Diuretics are the drugs which increase urinary flow. Clinically all drugs used concomitantly increase Na+ excretion and accompanying anion, mostly Cl-, thus in a nutshell, also produce natriuresis.
Na+ is a very important ion which determines ECF volume. If present in excess, positive sodium balance leads to increased blood volume. Negative sodium balance is associated with circulatory collapse leading to shock. Thus body must regulate sodium levels in the body.
Diuretics interfere with this balance, and may cause disturbance of:
- Water balance
- Ionic balance
Excretion of other ions like Ca++, Mg++, K+, Cl- and HCO3- is also disturbed.
Basic unit of kidney is nephron. There are about 1.3 million nephrons in each kidney. Processes occurring include tubular filtration, secretion and reabsorption.
From Bowman’s capsule, filtrate enters the proximal tubule.
- 85% NaHCO3 is reabsorbed.
- 40% NaCl is reabsorbed.
- A total of about 66% Na+ is reabsorbed
- About 65% K+ is reabsorbed
- About 100% glucose and amino acids are reabsorbed
- About 80% passive reabsorption of water occurs
Thus proximal tubule has tremendous reabsorption capacity.
Straight portion can be divided into S1, S2 and S3.
S2 has acid secretory mechanism which is important in the secretion of weak acids like diuretics, NSAIDS, uric acid, antibiotics (penicillin, cephalosporins) and forms basis of drug interactions of diuretics with uric acid. There are chances that diuretics may reduce the secretion of uric acid. Many diuretics increase the levels of uric acid in blood leading to hyperuricemia.
Similar to acids, for weak bases secretory mechanism is present in S1 and S2. Procainamide, creatinine, choline are secreted actively in S1 and S2.
Most diuretics act within the nephron. Secretion is one way to reach the binding site.
No mechanism is present for reabsorption of Na+ and Cl-. It is permeable to water. Medullary interstitium is more hypertonic and can extract water out. Thus urine gets concentrated.
Ascending thick limb
- 25-30% of NaCl is reabsorbed in ascending thick limb. The mechanism is different and involves N+ K+ 2Cl- cotransporter (symporter)
- Passive reabsorption of Ca++, Mg++ occurs as well.
This segment dilutes the urine.
Distal Convoluted Tubule
- NaCl is reabsorbed about 8-10%. Separate transporter, NaCl symporter is present.
- Separate mechanism is present for Ca++ reabsorption under parathyroid influence.
- If diuretic is acting in the ascending thick limb, Mg++ and Ca++ reabsorption is also inhibited, but will be reabsorbed in the distal tubule.
- Aldosterone acts Na+ is reabsorbed while K+ is excreted.
- Only reabsorption of 2-5% NaCl occurs. Separate mechanism is present for Na+ reabsorption and K+ and H+ secretion.
If less Na+ is reabsorbed before this segment, more of it reaches and this segment finally determines the amount of Na+ loss.
Loop and thiazide diuretics cause hypokalemia and alkalosis.
More is the Na+ load reaching this segment; more is reabsorbed along with more excretion of K+ and H+.
Watery channels are ADH dependent. (dilutes urine determined by conc.)
Water reabsorption occurs under the influence of ADH.
Classification is based on:
- mechanism of action
Thiazide – related compounds (same actions, structure different)
- potassium canrenoate
Adenosine receptor antagonist
Rolofylline – awaiting FDA approval