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Pharm - Cardiovascular > Diuretics > Flashcards

Diuretics Flashcards

1
Q

Proximal tubule - what solutes?

A

-Reabsored: NaHCO3, NaCl, H2O, glucose, amino acids,…

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2
Q

Where is K reabsorbed?

A

compulsively 65% at the proximal tubule

and regulated at the distal convoluted tubule

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3
Q

Acetazolamide -

  • Where does it act?
  • what substrate?
  • what enzyme/receptor?
  • how does it work?
A
  • proximal convoluted tubule
  • sodium bicarb
  • carbonic anhydrase inhibitor
  • reabsorbing less sodium so more sodium in tubule = more water in tubule
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4
Q

Osmotic agents

  • where does it act?
  • What substrate?
  • how does it work?
A
  • proximal convoluted tubule, thin descending loop, collecting duct
  • water is manipulated
  • osmotic agents are filteredand not reabsorbed so water moves into tubule to be with the osmotic agent.
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5
Q

Loop agents:

  • where does it act?
  • what substrate?
  • what enzyme/receptor?
  • How does it work?
A
  • Thick ascending limb
  • Na/K/Cl
  • Na/K/Cl co-transporter blocker
  • block sodium reabsorption = block reuptake of water
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6
Q

Thiazides

  • where does it act?
  • what substrate?
  • what enzyme/receptor?
  • How does it work?
A
  • Distal convoluted tubule?
  • NaCl
  • NaCl Co-transporter
  • blocked re-uptake of Na = no reuptake of water
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7
Q

Aldosterone antagonists

  • where does it act?
  • What substrate?
  • what enzyme/receptor?
  • How does it work?
A
  • Collecting tubule
  • its actions affect reuptake of NaCl
  • antagonist to the aldosterone receptor
  • bind antagonizing the aldosterone receptor we reduce the reabsorption of NaCL = water does not get reabsorbed
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8
Q

ADH antagonists

  • where does it act?
  • what substrate affected?
  • What enzyme/receptor?
  • How does it work?
A
  • collecting duct
  • H2O
  • blocks ADH pore from being inserted into collecting duct membrane = cant bring water back in
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9
Q

Glomerulus

1) Functions
2) Water permeability?
3) Primary transporters and drug targets at apical membrane?
4) diuretic with major action?

A

1) formation of glomerular filtrate
2) Extremely high H20
3) No transporters or anything
4) No diuretic

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10
Q

Proximal convoluted tubule (PCT)

1) Functions
2) Water permeability?
3) Primary transporters and drug targets at apical membrane?
4) diuretic with major action?

A

1) Reabsorption of 65% filtered Na,K,Ca, and Mg; 85% of NaHCO3; and nearly 100% of glucoase and amino acids; isosmotic reabsorption of water
2) VERY HIGH H20
3) Na/H Exchanger (NHE3); Carbonic anhydrase
4) carbonic anhydrase inhibitors

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11
Q

Proximal tubule ,straight segments

1) Functions
2) Water permeability?
3) Primary transporters and drug targets at apical membrane?
4) diuretic with major action?

A

1) secretion and reabsorption of organic acids and bases (uric and most diuretics)
2) Very high H2O
3) Acid and base transporters
4) No drugs

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12
Q

Thin descending limb of henles loop

1) Functions
2) Water permeability?
3) Primary transporters and drug targets at apical membrane?
4) diuretic with major action?

A

1) passive reabsorption of water
2) HIGH H2O
3) aquaporin
4) No drugs

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13
Q

Thick ascending limb of henle’s loop

1) Functions
2) Water permeability?
3) Primary transporters and drug targets at apical membrane?
4) diuretic with major action?

A

1) active reabsorption of 15-25% of filtered Na, K, Cl; secondary to reabsorption of Ca and Mg
2) Very Low H2O
3) Na/K/2Cl (NKCC2)
4) NKCC inhibitors or loop diuertics

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14
Q

Distal convoluted tubule

1) Functions
2) Water permeability?
3) Primary transporters and drug targets at apical membrane?
4) diuretic with major action?

A

1) active reabsorption of 4-8% of filtered Na and Cl; Ca reabsorption under parathyroid hormone control
2) Very low H2O
3) Na/Cl (NCC)
4) Thiazides

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15
Q

Cortical collecting tubule

1) Functions
2) Water permeability?
3) Primary transporters and drug targets at apical membrane?
4) diuretic with major action?

A

1) Na reabsorption 2-5% coupled to K and H secretion
2) Variable H2O
3) Na channels (ENaC), K channels, H transporer, aquaporins
4) K sparing diuretics (Sparing as in we CANT get rid of the K)

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16
Q

Medullary Collecting duct

1) Functions
2) Water permeability?
3) Primary transporters and drug targets at apical membrane?
4) diuretic with major action?

A

1) water reabsorption under vasopressin control
2) variable H2O
3) Aquaporins
4) Vasopressin antagonist

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17
Q

prototypical carbonic anhydrase inhibitor is…

A

acetazolamide

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18
Q

Carbonic anhydrase is present in what tissues?

A 
ciliary body
kidney
erythrocyte
gut
choroid plexus
glial cells
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19
Q

Carbonic anhydrase Inhibitors (CAIs)

-MOA?

A

AT THE NEPHRON LEVEL:

1) blockage of CA (both II and IV) causes major loss of HCO3- in the urine - Decreases RBF and GFR (specifically: H from inside cell exchanged for Na inside tubule via Na/H exchanger. Na pumped into interstitial fluid. H in tubule now combines with HCO3 to form H2CO3. H2CO3 rapidly degraded to CO2 and H20 by CAIV. CO2 difuses into cell and made back into H2CO3. via CAII. H2CO3 disociates into H and HCO3- again… cycle repeats)
2) blocks CA II that is involved with new HCO3- formation via formation of titratable acid and via the secretion of ammonium ion = Less HCO3- = metabolic acidosis!
3) inhibit secretion of titratable acid and NH4+ secretion = metabolic acidosis!

–>increasing bicarb excretion–> increase Na and Cl excretion–> increase K excretion and getting diuresis

  • diuresis and metabolic acidosis are main goals.
  • metabolic acidosis is more desired effect
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20
Q

Carbonic anhydrase inhibitors

- Clinical indications

A

1) Glaucoma: CA is in ciliary body - inhibition here causes decreased aqueous humor production and decreased intraocular pressure. topical treatment=no diuretic and/or systemic metabolic effects
2) Acute mountain sickness: weakness, dizziness, insomnia, headache, and nausea if climber goes above 3000m. Serious cases get pulmonary or cerebral edema. CA in coroid plexus=block decreases CSF formation. block decreases pH of CSF in brain= increased ventilation and diminished symptoms
3) Urinary alkalinization: uric acid, cystine, and other weak acids are most easily reabsorbed from acidic urine=excretion can be enhanced by increasing urine pH with CAIs. Short lasting effects. Prolonged therapy=may need to administer HCO3
4) Edema states: CAIs rarely used for edema anymore. Can be combined with NKCC or NCC inhibitors

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21
Q

CAIs - Adverse effects:

A

1) hyperchloremic metabolic acidosis: results from chronic reduction of body HCO3- stores by CAI and limits the diuretic efficacy of the drugs to 2-3 days. unlike diuresis, acidosis persists as long as drug continued (CL COMES INTO CELL FOR BICARB but if not bringing bicarb back = not losing Cl)
2) Renal stones: phosphaturia and hypercalciuria occur during the bicarbonaturic response to CAIs. Renal excretion of solubilizing factors may decrease with chronic CAI use. Ca salts are insoluble at alkaline pH = potential for renal stone formation
3) Renal potassium wasting: can occur bc Na presented to the collecting tubule is partially reabsorbed, increasing the lumen negative electrical potential in that segment and enhancing K secretion. Can counter this effect by administering KCl

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22
Q

CAIs - Contraindications:

A

with use get inhibitor induced alkalinization of the urine which decreases urinary excretion of NH4+ = hyperammonemia and hepatic encephalopathy in patients with cirrhosis

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23
Q 
Osmotic diuretics - 
MOA?
example drug?
Sites of action?
Effect on K?
A
  • osmotically active agents that are freely filtered and not reabsorbed cause water to be retained in the relevant segments
  • mannitol
  • proximal tubule & thin limbs of loop of henle (MAIN)
  • due to increased distal flow - K secretion is stimulated
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24
Q

Osmotic diuretics- clinical applications:

A

1) prophylaxs for acute renal failure (ARF)- Acute tubular necrosis (ATN) = intrinsic ARF - mannitol reduces GFR associated with ATN when administered before the ischemic insult or offending nephrotoxin
2) Cerebral edema: osmotic diuretics alter starling forces so that water leaves cells and reduces intracellular volume = reduced intracranial pressure in neurologic conditions
3) Dialysis disequilibrium syndrome: too fast removal of soluted from the ECF by hemodialysis or peritoneal dialysis=reduction in the osmolality of the ECF. due to latter, water moves from ECF to intracellular compartment=hypotension and CNS symptoms (headache, nausea, muscle cramps, restlessness, CNS depression and convulsions. Osmotic diuretics increase osmolality of the ECF compartment whcih brings water back into the ECF
4) acute attacks of glaucoma: osmotic diuretics increase plasma pressure whcih removes water from the eye=reduce Intra ocular pressre

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25
Q

Renal protection by mannitol - MOA:

A

1) removal of obstructing tubular casts
2) dilution of nephrotoxic substances in the tubular fluid
3) reduction of swelling of tubular elements via osmotic extraction of water

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26
Q

Osmotic diuretics - Adverse effects:

A

1) expansion of extracellular fluid volume = may cause frank pulmonary edema in patients with HF or pulmonary congestion
2) hyponatremia: extraction of water also causes hyponatremia = headache, nausea, vomiting
3) Hypernatremia: loss of water in excess of electrolytes can cause too much Na and dehydration

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27
Q

Osmotic Diuretics - contraindications:

A

1) anuira due to severe renal disease or who are unresponsive to test doses of drugs
2) impaired liver function: urea should not be used - risk elevation of blood ammonia levels
3) active cranial bleeding: both mannitol and urea and a no-no
4) hyperglycemia: glycerin is metabolized and can cause hyperglycemia

28
Q

Loop diuretics -

general MOA:

A
  • also termed NKCC inhibitors
  • selectively inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle
  • huge potential here since so much NaCl absorptive capacity = very efficacious
29
Q

Osmotic diuretics drugs:

A

mannitol
glycerin
isosorbide
urea

30
Q

Loop diuretic drugs:

A

Furosemide
bumetanide
ethacrynic acid

31
Q

NKCC inhibitors specific MOA:

A

1) inhibit Na/K/2Cl cotransporter = inh reabsorption of solute from Thick ascending limb segments
2) reduce proximal fluid reabsorption modestly
3) increase fractional Ca excretion by 30% by decreasing the lumen-positive transepithelial potential that promotes paracellular Ca reabsorption
4) increase fractional Mg excretion by 60% by decreasing voltage dependent paracellular transport (Mg and Ca absorbed paracellularly - aka between the tubular cells of Thick ascendi - so NKCC stops this process fro happening)
5) VENODILATION decreases right atrial and pulmonary capillary wedge pressure within minutes via IV

32
Q

Specific additional MOA for furosamide:

A
  • NKCC inhibitor/loop diuretic

- - Causes **VENODILATION: decreases right atrial and pulmonary capillary wedge pressure within minutes via IV

33
Q

NKCC - clinical applications:

A
  • *1) Acute pulmonary edema: rapid increase in venous capacitance (venodilation) in conjunction with a brisk natriuresis reduces left ventricular filling presures and rapidly relives pulmonary edema
  • *2) chronic congestive heart falure: to minimize venous and pulmonary congestion. Diuretics cause significant reduction in mortality and the risk of worsening HF as well as an improvement in exercise capacity
  • *3) (acute renal failure) Nephrotic syndrome: edema of nephrotic syndrome often is refractory to other classes of diuretics. loop diuretics are often the only drug capable of reducing the massive edema associated wti this renal disease
    4) liver cirrhosis: loop diuretics tx edema and ascites of liver cirrhosis. Careful to not induce encephalopathy or hepatorenal syndrome
    5) drug overdose: loop diuretics can be used to induce a forced diuresis to facilitate more rapid renal elimination of the offending drug
  • *6) hypercalcemia- loop diuretics, combined with isotonic saline administration to prevent volume depletion, used to treat hypercalcemia
    7) hyponatremia: loop diuretics interfere with the kidneys capacity to produce concentrated urine. = loop diuretics combined with hypertonic saline are useful for the treatment of life threatening hyponatremia
34
Q

NKCC - adverse effects

A

1) hyponatremia: too much loop diuretic use can cause serious depletion of total body Na. manifests as: hyponatrema, extracellular fluid volume depletion associated hypotension, reduced GFR, circulatory collapse, thromboembolic episodes, and in patients with live disease hepatic encephalopathy
* ***2) hypokalemia: if K dietary is not a lot = problems –> cardiac arrhythmias, esp in patients taking cardiac glycosides
3) hypocalcemia & hypomagnesia: inc Mg and Ca excretion may result in low later=cardiac arrhythmias and tetany respectively
4) ototoxicity: manifests as tinnitus, hearing impairment, deafness, vertigo, and a sense of fullness in the ears. Hearing impairment and deafness usually but not always reversible. most often occurs with quick IV administration
5) hyperuricemia: leads to gout

35
Q

NKCC - contraindications:

A

Do not use if:

1) severe Na and volume depletion
2) hypersensitivity to sulfonamides (sulfanamide based loop diuretics)
3) anuria unresponsive to a trail dose of loop diuretic

36
Q

Why is adverse effect of Hypokalemia for NKCC super important?

A

NKCC used extensively in people with CHF who have digoxin and other antiarrhythmics so you can imcrease risk of adverse effects for other drugs if K is low

monitor these patients!

37
Q

Thiazides and Sulfonamide compounds

  • Drug names;
  • MOA?
A

1) chlorthiazides, metolazone; indapamide
2) MOA:
- inh Na transport predominantly in the distal collecting ducts by blocking the Na/Cl co transporter (NCC - DIF FROM THICK ASCENDING BC K IS NOT TRANSPORTED HERE)
- some has CAI inhibitory activity
- increase Ca reabsorption
- vasodilation- weaker effect that NKCC inhibitors

38
Q

thiazides and sulfonamides-

clinical indications:

A

1) edema states due to congestive heart failure, hepatic cirrhosis, and renal disease: most thiazide diuretics are ineffective when GFR <30-40ml/min (EXCEPT WITH METOLAZONE AND INDAPAMIDE)
2) hypertension: alone or combo with other antihypertensives - should only use low doses bc higher dose = adverse effect- best intial therapy for uncomplicated hypertension
3) calcium nephrolithiasis - reduce urinary excretion of Ca
4) nephrogenic diabetes insipidus: reduce urine volume by up to 50% in the s patients - by: inc renal Na reabsorption; recovery of aquaporin-2 abundance; recovery of NCC, ENaC
5) Hypercalciuria - high calcium in urine = stones!

39
Q

Why use thiazides to treat HTN patients?

He didnt go through this in class

A
  • inexpensive,
  • same good efficacy
  • well tolerated
  • once daily dose
  • no dose titration
  • few(er) contraindications
  • additive/synergistic effects when in combo with other drugs
40
Q

Thiazides & sulfonamides -
Adverse effects:
(He didnt go through this in class)

A

1) hypokalemic metabolic acidosis and hyperuricemia (similar to loop diuretics)
2) impaired glucose tolerance: a) hyperglycemia in patients who arediabetics or even mildly abn glucose tolerance tests
b) can be reversible with correction of hypokalemia
3) hyperlipidemia: 5-15% inc in total serum cholesterol and LDL - may return to norm if drug used for long time
4) hyponatremia: combo effect of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst - can be prevented by reducing drug dose or limiting water intake
5) alergic reactions: cross reactivity with other members of this chem grouop = photosensitivity or generalized dermatitis- some serious allergic rxn=hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis

41
Q

MOA for impaired glucose tolerance with thiazides and sulfonamides:
(He didnt go through this in class)

A
  • thiazides impair pancreatic insulin release and decrease tissue glucose utilication
  • can be reversible with correction of hypokalemia
42
Q

thiazides and sulfonamides
contraindications:
(He didnt go through this in class)

A

hypersensitivity to sulfonamides

43
Q

(loop diuretics) furosamide vs thiazides & sulfonamides - what happens to Ca?

A 
Furosamide = INCREASE EXCRETION OF CALCIUM
thiazides/sulfonamides = DECREASE EXCRETION OF CALCIUM
44
Q

Inh of renal epithelial Na channels

  • Drugs?
  • MOA?
A
  • amiloride & triamterene
  • (Amiloride) MOA: blocks epithelial Na channels in the luminal membrane of principal cells in the late distal tubule and collecting duct by competing with Na for negatively charged areas within the Na channel pore
45
Q

Inhibitors of renal epithelial Na channels

The drugs:

A

amiloride and triamterene

46
Q

inhibitors of renal epithelial Na channels:

-Clinical application:

A
  • Used in combo with other diuretics.
  • weak as single agent
  • augment the diuretic and antihypertensive response to thiazide and loop diuretics
  • reduce K excretion –> offset the kaliuretic effects of thiazide and loop diuretics
47
Q

Inhibitors of renal epithelial Na channels

-adverse effects:

A
  • **1) hyperkalemia: can be life threatening. DO NOT USE IN PATIENTS WITH HYPERKALEMIA (AKA PATIENTS WITH RENAL FAILURE, OTHER DIURETICS THAT SPARING K, PATIENTS TAKING ACE INHIBITORS, PATIENTS TAKING K SUPPLEMENTS, PATIENTS ON Na CHANNEL INH)
    2) Glucose intolerance and photosensitization
    3) interstitial nephritis and renal stones
48
Q

Inhibitors of renal epithelial Na Channels:

contraindications:

A

HYPERKALEMIA!

49
Q

Long story short on why hyperkalcemia is bad with Inh of renal epithelial Na channels?

A

-WE PREVENT REUPTAKE OF NA WITH THIS DRUG BUT ON BASOLATERAL MEMBRANE NA IS NEEDED FOR NA/K SYMPORT = SO WE LOOSE ABILITY TO PULL K INTO CELL FROM INTERSTITIAL FLUID

50
Q

Two segments of nephron important for K excretion:

A

1) Proximal convoluted tubule: 65%

2) Late distal convoluted tubule

51
Q

Aldosterone receptor antagonists:

- DRUGS?

A

spironolactone

eplerenone

52
Q

Aldosterone receptor antagonisms

-MOA?

A

1) diuretic effect: competitively inh the binding of aldosterone to MRs (Aldosterone antagonists) = *less Na uptake & less K excretion
2) additional effects:
a) spironolactone increases probability of survival of heart falure with standard therapy to 45-65%
b) prevent L ventricular remodeling and fibrosis: latter major mech that leads to dev and progression of HF.
c) prevention of sudden cardiac death: by promoting K and Mg loss while inc the incidence of ventric arrhythmia-reduces cardiac fibrosis, inproves HR variability, reduce QT dispersion and reduce early morning rise in HR in pt with HF -less hypokalemia= less sudden death
d) hemodynamic effects: antihypertensive properties - BP reduction also slows the progression LV remodeling and incidence of cardiovascl events
3) Vascular effects:
a) decreased vascular NADPH oxidase activity
b) reduced generation of reactive oxygen species
c) reversal of endthelial dysfunction - spironolactone inc NO bioactivity = improves vasodilator dysfunction and slows thrombotic response to injury

53
Q

Physiology of Aldosterone?

Where do the aldosterone receptor antagonists bind?

A
  • aldosterone enters epith cells in late distal tubule and collecting ducts from the basolateral membrane and binds mineralocorticoid receptors (MRs).
  • aldosterone induced proteins (AIPs) expressed = increase Na conductance of the limunal membrane and basolateral Na pump activity
  • results in transepitehelial NaCl transport enhances = lumen negative transepit voltage increased
  • ==>increased driving force for secretion of K and H into the tubular lumen

–> RECEPTOR ANTAGONISTS BIND THE MR RECEPTORS!

54
Q

What is the only diuretic that does not require access to the tubular lumen to induce diuresis?

A

spironolactone and eplerenone (aldosterone receptor antagonists)

55
Q

Aldosterone receptor antagonists:

clinical applications:

A

1) edema and hypertension (with thiazides or loops bc we want to prevent K loss but have urine loss)
2) primary hyperaldosteronism - tumors that secrete aldosterone!
3) refractory edema (edema causes hyponatremia bc a lot of fluid in tissues = more aldosterone secretion) associated with secondary aldosteronism (cardiac failure, hep cirrhosis, nephrotic syndrome, severe ascites)
4) hep cirrhosis
5) added to standard therapy for HF

56
Q

diuretic of choice for Hepatic Cirrhosis?

A

aldosterone receptor antagonist- spironolactone and eplerenone

57
Q

aldosterone receptor antagonists - adverse effects:

A
  • *1) hyperkalemia - this drug spares K! WE SAVE K! dangerous for cardiac function
    2) metabolic acidosis in cirrhotic patients
    3) Effects due to binding to other steroid receptors:
    a) gynecomastia
    b) impotence
    c) decreased libido
    d) hirsutism
58
Q

K sparing agents? (WE SAVE K)

A
  • aldosterone receptor antagonists

- direct epithelium Na channel blocker (amiloride

59
Q

Has CAI activity?

A

acetazolamide and thiazide diuretics some too

60
Q

Ca sparing agents?

A

Thiazides/Sulfamides

61
Q

Aldosterone saves and looses what ions?

A

SAVE K

LOOSE Na

62
Q

Thiazides/Sulf save/looses what ions?

A

SAVE Ca

LOOSE Na, Cl and K

63
Q

Osmotics save/loose what ions?

A

LOOSE K

64
Q

Direct epithelial Na channel blocker saves/looses what ions?

A

SAVE K

LOOSE Na

65
Q

CAI save/looses what ions?

A

LOOSE Na, Cl, K, HCO3-

66
Q

LOOPS/NKCC save/loose what ions?

A

LOOSE Ca, Mg, K, Na, Cl

Pharm - Cardiovascular (6 decks)

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