Diuretics & RAAS Antagonists Flashcards
1
Q
Loop diuretics (Furosemide): Site/MOA @ nephron
A
- Inhibit NaCl transport (Na+-K+2Cl- transporter) in the ascending limb of the loop of henle – more Na+, K+, and Cl- are retained in the urine
- Associated with increased Mg2+ and Ca2+ excretion
- Increase renal blood flow (via effect on renin-angiotensin system)
2
Q
Loop diuretics (Furosemide): Pharmacokinetics
A
- Rapid oral absorption; extremely rapid IV response
- Excreted by renal secretion and filtration
- Furosemide duration of effect is 2-3 hours
3
Q
Loop diuretics (Furosemide): Role in HF therapy
A
- Preferred class of diuretics in CHF due to greater efficacy
- Used in HF patients with volume overload in conjunction with salt restriction
- Furosemide is first line; if lack of response can increase dose or switch to bumetanide or torsemide
- Patients with HF have reduced diuretic response due to decreased drug delivery to kidney due to decreased renal blood flow and hypoperfusion activation of RAAS
- Refractory edema – may need to add a thiazide to block distal tubule Na+ reabsorption; may also add aldosterone antagonist
- Acute pulmonary edema
4
Q
Loop diuretics (Furosemide): Adverse effects
A
- Hypokalemic metabolic alkalosis via enhanced secretion of K+ and H+
- Hypokalemia predisposes to ectopic pacemakers and arrhythmias
- Ototoxicity
- Hyperuricemia
- Hypomagnesemia
- Overdose –> rapid blood volume depletion
5
Q
Thiazides (Hyrdrochlorothiazide): Site/MOA @ nephron
A
- Inhibit the Na+/Cl- cotransporter and increase urinary excretion of NaCl (a modest diuretic effect since only 5-10% of filtered Na+ is reabsorbed here)
- Increase reabsorption of Ca2+ (lowering of intracellular Na+ drives Ca2++ exchanger)
6
Q
Thiazides (Hyrdrochlorothiazide): Pharmacokinetics
A
- Oral absorption, best tolerated early in the day
- Hydrochlorothyozide – twice daily dosing
- Secreted by organic acid secretory system; competition with uric acid secretion may precipitate gout attacks
7
Q
Thiazides (Hyrdrochlorothiazide): Role in HF therapy
A
- First line for mild hypertension
- Tx for Hypercalcuria – increased reabsorption of Ca2+ –>reduced urinary excretion –> decreases incidence of kidney stones
- CHF/refractory edema: synergistic diuretic effect with loop diuretics
8
Q
Thiazides (Hyrdrochlorothiazide): Adverse effects
A
- Hypokalemia –> predisposition to ectopic pacemakers; contraindicated in patients with arrhythmias, MI, angina
- Hyperuricemia – avoid in patients with gout
- Impaired carbohydrate tolerance (hyperglycemia, glucosuria) and hyperlipidemia
9
Q
Potassium-sparing diuretics: Site/MOA @ nephron
A
- In the collecting tubule, the driving force for Na+ into the cell exceeds that for K+ exit so Na+ enters the cell from the lumen and the lumen becomes negative, driving Cl- into cells and K+ into the urine;
- thus, K+ excretion is coupled to Na+ reabsorption and ALL diuretics that cause a greater delivery of Na+ to this site via greater tubular flow will enhance K+ excretion
- Aldosterone, through effects on gene transcription, increases both the number and activity of Na+ and K+ membrane channels, as well as the Na/K ATPase
- Diuretics that block the Na+ channel or antagonize the aldosterone receptor will decrease Na+ reabsorption and _decrease K+ excretion _
10
Q
Aldosterone Antagonists (Sprionolactone): Site/MOA
A
- competitive antagonist at aldosterone receptor
- prevents enhancement of protein synthesis; blockade of aldosterone effect at collecting tubule
- –> less Na+ is reabsorbed, lumen potential becomes more positive, and less K+ ions move into the urine
- Promotes only moderate increase in Na+ excretion; mild diuresis when used alone
11
Q
Aldosterone Antagonists (Sprionolactone): Pharmacokinetics
A
- Poor oral absorption
- dosed 1-2x/day with slow onset of action
12
Q
Aldosterone Antagonists (Sprionolactone): Clinical uses
A
- Congestive heart failure
- Block aldosterone receptors on the heart – anti-remodeling action, blocking deleterious effects of aldosterone on the heart (hypertrophy, fibrosis)
- Raises serum potassium to counter risk of hypokalemia-induced arrhythmias resulting from K+ wasting diuretics
- Hyperaldosteronism
- HTN
13
Q
Aldosterone Antagonists (Sprionolactone): Adverse Rxns
A
- Hyperkalemia –> arrhythmias
- Endocrine abnormalities (gynecomastia with spironolactone via secondary blockage of androgen receptor ~10%)
14
Q
ACE inhibitors (Lisinopril): Site/MOA
A
- Inhibits ACE conversion of AI to AII, blocking AII induced vasoconstriction; results in decreased pre-load and afterload
- Decreases AII-induced release of aldosterone, which moderates the myocardial hypertrophy and remodeling response
- Decreases bradykinin inactivation, increasing vasodilation
- Improves endothelial function via enhancement of NO action
- Reduces sympathetic activity
15
Q
ACE inhibitors (Lisinopril): Pharmacokinetics
A
- Well absorbed orally
- All except Lisinopril and captopril are pro-drugs that are metabolized to the active drug in the liver
- Active metabolites are eliminated by the kidney, requiring dosage adjustment in patients with renal insufficiency
- Once daily dosing for most agents
