Niger J Paed 2012; 39 (4):206 –211  
Adedoyin OT  
Bello AO  
Mohammed SS  
Diuretics use in Paediatric practice  
with focus on Furosemide  
Accepted: 28th February 2012  
Abstract Diuretics remain a com- ground of challenges in our center  
mon medication in Paediatric prac- with regards to the use of  
tice and possibly one of the most frusemide, this review is specifi-  
important drugs in Nephrology cally focused on addressing factors  
practice. Understanding their that may affect frusemide efficacy,  
mechanism, appropriate rationale possible cause of resistance and  
for use and prompt identification of drug interactions that may occur  
side-effects allows for high efficacy following its use.  
Adedoyin OT  
Bello AO, Mohammed SS  
Department of Paediatrics,  
University of Ilorin Teaching  
Hospital, Ilorin, Nigeria  
and safety in their use. On the back-  
trolytes and waste products. Each human kidney has  
over one million nephrons. The nephron is the func-  
Disorders affecting fluid volume and electrolyte compo-  
sition are common problems in clinical practice. Drugs  
that block the transport functions of the renal tubules are  
valuable tools in the treatment of these disorders. Vari-  
ous agents that increase urine flow have been described  
since antiquity but it was in 1957 that a practical and  
powerful agent; chlorothiazide became available for  
widespread use as diuretics.  
tional unit of the kidney.  
The nephron is made up of glomerulus, proximal tubule,  
loop of Henle, distal tubule and the collecting ducts.  
Technically, the term ‘diuresis’ signifies an increase in  
urine volume, while ‘natriuresis’ denotes an increase in  
renal sodium excretion. Because natriuretic drugs almost  
always also increase water excretion, they are usually  
called diuretics.  
Thus, diuretics are agents that enhance urine formation  
by altering the total solute content of the extracellular  
compartment and water balance. An ideal diuretic would  
be one that caused the excretion of “extra” urine with an  
electrolyte composition similar to that of normal plasma.  
No such diuretic exists.  
It is important for a practitioner to be armed with the  
knowledge of the mechanism of action of diuretic drugs  
and appropriate recognition and respect for their poten-  
tial side effects in order to use them with a high degree  
of efficacy and safety.  
To understand the actions of diuretics, it is necessary to  
first review how the kidneys filter fluid and form urine.  
Nephron physiology  
The kidney is the main organ of excretion of water, elec-  
Processes involved in urine formation are:  
Glomerular filtration  
Tubular reabsorption  
Tubular excretion  
All these processes occur in the nephron  
Proximal tubule  
Loop of Henle  
Distal tubule  
Loop of Henle  
The thin limb is permeable to H O, while the thick por-  
tion is impermeable to H  
In the thin limb, H O is reabsorbed by osmotic forces  
created by the medullary interstitium.  
Presence of non-permeable solute will oppose H O ex-  
traction. NaCl is actively reabsorbed in the thick limb  
Glomerular filtration  
through Na /K /2Cl cotransporter located in the luminal  
membrane. Because this portion is impermeable to H O,  
As blood passes through the glomerular capillaries, the  
plasma is filtered through the glomerular capillary walls.  
The ultrafiltrate, which is cell free, contains all the sub-  
stances in the plasma except proteins (such as albumin  
and the globulins). The substances in the ultra-filterate  
are electrolytes, glucose, phosphate, urea, creatinine,  
peptides, low molecular weight proteins.  
salt reabsorption dilutes tubular fluid. Excess K accu-  
mulates within the cells, it diffuses into the tubular lu-  
men to create a lumen-positive electrical potential. This  
electrical potential provides a driving2+force for reabsorp-  
tion of cations such as Mg and Ca via the paracellu-  
lar pathway.  
The filtrate is collected in Bowman's space and enters  
the tubules.  
Tubular reabsorption and excretion  
Proximal Convoluted Tubule (PCT)  
solutes are reabsorbed in the early PCT. H  
sorbed passively to maintain osmolality of the luminal  
fluid. NaHCO reabsorption at the PCT is dependent on  
, NaCl, glucose, amino acids, and other organic  
O is reab-  
the carbonic anhydrase (CA). Na /H exchanger allows  
Na to enter the cell from the tubular lumen in exchange  
for an H from inside the cell. Na /K ATPase located  
on the basolateral membrane pumps the reabsorbed Na  
into the interstitium.  
In the late PCT the residual luminal fluid contains pre-  
dominantly NaCl. A poorly defined exchanger, the Cl /  
base exchanger is activated by the free H in the dista+l  
portion of the PCT. The net effect of parallel Na /H  
exchange and Cl /base exchange is NaCl reabsorption.  
Distal convoluted tubule  
2 2  
Because the PCT is highly permeable to H O, H O is  
reabsorbed in direct proportion to salt reabsorption.  
Thus the luminal fluid osmolality and Na concentration  
remain nearly constant along the length of the PCT. The  
concentration of non-permeable solute in the tubular  
fluid will rise.  
This segment is relatively impermeable to H O; thus  
luminal fluid is further diluted with NaCl reabsorp- tion.  
NaCl is reabsorbed via a neutral Na and Cl co-  
transport. Ca is actively re+absorbed by the DCT  
epitheli2a+l cell via an apical Ca channel and basolateral  
Na /Ca exchanger. This process is regulated by para-  
thyroid hormone (PTH).  
Loop diuretics  
Thiazide diuretics  
Potassium-sparing diuretics  
Na channel blockers  
Aldosterone antagonists  
Others - mercurial, xanthines, etc  
Collecting tubule  
As the final site of NaCl reabsorption, this segment is  
responsible for volume regulation and for determining  
the final Na concentration of urine. The principal cells  
are the site of Na , K , and H O transport. The interca-  
lated cells are the primary sites of H secretion. There  
are no co-transport systems in the principal cells, rather  
they have separate ion channels for Na and K . The  
Tubular transport and site of action of diuretics  
driving force for Na entry exceeds that of K exit, Na  
Carbonic anhydrase (CA) inhibitors - Acetazolamide,  
reabsorption predominates K secretion – this leads to  
lumen-negative electrical potential. The lumen-negative  
electrical potential drives the transport of Cl back to the  
blood, it also pulls K out of the cell through the apical  
membrane K channel. The reabsorption of Na via the  
They are weak diuretics, used clinically to correct  
acid-base disturbances (alkalosis) and reduction of  
aqueous humour formation in glaucoma, rather than  
for diuretic action.  
epithelial Na channel and its coupled secretion of K is  
regulated by aldosterone. Antidiuretic hormone (ADH)  
is a key determinant of final urine concentration. Perme-  
ability of principal cells to H O is increased by ADH-  
induced fusion of vesicles preformed water channels  
with the apical membranes.  
Act by inhibit-ing CA at the PCT, Inhibition of CA  
inhibits HCO absorption from tubule.  
3 2  
Presence in lumen of HCO reduces Na and H O  
Osmotic diuretics – Mannitol, Urea, Sorbitol  
The PCT and the descending limb of Henle’s loop are  
freely permeable to H O. Osmotic agent that is not reab-  
sorbed causes H O to be retained in these segments and  
promote diuresis.  
Such agents can be used to reduce increased intracranial  
pressure and to promote prompt removal of renal toxins.  
They must be given parenterally because they are poorly  
absorbed in the GIT and also cause osmotic diarrhea.  
Loop diuretics – furosemide, bumetanide, torsemide,  
ethacrynic acid  
They are often described as "high ceiling" diuretics  
due to their high diuretic potential.  
They can cause up to 20% of the filtered load of  
Classification of diuretics  
NaCl and H O to be excreted- in the urine. They act  
+ +  
by inhibiting the Na /K /2Cl co-transporter in the  
thick ascending limb of the loop of Hen+le, they also  
Diuretics are classified according to their mechanism  
and site of action within the nephron.  
interfere with the reabsorption of K , Ca , and  
Carbonic anhydrase inhibitors  
Osmotic diuretics  
Mg in the loop.  
chlorothiazide, hydrochlorothiazide,  
benzthiazide, chlorthalidone,  
Furosum- ide’s mechanism of action is by inhibiting Na /  
Exert their diuretic effect by inhibiting the Na /Cl  
co-transport in the early distal convoluted tubules.  
K /2Cl transporter in the thick ascending loop of Henle.  
This inhibits the reabsorption of NaCl leading to in-  
They elicit a weaker diuretic response compared to  
the loop diuretics.  
Increase the loss of K and Mg , but reduce Ca  
creased NaCl and H O excretion.  
Furosemide is available for both oral and parenteral ad-  
ministration. Its onset of action is rapid, usually within  
0 minutes after oral and five minutes after intravenous  
administration. It produces peak diuresis in about two  
hours, with a total duration of diuretic action of approxi-  
mately six to eight hours.  
Na channel blockers – Amiloride, triamterene  
They act by blocking the Na channels in the lu-  
minal membrane of the principal cells of the cortical  
collecting ducts. This reduces the Na entry through  
the luminal membrane and hence the net reabsorp-  
tion of NaCl. Action is independent of aldosterone.  
They have weak diuretic effect.  
Furosemide is extensively bound to plasma proteins and  
is eliminated in the urine by both glomerular filtration  
and tubular secretion. Approximately a third of an ad-  
ministered dose is excreted by the liver into the bile,  
from where it may be eliminated in the feces.  
Aldosterone antagonists - spironolactone  
Act at the late distal tubule and the cortical collect-  
ing tubule and competes with aldosterone for recep-  
tor sites in DCT and the collecting tubule.  
Conventional: 1- 2mg/kg/dose, maximum of 6mg/kg/  
day. Higher dose may be given in certain situations – up  
to 600mg/day  
Results in decreased Na reabsorption in DCT and  
the collecting tubule and promotes Na and wate+r  
loss. Decreased Na reabsorption balanced by K  
retention at this site (and H ) K sparing.  
Furosemide (Frusemide)  
Furosemide is available in tablets for oral administration  
and injectable for I.V. administration.The tablets are a  
white to off-white odorless crystalline powder. They are  
available in dosage strengths of 20, 40 and 80 mg. The  
injection comes as 20mg/2ml; clear colourless solution.  
The most efficacious agent available for inducing  
marked water and electrolyte excretion.  
It can increase diuresis even in patients who are  
already responding maximally to other diuretics. It  
has no significant pharmacological effects other  
than on renal function.  
00mg tablet and 250mg injection also available for use  
in selected patients who do not respond to conventional  
Chemical properties  
Clinical use of diuretics  
It is an anthranilic acid derivative  
It is practically insoluble in water  
Sparingly soluble in alcohol  
Freely soluble in dilute alkali solutions and insolu-  
ble in dilute acids.  
Diuretics interfere with sodium reabsorption and lower  
extracellular fluid volume. Therefore useful in the fol-  
lowing conditions:  
Heart failure and pulmonary oedema.  
Chronic kidney disease  
Acute renal failure  
Liver cirrhosis  
Diabetes insipidus.  
Prevent cardiovascular complications of chronic  
kidney disease.  
Chemically, it is 4chloro-N-furfuryl-5-  
sulfamoylanthranilic acid  
Potentiate the effect of antihypertansive and for  
resistant hypertension.  
Adverse effects of diuretics  
The structural formula of furosemide  
Hypovolaemia (Loop and thiazides)  
Hypokalaemia (Loop, thiazides, carbonic anhy  
Hyperkalaemia (K sparing diuretics)  
Hyponatraemia (Loop and thiazides)  
Hypocalcaemia (hypercalciuria)  
Tubular socretory  
Rate of absorption  
Time course of  
Maximal response  
Nipple tenderness, erectile dysfunction, menstrual  
irregularities (spironolactone)  
Hypomagnesaemia (thiazide and loop)  
Metabolic alkalosis (Thiazides and loop)  
Metabolic acidosis (K sparing diuretics&carbonic  
anhydrase inhibitors)  
Altered dose response  
Braking phenomenon  
Allergic reaction similar to those seen in sulphona-  
mide containing drugs.  
Interstitial nephritis (loop).  
Diuretic excretion rate  
Osmotic diarrhea .  
Sigmoidal-shaped-dose-response relationship  
Systolic blood pressure120m 110 –  
A- Represents pharmacokinetic determinants of  
diuretic response for an orally administered diuretic.  
Threshold: Diuretic delivery rate sufficient to pro-  
duce first diuresis.  
Efficiency: Rate of delivery that produces optimal  
response for any amount of diuretic  
Baseline GFR(ml/  
min/1.73m )  
Serum K (For thiazide  
and loop) mmol/l  
Serum K (For K spar-  
ing diuretics) mmol/l  
Interval (weeks)  
Maximal response: Delivery at which no addi-  
tional diuretic response can occur.  
2 weeks  
B- Represents altered pharmacodynamic determi-  
nants in diuretic resistance. This is termed the  
breaking phenomenom, it occurs in both long and  
short-term therapy. Due to the haemodynamic and  
neurohumoral changes produced by rapid diuresis it  
causes a rebound antinatriuretic effect. This can be  
overcome by administering multiple doses.  
Principles for monitoring for adverse effects when initi-  
ating diuretics  
Measuring baseline blood pressure, glomerular fil-  
tration rate and serum potassium.  
Counselling to reduce risk of volume depletion or  
rapid volume loss, hypokalaemia and allergic re-  
Resistance to frusemide  
Due to alteration in pharmacokinetic determinants  
of tubular delivery  
Pharmacodynamic determinants of diuretic action in  
the tubular space.  
Determine interval for follow-up measurement.  
Counselling mothers of child bearing age of poten-  
tial side-effects especially spironolactone.  
High dietary sodium intake: Can be ascer-  
tained by estimating sodium excretion rate. If >  
Monitoring for adverse drug reactions  
sodium intake.  
00mmol/day may suggest excessive dietary  
Factors affecting efficacy of frusemide  
Independent cause of increased tubular reab-  
sorption of sodium e.g NSAIDS.  
Diuretic tolerance causing a breaking phe-  
Excessive exposure of distal tubule to high  
sodium load resulting in distal tubular hypertro-  
phy and an excessive recapturing of sodium  
delivered from proximal locations.  
This can be altered by combining thiazide type  
diuretic with a loop diuretic.  
Onset time: Intravenous– five minutes; Oral- 30  
Half life is two hours and last 4-6 hours.  
Diuretic action is a co-ordinated process and relies  
on adequate amount of drug reaching the site of  
For the intravenous bioavailability at the tubules  
and loop not affected  
In oral administration rate and extent of absorption  
of a diuretic become an important consideration.  
Absorption could vary from 10-100%. This makes  
efficacy when given orally essentially a clinical  
Drug interactions with frusemide  
Drugs that make frusemide less effective: NSAIDS  
and Phenytoin.  
Increase risk of ototoxicity: Aminoglycosides and  
Ethacrynic acid.  
Increases risk of hypokalaemia: Corticoster-  
oids,Laxatives and Liquorice  
Increase risk of hyperuricaemia (gout): Cycsporine.  
Reproduced with kind permission of the Department of  
Paediatrics and Child Health of the University of Ilorin  
Teaching Hospital, Ilorin Nigeria owners of the Ilorin  
Paediatric Digest 2012  
Conflict of interest: None  
Funding: None  
Modern Pharmacology With Clini-  
3. Renal Physiology and Control of  
Micturition, Morhason-Bello, I.O.  
FWACS Department of OBGYN  
University College Hospital,  
TURES August 2010.  
Katzung Basic and Clinical Phar-  
macology, 9th edition  
cal Applications by Charles R.  
Craig and Robert E. Stitzel, 6th