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DIURETICS
Definition:
drugs that increase urine volume.
Classification:
a) Pre-renal (Extra-renal) diuretics:
They increase urine output without acting on the nephrons, examples include:
1. Methylxanthines (theobromine, theophylline, caffeine), dopamine, dobutamine, and
cardiac glycosides (digitalis) increase renal blood flow and glomerular filtration rate
(GFR) by increasing COP and/or causing renal vasodilatation.
(Methylxanthines have also renal action- Cardiac glycosides have diuretic action in
patients with heart failure only).
2. Water and ethyl alcohol inhibit A.D.H.
3. Plasma expanders as dextran.
b) Renal diuretics: they act on the nephrons and may be classified into:
1. Thiazide diuretics: they are moderate efficacy- they inhibit Na+ transport in proximal
segment of distal convoluted tubules (DCT).
2. Loop diuretics: they are high efficacy diuretics- they inhibit Na+ transport in the loop of
Henle.
3. K+-sparing (retaining=conserving) diuretics: they are low efficacy diuretics- they are
either aldosterone antagonists as spironolactone, or non-aldosterone antagonists as
amiloride and triamterene.
4. Carbonic anhydrase inhibitor(CAIs): they inhibit Na+/H+ exchange in proximal
convoluted tubules (PCT) mainly. They are low efficacy and are self-limiting because
they cause acidosis (see later).
5. Acidifying diuretics: as NH4Cl, they are also self-limiting diuretics due to acidosis.
6. Osmotic diuretics: as Mannitol.
N.B.:
Thiazide diuretics, loop diuretics, K+-sparing diuretics, and CAIs are known as "Natriuretics"
or "Saluretics" because they increase urinary excretion of Na+ with its iso-osmotic water.
Thiazide Diuretics
Source: Synthetic.
Pharmacokinetics:
1. Well absorbed orally.
2. Pass placental barrier and may cause teratogenicity.
3. Excreted in PCT to (act from the inner side of the nephron) by active secretion thus
reducing secretion of uric acid leading to hyperuricemia. Probenicid reduces active
transport of thiazides and reduces their diuretic action.
Pharmacodynamics:
URINE BLOOD
1. Excess Na+ (natriuresis). 1. Hyponatremia.
2. Excess water (diuresis). 2. Hypovolemia (moderate).
3. Excess Cl- (chloruresis). 3. Hypochloremia.
4. Excess K+ (kaluresis). 4. HYPOKALEMIA.
5. Excess H+ (acidic urine). 5. Alkalosis.
6. Excess Mg2+. 6. Hypomagnesemia.
7. Less Ca2+. 7. Hypercalcemia.
8. Less uric acid. 8. Hyperuricemia.
3. Antihypertensive action:
a) Arteriolar V.D.: this is the most important mechanism and can be explained by:
Depletion of Na+ from the wall of arterioles thus reducing the vasoconstrictor
(pressor) response to noradrenaline and angiotensin.
Increasing synthesis of vasodilator PGs (that is why NSAIDs may partially
antagonize the antihypertensive action of thiazides).
Opening of K+ channels leading to hyperpolarization and V.D.
Block of Ca2+ channels in arterioles causing V.D.
b) Diuretic action: this is of little importance in the antihypertensive action of thiazides.
Therapeutic uses:
1. Treatment of edema which is either: Cardiac (in mild and moderate congestive heart
failure), Renal, or Hepatic edema.
2. Treatment of mild and moderate hyperternsion: thiazides are preferred to loop diuretics
because they are arteriodilators Except in cases of emergency hypertension and in
patients with renal impairment where loop diuretics are preferred (loop diuretics can be
given I.V. and they increase renal blood flow).
3. Treatment of nephrogenic diabetes insipidus.
4. Treatment of idiopathic hypercalciurea and recurrent calcium stones.
5. Treatment of pre-menstrual tension syndrome.
3. Hypovolemia.
5. Hypochloremic alkalosis.
6. Hypotension. 2. Hypotension.
8. Hyperlipidemia.
12.Teratogenicity. 7. Pregnancy.
Drug interactions:
1. With digitalis: Hypokalemia is the most important precipitating factor of digitalis toxicity.
2. With steroids: steroids cause Na+ and water retention thus antagonize the diuretic effect
of thiazides but more seriously they cause hypokalemia.
3. With sulphonamides: cross allergy.
4.
With K+-sparing diuretics: synergism and correction of serum K+.
5. With ACE inhibitors and AT1 antagonists: synergism and correction of serum K+.
6. With insulin and oral hypoglycemic drugs: thiazides antagonize the action of these drugs.
7. With uricosuric drugs (drugs that increase uric acid excretion in urine): thiazides
antagonize the action of these drugs.
8. With Probenicid: probenicid decreases active transport of thiazides and antagonizes their
diuretic action.
9. With NSAIDs: NSAIDs antagonize the antihypertensive action of thiazides because they
cause Na+ and water retention and inhibit the synthesis of vasodilator PGs.
Preparations:
1. Short acting thiazides:
Chlorthiazide and Hydrochlorothiazide (given/6-12 hours).
2. Long acting thiazides:
Chlorthalidone, Metolazone, and Polythiazide (given once daily).
3. Thiazide analogues: they are similar to thiazides in action but not in chemical structure.
Examples include:
a) Indapamide: weak diuretic but it causes arteriodilatation as thiazides (most probably
due to calcium channel block. Used in treatment of hypertension in sub-diuretic dose,
and is excreted in bile (long acting given once daily).
b) Diazoxide: it is a vasodilator drug (opens K+ channels) related to thiazides but is Not a
diuretic. It is given I.V. in emergency hypertension.
c) Metolazone.
2. Chemistry:
some are related to sulphonamides as frusemide (they inhibit carbonic anhydrase which
contributes very mildly to their diuretic action but may cause allergic reactions and cross
allergy with sulphonamides) but others are not sulphonamide derivatives as ethacrynic
acid.
3. Pharmacokinetics:
Well absorbed orally, and can be given by I.V. and I.M. injection (useful in
emergencies).
Highly bound to plasma proteins and can displace other drugs as warfarin leading to
toxicity (bleeding in case of warfarin).
Pass placental barrier and may cause teratogenicity (fetotoxicity).
Loop diuretics are actively secreted in PCT and-as thiazides- act from the inner side of
the nephron. They interfere with active tubular secretion of uric acid leading to
hyperuricemia, and probenicid reduces their diuretic effect.
Partly metabolized by the liver.
4. Pharmacodynamics:
1. Diuretic action: characterized by:
a) Onset: rapid onset.
b) Duration: short duration.
c) Efficacy: high efficacy (the most potent available diuretics).
d) Site of action: loop diuretics inhibit reabsorption of Na+, K+, and 2Cl- (co-transport)
from the thick segment of the ascending limb of loop of Henle leading to excess
excretion of these electrolytes in urine with iso-osmotic water. In addition; loop
diuretics decrease osmolarity of the medulla of the kidney and consequently
decrease water reabsorption from the collecting tubules causing potent diuresis.
e) Part of excess Na+ reaching DCT is reabsorbed in exchange for K+ (mainly) and H+
(to a less extent).
f) Urine will also contain excess Mg2+ and excess Ca2+.
In conclusion loop diuretics will produce the following changes in urine and in blood
Urine Blood
1. Excess Na+ (natriuresis). 1. Hyponatremia.
2. Excess water (diuresis). 2. Hypovolemia (marked).
3. Excess Cl- (chloruresis). 3. Hypochloremia.
4. Excess K+ (kaluresis). 4. HYPOKALEMIA.
5. Excess H+ (acidic urine). 5. Alkalosis.
6. Excess Mg2+. 6. Hypomagnesemia.
7. Excess Ca2+ (calciurea). 7. Hypocalcemia.
8. Less uric acid. 8. Hyperuricemia.
2. Loop diuretics increase renal blood flow: they are the diuretics of choice in renal
insufficiency. This is because loop diuretics increase synthesis of vasodilator PGs (PGE
and PGI) in the kidney, this action is antagonized by NSAIDs. (Remember that
thiazides reduce RBF and GFR).
3. Antihypertensive action: this is due to their diuretic action and NOT due to
arteriodilatation.
(In contrast to thiazides; loop diuretics cause venodilatation but not arteriodilatation).
4. Hyperlipidemia: as thiazides; loop diuretics increase LDL-cholesterol and triglycerides.
5. Hyperglycemia: loop diuretics decrease insulin release from the pancreas less
markedly than thiazides.
5. Therapeutic uses:
a) Edema: loop diuretics are used in severe, acute, and refractory edema (combined
with K+-sparing diuretics) which may be cardiac (due to congestive heart failure),
renal, or hepatic edema.
b) Loop diuretics are given I.V. in acute left ventricular failure (LVF) as they cause
diuresis and venodilatation which decreases pre-load). Also used in cerebral edema.
c) Hypertension: loop diuretics are preferred to thiazides in the following conditions:
Hypertension in patients with renal insufficiency.
Emergency hypertension.
Resistant hypertension.
Severe hypertension, especially with other antihypertensive drugs that may cause
Na+ and water retention as arteriodilators.
d) Acute renal failure.
e) Hypercalcemia.
3. Hyponatremia.
4. Hypomagnesemia.
5. Hypotension. 2. Hypotension.
6. Hypochloremic alkalosis.
7. Hypocalcemia.
10.Hyperuricemia. 5. Gout.
11.Hyperlipidemia.
12.Teratogenicity. 6. Pregnancy.
6. Drug interactions:
Preparations:
1. Sulphonamide derivatives: Frusemide (Lasix)- Bumetanide- Torsemide.
2. Non-sulphonamide derivatives: Ethacrynic acid.
3-Onset and Slow onset, may be short acting, Rapid onset and short
duration: or long acting. duration.
Common Characteristics:
1. Route of administration: they are given orally only.
5. Diuretic action: inhibit Na+/K+ exchange mainly and inhibit Na+/H+ exchange to a lesser
extent. This causes excretion of Na+, Cl-, and water in urine and retention of K+
(hyperkalemia) and H+ (metabolic acidosis).
7. Unlike thiazides and loop diuretics: they do not cause hyperglycemia, hyperlipidemia, or
hyperuricemia (they have mild uricosuric action) and are not related to sulphonamides
(no cross allergy and no carbonic anhydrase inhibition).
8. Classification: they are classified according to their mechanism of action into 2 groups:
a) Aldosterone antagonists: e.g. Spironolactone- Canrenone (active metabolite of
spironolactone) Eplerenone.
They are competitive antagonists with aldosterone for specific intraceullar
(cytoplasmic) mineralocorticoid receptors in cells of DCT and collecting tubules.
b) Non-Aldosterone antagonists: e.g. Amiloride and Triamterene: they inhibit Na+ influx
by blocking Na+-channels in the luminal membrane of DCT and collecting tubular cells.
1) Aldosterone Antagonists:
a) Spironolactone (Aldactone):
1. Source: Synthetic.
2. Chemistry: Steroid.
3. Pharmacokinetics:
Absorbed orally.
Converted in the liver into canrenone (active metabolite).
Delayed onset and long duration.
Passes B.B.B.
4. Pharmacodynamics:
Mechanism of action:
Competitive antagonists with aldosterone for mineralocorticoid receptors in DCT and
cortical collecting tubules leading to inhibition of Na+/K+ exchange (mainly) and
inhibition of Na+/H+ exchange.
5. Pharmacological actions:
a) Low efficacy diuretic action by increasing Na+,Cl-, and water excretion in urine.
b) Retention of K+ in blood leading to "Hyperkalemia".
c) Retention of H+ in blood leading to "Metabolic acidosis" and decrease H+ excretion
in urine causing slight alkalinization of urine.
d) No hyperuricemia, hyperglycemia, or hyperlipidemia (unlike thiazides and loop
diuretics).
6. Therapeutic uses:
a) Being weak diuretics they are usually combined with thiazide diuretics or loop
diuretics in treatment of edema and hypertension; to achieve synergism and
maintain normal blood potassium.
b) Treatment of refractory edema and resistant hypertension due to
Hyperaldosteronism which is either primary (Conn's syndrome) or more commonly
secondary to liver cirrhosis, nephrotic syndrome, and congestive heart failure.
They are given alone or combined with thiazide or loop diuretics.
c) Alternative to thiazides and loop diuretics whenever they are contraindicated in
allergy to sulphonamides, D.M., and gout.
7. Adverse effects:
a) Hyperkalemia especially in: renal impairment-drugs that inhibit renin release as -
blockers, NSAIDs (inhibit PGI2 which stimulates renin release)-ACE inhibitors and
AT antagonists.
b) Metabolic acidosis.
c) Hypersensitivity reactions as skin rash.
d) Gut upset: gastritis, diarrhea, gastric bleeding.
e) CNS disturbances: headache, drowsiness, confusion, and lethargy.
f) Feminization (Gynecomastia) and impotence in males, and irregular menstruation
and masculanization in females (deepening of voice and hirsutism) due to steroid
structure.
8. Drug interactions:
a) With thiazide and loop diuretics: synergism in diuretic action and maintain normal
blood K+.
b) With ACE inhibitors, AT antagonists, -blockers, and NSAIDS: severe hyperkalemia.
c) With Carbenoxolone( aldosterone-like drug derived from liquorice and acts as a
mucosal protective agent in treatment of peptic ulcer): spironolactone antagonizes
the action of liquorice on the stomach.
b) Eplerenone:
Similar to spironolactone but is non-steroid and accordingly no gynecomastia or
menstrual disturbances occur.
2) Non-Aldosterone Antagonists:
1. Source: Synthetic.
2. Pharmacokinetics:
Absorbed orally.
Amiloride is excreted unchanged in urine. Triamterene is mainly metabolized in
the liver (shorter duration of action).
3. Pharmacodynamics:
Mechanism of action: inhibit Na+ influx by blocking Na+ channels in DCT and cortical
collecting tubules (they do not compete with aldosterone) thus reducing Na+/K+
exchange and to a lesser extent Na+/H+ exchange.
4. Actions:
As Spironolactone:
Weak diuretic action- Hyperkalemia- Metabolic acidosis.
5. Therapeutic uses:
a) Amiloride and Triamterene are added to thiazides or loop diuretics in treatment of
edema (cardiac edema due to heart failure-renal edema - hepatic edema) to achieve
synergism and more importantly to correct hypokalemia induced by thiazides and
loop diuretics.
b) Amiloride can be used in lithium-induced nephrogenic diabetes insipidus.
6. Adverse effects:
a) Hyperkalemia especially in renal impairments and other drugs (see
Spironolactone).
b) Metabolic acidosis.
c) Hypersensitivity reactions: photosensitivity.
d) Gut upset.
e) Triamterene causes renal stones and may precipitate acute renal failure if given
with indomethacin (NSAID).
Osmotic Diuretics:
They are pharmacologically inert substances.
They are freely filtered by the glomeruli but are not or incompletely-reabsorbed, so
they are excreted in urine with iso-osmotic water and diuresis occurs. They increase
urinary Na+, Cl-, K+, Mg2+, HCO3- and Ca2+.
Examples:
a) Mannitol:
Polysaccharide given by I.V.infusion.
Uses:
1. Acute elevation of intra-cranial pressure (ICP).
2. Acute elevation of IOP (acute narrow angle glaucoma=acute congestive glaucoma).
3. Prevent Acute renal failure.
Adverse effects:
Nausea and vomiting-Allergy-Transient expansion of extracellular fluid volume and
may aggravate acute heart failure.
Contraindications:
Acute L.V.F. (acute pulmonary edema=cardiac asthma).
b) Glucose I.V.
c) Glycerin and isosorbide: given orally in acute narrow angle glaucoma.
Methylxanthines:
Examples:
Caffeine,Theobromine, Theophylline, and Aminophylline.
Diuretic action:
1. Pre-renal action by increasing COP and V.D. of renal blood vessels.
2. Renal action: inhibit Na+ reabsorption from PCT.
Uses:
Aminophylline is given very slowly I.V. in acute L.V.F.
Cardiac glycosides:
Cardiac glycosides (digitalis) have diuretic action only in patients with congestive heart
failure by pre-renal action as they increase COP in these patients (see CVS pharmacology).
Dopamine:
Diuretic action occurs with moderate rate of infusion (stimulates D1-receptors causing renal
V.D. and increase renal blood flow) and with moderate rate of infusion (stimulate 1-
receptors causing increased COP).
Anti-Diuretics
1. ADH and drugs that increase release of ADH as morphine, nicotine, barbiturates, and
yohimbine.
2. Thiazide diuretics are anti-diuretics only in nephrogenic diabetes insipidus.
3. Amiloride is anti-diuretic in lithium-induced diabetes insipidus.
4. Chlorpropamide (anti-diabetic) is ADH like and is used in pituitary diabetes insipidus.
5. Vasoconstrictors as adrenaline and serotonin decrease renal blood flow and act as anti-
diuretics.
ADH Antagonists
1. Lithium carbonate: Antimanic and mood stabilizer. It induces nephrogenic diabetes
insipidus which is treated by amiloride.
2. Methoxyflurane: Inhalation halogenated general anaesthetic which may induce
nephrogenic diabetes insipidus.
3. Demeclocycline: Tetracycline antibiotic that may cause nephrogenic diabetes insipidus,
and is used to treat excess ADH secretion (Syndrome of Inappropriate ADH=SIADH).
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