2. Diuretics
Agents which promote the formation of
urine by the kidney
Greek "dia-", thoroughly +
"ourein", to urinate
= to urinate thoroughly.
3. ALLHAT trial (JAMA. 2002;288:2981-
2997)
randomized, double-blind, active-
controlled clinical trial
February 1994 through March 2002.
Inclusion:
◦ 33357 participants
◦ 55 years or older with hypertension
◦ at least 1 other CHD risk factor
◦ 623 North American centers.
4. ALLHAT trial
Intervention: Randomised to receive
◦ chlorthalidone, 12.5 to 25 mg/d (n=15255);
◦ amlodipine, 2.5 to 10 mg/d (n=9048);
◦ lisinopril, 10 to 40 mg/d (n=9054)
Doxazosin arm was prematurely terminated
Follow-up of approximately 4 to 8 years.
Primary outcome: combined fatal CHD or
nonfatal MI
Secondary outcomes: all cause
mortality, stroke, combined CHD (primary
outcome, coronary revascularization, or
angina with hospitalization), and combined
CVD (combined CHD, stroke, treated angina
without hospitalization, heart failure [HF], and
peripheral arterial disease).
5. ALLHAT trial-Results
Primary end points: no difference
All cause mortality: no difference
Five-year systolic blood pressures were
significantly higher in the amlodipine
(P=.03) and lisinopril (P.001) groups
compared with chlorthalidone
Amlodipine vs chlorthalidone: secondary
outcomes were similar except for a
higher 6-year rate of HF with amlodipine
Lisinopril vs chlorthalidone : lisinopril had
higher 6-year rates of combined CVD
6. ALLHAT trial
Conclusion:
“Thiazide-type diuretics are superior in
preventing 1 or more major forms of
CVD and are less expensive. They
should be preferred for first-step
antihypertensive therapy.”
Fallout:
JNC 7 hypertension guidelines
recommended that thiazides should
be the first line antihypertensive
7. Hypertension in CKD
50% to 75% of individuals with GFR
60 mL/min/1.73 m2 (CKD Stages 3-5)
have hypertension.
Central role of kidney in BP
homeostasis: Guyton’s Hypothesis
9. Mechanism of Na retention in
CKD
Decreased filtered
load of Na
Sodium
and fluid
overload
Increased
compensatory
retention in tubules
Patients with CKD have a 10 to 30% increase in
extracellular and blood volume, even in the absence of
overt edema Am J Med 72: 536–550, 1982
10. Diuretics as Antihypertensives in
CKD
Facilitates responses to other
Antihypertensives
Decreased Increased Reverses
Lowering
tubular Na Na ECF
BP
absorption excretion expansion
Salt Restriction
14. Loop diuretics
Bumetanide and torsemide have
better oral bioavailability than
furosemide —› doubling oral dose of
furosemide
Vd inversely varies with albumin
concentration
50% furosemide metabolized by
kidney(glucuronidation)
Torsemide and bumetanide
metabolized exclusively in liver
15. Loop diuretics
Duration of action:
torsemide >furosemide>bumetanide
In CKD:
◦ t½ of furosemide is prolonged:
accumulates leading to toxicity,
◦ Fe of unchanged drug increases: greater
natriuresis
◦ Renal clearance of active LD decreased
in prop to CCl
16. Loop diuretics
In CKD:
◦ Competition for luminal transport with
other OA (eg urate)
◦ Metabolic acidosis decreases tubular
secretion
◦ Hypoalbuminemia: increases metabolism
in S1 segment and decreases tubular
secretion in S2 segment of PT
18. Thiazide and thiazide like
diuretics
?Class effect as antihypertensives
Decreases Ca excretion
Decreases urate clearance
Impairs maximal urinary dilution but not
maximal concentration, along with
increases AQP2 expression, makes
hyponatremia 12 times more common
than loop diuretics.
19. Thiazide and thiazide like
diuretics
In CKD:
◦ Poor diuretics when CCl <30ml/min
◦ Indapamide and bendroflumethiazide are
metabolized in the liver: limits
accumulation in renal failure
◦ Metolazone found to have synergistic
action with loop diuretics in very low GFR
even where other thiazides are not very
effective
20. Potassium Sparing Diuretics
Amiloride and triamterine are organic
cations
AR antagonists are competitive
antagonists
These drugs produce only modest
natriuresis
More effective than furosemide in
cirrhotic ascites
21. Potassium Sparing Diuretics
In CKD:
◦ Not very useful as primary drugs
◦ Can be of adjunctive use in resistant
hypertension
◦ Hyperkalemia is a dreaded complication
◦ May reduce proteinuria in CKD (?retards
disease progression)
Kidney Int. 2006 Dec;70(12):2116-23.
◦ Has role in preventing cardiac remodeling
22. Misc. diuretics
Osmotic Diuretics:
◦ have been tried in ARF
◦ In CKD-can cause expansion of
ECV, hemodilution, MA, can ppt ARF in
high doses
CAI:
◦ Development of life threatening MA limits
use in CKD
25. Diuretic Resistance in CKD
Highdietary intake of sodium (i.e.
Urinary Na >100mmol/day)
Pharmacokinetics:
Decreased delivery
Decreased secretion in PT by OAT-1
Intratubular binding of secreted
diuretic to filtered albumin.
26. Diuretic Resistance in CKD
Pharmacodynamics:
Reduced number of functioning
nephrons and decreased Na filtered
load
Diuretic Braking phenomenon
27. Braking Phenomenon
Postdiuretic fluid and Na retention
Compensation by Na retaining
hormones/ upregulation of ion
transporters along the TALH/
Structural and functional changes in
the distal nephron segments
Co-administration with thiazide-
supraadditive (sequential duiretic
28. Braking Phenomenon
Clinical implications of this
phenomenon:
◦ Salt retention should always be advised in
all patients who are on diuretics
◦ Addition of a second diuretic increases
natriuresis
◦ Use of a long acting drug /more frequent
/iv administration has more effect
◦ Diuretic therapy should not be stopped
abruptly unless Na intake is curtailed
31. Newer agents
Adenosine type I receptor antagonists:
◦ Disrupts TGF and GTF and thus decreases
proximal resorption and increases GFR
◦ Used in diuretic resistant CHF
◦ Use in CKD is equivocal
Vasopressin Antagonists:
◦ Vaptans(conivaptan, tolvaptan, lixivaptan)
◦ Allows free water loss without natriuresis
◦ Predominantly used to treat eu/hypervolemic
hyponatremia
32. KDOQI GUIDELINE 12: USE OF DIURETICS
IN CKD
12.1 Most patients with CKD should be
treated with a diuretic (A).
12.1.a Thiazide diuretics given once daily
are recommended in patients with GFR
≥30 mL/min/1.73 m2 (CKD Stages 1-3) (A);
12.1.b Loop diuretics given once or twice
daily are recommended in patients with
GFR <30 mL/min/1.73 m2 (CKD Stages 4-5)
(A);
33. KDOQI GUIDELINE 12: USE OF
DIURETICS IN CKD
12.1.c Loop diuretics given once or twice
daily, in combination with thiazide
diuretics, can be used for patients with
ECF volume expansion and edema (A).
12.1.d Potassium-sparing diuretics should
be used with caution:
◦ 12.1.d.i In patients with GFR <30 mL/min/1.73
m2 (CKD Stages 4-5) (A);
◦ 12.1.d.ii In patients receiving concomitant
therapy with ACE inhibitors or ARBs (A);
◦ 12.1.d.iii In patients with additional risk
factors for hyperkalemia (A).
34. KDOQI GUIDELINE 12: USE OF
DIURETICS IN CKD
12.2 Patients treated with diuretics should be
monitored for:
◦ 12.2.a Volume depletion, manifest by hypotension
or decreased GFR (A);
◦ 12.2.b Hypokalemia and other electrolyte
abnormalities (A).
◦ 12.2.c The interval for monitoring depends on
baseline values for blood pressure, GFR and
serum potassium concentration
12.3 Long-acting diuretics and combinations
of diuretics with other antihypertensive
agents should be considered to increase
patient adherence (B).
Guytons hypothesis; all mechanisms are one way or the other linked to decreasing the filtered load of Na which causes a secondary increase in SVR and hypertension
91-99% bound to albumin
Met acidosis causesdepolarisation of memb potential of PT cells which decreases OA transport.
Na decreases intracellularly, increases Na-Ca exchange in the basolateralDecreasedClintracellularly, increase abs of Ca via TRPV5Increased prox abs of Ca due to Ecv depletionLoop causes Ca loss due to decrease lumen positivityUratecl is dec due to ECV depletion and competition for tubular uptake: loop initially causes increase excretion due to decrease abs initially from prox but later causes decreased clearance due to volume depletion
ARF ppt by vasoconstriction,
Decreased delivery is due to decreased blood flow (renal perfusion) and wider Vd due to hypoalbuminemiaDecreased secretion is due to competition due to metabolic acidosis and accumulated organic anions(urates)
To overcome this compensation loop Diu must be administered continuouslyCell hypertrophy of the DCT and CD in presence of aldosterone, increased no of thiazide sensitive co-transporters in the apical membrane and Na-K ATPase in basolateral