Diuretics Flashcards
Classification of Diuretic drugs
- Carbonic anhydrase inhibitors in PCT
- Osmotic diuresis (‘aquaretic’) in entire tubule
- Loop diuretics in Ascending limb
- Thiazide diuretics in early distal
- K sparing in early collecting
- Aldosterone antagonists in early collecting
What are the K+ excreting diuretics?
CA inhibitors, loop diuretics, and Thiazides are K+ excreting diuretics
- incresing HCO3- concentration in collecting tubule
- incresingNa+ concentration in collecting tubule
- increasing Aldosterone secretion (secondary hyperaldosteronism)
Mechanism of CA inhibitors
Inhibition of carbonic anhydrase enzyme [CO2 + H2O ⇌ H2CO3 ⇌ H+ + HCO3-] - Diuresis (loss of NaHCO3 in the proximal convoluted tubule) – self-limiting process within 2-3 days - Metabolic acidosis (due to bicarbonate depletion) - K+ wasting (excess Na+is reabsorbed in the collecting tubule in exchange for K+ excretion)
2 CA inhibitors
Acetazolamide (B22), Dorzolamide (not in the list)
Acetazolamide (B22), Dorzolamide (not in the list) - Mode of action
- Renal
1. Inhibition of CA in proximal convoluted tubule -> prevents the formation of HCO3- and H+ - decreasing HCO3- and Na+ reabsorption
- Alkalic urine (increasing pH)
- Metabolic acidosis
- increasing K+, Ca2+, Pi excretion
- Diuresis
- Delayed consequences:
- decreasing plasma HCO3- -> decreasing HCO3- filtration -> decreasing Na+ excretion -> decreasing diuresis
- increasing H+ secretion due to acidosis -> acidic urine
- Tolerance (after 1wks): decreasing plasma HCO3-> decreasing filtrated HCO3 -> decreasing Na loss -> decreasing water loss
- Extrarenal
1. decreasing production of aqueous humor
2. decreasing production of CSF
3. decreasing production of gastric and pancreatic juice
Acetazolamide (B22), Dorzolamide (not in the list) - Indication
- Glaucoma
• It causes decreasing production of aqueous humor and decreasing intraocular pressure in patients with chronic open-angle glaucoma.
- Probably by blocking CA from ciliary body of the eye
2. Acute mountain sickness prophylaxis
• It prevents weakness, breathlessness, dizziness, nausea, cerebral and
pulmonary edema.
- Metabolic alkalosis
- Urinary alkalization
* E.g. aspirin poisoning - Severe hyperphosphatemia
- Adjacent therapy:
- Epilepsy
- Refractory edema (doesn’t respond to normal diuretic treatment)
- CSF leakage
Acetazolamide (B22), Dorzolamide (not in the list) - Pharmacokinetics and Adverse effects
- Pharmacokinetics
- 90% protein bound
- Renal elimination (active tubular
secretion + passive reabsorption) - Administration:
• Oral
• IV
- Adverse effects
- Hyperchloremic metabolic acidosis
- Hypokalemia
- Paresthesia
- Somnolence
- Renal stones (Ca-phosphate, cysteine)
- BM suppression
- Hypersensitivity reactions (sulphatecontaining
drugs)
Contraindications: - Sulphonamide sensitivity
- Severe kidney and/or hepatic
disorders
4 osmotic diuretics
Glycerol (B23), Mannitol (B23), Isosorbide (not in the list), Urea (not in the list)
Glycerol (B23), Mannitol (B23), Isosorbide (not in the list), Urea (not in the list)
-Mode of action
- They increases osmolarity in the tubular fluid and
prevent further water reabsorption -> osmotic diuresis - Hyperosmosis in the blood ->increasing EC volume -> increasing GFR
- decrasing ADH secretion
Glycerol (B23), Mannitol (B23), Isosorbide (not in the list), Urea (not in the list)
-Indication, side effects, and contraindication
Indication
- Brain edema : urea and mannitol infusion
- Acute kidney failure (shock kidney) : Mannitol infusion with loop diuretics
- Refractory edema (when it is induced by kidney or liver disorders)
- Glaucoma (acute severe- Glaucoma attack)
- Cystic fibrosis (mannitol spray)
Side effects
Heart failure, increased extracellular fluid volume (too strong osmotic effects), hyponatremia
Contraindication
Liver cirrhosis, Heart failure
4 Loop diuretics
Etacrynic acid (B22)
Furosemide (B22)
Bumetanide (not in the list)
Torsemide (not in the list)
Mode of action
Etacrynic acid (B22)
Furosemide (B22)
Bumetanide (not in the list)
Torsemide (not in the list)
It blocks NKCC2 in the TAL:
- Na+ and K+ stay in the TAL -> diuresis
- Negative potential (as K+ doesn’t leak out) -> increasing Ca2+
and Mg2+ excretion - decreasing osmotic gradient
- decreasing uric acid secretion
- Deceit of macula densa (due to decreasing Na+ inside juxtaglomerular cells):
• increasing COX2 expression -> increasing PGE2 - increasing renin release
- increasing RBF
- decreasing ¯ pulmonary congestion
Indication
Etacrynic acid (B22)
Furosemide (B22)
Bumetanide (not in the list)
Torsemide (not in the list)
1. Acute pulmonary edema (LV failure)
• Improvement of venous tone
2. Congestive heart failure
3. Refractory edema
4. Acute/chronic kidney failure
5. Hypertension
• Not 1st line
• In the case of impairment of kidney function
6. Poisoning (forced diuresis)
• E.g. Br, Fl, J (not Li!!!)
• Risk of dehydration if the fluid is not replenish, thus usually given
with an infusion
Pharmacokinetics and Adverse effects
Etacrynic acid (B22)
Furosemide (B22)
Bumetanide (not in the list)
Torsemide (not in the list)
- Pharmacokinetics
- Furosemide :
- taken orally(only 50% is absorbed) or i,v
- 20-80mg in the morning
-Torsemide
- taken orally, better absorption, fast
- 2.5-20mg
-Bumetanide
- taken orally, 40times potent than furosemide, fast, short duration of action
- 0.5- 2mg
- Adverse effects
- Hypokalemia, Hypocalcemia, Hyperuricemia, Hyperuricemia
- Hypovolemia, Hypomagnesemia
- Metabolic alkalosis
2 Thiazides and 4 related compounds (one each in the list)
Thiazides:
Bendroflumethiazide (not in the list)
Hydrochlorothiazide (B22)
Related compounds:
Indapamide (B22)
Clorthalidone (not in the list)
Metolazone (not in the list)
Clopamide (not in the list)
Thiazide - mode of action
Inhibits Na+ and Cl- transporters in DCT
- increasing Na+ and Cl- excretion
- increasing K+ and Mg2+ excretion
- increasing Ca2+ absorption -> Hypercalcemia
Stimulation of luminal PTH-dependent Ca2+ channel as there is decreasing Na+ inside the cell -> increasing activity of Na+/Ca2+ antiporter
Consequences
Diuretic
Hypokalemia, hypomagnesomia
Metabolic alkalosis
Hypercalcemia
Mode of action of aldosteron receptor antagonists
- Aldosterone acts on these cells. It is released in hyponatremia, hyperkalemia or due to renin release.
- It can induce the expression of different genes:
o ENaC -> increasing [Na+]IC -> increasing IC potential -> K+ efflux to tubular lumen
o Na+/K+ or Na+/H+ antiporters -> Na+ + water retention and K+, H+ will be excreted.
o Na+/K+ ATPase - These K+-sparing diuretics can affect the aldosterone receptor.
Aldosterone receptor antagonists:
Spironolactone, Eplerenone
- Inhibition of the expression of aldosterone dependent
Na+/K+ ATPase and Na+ transporters (Na+/K+ or Na+/H+ antiporters)
• Na+ excretion -> diuresis
• K+ reabsorption increasing
Mode of action
Amiloride (B23)
Triamterene (not in the list)
Inhibition of ENaC:
- decreasing Na+/K+ exchange ->
• Na+ excretion
• Diuresis
• Ø K+ loss
Mode of action
ADH antagonists
- Li+ salts (not in the list), Demeclocycline (not in the list)
- Inhibition of cAMP-mediated processes
- SIADH, Hyponatremia
- Metabolized in the liver
- Nausia, Thirst, Polyuria, Dehydration, Hypoglycemia
- Conivaptan (not in the list), Tolvaptan (B23)
- ADH (V2) antagonists
- SIADH, Hyponatremia
- Metabolized in the liver
- Nausia, Thirst, Polyuria, Dehydration, Hypoglycemia
