01-09 PHARM of Diuretics Flashcards
1. Distinguish classes of diuretics w/ respect to: —sites & MoAs —effect on urinary lytes & vol —therapeutic use —ADRs 2. Explain role of Rxs in prevention, tx, and pathogenesis of pts w/ renal dz. 3. Describe the rationale for drugs dosage modifications in pts w/ renal impairment
Sketch nephron and put sites of diuretic action
[IMAGE q1] see diagram slide 9
List 5 classes of diuretics.
carbonic anhydrase inhibitors loop diuretics thiazide diuretics K-sparing diuretics osmotic diuretics
Manitol —SoA —MoA —effect on urinary lytes & vol —therapeutic use
SoA: PT and descending LoH
MoA: osmotic diuretic (filtered but not reabs)
Effect on urinary lytes & vol: ↓ tonicity of medulla, greater urine volume
Therapeutic use: glaucoma (acute ↓ P_intraocular); cerebral edema; used to be for AKI
ADRs
Carbonic Anhydrase Inhibitors —Examples —SoA —MoA —Effect on urinary lytes & vol —Therapeutic use —ADRs
—Examples: sulfanilamide → acetazolamide; (loops and thiazides have some CAI effect, too!)
—SoA: PT (CT)
—MoA: In PT: blocks HCO3- reabs & 2°ly Na+ reabs (In CT: H+ & K+ are reabs in exchange for Na+; when you ↓ availability you ↑ K+ wasting)
—Effect on urinary lytes & vol:
—Therapeutic use: limited usage b/c cause metab acidosis that leads to loss of diuretic effect
——metabolic alkalosis
——familial hypoK+ periodic paralysis (shift K+ cell → plasma)
——open-angle glaucoma (↓ HCO3 secretion into aqueous humor)
——Mountain Sickness Prophylaxis (generates metab acidosis → stims resp)
—ADRs: Hypokalemia, Ca stones b/c alk’d urine, hypersensitivity rxns b/o sulfonamide residue
Thiazides —Examples —SoA —MoA —Effect on urinary lytes & vol —Therapeutic use —ADRs
Examples:
—chlorthalidone, HCTZ
SoA
—DCT
MoA:
—inhibits NaCl symporter (“thiazide-sensitive contransporter” TSC) → excretion of Na+ and Cl-;
—variable degree of CA inhib → ~alkalosis
—↓ intracellular [Na+] → revs basolateral NCX → ↑ Ca2+ resorption as Na+ comes from blood into cell
—↑ distal luminal [Na] → ↑ K+ excretion & Ca2+ reabsorption (elderly ♀ bones)
Effect on urinary lytes & vol: blocked diluting capacity
Therapeutic use: —first-line HTN (good for geri ♀ w/ osteopenia) —edema —calcium nephrolithiasis —nephrogenic DI (?MoA)
ADRs —HypoK+ —HypoNa+ \_\_\_\_\_\_\_\_\_\_ —Hyperuricemia —Hyperglycemia (?via hypoK+) hyperlipidemia (?MoA) \_\_\_\_\_\_\_\_\_\_ —hypersensitivity rxns
Loop Diuretics —Examples —SoA —MoA —Effect on urinary lytes & vol —Therapeutic use —ADRs —Interactions —Pharmacokinetic Notes
Examples:
—furosemide
SoA
—ascending LoH
MoA:
—block Na+/K+/2Cl- co-trans
—↑ distal Na+ delivery → ↑ K+ elimination
—↑ Ca & Mg excretion due to ↓ ascend limb reabs
——normally: K would leak back out into lumen through channel → net luminal [+]Q → para-cellular Mg2+/Ca2+ reabsorption
—venodialator
Effect on urinary lytes & vol:
—blocks urinary dilution AND concentrating ability (can elim medullary gradient)
Therapeutic use:
—acute pulm edema: venous ↑ capacitance
—other edema
—refractory HTN
ADRs —volumen depletion (H2O & Na+) —hypoK+ —hypoCa++ —hypoMg++ —R-A-A-S activation b/c low Na @ macula densa → tubuloglomerular feedback —hyperuricemia —ototoxicity (reversible): lyte flux in cochlear cells —hypersensitivity rxn
Interactions
—NSAIDs: Pgs contrib to diuretic
—OAT tubular secretion inhibitors: probenecid, penicillins, anionic metabolites
Pharmacokinetics:
—95% bound to albumin (∆s cause ∆s in levels)
—furosemide T1/2 only 1-2 hrs
Shared ADRs of thiazides and loops
- hypokalemia!
- uricosurics
- same natriuetic Emax
- decrease renin release??
^^ didn’t she say in increased it?
K+-sparing diuretics —Examples —SoA —MoA —Effect on urinary lytes & vol —Therapeutic use —ADRs —Interactions —Pharmacokinetic Notes
Examples:
—amiloride, triamterene
—spironolactone, eplerenone (indirect)
SoA
—principal cells of late DTs and CDs
MoA:
—directly inhib ENaC…OR…
—indirectly by antagonism of Aldo at MR
—decrease K+ excretion: this is because there is a basolateral Na+/K+-exchanging ATPase; as less Na+ gets into cell from urine less K+ is pumped from blood into cell
Effect on urinary lytes & vol:
—
Therapeutic use:
—always w/ loop or thiazides
—hyerpaldosteronism (cirrhotic edema, nephrosis, heart failure)
—Add to loop or ACEIs w/ HF pts to ↑ survival
—ENaC Inhibs only: co-admin w/ Li+ (which is taking up in place of Na+ and inhibits ADH distally) → blocks Li uptake into principal cells → prevents Li-nephrogenic DI
ADRs (Spiro)
—hyperkalemia
—gynecomastia/impotence → b/c not specific to MR (eplerenone is more specific to MR)
Both ENaC and MR blockers…
- are generally used as monotherapy
- may cause hyperkalemia
- decrease natriuesis
- decrease adrenal aldo secretion
- interact w/ a cytosolic receptor
- may cause hyperkalemia
Causes of diuretic resistance
- decr renal drug clearance due to decr RBF and tubular transport
- hypoNa+ (nothing to natriuese!)
- sodium retention from RAAS
- increase ENaC/distal reabsorption
ACEI/ARB nephroprotective MoA?
vasodilate EA → decr glom cap P → inhib A2-producing mesangial cell growth
Rx for Central DI?
desmopressin
Rx for nephrogenic DI?
thiazides
amiloride
Three classes of immunosuppressants
—Subclasses
—Examples
Ab’s to T-cell membrane antigens
—Anti-IL-2 mabs
—Anti-ATG (human thymocyte antigen) polyclonals
T & B cell replication inhibitors
—pruine antimetabolites: mycophenolate, azathioprine
inhibitors of intracellular T-cell signalling
—glucocorticoids
—calcineurin inhibitors: cyclosporine, tacrolimus (newer analogue)
—mTOR agents: sirolimus
Give six examples of nephrotoxic drugs
- radiocontrast
- cisplatin
- amphotericin B
- aminoglycosides (e.g. gentamicin)
- calcineurin inhibitors =(
- analgesics
