ACE Inhibitor - To prevent the increase in angiotensin-II and aldosterone that occur as a result of the thiazide administration (thereby reducing the loss of potassium).
- Propranolol - To reduce the thiazide-induced increase in angiotensin-ll and aldosterone by reducing the SNS-induced release of renin from the juxtaglomerular apparatus.
