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PHARMACOLOGY - Renal > Diuretics and Aquaretics > Flashcards

Diuretics and Aquaretics Flashcards

1
Q

What drug acts as a carbonic anhydrase inhibitor?

A

Acetazolamide

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2
Q

What drug acts an osmotic diuretic?

A

Mannitol

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3
Q

What drugs act as loop diuretics?

A
  • Furosemide
  • Torsemide
  • Bumetanide
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4
Q

What diuretics act predominantly in the distal convoluted tubule?

A
  • Hydrochlorothiazide*
  • Metolazone
  • Spironolactone*
  • Amiloride*
  • Chlorthaliodone*
  • Eplenerone
  • Triamterene*
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5
Q

What drugs act on the collecting ducts by V2R agonism?

A
  • Arginine Vasopressin

* Desmorpressin [DDAVP]

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6
Q

What drugs act on the collecting ducts by V2R antagonism?

A
  • Conivaptan

* Tolvaptan

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7
Q

What diuretic is known to cause acidosis?
• describe how this happens?
• how does this drug have a diuretic effect?

A

Acetazolamide
• Inhibits Carbonic Anhydrase which results in more Na+ HCO3- being lost in the urine
• Cl- gets reabsorbed instead and combines with H+ in the blood to make HCl =>

Diuretic Effect:
• Increases Solute concentration and thus leads to more fluid being in the tubule

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8
Q

Why does acetazolamide only have a weak diuretic effect?

A

• We don’t have that much HCO3- in the blood

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9
Q

What are the Clinical Uses of Anhydrase Inhibitors?

• name them.

A 
Clinical Uses: 
• Alkalinize Urine (cystinuria) 
• Reduce intra ocular pressure 
• Given Prophylactically for Mountain Sickness 
• LIMITED USE as Diuretic

Acetazolamide

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10
Q

What are the Side Effects of the Carbonic Anhydrase Inhibitors?
• Name them

A

Acetazolamide

  • Metabolic Acidosis
  • Markedly increase K+ loss in the urine (ACUTE EFFECT ONLY)
  • AVOID in Advanced renal failure
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11
Q

What is the key chemical characteristics of osmotic diuretics?

A

•Small molecules that are filtered (make it through glomerulus) but NOT reabsorbed by the kidney

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12
Q

Osmotic Diuretics
• MOA (minor, major)
• Location of Action

A

MOA:
Minor Effect = PROXIMAL CONVOLUTED TUB.
• Osmotically inhibits Na+ and H2O reabsorption

MAJOR EFFECT = Loop of HENLE:
• Extracts Water from peripheral tissues and decreases blood viscosity

  • Increases Medullary Renal Blood Flow and Reduces its Tonicity
  • Impairs water reabsorption by THIN DESCENDING Limb of LOH
  • Impairs NaCl and urea extraction by THIN ASCENDING limb of LOH
  • Interfere with transport processes in the TALH
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13
Q

What is the Net effect and Clinical use of Osmotic Diuretics?
• name one.

A

Net Effect:
• Significantly Increase Urine with Small increments of NaCl and other ions

Clincial uses:
• Treatment of Dialysis disequilibrium syndrome
• Reduce intra cranial pressure*MAIN USE
• Reduce Intraocular pressure

MANNITOL

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14
Q

What are some side effects of osmotic diuretics?

• name one

A

Side Effects:
• Volume Overload
• High Doses are Toxic in Renal Failure
• Contraindicated in Cardiac Failure

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15
Q

What group of diuretic drugs works to inhibit NK2C symporters?
• where does this inhibition occur?
• Why does this work?

A

LOOP DIURETICS block Cl- channel in NK2C

Where:
• Thick Ascending Loop of Henle

Why does it work?
• Prevents Macula Densa (which is present right after the LOH) from sensing NaCl

  • Stimulates biosynthesis of prostaglandins (by macula densa) which REDUCE Na+ reabsorption in the distal nephron and ANTAGONIZE ADH; also Redistributes blood flow from cortex to juxtaglomerulus
  • Increase Total Renal Blood Flow
  • Maintains GFR by increasing % of the filtration fraction
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16
Q

What is the Effect of Loop Diuretics on Total Renal Blood Flow?
• GFR?
• name them.

A

Furosemide, Bumetanide, Torsemide

  • Increases Total Renal Blood Flow
  • Maintain the GFR by increasing the % of the FILTRATION FRACTION
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17
Q

What is the Effect of Loop Diuretics on Renin Release?
• intra-renal and extra-renal effects?
• Name them.

A

Furosemide, Bumetanide, Torsemide

Renin Intra-Renal:
•Inhibits the Macula Densa

Renin Exta-Renal:
• Reflexely activates sympathetic Nervous System

• Stimulates Intrarenal Baroreceptor Mechanisms

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18
Q

What is the NET EFFECT of the loop Diruretics?

• Name them.

A

Furosemide, Bumetanide, Torsemide

  • Cause COPIOUS DIURESIS and SIGNIFICANT NaCl loss - Most potent diuretics at mobilizing NaCl
  • Increased Urinary Excretion of K+/H+
  • Increased excretion of Ca2+ and Mg2+
  • OVERALL THESE IMPAIR THE ABILITY OF THE KIDNEY TO CONCENTRATE URINE
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19
Q

At what GFR do you consider using Loop Diuretics?

• why?

A

• People with a GFR lower than 30 mL/min should be on loop diuretics

why:
• Loop Diruretics are SECRETED into the PROXIMAL CONVOLUTED tubule rather than filtered through the glomerulus

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20
Q

What are some of the principle uses of Loop Diuretics?

• name them

A

Furosemide, Bumetanide, Torsemide

EDEMA: cadiac/hepatic/renal/pulmonary
HYPERCALCEMIA: mobilizes Ca2+
WASHOUT: increases urine flow
ANTIHYPERTENSIVE

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21
Q

How do Loop Diuretics help treat pulmonary edema?

• Name them

A

Furosemide, Bumetanide, Torsemide

  • Relaxes Pulmonary Veins - decreased pulmonary wedge pressure
  • Increase Compliance of Pulmonary Vessels
  • Increase Peripheral Venous Capacitance
  • REDUCES PRELOAD (aka LV Filling Pressure)
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22
Q

If you were giving a loop diuretic to treat someone for hypercalcemia, how would you administer it?

A

• Give it in NORMAL SALINE

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23
Q

Furosemide:
• Methods of Administration
• Therapeutic window?
• Dosing Problems

A

Loop Diuretic that’s given Orally, IV, or IM

Method of Administation:
• PO, IV, IM

Therapeutic Window:
• Large Margin of Safety

Dosing Problems:
• Requires Delivery to the Luminal Symporter
• In RENAL DISEASE there is IMPAIRED secretion and consequently the Dose-Response curve is shifted RIGHT

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24
Q

Why is Furosemide contraindicated with Warfarin?

A

• Both Drugs are protein bound

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25
Q

How long does it take Furosemide to kick in?
• how long until its effects are gone?
• MOA

A

~30 min to kick in and lasts ~8 hours with a 1.5 hour half life

MOA:
• Loop Diuretic so it blocks NK2C channels
• Prevents Urine Concentration

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26
Q

What are drugs that Furosemide is contraindicated with and why?

A
  • Interactions with Li+ - it deceases Li+ excretion, MUST REDUCE Li+ dose in this case
  • Indomethacin - this inhibits prostaglandins that are vital for Macula Densa sensing (NSAIDs will do the same thing)
  • Probenecid - drug used in gout
  • Warfarin - 99% bound to protein bound
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27
Q

What are some side effects of furosemide?

A
  • Volume and Na+ Depletion
  • HYPOKALEMIA and METABOLIC ALKALOSIS
  • REQUIRES INITIAL MONITORING
  • Elevates BUN (via effects on distal convoluted tubule)
  • Hyperglycemia and Hyperuricemia

• Ototoxicity and Sialadenitis (inflammation of Salivary Glands)

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28
Q

Compare the Potency of Furosemide and Bumetanide?

A

Bumetanide = 40x as potent than furosemide

• only 1 mg once daily needed

Not protein bound so GOOD SUBSTITUTE FOR FUROSEMIDE in patients recieving Warfarin

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29
Q

What make Torsemide differenent from other loop diuretics?

A
  • LOWERS BLOOD PRESSURE

* Only needs 1 daily dosing rather than 2x a day dosing like Furosemide and Bumetanide

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30
Q

Distal Convoluted Tubule and Collecting Ducts
• Amount of Sodium Reabsorbed
• Types of Sodium Channels?

A

Up to 5% of Na+ filtered at the glomerulus may be reabsorbed here

3 types of Na+ channels:
1. Na+-Cl- Symporter in the Na+-K+ aldosterone-independent Segment

2 types of ENaC:

  1. Amiloride-Sensitive, cyclic nucleoside gated cation (CNG) channel
    - –> aka Aldosterone Sensitive
  2. Low-conductance highly-selective Na+ ENaC channel
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31
Q

What group of diuretics is most often used chronically?

A

Benzothiadiazides (Thiazide Diuretics)

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32
Q

What is the MOA of the Thiazide Diuretics?

• Location of Action

A

• Bind to the CHLORIDE site of the NaCl Symporter in the Na+-K+ ALDOSTERONE-INDEPENDENT segment of the Distal Tubule

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33
Q

What are the Pharmacological Effects of Thiazide Diuretics?

A

Pharm. Effects:
• Moderate Loss of Na+, K+ (HYPOKALEMIA), Cl-
• Elevation of Excreted Urinary Potassium
• Increased Excretion of Titratable acid b/c of increased delivery of Na+ to the distal tubule
• DECREASED Ca2+ excretion, INCREASED Mg2+ excretion

34
Q

What side effects of Thiazide Diuretics are associated with chronic Thiazide use?

A

Sodium Loss and VOLUME CONTRACTION with REDUCED GFR

35
Q

Why do Thiazide Diuretics cause reduced urinary excretion of Ca2+?

A

Proximal Convoluted Tubule is acted on in a way that leads to more Ca2+ getting taken up by the body

36
Q

What are the Therapeutic Effects of Benzothiadiazides?

A
  • Diuretic - less edema in CHF, Cirrhosis, and nephrotic syndrome
  • Hypercalcuria (Osteoporosis) and Renal Calcium Stones
  • Antihypertenssive or to AUGEMENT action of other antihypertensives
  • NEPHROTIC Diabetes Insipidus
37
Q

T or F: like loop diuretics, thiazides require secretion into the tubular fluid to exert their effect.

A

True

38
Q

At what GFR do most Thiazides become ineffective?

• Exceptions?

A

GFR less than 30 or 40 mL/min

Exceptions: METOLAZONE and Indapamide

39
Q

What are the Class I and Class II thiazide diuretics?

• what is the difference in their utility?

A

Class I:
• Hydrochlorothiazide
• Chlorthalidone
**Good if GFR is above 50 mL/min

Class II:
• Metolazone (10X as potent as HCTZ)
• Indapamide (20x as potent as HCTZ)
*****Good if GFR is between 30 and 50 mL/min

Below 30 you’ll have to go to a loop diuretic

40
Q

Why can’t you just up the dose on someone’s Chlorthalidone if they start become edematous?

A
  • Therapeutic effects of Thiazides maxes out at 25mg

* anything above 25mg will just cause more side effects

41
Q

What are the 4 general Adverse effects of Thiazides?

A 
Depletion of Phenomena
• (K+) Hypokalemia 
• (Cl-) Hypochloremic Alkalosis
• (Na+) Dilutional Hyponatremia
• (Mg2+) Hypomagensemia

Retention Phenomena
• Hyperuricemia
• Hypercalcemia

Metabolic Changes
• Hyperglycemia
• Hyperlipidemia
• Hypersecretion of renin and aldosterone

Hypersensitivity and Other
• Pancreatitis
• Withdrawal Edema
• Sialadenitis
• Fever, Rash, Pupurea
42
Q

What metabolic changes can be prevented by controlling Hypokalemia associated with Thiazide use?

A

K+ is needed in the conversion of Proinsulin to Insulin

43
Q

What are the physiological actions of aldosterone?

• where does it act?

A

• Aldosterone - binds to INTRACELLULAR mineralcorticoid receptor in DISTAL CONVOLUTED TUBULE

Gene Expression Upregulated:
• ENaC Na+ channels (aka aldosterone induced channels)

Other Effects:
• Lumen-Negative Transepithelial NaCl transport is increased
• INCREASES K+ and H+ excretion

44
Q

What is the MOA of Aldosterone antagonists?
• Net Effect.
• name them.

A

Spironolactone and Eplenerone

MOA:
• Binds to Aldosterone receptor in the cytoplasm to prevent its translocation to the nucleus

• Reduces ENaC expression (less Na+ reabsorption)

Net Effect:
• Increased Urinary Excretion of Na+
• INHIBITION of K+ and H+

45
Q

Spironolactone
• Metabolism
• Side Effects

A

EXTENSIVE metabolism until CANRENONE (biologically active derivative) is made

Side Effects:
• Hyperkalemia
• Gynecomastia (man boobs), Hirsuitism, Uterine Bleeding

46
Q

Compare the side effects of Eplenerone and Spironolactone.

A

Eplenerone has much few side effects because it binds more specifically to ALDOSTERONE receptor and less on Androgen receptors than spironolactone

47
Q

What drug combination is typically used with the aldosterone inhibitors?

A

Spironolactone or Eplenerone are typically combined with THIAZIDE diuretics to balance the Hyper and Hypokalemic effects of each drug respectively

48
Q

What are the clinical uses of the aldosterone inhibitors?

A
  • Diuretics, tyically in combination with HCTZ
  • Treatement of CHF
  • Management of Cirrhosis
49
Q

What are the two TRUE potassium Sparing Diuretics?

• MOA

A

Triametrene and Amiloride

MOA:
• Blockage of ENaC sodium channels to inhibit Na reabsorption in the late distal tubule

50
Q

How do Aldosterone blockers and Potassium Sparing diuretics differ in their effects of sodium depletion?

A

Aldosterone Receptor Blockers tend to INCREASE URINARY Na+ excretion

True Potassium Sparing Diuretics (Triametrene and Amiloride) have much less of a Na+ depleting effect

51
Q

What are the clinical uses of the Triametrene and Amiloride?
• side effects.

A

• Combined with Thiazides to increase Thiazide effectiveness and reduce HCTZ K+ excretion

Side Effects:
• Hyperkalemia (if given alone)
• Megaloblastic Anemia in pts. with Cirrhosis
• Trimterene sometime forms Kidney Stones

52
Q

T or F: Diuretics can be used as monotherapy.

A

True

53
Q

What drugs are ACE I’s certainly contrainidcated with?

A

DON’T GIVE WITH K+ Sparing Diuretics!!!

• this is because ACE Is are potassium sparing too

54
Q

What is the best monotherapy of HTN?

A

• Low Dose Diuretics or ACE Inhibitors

55
Q

In what patients are diuretics required to treat HTN?

A
  • Low Renin/Volume Dependent HTN
  • Typically seen in African Americans and the Elderly

Thiazides are good to use because they’re cheap

56
Q

What is the most popular drug prescribed for treatment of mild or moderate HTN?
• what about its dosing makes it easy?

A
  • Thiazide Diuretics
  • you can take one morning dose and it will provide a sustained effect and reduce K+ wastage during Nighttime

Remember never need to give more than 25mg

57
Q

Someone starts taking a thiazide diuretic and their blood pressure does not decrease. What are some possible explanations?

A
  • Overwhelming Dietary Sodium Intake

* Impaired Renal Capacity to Excrete Sodium

58
Q

What are some of the Clinical Uses of Loop Diuretics?

A
  • Used in patients with Severe HTN that are unresponsive to thiazides - often ppl. with RENAL INSUFFICIENCY, CARDIAC FAILURE, or CIRRHOSIS
  • IV administration in Acute Pulmonary Edema
59
Q

What drug-drug interaction commonly occurs with loop diuretics?

A

• NSAIDS with loop diuretics is the MOST COMMON CAUSE of diuretic resistance (because it relies on prostaglandins synsthesized by macula densa)

60
Q

T or F: K+ sparing diuretics are particularly useful in patients with hyperuricemia.

A

True

61
Q

What is the Drug of Choice in liver Cirrhosis? why?

A

Spironolactone - it can be titrated up to 400 mg/day

62
Q

T or F: K+ diuretics are one of the drugs of choice in renal insufficiency.

A

FALSE, K+ sparing diuretics are CONTRAINDICATED in Renal Insuffiency with GFR below 75 mL

63
Q

Where is ADH synthesized?

A

• Paraventricular and Supraoptic nuclei of the Hypothalmus

64
Q

When is ADH released?

A
  • Elevated Plasma Osmolarity >280 mOsm/Kg
  • Depletion of Extracellular Volume
  • Pain, nausea, hypoxia
65
Q

Where is the V1 receptor found?
• what pathway does it act through?
• End result of pathway activation?

A

V1 = Vascular Smooth Muscle

Pathway: Gq-PLC-IP3 pathway leading to Ca2+ mobilization

End Result: More Ca2+ in the cytoplasm = VASOCONSTRICTION

66
Q

Where is the V2 receptor found?
• what pathway does it act through?
• End result(s) of pathway activation?

A

V2 = principal cell in renal collecting ducts

Pathway: Gs-cAMP, PKA

PKA phosphorylates:
• Aquaporin-2 vesicles and targets to membrane
• Urea Transporter - VRUT/UT1

End Result:
• Increased permeability of H2O and Urea

67
Q

What is the point of increasing CD permeability to urea?

A

It allows for 4 times the osmolarity of plasma in the TALH

68
Q

What are some drugs that cause nephrogenic diabetes insipidus?
• how common is this?

A

LITHIUM!!!!, clozapine

• 50% of pts. on lithium will have IMPAIRED Renal function

69
Q

What is the most effective treatment for central diabetes insipidus?
• MOA
• how is it administered?

A

Desmopressin [DDAVP]
• Mimicks AVP/ADH effects

Administration:
• Nasally
• IV
• Oral Tablet

70
Q

What are some uses of Desmopressin [DDAVP] other than treatment of Diabetes Incipidis?
• explain why these can be used?

A
  • BLEEDING disorders (IV or nasal) increases circulating levels of Factor VIII and vWF via extrarenal V2 receptors
  • Nocturnal Enurisis (bed wetting in children )
71
Q

What other drugs besides DDAVP are used in treatment of Nephrogenic DI?
• side effects?
• Rational for using this treatment?

A

• Thiazide Diuretics - might reduce polyuria by 50%

Side Effects:
• Depletion of Extracellular Volume and Na+ (b/c you’re blocking the NC cotransporter)

Rational:
• Increased Na+ in the tubule lumen caused by thiazide blocking increases the resorptive capacities of the PCT reducing the vol. of H2O

72
Q

What are V1 Receptor Agonists used to treat?

• Rationale

A

Treatment:
• Post Operative Ileus
• Reduce bleeding in esophageal varices
• REDUCE BLEEDING DURING ACUTE HEMORRHAGIC GASTRITIS

Rational: Activation of V1R causes GI and Vascular Smooth muscle contraction

73
Q

What drugs are V1 Receptor Agonists?

• Administration

A

Terlipressin

Administration:
• IV
NOTE: the use of this drug is super restricted

74
Q

What is the Etiology of Syndrome of Inappropriate Secretion of ADH (SIADH)?

A

• Excessive production of ADH

***results in impaired H2O excretion and plasma HYPOosmolarity (hyponatremia)

75
Q

What are 3 drugs groups known to cause SIADH?

A
  • Psychotropics: SSRI, haloperidol and Tricyclic Anti-depressants
  • Sulfonylureas: Chloropropamide
  • Vinca Alkaloids: Vincristine and Vinblastine
76
Q

How are patients with SIADH treated?

A
  • Water Restriction
  • if SEVERE pts. may be treated with IV hypertonic saline
  • Loop Diuretics
  • Demeclocycline
  • Vaptans
77
Q

What does Demeclocycline do?

A

• Antagonizes AHD at V2 receptors

78
Q

What is the point of giving someone with SIADH loop diuretics?

A

• NO FUCKING CLUE

79
Q

Tolvaptan
• MOA
• indications for use
• Side Effects

A

MOA:
• V2 Receptor Antagonist

Indications:
• SIGNIFICANT hypervolemia and euvolemic hyponatremia
• Symptomatic Hyponatremia that has resisted correction with fluid restriction

TO BE USED ONLY IN THE HOSPITAL SETTING*

Side Effects:
• Hyperglycemia, GI disturbances, Clotting probs.

80
Q

What other drug shares the same MOA as Torvaptan?
• compare selectivity
• side effects that differ from torivaptan

A

• Conivaptan

  • Less Selective for V2R
  • May cause infusion Rxn

PHARMACOLOGY - Renal (2 decks)

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