1. Clinical Uses of CA-I - low ___ as diuretic - acute ___ sickness - metabolic ___ - glaucoma - urinary ___

efficacy mountain alkalosis alkalinization

Lecture 4: Renal Patho and Diuretics Flashcards by Reagan Smith

Diuretics decrease ___ due to decrease in ___ volume

Indication
- edema
- hypertension
- heart failure
- acute renal failure

BP, plasma

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which type of transport is likely a drug target?

active
- ATP-mediated
- symport
- antiport

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7 Classifications of Diuretics

inhibitors of carbonic anhydrase
osmotic diuretics
inhibitors of Na-K-Cl symport (LOOP)
inhibitors of Na-Cl symport (THIAZIDE)
inhibitors of renal epithelial Na channels
mineralocorticoid receptor antagonists
vasopressin antagonists

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Location of carbonic anhydrase inhibitors

proximal convoluted tubule

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Location of osmotic diuretic

PCT & descending limb of loop of henle

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Location of Loop diuretics

ascending thick limb of loop of henle

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Location of Thiazides

DCT

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Renal Drug handling

glomerular filtration depends on:
- GFR
- size of ___
- extent of plasma protein binding: only ___ drug is filtered

drug
unbound

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active secretion in PCT: OAT and OCT

active secretion depends on:
- amount of ___ binding
- the rate of ___ of the drug to the secretory site
- the degree of ___ of transporters
- the presence of drugs that can ___ for these transporter

Relatively ___ (competition)

plasma protein
delivery
saturation
compete

non-selective

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active secretion in PCT: OAT and OCT Direction

diffusion out of ___ to interstitial space
transport across ___ membrane
secretion across ___ membrane

capillary
basolateral
luminal

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drugs actively transported by OCT

amiloride
cimetidine
digoxin
metformin
morphine
procainamide
quinidine
ranitidine
triamterene
trimethoprim
vancomycin

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drugs actively transported by OAT

furosemide
thiazides
penicillin
cephalosporin
probenecid
NSAIDs

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Organic Anion Transporter (OAT): Probenecid and Penicillin

___ by probenecid at OAT to slow penicillin excretion and prolong activity
___ max blood concentration

competition
doubles

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1. Carbonic Anhydrase Inhibitors

Location: ___
inhibit both cytoplasmic and membrane bound CA
blocks reabsorption of ___

PCT
sodium bicarbonate (NaHCO3)

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1. CA-I

acetazolamide is used prophylactically for mountain sickness.
- effective due to metabolic ___ produced by the drugs counteracts the respiratory ___ that can result from hyperventilation in this condition.

acidosis, alkalosis

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1. Carbonic Anhydrase Inhibitors SAR

Derived from ___
1. sulfamoyl group essentinal for ___
2. sulfamoyl N unsubstituted to retain ___
3. derivatives with high partition coefficient and lowest pKa have > ___

Sulfanilamide
- diuresis
- activity
- potency

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1. Clinical Uses of CA-I

low ___ as diuretic
acute ___ sickness
metabolic ___
glaucoma
urinary ___

efficacy
mountain
alkalosis
alkalinization

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1. Toxicities of CA-I

___ metabolic acidosis
renal stones
renal ___ wasting
drowsiness/paraesthesia

hyperchloreic
stones
K

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2 Osmotic Diuretics

location(s): ___ , ___
larger, inert molecules
non - ___
altering renal medullary blood flow contributes to ___
example: ___

PCT, descending limb of loop of henle
reabsorbable
diuresis
mannitol

mannitol, glucose, urea, isosorbide, glycerine

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3) Na-K-2Cl symport inhibitor

aka ___ or ___ ceiling diuretics
act on ___ surface symport = must be in ___ for diuretic activity
___ response after IV admin
most ___ class (used for edema)
some possess weak ___ inhibitory activity
chronically reduce ___ acid secretion
problems with ___ , ___ , and ___ reuptake (wasting)

loop, high
luminal, lumen
rapid
potent
CA
uric
K, Ca, Mg

3 Na-K-2Cl symport inhibitor SAR

sulfamoyl group in ___-position essential for optimal diuretic activity
substituent at 1-positing must be ___ ; ___ group provides optimal diuretic activity. Other groups such as ___ may have diuretic activity.
activating group in ___-position can be Cl or CF3, phenoxy, alkoxy, anilino, benzly, benzoyl

5
acidic, carboxyl, tetrazole
4

3) Na-K-2Cl symport inhibitor Clinical use

edema
acute ___ edema
hypertension, heart failure
acute hyper____
hyper___
acute renal failure
___ overdose

pulmonary
hypercalcemia
hyperkalemia
anion

3) Na-K-2Cl symport inhibitor Toxicities

dehydration
hypo___ metabolic alkalosis
___toxicity
___uricemia
___magnesemia

hypokalemic
ototonicity
hyperuricemia
hypomagnesemia

3) Na-K-2Cl symport inhibitors

___ is a loop diuretic that is not derived from sulfonamides
- binds with bioavailable ___ to form active conjugate

ethacrynic acid (Adedcrin)
- thiol

# 4) inhibitors of Na-Cl symport - aka ___ diuretics - location: primary - ___, secondary - ___ - reduce ___ reuptake - Examples (3)

- thiazide - DCT - PCT - K - chlorothiazide, hydrochlorothiazide, and metolazone

# 4) inhibitors of Na-Cl symport SAR What is this?

chlorothiazide

# 4) inhibitors of Na-Cl symport SAR thiazides have 2 subclasses: thiazides and hydrothiazides. In the picture, the molecule on the left is a ___ and the right is ___

thiazide, hydrothiazides

# 4) inhibitors of Na-Cl symport Clinical Uses * hypertension * ___ failure * ___ due to idiopathic hypercalciuria * nephrogenic diabetes ___

* heart * nephrolithiasis * insipidus

# 4) inhibitors of Na-Cl symport toxicities * hypokalemic metabolic ___ * hyperuricemia * impaired ___ tolerance * hyperlipidemia * ___natremia

* alkalosis * carbohydrate * hyponatremia

Which of the following statements best explains why loop diuretics are far more effective than thiazide diuretics? A) loop diuretics increase renin secretion B) loop diuretucs are also weak inhibitors of CA C) the diuretic effect of thiazides undergoes partial tolerance D) The antihypertensive action of thiazides may reduce the glomerular filtration rate (GFR) E) more sodium is physiologically reabsorbed at the loop of henle than at the DCT

E) more sodium is physiologically reabsorbed at the loop of henle than at the DCT

# 5) inhibitors of renal epithelial Na Channels - aka ___ diuretics - location: late ___ and ___ - agents are relatively ___ diuretics - primarily used in ___with other diuretics - Examples (2)

* potassium-sparing * DCT, collecting duct * weak * combination * Amiloride, Triamterene

# 5) inhibitors of renal epithelial Na Channels Clinical Uses * adjunctive treatment with ___ or ___ diuretic in heart failure or hypertension

* thiazide, loop

# 5) inhibitors of renal epithelial Na Channels Tox/Contraindications toxicities: - hyper___ - hyperchloremic metabolic acidosis contraindications: - ___ supplements - ___ inhibitors

* hyperkalemia * K * ACE

# 6) mineralocorticoid receptor antagonists (MRA) * aka ___ antagonists, ___ diuretics * bind to ___ but do not stimulate ___ production * only diuretics that do not act within the ____ * example: ___ * strutures resemble ___

* aldosterone, potassium sparing * MR, AIP * tubular lumen * spironolactone * hormones | AIP = aldosterone induced proteins

# 6) mineralocorticoid receptor antagonists clinical uses - hypertension of heart failure with other diuretics - ___ excess - ___ (primary or secondary resulting from HF, hepatic cirrhosis, or nephrotic syndrome)

* mineralocorticoid * aldosteronism

# 6) mineralocorticoid receptor antagonists tox/contraindications Toxicities - hyper___ - hyperchloremic metabolic acidosis - ___ - impotence - benign ___ hyperplasia Contraindications: - ___ supplements - ___ inhibitors - chronic ___ insufficiency

* hyperkalemia * gynecomastia * prostatic - K - ACE - renal

# 7) Vasopressin Antagonists - vasopressin is also called ___ - V2 receptors = fluid ___ at the kidneys to increase ___ - V1 receptors = ___ of blood vessels to increase systemic vascular ___ - When bound to both V1 and V2, results in increase of ___ - Examples (2)

- ADH - reabsorption, blood volume - constriction, resistance - arterial pressure - Convaptan, Tolvaptan

# 7) Vasopressin Antagonists MOA 1. vasopressin is blocked from binding to the ___ receptor on the ___ membrane. 2. prevents aquaporins from relocating to the ___ membrane. 3. water cannot be ___ and is instead peed out as ___ urine 4. ___ plasma concentration is increased

1. V2, basolateral 2. luminal 3. reabsorbed, dilute 4. Na

# 7) Vasopressin Antagonists Conivaptan Dosing: IV ___ mg daily for ___ days Tolvaptan Dosing: PO ___ to ___ mg daily Which drug is more selective?

* 40 mg, 4 days * 15-60 mg * Tolvaptan (29.0 V2:V1 selectivity ratio vs 5.7)

# Pharmacokinetic/dynamic determinants of diuretic response * site of action is ___ * CA-I, furosemide, and thiazide diuretic are all highly bound to ___ = ___ not filtered * secretion is ___ = dose ___ * secretion of diuretics decreased with progressive renal failure, reducing their ___ * sensitivity to diuretics is reduced due to homeostatic responses in ___ (including hyperaldosteronism)

* luminal * plasma protein, secreted * saturable, dependent * effectiveness * CRF (chronic renal failure)

# Braking Phenomenon - water follows ___ - when Na excretion > Na intake, BW and ECF ___ - activation of ___ and ___ nervous system = braking phenomenon - when Na excretion = Na intake, BW and ECF stabilize at ___ level due to breaking effect - when Na excretion < Na intake, BW and ECF ___

* salt (Na) * decreased * RAAS, SNS, lower * rise

# Determinants of diuretic response Graph sodium excretion rate vs loop excretion rate Thank: what does the altered dose response relationship (braking) look like compared to normal

T or F: as CHF progresses, diuretic potency goes down

F; efficacy drops

T or F: CRF causes efficacy to shift, but potency can still be obtained with increased dose

F; caused POTENCY to shift, but EFFICACY can still be obtained with increased dose

T or F: combination of diuretics with different mechanisms is more effective than dose increases of a single agent

Location of renal epithelial Na channel inhibitors

Late DCT and collecting duct

Location of mineralocorticoid receptor antagonist

Late DCT and collecting duct

Location of vasopressin antagonists

Late DCT and collecting duct