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MWU Pharmacology II > Diuretics I and II > Flashcards

Diuretics I and II Flashcards

1
Q

Indicate some key properties of diuretics.

what do they do, how, edema, which ions do they regulate

A

The drugs or agents that cause increase in urinary output – by increasing sodium and water excretion

Specifically, capable of excreting Na+ and Cl-, the major ions present in the extracellular volume.

Increased Sodium levels in the system could lead to edema; diuretics by promoting natriuresis bring down edema.

Diuretics regulate K+, H+, Ca2+, and Mg2+, Cl−, HCO3−, and
H2PO4−,uric acid excretion

Also involved in maintaining hemodynamics

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2
Q

Diuretics – Clinical Uses (6)

A

Edema

High blood pressure/ Hypertension – (by promoting diuresis and natriuresis, diuretics decrease hypervolemia and hypernatremia bringing down the pre-load)

Heart Failure – (reduce edema and congestion)

Renal swelling/inflammation

Hepatic inflammation/ Cirrhosis

Glaucoma

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3
Q

Diuretics - Classification

6 classes

A
  1. Carbonic Anhydrase Inhibitors
  2. Osmotic Diuretics
  3. Loop Diuretics (Na+/K+/Cl- symporter inhibitors)
  4. Thiazide / thiazide like (Na+/Cl- symporter inhibitors)
  5. K+ sparing diuretics
  6. Non-specific cation channel inhibitors or cyclic nucleotide gated channel inhibitors
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4
Q

3 Carbonic Anhydrase Inhibitors

common ending?

A

Acetazolamide, Dichlorphenamide, and Methazolamide

amide ending

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5
Q

2 Osmotic Diuretics

A

Mannitol, Urea

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6
Q

4 Loop diuretics

A

Furosemide, Bumetanide, Ethacrynic acid, and Torsemide

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7
Q

5 Thiazide / thiazide like diuretics

A

Hydrochlorothiazide, Chlorthalidone, Chlorothiazide,
Indapamide and Metolazone

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8
Q

4 K+ sparing diuretics

A

Triamterene, Amiloride, Spironolactone and Eplerenone

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9
Q

Properties of Carbonic Anhydrase

major location, specific location of two types, role of CA

A

CA (enzyme) is prominently present in proximal convoluted
tubule

CA – type IV is present in luminal (brush border) and
basolateral membrane and CA- type II is present in cytoplasm.

CA plays a role in HCO3- reabsorption and acid excretion (H+)

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10
Q

What is the function of CA type IV and CA type II?

A

CA (type IV): rapidly decomposes H2CO3 -→ CO2 + H2O in
the presence of brush bordered CA type IV

CA (type II): CO2 is lipophilic membrane diffusible gas and
reacts with H2O in Cytoplasm by CA (type II) to form H2CO3 (unstable inside cytosol), which again breaks down to HCO3 - and H+

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11
Q

What is the function of the sodium hydrogen exchanger (NHE) and what does enhanced NHE activity result in?

A

The Sodium Hydrogen Exchanger (NHE) tries to
get rid of H+ ion in exchange for Sodium uptake

Enhanced NHE activity always maintains low H+
levels inside cells

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12
Q

MOA of Carbonic Anhydrase Inhibitors

A

Acetazolamide, Dichlorphenamide, and Methazolamide

MOA: Inhibit CA enzymes of both Type II and Type IV. CA inhibitors prevent;

a) CO2 uptake by decreasing H2CO3 break down

b) indirectly decrease the amount of Na+ re-absorbed from luminal fluid

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13
Q

Adverse Effects and Contraindications of CA Inhibitors

A

Adverse Effects:

**1) Systemic Metabolic Acidosis
**
2) Alkalinization of Urine

3) Skin Toxicity, sulfonamide like reactions (all drugs in this class have a sulfonamide moiety), allergic reactions

Contraindications:

Hepatic Cirrhosis: may increase ammonia levels and cause hepatic encephalopathy

Chronic Obstructive Pulmonary Disorder

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14
Q

Which diuretics act on the Loop of Henle, and what are their precise locations of action?

A

Osmotic Diuretics: Thin descending limb

Loop Diuretics: Thick Ascending Limb

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15
Q

Osmotic Diuretics - Mannitol: Location of action, MOA, what ions are excreted?

A

The major site being the loop of Henle and also act on proximal tubule (water permeable membranes)

MOA: By acting as an inert agent mannitol increases osmolarity, promoting water loss in lumen.

Always accompanied by excretion of Na+, K+, Ca2+, Mg2+, Cl−, HCO3−, phosphate (indirect effect due to osmolarity).

Thus, promoting enhanced urine output.

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16
Q

Osmotic Diuretics: Adverse Effects and Contraindications

A

Adverse effects:

dehydration, hyponatremia, with nausea and vomiting.

Contraindications:

Strictly prohibited in: Hepatic or Renal Insufficiency

Heart Failure or Pulmonary Congestion

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17
Q

What are high ceiling diuretics?

A

Loop Diuretics

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18
Q

Where do Loop diuretics act and what do they inhibit?

A

Site of action is thick ascending limb of loop of Henle

Na+K+2Cl- symport Inhibitors-

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19
Q

Loop Diuretics: MOA

A

MOA-Inhibitors of Na+-K+-2Cl− symport. This class bind to the Na+-K+-2Cl− symporter in the thick ascending limb.

The potential difference across the epithelial cells is reduced due to inhibition Na+-K+-2Cl− symporter (mainly due to Cl- linhibition) and this could also lead to decreased Ca2+ and Mg2+ reabsorption.

20
Q

Loop Diuretics: Adverse Effects

electrolyte, bp, ear

A

Acute and severe effects:

Hyponatremia, hypokalemia,
hypotension and collapse.

Hypotension is due to sympathetic reflex leading to RAAS pathway activation

Loop diuretics may cause Ototoxicity characterized by tinnitus, deafness and hearing loss. (An effect due to interference of ionic conductance in stria vascularis of cochlear region)

21
Q

Drug-Drug Interaction of loop diuretics

5

A

Probenecid competitively inhibits Organic anion transport system mediated secretion of Furosemide.

Aminoglycosides, NSAIDs, paclitaxel and cisplatin increases Ototoxicity when co-administered with loop diuretics

Co-administration with digitalis glycosides may cause arrhythmias

Increase plasma Lithium levels and toxicity

causes nephrotoxicity with Amphotericin B

22
Q

Thiazide / thiazide like diuretics: MOA, and the 5 drugs

What differentiates them from loop diuretics

A

Hydrochlorothiazide, Chlorthalidone, Chlorothiazide, Indapamide, and Metolazone

MOA - Inhibits Na+-Cl− symporter of Distal Convoluted Tubule.

Minimal effect on GFR , and Renin release/RAAS activation because they act at site past macula densa – which differentiate them from loopdiuretics

23
Q

Adverse Effects of Thiazide Diuretics

A

Thiazide diuretics may cause magnesium deficiency, mostly in geriatric population

Most importantly cause fluid and electrolyte imbalance,
especially hyponatremia, hypotension, hypokalemia,
hypochloremia

Erectile dysfunction

24
Q

Thiazide diuretics: Drug-drug interactions

A

A potentially lethal drug interaction - Thiazides vs Quindine (also class of QT interval prolonging drugs) -> causes polymorphic ventricular tachycardia (torsades de pointes) a fatal ventricular fibrillation.

25
Q

What are the 2 parts of the collecting duct?

A
  1. Cortical collecting duct
  2. Inner medullary collecting duct
26
Q

Function of principal cells, and what diuretics act on them?

A

Principal cells reabsorb water, and Na+ but promote K+ secretion

Principal cells are the site of action of aldosterone, and also K+-sparing diuretics.

27
Q

What maintains lumenal electric neutrality after ENaC mediated Na+ reabsorption leaves the lumen negatively charged?

A

K+ from principal cells or H+ from type A intercalated cells are secreted back into the lumen

28
Q

Which 2 diuretics act directly on Epithelial Na+ Channels (ENaC)?

A

Triamterene and Amiloride

29
Q

Which 2 reduce ENaC membrane expression?

A

Spironolactone and Eplerenone (mineralocorticoid receptor antagonists)

30
Q

Triamterene and Amiloride – MOA

A

Inihibit/block ENaC, located in the late distal convoluted tubule and collecting duct.

By inhibiting ENaC, they spare K+ loss.

31
Q

Adverse effects of Amiloride and Triamterene and contraindications

A

Hyperkalemia

Along with drugs like Trimethoprim, NSAIDs and ACE Inhibitors, increase the incidence of hyperkalemia

Contraindicated in geriatric patients, renal insufficiency and also in hypoaldosteronism

32
Q

MOA: Aldosterone- (Mineralocorticoid Receptor Ligand) induced Na+ uptake

A

MOA- Following entrance into the cell, Aldosterone forms a complex with its high affinity receptor, MR.

Aldosterone-MR complex enters nucleus and binds to responsive elements in DNA to activate the target genes and proteins collectively called Aldosterone induced proteins (AIP).

ENaC is one of the aldosterone
induced proteins.

33
Q

Aldosterone effect on serum and glucocorticoid stimulated kinase activity (SGK1)

A

Aldosterone also increases serum and glucocorticoid stimulated kinase activity (SGK1)

SGK1 by phosphorylating NEDD4/2 proteins prevents a NEDD4/2 mediated ubiquitination and lysosomal degradation of ENaC.

As a result, there is more ENaC in the membrane and more Na+ uptake

34
Q

MR Antagonists- Spironolactone, Eplerenone MOA:

A

MR antagonists prevent aldosterone induced increased expression of ENaC mRNA and protein.

MR antagonists also prevent aldosterone mediated NEDD4/2 inhibition by SGK1 promoting ENaC ubiquitination and lysosomal degradation decreasing the membrane localization of
ENaC

35
Q

Adverse effects of MR antagonists

which drug has less known adverse effects

A

➢Hyperkalemia

➢ Because of their ability to interfere with other steroid
receptors they cause gynecomastia, impotence,
decreased libido, hirsutism, and menstrual
irregularities – Eplerenone is MR specific antagonist
with reduced non-specific effects

36
Q

What are the 4 Natriuretic Peptides and where are they produced?

A

Atrial natriuretic peptide
(ANP), and Brain natriuretic peptide (BNP)- produced
by heart in response to stretch and stress, C-type
natriuretic peptide (CNP) by the endothelium and
kidneys, and Urodilatin in urine

37
Q

What channel do Natriuretic peptides act on, and what ions do they allow to pass?

A

Cyclic nucleotide gated cation (CNGC) channel allows Na+, K+, and NH4 + entry and is controlled by cyclic GMP

38
Q

What are the names of the recombinant natriuretic peptides?

A

Human recombinant ANP (carperitide, available only
in Asian subcontinent)

BNP (Nesiritide- a recombinant peptide known to inhibit CNGC function

39
Q

Natriuretic Peptides: MOA

receptors / what do they inhibit / prevent exit of what ion

A

Mechanism of Action:- The natriuretic peptides bind to the natriuretic peptide receptors (NPR- A and B isoforms). This binding triggers the conversion of GTP to cyclic GMP.

Cyclic GMP and PKG both inhibits the CNG Channel directly

PKG also prevent Na+ exit via the Na+, K+-ATPase (interstitial space).

40
Q

Natriuretic Peptides: Adverse effects, Contraindications and drug interactions

type of insufficiency, increase serum levels, increase in hypotension risk

A

Renal insufficiency and mortality have been reported with some short term studies

Increase in serum creatinine levels.

Oral ACE inhibitors may enhance the hypotension risks

41
Q

Where is ADH produced, what is it released in response to

A

Based on the stimulus, AVP is primarily synthesized in CNS, but also synthesized in heart and adrenal glands

When the blood osmolality increases, the osmoreceptors of the hypothalamus stimulate the synthesis of prohormone (VP) which then gets activated in posterior pituitary to release 8-AVP/ADH (active) from the secretory granules.

42
Q

Vasopression: MOA

What are V2 receptors

A

They act through V1a, V1b, and V2 receptors.

V2 is the major receptor in renal tissue specifically, in the principal cells of collecting duct and thick ascending limb

The antidiuretic hormone, 8-
Arginine Vasopressin (8-AVP) causes a rise in cAMP and PKA leading to translocation of Aquaporin 2 on membrane surface to imbibe/import more water
-through a G Protein mediated
signaling mechanism

43
Q

Vasopression / ADH Drug Interactions

A

➢Inhibitors of vasopressin secretion include atrial natriuretic
peptide, γ- aminobutyric acid, and opioids

➢ Nonsteroidal anti-inflammatory drugs (NSAIDs) particularly
indomethacin, and drugs like Carbamazepine and
Chlorpropamide increase antidiuretic effects of vasopressin

➢Lithium is of particular importance because of its use in the treatment of manic-depressive disorders inhibits vasopressin effects.

44
Q

Name 2 Vasopressin Agonists and some clinical indications

A

8 Arginine Vasopressin (AVP) Naturally Occurring – In mammals and humans

➢ Synthetic peptides –V 2 selective agonist – Desmopressin also termed Deamino AVP.

➢ Desmopressin has 3000(times) greater anti-diuretic function than the natural hormone

➢Clinical indications - Diabetes insipidus and Nocturia

45
Q

What are the Vasopression Receptor Antagonists and their respective receptors?

common ending

A

1) V2 specific antagonists: Mozavaptan, Tolvaptan and Lixivaptan

2) V1a / V2 antagonists: Conivaptan

common ending: vaptan

46
Q

What are Vasopressin Receptor Antagonists used to treat?

A

Used for hypervolemic hyponatremia- due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) or due to euvolemic hyponatremia

Clinically also used in polycystic
kidney disease

47
Q

V2 Receptor Antagonists- adverse effects and drug interactions

A

➢ Tolvaptan and Mozavaptan comes with a boxed warning - causes demyelination disorders.

-It could also result in coma and
death especially in patients with compromised hepatic function,
an effect due to rapid correction of hyponatremia.

➢Only administered in a hospital setting.

➢ Tolvaptan and Conivaptan are metabolized by CYP3A4, so CYP3A4 inhibitors like ketoconazole, indinavir and
clarithromycin should be avoided.

MWU Pharmacology II (8 decks)

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