Drugs Acting on Urinary tract system

Diuretics

These are drugs which cause a net loss of Na* and water in urine. Diuretics are among the most widely prescribeddrugs. Application of diuretics to themanagement of hypertension has outstrippedtheir use in edema. Availabilitv of diuretics hasalso had a major impact on the understanding ofrenal physiology.

CLASSIFICATION

1. High efficacy diuretics (lnhibitors of Na'-K-2Cl- cotransport)

S u I p h a m oy I d e riv ative s

Furosemide, Bumetanide, Torasemide

2. Medium efficacy diuretics (lnhibitors of Na--Cl- sympoft)

(a) Benzothiadiazines (thiazides)

Hydrochlorothiazide, Benzthiazide,Hydroflumethiazide, Clopamide

b) Thiazide like (related heterocyclics)Chiorthalidone, Metolazone, Xipamide,

Indaoamide.

3. Weak or adjunctive diuretics

(a) Carbonic anhydrase inhibitorsAcetazolamide

b) Potassium sparing diuretics

(l) Aldosteronnen t agonistS: pironolactone

(li) Inhibitors of renal epitheliol Na* chlnnel'.Triamterene, Amiloride.

(c) Osmotic diuretics

Mannitol, Isosorbide, Glycero

HIGH CEILING(LOOP)DIURETICS

(ln hibitorso f Na.-K.-2Cl-C otransport)

-Furosemide (Frusemide) Prototyped rugThe major site of action is the thick AscLH

(site II) where furosemide inhibits Na*- K*-2ClcotransportFurosemide has weak CAse inhibitory actionand increase HCO.- excretion as well; urinary pH may rise but the predominant urinary anionis Cl-; acidosis does not develop. Its action isindependent of acid-base balance of the body and it causes little distortion of the same; mildalkalosis occurs at high doses.

Molecular mechanism of action

: A glycoproteinwith 12 membrane sparuring domains has beenfound to function as the Na*-K*-2Cl- cotransporterin many epithelia performing secretory/absorbing function, including AscLH. Recently,distincr absorptiueo r secretoryis oforms of Na*-K*-2C1- cotransporter have been isolated. The former is exclusively expressed at the luminalmembrane of thick AsclH-furosemide attaches to the Cl- binding site of this protein to inhibitits transport function. The secretory form isexpressed on the basolateral membrane of most glandular and epithelial cells.

Pharmacokinetics

Furosemideisrapidlyabsorbedorally but bioavailability is about 60o/". In severe CHF oral bioavailability may be markedlyreduced. Lipid-solubility is low, and it is highly bound to plasma proteins. It is partly conjugated with glucuronic acid and mainly excreted unchanged by glomerular filtration as well as tubular secretion. Some excretion in bile anddirectly in intestine also occurs. Plasma t% averages 1-2 hour but is prolonged in patientswith pulmonary edema, renal and hepaticinsufficiency

Dose Usually 2G-80 mg once daily in the moming. Ln renal insufficiency, upto 200 rng 6 hourly has been given by i m /i.v. route In pulmonary edema 40-80 mg may be given iv.

.- Bumetanide

It is similar to furosemide in all respects, but is 40 times more potent. It induces very rapid diuresis and is highly effective in pulmonary edema. However, the site of action,ceiling effect, renal haemodynamic changes and duration of action are similar to furosemide. A secondary action in PT has also been demonstrated. It may act in some cases not responding to furosemide. Bumetanide is more lipid-soluble, 80-100% bioavailable orally, Plasma t1,h- 60 min, gets prolonged in renal and

hepatic insufficiency.

Dose:

 1-5 rng oral OD in the morning, 24 mg i.rn./i.v.,(max. 15 mg/day rn renal failure).

-Torasemide (Torsemide)

 Anotherhighceiling diuretic with properties similar to furosemide, but 3 times more potent. O:ral absorption is more rapid and more complete. The elimination t% (3.5 hours) and duration of action (4-8 hours) are longer. Torasemide has been used in edema and in hypertension.

Dose: 2.5-E mg OD in hypertension; 5-20 rng/day in edema; upto 100 mg BD in renal failure

Use of high ceiling diuretics

1.      Edema Diuretics are used irrespective ofetiology of edema---cardiac, hepatic or renal. The high ceiling diuretics are preferred in CHF for rapid mobilizatton of edema fluid.

2.Acute pulmonary edema (acute LVF, followingMl): Intravenous administration of furosemide

or its congeners produces prompt relief

3. Cerebral edema Though osmotic diureticsare primarily used, furosemide may be combinedto improve efficacy.

4. Hypertension High ceiling diuretics are indicated only in presence of renal insufficiency,CHF, in resistant cases or hypertensive emergencies;otherwise thiazides are preferred

5. Along with blood transfusion in severe anaemia, to prevent vascular overload.

6. Hypercalcaemia and renal calcium stones: because furosemide and its congeners increasecalcium excretion and urine flow, they may help to reduce serum calcium level.

THIAZIDE AND RELATED DIURETICS

(lnhibitors of Na.-Cl- sympoft

Chlorothiazide was synthesized as a Case inhibitor variant which produced urine that wasrich in Cl-, and diuresis occurrecl in alkalosrs as well as acidosis. A large number of congenerswere developed subsequently and the thiadiazine ring was replaced by other heterocyclic rings, but the type of activity remained the same

.MOA

These are medium efficacy diuretics with primary site of action in the cortical diluting segment or the early DT (Site III). Here they inhibit Nat-Cl- symport at the luminal membrane.They do not affect the corticomedullary osmotic gradient indicating lack of action at the medullary thick AscLH These d rugs gain accessto their site of action irinorganic acid secretory pathway in PT and then along the tubular fluid to early DT, where theybind to specific receptors located on the lumi::membrane. Like the Na*-K*-2Cl- cotranspt the Na*-CI- symporter is also a glycoprotein 12 membrane spanning domains that b,I thiazides but not furosemide or any other c of diuretics.

:-pharmacokinetics

 All thiazides and related  are well absorbed orally; are administered Basically by this route. Their action starts within 1 but the duration varies from 8-48 hours Most of the agents undergo little hepatic m etabolism and are excreted as such.

-Chlortharidone

It is a particularly long actingArgernt  with a t1/z 40-50 hours, used exclusively as antihvpertensive

-metolezone

In common with loop diuretics, itIs able to evoke a clinicallv useful response even

In severe renal failure tg.f.r. -tS mlTmin), and has marketed additive action when combined furosemide. An additional proximal tubular action has been demonstrated; PO4 reabsorptionthat occurs in PT is inhibited. It is excreted unchanged in urine.

-Xipamide

 It has a pronounced diuretic action similar to low doses of furosemide. Because oflonger duration of action-hypokalemia is more prominent.

-lndapamide

 It has little diuretic action in the usual doses, probably because it is highly lipidsolubie,is extensivelv metabolized and only small quantity of unchanged drr"rg is present in the tubular fluid. Hower.'er, it retains antihypertensirre action and is used for that purpose only.

Uses

1.      Edema Thiazides may be used for mild-tomoderate case

2. Hypertension Thiazides and related diuretics,especially chlorthalidone are one of the first line drugs

3. Diabetes insipidus Theyreduceurinevolume

4. Hypercalciuria withrecurrentcalciumstones in the kidney. Thiazides act by reducing Ca2* excretion.

Complications of high ceiling and thiazidetype diuretic therapy

Hypokalaemia,Acute saline depletion,Dilutional hyponatraemia,GIT and CNS disturbances,Hearing loss,Hearing loss.etc

lnteractions

1. Thiazides and high ceiling diuretics potentiate all other antihypertensir.es. This interactionis intentionally employed in therapeutics.

2. Hypokalaemia induced by these diuretics  Enhances digitalis toxicity  Increases the incidence of polymorphrc ventricular tachycardia due to quinidine and other antiarrhythmics Potentiates competitive neuromuscular blockers and reduces sulfonylurea action.

3. High ceiling diuretics and aminoglycoside antibiotics are both ototoxic and nephrotoxic produce additive toxicity; should be used together cautiously.

4. Cotrimoxazole given with diuretics has caused higher incidence of thrombocytopenia.

5. Indomethacin and other NSAIDs diminish the action of high ceiling diuretics.

POTASSIUM SPARING DIURETICS

These are either aldosterone antagonist or directly inhibit Na* channels in DT and CD cells to indirectly conserve K*

. Spironolactone (Aldosterone antagonist) It is a steroid, chemically related to the mineralocorticoid aldosterone. Aldosterone acts on the late DT and CD cells. by combining

with an intracellular mineralocorticoid receptor .Spironolactone is a mild saluretic because

majority of Na* has already been reabsorbedproximal to its site of action.

Pharmacokinetics The oral bioavailability of spironolactone from microfine powder tablet is

75%. k is highly bound to plasma proteins andcompletely metabolized in liver; converted to

active metabolites, the most important of which is Canrenoneth at is responsible for 1,/2-2/3 of

its action in aiao. The tr/z. of spironolactone is1-2 hours, while that canrenone is -18 hours.

It undergoes some enterohepatic circulation.

Dose: 25-50 mg BD-QID;

Interaction

1.      Given together with potassium supplement may cause hyperkalemia

2.      Aspirin blocks spironolactone action by inhibiting tubular secretion of canrenone.

3.      spironolactone increases plasma digoxin concentratlon.

Side effect

The side effects are drowsiness,

- a,b dominal upset ,h irsutism, gynaecomastia, impotence and menstrual irregularities

OSMOTIC DIURETICS

Mannitol

Mannitol is a nonelectrolyte of low molecular weight (182) that is pharmacologically inertcanbegiven in large quantities sufficient to raise osmolarity of plasma and tubular fluid. It is notmetabolized in the body; freely filtered at the lomerulus and undergoes limited reabsorption:

therefore excellently suited to be used as osmotic iuretic. Mannitol appears to limit tubular water

and electrolyte reabsorption in a variety of ways:

1. Retains water isoosmotically in PTdilutesluminal fluid which opposes NaClreabsorption.

2. Inhibits transport processes in the thick  cLH by an unknown mechanism.Quantitatively this appears to be the mostimportant cause of diuresis.

3. Expands extracellular fluid volume because it does not enter cells, mannitol. draws water from the intracellular ompartment)-increases g.f.r. and inhibits rein release.

4. Increases renalblood flow, especially to the medulla edullary hypertonicity is reduced-

corticomedullary osmotic gradient rs issipated-passive salt reabsorption rsreduced.

Though the primary action of mannitol is to ncrease urinary volume, excretion of all cations

and anions is also enhanced.

Administration

Mannitol is not absorbed orally s to be given i.v. as 10-20% solution. It rs xcreted with a t7z of 0.5-1.5 hour.

Usesindicationare

1.      Increased intracranial or intraocular tenslor(acute congestive glaucoma, head injury, stroke

2.      To maintain g.f.r. and urine flow in imperdingacute renal failure, e.g. in shock, severetrauma, cardiac surgery

3.      To counteractlow osmolality of plasma/ger

Mannitol is contraindicated in acute tubularnerosis, anuria, pulmonary edema; acute left

ventricular failure, CHF, cerebral haemorrhage.Headache due to hyponatraemia is common,

nausea and vomiting may occur; hypersensitivityreactlons are rare.

lsosorbide and glycerol These are orally active osmotrcdiuretics which ma1, be used to reduce intraocular or

intracranial tension Intravenous glycerol can causehaemolysis

Dose: 0 5-1 5 g/kg as oral solution

ELECTROLYTES AND WATER BALANCE

Solutions of are electrolytes given intravenously, to meet normal fluid and electrolytes requirements or to replenish substantial deficits or continuing losses, when the patient is nauseated or vomiting and is unable to take adequate amounts by mouth. When intravenous administration is not possible, fluid (as sodium chloride 0.9% or glucose 5%) can also be given by subcutaneous infusion (hypodermoclysis).

The nature and severity of the electrolyte imbalance must be assessed from the history and clinical and biochemical investigations. Sodium, potassium, chloride, magnesium, phosphate, and water depletion can occur singly and in combination with or without disturbances of acid-base balance; for reference to the use of magnesium and phosphates, Isotonic solutions may be infused safely into a peripheral vein. Solutions more concentrated than plasma, e.g. 20% glucose, are best given through an indwelling catheter positioned in a large vein.

-Intravenous sodium, Intravenous glucose , Intravenous potassium ,Bicarbonate and lactate , Water

·         Intravenous sodium

·         Sodium chloride in isotonic solution provides the most important extracellular ions in near physiological concentration and is indicated in sodium depletion which may arise from such conditions as gastro-enteritis, diabetic ketoacidosis, ileus, and ascites. In a severe deficit of from 4 to 8 litres, 2 to 3 litres of isotonic sodium chloride may be given over 2 to 3 hours; thereafter the infusion can usually be at a slower rate. Excessive administration should be avoided; the jugular venous pressure should be assessed, the bases of the lungs should be examined for crepitations, and in elderly or seriously ill patients it is often helpful to monitor the right atrial (central) venous pressure.

·         Chronic hyponatraemia arising from inappropriate secretion of antidiuretic hormone should ideally be corrected by fluid restriction. However, if sodium chloride is required for acute or chronic hyponatraemia, regardless of the cause, the deficit should be corrected slowly to avoid the risk of osmotic demyelination syndrome and the rise in plasma-sodium concentration should not exceed 10 mmol/litre in 24 hours. In severe hyponatraemia, sodium chloride 1.8% may be used cautiously.

·         Compound sodium lactate (Hartmann’s solution) can be used instead of isotonic sodium chloride solution during surgery or in the initial management of the injured or wounded.

·         Sodium chloride and glucose solutions are indicated when there is combined water and sodium depletion. A 1:1 mixture of isotonic sodium chloride and 5% glucose allows some of the water (free of sodium) to enter body cells which suffer most from dehydration while the sodium salt with a volume of water determined by the normal plasma Na⁺ remains extracellular. Maintenance fluid should accurately reflect daily requirements and close monitoring is required to avoid fluid and electrolyte imbalance. Illness or injury increase the secretion of anti-diuretic hormone and therefore the ability to excrete excess water may be impaired. Injudicious use of hypotonic solutions such as sodium chloride 0.18% and glucose 4% may also cause dilutional hyponatraemia especially in children and the elderly; if necessary, guidance should be sought from a clinician experienced in the management of fluid and electrolytes.

·         Combined sodium, potassium, chloride, and water depletion may occur, for example, with severe diarrhoea or persistent vomiting; replacement is carried out with sodium chloride intravenous infusion 0.9% and glucose intravenous infusion 5% with potassium as appropriate.

SODIUM CHLORIDE

Indications

  electrolyte imbalance—; nebuliser diluent; eye; oral hygiene; wound irrigation

Cautions

  restrict intake in impaired renal function, cardiac failure, hypertension, peripheral and pulmonary oedema, toxaemia of pregnancy

Side-effects

  administration of large doses may give rise to sodium accumulation, oedema, and hyperchloraemic acidosis

Dose

 Intravenous glucose

Glucose solutions (5%) are used mainly to replace water deficit and should be given alone only when there is no significant loss of electrolytes; prolonged administration of glucose solutions without electrolytes can lead to hyponatraemia and other electrolyte disturbances. Average water requirements in a healthy adult are 1.5 to 2.5 litres daily and this is needed to balance unavoidable losses of water through the skin and lungs and to provide sufficient for urinary excretion. Water depletion (dehydration) tends to occur when these losses are not matched by a comparable intake, as may occur in coma or dysphagia or in the elderly or apathetic who may not drink enough water on their own initiative.
Excessive loss of water without loss of electrolytes is uncommon, occurring in fevers, hyperthyroidism, and in uncommon water-losing renal states such as diabetes insipidus or hypercalcaemia. The volume of glucose solution needed to replace deficits varies with the severity of the disorder, but usually lies within the range of 2 to 6 litres.
Glucose solutions are also used to correct and prevent hypoglycaemia and to provide a source of energy in those too ill to be fed adequately by mouth; glucose solutions are a key component of parenteral nutrition
Glucose solutions are given in regimens with calcium and insulin for the emergency management of hyperkalaemia. They are also given, after correction of hyperglycaemia, during treatment of diabetic ketoacidosis, when they must be accompanied by continuing insulin infusion.
Sub-sections

GLUCOSE

Glucose BP is the monohydrate but Glucose Intravenous Infusion BP is a sterile solution of anhydrous glucose or glucose monohydrate, potency being expressed in terms of anhydrous glucose

Indications

  fluid replacement (see notes above), provision of energy hypoglycaemia

Side-effects

  glucose injections especially if hypertonic may have a low pH and may cause venous irritation and thrombophlebitis

Dose

  Water replacement, see notes above; energy source, 1–3 litres daily of 20–50% solution

GLUCOSE

(Dextrose Monohydrate)

  Glucose BP is the monohydrate but Glucose Intravenous Infusion BP is a sterile solution of anhydrous glucose or glucose monohydrate, potency being expressed in terms of anhydrous glucose

Indications

 

fluid replacement (see notes above), provision of .

energy; hypoglycaemia

Side-effects

 

glucose injections especially if hypertonic may have a low pH and may cause venous irritation and thrombophlebitis

Dose

Water replacement, see notes above; energy source, 1–3 litres daily of 20–50% solution

·         Glucose Intravenous Infusion (Non-proprietary)

Intravenous infusion, glucose or anhydrous glucose (potency expressed in terms of anhydrous glucose), usual strength 5% (50 mg/mL) and 10% (100 mg/mL); 25% solution, net price 25-mL amp = £2.21; 50% solution,⁽¹⁾ 25-mL amp = £3.80, 50-mL amp

In hospitals, 500- and 1000-mL packs, and sometimes other sizes and strengths, are available; also available as Min-I-Jet® Glucose, 50% in 50-mL disposable syringe

Intravenous potassium

Potassium chloride and sodium chloride intravenous infusion is the initial treatment for the correction of severe hypokalaemia and when sufficient potassium cannot be taken by mouth. Ready-mixed infusion solutions should be used when possible; alternatively, potassium chloride concentrate, as ampoules containing 1.5 g (K⁺ 20 mmol) in 10 mL, is thoroughly mixed with 500 mL of sodium chloride 0.9% intravenous infusion and given slowly over 2 to 3 hours, with specialist advice and ECG monitoring in difficult cases. Higher concentrations of potassium chloride may be given in very severe depletion, but require specialist advice.

Repeated measurement of plasma-potassium concentration is necessary to determine whether further infusions are required and to avoid the development of hyperkalaemia, which is especially likely in renal impairment.

Initial potassium replacement therapy should not involve glucose infusions, because glucose may cause a further decrease in the plasma-potassium concentration.

POTASSIUM CHLORIDE.

Indications

  electrolyte imbalance; see also oral potassium supplements

Cautions

for intravenous infusion the concentration of solution should not usually exceed 3 g (40 mmol)/litre; specialist advice and ECG monitoring renal impairment (avoid if creatinine clearance less than 10 mL/minute;Contra-indications

 plasma-potassium concentration above 5 mmol/litre

Side-effects

  rapid infusion toxic to heart

Dose

By slow intravenous infusion, depending on the deficit or the daily maintenance requirements,  -Bicarbonate and lactate

Sodium bicarbonate is used to control severe metabolic acidosis (pH < 7.1) particularly that caused by loss of bicarbonate (as in renal tubular acidosis or from excessive gastro-intestinal losses). Mild metabolic acidosis associated with volume depletion should first be managed by appropriate fluid replacement because acidosis usually resolves as tissue and renal perfusion are restored. In more severe metabolic acidosis or when the acidosis remains unresponsive to correction of anoxia or hypovolaemia, sodium bicarbonate (1.26%) can be infused over 3–4 hours with plasma-pH and electrolyte monitoring. In severe shock, for example in cardiac arrest, metabolic acidosis can develop without sodium or volume depletion; in these circumstances sodium bicarbonate is best given as a small volume of hypertonic solution, such as 50 mL of 8.4% solution intravenously; plasma-pH and electrolytes should be monitored.

Sodium lactate intravenous infusion is no longer used in metabolic acidosis because of the risk of producing lactic acidosis, particularly in seriously ill patients with poor tissue perfusion or impaired hepatic function.

1.          For chronic acidotic states, sodium bicarbonate can be given by mouth.

• SODIUM BICARBONATE
• SODIUM LACTATE

SODIUM BICARBONATE

Indications

  metabolic acidosis

Dose

By slow intravenous injection, a strong solution (up to 8.4%), or by continuous intravenous infusion, a weaker solution (usually 1.26%), an amount appropriate to the body base deficit

PREPARED BY:-

              MWENDI SIFUN YONA