This document discusses the use of diuretics in congestive heart failure (CHF). It defines CHF and describes the signs, symptoms, and pathophysiology. The main therapeutic objectives for CHF are to relieve symptoms, enhance quality of life, prevent complications, and prolong life. Diuretics are effective for symptomatic relief in CHF patients with edema by rapidly relieving dyspnea. The document reviews the different classes of diuretics, their mechanisms of action, pharmacokinetic profiles, dosages, adverse effects, interactions, and considerations for resistance. Combination diuretic therapy can be effective for patients who do not respond to single agents.

1. USE OF DIURETICS IN CONGESTIVE
HEART FAILURE
Pharm. Jimmy Aiden
Pharmacy Department
Federal Teaching Hospital, Gombe
7th August, 2015

2. Table of Content
OVERVIEW OF CHF
 Definition
 Signs and Symptoms
 Pathophysiology
 Therapeutic objectives
 Rationale for diuretics use in CHF
DIURETICS
 Definition of class
 Types
 Mode of Actions

3. Table of content
 Structural Activity Relationship
 Indications
 Pharmacokinetic profile
 Dosage
 Adverse effects
 Interactions
DISCUSSION
CONCLUSION
CASE STUDY

4. OVERVIEW

5. Definition
 Congestive Heart Failure is a complex clinical
syndrome that can result from any structural or
functional cardiac disorder that impairs the ability of
the ventricle to fill with or eject blood.
It may be graded as mild, moderate, or severe
depending upon whether symptoms such as dyspnea
and fatigue appear on ordinary physical exertion, on
little exertion, or at rest, respectively.

6. Definition
Another grading system (that of the New York Heart
Association) has four grades (grades I, II, III, IV), again
partly classified on appearance of symptoms in
relation to exertion (with grade IV representing the
most severe form).

7. Signs & Symptoms
 LEFT SIDED HF
 Pulmonary edema
- Dyspnea(SOB)
-Paroxysmal nocturnal dyspnea
-Orthopnea
 Decreased forward perfusion
-Activation of RAAS
-Worsens CHF due to fluid
retention
(www.medical-institution.com)
 RIGHTSIDED HF
 Dyspnea(SOB)
 Jugular venous
distention(JVD)
 Pitting edema
 Ascites
 Hepatomegaly(Nutmeg
liver)

8. Pathophysiology
Goodman & Gilman, 2008

9. Therapeutic Objectives
Relieve symptoms
Enhance quality of life
Prevent complications
Prolong life

10. Rationale for the use of
Diuretics in CHF
 They provide very effective symptomatic control in
patients with peripheral or pulmonary oedema and
rapidly relieve dyspnoea.

11. DIURETICS

12. Definition of class
 A diuretic is any substance that promotes the
production of urine.
 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.
 All diuretics increase the excretion of water from
bodies, although each class does so in a distinct way.

13. Types of diuretics
 Thiazide & Thiazide-like diuretics
 Bendroflumethiazide,Hydrochlorothiazide, Chlortalidone,
Indapamide, Metalozone
 Loop diuretics
 Furosemide, ethacrynic acid, Torsemide, bumetanide
 Potassium- Sparing diuretics
 Amiloride, Triamterene
 Osmotic diuretics
 Mannitol
 Carbonic anhydrase inhibitor
 Acetazolamide

14. Mode of Actions

15. Mode of Actions
 Thiazide & Thiazide-like diuretics
 Inhibit Na+ reabsorption at
the distal convoluted tubule
by blocking the inhibit Na+
and Cl- transporter.
 Increased K+/ Mg2+ excretion
And decreases Ca2+ excretion

16. Mode of Actions
 Loop diuretics
 Inhibits the Na+/K+/2Cl-
transporter at the ascending loop
of Henle; interfers with chloride
binding cotransport system,
causing increased excretion of
water, sodium, chlorine,
magnesium, and calcium.
 They reduce lumen-positive
potential that comes from
K+ recycling.

17. Mode of Actions
 Potassium-Sparing diuretics
 Inhibition of Na+/K+
ATPase pump at the collecting
duct of the renal tubule.
 Decreases Ca2+, Mg2+ and
H+ excretion

18. Structural Activity Relationship
Thiazides
1) The 2-position can tolerate small alkyl groups as CH3.
2) Substitutents in the 3-position determine
the potency and duration of action of the thiazides.
3) Saturation of C-N bond between the 3 and 4 positions of the
benzothiadiazine-1,1-dioxide nucleus increases the potency
of this class of diuretics approximately 3-10 fold.
4) Direct substitution of the 4-, 5-, or 8-position with an alkyl group
usually results in diminished diuretic activity,
5) Substitution of the 6-position with an activating group is essential
for diuretic activity. The best substituent include Cl-, Br-, CF3-, and
NO2- groups.
6) The sulfamoyl group in the 7-position is essential for diuretic
activity.
S
NH
NCl
H2NO2S
R
O
O 1
2
3
45
6
7
8

19. Structural Activity Relationship
Thiazides

20. Structural Activity Relationship
Loop Diuretics
1) The substituent at the 1-position must be acidic, The carboxyl group
provides optimal diuretic activity, but other groups, as tetrazole, may have
respectable diuretic activity.
2) A sulfamoyl group in the 5-position is essential for optimal high-ceiling
diuretic activity.
3) The activating group (x-) in the 4-position can be Cl- or CF3-, a phenoxy-,
alkoxy-, anilino-, benzyl-, or benzoyl- group
H2NO2S
X
H
N
COOH
R
1
2
3
4
5
6 H2NO2S
X
COOH
N
R
5
4 3
2
1
6

21. Structural Activity Relationship
Loop Diuretics

22. • 2,4,7-Triamino-6-phenyl-pteridine
• Para-substitution of phenyl ring with (-OH group) increase
activity
• The phenyl group can be replaced by small heterocyclic rings
• The amino groups must be un-substituted.
• It has a structural similarity to folic acid and certain
dihydrofolate reductase inhibitors, but it has little, if any, of
their activities.
Structural Activity Relationship
Potassium Sparing
N
NN
N
H2N NH2
NH2
1
2
3
4
5
6
7
8
Triamterene

23. N
N
Cl
H2N
C
NH2
NH C
NH2
NH2
O
1
4
2
Cl-
+
35
6
- Over 25,000 agents were examined in an
Attempt to discover an antikaliuretic with no hormonal activity .
- Optimal diuretic activity is observed when
1- The 6 position is substituted with chlorine.
2- The amino group at 3 , 5 position are unsubstituted .
3- the guanidino nitrogen are not substituted with alkyl group .
Amiloride
Structural Activity Relationship
Potassium Sparing

24. Indications
 Edematous states
 Heart failure
 Kidney diseases
 Ascites associated with Hepatic cirrhosis
 Idiopatic edema
 Non-Edematous states
 Hypertension
 Nephrolithiasis
 Hypercalcemia
 Diabetes insipidus

25. Pharmacokinetic profile
 Thiazides & Thiazide-like diuretics
 Thiazides have onset of action of 1-2hrs and duration of action
of 12-18hrs.
 Thiazides-like diuretics like metalozone has an onset of action
of 1-2hrs while its action last for a duration of 12-24hrs.
 Effective in the treatment of sodium and water retention,
although there is generally a loss of action in renal failure
(GFR<25mL/min). Metolazone has an intense action when
added to a loop diuretic and is effective at low GFR.

26. Pharmacokinetic profile
 Loop Diuretics
 Oral: Onset of action 0.5-1hr,<1hr and Duration of action 4-
6hrs, <8hrs for Furosemide and Torsemide respectively.
 Parenteral: Onset of action 5min, 10min and duration of
action is 2hrs and <8hrs for Furosemide and Torsemide
respectively.
 Extensively bound to plasma proteins and are eliminated in
the urine by both glomerular filtration and tubular secretion.
 Approximately a third of an administered dose is excreted by
the liver into the bile, from where it may be eliminated in the
feces. Only small amounts of these compounds appear to be
metabolized by the liver.

27. Pharmacokinetic profile
 Potassium-Sparing Diuretics
 Both triamterene and amiloride are effective after oral
administration. Diuresis ensues within 2 to 4 hours after
administration, although a maximum therapeutic effect may
not be seen for several days.
 Both drugs cause a modest (2–3%) increase in Na and HCO3
excretion, a reduction in K and H loss, and a variable effect on
Cl elimination.
 Approximately 80% of an administered dose of triamterene is
excreted in the urine as metabolites; amiloride is excreted
unchanged.

28. Dosages in CHF
 Thiazide & Thiazide-like diuretics
 Bendroflumethiazide: 5-10mg daily with a maintenance dose
of 2.5-10mg 1-3 times weelky
 Hydrochlorothiazide: 25mg daily, increased to 50mg daily if
necessary. Elderly; 12.5mg daily
 Metolazone: 5-10mg daily, 2.5mg daily when in combination
with loop diuretics. May be increased to 20mg/day based on
response and tolerance

29. Dosages in CHF
 Loop diuretics
 Furosemide, Oral: 40mg daily, maintenance dose of 20-40mg
daily, may be increased to 80mg daily or more in resistant
oedema. May also be increased by 20-40mg q6-8hrs; not to
exceed 600mg/day (Medscape). IV: 20-40mg, may be
increased by 20mg step q2hrs, not to exceed 200mg/dose.
 Torsemide: Initially 10-20mg once daily, may be increased by
doubling dose until desired diuretic response is obtained.
Maximum daily dose is 200mg.

30. Dosages in CHF
 Potassium-Sparing Diuretics
 Amiloride: 10mg daily in 1 or 2 divided doses, adjusted
according to response to a maximum of 20mg daily when
used alone. 5mg daily increased to 10mg if necessary to a
maximum of 20mg daily when used in combination with
thiazide or loop diuretics.
 Triamterene: Dyazide® (Triamterene 50mg + HCT 25mg) :
1 tab twice daily after meals, may be increased to 3 tabs daily.
Maintenance dose of 1 tab daily or 2 tabs on alternate days.

31. Adverse effects
 Thiazide diuretics
 Orthostatic hypotension
 Hypokalemic metabolic acidosis
 Hyperuricaemia
 Impaired glucose tolerance
 Hyponatremia
 Hyperlipidemia
 Weakness, fatigability
 Allergic reactions
 Impotence

32. Adverse effects
 Loop diuretics
 Hypokalemic metabolic alkalosis
 Ototoxicity
 Hypersensitivity reactions e.g urticaria, fever,
interstitial nephritis
 Hyperuricaemia
 Hypomagnesemia
 Severe dehydration
 Hypercalcemia e.g. in oat cell lung carcinoma
 Severe hyponatremia

33. Adverse effects
 Potassium-Sparing diuretics
 Hyperkalemia
 Hyperchloremic metabolic acidosis
 Kidney stones

34. Interaction
Diuretic and Example Interacting drugs
Loop diuretics e.g. Furosemide Aminoglycoside antibiotics, Salicylate,
Lithium, Phenytoin ,Amiodarone
Thiazide & Thiazide-like diuretics e.g.
Hydochlorothiazide
NSAIDS, Lithium, Cholestyramine, Alcohol,
Carbamazepine
Potassium-Sparing Diuretics e.g. Amiloride Potassium supplements, Spironolactone,
Eplerenone, Lithium

35. Interaction
 Drug-Disease interaction
 Prostatism (Urinary retention/ incontinence)
 Hyperuricaemia (Exacerbation of gout)
 Liver cirrhosis (Encephalopathy)
 Drug-Food interaction
 Alcohol
 High cholesterol diet
 High Potassium containing foods (Potassium-Sparing
diuretics)

36. Diuretics Combinations
 Loop Agents & Thiazides
 Some patients are refractory to the usual dose of loop diuretics or
become refractory after an initial response . Since these agents have a
short half-life (2–6 hr.), refractoriness may be due to an excessive interval
between doses.
 Loop agents and thiazides in combination often produce diuresis when
neither agent alone is effective.
 Metolazone is the thiazide-like drug used in patients refractory to loop
agents alone
 The combination of loop diuretics and thiazides can mobilize large
amounts of fluid, even in patients who have not responded to single
agents. Close hemodynamic monitoring is essential and outpatient use is
not recommended. K+-wasting is extremely common and may require
parenteral K+ administration with careful monitoring of fluid and
electrolyte status.

37. Diuretic Combinations
Potassium-Sparing & Loop Agents or Thiazides
 Hypokalemia develops in many patients taking loop
diuretics or thiazides.
 This can be managed by NaCl restriction or taking KCl
supplements.
 If not treated, addition of a K+-sparing diuretic can
lower K+ excretion.
 This should be avoided in renal insufficiency and in
those receiving angiotensin antagonists in whom life-
threatening hyperkalemia can develop.

38. Diuretics Resistance
 The effectiveness of many diuretics ultimately depends on
establishing a negative Na+ balance to mobilize edema fluid,
restriction of dietary Na+ intake is generally an essential part
of diuretic therapy.
 Therefore, one cause of therapeutic failure or apparent
patient refractoriness to diuretics could be the patient’s
continued ingestion of large quantities of NaCl
 Many diuretics (e.g., thiazides and loop diuretics) must reach
the tubular lumen before they begin to be effective. Because
these compounds are organic acids and are bound to plasma
proteins, they reach the luminal fluid by secretion.

39. Diuretic Resistance
 Any disease condition or drug that impairs secretion will
affect the access of the diuretics to the luminal fluid and
hence to their ultimate site of action.
 .For example, renal dysfunction may lead to a buildup of
endogenous organic acids that decrease drug secretion and
thereby alter the patient’s expected response to the diuretic.
 The concomitant administration of other drugs that are
substrates for the organic acid secretory system (e.g.,
probenecid or penicillin) may result in an apparent resistance
to diuretic action.
 It should now be obvious that in addition to disease and
electrolyte imbalances, the pharmacodynamic handling of the
diuretics themselves may be a factor in diuretic resistance.

40. Conclusion
 Diuretics have been the mainstay in the treatment of heart
failure, and continue to have an important role. They provide
very effective symptomatic control in patients with peripheral
or pulmonary oedema and rapidly relieve dyspnoea. If
symptoms of fluid retention are only mild, a thiazide diuretic,
such as bendroflumethiazide or hydrochlorothiazide, may be
adequate. However, in most cases, especially in moderate or
severe fluid retention, a loop diuretic such as furosemide will
be necessary.
 Reduction in fluid intake (<2000mL in 24hrs) may be
necessary for CHF patients who experienced recurrent fluid
retention despite sodium restriction and use of diuretics.

41. Conclusion
 Edema associated with heart failure is generally managed with loop
diuretics. In some instances, salt and water retention may become
so severe that a combination of thiazides and loop diuretics is
necessary.
 In treating the heart failure patient with diuretics, it must always be
remembered that cardiac output in these patients is being
maintained in part by high filling pressures. Therefore, excessive
use of diuretics may diminish venous return and further impair
cardiac output. This is especially critical in right ventricular heart
failure.
 Loop diuretics are the most efficacious diuretics because:
– large NaCl absorptive capacity of Thick ascending loop of henle
– the diuretic action of these drugs is not limited by acidosis

42. References
 Goodman and Gilman’s Manual of Pharmacology and Therapeutics 2008
 Hunt SA et al. ACC/AAAHA guidelines for the evaluation and management
of CHF in the adult: Executive summary: A report of the American College
of Cardiology/American Heart Association Task Force on Practice
Guidelines. Circulation 2001;104:2996–3007
 Bleich M and Greger R. Mechanism of action of diuretics. Kidney Int
1997;51:S11–S15.
 Brater DC. The use of diuretics in congestive heart failure. Semin Nephrol
1994;14:479–482.
 Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319:38–50.
 Ellison DH. Diuretic drugs and the treatment of edema: From clinic to
bench and back again. Am J Kidney Dis 1994;23:623–643.
 Suki WN. Use of diuretics in chronic renal failure. Kidney Int 1997;51:S33–
S35.

43. THANK YOU

44. Case study
A 60 year-old woman with a history of HTN and MI was admitted
to the hospital with complaints of dyspnea and increased pitting
oedema of the lower extremities. She admitted to not adhering
to her sodium-restricted diet for several weeks and that her
weight has recently increased from her usual 55kg to 68kg. At
the time of her last physician visit, her serum sodium level was
135mEq/L and serum creatinine was 1.3mg/dL. Laboratory
results present on admission included hyponatremia (Na
128mEq/L), elevated blood urea nitrogen (BUN 75mg/dL), and
an elevated serum creatinine level (2.0mg/dL). She was
diagnosed with CHF secondary to HTN and MI. The patient was
managed with Tabs Furosemide 40mg daily, Tabs Lisinopril 5mg
daily, and Tabs Hydrochlorothiazide 25mg daily.

45. Case study
 Commentary
Fluid volume overload was evidenced by pitting oedema, an
acute weight gain and dyspnea. Both the fluid volume excess
and the hyponatremia were due to the patient’s worsening CHF.
The increased BUN(N: 6-23mg/dL) and creatinine levels (N:0.6-
1.5mg/dL) reflected a reduced GFR secondary to a decreased
cardiac output. The symptoms that caused the patient to seek
medical attention were dyspnea and oedema, both of which
were associated with worsening cardiac failure. Water intake
should be restricted until the serum sodium level normalized.
Discharge instruction should include information about her new
medications and the need to adhere to her sodium-restricted
diet.

46. QUESTIONS, COMMENTS &
CONTRIBUTIONS