Lecture 4: Renal Patho and Diuretics Flashcards
Diuretics decrease ___ due to decrease in ___ volume
Indication
- edema
- hypertension
- heart failure
- acute renal failure
BP, plasma
which type of transport is likely a drug target?
active
- ATP-mediated
- symport
- antiport
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
Location of carbonic anhydrase inhibitors
proximal convoluted tubule
Location of osmotic diuretic
PCT & descending limb of loop of henle
Location of Loop diuretics
ascending thick limb of loop of henle
Location of Thiazides
DCT
Renal Drug handling
glomerular filtration depends on:
- GFR
- size of ___
- extent of plasma protein binding: only ___ drug is filtered
- drug
- unbound
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
active secretion in PCT: OAT and OCT Direction
- diffusion out of ___ to interstitial space
- transport across ___ membrane
- secretion across ___ membrane
- capillary
- basolateral
- luminal
drugs actively transported by OCT
amiloride
cimetidine
digoxin
metformin
morphine
procainamide
quinidine
ranitidine
triamterene
trimethoprim
vancomycin
drugs actively transported by OAT
furosemide
thiazides
penicillin
cephalosporin
probenecid
NSAIDs
Organic Anion Transporter (OAT): Probenecid and Penicillin
- ___ by probenecid at OAT to slow penicillin excretion and prolong activity
- ___ max blood concentration
- competition
- doubles
1. Carbonic Anhydrase Inhibitors
- Location: ___
- inhibit both cytoplasmic and membrane bound CA
- blocks reabsorption of ___
- PCT
- sodium bicarbonate (NaHCO3)
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
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
1. Clinical Uses of CA-I
- low ___ as diuretic
- acute ___ sickness
- metabolic ___
- glaucoma
- urinary ___
- efficacy
- mountain
- alkalosis
- alkalinization
1. Toxicities of CA-I
- ___ metabolic acidosis
- renal stones
- renal ___ wasting
- drowsiness/paraesthesia
- hyperchloreic
- stones
- K
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
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
- vasopressin is blocked from binding to the ___ receptor on the ___ membrane.
- prevents aquaporins from relocating to the ___ membrane.
- water cannot be ___ and is instead peed out as ___ urine
- ___ plasma concentration is increased
- V2, basolateral
- luminal
- reabsorbed, dilute
- 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
T
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
