Diuretics

Diuretics

1. General Considerations

A. These drugs promote a loss of Na+ and water from the body--increasing urine flow

B. Used for clinical management of many disorders

-Oedema, could be due to weak heart

-Hypertension

-Also used to reduce toxicity of substances--overdose

                                                       Classification:

                                     A.  according to the place of action:

1)    Glomerulus

-       glycosides

-       methylxantines

-       vasodiltors

2)    proximal convoluted tubule (PCT)

-       carboanhydrase inhibitors: acetazilamide (diacarb), sultiam

3)    thick ascending limb of the loop of Henle (TAL)

Furosemide, torsemide, Ethacrynic acid, bumetamide

4)    distal convoluted tubule(DCT) (initial portion)

a)    thiazide diuretics

-       hydrochorthyazide

-       cyclopentazide

-       polythiazide

-       Thiazide like diuretics

-       chlorothalidone

-       clopamide

-       indapamide

5)    Terminal portion of the cortical collecting tubule and collecting tubule:

   antagonists of aldosterone:

a)    Competitive aldosterone antagonists: spironolactone

b)    noncompetitive: amiloride, triamterene.

6)    All nephron:

 Osmotic diuretics: mannitole and urea

                                    B. According to the duration of action

   A. Rapid and shot action:

 from several minutes until 1 h; duration – 2-8 h:

–      osmotic diuretics: mannitol, urea,

Loop diuretics—(high ceiling diuretics)

 Furosemide (Lasix), Ethacrynic acid, Bumetanide, Torsemide

  B. Medium action:

        from 1-3 h; duration – 8-24 h:

•       Thiazide diuretics: hidroclorotiazidă, ciclotiazidă,

•       Thiazide like diuretics: clopamide, indapamid,

•       noncompetitive aldosterone antagoniats: amiloride, triamterene.

•       Carbonic Anhydrase Inhibitors: acetazolamide

  C. Lent and long action:

   from 2-4 h til 2-5 days; duration – 2-7 days

•       Thiazide  diuretics: polythiazide;

•       Thiazide like diuretics- chlortalidon,;

•       Competitive aldosterone antagonists: spironolactone

                                      C. According to the potency

   A. Very potent diuretics (high efficacy)—10-35% glomerular filtrate appears in the urine:

•       Osmotic diuretics: mannitol, carbamide, Glycerol

Loop diuretics—(high ceiling diuretics)

Furosemide (Lasix)

Ethacrynic acid

Bumetanide

Torsemide

   B. Moderately potent diuretics—5-10% glomerular filtrate appears in the urine. Moderate/intermediate efficacy.):

•       Thiazide diuretics:

Chlorthiazide	Polythiazide
Hydrochlorthiazide	Cyclothiazide
Methiclothiazide

•       Thiazide like diuretics- chlortalidon, clopamide,

•       Carbonic Anhydrase Inhibitors: acetazolamide

   C. Weak diuretics (low efficacy)—only 5% of the glomerular filtrate appears in the urine.

•       K⁺ sparing diuretics:  triamterene, amiloride, spironolactone

•       digitales, Xanthine derivatives, vasodilatores etc.

                           D. According to the mechanism of  action

•       inhibits epithelial proteins (receptors, channels):

1. Loop diuretics—(high ceiling diuretics)

Furosemide (Lasix), Ethacrynic acid, Bumetanide, Torsemide

•       2. hiazide diuretics:

Chlorthiazide	Polythiazide
Hydrochlorthiazide	Cyclothiazide
Methiclothiazide

•       3. Thiazide like diuretics- chlortalidon, clopamide,

c)    4. noncompetitive aldosterone antagoniats: amiloride, triamterene.

– triamteren, amilorid

–      promote osmotic diuresis:

        osmotic diuretics: mannitol, ureea

–      enzymes inhibitors:

–      Carbonic Anhydrase Inhibitors: acetazolamide

–      hormones antagonists:

–      Competitive aldosterone antagonists: spironolactone

–      increase glomerular filtration rate: glycosides, methylxantines, vasodiltors

Drugs 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 self-digestion 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 intensifies—the 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 (300–800 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 (0.5–1.5 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,     rehydron

         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

•1. Utilizate pentru corecţia hipocaliemiei

•Săruri de K: clorura de potasiu, acetat de potasiu, lactat de potasiu

•Preparate combinate: asparcam, panangină

•Diuretice: spironolactonă, triamteren

•2. Utilizate pentru corecţia hipocalciemiei

 clorura de calciu, gluconat de calciu, paratiroidină, ergocalciferol

   3. Utilizate pentru corecţia hipomagneziemiei

Sulfat de magneziu, clorură de magneziu, oxid de magneziu

 

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. 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.

C. Preparatele utilizate in dereglarile hidroelectrolitice

•1. Utilizate pentru corecţia hipocaliemiei

•Săruri de K: clorura de potasiu, acetat de potasiu, lactat de potasiu

•Preparate combinate: asparcam, panangină

•Diuretice: spironolactonă, triamteren

•2. Utilizate pentru corecţia hipocalciemiei

 clorura de calciu, gluconat de calciu, paratiroidină, ergocalciferol

   3. Utilizate pentru corecţia hipomagneziemiei

Sulfat de magneziu, clorură de magneziu, oxid de magneziu