Diuretics. Drugs wich are used in nephrolythiasis and gout treatment.

Drugs with influence upon acid-base balance.

Diuretics (saluretics) elicit increased production of urine (diuresis). In the strict sense, the
term is applied to drugs with a direct renal action. The predominant action of such agents
is to augment urine excretion by inhibiting the reabsorption of NaCl and water.
The most important indications for diuretics are:
Mobilization of edemas: In edema there is swelling of tissues due to accumulation
of fluid, chiefly in the extracellular (interstitial) space. When a diuretic is given, increased
renal excretion of Na+ and H2O causes a reduction in plasma volume with
hemoconcentration. As a result, plasma protein concentration rises along with oncotic
pressure. As the latter operates to attract water, fluid will shift from interstitium into the
capillary bed. The fluid content of tissues thus falls and the edemas recede. The decrease
in plasma volume and interstitial volume means a diminution of the extracellular fluid
volume (EFV). Depending on the condition, use is made of: thiazides, loop diuretics,
aldosterone antagonists, and osmotic diuretics.
Antihypertensive therapy. Diuretics have long been used as drugs of first choice
for lowering elevated blood pressure. Even at low dosage, they decrease peripheral
resistance (without significantly reducing EFV) and thereby normalize blood pressure.
Therapy of congestive heart failure.
By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in
afterload); cardiac output and exercise tolerance are increased. Due to the increased
excretion of fluid, EFV and venous return decrease (reduction in preload,). Symptoms of
venous congestion, such as ankle edema and hepatic enlargement, subside. The drugs
principally used are thiazides (possibly combined with K+-sparing diuretics) and loop
diuretics.
Prophylaxis of renal failure. In circulatory failure (shock), e.g., secondary to
massive hemorrhage, renal production of urine may cease (anuria). By means of diuretics
an attempt is made to maintain urinary flow. Use of either osmotic or loop diuretics is
indicated.
Each segment of the nephron:
- proximal convoluted tubule (PCT)
- thick ascending limb of the loop of Henle (TAL)
- distal convoluted tubule(DCT)
- cortical colecting tubule (CCT)
has a different mechanism for reabsorbing sodium and other ions.
1) PCT- this segment carries out isoosmotic reabsorption of amino acids, glucose, numerous
cations, sodium chloride, sodium bicarbonate.
This segment is responsible for 50% or more of the total reabsorbtion of Na.
Carbonic anhydrase ( the enzyme required for the bicarbonate reabsorption ) activates in this
segment.
2) TAL this segment pumps Na, K, chloride out of the lumen into the interstitium of the
kidney, Ca, Mg.
TAL is responsible for the reabsorption of 30-40% of the sodium filtered at the
glomerulus.
3) Distal convoluted tubule (DCT)

This segment actively pumps sodium and chloride out of the lumen of the nephron (10%
of sodium reabsorption). Calcium is also rebsorption in this segment under the control of
parathyroid hormone.
4) Cortical collecting tubule (CCT). The final segment of the nephron is the last tubular site
of sodium reabsorption and is controlled by aldosteron. This segment is responsible for
reabsorption 2-8% of the total filtered sodium. Reabsorption of water occurs in the
medullary collecting tubule under the control of antidiuretic hormone.
Carbonic anhydrase inhibitors:
Mechanism of action is inhibition of carbonic anhydrase in the brush border and intracellular
carbonic anhydrase in the PCT cell.
CAH catalyzes CO2 hydration/dehydration reactions:
H+ + HCO3 H2CO3H20 + CO2.
The enzyme is used in tubule cells to generate H+, which is secreted into the tubular fluid
in exchange for Na+.There, H+ captures HCO3, leading to formation of CO2 via the
unstable carbonic acid. Membrane-permeable CO2 is taken up into the tubule cell and
used to regenerate H+ and HCO3 . When the enzyme is inhibited, these reactions are
slowed, so that less Na+, HCO3 and water are reabsorbed from the fast-flowing tubular
fluid. Loss of HCO3 leads to acidosis. The diuretic effectiveness of CAH inhibitors
decreases with prolonged use. CAH is also involved in the production of ocular aqueous
humor. Present indications for drugs in this class include: acute glaucoma, acute
mountain sickness, and epilepsy, edema accompanied by significant metabolic alkalosis..
Dorzolamide can be applied topically to the eye to lower intraocular pressure in
glaucoma.
Effect: the major renal effect is bicarbonate diuresis (sodium bicarbanate is excreted)
Side effects: alkalinization of the urine by these drugs may cause precipitation of calcium salts
and formation of renal stones.. Patients with hepatic disease may develop hepatic
encephalopathy because of increased ammonia reabsorption.
Loop diuretics
Mechanism of action: This drugs inhibit the cotransport of sodium, potassium, and
chloride. With oral administration, a strong diuresis occurs within 1 h but persists for
only about 4 h. The effect is rapid, intense, and brief (high-ceiling diuresis). The site of
action of these agents is the thick portion of the ascending limb of Henles loop, where
they inhibit Na+/K+/2Cl cotransport. As a result, these electrolytes, together with water,
are excreted in larger amounts. Excretion of Ca2+ and Mg2+ also increases. Special toxic
effects include: (reversible) hearing loss, enhanced sensitivity to renotoxic agents.
Indications: pulmonary edema (added advantage of i.v. injection in left ventricular
failure: immediate dilation of venous capacitance vessels preload reduction);
refractoriness to thiazide diuretics, e.g., in renal hypovolemic failure with creatinine
clearance reduction (<30 mL/min); prophylaxis of acute renal hypovolemic failure;
hypercalcemia. Ethacrynic acid is classed in this group although it is not
a sulfonamide.
Summary
Effects: 1. the massive sodium chloride diuresis.
2. if tissue perfusion is adequate, edema fluid is rapidly excreted and blood volume
may be significantly reduced.
3. they inhibit sodium, potassium, chloride, transporter.

4. calcium excretion is significantly increased

5. ethacrynic acid is a moderately effective uricosuric drug.
6. hypokalemic alkalosis may result.
The loop diuretics also have potent pulmonary vasodilating effects: the mechanism is not
known
Indications: -treatment of edematous states.(heart failure and ascites)
2. acute pulmonary edema and cerebral edema
3. in hypertension
4. treatment of severe hypercalcemia.
5. intoxications
6. acute crisis of glaucoma
Side effects: Massive use of diuretics entails a hazard of adverse effects:
the decrease in blood volume can lead to hypotension and collapse;
blood viscosity rises due to the increase in erythro- and thrombocyte
concentration, bringing an increased risk of intravascular coagulation or
thrombosis.
they usually produce hypokalemic metabolic alkalosis.
hypovolemia and cardiovascular complications
ototoxicity
hypo K, Ca, Na, Mg,
hyperazothemia, hyperglycemia.
digestive deregulations,
nephrotoxicity
increase the glycosides toxicity
Thiazide and nonthiazide diuretics:
Mechanism of action: They inhibit sodium chloride transport in the early segment of the
distal convoluted tubule. Thus, reabsorption of NaCl and water is inhibited. Renal
excretion of Ca2+ decreases, that of Mg2+ increases. Indications are hypertension,
cardiac failure, and mobilization of edema.
Effects:
1. in full doses, thiazides produce moderate but sustained sodium and chloride diuresis
2. in the big doses they inhibit carboanhydrase
3. they increase reabsorption of calcium from the urine and decrease urine calcium
content
4. increase the quantity of glucose in the blood
5. they enhance effects of antidiuretic hormone and have antidiuretic effect in enuresis
and insufficiency of vasopresine
Indications:
1. hypertension
2. chronic therapy of edematous conditions such as heart failure.
3. chronic renal calcium stone formation
4. enuresis
5. glaucoma
6. insipid diabetes
Side effects:- hypo K, Na, Mg.
-they decrease the quantity of insulin
3

- hyperuricemia
- nausea, vomiting, vertigo
- dermatitis
Potassium-sparing diuretics
These agents act in the distal portion of the distal tubule and the proximal part of the
collecting ducts where Na+ is reabsorbed in exchange for K+ or H+. Their diuretic
effectiveness is relatively minor. These drugs are suitable for oral administration.
Mechanism of action: They are antagonist (competitive or noncompetitive) of aldosterone in
the collecting tubules. By combining with and blockng the intracellular aldosterone receptor,
they reduce the expression of genes controlling synthesis of sodium ion channels and Na, K,
ATP-ase.
Spironolactone has 24-72 h. duration of action. The mineralocorticoid aldosterone
promotes the reabsorption of Na+ (Cl and H2O follow) in exchange for K+. Its
hormonal effect on protein synthesis leads to augmentation of the reabsorptive capacity
of tubule cells. Spironolactone, as well as its metabolite canrenone, are antagonists at the
aldosterone receptor and attenuate the effect of the hormone. The diuretic effect of
spironolactone develops fully only with continuous administration for several days. Two
possible explanations are: (1) the conversion of spironolactone into and accumulation of
the more slowly eliminated metabolite canrenone; (2) an inhibition of aldosteronestimulated protein synthesis would become noticeable only if existing proteins had
become nonfunctional and needed to be replaced by de novo synthesis. A particular
adverse effect results from interference with gonadal hormones, as evidenced by the
development of gynecomastia (enlargement of male breast). Clinical uses include
conditions of increased aldosterone secretion, e.g., liver cirrhosis with ascites.
Amiloride and triamterene have duration of action of 12-24 hours. They blocking the
sodium channels in the same portion of the nephron. Both inhibit the entry of Na+, hence
its exchange for K+ and H+. They are mostly used in combination with thiazide diuretics,
e.g., hydrochlorothiazide, because the opposing effects on K+ excretion cancel each
other, while the effects on secretion of NaCl complement each other.
Effects: All three drugs cause an increase in sodium clearance and a decrease in potassium
and hydrogen ion excretion and therefore quality as potassium sparing diuretics. They may
cause hyperkalemic metabolic acidosis.
Indications:
1. edema with hypopotassemia, or hyperaldosteronism
2. hypertension
3. in association with other diuretics for hypopotassemia prevention
Side effects: hyperpotassemia.and hypoNa These drugs should never be given with
potassium drugs.
Spironolactone may cause endocrine abnormalities, including ginecomastia, and antiandrogenic effects. Also dyspepsia can occurs
Osmotic diuretics
Mode of action: They increase osmotic pressure of plasma, increase minute-volume of blood
and increase also the renal circulation and filtration.
Since NaCl and H2O are reabsorbed together in the proximal tubules, Na+ concentration
in the tubular fluid does not change despite the extensive reabsorption of Na+ and H2O.
Body cells lack transport mechanisms for polyhydric alcohols such as mannitol and

sorbitol, which are thus prevented from penetrating cell membranes. Therefore, they need
to be given by intravenous infusion. They also cannot be reabsorbed from the tubular
fluid after glomerular filtration. These agents bind water osmotically and retain it in the
tubular lumen. When Na ions are taken up into the tubule cell, water cannot follow in the
usual amount. The fall in urine Na+ concentration reduces Na+ reabsorption, in part
because the reduced concentration gradient towards the interior of tubule cells means a
reduced driving force for Na+ influx. The result of osmotic diuresis is a large volume of
dilute urine. Indications: prophylaxis of renal hypovolemic failure, mobilization of brain
edema, and acute glaucomacerebral edema, pulmonary edema, acute renal failure, in the
intoxications, shock cases, acute crisis of glaucoma, larynges edema. Side effects:
hypoNa, dehydrations, Rebound effect, headache, nausea, vomiting, thrombosis,
phlebitis, exacerbation of heart failure and pulmonary edema, acute renal failure.

Classification:
according to the place of action:
1) Glomerulus
- glycosides
- methylxantines
- vasodiltors
2) proximal convoluted tubule (PCT)
- carboanhydrase inhibitors
- acetazilamide (diacarb)
3) thick ascending limb of the loop of Henle (TAL)
- furosemide
- ethacrine acid
- bumetamide
4) distal convoluted tubule(DCT) (initial portion)
a) thiazide diuretics
- hydrochorthiazide
- cyclopentazide
- polythiazide
b) non thiazide diuretics
- chlortalidon
- clopamide
5) Terminal portion of the cortical collecting tubule and collecting tubule:
antagonists of aldosterone:
a) competitive: spironolactone
b) noncompetitive: amiloride, triamterene.
6) All nephron:
Osmotic diuretics: mannitol, urea.

Drugs with are used in gout treatment.

Classification
1. Uricozuric remedies
2. Uricoinhibitor remedies
- sulphinpyrazone
- allopurinol
- probenecid
- ethebenecid
- urodan
2. Active remedies in gout crisis
- colchicine
non steroid anti-inflammatory drugs :
glucocorticoids
- indomethacin,
prednisolone
- phenylbutasone,
methylprednesolone
- ibuprofen,
dexamethasone
- diclofenac
triamcinolone
Salycilates are contraindicated in gout because they increase the quantity of uric acid in
the blood
Gout is an inherited metabolic disease that results from hyperuricemia, an elevation in
the blood of uric acid, the end-product of purine degradation. The typical gout attack
consists of a highly painful inflammation of the first metatarsophalangeal joint
(podagra). Gout attacks are triggered by precipitation of sodium urate crystals in the
synovial fluid of joints. During the early stage of inflammation, urate crystals are
phagocytosed by polymorphonuclear leukocytes (1) that engulf the crystals by their
ameboid cytoplasmic movements (2). The phagocytic vacuole fuses with a lysosome (3).
The lysosomal enzymes are, however, unable to degrade the sodium urate. Further
ameboid movement dislodges the crystals and causes rupture of the phagolysosome.
Lysosomal enzymes are liberated into the granulocyte, resulting in its destruction by selfdigestion and damage to the adjacent tissue. Inflammatory mediators, such as
prostaglandins and chemotactic factors, are released (4). More granulocytes are attracted
and suffer similar destruction; the inflammation intensifiesthe gout attack flares up.
Treatment of the gout attack aims to interrupt the inflammatory response.
The drug of choice is colchicine, an alkaloid from the autumn crocus (Colchicum
autumnale). It is known as a spindle poison because it arrests mitosis at metaphase by
inhibiting contractile spindle proteins. Its antigout activity is due to inhibition of
contractile proteins in the neutrophils, whereby ameboid mobility and phagocytotic
activity are prevented. The most common adverseeffects of colchicine are abdominal
pain, vomiting, and diarrhea, probably due to inhibition of mitoses in the rapidly dividing
gastrointestinal epithelial cells. Colchicine is usually given orally (e.g., 0.5 mg hourly
until pain subsides or gastrointestinal disturbances occur; maximal daily dose, 10 mg).
Nonsteroidal anti-inflammatory drugs, such as indomethacin and phenylbutazone, are
also effective. In severe cases, glucocorticoids may be indicated. Effective prophylaxis
of gout attacks requires urate blood levels to be lowered to less than 6 mg/100 mL. Diet.
Purine (cell nuclei)-rich foods should be avoided, e.g., organ meats.Milk, dairy products,
and eggs are low in purines and are recommended. Coffee and tea are permitted since the
methylxanthine caffeine does not enter purine metabolism.
Uricostatics decrease urate production. Allopurinol, as well as its accumulating
metabolite alloxanthine (oxypurinol), inhibit xanthine oxidase, which catalyzes urate

formation from hypoxanthine via xanthine. These precursors are readily eliminated via
the urine. Allopurinol is given orally (300800 mg/d). Except for infrequent allergic
reactions, it is well tolerated and is the drug of choice for gout prophylaxis. At the start of
therapy, gout attacks may occur, but they can be prevented by concurrent administration
of colchicine (0.51.5 mg/d). Uricosurics, such as probenecid, benzbromarone (100
mg/d), or sulfinpyrazone, promote renal excretion of uric acid. They saturate the organic
acid transport system in the proximal renal tubules, making it unavailable for urate
reabsorption. When underdosed, they inhibit only the acid secretory system, which has a
smaller transport capacity. Urate elimination is then inhibited and a gout attack is
possible. In patients with urate stones in the urinary tract, uricosurics
are contraindicated.

Drugs with influence upon acid-base balance.

A) In dehydration states
1) saline solution
a) isotonic solution: sol. Ringer, NaCl 0,9%, acesol,
b) hypotonic sol. : NaCl 0,45% with glucose
c) hypertonic sol NaCl 5%, 10%, 20% or 40%
B) Plasma Volume Expanders
a) in shock Dextran40,70., polymers, polypeptides, gelatinol.
b) Systemic intoxications : haemodes
c) Digestive intoxications: enterodez
C)For correction of electrolyte deregulations
-in hypocalemia

rehydron

Plasma Volume Expanders

Major blood loss entails the danger of life-threatening circulatory failure, i.e.,
hypovolemic shock. The immediate threat results not so much from the loss of
erythrocytes, i.e., oxygen carriers, as from the reduction in volume of circulating blood.
To eliminate the threat of shock, replenishment of the circulation is essential. With
moderate loss of blood, administration of a plasma volume expander may be sufficient.
Blood plasma consists basically of water, electrolytes, and plasma proteins. However, a
plasma substitute need not contain plasma proteins. These can be suitably replaced with
macromolecules (colloids) that, like plasma proteins, (1) do not readily leave the
circulation and are poorly filtrable in the renal glomerulus; and (2) bind water along with
its solutes due to their colloid osmotic properties. In this manner, they will maintain
circulatory filling pressure for many hours. On the other hand, volume substitution is
only transiently needed and therefore complete elimination of these colloids from the
body is clearly desirable. Compared with whole blood or plasma, plasma substitutes offer
several advantages: they can be produced more easily and at lower cost, have a longer
shelf life, and are free of pathogens such as hepatitis B or C or AIDS viruses. Three
colloids are currently employed as plasma volume expanders the two polysaccharides,
dextran and hydroxyethyl starch, as well as the polypeptide, gelatin.

Dextran is a glucose polymer formed by bacteria and linked by a 1!6 instead of the
typical 1!4 bond. Commercial solutions contain dextran of a mean molecular weight of
70 kDa (dextran 70) or 40 kDa (lower-molecularweight dextran, dextran 40). The
chain length of single molecules, however, varies widely. Smaller dextran molecules can
be filtered at the glomerulus and slowly excreted in urine; the larger ones are eventually
taken up and de degraded by cells of the reticuloendothelial system. Apart from restoring
blood volume, dextran solutions are used for hemodilution in the management of blood
flow disorders. As for microcirculatory improvement, it is occasionally emphasized that
low-molecular-weight dextran, unlike dextran 70, may directly reduce the aggregability
of erythrocytes by altering their surface properties. With prolonged use, larger molecules
will accumulate due to the more rapid renal excretion of the smaller ones. Consequently,
the molecular weight of dextran circulating in blood will tend towards a higher mean
molecular weight with the passage of time. The most important adverse effect results
from the antigenicity of dextrans, which may lead to an anaphylactic reaction.
Hydroxyethyl starch (hetastarch) is produced from starch. By virtue of its
hydroxyethyl groups, it is metabolized more slowly and retained significantly longer in
blood than would be the case with infused starch. Hydroxyethyl starch resembles
dextrans in terms of its pharmacological properties and therapeutic applications.
Gelatin colloids consist of crosslinked peptide chains obtained from collagen. They are
employed for blood replacement, but not for hemodilution, in circulatory disturbances.