Diuretics I and II Flashcards
Indicate some key properties of diuretics.
what do they do, how, edema, which ions do they regulate
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
Diuretics – Clinical Uses (6)
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
Diuretics - Classification
6 classes
- Carbonic Anhydrase Inhibitors
- Osmotic Diuretics
- Loop Diuretics (Na+/K+/Cl- symporter inhibitors)
- Thiazide / thiazide like (Na+/Cl- symporter inhibitors)
- K+ sparing diuretics
- Non-specific cation channel inhibitors or cyclic nucleotide gated channel inhibitors
3 Carbonic Anhydrase Inhibitors
common ending?
Acetazolamide, Dichlorphenamide, and Methazolamide
amide ending
2 Osmotic Diuretics
Mannitol, Urea
4 Loop diuretics
Furosemide, Bumetanide, Ethacrynic acid, and Torsemide
5 Thiazide / thiazide like diuretics
Hydrochlorothiazide, Chlorthalidone, Chlorothiazide,
Indapamide and Metolazone
4 K+ sparing diuretics
Triamterene, Amiloride, Spironolactone and Eplerenone
Properties of Carbonic Anhydrase
major location, specific location of two types, role of CA
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+)
What is the function of CA type IV and CA type II?
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+
What is the function of the sodium hydrogen exchanger (NHE) and what does enhanced NHE activity result in?
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
MOA of Carbonic Anhydrase Inhibitors
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
Adverse Effects and Contraindications of CA Inhibitors
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
Which diuretics act on the Loop of Henle, and what are their precise locations of action?
Osmotic Diuretics: Thin descending limb
Loop Diuretics: Thick Ascending Limb
Osmotic Diuretics - Mannitol: Location of action, MOA, what ions are excreted?
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.
Osmotic Diuretics: Adverse Effects and Contraindications
Adverse effects:
dehydration, hyponatremia, with nausea and vomiting.
Contraindications:
Strictly prohibited in: Hepatic or Renal Insufficiency
Heart Failure or Pulmonary Congestion
What are high ceiling diuretics?
Loop Diuretics
Where do Loop diuretics act and what do they inhibit?
Site of action is thick ascending limb of loop of Henle
Na+K+2Cl- symport Inhibitors-
Loop Diuretics: MOA
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.
Loop Diuretics: Adverse Effects
electrolyte, bp, ear
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)
Drug-Drug Interaction of loop diuretics
5
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
Thiazide / thiazide like diuretics: MOA, and the 5 drugs
What differentiates them from loop diuretics
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
Adverse Effects of Thiazide Diuretics
Thiazide diuretics may cause magnesium deficiency, mostly in geriatric population
Most importantly cause fluid and electrolyte imbalance,
especially hyponatremia, hypotension, hypokalemia,
hypochloremia
Erectile dysfunction
Thiazide diuretics: Drug-drug interactions
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.
What are the 2 parts of the collecting duct?
- Cortical collecting duct
- Inner medullary collecting duct
Function of principal cells, and what diuretics act on them?
Principal cells reabsorb water, and Na+ but promote K+ secretion
Principal cells are the site of action of aldosterone, and also K+-sparing diuretics.
What maintains lumenal electric neutrality after ENaC mediated Na+ reabsorption leaves the lumen negatively charged?
K+ from principal cells or H+ from type A intercalated cells are secreted back into the lumen
Which 2 diuretics act directly on Epithelial Na+ Channels (ENaC)?
Triamterene and Amiloride
Which 2 reduce ENaC membrane expression?
Spironolactone and Eplerenone (mineralocorticoid receptor antagonists)
Triamterene and Amiloride – MOA
Inihibit/block ENaC, located in the late distal convoluted tubule and collecting duct.
By inhibiting ENaC, they spare K+ loss.
Adverse effects of Amiloride and Triamterene and contraindications
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
MOA: Aldosterone- (Mineralocorticoid Receptor Ligand) induced Na+ uptake
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.
Aldosterone effect on serum and glucocorticoid stimulated kinase activity (SGK1)
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
MR Antagonists- Spironolactone, Eplerenone MOA:
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
Adverse effects of MR antagonists
which drug has less known adverse effects
➢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
What are the 4 Natriuretic Peptides and where are they produced?
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
What channel do Natriuretic peptides act on, and what ions do they allow to pass?
Cyclic nucleotide gated cation (CNGC) channel allows Na+, K+, and NH4 + entry and is controlled by cyclic GMP
What are the names of the recombinant natriuretic peptides?
Human recombinant ANP (carperitide, available only
in Asian subcontinent)
BNP (Nesiritide- a recombinant peptide known to inhibit CNGC function
Natriuretic Peptides: MOA
receptors / what do they inhibit / prevent exit of what ion
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).
Natriuretic Peptides: Adverse effects, Contraindications and drug interactions
type of insufficiency, increase serum levels, increase in hypotension risk
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
Where is ADH produced, what is it released in response to
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.
Vasopression: MOA
What are V2 receptors
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
Vasopression / ADH Drug Interactions
➢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.
Name 2 Vasopressin Agonists and some clinical indications
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
What are the Vasopression Receptor Antagonists and their respective receptors?
common ending
1) V2 specific antagonists: Mozavaptan, Tolvaptan and Lixivaptan
2) V1a / V2 antagonists: Conivaptan
common ending: vaptan
What are Vasopressin Receptor Antagonists used to treat?
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
V2 Receptor Antagonists- adverse effects and drug interactions
➢ 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.
