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USE OF DIURETICS IN CONGESTIVE HEART FAILURE
Pharm. Jimmy AidenPharmacy Department
Federal Teaching Hospital, Gombe7th August, 2015
Table of ContentOVERVIEW OF CHF Definition Signs and Symptoms Pathophysiology Therapeutic objectives Rationale for diuretics use in CHFDIURETICS Definition of class Types Mode of Actions
Table of content Structural Activity Relationship Indications Pharmacokinetic profile Dosage Adverse effects InteractionsDISCUSSIONCONCLUSIONCASE STUDY
OVERVIEW
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.
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).
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)
Pathophysiology
Goodman & Gilman, 2008
Therapeutic Objectives
Relieve symptomsEnhance quality of lifePrevent complicationsProlong life
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.
DIURETICS
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.
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
Mode of Actions
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
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 ofwater, sodium, chlorine, magnesium, and calcium.
They reduce lumen-positive potential that comes from K+ recycling.
Mode of Actions
Potassium-Sparing diuretics Inhibition of Na+/K+
ATPase pump at the collectingduct of the renal tubule.
Decreases Ca2+, Mg2+ andH+ excretion
Structural Activity RelationshipThiazides
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.
SNH
NCl
H2NO2S
R
OO 1
2
3
456
7
8
Structural Activity RelationshipThiazides
Structural Activity RelationshipLoop 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
XHN
COOH
R
1
2
34
5
6 H2NO2S
X
COOH
N
R
5
4 32
1
6
Structural Activity RelationshipLoop Diuretics
• 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 RelationshipPotassium Sparing
N
NN
N
H2N NH2
NH2
12
3
456
78
Triamterene
N
N
Cl
H2N
C
NH2
NH C
NH2NH2
O
1
4
2
Cl-+
35
6
- Over 25,000 agents were examined in anAttempt 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 RelationshipPotassium Sparing
Indications
Edematous states Heart failure Kidney diseases Ascites associated with Hepatic cirrhosis Idiopatic edema Non-Edematous states Hypertension Nephrolithiasis Hypercalcemia Diabetes insipidus
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.
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.
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.
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
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.
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.
Adverse effects
Thiazide diuretics Orthostatic hypotension Hypokalemic metabolic acidosis Hyperuricaemia Impaired glucose tolerance Hyponatremia Hyperlipidemia Weakness, fatigability Allergic reactions Impotence
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
Adverse effects
Potassium-Sparing diuretics Hyperkalemia Hyperchloremic metabolic acidosis Kidney stones
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
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)
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.
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.
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.
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.
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.
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
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.
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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.
Case study
CommentaryFluid 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.
QUESTIONS, COMMENTS & CONTRIBUTIONS
