CVPR 03-28-14 11am-Noon Diuretics-RAAS Antagonists - French Flashcards
Diuretics – when to use
Often used 1st to reverse Na/water retention & relieve signs of symptoms of volume overload (dyspnea & peripheral edema); May be used chronically or acutely
Preferred type of diuretic
Loop diuretics preferred b/c of efficacy, but can be augmented with thiazide diuretic; Most commonly used is furosemide, but some pts respond better to torsemide or bumetanide due to better & more reliable absorption
Angiotensin converting enzyme inhibitors (ACEIs) – when to use
Started during or after optimization of diuretic therapy; 1st at low doses then titrate up to goal dose
ACEIs – effects
Produce vasodilation & decreased aldosterone activation, plus anti-remodeling effects
Angiotensin II Receptor (AT-1) Blockers (ARBs) – when to use
Used in pts intolerant to ACEIs (usually due to cough) but NO apparent benefit from dual therapy w/ACEI + ARB
Aldosterone Antagonists (aka Mineralocorticoid receptor antagonists, MRA) – when to use
Added to therapy for NYHA class II with LVEF <35%
Aldosterone Antagonists (MRAs) – what must be monitored
Must carefully monitor for serum potassium (30ml/min)
Aldosterone Antagonists (MRAs) –action
Blocks aldosterone effect on kidney, producing additional sodium loss (since ACEI/ARBs block of aldosterone is incomplete) PLUS anti-remodeling effects
Spironolactone vs. Eplerenone (Aldosterone antagonists/MRAs)
If endocrine side effects occur with spironolactone, can use eplerenone (much more expensive)
Site of action of diuretic agents
Almost all effect lumenal (urine) surfaces of renal tubule cells
Mechanisms of diuretic agents
- Interact w/membrane transport proteins (thiazides, furosemide, triamterene)….. 2. Specifically interact w/ enzymes (acetazolamide) or hormone receptors (spironolactone)….. 3. Prevent water reabsorption bia osmotic effects (mannitol)
Movement of Na+ between compartments in the kidney
Na+ is the major extracellular cation & its movement between compartments is controlled by regulated active transport via Na+-K+-ATPase activity at the interstitial (blood) surface —> produces gradient needed for Na+ reabsorption from urine back into blood; But, NO diuretics act via inhibition of Na+-K+-ATPase
How diuretics work
No current diuretics can inhibit the Na+-K+ ATPase pump; Rather, diuretic agents decrease Na+ reabsorption at various sites in the nephron, resulting in increased amounts of Na+ (and other ions) entering urine along with H2O entering passively to maintain osmotic equilibrium.
Events in Proximal Convoluted Tubule
- Almost all of glucose, amino acids, NaHCO3, and other metabolites are reabsorbed here, along with 60-70% of Na+ (w/Cl- & H2O following passively)…. 2. H+ ion + enzyme carbonic anhydrase (CA) on luminal surface —> reabsorption of HCO3- (& exchange of H+ for Na+); …….. Site of organic acid (diuretics, antibiotics) and base (procainamide) secretion.
Acetazolamide & the PCT
Inhibition of CA (carbonic anhydrase) by acetazolamide results in retention of HCO3- in lumen (urine) with mild alkaline diuresis.
Significance of PCT for drugs
Important site for delivery of diuretics to their specific site of action in nephron and for potential drug-drug interactions.
Carbonic Anhydrase (CA) Inhibitor
Acetazolamide (Diamox)
Pharmacodynamics (Actions) of CA inhibitors (Acetazolamide)
Inhibition of carbonic anhydrase enzyme depresses NaHCO3 reabsorption in proximal tubule; Also inhibits formation of aqueous humor & CSF that is dependent on HCO3- transport;
Pharmacokinetics of CA inhibitors (Acetazolamide)
Well absorbed orally….Effects in 30 min … Duration of 12 hrs… Secreted into proximal tubule
Clinical Uses of CA inhibitors (Acetazolamide)
Major use is NOT as diuretic agent and NOT used in HF; Rather, used in Glaucoma (topical), Acute mountain sickness (systemic admin.; slows pulm./cerebral edema)
Adverse Reactions / Toxicities of CA inhibitors (Acetazolamide)
Minor: Loss of appetite, drowsiness, confusion, tingling in extremities, hypersensitivity rxns…..Hyperchloremic metabolic acidosis, renal stones (via increase in urinary pH), K+ wasting
Events in the Loop of Henle (thick ascending limb)
Water removal (from lumen) occurs in descending limb as a result of hypertonic osmotic forces generated in interstitial spaces; H2O removal opposed if impermeable solutes present (HCO3-, glucose, osmotic diuretics)….. Ascending limb is impermeable to H2O, but active NaCl reabsorption occurs in ascending limb via Na+-K+-2Cl- cotransporter (NKCC2 on the luminal side)
Action of NKCC2 (Na+-K+-2Cl- cotransporter)
Cotransporter itself is electrically neutral, but its action leads to excess intracellular K+ which then back diffuses into lumen —> lumen positive potential —> drives reabsorption of cations Mg++ and Ca++
Loop of Henle Agents (High Ceiling Diuretics) – Pharmacodynamics (Actions)
Inhibit NaCl transport (Na+-K+-2Cl–transporter) in thick ascending limb of loop of Henle
Effects of Loop of Henle Agents (High Ceiling Diuretics)
Loop diuretics have greatest diuretic effect b/c of the large capacity of this segment…. Associated with: 1. Increased Mg++, Ca++ excretion (diminish lumen-positive potential)…. 2. Increased renal blood flow (via effect on RAAS & PGs systems) ….. 3. Retain substantial diuretic effect even if renal function is compromised.
Pharmacokinetics of Loop of Henle Agents
Rapid oral absorption; Extremely rapid IV diuretic response (IV may be required initially in some HF pts due to congestion-related interference w/ oral absorption); Handled by renal secretion and filtration; Duration of effect 2-3 hrs for furosemide, 4-6 hrs for torsemide, 6 hours for bumetanide
Clinical Uses of Loop Diuretics
- Congestive heart failure - Preferred diuretic class b/c of greater efficacy – 1. HF w/ volume overload (to eliminate signs of fluid retention - pulmonary congestion & peripheral edema)….. 2. Acute pulmonary edema ….. 3. Refractory edema (Loops used if no response to Na+ restriction or thiazide diuretic; esp. if renal disease & fluid overload present) ….. 4. Hypercalcemia given w/saline infusion (to prevent extracellular fluid (ECF) volume depletion)
Efficacy of loop diuretics is enhanced by…
salt restriction (< 2 g/day)
Furosemide vs. Other Loop diuretics
Most commonly used loop diuretic; If lack of response, can increase dose or can switch to bumetanide or torsemide (both are more reliable bioavailability; torsemide has longer duration)
Diuretic response in HF Patients
Reduced diuretic response related to decreased drug delivery to kidney due to decreased RBF & hypoperfusion activation of RAAS and SNS