Carbonic anhydrase inhibitors act on the proximal convoluted tubule.
Dorzolamide and Brinzolamide are used topically for treatment of glaucoma.
Any diuretic acting at the proximal convulated tubule must be strong. These diuretics are weak and are chemically sulphonamides (associated with allergic manifestations)
Drugs are well absorbed orally. When used produce HCO3- secretion producing urinary alkylation within 30 minutes. Maximum effect is observed within 2-3 hours. Single dose effect persists for 12 hours.
Mechanism of action
1. Site of Action
Proximal convoluted tubule
2. How reaches site of action??
By tubular secretion
3. Normal physiological events
Sodium potassium pump is present in every portion of nephron. It pumps Na+ from intracellular space to interstitium, thus Na+ is reabsorbed and is decreased intracellularly. This is used by Na+H+ antiporter (NHE3) which pumps Na+ inside and H+ outside into the lumen, where H+ combines with HCO3- to form carbonic acid. Carbonic acid is acted upon by carbonic anhydrase, regenerating CO2 which is reabsorbed and forms carbonic acid once again. Once it is again acted upon by carbonic anhydrase HCO3- is produced, which is pumped into interstitium, while H+ is reused.
In later portion of nephron, not enough HCO3- remains. Decrease in pH stimulates Cl- base transporter. Cl- is pumped inside the cells, while base moves to the lumen.
4. What drug does??
Diuretic inhibits the luminal carbonic anhydrase and cytoplasmic carbonic anhydrase. This reabsorption of NaHCO3 does not take place. NaCl passive reabsorption dos not take place and there is loss of water as well.
In the distal portion of nephron, mechanism for is independent of HCO3- reabsorption. Most of NaCl is reabsorbed in distal portion.
Although carbonic anhydrase inhibitors act on proximal tubule, still they are weak because:
- Action of diuretics is blunted by distal portion
- Not enough HCO3- is present, depletion of HCO3- and excess of H+ occurs in plasma leading to metabolic acidosis
5. Ionic changes
Increased excretion of NaHCO3 momentarily, then over.
6. Circulatory changes
Located near distal convoluted tubule are specialized cells called macula densa. If increased Na+ reaches the distal tubule, tubuloglomerular feedback immediately reduces blood flow. Because it is active under influence of carbonic anhydrase inhibitors, this is another reason for decrease in action of carbonic anhydrase inhibitors.
Topically applied and instilled into eye.
1. Treatment of Glaucoma
HCO3- is secreted in aqueous humour similar to kidneys. When decreased secretion of HCO3- within eye by ciliary processes occurs, decreased production of aqueous humour occurs. Acetazolamide is still used.
2. Urinary Alkalinization
As increased HCO3- is lost, alkaline urine is produced, which enhances the excretion of weak acids, uric acid, aspirin, etc.
3. Metabolic alkalosis
Normally treated by volume replenishment and K+ replenishment, but sometimes in settings of CCF, these can be used to reverse metabolic alkalosis and produce dieresis as well. They produce an excess of H+ in plasma.
4. Acute mountain sickness
Those who rapidly ascend to 3000 feet or more, develop pulmonary edema, cerebral edema. CSF is produced by choroid plexus, which secretes HCO3- and water under carbonic anhydrase influence. If blocked, decreased production of CSF occurs. Thus, can be utilized in high altitude sickness. These drugs are more important if used prophylactically.
Acetazolamide may be effective as metabolic alkalosis suppressive activity occurs on abnormal electrical activity of brain. Thus these drugs can be used when others fail.
As alkaline urine is produced, increased phosphate and Ca++ are excreted.
3. Hypokalemic periodic paralysis
Patient suffers from paralysis and weakness, but recovers automatically. Genetic disorder, these drugs may be used.
1. Hyperchloremic metabolic acidosis
HCO3- is lost in urine while Cl- is reabsorbed distally, combined effect produces hyperchloremic metabolic acidosis.
2. Renal stones
As alkaline urine is produced, increased phosphates are lost along with calcium, which do not remain soluble and may precipitate.
3. K+ wasting
As increased sodium reaches the distal portion and collecting tube, increased reabsorption occurs along with increased K+ loss, which sometimes manifests in form of weakness.
4. Paresthesias & drowsiness
5. Allergic manifestations
Bone marrow suppression, interstitial nephritis
If liver is not functioning, ammonia is not handled properly, leading to hyperammonemia hepatic encephalopathy.
NH4+ is converted into NH3 and is reabsorbed. H+ combines with bicarbonates.