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Pharmacology > Diuretics > Flashcards

Diuretics Flashcards

1
Q

How kidneys control ECF volume

A

Adjusting NaCl and H2O excretion

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2
Q

Diuretics

A

Increase urine volume and increase Na excretion and Cl excretion

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3
Q

Acetazolamide

A

Acts on PCT
CA inhibtor
Inhibits 85% of NaHCO3 reabsorption

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4
Q

Mannitol

A

Osmotic diuretic

Limits water reabsorption in water-permeable segments of nephron (PCT, thin descending limb, and CT with ADH)

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5
Q

Furosemide

A

Loop diuretic

Inhibits Na/K/2Cl cotransport in thick ascending limb

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6
Q

Thiazides

A

Inhibit NaCl co-transport in DCT

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7
Q

K sparing diuretics

A

Act on CT

Inhibition aldosterone actions or directly blocking Na channels

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8
Q

ADH antagonist

A

Prevent ADH-stimulated reabsorption of H2O in collecting tubulue

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9
Q

Diuretic Pharmacology

A

Primarily preventing Na entry into tubule cell
Diuretics enter tubule fluid, site of action determines which electrolyes will be affected
EXCEPT for spironolactone and some ADH antagonists, diuretics generally exert effects on luminal side of nephron

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10
Q

Entry into tubule

A

Mannitol: filtration at the glomerulus
Most other diuretics are tightly protein bound- get secreted across proximal tubulue (organic acid or base secretory pathway)

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11
Q

Tubule epithelial cells

A

Have Na/K ATPase on basolateral (blood) side
Pumps 3 Na out and 2 K in
Keeps Na concentration down so Na will leave lumen
Luminal side has pathways for passive movement of Na down its electrochemical gradient (Na/H exchangers)

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12
Q

Acetazolamide

MoA

A

Reversible inhibition of CA
Inhibits reabsorption of HCO3 in proximal tubule (more is peed out, less HCO3 in blood, blood more acidic)
Na accompanies HCO3 as it is excreted, and water goes with

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13
Q

Acetazolamide

Pharmacokinetics

A

Well absorbed PO
Effect begins within 30 minutes, max at 2 hours, duration 12 hours
Renally secreted via organic acid transporter

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14
Q

Acetazolamide

Adverse Effects

A

Metabolic acidosis
Hypokalemia
Ca phosphate stones
Drowsiness, paresthesia, hypersensitivity rxns

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15
Q

Acetazolamide

Contraindications

A

Cirrhosis (increased urine pH reduces NH3 secretion and increases serum NH3)
Tubular fluid is more alkaline (from the extra bicarb), NH3 is less likely to be protonated to NH4 and trapped/excreted. Goes back into blood

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16
Q

Acetazolamide

Clinical Indications

A

Weak diuretic agent, good as backup
Glaucoma
Urinary alkalinazation: drug overdose/stone removal
Acute mountain sickness: this drug can buy some time by acidifying the blood and reducing hemoglobin’s affinity to O2, releasing it to tissues. Also acidifying blood increases ventilation

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17
Q

Other CA inhibitors

A

Dichlorphenamide (30x more potent than acetazolamide)
Methazolamide (5x more potent)
Dorzolamide (topical for ocular use, reduces pressure)

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18
Q

Mannitol

MoA

A

Osmotic diuretic
Proximal tubulue and descending loop of Henle, collecting ducts (with ADH present)
IV causes expansion of IV volume
Powerful diuretic once it reaches the kideny

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19
Q

Mannitol

Pharmacokinetics

A

NOT ORALLY ABSORBED
Must be injected IV to reach kidney
1/2 life is 1.5 hours

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20
Q

Mannitol

Adverse Effects

A

If kidney filtration is impaired
More mannitol stays in blood, increases blood volume, capillary filtration, more fluid in ECS, hyponutremia, edema
Acute pulmonary edmea, dehydration, headache, nausea, vomiting

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21
Q

Mannitol

Contraindications

A

Congestive heart failure
Renal failure
Pulmonary edema

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22
Q

Mannitol

Clinical Indications

A 
Maintain or increase urine volume
Used in acute renal failure
May promote renal excretion of toxic substances (dyes, drugs)
Reduce intracranial pressure
Reduce intraocular pressure
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23
Q

Thick Ascending Limb of Loop of Henle

A

Impermeable to H2O
Na/K/2Cl cotransporter
Na gradient from Na/K ATPase drives the gradient
Influx of K from both sides raises the intracellular [K]
K diffuses back into the lumen creating a (+) charge in lumen
(+) charge in lumen causes Mg2+ and Ca2+ to leave lumen via paracellular diffusion

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24
Q

Loop Diuretics

MoA

A

Big one: Furosemide (LASIX)
Block Na/K/2Cl transporter in apical membrane
More Na and K in lumen, urine is more diluted (more fluid stays in lumen)
Increases excretion of Na, K, Ca, Mg, and water
MOST EFFECTIVE CLASS
Also, something with prostaglandin production, causes renal venodilation

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25
Q

Loop Diuretics

Pharmacokinetics

A

Rapid oral absorption
Short half life
Renally secreted via organic acid transporter

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26
Q

Loop Diuretics - Furosemide

Adverse Effects

A 
Lasix
Hyponatremia, hypokalemia, hypomagnesemia
Dehydration
metabolic alkalosis
Mild hyperglycemia
Ototoxicity
Hypersensitivity rxns
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27
Q

Loop Diuretics - Furosemide

Clinical Indications

A

Acute pulmonary edema, CHF edema, acute hypercalcemia, acute hyperkalemia, hypertension

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28
Q

Additional Loop Diuretics

Bumetanide

A

40x more potent
Shorter half-life
50% metabolized by the liver

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29
Q

Additional Loop Diuretics

Torsemide

A

Longer half life than lasix
Longer duration of action
Better oral absorption
80% metabolized by the liver

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30
Q

Additional Loop Diuretics

Ethacrynic Acid

A

Last resort, only used when hypersensitive to others
No CA inhibition
Nephrotoxic and ototoxic
Worse side effects

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31
Q

Distal Convoluted Tubule

A

Na/Cl contransporter
Na gradient drives this
Ca reabsorption is controlled by PTH (regulates production of Ca channels in luminal border)
Basolateral Na/Ca pump (Ca pumped into blood)

32
Q

Thiazide Diuretics - Hydrochlorothiazide

MoA

A

Inhibits apical Na/Cl cotransporter (into cell) in distal tubule
Produces mild diuresis
Results in increased Ca reabsorption

33
Q

Thiazide Diuretics - Hydrochlorothiazide

Pharmacokinetics

A

Good oral absorption and renal elimination

Half life of 2.5

34
Q

Thiazide Diuretics - Hydrocholorothiazide

Hypercalcemic Effects of Thiazide Diuretics

A

Inhibition of apical Na/Cl cotransporter decreases intracellular Ca
Na/Ca pump will compensate by increases Na pumped into cell and Ca pumped out of cell into blood

35
Q

Thiazide Diuretics - Hydrochlorothiazide

Adverse Effects

A

Hyponatremia and **hypokalemia
Dehydration
**Metabolic alkalosis
Hyperuricemia (competes with organic acid transporter that also transports uric acid)
Hyperglycemia (thought to be secondary to hyperkalemia)
Hyperlipidemia (increased LDL)
Weakness, fatigue, parathesias and hypersensitivity

36
Q

Thiazide Diuretics - Hydrochlorothiazide

Clinical Indications

A

Hypertension
Congestive heart failure
Reduce Ca excretion to prevent kidney stones

37
Q

Collecting Tubule

Principal Cells

A

Na and K Channels
Na gradient in lumen drives Na back into cell
K effluxes out of cells into lumen
More Na in than K out, (-) lumen, drives paracellular K secretion
Aldosterone regulates expression of basolateral Na/K ATPase and channels
ADH regulates water channels and water absorption (segment is usually impermeable to water until ADH acts on it)

38
Q

Collecting Tubule

Intercalated Cells

A

Luminal: proton pumps transport H into lumen, the H ATPase is regulated by aldosterone
Basolateral: HCO3/Cl is passive countertransporter

39
Q

Hypokalemia

CA inhibitors

A

Acetazolamide
Proximally increases HCO3 (in proximal convoluted tubule)
Increase in luminal HCO3 increases (-) charge of lumen
More K is effluxed into lumen to counteract the (-) charge
Less K in the blood

40
Q

Hypokalemia

Loop and Thiazide Diuretics

A

Inhibition of apical Na/Cl cotransporter in distal convoluted tubule decreases Na/Cl going into cell, more hangs out in the lumen, lumen is more (-)
More (-) lumen encourages more K effluxed from cell into lumen. Less K in blood.

41
Q

Metabolic Alkalosis

Loop and Thiazide Diuretics

A

Increased Na and Cl from inhibition of cotransporter in distal convoluted tubule makes lumen more (-)
More H will be pumped from intercalated cells into lumen
Concurrently HCO3 will go into the blood, blood is alkalotic

42
Q

K Sparing Diuretics

A

Given to avoid hypokalemia
NEVER BE GIVEN IN HYPERKALEMIA or if pts are on drugs/have disease states that can cause hyperkalemia:
Diabetes mellitus, multiple myeloma, tubulointerstitial renal disease, and renal insufficiency
K supplements and ACEi

43
Q

Spironolactone

MoA

A

Competetive inhibition of aldosterone receptor
Anti-androgenic effects (decrease testosterone synthesis, competitive inhibition of DHT receptor)
Mild diuresis from decreased Na reabsorption (secondary to aldosterone inhibition)
“Sparing” of K and H also secondary

44
Q

Spironolactone

Pharmacokinetics

A

Slow onset of action, takes DAYS

Liver metabolism to several active metabolites

45
Q

Spironolactone

Adverse Effects

A

Hyperkalemia
Metabolic acidosis
Gynecomastia, amenorrhea, impotence, decreased libido
Gi upset, peptic ulcers
CNS effects: headache, fatigue, confusion, etc

46
Q

Eplerenone

A

More expensive than spironolactone
Competitive antagonist of aldosterone binding to MR
Does not inhibit testosterone binding
Does not induce gynecomastia or other anti-androgenic side effects

47
Q

Spironolactone

A

Primary hyperaldosteronism
Secondary hyperaldosteronism (renin-angiotensin system activated)
Liver cirrhosis
Hypertesion

48
Q

Amiloride

MoA

A

Blocks Na channels in principal cells

Blocking Na influx decreases the driving force for K efflux so K IS SPARED

49
Q

Amiloride

Pharmacokinetics

A

1/2 life of 21 hours
Secreted into tubule via organic base transporter
Excreted unchanged by the kidney

50
Q

Amiloride

Adverse Effects

A

Hyperkalemia (NSAIDs can exacerbate this)
GI upset: nausea, vomiting, diarrhea
Muscle cramps
CNS effects: headache, dizziness, etc

51
Q

Amiloride

Clinical Indications

A

Edema
Hypertension
Usually used in combination with other diuretics to reduce K loss
Not very efficacious by themselves

52
Q

Triamterene

MoA

A

Blocks Na channels in principal cells

Blocking Na influx decreases driving force for K efflux so K is “spared”

53
Q

Traimteren

Pharmacokinetics

A

1/2 life of 4 hours
10X less potent than AMILORIDE
Liver metabolizes the drug to it active form
Active metabolite secreted into proximal tubule using the organic base transporter

54
Q

ADH Antagonists

A

Antagonize ADH, decrease water channel insertion, decreases water reabsorption in collecting tubule

55
Q

ADH Antagonists

Demeclocycline

A

Tetracycline antibiotic

Nephrotoxic

56
Q

ADH Antagonists

Litium

A

Psych drug used for mania

Nephrotoxic

57
Q

ADH Antagonists

Tolvaptan

A

Selective antagonist of vasopressin V2 receptor
Induces increased, dose-dependent production of dilute urine
Does not alter serum electrolyte balance
Orally available
1/2 life 6 hours

58
Q

V2 receptor antagonists

A

Tolvaptan
Mozavaptan
Lixivaptan

59
Q

V1 and V2 receptor antagonist

A

Conivaptan

60
Q

Diuretics and Edema

A

Diuretics tend to decrease capillary hydrostatic pressure and increase plasma oncotic pressure
Favor absorption over filtration

61
Q

Kidney Diseases

A

Most cause retention of Na and H2O
Renal insufficiency reduces efficacy of most diuretics (reduced glomerular filtration)
Diabetic nephropathy (associated with hyperkalemia) can be treated with THIAZIDES or LOOP DIURETICS

62
Q

Hepatic Cirrhosis

A

Portal hypertension, hypoalbuminemia
Reduction in plasma volume
Activates renin-angiotensin-aldosterone system
Secondary hyperaldosteronism results in Na retention in kidney
Associated with edema and acites
RESISTANT to loop diuretics
Spironolactone is effective

63
Q

Diuretics and Congestive Heart Failure

A

Renin-angiotensin-aldosterone system activated, Na retention and edema
Thiazide or loop diuretics can cause K loss if aldosterone is high
Hypokalemia can lead to coronary events/stroke/death
Spironolactone may be effective adjunct/alternative to prevent hypokalemia-induced cardiac dysfunction
ACEi may be combined with thiazide or loop diuretics, but NOT WITH SPIRONOLACTONE

64
Q

RHF (chronic)

A

ECFV redistributes from arterial to venous circulation
Venous, hepatic, splenic congestion
Peripheral tissue edema
ORAL LOOP DIURETICS

65
Q

LHF (acute)

A

Increased hydrostatic pressure in lung capillaries
Pulmonary edema
Life-threatening, need rapid, aggressive therapy
I.V. LOOP DIURETIC

66
Q

Hyponatremia

A

Serum Na below 136 mEq/L
Symptoms: Headache, fatigue, hallucinations, respiratory arrest, seizures, coma, death
Associated with hypovolemia, euvolemia, hypervolemia
ADH receptor antagonists can increase serum [Na]
Tolvaptan, mozavaptan, lixivaptan, conivaptan

67
Q

Uncomplicated Hypertension

A

THIAZIDE diuretic

68
Q

Patients with BP that is more than 20 over systolic goal or 10 diastolic goal

A

Use two agents

Usually one is a THIAZIDE diuretic

69
Q

Nephrogenic Diabetes Insipidus

A

Loss of ADH effects
ADH binds to V2 vasopressin receptors on principal cells
AC -> cAMP -> PKA -> Aquaporin 2 channels and H2O reabsorption
In insipidus this does not work, we cannot concentrate the urine and end up peeing a ton
THIAZIDE use, don’t know MoA

70
Q

Kidney stones

A

Contain Ca, usually occur in hypercalciuria

THIAZIDE diuretics decrease [Ca] in urine by promoting Ca reabsorption in distal convoluted tubule

71
Q

Hypercalcemia

A

Serum calcium > 14 mg/dL
Nausea, vomiting, AMS, abdominal pain, constipation, lethargy, depression, weakness and vague muscle/joint aches, polyuria, headache, coma
LOOP DIURETIC
Avoid thiazides because they INCREASE reabsorption of Ca

72
Q

Diuretic Resistance

NSAIDs

A

NSAIDs increase expression of Na/K/2Cl

Compete for organic acid transporter

73
Q

Diuretic Resistance

CHF or Renal failure

A

Decreases delivery of diuretics to tubule

Also build-up of organic acids competes for secretory transport into tubule

74
Q

Diuretic Resistance

Nephrotic Syndrome

A

Protein in tubule bind to diuretic drugs and limits their actions

75
Q

Diuretic Resistance

Hepatic Cirrhosis

A

Decreased GFR causes increased PCT absorption of Na
Decreased delivery of Na to distal nephron decreases effect of drugs that target Na transporters or channels in these segments

76
Q

Combination Therapy

Loop + Thiazide Diuretics

A

Only in patients refractory to one or the other

May be too robust -> K wasting

77
Q

Combination Therapy

K sparing + Loop or Thiazide

A

Prevents hypokalemia

Avoid in renal insufficiency

Pharmacology (44 decks)

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