Download Low efficacy diuretics

Low efficacy diuretics
Dr. Iman
-
Potassium – sparing diuretics:Act on the collecting tubule.
Inhibit both Na+ reabsorption and K+ excretion..
Used in combination with thiazide to Rx hypertension (major use).
No exogenous K+ is needed.
Monitor K+ level.
A – Spironolactone :Mechanism of action:-
- Synthetic steroid that antagonizes aldosterone at intracellular cytoplasmic receptor
sites.
- Spironolactone – receptor complex is inactive and it will prevent translocation of the
receptor complex into the nucleus of the target cell, thus, it can not bind to DNA.
- The result is a failure to produce proteins that are normally synthesized in response to
aldosterone.
- These proteins normally stimulate Na+ / K+ exchange sites of the collecting tubule.
- Thus, a lack of mediator proteins prevents Na+ reabsorption and K+ and H+ secretion.
- In patient of high aldosterone levels in blood vessels → ↑ Na + retention.
- Spironolactone → ↑ Na+ excretion and retention of K+.
- Spironolactone effects depend on renal PGs synthesis.
- Eplerenone is a new aldosterone receptor antagonist with action comparable to
spironolactone but may have less endocrine effects
Therapeutic uses:a)Diuretic → low efficacy in mobilizing Na+.
- Advantage of retention K+.
- It is given in conjunction with thiazide or loop diuretics to prevent K+ excretion.
- Diuretic of choice in hepatic cirrhosis.
b) Secondary hyperaldosteronism, spironolactone is the only K+ sparing
diuretic that used alone to induce net negative salt balance as in nephrotic syndrome &
liver cirrhosis .
c) Heart failure → prevents the remodeling that occurs as compensation for
progressive failure particularly in those with reduced ejection fraction. .
d) In states of mineralocorticoid excess due to primary hypersecretion
{Conn's syndrome, ectopic ACTH production}.
. e) Resistant hypertension:
often responds well to aldosterone antagonists.This effect can be seen
in those with or without elevated aldosterone levels.
f. Ascites: Accumulation of fluid in the abdominal cavity (ascites)
is a common complication of hepatic cirrhosis.
g. Polycystic ovary syndrome:
. It blocks androgen receptors and inhibits steroid synthesis at
high doses, thereby helping to offset increased androgen levels
seen in this disorder
Pharmacokienetics:- Spironolactone and eplerenone Completely absorbed orally.
- Strongly bound to plasma proteins.
Rapidly converted to an active metabolite, Canrenone which has
mineralocorticoid blocking activity
. Spironolactone is a potent inhibitor P-glycoprotein
Ion transport pathways across the luminal and basolateral membranes of
collecting tubule and collecting duct cells. Inward diffusion of Na+ via the
epithelial sodium channel (ENaC) leaves a lumen-negative potential, which drives
reabsorption of Cl– and efflux of K+. (R, aldosterone receptor.)
-
-
Adverse effects:Gastric upsets (frequent), can cause peptic ulcer.
Gynecomastia in male and menstrual irregularities in female (similar to sex steroid
structures) → acts at receptors in other organs.
So it will not be given in large doses on a chronic basis.
At low doses, can be used chronically with few side effects.
Hyperkalemia, nausea, lethargy and mental confusion
. In patients with Addison disease, no diuretic effects
Potassium-sparing diuretics should be used with caution with other medications that
can induce hyperkalemia, such as angiotensin-converting enzyme inhibitors and
potassium supplements.
B – Triamterene and Amiloride
Block Na+ transport channels → ↓ Na+ / K+ exchange.
Their action dose not depend on the presence of aldosterone.
They have diuretic effect in primary adrenal insufficiency (Addison disease).
Low efficacy.
Used in combination with other diuretics.
S.E. is leg cramps.
↑ Uric acid and K+ retention.
Carbonic anhydrase inhibitors
- Inhibit the enzyme carbonic anhydrase (C.A) in the proximal tubular epithelium.
- They are much less efficacious than thiazides or loop diuretics.
Acetazolamide:-
Mechanism of action:Inhibits C.A enzyme in the cytoplasm and other apical membrane of the proximal
tubular epithelium.
C.A catalyzes the reaction of CO2 and H2O → H2CO3, which ionizes to H+ and
HCO3-.
The decreased ability to exchange Na+ for H+ in the presence of acetazolamide →
mild diuresis.
HCO3- is retained in the lumen, ↑ PH of urine.
The loss of HCO3- → hyperchloremic metabolic acidosis. And ↓ efficacy after several
days of Rx due to reduction in HCO3- stores (pool).
Pharmacokinetics:-
- Oral, once / day, secreted by proximal tubules.
Therapeuticuses:1. Rx of glaucoma.
- The common use for acetazolamide is to reduce high intraocular pressure of chronic
open angle glaucoma by decreasing the production of aqueous humor, probably by
blocking C.A in the ciliary body of the eye.
- Pilocarpine is preferred for acute attack because of its immediate action.
- Dorzolamide, Brinzolamide are topical C.A inhibitors, cause no systemic effects.
2. Mountain sickness
- Less commonly, acetazolamide used prophylactically in Rx of acute, mountain
sickness among healthy unacclimatised individuals who rapidly ascend above 10,000
feet. (Mountain climbers).
- Acetazolamide prevents weakness, breathlessness, dizziness, nausea, and cerebral as
well as pulmonary edema characteristic of the syndrome due to hypoxia and
alkalosis, and to ↑ respiratory drive and maintain arterial O2 tension.
- Give Rx once daily for 5 days at night before the ascent
- Dexamethasone can also be used.
3. Urinary alkalinization
- To enhance the excretion of uric acid, cyctine (insoluble in acid urine) and
weak acids like aspirin,& in cystinuria.
- The effect is of short duration of action and need bicarbonate infusion to maintain
continuing bicarbonate diuresis.
4. Reduction of total body bicarbonate stores
- In cases of chronic metabolic alkalosis which resist other diuretics.
- And in posthypercapnic metabolic alkalosis.
.
5. In some forms of hypokalemic periodic paralysis with some antiepileptics.
Therefore used as adjuvant to antiepileptic Rx(open potassium&calcium channels).
S.E.:- Metabolic acidosis.
- K+ depletion.
- Renal stone formation due to phosphateuria, or hypercalciuria, because calcium is
insoluble in alkaline urine.
- Drowsiness, paresthesia, after large doses ,taste alteration and hypersensitivity
reaction.
Contraindication:In liver cirrhosis because, alkalinization of urine will ↓ urinary trapping of NH4+ →
hepatic encephalopathy.
1.
-
-
Agents that enhance waterexcretion
Osmotic diuretics:Are small molecular weight hydrophilic substances that are filtered by the glumerulus
but not reabsorbed by the renal tubules → ↑ osmolarity of urine.
They prevent reabsorption of water (and by complex mechanisms, Only a small
amount of additional salt may also be excreted),
Act principally in the proximal convoluted tubule and probably in the descending
loop of Henle.
The result is that urine volume ↑ according to the load of osmotic diuretics.
e.g. Mannitol. (is not absorbed when given orally and should be given intravenously).
They ↑ water excretion and not preferred in cases with Na+ retention.
Uses:-They are used to maintain urine flow following acute toxic ingestion of substances
capable of producing acute renal failure.
To ↓ intracranial pressure.
Acute renal failure due to shock, drug toxicities, and trauma..
To ↓ intraocular pressure.
Mannitol present in extracellular space will extract water from the cells causing
hyponatremia (until diuresis occurs ),leading to expantion of extacellular water, so it
is contraindicated in pulmonary odema & congestive heart failure
Dehydration on the other hand can occur if water is not replaced.
2. ADH antagonists:- ADH (vasopressin) acts on: V1 receptors on vascular smooth muscle liver and other
tissues, V2 receptors which is coupled to adenylyl cyclase, and regulate opening of
the water channels (aquaporin) in cells of the renal collecting ducts.
- In the absence of ADH, C.D is impermeable to water → diluted urine.
- ADH secretion is regulated by serum osmolarity (↑ osmotic pressure of blood and by
drugs like nicotine → ↑ ADH secretion, ↓ osmotic pressure, and alcohol → ↓ ADH
secretion).
- Some tumors like oat – cell lung cancer can make vasopressin or called ADH – like
peptide → SIADH – syndrome of inappropriate ADH secretion → H2O retention.
- ADH antagonists are useful to induce water diuresis e.g.:1) Li+ salts (their levels in blood must be monitored closely).
2) Tetracycline derivative – demeclocycline.
They inhibit ADH effects at the collecting tubule by reducing the formation of cAMP
in response to ADH and interfere with the actions of cAMP in the collecting tubule
cells.
Uses:1. SIADH.
2. Other cases of elevated ADH.
E.g.in response to ↓ effective circulating blood volume e.g. heart failure,
liver disease and as for SIADH, H2O restriction is the Rx of choice and if
it has failed → demeclocycline may be considered.
Toxicity:1. Nephrogenic diabetes insipidus: Check serum Na+ level closely, otherwise SIADH is replaced by nephrogenic D.I and
hypernatremia → Rx by thiazides or amiloride.
2. Renal failure: By Li+ salts and demeclocycline.
 Li+ → chronic interstitial nephritis
.
3.Others → due to Li+ therapy → cardiotoxicity, thyroid dysfunction, leukocytosis,
mental obtundation and tremulousness.
- Demeclocycline should be avoided in liver disease.