diuretics Flashcards
What is known as diuretics?
*Drugs which increase excretion of water
and electrolytes (especially Na+).
*The key process,
which regulates amount of excreted water and electrolytes, is reabsorption.
Places of action in the nephron.
Refer to the lecture.
(Proximal tubule, Thin descending limb of loop of henle, Thick Ascending limb of loop of henle, Distal convulated tubules, Collecting tubules)
Classification of diuretics?
torsemide, bumetanide, etacrynic acid
- Carbonic anhydrase inhibitors
●acetazolamide - Loop diuretics
●furosemide,
●torasemide - Thiazide and thiazide-like diuretics
●hydrochlorothiazide,
●chlorothiazide,
●chlorthalidone,
●indapamide - K+-sparing diuretics
●spironolactone,
●triamterene,
●amiloride - Osmotic diuretics
●mannitol
The sites of action of diuretics?
> Carbonic anhydrase inhibitors
Proximal tubule
> Loop diuretics
Ascending limb of the Henle’s loop
> Thiazide and thiazide-like diuretics
Distal tubule
> K+ -sparing diuretcs
Collecting ducts
> Osmotic diuretics
Proximal tubule,
descending limb of the Henle’s loop
Carbonic anhydrase inhibitors
(Features, Main adverse effect)
> Diuretics of low efficiency.
Due to inhibition of carbonic
anhydrase.
> Decrease reabsorption of Na+ &
HCO3.
Therefore decrease amount in blood.
> Decrease secretion of H+
Therefore increase the amount in
blood.
Main adverse effect - Metabolic acidosis
Carbonic anhydrase inhibitors.
(Applications)
> open-angle glaucoma
(reduce formation of ocular fluid)
> epilepsy (petit mal)
(possibly due to the decrease of cerebrospinal fluid production)
> acute mountain sickness
metabolic alkalosis (Decrease blood pH)
The loop diuretics? (separate part of the textbook)
Loop diuretics (furosemide, torasemide - INN (torsemide - USAN),
ethacrynic acid) are used only if thiazide diuretics are ineffective
(for example, for the treatment of arterial hypertension combined with congestive heart failure).
The best representative of this group torasemide (torsemide), due to its long duration of action which allows once a day administration.
The loop diuretics are the most powerful and due to this, they (especially in high doses) can cause severe and even dangerous electrolytes disturbances in the organism
(hypokalemia,
hypocalcemia,
hypomagnesemia)
&
ototoxicity (irreversible deafness).
Deafness is caused more often by the administration of
ethacrynic acid,
especially in a combination with other ototoxic drugs.
Loop diuretics?
(Features, Main application, Adverse effects)
The main application:
- The loop diuretics are rapidly acting diuretics of high efficacy, so they are especially helpful in urgent states when a rapid effect is required.
- The influence on the electrolyte balance:
due to the inhibition of reabsorption they decrease the concentration of Na+, K+, Cl-, Ca++, Mg++.
> severe arterial hypertension (they decrease the blood pressure due to the decreased blood volume as a consequence of increased excretion of electrolytes and water)
> pulmonary edema, brain edema (decrease the BP due to the decreased blood volume as a consequence of increased excretion of electrolytes & water)
> Congestive heart failure
(decrease of the blood volume leads to the decrease of cardiac overload,
the disappearance of edema)
> acute hypercalcemia
> acute renal failure (increase the urine flow in an initial stage of this disorder)
> liver cirrhosis: to reduce edema and ascites, which develop in the liver cirrhosis due to the increased portal pressure and reduction of the oncotic pressure
> hypovolemia (excretion of a high amount of water leads to a significant decrease of the blood volume, which can be dangerous for a patient);
> hypokalemia;
hypocalcemia;
hypomagnesemia;
hyperuricemia (hypovolemia can contribute to the increased reabsorption of the uric acid);
hypokalemic metabolic alkalosis (hypokalemia leads to increased secretion of H+ in collecting tubules);
»ototoxicity (more common of etacrynic acid).
Advantages of torasemide over furosemide?
- longer duration of action
(furosemide is administered 2 – 3 times daily,
torasemide – once daily; - lower risk of hypokalemia
(Rapid & Prolonged effects)
(the duration of the action of torasemide is 4–6 hours versus 2–3 hours for furosemide).
> > > Torasemide also cause less K+ loss.
Additional mechanism of action of torasemide –block of aldosterone receptors./ Torasemide also causes less K+ loss (possibly, due to the inhibition of synthesis of aldosterone or block of its receptors)
Clinical data showed advantage of torasemide over furosemide in the treatment of congestive heart failure
(by influence on mortality and cardiac function)
Thiazides and thiazide-like diuretics?
(other part in text book)
> diuretics
(hydrochlorothiazide, indapamide, and others) are the main group of the diuretics for
the treatment of hypertension because:
1) they have a long duration of action, so they can be administered once daily;
2) they possess a sufficient antihypertensive effect;
3) they are not expensive;
4) they are safe for a long-term administration
(e.g. the risk of hypokalemia is low when used < 25 mg/day of hydrochlorothiazide or an equivalent dose of other thiazides);
5) they can be used at any stage of hypertension.
The mechanism of the antihypertensive effect of diuretics is due to a decrease in the sodium content in the body.
This leads to the decrease of the blood volume and dilation of the arterioles because the removal of Na* from the arteriolar walls reduces their sensitivity to vasoconstrictive sympathetic impulses and causes them to dilate.
Thiazides and thiazide-like diuretics?
(MOA)
> thiazides and thiazide-like diuretics inhibit the
reabsorption of Na+ and Cl– in the distal convoluted tubules
consequently,
reabsorption of water also is inhibited.
Thiazides and thiazide-like diuretics are diuretics of moderate efficacy.
Influence on electrolyte balance:
thiazides decrease the blood level of Na+ and Cl– due to the inhibition of their reabsorption;
also they decrease K+ in the blood due to the increase of K+ excretion in collecting tubules.
On the contrary,
the amount of Ca++ in the blood increases due to increased Ca++ reabsorption in exchange for Na+ by the Na+ / Ca++ exchanger on the basolateral membrane of the epithelial cell of the distal convoluted tubule
(caused by the decrease in Na+ amount inside the cell).
The increase of K+ excretion by thiazides and thiazide-like diuretics can be linked to inhibition of Na+ reabsorption in the distal convoluted tubule;
urine in the collecting tubules has more Na+,
so reabsorption of Na+ in this part of the nephron is increased,
as a consequence,
the excretion of K+ increases.
Indapamide also has vasodilator properties due to the block of Ca++ channels.
Thiazides and thiazide-like diuretics.
(Features, Application, MOA)
(application)
Arterial hypertension
Congestive heart failure
hepatic cirrhosis
diabetic insipidus;
associated with hypercalciuria.
Thiazides can be used in the same conditions as the loop diuretics, but
due to the milder effect and longer duration of the action, they are better for long-lasting therapy.
They are used more widely than the loop diuretics
in the treatment of arterial hypertension. Contrary to the loop diuretics, thiazides do not cause hypovolemia.
The mechanism of a hypotensive effect of thiazides and thiazide-like diuretics in a long-term treatment of arterial hypertension includes
not only
the decrease of the blood volume but
also the decrease of the peripheral vascular resistance due to the vasodilation;
the mechanism of this vasodilator effect is not known but may be linked to Na+ loss.
Ca++ channel blocking properties of indapamide also contribute to the vasodilation and
the decrease of the blood pressure
Adverse effects,
>hypokalemia;
> hyperuricemia;
> impaired carbohydrates tolerance, hyperglycemia
(possibly, due to the decreased secretion of insulin and decreased sensitivity to insulin;
this effect is partially linked with hypokalemia);
> hyperlipidemia
(thiazides increase the level of cholesterol and LDL by an unknown mechanism, which may be a response on the blood volume decrease)
K+-sparing diuretics?
(MOA & Application)
Mechanism of the action:
>K+-sparing diuretics act in collecting tubules,
blocking the reabsorption of Na+ and secretion of K+.
>Spironolactone and eplerenone are competitive aldosterone receptor antagonists,
they block
aldosterone receptors.
> Triamterene and amiloride directly block the transport of Na+ from the urine to the epithelial cells.
K+ sparing diuretics are diuretics of low efficacy.
Influence on electrolyte balance
(they decrease the concentration of Na+ & increase the concentration of K+ in the blood)
Application…
> congestive heart failure;
arterial hypertension;
hepatic cirrhosis;
primary hyperaldosteronism
(mainly aldosterone receptor antagonists
spironolactone or eplerenone).
> Diuretic effect of K+-sparing diuretics is relatively weak, so they have a low impact on the blood volume.
Noteworthy,
they prevent the development of hypokalemia caused by other diuretics,
so they are often combined with them (especially with thiazides).
> It is known that aldosterone promotes the development of the connective tissue
in the heart
and vessels.
> Therefore, the additional beneficial effect of aldosterone receptor antagonists is the decrease of fibrotic processes in the
heart (important for congestive heart failure) and vessels (important for arterial hypertension).
K+ sparing diuretics
(The main adverse effects)
> > The main adverse effect of the K+-sparing diuretics is hyperkalemia.
also they can cause acidosis due to the inhibition of H+ secretion in the intercalated cells.
> Spironolactone also can cause sexual disorders (impotence, gynecomastia)
because it can bind not only to aldosterone receptors but also to receptors for other steroidal hormones (including sex hormones).
> Eplerenone is a selective aldosterone receptor antagonist and
does not cause sexual problems.
> K+-sparing diuretics are contraindicated in renal failure because in this condition there is a high risk of hyperkalemia.
Osmotic Diuretics? (MOA)
The mechanism of the action:
> osmotic diuretics inhibit the reabsorption of water by increasing osmotic pressure in the lumen
(they are easily excreted by glomerular filtration and the increase of the osmotic pressure of the urine).
> The action of the osmotic diuretics occurs in parts of the nephron permeable for water
(proximal tubule and descending limb of the
Henle’s loop).
> Osmotic diuretics are diuretics of high efficacy (relating to the excretion of water)
but weak natriuretic
(low influence on excretion of Na+).
> Influence on electrolyte balance: the osmotic diuretics only slightly
increase excretion of Na+, K+, Cl–, Ca++, Mg++, HCO-3
