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DIURETICS
Introduction:
By definition, diuretics are drugs that increase the rate of urine flow; however,
clinically useful diuretics also increase the rate of excretion of Na + (natriuresis) and of
an accompanying anion, usually Cl-. NaCl in the body is the major determinant of
extracellular fluid volume, and most clinical applications of diuretics are directed
toward reducing extracellular fluid volume by decreasing total-body NaCl content. A
sustained imbalance between dietary Na+ intake and Na+ loss is incompatible with
life. A sustained positive Na+ balance would result in volume overload with
pulmonary edema, and a sustained negative Na+ balance would result in volume
depletion and cardiovascular collapse. Although continued administration of a diuretic
causes a sustained net deficit in total-body Na+, the time course of natriuresis is finite
because renal compensatory mechanisms bring Na+ excretion in line with Na+ intake,
a phenomenon known as diuretic braking. These compensatory, or braking,
mechanisms include activation of the sympathetic nervous system, activation of the
renin-angiotensin-aldosterone axis, decreased arterial blood pressure (which reduces
pressure natriuresis), hypertrophy of renal epithelial cells, increased expression of
renal epithelial transporters, and perhaps alterations in natriuretic hormones such as
atrial natriuretic peptide.
Diuretics not only alter the excretion of Na + but also may modify renal
handling of other cations (e.g., K+, H+, Ca2+, and Mg2+), anions (e.g., Cl-, HCO3 -, and
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H2PO4 -), and uric acid. In addition, diuretics may alter renal hemodynamics
indirectly.
Objectives(1) :
3) Understand the mechanisms of action and major side effects of the prototype
diuretic drugs.
• Diuretics are the agents which increase the rate of urine formation.
• Diuretics are effective for the treatment of oedema have been available since
16th century.
• Most modern diuretics were developed when side effects of antibacterial drugs
were noted, which included changes in urine composition and output.
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• Diuretics are the most commonly prescribed drugs in the USA and can be
quite efficacious but they can also have an extremely wide range of adverse
effects.
• Once diuretic enters the tubular fluid, the nephron site at which it acts
determines its effect. In addition, the site of action also determines which
electrolytes, other than Na+ will be affected.
• All diuretics except spironolactone exert their effects from the luminal side of
the nephron.
• It is necessary for diuretics to get into the tubule fluid in order to be effective.
Anatomy of Kidney(10)
Location
The paired Kidneys are reddish, kidney bean shaped organ located just above
the waist between the peritoneum &the posterior wall of abdomen . Because their
position is posterior to the peritoneum of the abdominal cavity , they are said to be
retroperitoneal The kidneys are located between the levels of the last thoracic & third
lumbar vertebrae , a position where they are partially protected by the 11th & the 12th
pairs of ribs The right kidney is slightly lower than the left .
External anatomy -
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1) Renal hilus - Near the center of concave boarder is a deep vertical fissure
2) Layers of kidney –
4) Renal papilla - The base of each pyramid faces the renal cortex , its apex
7called renal papilla .
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6) Minor & major calyces – The papillary ducts drain into cup – like structures.
7) Renal pelvis – Form major calyces , urine drains into a single large cavity
called renal pelvis .
8) Renal sinus – Hilus expands into a cavity within kidney called renal sinus
Kidney constitutes 0.5% of total body mass, they receive 20-25 % of the resting
cardiac output , via left and right renal arteries ,
4) Vasa recta - Extending from efferent arteriole which are long ,loop shaped
capillaries .
7) Renal vein - Blood leaves the kidney through a single renal vein that exits at
renal hilus & carries venous blood to inferior vena cava.
The nephron is a tube, closed at one end , open at the other . It consists of –
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3) Proximal convoluted tubule – coiled & lined with cells carpeted with
microvilli & stuffed with mitochondria .
4) Loop of Henle – It makes a hairpin turn & returns to Distal convoluted tubule.
The fluid that enters the capsular space is called glomerular filtrate on an
average, the daily volume of glomerular filtrate in adults is 150 lit in females and 180
lit. In males more than 99% of glomerular filtrate returns to the blood stream via
tubular reabsorption & only 1-2 lit are excreted as urine .
1) Glomerular filtration
2) Tubular reabsorption
3) Tubular secretion
1) Glomerular filtration :
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Fluid is driven from the capillaries into the tubular capsule (Bowman’s
capsule) by hydrodynamic force. It crossed three layers the capillary
epithelium, the basement membrane and the epithelial cell layer of the
capsule. These from a complex filter that excludes large molecules. Normally
all constituents in the plasma, except plasma proteins, appear in the filtrate
&the blood which passes through the efferent arteriole to the particular
capillaries has a higher concentration of plasma proteins & thus higher
osmotic pressure than normal.
The amount of filtrate formed in all the renal capsule of both kidneys each min
is glomerular filtration rate.
In adults, GFR averages 125ml/min in males & 105 ml/min in females. It GFR
is too high, needed substances may not reabsorbed & are lost in urine. It the GFR is
too low, nearly all the filtrate may be reabsorbed and certain waste products may not
be adequately excreted.
GFR is directly related to pressures that determine net filtration pressure. Any
change in net filtration pressure will affect GFR. In case of severe blood loss, mean
arterial pressure reduces & decreases glomerular blood hydrostatic pressure G.F.R. In
case of severe blood loss, mean arterial pressure reduces & decreases glomerular
blood hydrostatic pressure G.F.R. is nearly constant when mean arterial blood
pressure is anywhere in between 80-180 mm Hg .
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blood flow Constriction of afferent arteriole, decreases blood flow into the
glomerulus, whereas dilation of afferent areteriole increases blood flow.
a) Renal autoregulation
b) Neural regulation
c) Hormonal regulation
The kidney themselves helps to maintain a constant renal blood Flow & GFR .
Despite normal, everyday changes in B.P (e.g. exercise) this capability is called
renal auto regulation. It consists of a feedback mechanism. As blood pressure
rises, however, the elevated blood pressure stretches the walls of afferent
arteriole. In response, smooth muscle fibers in the wall of afferent arteriole
contract, which narrows the arterioles lumen. As a result renal blood flow leaves
thus reducing GFR to its previous level & vice versa.
The blood vessels of kidney are supplied by sympathetic ANS fibers that
release nor-epinephrine (NE). NE causes vasoconstriction through activation of
alpha1 receptor. At rest, sympathetic stimulation is moderately low & GFR is
normal. With moderate sympathetic stimulation both afferent & efferent
arterioles constricts to the same degree. Blood flow into & out of glomerular is
restricted to same extent, which decreases GFR slightly. With greater
sympathetic stimulation, vasoconstriction of afferent arteriole predominates. As a
result, blood flow through glomerular capillaries is greatly decreased & GFR
drops. This lowering of renal blood flow has two consequences
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In the epithelium of the tubules, the apex or luminal surface of each cell is surrounded
by a Zonula accludens , a specialized region of membrane that from a tight junction
between it & neiglbouring cells. The movement of ions & water through the cell and
between the cells through zonulae occludentes. The tightness or leakiness of the
epithelium of various portions of nephron is important factor in their function Tight
epithelium is found in dlistal portion of nephron which is the site of action of major
hormones involved in the control of NaCl & water excretion.
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About 60-70% filtered load of Na+& water is reabsorbed in PCT. The most
imp. mechanism for Na+ entry into the cell from the filtrate is the Na+/H+ exchanger.
Glucose , amino acids are also reabsorbed along with Na+. sodium is transported out
of the cell into the interstitial &then into the blood by primary active transport
mechanism of the nephron , the Na+/ K+/ATP –ase in basolateral membrame. Cl-
absorption is largely passive, some diffuses through zonula occludens . Bicarbonate is
returned to the plasma mainly in PTC. By an indirect method involving action of
carbonic anhydrase. Remaining 30-40% of the filtrate passes onto the Henle’s loop.
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The descending limb is highly permeable to water, which moves out passively.
In juxtamedullary nephrons with long loops, there is extensive movement of water
eventually reaching the tip of the loop has high osmolality.
The ascending limb has very low permeability to water that 20-30% of filtered
Na+ is reabsorbed Both Na+ & Cl- move into the cell by a co-transport system
involving Na+/ K+/2Cl-. This process is driven by the electrochemical gradient for Na+
produced by the Na+/ K+/ATP ase in the basolateral memberance. Most of the K+
taken into the cell by co-transport system cycles back to the lumen through potassium
chancel but some K+ is reabsorbed along with Mg+2& Ca2+. Loop of Henle is
sometimes referred as diluting segment because absorption of NaCl with very little
water result in marked dilution of filtrate .
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Several distal tubules empty into each collection tubule & the collection tubules join
to from collecting ducts. Collecting tubule has two diff. cell types –
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CLASSIFICATION (1 & C)
20%
100%
GFR 180 L/day
Plasma Na 145 mEq/L
Filtered Load 26,100 mEq/day
0.5%
Volume 1.5 L/day
Urine Na 100 mEq/L
Na Excretion 155 mEq/day
1. PCT
Osmotic diuretics-
2. Loop
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3. DCT
4. Collecting Duct
Aldosterone antagonists-
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anhydrase ,it further dissociates into H+ and HCO3- These HCO3- ions go to basolateral
membrane and H+ ion are exchanged with Na+ in the lumen . The filtered bicarbonate
ions are associated with H+ ions , which form H2CO3 which immediately
dissociates in CO2 and H2O ( requiring carbonic anhydrase activity ) which is
reabsorbed . This action is like a circuit, so bicarbonate ions are reabsorbed for every
H+ secretion .Carbonic anhydrase inhibitors act in this stage and there is loss of
NaHCO3 .
b) Therapeutic Uses
Carbonic anhydrase inhibitors are not used for their diuretic properties. Rather
these agents are used to reduce intraocular pressure in the treatment of glaucoma. This
is because these agents inhibit intraocular carbonic anhydrase and thus the formation
of aqueous humor. Carbonic anhydrase inhibitors are also used to treat epilepsy and
motion sickness.
(1&6)
THIAZIDE DIURETICS
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a. Mechanism of Action
Thiazide diuretics are secreted into the tubular fluid by proximal tubule
cells. These agents act in the distal convoluted tubule and block a Na+, Cr
symporter that is associated with the luminal membrane. This transport system
moves both Na+ and cr into the cell using the free energy produced by the Na+,
K+, ATPase. The Na+ is pumped out of the epithelial cell via this transport system
in the basolateral membrane. The Cl- exits the cell via a Cl channel. Because
thiazides are related in structure to carbonic anhydrase inhibitors, some of these
agents have weak carbonic anhydrase activity.
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The likelihood of side effects with the thiazides increases with the plasma
concentration of the drug. These drugs were introduced in the 1950s and early
clinical trials were carried out with high drug concentrations (200 mg/day)
designed to produce significant diuresis. As a consequence many side effects were
reported. However, more recently, clinical trials have showed that low doses of
thiazide diuretics (12-25 mg/day) are actually more effective than higher doses in
reducing cardiovascular events. The reported side effects are provided below. In
many instances the likelihood of observing a particular side effect and the severity
is dependent on the dose of diuretic. Potential side effects of diuretic drugs
include;
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d. Clinical Uses
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Furosemide
Ethacrynic Acid
Bumetanide
Torsemide
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a) Mechanism of Action
Like thiazides these agents must be secreted into the tubular fluid by
proximal tubule cells. In the thick ascending loop Na+ and Cl- reabsorption is
accomplished by a Na+, K+,Cl- symporter. The thick ascending limb has a high
reabsorptive capacity and is responsible for reabsorbing 25% of the filtered load
of Na+. The loop diuretics act by blocking this symporter. Because of the large
absorptive capacity and the amount of Na+ delivered to the ascending limb, loop
diuretics have a profound diuretic action. In addition, more distal nephron
segments do not have the reabsorptive capacity to compensate for this increased
load. The osmotic gradient for water reabsorption is also reduced resulting in an
increase in the amount of water excreted.
Loop diuretics cause a significant increase in Na+,K+ and Cl- excretion. Ca2+
and Mg2+ excretion are also enhanced. Loop diuretics block the Na+, K+, Cl-
symporter in the macula densa. As a result the tubuloglomerular feedback
mechanism is blocked & because of this loop diuretics maintain renal blood flow.
3. Hypotension
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Agents, such as probenecid, that block secretion into the into the distal tubule
will decrease the response to high ceiling diuretics.
d) Clinical Uses
(1&6)
POTASSIUM SPARING DIURETICS
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1. Na + Channel Inhibitors
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triamterene block the epithelial Na + channel. As a result the driving force for K+
secretion is eliminated, hence K+ secretion ceases, The diuretic effect is modest.
2. Aldosterone antagonists
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Osmotic Diuretics
Glycerin
Isosorbide
Mannitol
Urea
a) Mechanism of Action
Osmotic diuretics are freely filterable but not reabsorbed and prevent H20
reabsorption in the proximal tubule. Osmotic diuretics also extract H20 from systemic
body compartments. This expands extracellular fluid volume and increases renal blood
flow. This increase in blood flow removes NaCI and urea from the renal medulla. The
loss of these solutes decreases the medullary toxicity and hence the ability to generate
a concentrated urine.
c) Clinical Uses
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Osmotic diuretics maintain renal blood flow in patients with acute renal failure.
These agents can also be used to treat increases in intraocular pressure in glaucoma
as well as reduce cerebral edema.
(5)
PHARMACOKINETICS
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furosemide may be clinically important; patients with heart failure treated with a
completely absorbed loop diuretic (torsemide) may require hospitalization less
often and have a better quality of life than patients treated with furosemide. The
amount increased exposure to solute causes hypertrophy of distal nephron
segments, with concomitant increases in the reabsorption of sodium. Sodium that
escapes from the loop of Henle is therefore reabsorbed at more distal sites,
decreasing overall diuresis. The result is long-term tolerance of the loop diuretic.
(3)
DIURETIC RESISTANCE
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Other causes
• Poor absorption
Faced with resistance to loop diuretics, the clinician has several options:
1) Bed rest
2) Increase in dose
3) Combination therapy
(1)
1. Renal Insufficiency
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A frequent question is what is the largest single dose of a loop diuretic that
can be given to a patient with severe renal insufficiency? The maximal natriuretic
response occurs with intravenous bolus doses of 160 to 200 mg of furosemide or
the equivalent doses of bumetanide and torsemide, and nothing is gained by using
larger doses. Some patients may require these large doses several times a day. The
maximal response is the excretion of about 20 percent of filtered sodium. In a
patient with a creatinine clearance of 15 ml per minute, this means that about 25
mmol of sodium will be excreted. If the patient ingests 75 mmol of sodium per
day, then the single dose of 25 mmol to be excreted must be administered three
times per day, and sodium will be retained if the intake is higher. Single
intravenous bolus doses of 160 to 200 mg can occasionally cause transient tinnitus
but this effect can be minimized by administering the dose over a period of 20 to
30 minutes.
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the physician should administer larger oral doses of furosemide or a maximal oral
dose of either bumetanide or torsemide.
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100 mg of hydrochlorothiazide per day; those with more severe disease require
100 to 200 mg per day. Thiazides can be administered once or twice a day.
(1&6)
2. The Nephrotic Syndrome
(1&6)
3. Cirrhosis
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The mainstay of diuretic therapy for patients with cirrhosis who have edema is
spironolactone, because secondary hyperaldosteronism is an important cause of
sodium and water retention in such patients. Spironolactone causes only a moderate
diuresis, which is desirable because greater diuresis may compromise the
intravascular volume Even if patients need additional diuretics, spironolactone should
be continued Repeated large-volume paranthesis may be used to minimize the need
for more potent diuretics.
The initial dose of spironolactone is usually 50 mg per day. The drug and its
active metabolites have sufficiently long half-lives that once-daily administration is
adequate Its biologic half-life is such that three to four days of treatment are needed to
attain steady-state effects. The dose can be increased to as much as 400 mg per day,
although doses higher than 200 mg per day are often poorly tolerated.
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( 1, 5, 9 )
4. Congestive Heart Failure
Patients with edema caused by mild congestive heart failure should be treated
initially with a thiazide diuretic but most will require a loop diuretic. In patients with
normal or nearly normal renal function, the delivery of loop diuretics to the tubular
fluid is normal. The rate of absorption of loop diuretics is slowed in diuretic therapy
that may be increased by administering a mixture of albumin and a loop diuretic; in
several patients with severe hypoalbuminemia, an infusion of 30 mg of furosemide
mixed with 25 g of albumin enhanced diuresis. However, in most patients with the
nephrotic syndrome (and in those with cirrhosis ), renal tubular secretion of
furosemide is normal (unless the patient also has renal insufficiency), and combined
infusions are therefore unnecessary. This conclusion may not be applicable to patients
with serum albumin concentrations of less than 2 gm per deciliter. In such patients, it
may be reasonable to try combined infusions.
5. Hypertension: ( 6 )
Diuretics and or beta blockers are currently recommended as the first-line drug
therapy for hypertension. Low dose diuretic therapy is safe & effective in preventing
stroke, myocardial infarction, congestive heart failure & total mortality,
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Recent data suggest that diuretics are superior to beta blocker in older adults,
Clinically, the thiazides have long been mainstay of antihypertensive medication,
since they are inexpensive, convenient to administer, & well tolerated, 1< They are
effective in reducing systolic & diastolic blood pressure.
EVALUATION : ( 7 )
In vitro methods
In vivo methods
• Clearance methods
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Male Wistar rats weighing 100–200 g are used. Three animals per group are
placed in metabolic cages provided with a wire mesh bottom and a funnel to
collect the urine. Stainless-steel sieves are placed in the funnel to retain feces and
to allow the urine to pass. The rats are fed with standard diet (Altromin® pellets)
and water ad libitum. Fifteen hours prior to the experiment food and water are
withdrawn. Three animals are placed in one metabolic cage. For screening
procedures two groups of three animals are used for one dose of the test
compound. The test compound is applied orally at a dose of 50 mg/kg in 5.0 ml
water/kg body weight. Two groups of 3 animals receive orally 1 g/kg urea.
Additionally, 5 ml of 0.9% NaCl solution per 100 g body weight are given by
gavage. Urine excretion is recorded after 5 and after 24 h. The sodium content of
the urine is determined by flame photometry. Active compounds are tested again
with lower doses.
EVALUATION
Urine volume excreted per 100 g body weight is calculated for each group.
Results are expressed as the “Lipschitz-value”, i.e., the ratio T/U, in which T is the
response of the test compound, and U, that of urea treatment. Indices of 1.0 and
more are regarded as a positive effect. With potent diuretics, Lipschitz values
of2.0 and more can be found. Calculating this index for the 24 h excretion period
as well as for 5 h indicates the duration of the diuretic effect. Similar to urine
volume, quotients can be calculated for sodium excretion Dose-response curves
can be established using various doses. Loop diuretics are characterized by a steep
dose-response curve. Saluretic drugs, like hydrochlorothiazide, show Lipschitz
values around 1.8, whereasloop diuretics (or high ceiling diuretics) like
furosemide,bumetanide or piretanide reach values of 4.0 and more.
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PROCEDURE
Male Wistar rats weighing 100–200 g fed with standard diet (Altromin®
pellets) and water ad libitum are used. Fifteen hours prior to the test, food but not
water is withdrawn. Test compounds are applied in a dose of 50 mg/kg orally in
0.5 ml/100 g body weight starch suspension. Three animals are placed in one
metaboliccage provided with a wire mesh bottom and a funnel to collect the urine.
Two groups of 3 animals are used for each dose of a test drug. Urine excretion is
registered every hour up to 5 h. The 5-h urine is analyzed by flame photometry for
sodium and potassium and argentometrically by potentiometrical end point
titration(Chloride-Titrator Aminco) for chloride. To evaluate compounds with
prolonged effects the 24 h urine is collected and analyzed. Furosemide (25 mg/kg
p.o.),hydrochlorothiazide (25 mg/kg p.o.), triamterene(50 mg/kg p.o.), or
amiloride (50 mg/kg p.o.) are used as standards.
EVALUATION
The sum of Na+ and Cl– excretion is calculated as parameter for saluretic
activity.The ratio Na+/K+ is calcu lated for natriuretic activity. Values greater than
2.0 indicate a favorable natriuretic effect. Ratios greater than 10.0 indicate a
potassium-sparing effect.The ratio (ion quotient) is calculated to estimate carbonic
anhydrase inhibition. Carbonic anhydrase inhibition can be excluded at ratios
between 1.0 and 0.8. With decreasing ratios slight to strong carbonic anhydrase
inhibition can be assumed.
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Dogs have been extensively used to study renal physiology and the action of
diuretics. Renal physiology of the dog is claimed to be closer to man than that of
rats. Oral absorbability of diuretic substances can appropriately be studied in dogs.
Using catheters, interval collections of urine can be made with more reliability
than in rats. Simultaneously, blood samples can be withdrawn to study
pharmacokinetics.
PROCEDURE
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EVALUATION
Urine volume, electrolyte concentrations and osmolality are averaged for each
group. The values are plotted against time to allow comparison with pretreatment
values as well as with water controls and standards. The non-parametric U-test is
used for statistical analysis.
PROCEDURE
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obtained in the middle of each clearance period. After the control period,
compounds to be tested are administered and further clearance tests are
performed. Hydropenia is induced by withdrawing the drinking water 48 h before
experiment.
On the day before the experiment 0.5 U/kg body weight of vasopressin in oil
is injected intramuscularly. On the day of the experiment 20 mU/kg vasopressin is
injected i.v., followed by infusion of 50 mU/kg per hour vasopressin. To
accomplish constant urine flow 5% NaCl solution is infused at 1 ml/min per kg
body weight up to i.v. administration of a compound to be tested, followed by i.v.
infusion of 0.9% NaCl solution at a rate equal to the urine flow. Glomerular
filtration rate (GFR) and renal plasma flow (RPF) are measured by the clearance
of inulin and para-aminohippurate, respectively. Therefore, appropriate infusi on
of inulin (bolus of 0.08 g/kg followed by infusion of 1.5 mg/kg per min) and para-
aminohippurate (bolus 0.04 g/kg followed by infusion of 0.3 mg/kg per min) are
initiated. Inulin and para-aminohippurate are measured according to Walser et al.
(1955) and Smith and al (1945), respectively.
EVALUATION
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References
4. Pharmacology Fifth Edition H.P. Rang , M.M. Dale, J.M. Ritter, P.K. Moor.
354-358
Web Addresses:
a. www.sciencedirect.com
b. www.pubmed.com
c. www.diuretics.com
d. www.healthcenter.com
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