Diuretics

Front 1

% of salt reabsoprtion, MOA, and diuretic acting at that site for . . .
1. PCT
2. LOH
3. DCT
4. collecting duct

Back 1

1. 67%; Na/H antiporter, Na/H/2Cl symporter; carbonic anhydrase inhibitors, osmostic agents
2. 25%; Na/K/2Cl symporter; loop agents
3. 5%; NaCl symporter, Na channels; thazides
4. 3%; Na channels; KSDs, ARAs

Front 2

How do drugs that aren't filtered by the glomerulus get into the PCT?

Back 2

organic anion transporters and organic cation transporters actively secrete drug into tubule

Front 3

Examples of Osmotic Drugs

Back 3

mannitol (IV), urea (IV), glycerin (PO), isosorbide (PO)

Front 4

2 MOA's of Osmotic Drugs

Back 4

1. limits water resorption in the PCT> increased serum osmolality > water pulled out of cells, increasing ECF volume
(only effects H2O, not electrolytes)
2. expansion of ECF > decreased renin release and blood visocisity > increased renal blood flow

Front 5

Adverse Effects of Osmotic Drugs
1. In general
2. Urea
3. Glycerin

Back 5

1. worsen volume status in pts with heart failure, ESLD, etc, cause hyponatremia initially followed by dehydration and hypernatremia, bloating/diarrhea (ex: eating too many sugar free candies)
2. extravasation/thrombosis, inducing encephalopathy in cirrhotic pts, contraindicated w/ active cranial bleeding (mannitol too)
3. hyperglycemia

Front 6

Therapeutic Uses of Osmotic Drugs

Back 6

-reducing cerebral edema (mannitol/urea)
-prophylaxis against acute renal failure (not superior to NS/hydration)
-second line (After loop drugs) therapy for oliguric renal failure
-acute glaucoma attacks, perioperatively for ocular surgery

Front 7

Examples of Carbonic Anhydrase Inhibitors

Back 7

"-amide": acetazolamide (most common), brinzolamide, dorzolamide, dichlorphenamide, methazolamide

Front 8

Effect of Carbonic Anhydrase Inhibitors on Urinary electrolytes and pH changes

Back 8

-NaCl: +
-NaHCO3: +++
-K: +
-body pH: decreased

Front 9

Carbonic Anhydrase MOA
1. N/K ATPase
2. N/H exchanger
3. Carbonic anhydrase (type IV)
4. Carbonic anhydrase (type II)
5. Na/HCO3 co-transporter
**what happens when carbonic anhydrase inhibitor is present?

Back 9

1. provedes chemical gradient to allow Na+ resorption from lumen into interstitum
2. resorbes Na+ and secrete H+ into lumen which interacts with bicarb to form H2CO3 (carbonic acid)
3. normally carbonic anhydrase (type IV) breaks down H2CO3 into CO2 and H2O which diffuse back into cell
4. CO2 with the help of carbonic anhydrase (type II) combines with water reforming H2CO3 which freely dissociates into H+ and bicarb
5. pumps bicarb and Na+ into interstitium (aids in reabsorption of water from tubule)
**filtered bicarb isn't broken down and taken back into cell > inc urine pH, dec body pH; inhibits ultimate water resorption

Front 10

Osmotic Drugs Pk
-dosing
-how does it get into tubule?

Back 10

-give large doses
-passively filtered through glomerulus

Front 11

Carbonic Anhydrase Inhibitor MOA

Back 11

Front 12

Physiologic Effects of Carbonic Anydrase Inhibitors
1. urine and body pH
2. Na delivery
to TAL
3. K and PO4
4. tachyphylaxis
5. TGF

Back 12

1. bicarbonate uria (ph 8), non-AG hyperchloremic metabolic acidosis
2. increased delivery of Na and water to TAL
3. excretion of K and PO4
4. tachyphylaxis b/c eventually less bicarb is available (needed for drug to work)
5. enhanced TGF, owing to increased Na deliver to JG (dec GFR and renal blood flow)

Front 13

Adverse Reactions of Carbonic Anhydrase Inhibitors

Back 13

1. contain Sulfur: rash, BM suppression, interstitial nephritis
2. rare hepatotoxicity
3. drowsiness/paresthesias at high doses
4. bicarbonaturia/metabolic acidosis: NH4>NH3 may lead to encephalopathy, Ca3(PO4) precipitation (stomes), may worsen acidosis
5. PG category C

Front 14

Drug Interactions of Carbonic Anhydrase Inhibitors

Back 14

1. weak organic bases (dextroamphetamine, quinidine) more likely non-ionized
2. weak organic acids (phenobarbital, ibuprofen) more likely ionized
3. additive hypokalemia (loops, amp B, steroids)

Front 15

Therapeutic Uses of Carbonic Anydrase Inhibitors

Back 15

1. weak diuretics by themself (chronic use limited by tachyphylaxis and acidosis)
2. decreased intraocular pressure for glaucoma
3. anti-seizure
4. prophylaxis for altitude sickness
5. treatment of metabolic alkalosis (when giving Na isn't an option)

Front 16

Loop Agents effect on Urinary Electrolytes and pH changes

Back 16

-NaCl: ++++
-NaHCO3: 0
-K: +
-body pH: decreases

Front 17

Loop MOA

Back 17

1. inhibit Na/K/Cl symporter on luminal side (normally pumps 1Na, 1K, 2Cl- into cell)
2. minimizes Na/K/Ca/Mg/NH4 resorption
3. lack of cation resoprtion decreases interstitial osmolality decreasing the drive to resorb more water from the collecting duct
4. disrupt transepithelial potential differences (more neg cell), favoring loss of Mg and Ca

Front 18

Physiologic Effects of Loops
1. Na, Ca, Mg
2. uric acid
3. TGF
4. renin production
5. effect on blood vessels

Back 18

1. increase Na/Ca/Mg excretion
2. cause uricosuria acutely, but hyperuricemia w/ chronic use
3. TGF is negligible
4. Na flux across macula densa leads to increased renin production; exacerbated by volume depletion
5. cause vasodilation (esp frosemide)

Front 19

Examples of Loop Diuretics

Back 19

furosemide, bumetanide, ethacrynic acid (only one w/o S), torsemide

Front 20

Adverse Rxns of Loops

Back 20

1. Na/volume depletion (hypotension, renal insuffiency)
2. hypokalemia (arrhythmia), hypocalcemia (tetany), hypomagnesemia (arr), metabolic alkalosis
3. ototoxicity
4. rash, photosensitvity, BM suppression
5. PG category C (except ethacrynic acid which is category B)

Front 21

Drug Interactions of Loops

Back 21

1. AGs: ototoxicity
2. salicylates/warfarin: albumin displacement
3. anti-DM agents: hyperglycemia
4. NSAIDS: block natriuretic/diuretic effects (in Na resorption in PCT)
5. probenecid: compete for OASP (Shift dose curve to right)
6. thiazides: duresis, dehydration (sometimes combo used in pts more resistant to diuretics)

Front 22

Therapeutic Uses of Loops

Back 22

1. CHF
2. HTN (second line- thiazides first choice b/c take less often)
3. nephrotic syndrome
4. ascites (w/ spironalactone)
5. hypercalcemia, hyponatremia (SIADH)
6. diuresis w/ significant renal disease (inc dose so you can get enough into tubule)
7. forced diuresis to minimize toxicity (uncommon)

Front 23

Thiazide Effect on Urinary Electrolytes and Body pH

Back 23

-NaCl: ++
-NaHCO3: +
-K: +
-body pH: increases

Front 24

Examples of Thiazide Diuretics

Back 24

all end in "-azide" except chlorthalidone, indapamide, metolazone

Front 25

Thiazide MOA

Back 25

1. inhibit NaCl cotransporter in DCT which prevents NaCl reabsorption
3. causes Na/Ca anti-transporter to work harder (more Ca pumped into intersititum)

Front 26

Physiological Effects of Thiazides
1. affect on collecting duct
2. TGF effect
3. effect on Ca and Mg
4. carbonic anhydrase
5. uric acid

Back 26

1. allow water resorption from CD (unlike loops) since they don't act on TAL
2. no effect of TGF, renal blood flow, or renin production
3. hypercalcemia (reduced secretion into lumen; opp of loops), hypomagnesemia

Front 27

Adverse Reactions of Thiazides

Back 27

1. ED
2. hypovolemia, hypokalemia, hyponatremia, hypochloremia, hypomagnesemia, hyperuricemia, hypercalcemia, metabolic alkalosis
3. impaired glucose tolerance (unmask latent DM2)
4. worsened FLP (inc LDL and trigs)
5. sulfonamide allergy (rash, SJ, TEN, etc)

Front 28

Drug Interactions of Thiazides

Back 28

1. hypokalemia (w/ concurrent agents)
2. agents that may cause SIADH and promote hyponatremia (SSRIs, vasopressin, carbamazepine, sulfonylureas)
3. Hypercalcemia (tamoxifen, calcium carbonate, calcitriol)
4. hypomagnesemia (AGs, loops, cisplatin)
5. lithium toxicity (competition for OASP)
6. volume depletion (loop + thiazide)

Front 29

Therapeutic Uses of Thiazides

Back 29

1. edematous states (second line to loop, b/c not as potent)
2. HTN (first line)
3. Calcium nephrolithiasis (prevents Ca secretion into tubule)
4. nephrogenic diapetes insipidus (MOA unknown)
5. PG category C

Front 30

Thiazide Dosage: 25-50mg PO QD

Back 30

-depends on what you are using drug for (anti-HTN effect at lower dose than diuretic effect)
-higher dose provides no additional benefit for HTN and may increase toxicity
-start on lowest dose when combined w/ loop
-ineffective w/ CrCl <30mL/min

Front 31

Examples of Potassium Sparing Drugs ( 2 classes)

Back 31

1. potassium sparing diuretics (KSDs): tiamterene, amiloride (weak bases unlike other DUs)
2. Alodosterone receptor antagonists (ARAs): spironolactone, eplerenone

Front 32

KSD MOA

Back 32

1. block Na channels from luminal side of collecting duct
2. decreasing Na reabsorption results in less potassium excretion
3. minimizes H+ secretion by blocking membrane depolarization w/in alpha-intercalated cells (metabolic acidosis)

Front 33

ARA MOA

Back 33

1. bind recceptors in cell cytoplasm, preventing the binding of aldosterone
2. prevents increased Na+ channel activity, upregulation of basolateral Na/K ATPase, and less permeable tight junctions induced by aldosterone
3. net result is less Na+ and water resorption

Front 34

Physiologic Effects of . . .
1. KSDs
2. ARAs

Back 34

1. eliminate lumen-negative potential, minimizing K, Mg, Ca secretion; no effect on renin/TGF
2. similar to KSDs, but natriuresis depends on endogenous levels of aldosterone (more aldosterone, more potent effect); block steroid synthesis

Front 35

Pk of KSDs and ARAs
1. triameterene and liver function
2. spironolactone
3. eplerenone oral absorption

Back 35

1. triamterene is metabolized to active metabolite by liver; bad choic for decreased liver function pts
2. spironolactone is metabolized to active metabolite (canrenone); enterohepatic circulation
3. eplerenone as oral F of 100%

Front 36

Adverse Effects of . . .
1. both KSDs and ARAs
2. only KSDs
3. only ARAs

Back 36

1. severe hyperkalemia and metabolic acidosis
2. megaloblastic anemia (triamterene inhibits folate pathway), rarely causes hyperglyc, interstitial nephritis, renal stones, photosensitivity, PG risk B (risk for placental dehydration)
3. decreased steroids (gynecomastia, impotence, etc- eplerenone may have fewer anti-androgen SEs), diarrhea/gastritis (spiron- caution in PUD), eplerenone not used w/ CrCl <50, spiron PG class D, Eplerenone PG class B

Front 37

KSD Effect on Urine Electrolytes and Body pH

Back 37

1. NaCl: +
2. NaHCO3: +
3. K: 0
4. body ph: decreases (minimizes H+ secretion)

Front 38

Drug Interactions of KSDs and ARAs

Back 38

drugs that increase risk of hyperkalemia (ACE inhibitors, K+ supplements, NSAIDs)

Front 39

Therapeutic Uses of KSDs

Back 39

1. minor diurect role (only 3% Na load available)
2. used in conjuction w/ potent diuretic (loops) to minimize hypokalemia
3. aerosolized amiloride: assists CF pts w/ mucociliary clearance
4. diabetes insipidus secondary to lithium toxicity (blocks lithium transport into tubule)

Front 40

Therapeutic Uses of ARAs

Back 40

1. combo w/ potent diuretics to minimize hypokalemia
2. spironolactone for Class III/IV CHF
3. primary and secondary hyperaldosteronism (cirrhosis w/ ascites, nephrotic syndrome, etc)
4. eplerenone for CHF post-MI or HTN

Front 41

ADH/Vasopressin
1. how's is produced
2. what stimulates it's release
3. what inhibits it's release
4. what happens to urine w/ increased ADH release

Back 41

1. made by supraoptic and paraventricular nuclei, then transported to posterior pituitary
2. hyperosmolality (>280mOsm/L) and hypotension/hypovolemia (also angiotensin II/III, vincristine, cyclophosphamide, TCAs, nicotine, epinephrine, SSRIs can inc release)
3. ethanol, phenytoin, glucocorticoids, fluphenazine, haloperidol, promethazine, butorphanol
4. ADH increases osmolality of urine (more water resorption)

Front 42

Physiologic Effects of ADH
1. V1
2. V2
3. body temp
4. procoagulants
5. contractions of...

Back 42

1. constriction promotes max solute concentration capcity in medullary
2. increased water reabsorption
3. natural antipyretic factor
4. increases concentrations of factor VIII, and vWF
5. uterine and GI contractions

Front 43

ADH action on kidney

Back 43

1. ADH binds V2 and causes stimulation via G protein and inc cAMP production
2. aquoaporins (AQP2) form in luminal membrane allowing water to be resorbed
3. inc permeability of collecting duct to urea
4. stimulates NaCl resorption in TAL, DT, and collecting duct

Front 44

Therapeutic Uses of ADH

Back 44

1. Central Diabetes Insipidus: give ADH preparations (pitressin, desmopressin)
2. Nephrogenic Diabetes Insipidus: remove offending drugs, consider amiloride for Li-induced DI, thiazides reduce urine volume

Front 45

Adverse Effects of ADH

Back 45

1. nasal irritation
2. V1 mediated: cutaneous vasoconstriction and facial pallor, N, belching, cramping, urge to defecate
3. V2 mediated: water intoxication (hyponatremia)

Front 46

Tolvaptan (new drug; $312-625 per day!)
1. MOA
2. therapeutic uses
3. drug interactions
4. boxed warning
5. contraindications

Back 46

1. selective V2 antagonist in collecting duct (dec water resorption, inc serum Na)
2. treating significant hyponatremia (hypervolemic- CHF, liver disease, euvolemic- SIADH)
3. substrate for CYP3A and Pqp
4. only start in hospital to decrease risk of overly rapid correction of serum Na
5. inhability of pt to respond to thirst, hypovolemic hyponatremia (V/D), hypotension, renal failure, concomitant use w/ strong CYP3a inhibitor

Front 47

Loops MOA

Back 47

Front 48

Thiazide MOA

Back 48

Front 49

KSD MOA

Back 49

Front 50

ARA MOA

Back 50

Front 51

ADH MOA

Back 51