Pharmacology

1. Asian Medical Institute Memorial S.Tentishev
Department of Interprofessional discipline
Subject - Basic and clinical Pharmacology
Teacher - Temirbekovа Gulnura

2. Lecture:№6
Theme: Diuretics

3. Diuretics are drugs that increase the
volume of urine excreted.
1- THIAZID DIURETICS
Thiazides are the most widely used diuretics.
They are sulfonamide derivatives.

4. Chlorothiazide [klor-oh-THYE-ah-zide] was
the first orally active diuretic that was able to act
on the severe edema often seen in cirrhosis of the
liver and heart failure with minimal side effects.
Hydrochlorothiazide is more effective, so the
required dose is much lower than that of
chlorothiazide, but the effectiveness is
comparable to that of the original drug.

5. 1. Mechanism of action: Thiazide and
thiazide-like diuretics act mainly in the cortical
region of the ascending loop of the Henle and the
distal convoluted tubule to reduce the reabsorption
of Na+, apparently by inhibiting the Na+/Cl-
cotransporter on the luminal membrane of the
tubules
(Figure 18.2).

7. They have less effect on the proximal tubules.
As a result, these drugs increase the
concentration of Na+ and Cl- in the tubular
fluid. [Note: Since the site of action of
thiazide derivatives is on the lumen
membrane, these drugs must be excreted in
the tubular lumen to increase efficiency.

8. Therefore, with a decrease in renal function,
thiazide diuretics lose their effectiveness.]
The effectiveness of these agents can be
reduced with the simultaneous use of
NSAIDs, such as indomethacin, which
inhibits the production of renal
prostaglandins, thereby reducing blood flow
to the renal blood.

9. 2. Actions:
Increased excretion of Na+ and Cl-: Thiazide and
thiazide-like diuretics cause diuresis with increased
excretion of Na+ and Cl-, which can lead to the
excretion of very hyperosmolar (concentrated) urine.
Loss of K+: Since thiazides increase Na+ in the
filtrate in the distal tubules, more K+ is also
exchanged for Na+, which leads to a permanent loss of
K+ from the body with prolonged use of these drugs.
Thus, K+ serum should be measured periodically
(more often at the beginning of therapy) to monitor the
development of hypokalemia.

10. Mg2+ loss: Magnesium deficiency requiring
supplementation can occur with chronic use of
thiazide diuretics, especially in elderly patients.
The mechanism of magnesia is not understood.
Reduced urinary calcium excretion: Thiazide
and thiazide-like diuretics reduce urine Ca2+
content by promoting Ca2+ reabsorption in the
distal tortuous tubules, where parathyroid
hormone regulates reabsorption.

11. This effect contrasts with loop diuretics,
which increase the concentration of Ca2+ in
the urine.
Decreased peripheral vascular resistance:
The initial decrease in blood pressure is the
result of a decrease in blood volume and
therefore a decrease in cardiac output.

12. 3. Therapeutic use:
Hypertension: Clinically, thiazides are the basis of
antihypertensive drugs because they are inexpensive,
easy to use and well tolerated. They effectively lower
blood pressure in most patients with mild to moderate
essential hypertension.
Blood pressure can be maintained with a daily dose of
thiazide, which causes lower peripheral resistance
without having a serious diuretic effect. Some patients
may take only thiazides for years; however, many
patients require additional medications to control their
blood pressure.

13. Heart failure:
Loop diuretics (not thiazides) are the diuretics of
choice when reducing extracellular volume in heart
failure. However, thiazide diuretics may be added if
additional diuresis is needed. With simultaneous
administration, thiazides should be administered 30
minutes before taking loop diuretics to give thiazide
time to reach the site and produce an effect.
Hypercalciuria: Thiazides may be useful in the
treatment of idiopathic hypercalciuria because they
inhibit the excretion of Ca2+ in the urine.

14. 4. Pharmacokinetics:
The drugs are effective orally. Most thiazides take
1 to 3 weeks to provide a stable reduction in blood
pressure, and they show a long half-life
Side effects:
These are mainly related to problems in fluid and
electrolyte balance.

15. Potassium depletion: Hypokalemia is the most
common problem with thiazide diuretics, and it
can predispose patients who take digoxin.
Hyponatremia: Hyponatremia can develop due to
an increase in ADH as a result of hypovolemia, as
well as a decrease in the dilution capacity of the
kidneys and an increase in thirst. Limiting water
intake and reducing the dose of a diuretic can
prevent hyponatremia.

16. Hyperuricemia: Thiazides increase serum uric
acid by reducing the amount of acid secreted by
the organic acid system. Being insoluble, uric
acid is deposited in the joints and can cause a
gout attack in predisposed people. Therefore,
thiazides should be used with caution in
stationary patients with gout or high uric acid
levels.
Hypercalcemia: Thiazides inhibit the secretion
of Ca2+, which sometimes leads to
hypercalcemia (elevated levels of Ca2+ in the
blood)

17. Thiazide-like diuretics These compounds do
not have a thiazide structure, but like thiazides,
they have an unsubstituted sulfa group and
therefore share their mechanism of action.
Therapeutic uses and side effects are similar to
thiazides.
Chlorthalidone: Chlorthalidone [klor-THAL-i-
done] is a non-thiazide derivative that behaves
pharmacologically as hydrochlorothiazide. It has
a longer duration of action and is therefore often
used once a day of hypertension treatment.

18. Indapamide: [in-DAP-a-mide] is a lipid-
soluble, non-thiazide diuretic that has a long
duration of action. Indapamide is
metabolized and excreted by the
gastrointestinal tract and kidneys.

19. 2-LOOP DIURETICS

20. Bumetanide [ byoo-MET-ah-nide],
Furosemide [fur-OH-se-mide],
Torsemide [TOR-se-mide] and
Ethacrin [eth-a-KRIN-ik]
acid exert their main diuretic effect on the
ascending limb of the Henle loop
(Figure 18.2).

21. Of all the diuretics, these drugs have the highest
efficiency in mobilizing Na+ and Cl- from the
body. They produce copious amounts of urine.
Furosemide is the most commonly used of these
drugs. Bumetanide and torsemide are
much more potent than furosemide, and the use of
these agents is increasing. Ethacrynic acid is
used infrequently due to its adverse exposure
profile

22. 1. Mechanism of action: Loop diuretics inhibit
Cotransport Na+/K+/2Cl- in the lumen membrane
in the ascending limb of the Henle loop.
Therefore, the reabsorption of these ions is
reduced. These agents have the greatest diuretic
effect of all diuretics, since the ascending limb
accounts for reabsorption from 25% to 30% of the
filtered NaCl, and subsequent areas cannot
compensate for the increased load of Na +.

23. 2. Actions: Loop diuretics
act quickly, even in patients
with poor function or lack of
response to other diuretics.
Changes in urine composition
induced by loop diuretics are
shown in Figure 18.6.

24. NSAIDs inhibit the synthesis of renal prostaglandins
and can reduce the diuretic effect of loop diuretics.
3. Therapeutic use: Loop diuretics are the drugs of
choice that support acute pulmonary edema and
acute/chronic peripheral edema caused by heart failure
or kidney failure. Because of their rapid onset of
action, especially when administered intravenously,
the drugs are useful in emergency situations such as
acute pulmonary edema.

25. 4. Pharmacokinetics: Loop diuretics are
administered orally or parenterally. Their
duration of action is relatively short (2 to 4
hours), which allows patients to predict
window diuresis.
5. Side effects: Figure 18.7 summarizes the
side effects of loop diuretics.

27. Ototoxicity: Reversible or permanent hearing loss can
occur with loop diuretics, especially when used in
combination with other ototoxic drugs (e.g.,
aminoglycoside antibiotics).
Ethacrynic acid most commonly causes deafness.
Although not common, vestibular function can also be
affected, causing dizziness.
Hyperuricemia: Furosemide and ethacrynic acid
compete with uric acid for the secretory system of the
kidneys, thereby blocking its absorption and, in turn,
causing or aggravating gout attacks

28. Acute hypovolemia: Loop diuretics can cause a severe
and rapid decrease in blood volume, with the possibility
of hypotension, shock and cardiac arrhythmias.
Potassium depletion: A heavy load of Na+ present in
the collecting tubules leads to an increase in the
exchange of Na+ tubules to K+, which leads to the
possibility of hypokalemia. Loss of K+ from cells in
exchange for H+ leads to hypocalymic alkalosis. The
use of potassium-sparing diuretics or supplements with
K + can prevent the development of hypokalemia

29. Hypomagnesemia: Chronic use of loop diuretics
in combination with a low dietary intake of Mg2+
can lead to hypomagnesemia, especially in the
elderly. This can be corrected with an oral
supplement.

30. 3-POTASSIUM-SPARING
DIURETICS

32. The main use of potassium-sparing agents is in the
treatment of hypertension (most often in
combination with thiazide) and heart failure
(aldosterone antagonists). It is imperative that
potassium levels are carefully monitored by
inpatients receiving potassium-sparing diuretics.
These drugs should be avoided in patients with
renal dysfunction because of the increased risk of
hyperkalemia.

33. Within this class, there are drugs with two
different mechanisms of action: aldosterone
antagonists and sodium channel blockers.
Antagonists of Aldosterone:
Spironolactone and eplerenone

34. 1. Mechanism of action: Spironolactone [spear-
oh-no-LAK-tone] is a synthetic steroid that
counteracts aldosterone at intracellular receptor
sites, making the spironolactone receptor complex
inactive. It prevents the translocation of the
receptor complex into the nucleus of the target
cell, which ultimately leads to the inability to
produce mediator proteins that normally stimulate
N +/K+-exchange sections of the collecting
tubule.

35. Thus, the lack of mediator proteins prevents
the reabsorption of Na+ and, consequently,
the secretion of K+ and H+. Eplerenone [eh-
PLEH-reh-none] is another aldosterone
receptor antagonist that has actions
comparable to those of spironolactone,
although it may have fewer endocrine effects
than spironolactone.

36. 2. Actions: In most edematous conditions,
the level of aldosterone in the blood is high,
causing a delay in Na+. Spironolactone
counteracts the activity of aldosterone, which
leads to a delay in K+ and the excretion of
Na+ (Figure 18.8). Like thiazides and loop
diuretics, the effect of these agents can be
reduced with the introduction of NSAIDs.

37. 3. Therapeutic use:
Diuretic: Although aldosterone antagonists are
low in mobilizing Na+ from the body compared to
other diuretics, they have the beneficial property
of inducing an increase in K+. These agents are
often prescribed alongside thiazide or loop
diuretics to prevent the excretion of K+ that would
otherwise occur with these drugs.

38. Secondary hyperaldosteronism: Spironolactone
is particularly effective in clinical situations
involving secondary hyperaldosteronism, such as
cirrhosis of the liver and nephrotic syndrome.
4 Pharmacokinetics: Both spironolactone and
eplerenone are absorbed after oral administration
and are reliably bound to plasma proteins.
5. Side effects: Spironolactone can cause
indigestion. Hyperkalemia, nausea, and confusion
may occur.

39. Triamterene and amyloride [trye-AM-ter-een]
and amiloride [a-MIL-oh-ride] block the
Transport Channels+, resulting in a decrease in
Na+/K+ exchange. Although they have a K+-
sparing diuretic effect similar to those of
aldosterone antagonists, their ability to block
Na+/K+-exchanges in the collecting tubule is
independent of the presence of aldosterone.

40. Like aldosterone antagonists, these agents are not
very effective diuretics. Like triamterene, both
amiloride are commonly used in combination with
other diuretics, usually because of their potassium
properties. Like aldosterone antagonists, they
prevent the loss of K+, which occurs with thiazide
and loop diuretics. Side effects of triamterene
include increased uric acid, kidney stones, and K+
retention.

41. Carbonic anhydrase inhibitor
acetazolamide [ah-set-a-ZOLE-a-mide] and other
carbonic an hydrazine hesitators are more often
used for their other pharmacological actions than
for their diuretic effect, since they are much less
effective than the thiazide or loop diuretics.

42. Acetazolamide
1. Mechanism of action:
Acetazolamide inhibits
carbonic anhydrase
located intracellularly
(cytoplasm) and on the
apical membrane of the
proximal tubular
epithelium (Figure 18.9)

43. Carbonic anhydrase catalyzes the reaction of CO2 and
H2O, which leads to H2CO3, which spontaneously
ionizes into H+ and HCO3- (bicarbonate).] A decrease
in the ability to exchange Na+ for H+ in the presence
of acetazolamide leads to mild diuresis.
Additionally, HCO3- persists in the lumen, with a
pronounced deletion in the pH of urine. Loss of
HCO3- causes hyperchloremic metabolic acidosis and
a decrease in diuretic efficacy after several days of
therapy.

44. 2. Therapeutic use:
Glaucoma: Acetazolamide reduces the production of
aqueous humor and reduces intraocular pressure in
patients with chronic open-angle glaucoma, likely by
blocking carbonic anhydrase in the ciliary body of the
eye.
Altitude sickness: Acetazolamide can be used in the
prevention of acute mountain sickness.
Acetazolamide prevents weakness, shortness of
breath, dizziness, nausea and brain, as well as
pulmonary edema characteristic of the syndrome.

45. 3. Pharmacokinetics: Acetazolamide can be
administered orally or intravenously.
4. Side effects: Metabolic acidosis (mild),
potassium depletion, kidney stones, drowsiness
and paresthesia.

46. 4-OSMOTIC DIURETICS

47. A number of simple, hydrophilic chemicals that
are filtered through the glomerulus, such as
Mannitol [MAN-i-tol] and Urea [yuREE-
ah], lead to some degree of diuresis. Filtered
substances that do not reabsorb little or no at all
will cause an increase in urine output.
The presence of these substances leads to a higher
osmolarity of the tubular fluid and prevents
further reabsorption of water, which leads to
osmotic diuresis. Only a small amount of extra
salt can also be excreted.

48. Because osmotic diuretics are used to increase water
excretion rather than Na+, they are not useful for
treating conditions in which Na+ retention occurs.
They are used to maintain urine flow after acute toxic
intake of substances that can cause acute renal failure.
Osmotic diuretics are the mainstay of treatment for
patients with increased intracranial pressure or acute
renal failure due to shock, drug toxicity, and trauma.
Maintaining the flow of urine preserves long-term
kidney function and can save the patient from dialysis.

49. Side effects include extracellular water expansion
and dehydration, as well as hypo- or
hypernatremia.
The expansion of extracellular water occurs
because the presence of mannitol in the extraoral
fluid extracts water from the cells and causes
hyponatremia until diuresis occurs.

50. •THE END