From Knauf

1
Loop DiureticsLoop of Henle
ThiazidesDistal tubule
CA InhibitorsProximal tubule
5
Antikaliuretics
Thick Ascending Limb
70
4.5
Collecting duct
20
100GFR 180 L/day Plasma Na 145 mEq/LFiltered
Load 26,100 mEq/day
0.5 Volume 1.5 L/dayUrine Na 100 mEq/L Na
Excretion 155 mEq/day
From Knauf Mutschler Klin. Wochenschr. 1991
69239-250
2
Principles important for understanding effects of
diuretics

• Interference with Na reabsorption at one nephron
  site interferes with other renal functions linked
  to it
• It also leads to increased Na reabsorption at
  other sites
• Increased flow and Na delivery to distal nephron
  stimulates K (and H ) secretion

3
Principles important for understanding effects of
diuretics

• Diuretics act only if Na reaches their site of
  action. The magnitude of the diuretic effect
  depends on the amount of Na reaching that site
• Diuretic actions at different nephron sites can
  produce synergism
• All, except spironolactone, act from the lumenal
  side of the tubular cellular membrane

4
NH2
Prontosil
SO2 NH2
N
N
NH2
SO2NH2
NH2
Sulfanilamide
SO2NH2
Cl
SO2NH2
p-chlorobenzene sulfonamide
Cl
SO2NH2
SO2NH2
1,3 disulfonamide 6 cholrobenzene
SO2
Cl
N
Cholrothiazide
N
C
5
THIAZIDE DIURETICS

• Secreted into the tubular lumen by the organic
  acid transport mechanisms in the proximal tubule
• Act on the distal tubule to inhibit sodium and
  chloride transport and result in a modest
  diuresis
• Increase renal excretion of potassium, magnesium
• Reduce calcium and urate excretion
• Not effective at low glomerular filtration rates
• Impair maximal diluting but not maximal
  concentrating ability

6
General Structure of Thiazide Diuretics
7
Inhibition of high-affinity 3H-metolazone binding
by ions
Ion Control
NaF 1439
LiCl 41
NaCl 200.5
KCl 442
Choline chloride 367
NaBr 242
NaI 251
KI 122
Na acetate 825
K acetate 955
Disodium sulfate 15222
Dipotassium sulfate 11812
Trisodium citrate 1125
Data from Beaumont et. Al. Thiazide diuretic
drug receptors in rat kidney identification with
3Hmetolazone. Proc. Natl. Acad. Sci. USA 1988,
852311-2314.
8
Correlation of the daily clinical doses of
thiazide diuretics with their affinity for
high-affinity 3H-metolazone binding sites in rat
kidney. Correlation coefficient r0.7513.
From Beaumont et al. Thiazide diuretic drug
receptors in rat kidney identification with
3Hmetolazone. Proc. Natl. Acad. Sci. USA 1988,
852311-2314.
9
Thiazides - Pharmacokinetics

• Rapid GI absorption
• Distribution in extracellular space
• Elimination unchanged in kidney
• Variable elimination kinetics and therefore
  variable half-lives of elimination ranging from
  hours to days.

10
CLINICAL USES Of THIAZIDES-1

• 1) HYPERTENSION
• Thiazides reduce blood pressure and associated
  risk of CVA and MI in hypertension
• they should be considered first-line therapy in
  hypertension (effective, safe and cheap)
• Mechanism of action in hypertension is uncertain
  involves vasodilation that is not a direct
  effect but a consequence of the
  diuretic/natriuretic effect

11
Schematic drawing of temporal changes in mean
arterial pressure (MAP), total peripheral
vascular resistance (TPR), cardiac output (CO)
and plasma volume (PV) during thiazide treatment
of a hypertensive subject
From Birkenhäger, WH Diuretics and blood
pressure reduction physiological aspects. J.
Hyperten. 1990, 8 (Suppl 2) S3-S7.
12
From Birkenhäger, WH Diuretics and blood
pressure reduction physiological aspects. J.
Hyperten. 1990, 8 (Suppl 2) S3-S7.
13
From Birkenhäger, WH Diuretics and blood
pressure reduction physiological aspects. J.
Hyperten. 1990, 8 (Suppl 2) S3-S7.
14
CLINICAL USES OF THIAZIDES-2

• 2) EDEMA (cardiac, liver renal)
• 3) IDIOPATHIC HYPERCALCIURIA
• condition characterized by recurrent stone
  formation in the kidneys due to excess calcium
  excretion
• thiazide diuretics used to prevent calcium loss
  and protect the kidneys
• 4) DIABETES INSIPIDUS

15
ADVERSE EFFECTS OF THIAZIDES-1

• Initially, they were used at high doses which
  caused a high
• incidence of adverse effects. Lower doses now
  used cause
• fewer adverse effects. Among them are
• HYPOKALEMIA
• DEHYDRATION (particularly in the elderly) leading
  to POSTURAL HYPOTENSION
• HYPERGLYCEMIA possibly because of impaired
  insulin release secondary to hypokalemia
• HYPERURICEMIA because thiazides compete with
  urate for tubular secretion

16
ADVERSE EFFECTS OF THIAZIDES-2

• HYPERLIPIDEMIA mechanism unknown but cholesterol
  increases usually trivial (1 increase)
• IMPOTENCE
• HYPONATREMIA due to thirst, sodium losloss,
  inappropriate ADH secretion (can cause confusion
  in the elderly), usually after prolonged use

17
ADVERSE EFFECTS OF THIAZIDES-3

• Less common problems
• HYPERSENSITIVITY - may manifest as interstitial
  nephritis, pancreatitis, rashes, blood dyscrasias
  (all very rare)
• METABOLIC ALKALOSIS due to increased sodium load
  at the distal convoluted tubule which stimulates
  the sodium/hydrogen exchanger to reabsorb sodium
  and excrete hydrogen
• HYPERCALCEMIA

18
LOOP DIURETICS

• Secreted in proximal tubule by acid mechanisms
• Act on the ascending loop of Henle to inhibit
  sodium and chloride transport
• Cause a greater natriuresis than thiazides
• Effective at low glomerular filtration rates (as
  occur in chronic renal failure), where thiazides
  are ineffective
• Increase potassium, calcium and magnesium
  excretion
• Decrease urate excretion
• Impair maximal concentrating and diluting capacity

19
From Martinez-Maldonado, M, and Cordova, HR
Cellular and molecular aspects of the renal
effects of diuretic agents. Kidney Int. 1990,
38632-641.
20
LOOP DIURETICS

• Additional non-tubular effects
• 1. Renal Vasodilation and redistribution
  of blood flow
• 2. Increase in renin release
• 3. Increase in venous capacitance
• These effects mediated by release of
  prostaglandins from the kidney.

21
From Brater, DC. Pharmacodynamic considerations
in the use of diuretics. Ann. Rev. Pharmacol.
Toxicol 1983, 2345-62.
22
Loop Diuretics - Pharmacokinetics

• Rapid GI absorption. Also given i.m. and i.v.
• Extensively protein bound in plasma
• Short half-lives in general
• Elimination unchanged in kidney or by
  conjugation in the liver and secretion in bile.

23
From Brater, DC. Pharmacodynamic considerations
in the use of diuretics. Ann. Rev. Pharmacol.
Toxicol 1983, 2345-62.
24
CLINICAL USES OF LOOP DIURETICS

• EDEMA due to CHF, nephrotic syndrome or cirrhosis
• Acute heart failure with PULMONARY EDEMA
• HYPERCALCEMIA
• not in widespread use for the treatment of
  hypertension (except in a few special cases e.g.
  hypertension in renal disease)

25
Adverse Effects of Loop Diuretics similar to
thiazides in many respects

• Hypokalemia, metabolic alkalosis,
  hypercholesterolemia, hyperuricemia,
  hyperglycemia, hyponatremia
• Dehydration and postural hypotension
• Hypocalcemia (in contrast to thiazides)
• Hypersensitivity
• OTOTOXICITY (especially if given by rapid IV
  bolus)

26
Edema Therapeutic Considerations

• Therapy is palliative (except with pulmonary
  edema).
• Need a mild sustained response.
• Specific consideration to potassium homeostasis,
  i.e. supplement with K-salt or use K-sparing
  diuretic.
• Therefore, in most cases start with a thiazide.
• If resistant, move to Loop diuretic.

27
FE Na ()
From Brater, DC. Pharmacology of Diuretics. Am.
J. Med. Sci. 2000, 31938-50.
28
Conditions treated with Diuretics

• Edema
• Hypertension
• Nephrogenic Diabetes Insipidus
• Syndrome of Inappropriate ADH Secretion (SIADH)
• To increase or decrease Ca, K or H ion
  excretion.

29
Diuretic Resistance

• Compensatory Mechanisms (RAAS, SNS)
• Failure to reach tubular site of action
• a - Decreased G.I. absorption
• b - Decreased secretion into tubular lumen
• (e.g. uremia, decreased kidney perfusion)
• c - Decreased availability in tubular lumen
• (e.g. nephrotic syndrome)
• Interference by other drugs (e.g. NSAIDs)
• Tubular adaptation (chronic Loop diuretic use)
• Can Use Combination of Diuretics
• to Induce a Synergistic Effect

30
Maximum Doses of Loop Diuretics
Clinical Condition Dose of furosemide (mg) Dose of furosemide (mg)
intravenous Oral
Renal Insufficiency 0 lt ClCr lt 50 80 160
Renal Insufficiency ClCr lt 20 200 400
Nephrotic Syndrome 120 240
Cirrhosis 40 80
Congestive Heart Failure 40-80 80-160
Data from Brater, DC. Pharmacology of Diuretics.
Am. J. Med. Sci. 2000, 31938-50.