Title: From Knauf
1Loop 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
2Principles 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
3Principles 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
4NH2
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
5THIAZIDE 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
6General Structure of Thiazide Diuretics
7Inhibition of high-affinity 3H-metolazone binding
by ions
Data from Beaumont et. Al. Thiazide diuretic
drug receptors in rat kidney identification with
3Hmetolazone. Proc. Natl. Acad. Sci. USA 1988,
852311-2314.
8Correlation 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.
9Thiazides - 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.
10CLINICAL 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
11Schematic 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.
12From Birkenhäger, WH Diuretics and blood
pressure reduction physiological aspects. J.
Hyperten. 1990, 8 (Suppl 2) S3-S7.
13From Birkenhäger, WH Diuretics and blood
pressure reduction physiological aspects. J.
Hyperten. 1990, 8 (Suppl 2) S3-S7.
14CLINICAL 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
15ADVERSE 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
16ADVERSE 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
17ADVERSE 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
18LOOP 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
19From Martinez-Maldonado, M, and Cordova, HR
Cellular and molecular aspects of the renal
effects of diuretic agents. Kidney Int. 1990,
38632-641.
20LOOP 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.
21From Brater, DC. Pharmacodynamic considerations
in the use of diuretics. Ann. Rev. Pharmacol.
Toxicol 1983, 2345-62.
22Loop 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.
23From Brater, DC. Pharmacodynamic considerations
in the use of diuretics. Ann. Rev. Pharmacol.
Toxicol 1983, 2345-62.
24CLINICAL 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)
25Adverse 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)
26Edema 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.
27FE Na ()
From Brater, DC. Pharmacology of Diuretics. Am.
J. Med. Sci. 2000, 31938-50.
28Conditions treated with Diuretics
- Edema
- Hypertension
- Nephrogenic Diabetes Insipidus
- Syndrome of Inappropriate ADH Secretion (SIADH)
- To increase or decrease Ca, K or H ion
excretion.
29Diuretic 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
30Maximum Doses of Loop Diuretics
Data from Brater, DC. Pharmacology of Diuretics.
Am. J. Med. Sci. 2000, 31938-50.