Unit 4 - Diuretics Flashcards
What is a diuretic?
Agent that causes an increase in urine volume
What is a natriuretic?
Agent that causes an increase in renal sodium excretion
Natriuretic - almost always also increase water loss so lumped in with diuretics
What is an aquaretic?
Agent that causes an increase in excretion of solute-free water
Osmotic diuretics and antidiuretic hormone antagonists are aquaretics
What are the main clinical uses for diuretics?
Treating
- cardiac failure
- oedema
- hypertension
- liver disease
- some types of renal disease
- overdose or poisoning to promote excretion
- abuse
- eating disorders to lose weight
Where is carbonic anhydrase predominantly found in the nephron?
Proximal convoluted tubule?
What is the function of carbonic anhydrase in the proximal convoluted tubule?
- catalyses the dehydration of H2CO3 at luminal membrane
- catalyses the rehydration of CO2 in the cytoplasm
Carbonic anhydrase (CA) is a zinc metalloenzyme that catalyzes the reversible hydration of CO2 according to the reaction: H+ + CO3- H2CO3 CO2 + H2O
What is the effect of inhibiting carbonic anhydrase in the proximal convoluted tubule?
Less H+/Na+ exchange takes place
- diuresis occurs
What is the prototypical carbonic anhydrase inhibitor?
Acetazolamide
What are the pharmacokinetics of acetazolamide?
Well absorbed after oral administration
- diruesis apparent within 30 minutes
- maximal effect at 2 hours
- persists for 12 hours
What are the pharmacodynamics of acetazolamide?
Profoundly depress HCO3- reabsorption in proximal tubule
- at maximal safe dosage, 85% of the resorptive capacity of the proximal tubule for HCO3- inhibited
- 45% over whole kidney
- efficacy decreases over several days use
HCO3- depletion leads to increased NaCl reabsorption by the remainder of the nephron
What are the clinical indications for acetazolamide?
- glaucoma
- urinary alkalinisation
- acute mountain sickness
- metabolic alkalosis
- adjuvant in epilepsy
- CSF leakage
How does acetazolamide treat glaucoma?
Reduction in aqueous humour formation by carbonic anhydrase inhibitors decreases intraocular pressure
- dorzolamide and brinzolamide used topically
How does acetazolamide cause urinary alkalinisation?
Uric acid and cysteine are relatively insoluble in acidic urine and may form stones
- cystineurea - raise pH to 7 - 7.5
- uric acid - raise pH to 6 - 6.5
Urinary alkaline - In the absence of HCO3- only lasts 3 days therefore give oral HCO3. Monitor pH - can end up with Calcium stones
Cysteineurea - poor reabsorption of cysteine
How does acetazolamide treat acute mountain sickness?
Decreases Cerebrospinal fluid (CSF) formation and the pH of CSF in the brain
What is hyperchloremic metabolic acidosis, caused by toxicity from acetazolamide?
Chronic reduction of body HCO3-
How does acetazolamide cause renal stones?
Build up of phosphates and calcium in the urine
- relatively insoluble in alkaline conditions
How does acetazolamide cause renal potassium wasting?
Increased Na+ in the collecting tubule is partially reabsorbed enhancing K+ excretion
- administer potassium chloride or potassium sparing diuretic
How do loop diuretics work?
Selectively inhibit NaCl reabsorption in the thick ascending limb
- most efficacious diuretic agents available
Give an example of a prototypical loop diuretic
Furosemide
What are the pharmacokinetics of loop diuretics?
Rapidly absorbed
Eliminated by the kidney by glomerular filtration and tubular secretion
- absorption of furosemide 2 - 3 hours
- duration of action 2 - 3 hours
What are the pharmacodynamics of loop diuretics?
Inhibit NaK2Cl transporter on the luminal membrane
Inhibits reabsorption of NaCl
- movement of water across cell is reduced
- direct effects on blood flow through several vascular beds
- induces COX-2 which participates in the synthesis of prostaglandins and arachidonic acid
- increased renal blood flow
- reduced pulmonary congestion
- left ventricular filling pressures in heart failure
Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid,
Loop diuretics are organic anions that inhibit the Na+/K+/2Cl− co-transporter, a member of the solute carrier family 12 (SLC12A1), also termed NKCC2, which is expressed on the apical membranes of medullary and cortical TAL cells and macula densa segments. Expression of NKCC2 is increased by prolonged infusion of saline or furosemide. They are potent diuretics (25% of Na+ reabsorption occurs in TAL). Loop diuretics also inhibit NaCl transport in short descending limbs of the loop of Henle and collecting ducts. Reduction in the medullary concentrating gradient due to inhibition of solute reabsorption in the water-impermeable TAL leads to impaired free water excretion during water loading and reabsorption during dehydration. Loop diuretics increase the fractional excretion of Ca2+ by up to 30% by decreasing the lumen-positive transepithelial potential that promotes paracellular Ca2+ reabsorption from the lumen. The loop of Henle is the major nephron segment for reabsorption of Mg2+; loop diuretics increase fractional Mg2+ excretion by more than 60%, also by diminishing voltage-dependent paracellular transport.
What are the clinical indications for the use of loop diuretics?
Pulmonary oedema
Oedematous conditions
Acute hypercalcaemia
Hyperkalemia
- mild or after acute management of severe hyperkalemia by other measures
Acute renal failure
- can increase the rate of urine flow and enhance potassium excretion in acute failure
Anion overdose
- toxic ingestions of bromide, fluoride and iodide
How do loop diuretics cause hypokalaemic metabolic alkalosis?
Increased secretion of K+ and H+
- urine becomes more acidified so rest of body becomes more alkaline
What is ototoxicity?
Ototoxicity is when a person develops hearing or balance problems due to a medicine.
Dose related hearing loss
- usually reversible
Ototoxicity - more common in diminished renal function and receiving other ototoxic e.g. aminoglycosides
How do loop diuretics cause hyperuricemia?
Can precipitate attacks of gout
- hypovolemiea associated enhancement of uric acid reabsorption in proximal tubule
How do loop diuretics cause hypomagnesemia?
Chronic use of loop agents
Hypomagnesemia - more common in patients with dietary magnesium deficiency
How do loop diuretics cause allergic and other reactions?
Loop diuretics are sulphonamides (except ethacrynic acid)
- skin rash
- eosinophilia
- interstitial nephritis
How do thiazides work?
Inhibit NaCl transport in the distal convoluted tube (not proximal)
What is the prototypical thiazide agent?
Hydrochlorothiazide
What are the pharmacokinetics of thiazides?
All can be administered orally
- all secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid
What are the pharmacodynamics of thiazides?
Block NaCl reabsorption from the luminal side of epithelial cells in the distal convoluted tubule
- unlike loop diuretics which inhibit Ca2+ reabsorption in the thick ascending limb, thiazides enhance Ca2+ reabsorption
- don’t cause hypercalcaemia but they can mask it
- action partly depends on renal prostaglandin production and therefore can be inhibited in certain conditions by NSAIDs
What are the indications for thiazides?
Hypertension
Heart failure
Nephrolithiasis due to idiopathic hypercalciuria
- causing stones
Nephrogenic diabetes insipidus
- improper response to ADH
- reduces ability of kidney to concentrate urine by removing free water
Nephrogenic diabetes insipidus is caused by an improper response of the kidney to ADH, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water
What are the side effects of thiazides?
Hypokalaemic metabolic alkalosis Increased hyperuricemia Impaired carbohydrate tolerance Hyperlipidemia Hyponatremia Allergies and other reactions
How do thiazides cause hypokalaemic metabolic alkalosis and increased hyperuricemia?
Similar to loop diuretics
How does thiazide toxicity cause impaired carbohydrate tolerance?
Hyperglycaemia can occur in those who are overtly diabetic or have mildly impaired glucose tolerance. Impaired insulin release and diminished tissue utilisation of glucose
what can thiazide toxicity cause ?
Hypokalaemic metabolic alkalosis & increased hyperuricemia - similar to loop diuretics
Impaired carbohydrate tolerance - hyperglycaemia can occur in those who are overtly diabetic or have mildly impaired glucose tolerance. Impaired insulin release and diminished tissue utilisation of glucose
Hyperlipdemia - 5 - 15% increase in total serum cholesterol
Hyponatremia - hypovolemia induced elevation of ADH, reduction in the diluting capacity of kidneys and increased thirst
Allergic and other reactions - similar to loop diuretics. Serious allergic reactions are rare.
Ototoxicity - more common in diminished renal function and receiving other ototoxic e.g. ahminoglycosides
Hypomagnesemia - more common in patients with dietary magnesium deficiency
How do potassium sparing diuretics work?
Prevent potassium secretion by antagonising the effects of aldosterone in collecting tubules
Direct antagonism of mineralocorticoid receptors - spironolactone, eplerenone
Inhibition of sodium influx via ion channel on the luminal membrane - amiloride, triamterene
Give two examples of potassium sparing diuretics which are antagonists of mineralocorticoid receptors
Spironolactone
Eplerenone
What are the pharmacokinetics of potassium sparing diuretics?
Spironolactone
- substantial inactivation by the liver
- slow onset of action
- several days for full therapeutic effect
Eplenerone
- spironolactone analogue with greater selectivity for mineralcorticoid receptor
- several hundred fold less active on androgen and progesterone receptors
What are the pharmacodynamics of potassium sparing diuretics?
Reduce absorption of Na+ in the collecting tubule and ducts
- potassium absorption and secretion at this site regulated by aldosterone
- spironolactone and eplerenone bind to mineralocorticoid receptors and blunt aldosterone activity
- amiloride and triamterene directly interfere with Na+ entry through the epithelial Na+ channels
- action partly depends on renal prostaglandin production and therefore can be inhibited in certain conditions by NSAIDs
What are the indications for use of potassium sparing diuretics?
Most useful in states of mineralocorticoid excess or hyperaldosteronism
- primary hypersecretion
- Conn’s syndrome
- ectopic adrenocorticotropic hormone production
- secondary hyperaldosteronism induced by heart failure, hepatic cirrhosis, nephrotic syndrome
- thiazide or loop diuretics can cause secondary hyperaldosteronism
What is the toxicity of potassium sparing diuretics?
Hyperkalaemia Hyperchloremic Metabolic Acidosis Gynecomastia Impotence Benign prostatic hyperplasia (with spironolactone)
How does toxicity of potassium sparing diuretics cause ?
Hyperkalemia - Exacerbated by renal disease
- maximum potassium secretion is reduced
Concomittant use of drugs that reduce/inhibit renin or angiotensin II activity
Potassium sparing!!
Hyperchloremic Metabolic Acidosis - inhibition of H+ secretion in parallel with K+ secretion
Gynecomastia, impotence, and benign prostatic hyperplasia with spironolactone
What effect do diuretics have on urinary electrolytes?
+ = increase - = decrease
Carbonic anhydrase inhibitors: NaCl + NaHCO3 +++ K+. + Body PH - acidosis
Loop Agents: NaCl ++++ NaHCO3 0 K+. + Body PH - Alkalosis
Thiazides: NaCl ++ NaHCO3 + K+. + Body PH - Alkalosis
Loop Agents + Thiazide NaCl +++++ NaHCO3 + K+. ++ Body PH - Alkalosis
K+ Sparing agents NaCl + NaHCO3 (+) K+. - Body PH - acidosis
