Heart Failure [HF]

1
Heart Failure HF
2
Definition of HF

• 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
• As a consequence the heart
  fails to pump sufficient blood to meet the body's
  metabolic needs.

3
Cardiovascular consequences of heart failure.
4
Diagnosis of HF Signs and symptoms
Arterial Peripheral hypoperfusion Cardiac Cardiomegaly Venous congestion
Fatigue Pallor Renal impairment Confusion Circulatory failure Dilation Tachycardia Regurgitation Cardiomyopathy Ischemia, arrhythmias Dyspnea Oedema Hypoxia Hepatomegaly Raised venous pressure
5
Hepatojugular reflux
6
Investigations of HF
7
Investigations of HF
comment Investigation
To assess respiratory gas exchange Blood gas analysis
Plasma BNP likelihood of a diagnosis of HF screening test Fasting blood glucose for DM Full blood count for anemia Renal function testsserum urea and creatinine Liver function tests AST, ALT enzymes Thyroid function tests for thyrotoxicosis Blood test
8
Investigations of HF
comment Investigation
For - enlarged cardiac shadow - consolidation in the lungs Chest radiography X-ray
For arrhythmias left or right ventricular hypertrophy Abnormal ECG requires furhter investigations ECG electrocardiography
Confirm the diagnosis of heart failure and any underlying cause e.g. valvular heart disease Echocardiography
9
DD of Dyspnea shortness of breath

• Cardiac
• Heart failure
• Angina retrosternal pain radiates to arm and
  jaw-pain ppt by exertion, relieved by rest
• Pulmonary embolism acute dyspnea- hemoptysis
  diagnosed by pulmonay angiography
• Pulmonary hypertension Ausc. accentuated 2nd
  heart sound- dullness in the 2nd intercostal
  space
• Other causes
• Respiratory disease bronchitis longer in
  duration- normal heart and ECG exam. diffuse
  rhonchi
• Anemia CBC
• Obesity BMI and normal chest and heart
  examination
• History of Drug intake ?-blockers in asthmatic
  patient- exacerbation of heart failure by
  ?-blockers, NSAIDS, Diltiazem

10
DD of generalized edema

• Cardiac occurs in the dependent parts of the
  body ankle, sacral- bilateral pitting
  edema-edema of LL preceeds ascites
• Renal nephritic or nephrotic syndrome, first
  appears in eye lids and is associated with
  polyurea or oliguria-hematuria
• Hepatic edema of LL and ascites features of
  liver cirrhosis cirrhosis- splenomegaly-
  jaundice
• Nutritional long history of inadequate diet or
  diarrhea. First in LL associated with features of
  nutritional deficiency
• Drugs fluid retention from steroids, NSAIDs,
  nifedipine and amlodipine CCBs

11
Goals and guidelines of therapy

• The ACC/AHA Task Force recommends that most
  patients with HF should be routinely managed with
  a combination of four types of drugs
• A Diuretic,
• An ACE Inhibitor,
• A ?-adrenergic Blocker,
• And (Usually) Digitalis.
• An Aldosterone Antagonist (E.G., Spironolactone)
  Is A Fifth Class Of Drug Recommended For Patients
  With Advanced HF.

12
Goals and guidelines of therapy

• The ultimate goal is to
• prolong survival in individuals
• and reduce mortality rates within the population
  of patients with HF.
• Short of a heart transplant, none of the
  treatment measures are curative.

13
Main guidelines of therapy

• medical management of HF includes
• correction of underlying disease states (e.g.,
  hypertension, ischemic heart disease,
  arrhythmias, lipid disorders, anemia, or
  hyperthyroidism)
• moderate physical activity
• immunization with influenza and pneumococcal
  vaccines to reduce the risk of respiratory
  infections, and discontinuation of possible
  drug-induced causes.
• A sodium-restricted diet and diuretics are
  required if fluid retention is evident.
• Amiodarone is indicated in the treatment of
  symptomatic ventricular tachycardia and atrial
  fibrillation associated with HF.

14

• MANAGEMENT
• OF
• HEART FAILURE

15
Physical Activity

• Edema can be minimized by use of elastic stocks
• During acute exacerbations, bed rest and
  restricted physical activity
• Renal perfusion is increased in the prone
  position, resulting in diuresis

16
Sodium-Restricted Diet

• In patients with hypertension or evidence of
  fluid retention, but is not required in all
  patients.
• Dietary sodium can be reduced to 2 to 4 g of NaCl
  is more palatable and leads to better adherence
  than a severely salt-restricted diet.

17
Drug therapy of HF
18
Ion movements during the contraction of cardiac
muscle. ATPase adenosine triphosphatase.
19
1-Diuretics in HF

• are indicated in patients with circulatory
  congestion (pulmonary and peripheral edema)
  and/or cardiac distension (enlarged heart on
  chest radiograph).
• They produce symptomatic relief more rapidly than
  other drugs for HF.
• However, monotherapy with diuretics is
  discouraged, diuretics should be combined with an
  ACE inhibitor and a ß-blocker unless
  contraindications exist.

20
1-Diuretics in HF

• By enhancing renal excretion of sodium and water,
  diuretics diminish vascular volume, thus
  relieving ventricular and pulmonary congestion
  and decreasing peripheral edema.
• If diuresis is too vigorous, intravascular volume
  depletion
• hypotension
• paradoxical decrease in CO
• Weight loss exceeding 1 kg/day is to be avoided
  except in patients with acute pulmonary edema.

21
1-Diuretics in HF

• Diuresis after IV administration
• The onset of response after an IV injection of
  loop diuretics is 10 minutes or less,
• peaking within the first 30 minutes,
• and usually abating within 2 hours.
• Diuresis after oral administration
• usually begins 30 to 90 minutes after the oral
  administration of loop diuretics
• it peaks within the first or second hour
• and lasts for 6 to 8 hours.

22
Monitoring Parameters with Diuretics
? CHF symptoms Weight loss not more than 1 Kg/day ideal weight achieved
Signs of volume depletion    Hypotension ? CO Weakness  , dizziness,    ? Urine output
23
Aldosterone Antagonists (e.g., eplerenone and
spironolactone)

• The Randomized Aldactone Evaluation Study
  Investigators found that
• protective effect of spironolactone was related
  more to a reduction in aldosterone-induced
  vascular damage and myocardial or vascular
  fibrosis than to its diuretic effect.
• Similarly, with 25 to 50 mg of eplerenone
  reduced mortality was observed in patients with
  left ventricular dysfunction following a recent
  MI
• NO EVIDENCE that the direct acting potassium
  sparing diuretics amiloride or triamterene exert
  a similar protective effect.

24
2-Angiotensin-Converting Enzyme Inhibitors

• Drugs with vasodilating properties have become a
  primary treatment modality of HF.
• Arterial dilation provides symptomatic relief of
  HF by decreasing arterial impedance (afterload)
  to left ventricular outflow.
• Venous dilation decreases left ventricular
  congestion (preload).
• The combination of these two properties provides
  additive benefits to alleviate the symptoms of HF
  and increase exercise tolerance.

25
Angiotensin-Converting Enzyme Inhibitors

• ACE inhibitors are not only vasodilators but they
  also favorably modify cardiac remodeling
• they have a more tolerable side effect profile.
• they slow the rate of mortality in HF more than
  the hydralazine-nitrate combination
• These advantages, led ACC/AHA to recommend ACE
  inhibitors as the drugs of choice for initial
  therapy,

26
2- Angiotensin-Converting Enzyme Inhibitors

• The 2001 ACC/AHA guidelines state
• ACE inhibitors should be prescribed to all
  patients with HF due to left ventricular systolic
  dysfunction unless they have a contradiction to
  their use or have been shown to be unable to
  tolerate treatment with these drugs.
• ACE inhibitors should not be prescribed without a
  diuretic in patients with current or recent
  history of fluid retention. prescribers should
  ensure that the appropriate doses of diuretics
  before and during treatment with these drugs.
• Their value in diastolic failure still is being
  investigated.

27
Effect of enalapril on the mortality of patients
with congestive heart failure.
28
2- The Angiotensin Receptor Blockers ARBs

• A related class of drugs are the angiotensin
  receptor inhibitors (candesartan Atacand,
  eprosartan Teveten, irbesartan Avapro,
  losartan Cozaar, olmesartan Benicar,
  telmisartan Micardis, and valsartan (Diovan).
• Advantages over ACEIs
• The receptor inhibitors offer theoretic
  advantages over ACE inhibitors by being
• more specific for angiotensin II blockade
• with a lower risk of drug-induced cough.

29
ARBs

• Mechanism of action
• Block Ang II receptor type I
• Advantages over ACEIs
• Does not block type II angiotensin II receptors ?
  so maintain antiproliferative and VD effect
• Bradykinin is converted to kinins so no dry cough
  
• Disadvantages against ACEIs
• No action on type IV angiotensin II receptor?
  thrombotic tendency
• No maintainance of bradykinin ? no additional VD

30
2-The Angiotensin Receptor blockers ARBs

• Advantages of ACEIs over ARBs
• More importantly, there is evidence that ACE
  inhibitors have a more favorable effect on
  prevention of cardiac remodeling by unclear
  mechanisms.
• Currently, ARBs are reserved for use in those who
  fail to tolerate ACE inhibitors (e.g., angioedema
  or intractable cough) or during pregnancy.

31
The Angiotensin Receptor blockers ARBs

• Clinical trials on ARBs
• Preliminary results of clinical trials with
  several of the angiotensin-receptor blockers
  (ARBs) have been encouraging, but more data are
  needed relative to their effects on restricting
  cardiac remodeling and reducing mortality.
• There have been more clinical trials with
  losartan, but only valsartan has FDA approved
  labeling for treatment of HF.

32
Effects of angiotensin-converting enzyme (ACE)
inhibitors
33
Doses of ACEIs and ARBs
First dose hypotension may occur. Adjust dose in renal failure Hyperkalemia cough Target 10-20 mg/twice daily Start 2.5 mg/day Target 10 mg/once daily Start 2.5 mg/day ACEIs Enalapril Ramipril
Comparable effectiveness with ACEIs Follow-up of renal function possibility of hyperkalemia Target 160 mg/ twice daily Start 40 mg/day Target 32 mg/ once daily Start 4-8 mg/day ARBs Valsartan Candesartan
34
3-ß-Adrenergic Blocking Agents

• Cardiac adrenergic drive initially supports the
  performance of the failing heart, but long-term
  activation of the sympathetic nervous system
  exerts deleterious effects that can be
  antagonized by the use of ß-blockers.
• Extended release metoprolol (Toprol XL) and
  carvedilol are FDA approved for use in HF.

35
3-ß-Adrenergic Blocking Agents

• While some patients can initially have a
  temporary worsening of symptoms,
• continued use results in improved quality of
  life,
• fewer hospitalizations,
• and most importantly, longer survival.
• The AHA/ACC guidelines state that ß-blockers
  should be prescribed to all patients with stable
  HF due to left systolic dysfunction and with mild
  to moderate symptoms unless they have a
  contraindication to their use or have been shown
  to be unable to tolerate treatment with these
  drugs. Generally they are used in combination
  with diuretics and an ACE inhibitor (with or
  without digoxin).

36
Cumulative mortality in patients with heart
failure treated using placebo or metoprolol
37
3-ß-Adrenergic Blocking Agents

• ß-Blockers are also an important part of the
  treatment of patients with HF symptoms due to
  diastolic failure,. For these patients a
  nonselective ß-blocker like propranolol can be a
  therapy of choice in selected patients by
• slowing the HR
• allowing improved ventricular filling.

38
4-Digitalis Glycosides (Digoxin)

• Mechanism of action Digitalis glycosides binds
  to and inhibits sodium-potassium (Na-K)
  adenosine triphosphatase (ATPase) in cardiac
  cells, decreasing outward transport of sodium and
  increasing intracellular concentrations of
  calcium within the cells. Calcium binding to the
  sarcoplasmic reticulum causes an increase in the
  contractile state of the heart.

39
Mechanism of action of cardiac glycosides, or
digitalis. ATPase adenosine triphosphatase
40
4- Digitalis Glycosides (Digoxin)

• Recent evidence suggests that even at serum
  concentrations below those associated with
  positive inotropism
• , digoxin has beneficial autonomic effects by
  reducing sympathetic tone and stimulating
  parasympathetic (vagal) responses.

41
4-Digitalis Glycosides (Digoxin)

• In addition to effects on contractility, digoxin
  decreases the conduction velocity and prolongs
  the refractory period of the atrioventricular
  (AV) node.
• This AV nodeblocking effect prolongs the PR
  interval and is the basis for use of digoxin in
  slowing the ventricular response rate in patients
  with atrial fibrillation and other
  supraventricular arrhythmias.

42
4- Digitalis Glycosides (Digoxin)

• In the past few years, several studies have
  confirmed that digoxin should be considered to
  improve the symptoms and clinical status of
  patients with HF, in combination with diuretics,
  an ACE inhibitor, and a ß-blocker.

43
4- Digitalis Glycosides (Digoxin)

• Digoxin can be used early to reduce symptoms in
  patients who have started, but not yet responded
  to, treatment with an ACE inhibitor and a
  ß-blocker.
• Alternatively, treatment with digoxin can be
  delayed until the patient's response to an ACE
  inhibitor and ß-blocker has been defined and used
  only for those patients who remain symptomatic
  despite the other drugs.
• Monotherapy with digoxin or in combination with
  only a diuretic is no longer recommended.

44
4- Digitalis Glycosides (Digoxin)

• Digoxin can also be considered in patients with
  HF who also have chronic atrial fibrillation,
  although ß-blockers may be more effective than
  digoxin in controlling the ventricular response,
  especially during exercise.
• the digitalis glycosides are not useful in
  diastolic HF and, in fact, may worsen this form
  of left ventricular dysfunction.

45
4- Digitalis Glycosides (Digoxin)

• Most clinicians prefer to use the brand name
  product (Lanoxin) with a high bioavailability
  from other digoxin preparations.
• Digoxin's rapid onset of action (30 to 60
  minutes) corresponds with peak plasma levels.
  Maximum effects from a single dose are observed 5
  to 6 hours after drug administration, a time at
  which drug distribution in the body is complete.
  Digoxin has a steady-state volume of distribution
  averaging 6.7 L/kg of lean body weight (range, 4
  to 9 L/kg). New evidence indicates therapeutic
  benefit and greater safety by targeting serum
  concentrations in the range of 0.5 to 1.2 ng/mL

46
4-Digitalis Glycosides (Digoxin)

• Digoxin has a half-life (t½) of 1.6 to 2 days (36
  to 40 hours) and is characterized by first-order
  pharmacokinetics.
• With renal impairment, the half-life of digoxin
  is prolonged, reaching 4.4 days or more in total
  anuria.

At a creatinine clearance of 100 mL/min, the
percent eliminated per day is 35, whereas at a
creatinine clearance of 0 (i.e., anuria), the
percent eliminated per day is 14,
47
5-Other Vasodilating Drugs Hydralazine and
Nitrates

• Although ACE inhibitors have become the
  vasodilator drug of choice, the first
  vasodilators to be used in patients with HF were
• hydralazine and nitrates.
• Hydralazine (Apresoline) is a potent arterial
  dilating agent that provides symptomatic relief
  of HF by decreasing arterial impedance
  (afterload) to left ventricular outflow.
• Nitrates (e.g., nitroglycerin NTG, isosorbide
  dinitrate, and isosorbide mononitrate) have
  venous dilating properties that decrease left
  ventricular congestion (preload).
• Used in combination, these two agents have
  additive benefits in alleviating the symptoms of
  HF and increasing exercise tolerance.

48
7-Other Inotropic Agents

• Previous doubt about the clinical effectiveness
  of digitalis derivatives and concern over their
  potential for toxicity prompted a search for
  alternative positive inotropic drugs.
• IV Dopamine and dobutamine, both of which are
  sympathomimetics, are commonly used in acute
  cardiac emergencies, but their use is limited by
  the need for IV administration in cardiogenic
  shock.
• Dopamine is more effective as an arterial
  dilator, especially in the kidney, whereas
  dobutamine has more potent inotropic properties

49
Other Inotropic Agents

• Amrinone and milrinone, nonsympathomimetic
  inotropes (phosphodiesterase inhibitors), are
  associated with an unacceptably high incidence of
  side effects (thrombocytopenia and increased
  death rates) when given orally, but are available
  in parenteral form for short-term use in severe
  HF via enzyme inhibition results in increased
  cyclic AMP levels in myocardial cells and thus
  enhances contractility. Their activity is not
  blocked by propranolol.
• Because they are phosphodiesterase inhibitors,
  they also act as vasodilators.
• All inotropes are relatively contraindicated in
  diastolic HF.

50
Calcium Channel Blockers

• Amlodipine (Norvasc), felodipine (Plendil),
  isradipine (DynaCirc), nifedipine (Adalat,
  Procardia), and nicardipine (Cardene) are
  examples of calcium antagonists with arterial
  vasodilating and antispasmodic properties.
• They offer the theoretic advantage of being
  afterload-reducing agents in HF, but their
  applicability in systolic dysfunction is
  diminished by negative inotropic effects.

51
Calcium Channel Blockers

• Among these drugs, only amlodipine and felodipine
  have been documented to be safe in HF (i.e., do
  not make HF worse)
• Until more data are available, calcium channel
  blockers other than amlodipine and felodipine are
  contraindicated in patients with systolic
  dysfunction.
• On the other hand, the negative inotropic effects
  of some calcium antagonists, especially that of
  verapamil (Calan, Isoptin, Verelan), is an
  indication for use in diastolic HF.

52
HF case

• A.J., a 58-year-old man, is admitted with a chief
  complaint of increasing shortness of breath (SOB)
  and an 8 kg weight gain. Two years before
  admission, he noted the onset of dyspnea on
  exertion (DOE) after 1 flight of stairs,
  orthopnea, and ankle edema. Since that time, his
  symptoms have progressed despite intermittent
  hydrochlorothiazide (HCTZ) therapy. Three weeks
  before admission, he noted the onset of episodic
  bouts of paroxysmal nocturnal dyspnea (PND).
  Since then he only has been able to sleep in a
  sitting position. A.J. notes a productive cough,
  nocturia (2 to 3 times/night), and mild,
  dependent edema.

53
HF case

• A.J.'s other medical problems include a long
  history of heartburn a 10-year history of
  osteoarthritis, managed with various nonsteroidal
  anti-inflammatory drugs (NSAIDs) chronic
  headaches and hypertension, which has been
  poorly controlled with HCTZ and propranolol
  (Inderal). A strong family history of diabetes
  mellitus is also present.

54
HF case

• Physical examination reveals dyspenia, cyanosis,
  and tachycardia. A.J. has the following vital
  signs BP, 160/100 mm Hg pulse, 100 beats/min
  and respiratory rate, 28 breaths/min. He is 166
  cm tall and weighs 78 kg. His neck veins are
  distended. On cardiac examination an S3 gallop is
  heard point of maximal impulse (PMI) is at the
  sixth intercostal space (ICS), 12 cm from the
  midsternal line (MSL). His liver is enlarged and
  tender to palpation, and a positive hepatojugular
  reflux (HJR) is observed. He is noted to have 3
  pitting edema of the extremities and sacral
  edema. Chest examination reveals inspiratory
  rales and rhonchi bilaterally.

55
HF case

• The medication history reveals the following
  current medications
• HCTZ (Hydrodiuril) 25 mg QD one a day
• propranolol (Inderal) 80 mg TID 3 times a day
• ibuprofen (Motrin) 600 mg QID 4 times a day
• ranitidine (Zantac) 150 mg HS before sleep at
  bed time and
• Mylanta Double Strength 15 mL as needed up to QID
  used for an antacid and antiflatulent
  preparation .
• He has no allergies and no dietary restrictions.

56
HF case

• Admitting laboratory values include the
  following
• hematocrit (Hct), 41.1 (normal, 40 to 45)
• white blood cell (WBC) count, 5,300/mm3 (normal,
  5,000 to 10,000/mm3)
• Na, 132 mEq/L (normal, 136 to 144 mEq/L)
• potassium (K), 3.2 mEq/L (normal, 3.5 to 5.3
  mEq/L)
• chloride (Cl), 90 mEq/L (normal, 96 to 106
  mEq/L)
• bicarbonate, 30 mEq/L (normal, 22 to 28 mEq/L)
• magnesium (Mg), 1.5 mEq/L (normal, 1.7 to 2.7
  mEq/L)
• fasting blood sugar (FBS), 120 mg/dL (normal, 65
  to 110 mg/dL)
• uric acid, 8 mg/dL (normal, 3.5 to 7 mg/dL)
• blood urea nitrogen (BUN), 40 mg/dL (normal, 10
  to 20 mg/dL)
• serum creatinine (SrCr), 0.8 mg/dL (normal, 0.5
  to 1.2 mg/dL)
• alkaline phosphatase, 120 U (normal, 40 to 80 U)
  and
• aspartate aminotransferase (AST), 100 U (normal,
  0 to 35 U).
• The chest radiograph shows cardiomegaly.

57
HF CASE

• What signs, symptoms, and laboratory
  abnormalities of HF does A.J. exhibit?

58
What are the therapeutic objectives in treating
A.J.?

• Cure is not a feasible therapeutic objective in
  patients with any form of HF.
• The immediate objective for A.J. is to
• provide symptomatic relief as assessed by a
  reduction in his complaints of SOB and PND,
• an improved quality of sleep,
• and increased exercise tolerance.
• Parameters used to measure success in meeting
  this objective include
• reduced peripheral and sacral edema,
• weight loss,
• slowing of the HR to lt90 beats/min,
• normalization of BP

59
Bed rest and a 3-g sodium diet were ordered. Why
should A.J. continue his diuretic therapy?

• Excessive volume increases the workload of a
  compromised heart, and diuretics are an integral
  part of therapy.
• This is especially true if volume overload is
  symptomatic (e.g., pulmonary congestion) as in
  A.J. Diuretics produce symptomatic improvement
  more rapidly than any other drug for HF.

60
Furosemide and Other Loop DiureticsIt is decided
to begin a combination regimen of furosemide and
an ACE inhibitor in A.J. What route, dose, and
dosing schedule of furosemide should be used?

• Furosemide is the most commonly used loop
  diuretic for HF because of greater clinical
  experience and low cost.
• Typically, a patient's treatment is initiated
  with 20 to 40 mg of oral or IV furosemide given
  as a single dose and monitored for
  responsiveness. If the desired diuresis is not
  obtained, the dose can be increased in 40- to
  80-mg increments over the next several days to a
  total daily dose of 160 mg/day, usually divided
  into two doses.

61
Examine A.J.'s laboratory values . Can any of the
abnormal values be attributed to the HCTZ A.J.
was taking? What is the significance of these
abnormalities?

• Azotemia
• A.J. has an elevated BUN (40 mg/dL) but a normal
  serum creatinine (0.8 mg/dL). Normally, a
  BUN-to-creatinine ratio of 10 to 201 is seen.
  Progressive renal failure is characterized by an
  elevation of both BUN and creatinine., A
  disproportionately elevated BUN relative to
  creatinine is indicative of prerenal azotemia due
  to poor renal perfusion occuring in HF

62
Examine A.J.'s laboratory values . Can any of the
abnormal values be attributed to the HCTZ A.J.
was taking? What is the significance of these
abnormalities?

• Hyponatremia (low serum sodium concentration)
  reflects the dilutional effect of extra free
  water in the plasma on sodium concentration.

63
Examine A.J.'s laboratory values . Can any of the
abnormal values be attributed to the HCTZ A.J.
was taking? What is the significance of these
abnormalities?

• Hypochloremic Alkalosis
• A.J.'s low serum chloride of 90 mEq/L concurrent
  with an elevated serum bicarbonate (total CO2) of
  30 mEq/L signifies hypochloremia with a metabolic
  alkalosis.
• Hypomagnesemia
• A.J.'s serum magnesium level is 1.5 mEq/L. This
  could either be a result of magnesium diuresis
  induced by his diuretic therapy or malabsorption
  secondary to binding of magnesium ions in the
  intestines by his antacids.

64
Examine A.J.'s laboratory values . Can any of the
abnormal values be attributed to the HCTZ A.J.
was taking? What is the significance of these
abnormalities?

• Hyperglycemia
• A.J. has a fasting blood sugar of 120 mg/dL,
  which is only slightly elevated and, It also
  could represent a stress-related diabetic
  reaction.
• However, hyperglycemia and glucose intolerance
  have been reported to occur during treatment with
  thiazide diuretics
• Because A.J. has a family history of diabetes, he
  could be at increased risk. At this time A.J.'s
  blood sugar needs further monitoring, but no
  specific therapy is required.

65
Examine A.J.'s laboratory values . Can any of the
abnormal values be attributed to the HCTZ A.J.
was taking? What is the significance of these
abnormalities?

• Hyperuricemia
• Increases of 1 to 2 mg/dL in uric acid levels are
  common during thiazide administration.
• Most patients who develop elevated uric acid
  levels during treatment with diuretic agents
  remain asymptomatic and need not be treated.
• Only those with uric acid levels persistently gt10
  mg/dL, as well as those with a history of gout or
  a familial predisposition, should be considered
  for treatment with urate-lowering agents

66
Examine A.J.'s laboratory values . Can any of the
abnormal values be attributed to the HCTZ A.J.
was taking? What is the significance of these
abnormalities?

• Liver Function
• A.J.'s elevated alkaline phosphatase and AST
  probably are not indicative of any drug-related
  toxicity. Although cholestatic jaundice has been
  reported with thiazide diuretics, the elevated
  liver function tests most likely are the result
  of hepatic congestion from right-sided HF.

67
The physician gave A.J. one 1-g dose of magnesium
sulfate and three 20-mEq doses of potassium
chloride IV. This raised his serum magnesium to
2.0 and his potassium to 3.9 mEq/L. Should he
receive prophylactic magnesium or potassium
supplementation? What is the best drug and
appropriate dose?

• A fall in serum potassium concentration can be
  seen within hours of the first dose of a
  diuretic, and the maximum fall usually is reached
  by the end of the first week of treatment. When
  diuretics are stopped, it can take several weeks
  for serum potassium to return to normal.
• When dose of diuretic is to be increased and
  digitalis therapy is considered, potassium
  supplementation is warranted.

68
The physician gave A.J. one 1-g dose of magnesium
sulfate and three 20-mEq doses of potassium
chloride IV. This raised his serum magnesium to
2.0 and his potassium to 3.9 mEq/L. Should he
receive prophylactic magnesium or potassium
supplementation? What is the best drug and
appropriate dose?

• If potassium replacement is prescribed, only
  potassium chloride (KCl) should be used because
  all potassium-wasting diuretics can cause
  hypochloremic alkalosis if the chloride ion is
  not replaced, alkalosis and hypokalemia will
  persist, even if large quantities of potassium
  are given.
• Slow K and Kaon-Cl are used

69

• It is difficult to predict the dose of KCl that
  will be required to maintain proper potassium
  balance. Many patients do well with 20 mEq/day

70

• Would use of a potassium-sparing diuretic such as
  triamterene offer any advantage over a potassium
  supplement to prevent or treat hypokalemia?
• The potassium-sparing diuretics (amiloride and
  triamterene) may be more effective in preventing
  or correcting the fall in serum potassium than
  potassium supplements.

71
After a single 40 mg IV dose of furosemide, A.J.
is begun on 40 mg of furosemide each morning and
KCl tablets 20 mEq BID. How should his therapy be
monitored?

• A.J. needs to be monitored for both an
  improvement in his HF and for side effects.
• Subjectively, the clinician should monitor for
  decreased pulmonary distress and an increased
  exercise tolerance, demonstrating control of HF.
• Objective monitoring parameters for disease
  control include weight loss (ideal, 0.5 to 1
  kg/day until ideal weight is achieved), a
  decrease in edema, flattening of neck veins, and
  disappearance of the S3 gallop and rales. Because
  A.J. has hypertension, his BP also requires
  monitoring with a goal to reduce to lt120/80 mm Hg.

72
Case

• You are consulted on another patient whose
  initial history was similar to A.J.'s. After
  nearly 2 years of relatively good HF control on a
  regimen of 40 mg furosemide, 20 mg QD lisinopril,
  200 mg QD metoprolol extended release, and 0.125
  mg QD digoxin, urinary output diminished about 1
  week ago and edema increased significantly.
  Nonadherence to drug therapy and salt restriction
  was ruled out. The dose of furosemide was
  increased to 80 mg 2 days ago without much
  effect. Should the dose of furosemide be
  increased further? Could another diuretic be
  added to the therapy?

73
Answer

• many patients develop a blunted diuretic response
  with continued therapy for unknown reasons or due
  to failure of its transport to their site of
  action in case of HD.
• Most clinicians choose a combination of
  metolazone plus furosemide or bumetanide based on
  demonstrated value in the literature and clinical
  experience. A small dose of metolazone (5 mg) is
  first added to the furosemide therapy, doubling
  the dose of metolazone every 24 hours until the
  desired diuretic response is achieved.

74
Digoxin and ACEIs in HF

• Vasodilators are first-line therapy, with digoxin
  being added in patients with either
• supraventricular arrhythmias,
• failure to achieve symptomatic relief with
  vasodilators alone,
• or intolerable side effects from vasodilators.

75
Critics over digitalis use

• However, critics raised concerns that symptom
  relief was less in patients with normal sinus
  rhythm than in those with supraventricular
  arrhythmias. The most vocal critics claimed that
  the risk of digitalis toxicity did not warrant
  using this class of drugs in patients with normal
  sinus rhythm.

76

• In the case of A.J., his physician should be
  discouraged from starting digoxin at this time.
  Instead, he should be counseled to continue with
  the already prescribed ACE inhibitor in addition
  to continuing the furosemide.
• A strong argument can be made for starting a
  ß-blocker such as metoprolol or carvedilol now or
  within the next few days.
• Based on your advice, A.J.'s doctor has decided
  to withhold digoxin and assess the response to
  just one drug (i.e., the ACE inhibitor) for now.

77
What ACEI drug is preferred?

• There does not seem to be a significant
  difference in side effects between agents. Based
  on these factors, no one drug is preferred over
  another.

78
ACEIs versus ARBs

• when A.J. is not tolerating enalapril,
  discontinuation of his enalapril and initiation
  of valsartan is justified.

79
Effect of ACEIs and ARBs on renal function

• In the case of low-pressure or low-flow states,
  the renin-angiotensin-aldosterone system is
  activated to maintain intraglomerular pressure.
  When patients with low-pressure states are given
  ACE inhibitors or ARBs, the protective mechanism
  of efferent vasoconstriction is inhibited and
  renal function can significantly and rapidly
  worsen.
• Conversely, in patients with hypertensive renal
  disease, glomerular function actually can improve
  because the ACE inhibitors lower afferent
  pressure and help protect the kidney.

80
Interaction between aspirin and ACEIs

• Several studies suggest that
• aspirin may attenuate the beneficial affects of
  ACE inhibitors when given together in patients
  with HF and other cardiovascular disorders.
• The proposed mechanism is inhibition of
  prostaglandin formation by aspirin, thus
  counteracting the clinical effects of ACE
  inhibitors that rely in part on prostaglandins to
  elicit their positive hemodynamic effects.
• The significance of this interaction is still
  being debated.

81
?-blockers in HF

• Returning to the case of A.J., we are now 6 weeks
  into his treatment, his regimen was changed to
  valsartan 40 mg BID in place of enalapril. After
  starting valsartan, his cough disappeared over
  the next 7 to 10 days. During that same time, he
  noted more fatigue and increased nighttime
  dyspnea. These symptoms improved after his dose
  of valsartan was increased incrementally to 80 mg
  BID. At the same time, his physician wants to
  reconsider the need to start a ß-blocker. Is this
  a good time to start a ß-blocker?

82

• the use of ß-blockers is associated with a
  consistent 30 reduction in mortality and a 40
  reduction in hospitalizations in patients with
  HF.
• The 2001 ACC/AHA guidelines state that because
  metoprolol and carvedilol have been shown to
  reduce HF symptoms and reduce mortality, they
  should be prescribed to all patients with stable
  HF due to left ventricular systolic dysfunction,
  unless there is a contraindication to their use.
• They should be part of the primary treatment
  plan, usually in combination with a diuretic, and
  ACE inhibitor and often with digoxin.

83

• Another common misperception is that patients who
  have mild symptoms or who appear clinically
  stable on diuretics and ACE inhibitors (with or
  without digoxin) do not require additional
  treatment.
• However, even these patients should receive a
  ß-blocker to slow the rate of disease progression
  and reduce the risk of sudden death.

84

• Treatment with a ß-blocker should be initiated at
  low doses, followed by gradual increments in dose
  every 1 to 2 weeks as tolerated by the patient.
• Transient bradycardia, hypotension, and fatigue
  are common during the first 24 to 48 hours when
  ß-blockers are first started or during subsequent
  incremental increases in dosage.
• Thus, patients should be monitored daily for
  changes in vital signs (pulse and blood pressure)
  and symptoms during this up-titration period.

85

• With ß-blocker administration to A.J. patient
• Bradycardia, heart block and hypotension
  complications are accompanied by dizziness, or
  blurred vision can occurred ? this needs dose
  reduction of the ß-blocker and/or ACE inhibitor
  or slower up titration may be necessary.

86

• Today, A.J.s wife brought him to the ED because
  she could no longer care for him. His chief
  complaints are weakness, dizziness, extreme SOB,
  and inability to get out of bed. His weight has
  increased to 80 kg. His BP is considerably lower
  at 128/83 mm Hg with a postural drop to 112/75 mm
  Hg. Abnormal laboratory values on admission are
  BUN, 31 mg/dL and serum creatinine, 1.4 mg/dL.
  His K is 4.3 mEq/dL. An ECG shows a HR of 98
  beats/min. His valsartan is held for 24 hours
  while he is diuresed with several 40- and 80-mg
  boluses of IV furosemide. The plan is to
  reinstitute valsartan and to begin a digitalis
  glycoside. Is digitalis indicated for A.J.? What
  digitalis preparation should be prescribed?

87
Digoxin administration to A.J. patient

• the ACC/AHA guidelines indicate that
• digoxin can be used early to reduce symptoms in
  patients who have been started on, but not yet
  responded symptomatically to an ACE inhibitor or
  ß-blocker.
• Alternatively, digoxin can be delayed until the
  patient's response to ACE inhibitors and
  ß-blockers has been defined and used only in
  patients who remain symptomatic.
• A.J. fits the latter situation and thus is a
  logical candidate for adding digoxin as a fourth
  therapeutic intervention. It could be argued that
  both a ß-blocker and digoxin should have been
  started at the onset of his treatment a year ago,
  but A.J.'s physician was reluctant to make
  multiple interventions simultaneously.

88
Digoxin administration to A.J. patient

• Digoxin is also prescribed routinely in patients
  with HF and concurrent chronic atrial
  fibrillation, but ß-blockers may be more
  effective in controlling the ventricular
  response, especially during exercise.
• Digoxin should be avoided if the patient has
  significant sinus or atrioventricular block,
  unless the block is treated with a permanent
  pacemaker.

89
Digoxin administration to A.J. patient

• It should be used cautiously in patients taking
  other drugs that can depress sinus or AV nodal
  function (e.g., amiodarone or ß-blockers),
  although patients usually will tolerate this
  combination.

90
Gender difference in response to digoxin

• increased risk of death among women taking
  digoxin is an interaction between
  hormone-replacement therapy and digoxin.
  Progesterone might increase serum digoxin levels
  by reducing digoxin renal tubular excretion.

91
LD and MD of digoxin

• A patient with normal renal function (t½ 1.8
  days) given a daily dose of 0.125 mg of digoxin
  will reach peak serum concentration in
  approximately 7 days.
• The target therapeutic serum digoxin
  concentration is 0.5 to 1.2 ng/mL (mean, 0.75
  ng/mL).
• smaller doses of digoxin are given to patients
  with impaired excretion rates (e.g., those with
  renal failure, older patients)
• No more therapeutic benefit from LD ? not used
  now

92
Treatment options for various stages of heart
failure. ACE Angiotensin-converting enzyme ARB
angiotensin receptor blockers.
93
Drug interaction in HF
NSAIDs antagonism of hypotension, increased risk of renal impairment Diuretics enhancement of hypotension, increased risk of hyperkalemia with K-sparing diuretics Cyclosporin increased risk of hyperkalemia Lithium impairment of lithium excretion ACEIs or ARBs
94
Drug interaction in HF
NSAIDs decreased effect of diuretics Lithium impairment of lithium excretion Carbamazepine ? risk of hyponatremia Diuretics
Amiodarone ? risk of bradycardia Diltiazem, verapamil ? risk of bradycardia and heart block ?-blockers
95
Drug interaction in HF
Amiodarone, propafenone, quinidine ? digoxin level ? need to halve MD of digoxin Verapamil ? risk of AV block Diuretics ? risk of hypokalemia ? ? risk of toxicity Digoxin
Digoxin spironolactone interfers with the measurements of plasma levels of digoxin? inaccurate interpretation spironolactone
96
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