Pm_Renal_Pharma_Diuretics_I&ii

Front 1

3 Types of Diuretic Agents?

Back 1

1. Osmotically Active, not reabsorbed
2. Ibx of Na+ Reabsorbtion
3. Ibx K+ Excretion --NOT used alone for Diuresis

Front 2

Which Diuretics (DUs) work at PCT

Back 2

Osmotic DUs
&Carbonic Anhydrase Ibx

Front 3

List the type of DUs that work at the following points of Nef:
TAL:
Duct:
DCT:

Back 3

TAL: Loop DUs
Duct: K+ Sparing DUs (K+ SDUs)
DCT: Thiazides

Front 4

What 2 locations do Osmotically Active DUs work at

Back 4

PCT and
Descending Loop (note--until Late DCT/Duct this is the last place water is reabsorbed--thus last place to block it diuretically)

Front 5

Name 4 props necessary for Osmotic DUs?

Back 5

1.Solutes--h2o soluble, good distribution
2. Relatively Non-Reaborbed and relatively Non-Active or Inert

have to "hold" onto water from (swollen soma cells) all the way to Nef and thru PCT

Front 6

What is 1 drug that is prototype Osmotic DU?
What are other 3

Back 6

Mannitol (IV) --know this one

+ Urea (IV) , Glycerin, Isosorbide

Front 7

Good usage of Osmotic DUs ?

Back 7

Edema in Brain and Eye
--Not really used in HTN

Temp. Raises Osmolarity of Plasma--puls H20 out of tissue

ie: Cerebral Edema, IntraCranial P./traumatic head injuries
--Intraocular Pr.

Front 8

What is downstream effect of Mannitol after Tx for Edema/Brain/Eye swelling?
Any thing with Salts?

Back 8

Mannitol, being inert and non-reabsorb stays in Lumen of Kids and holds water = diuresis

There appears to a decrease in NaCl reabsorption in Descending Limb too with Manitol due to Volume Expansion

Front 9

What is Mannitol an Antidote for?

Back 9

Severe Li+ Toxicity
--Osmotic Diuretics cause Loss of Electrolytes non selectively

--among them = Na, K, Ca, Mg, Cl, Bicarb, and PO4 are excreted a bit too

Front 10

AEs of Osmotic DUs if too rapid infusion

Back 10

Pulm Edema-- solute can stay in blood/if cant get into kidney/bad kidney
Watch in CHF or Pts who are anuric
N/V and Headache
Dilutional Hyponatremia

AEs even in healthy kidney
Hypernatremia
Dehydration

Front 11

What are contraindications for Mannitol and Urea Osmotic DUs

Back 11

Active Cranial Bleeding

Front 12

What AEs for other 2 Osmotic DUs, Urea and Glycerin?

Back 12

Urea: Thrombosis and Pain
--don't use in Hepatic Insufficiency -- get elevated NH3

Glycerin: Hyperglycemia

Front 13

What specifically do Loop DUs block?
How do they get there?

Back 13

Are anionic acids that block the Cl- spot on Na/2CL/K symporter on lumenal side.

Get there via Tubular SECRETION!!!! not filtration = OAT

Front 14

What do Loop DUs block not directly related to diuresis?

Back 14

Ca and Mg reabsorption
--the Elec. Grad spaning lumen-cell-interstitium is disrupted no longer favoring into Cell from Lumen
--ie When Na/2Cl/K is blocked, there is less K to be Channeled out =less loss of Cation in Lumen, which WOULD have been replaced by these 2 Cats from the Lumen

Front 15

Moving on to Loop Diuretics which work where?

Back 15

Thick Ascending Loop of Henle
aka
High Ceiling DUs--ie, can block 20-25% of the filtered Na/Cl here and 10% of Water, where as theres limited capacity to reabsorb Na downstream (DCT)--~5% is R. there.

Front 16

What are the 3 prominent Sulfonamides Loop DUs
+ 1 that is not sulfa, but still an acid.

Back 16

Furosemide
Bumetanid
Torsemide

Ethacrynic Acid

Bind to Cl- part of Na/2Cl/K transporter

Front 17

What 4 Things are Increased in Urine with Loop DUs and 1 thing is decreased in Urine

Back 17

Increased:
Na, K+, Mg/Ca, Volume

Decreased:
Urate --with chronic use

Front 18

How are these 4 Loop DUs cleared

Back 18

ALL are mixed Renal and Liver

Front 19

Which Loop DU is preferred in CHF to dec Hospitalizations and inc Quality of Life?

Back 19

Torsamide
--has better bioavail oral than Furosemide too

Front 20

Of the Loop DUs, which are Extensively Protein Bound/Not Filtered,with Furosemide and Bumetanide how would you describe their onset? Peak Effect? and Duration?

Back 20

PO 15-20mins onset
with IV: Furosemide less than 5 mins rapid diuresis,
Rapid Peak Effect: 1-2 hours(oral) 30-45mins IV)

both have moderate duration, 4-6hours PO, 2-3 hours IV

Front 21

Which Loop DU has the greatest and least Bio Availability?

Back 21

Ethacrynic Acid: 100%
Furosemide: 60%/ variable

Torsemide and Bumetanide are both ~80%
bumetanide is very potent

Front 22

Indications for Loop DUs in Acute and Chronic settings?

Back 22

Acute PEdema:
1. From CHF, 2. From Emergency
Chronic CHF (will lower progression--improve ability to excercise)
--Edema assc/ Cirrhosis, Renal Dz, NEphrotic synd
HTN--but use limited by short half life

Front 23

What Lyte imbalance are Loop DUs useful for

Back 23

Symptomatic Hypercalcemia
--note: Tx the Sx of Hyper, but don't cause Hypo


note: Tx of HTN is complicated by their short t1/2

Front 24

What is key consideration for choosing type of DU with Pulmonary Edema
--think

Back 24

Loop DUs Alleviate PE
but
Osmotic DUs can PROVOKE it--not osmotically, but large bolus has effect on heart which if failing can .....

Front 25

AEs of Loop DUs
(4 lytes, 1 compound, fluid balance?)

Back 25

Acute Hypovolemia with Aldosterone Release
HypoNa
HypoK (K wasting downstream)
"HypoCa" (in osteoporotics)
HypoMg
Metabolic Acidosis (loss of Cl-)
HyperUricemia-->urate retention-->gout

Front 26

What other system doe Loop DUs affect?

Back 26

Ototoxicites
--deafness, tinnitus, vertigo
--Worse with Ethacrynic Acid
--additive iwth Aminoglycs--which have Oto as well

Front 27

What 2 common diseases might you avoid Loop DUs due to change in Lytes/Molecules?

Back 27

Gout--retention of urate

Osteoporosis--loss of Ca R (along with Mg)

Diabetics? due to hyperglycemia

Front 28

What are Contraindications for Loop DUs except Ethacrynic Acid?

Back 28

Hypersensitivity to Sulfonamides
--esp Furosemide and Bumetanide

Front 29

What is main potential interaction for Loop Diuretics
--think about CHF

Back 29

Interaction with Digoxin
-Mores susceptible to Dig Tox

Loops alone can cause HypoKalemia -- low serum K increases digoxin induced arrhys

Front 30

What is main potential interaction for Loop Diuretics
--think about Kidneys?

Back 30

NSAIDs
-blunt loop DU response
--ibx OAT of Loops into Lumen
--block PG-dependent renal blood flow

--NSAIDs reduce the DU effect in all

Front 31

Moving on to Thiazide DUs which work where?
What transporter

Back 31

DCT
-ibx Na Reabsorbtion
---disrupt Na/Cl Co-Transporter

Front 32

What do Thiazides do to Ca

Back 32

Enhance Ca Reabsorbtion (R)
while Loop DUs disrupt its R

Front 33

How do Thiazide DUs, which block the Na/Cl cotransporter into the DCT cell, enhance Ca R?

Back 33

On DCT, apical: Ca++ Channel
DCT. Basolateral: Ca/Na Antiport (Ca to blood)
--with Na/CL blocked,= Na deficit in DCT cell
-Deficit fixed by pumping Na in from Interstitium with Na/Ca antiporter = Ca deficit in cell as its sent to interstitium
=gradient for Ca to be R. from lumen
boom!

Front 34

What is effect of DU based on dosage regarding Loop DUs and Thiazide DUs

Back 34

Thiazides are Low Ceiling DUs, ie >90% NaCl has already been R. before DCT. Thus after effective dose, no increase in DU = modest DU to begin with

Whereas with Loop DUs, high Ceiling, there is an extended dose dependent increase in NaCl excretion as 20-25% of Na/Cl is R. in LOH.

Front 35

With thiazide DUs, what is Increased in Urine (3 things) and Decreased i Urine (2 things)

Back 35

Increased: Na, K and Volume (note K wasting)
Decreased: Urate, Ca (note Ca is inc. in urine/wasted with Loops)

note: inc. thiazide will only inc AE, not DU effect

Front 36

What are the 5 sulfonamide Thiazide Diuretics?

note: all are sulfas, some are benzothiadiazines--fyi

Back 36

--3 ___chlorothias__ + 2 oddballs
Chlorothiazide
Hydrochlorothiazide
Chlorthalidone

Indapamide
Metalozone

Front 37

General PKs of Thiazides

Back 37

good PO, rapid absorb
Diuresis in 1hour
variable T1/2 in this class (1 hour -->48 hours)

Front 38

As loops DONT get filtered to site of action, how do Thiazides get to DCT?

note: loops not at all b/c their highly PPB acids

Back 38

filtered/GLom
AND
Secreted via OATs

Front 39

When are Metolazone and Indapamide Thiazide DUs most useful?

Back 39

when GFR is low
<40 ml/min

Front 40

HOw else is Metolazone a DU

Back 40

Carbonic Anhydrase Ibx--weakly
thus it Increase Bicarb and Phos in urine

Front 41

What is indication for Thiazide DUs?

Back 41

HTN--1st line Tx
--reduce BP and accomp risk of MI and Strokes

Best Initial Tx in Uncomplicated HTN
--evidence from ALLHAT, JNC7 Trials

--Note: takes 7 days for BP to stabalize. anti HTN effect is unknown--vasodilation

Front 42

What are other indications of Thiazide DUs

Back 42

Nephrolithiasis due to Idiopathic HyperCalcemia via INcreasing SERUM Ca, taking AWAY form URine
---counterintuitive as it raises Ca levels in blood

--Also good for Edema (CHF, Nephrotic syndrome)
--Nephrogenic D. Insipidus---paradoxical effects???

Front 43

AEs of Thiazide DUs not related to Lytes?

Back 43

Volume Depeltion-->Orthostatic Hypotension
--will result in aldosterone release

this is bothersome Sx, whereas the HTN being Tx prolly wasnt = compliancy issue

Front 44

AEs of Thiazides regarding Lytes?

Back 44

HypoK
HypoNa
HypoCL-
Metabolic ALKALOSIS
HypoMg
HyperUrecemia --can precip Gout (chronic use)

HYPERCalcemia --for realzies
--opp to Loop Diuretics

Front 45

AEs (not direct lyte imbalances) for Thiazide DUs

Back 45

Dec. Glucose Tolerance--unmasks DM
Allergic Sulfa Rxn
ED/Impotence

-Inc. LDL/Dyslipidemia--again, not clinically sig.

Front 46

Drug Interaction of Thiazide DUs

Back 46

Thiazides + Quinidine
= Prolonge QT = lethal

Hypokalemia -> Torsades de pointes -.Vtach--.death

Front 47

Other Drug Interaction for thiazides shared with other DU?

Back 47

Dig Tox
NSAID blunting effects --block glom filtration/OAT of Thiazides by interefering with Renal Blood flow

Front 48

See iMportatant Table on page

Back 48

82

Front 49

Which DU are good for Osteoporotic fems, which is bad

Back 49

Thiazides good--effect stops when drug stopped

Loops Bad

Front 50

Moving on to K+ Sparing DUs (K+ SDUs)

Back 50

which are used with HTN, Refractory Edema and HF
in combo with other DUs

Front 51

What are 3 Primary Indications for use of K+ SDUs?
When are they DOC?

Back 51

Prevent K+ from Other DUs
Primary Aldosteronism
Secondary Aldosteronism

DOC in: Edema/Ascites from chronic ETOH; & Hepatic Cirrhosis

Front 52

With K+ SDUs use with other Diuretics, what Dz process indicate their use?

Back 52

HTN
Refractory Edema
Heart Failure (need K, else arrhys)

Front 53

Important!
What are the 4 MOA for which Thiazides and Loops Waste K+
-3 osmo/transporter mechs, 1 hormonal

Back 53

"Increased Urine Flow"--volume thru = less time to grab K
Increased Na in CD
Increased Na/K Exchange (later in Nef I believe)
Increased Aldosterone

Front 54

Note on Mech for inc Na/K exchange in DCT/CD:
Principle Cells have:
Na Channels and K Channels on lumen
3Na/2K ATPase on Basolateral

Back 54

PC Cell do DCT wants to grab the Na, elevated from Thia/Loops in lumen = inc Na in Cell = inc Na out 2 K in cell
=K overload in cell = Out channel into Lumen

All of which are Aldosterone Sensitive mechanisms too

Front 55

What are the 2 types of K+ SDUs agents?
What is basic mech for each

Back 55

Steroidal K+ SDU -- Aldosterone Antags
Non-Steroidal K+ SDU -- Na+ Channel Antags

Front 56

The 2 Steroidal K+ SDU/ Aldosterone (Rec) Antag drugs?

Back 56

Spironolactone -- prodrug
Eplerenone --more selective

Front 57

The 2
Non-Steroidal K+ SDU / Na Channel Blocker drugs?

Back 57

Triamterene
Amiloride

Front 58

What are 3 of the 4 K+ SDUs (steroid&non) drugs jacked up with? Which 3?

Back 58

Comboed with Thiazide
-Triamterene and Hydrochlorthiazide
-Spironolactone and Hydrochlorthiazide
-Amiloride and Hydrochlorthiazide

Front 59

If Aldosterone Receptor anatagonists are used, what channels/transporters are affected?
(ie how do Spirono and Eplero work)

Back 59

-K+ Channel (how K-->lumen) expressed less
-Na Channel (lumenal) expressed less (how Na builds intracellularly to increase the Na/K ATPase act.)
-Na/K ATPase expressed less--brings K into cell from blood

Front 60

How do the steroidal K+ SDUs get to site of action?

Back 60

Enter Cells via basolateral membrane
--NOT filtered OR Secreted by an OAT
---are hormones in blood

Front 61

With K+ SDUs, what is 2 things are inc. in urine and 3 dec. in urine?

Back 61

Inc: Na+ and Volume

Dec: H+, K+ and Ca+

Front 62

Non diuretic/lytes imbalance AE of Spironolactone

Back 62

Weak Androgen Receptor Antagonist
=predicatable

Front 63

Why does Spironolactone have such a slow onset?

Back 63

Needs hepatic bioactivation --its a prodrug --> Canrenone
before it can disrupt aldosterone mediated gene expression

Front 64

What is the active metabolite in spironolactone

Back 64

Canrenone
- longer half life too

Front 65

What are major AEs of Spironolactone?

Back 65

HyperKalemia--life threatening by itself

Endocrine/androgen related: Gynecomastia, Impotence, Menstrual Irregs, Dec. Libido

Front 66

Why is Eplerenone better?
Better AE?

Back 66

Eplero is selective for Aldosterone Receptor: lower incidence of Endocrine AEs

-watch [] as it is metab by CYP3A4, so 3A4 Ibx inc its []

Stil can cause Hyper K = death

Front 67

How do Amiloride and Triamterene work as K+ SDU?

Back 67

Block (not dec expression) Na+ Channel in Principle Cell
-=less Na R. from Urine = less drive for Na/K ATPase = less K buildup in PC of DCT = less kicked out
fuck yea! ninja turtles

Front 68

When are Triamterene and Amiloride indicated?

Is one better?

Back 68

Often with Loop/Thias for Edema or HTN Tx
--Amiloride is more potent/less toxic than Triamterene

Front 69

Which is DOC for special Lyte Disturbance

Back 69

Amiloride is DOC for Li+ Nephrogenic Diabetes
--blocks Li transport into CD cells

Front 70

Brief Note on comparative PK for Amiloride and Triamterene K spareres?

Back 70

Tria--60% PPB, Hepatic Metab, active metabs

Amilor--Free, Not Metabed, Excreted in Urine

BOTH secreted by OCTs in PCT!!!!

not really important card

Front 71

What are important AE s for Na Channel Antag K+ SDU drugs?

Back 71

HyperKalemia!!!

--DO NOT use in COMBO iwth Spironolactone as K+ sparing is additive
--Caution with ACEs

Front 72

Moving on to Carbonic Anhydrase Ibx, which work where?

Back 72

In the PCT motha f.er

Front 73

What is basic MOA for Carbonic Anhydrase Ibx (CAIbx) aside from obvious

Back 73

Drive Bicarb down tube, along follows Na = less R. of both
= holds onto Water in spite of some of the Na R. downstream
--thus CAIbx not as potent

Front 74

What is the prototypical drug for CAIbx Agents/ NaHCO3 Diuretics?

specific MOA to inc. Na and Bicarb in Lumen?

Back 74

Acetozolamide
--block R of bicarb ion, prevents Na/H exhange

Front 75

What are 2 main pharmco effects of Acetazolamide?

Back 75

Sodium Bicarb Diuresis
Metabolic Acidosis
---blocks the Na/H exchanger = H+ buildup in Cell

Front 76

What are 4 main things inc in urine with Acetazolamide CAIBx?

Back 76

Na (tho amply R.ed downstream)
K+
Bicarb
Volume

Front 77

Indications for CAIbx/Acetazolamide?
none so obvious, but make sence (4 named)

Back 77

1. Urinary Alkalinization
2. Metabolic Alkalosis
3. Glaucoma
4. Acute Mountain Sickness
----prevent it

Front 78

Note on these eCards?

Back 78

MOST to ALL of lecture inlcuded
---when study, glance at pictures for Channel/Trans clarifications and look for few slides with Red Circles.