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					CONGESTIVE CARDIAC FAILURE
     PROF. DR. SHAH MURAD
        HOD, Pharmacology
       FM&DC, Abbottabad
     shahhmurad65@gmail.com
CCF




      2
What is congestive heart failure?




                                    3
What causes congestive heart failure?




                                        4
What are the symptoms of congestive heart
               failure (CHF)?




                                            5
How is congestive heart failure diagnosed?




                                             6
What is the treatment of congestive heart
                  failure?




                                            7
Lifestyle modifications are needed




                                     8
Medications are needed




                         9
Heart transplant may be needed




                                 10
Other mechanical therapies may be required




                                             11
What is the long term outlook for patients with
 congestive heart
 failure?....................................>>>>>>>
PROGNOSIS




                                                       12
• Congestive heart failure (CHF) is a condition in
  which the heart's function as a pump to deliver
  oxygen rich blood to the body is inadequate to meet
  the body's needs.



                                                    13
Congestive heart failure can be caused
                 by:

• diseases that weaken the heart
  muscle,
• diseases that cause stiffening of
  the heart muscles, or
• diseases that increase oxygen
  demand by the body tissue
  beyond the capability of the heart
  to deliver.                          14
• The heart has two atria (right atrium and left atrium) that make up
  the upper chambers of the heart, and two ventricles (left ventricle
  and right ventricle) that make up the lower chambers of the heart.

• The ventricles are muscular chambers that pump
  blood when the muscles contract (the contraction
  of the ventricle muscles is called systole).




                                                                15
• Many diseases can impair the pumping action
  of the ventricles.

• For example, the muscles of the ventricles can
  be weakened by heart attacks or infections
  (myocarditis).



                                               16
• The diminished pumping ability of the ventricles
  due to muscle weakening is called systolic
  dysfunction.

• After each ventricular contraction (systole) the
  ventricle muscles need to relax to allow blood from
  the atria to fill the ventricles.

• This relaxation of the ventricles is called diastole.



                                                      17
• Diseases such as hemochromatosis or amyloidosis
  can cause stiffening of the heart muscle and impair
  the ventricles' capacity to relax and fill; this is
  referred to as diastolic dysfunction.
• The most common cause of this is longstanding high
  blood pressure resulting in a thickened
  (hypertrophied) heart.


                                                 18
• In some patients, although the pumping
  action and filling capacity of the heart may be
  normal, abnormally high oxygen demand by
  the body's tissues (for example, with
  hyperthyroidism) may make it difficult for the
  heart to supply an adequate blood flow (called
  high output heart failure).



                                                19
• In some patients one or more of these factors
  can be present to cause congestive heart
  failure.

• Our focus is primarily on congestive heart
  failure that is due to heart muscle weakness
  >>>>>>>systolic dysfunction.


                                                  20
• Congestive heart failure can affect many organs of
  the body.
• For example, the weakened heart muscles may not
  be able to supply enough blood to the kidneys,
  which then begin to lose their normal ability to
  excrete salt (sodium) and water.

• This diminished kidney function can cause to body
  to retain more fluid.                          21
• The lungs may become congested with fluid
  (pulmonary edema) and the person's ability to
  exercise is decreased.

• Fluid may likewise accumulate in the liver,
  thereby impairing its ability to rid the body of
  toxins and produce essential proteins.


                                                     22
• The intestines may become less efficient in
  absorbing nutrients and medicines.




• Over time, untreated, worsening congestive
  heart failure will affect virtually every organ in
  the body.
                                                   23
         Symptoms of heart failure
• Shortness of breath, which occurs with exertion as
  the disease progresses.
• Lying flat increases blood return to the heart; thus
  patients may complain of shortness of breath
  (orthopnea) when lying down.




                                                    24
• Another symptom is
  paroxysmal nocturnal
  dyspnea, a term used to
  describe wakening in the
  middle of the night with
  shortness of breath that is
  more long-lasting than
  simple orthopnea.




                                25
• Patients often describe
  having to stand by a
  window to try to catch their
  breath.




                                 26
• Patients end up sleeping on
  two or three pillows to
  elevate the head and chest,
  or in a recliner.




                                27
• Increasing shortness of
  breath can be tempered by
  the medications; however,
  over time, the symptoms
  worsen and quality of life
  suffers.




                               28
• Eventually, the disease wins,
  breathing fails, and so does
  the patient.




                                  29
30
• Many disease processes
  can impair the pumping
  efficiency of the heart to
  cause congestive heart
  failure. E.g.
• coronary artery disease,
• high blood pressure
  (hypertension),
• longstanding alcohol
  abuse, and
• disorders of the heart
  valves.

                               31
• Less common causes
  include viral infections
  of the stiffening of the
  heart muscle, thyroid
  disorders, disorders of
  the heart rhythm




                             32
• In patients with underlying heart disease,
  taking certain medications can lead to the
  development or worsening of congestive heart
  failure.




                                             33
• This is especially true
  for those drugs that can
  cause sodium retention
  or affect the power of
  the heart muscle.




                             34
• Examples of such
  medications are the
  commonly used
  nonsteroidal
  antiinflammatory drugs
  (NSAIDs), which include
  ibuprofen and naproxen
  as well as certain steroids,
  some diabetic
  medication, and some
  calcium channel blockers.

                                 35
• The symptoms of
  congestive heart failure
  vary among individuals
  according to the
  particular organ
  systems involved and
  depending on the
  degree to which the
  rest of the body has
  "compensated" for the
  heart muscle weakness.

                             36
• An early symptom of
  congestive heart failure
  is fatigue.
• While fatigue is a
  sensitive indicator of
  possible underlying
  congestive heart failure,
  it is obviously a
  nonspecific symptom
  that may be caused by
  many other conditions.

                              37
• The person's ability to
  exercise may also
  diminish.


Patients may not even
  sense this decrease and
  they may
  subconsciously reduce
  their activities to
  accommodate this
  limitation.
                            38
• As the body becomes overloaded with fluid
  from congestive heart failure, swelling
  (edema) of the ankles and legs or abdomen
  may be noticed.




                                              39
• In addition, fluid may
  accumulate in the
  lungs, thereby causing
  shortness of breath,
  particularly during
  exercise and when lying
  flat.

• In some instances,
  patients are awakened
  at night, gasping for air.
                               40
• Some may be unable to
  sleep unless sitting
  upright.



• The extra fluid in the
  body may cause
  increased urination,
  particularly at night.

                           41
• Accumulation of fluid in
  the liver and intestines
  may cause nausea,
  abdominal pain, and
  decreased appetite.




                             42
                ∆ of CCF
• The diagnosis of congestive heart failure is most
  often a clinical one that is based on knowledge of
  the patient's pertinent medical history, a careful
  physical examination, and selected laboratory tests.




                                                  43
• A thorough patient history may disclose the
  presence of one or more of the symptoms of
  congestive heart failure described above.

• In addition, a history of significant coronary artery
  disease, prior heart attack, hypertension,
  diabetes, or significant alcohol use can be clues.

                                                     44
• The physical examination is focused on
  detecting the presence of extra fluid in the
  body (breath sounds, leg swelling, or neck
  veins) as well as carefully characterizing
  the condition of the heart (pulse, heart size,
  heart sounds, and murmurs).



                                                   45
• Useful diagnostic tests include the
  electrocardiogram (ECG) and chest x-ray to
  explore the possibility of previous heart
  attacks, arrhythmia, heart enlargement, and
  fluid in and around the lungs.




                                                46
• Perhaps the single most useful diagnostic test is the
  echocardiogram, in which ultrasound is used to
  image the heart muscle, valve structures, and blood
  flow patterns.




                                                   47
• The echocardiogram is very helpful in
  diagnosing heart muscle weakness.

• In addition, the test can suggest possible
  causes for the heart muscle weakness (for
  example, prior heart attack, and severe valve
  abnormalities).

                                             48
• Nuclear medicine studies assess the overall
  pumping capability of the heart and examine the
  possibility of inadequate blood flow to the heart
  muscle.

• Heart catheterization allows the arteries to the
  heart to be visualized with angiography (using dye
  inside of the blood vessels that can be seen using x-
  ray methods).                                    49
• During catheterization the pressures in and around
  the heart can be measured and the heart's
  performance assessed.
• In rare cases, a biopsy of the heart tissue may be
  recommended to diagnose specific diseases.
• This biopsy can often be accomplished through the
  use of a special catheter device that is inserted into
  a vein and maneuvered into the right side of the
  heart
                                                     50
• Another helpful diagnostic test is a blood test called
  a BNP or brain natriuretic peptide level.

• This level can vary with age and gender but is
  typically elevated from heart failure and can aid in
  the diagnosis, and can be useful in following the
  response to treatment of congestive heart failure.

                                                    51
• The choice of tests depends on each patient's
  case and is based on the suspected diagnoses.




                                              52
               Treatment of CCF
• After congestive heart failure is diagnosed,
  treatment should be started immediately.

• Perhaps the most important and yet most neglected
  aspect of treatment involves lifestyle modifications.

• Sodium causes an increase in fluid accumulation in
  the body's tissues.

                                                   53
• Because the body is often congested with
  excess fluid, patients become very sensitive to
  the levels of intake of sodium and water.




                                                54
• Restricting salt and fluid intake is often
  recommended because of the tendency of fluid to
  accumulate in the lungs and surrounding tissues.




                                              55
• An American "no added salt" diet can still contain 4
  to 6 grams (4000 to 6000 milligrams) of sodium per
  day.

• In patients with congestive heart failure, an intake
  of no more than 2 grams (2000 milligrams) of
  sodium per day is generally advised.

                                                    56
• Reading food labels and paying close attention
  to total sodium intake is very very very
  important !!!!!!!




                                               57
• The total amount of fluid consumed must be
  regulated.

• Although many patients with congestive heart
  failure take diuretics to aid in the elimination of
  excess fluid, the action of these medications can
  be overwhelmed by an excess intake of water
  and other fluids.
                                                   58
            "drinking
• The maxim that
 eight glasses of water a
 day is healthy" certainly does
 not apply to patients with congestive
 heart failure.




                                         59
• In fact, patients with more advanced cases of
  congestive heart failure are often advised to limit
  their total daily fluid intake from all sources to 2
  quarts.




                                                     60
• The above guidelines for sodium and fluid
  intake may vary depending on the severity of
  congestive heart failure in any given patient
  and should be discussed with the patient's
  physician.




                                                  61
• An important tool for monitoring an appropriate
  fluid balance is the frequent measurement of body
  weight.

• An early sign of fluid accumulation is an increase in
  body weight.
• This may occur even before shortness of breath or
  swelling in the legs and other body tissues (edema)
  is detected.                                      62
• A weight gain of two to three pounds over two
  to three days should prompt a call to the
  physician, who may order an increase in the
  dose of diuretics or other methods designed
  to stop the early stages of fluid accumulation




                                               63
• Aerobic exercise, once discouraged for congestive
  heart failure patients, has been shown to be
  beneficial in maintaining overall functional capacity,
  quality of life, and perhaps even improving survival.

• Each patient's body has its own unique ability to
  compensate for the failing heart.

                                                      64
• Given the same degree of heart muscle weakness,
  patients may display widely varying degrees of
  limitation of function.

• Regular exercise, when tailored to the patient's
  tolerance level, appears to provide significant
  benefits and should be used only when the
  patient is compensated and stable.
                                                     65
   Addressing potentially reversible
               factors
• Depending on the underlying cause of congestive
  heart failure, potentially reversible factors should
  be explored.
• For example, in certain patients whose CCF is
  caused by inadequate blood flow to the heart
  muscle, restoration of the blood flow through
  coronary artery surgery or catheter procedures
  (angioplasty, intracoronary stenting) may be
  considered.
                                                   66
• Congestive heart failure that is due to severe
  disease of the valves may be alleviated in
  appropriate patients by valve surgery.




                                                   67
• When congestive heart failure is caused by chronic,
  uncontrolled high blood pressure (hypertension),
  aggressive blood pressure control will often
  improve the condition.




                                                  68
• Likewise, heart muscle weakness that is due to
  longstanding, severe alcohol abuse can improve
  significantly with abstinence from drinking.

• Congestive heart failure that is caused by other
  disease states may be similarly partially or
  completely reversible by appropriate measures.

                                                     69
                   Medications
• Until recently, the selection of medications available
  for the treatment of congestive heart failure was
  frustratingly limited and focused mainly on
  controlling the symptoms.

• Medications have now been developed that both
  improve symptoms, and, importantly, prolong
  survival.


                                                    70
             DRUGS USED IN CCF

• ACE inhibitors
• Beta blockers
• Cardiac glycosides
•   Diuretics
•   Vasodilators
•   Sympathomimetic inotropic drugs
•   Phosphodiesterase III inhibitors
•   Miscellaneous drugs                71
• ACE inhibitors have been used for the treatment of
  hypertension for more than 20 years.

• This class of drugs has also been extensively studied in the
  treatment of congestive heart failure.




• These medications block the formation of angiotensin II, a
  hormone with many potentially adverse effects on the
  heart and circulation in patients with heart failure.  72
• These drugs have demonstrated a remarkable
  improvement of symptoms in patients, prevention of
  clinical deterioration, and prolongation of survival.
• In addition, they have been recently been shown to
  prevent the development of heart failure and heart
  attacks.

• The wealth of the evidence supporting the use of these
  agents in heart failure is so strong that ACE inhibitors
  should be considered in all patients with heart failure,
  especially those with heart muscle weakness.

                                                          73
• ACE inhibitors reduce pre and after load on
  heart
• Captopril,enalapril,losartan,prazosin are orally
  active medium efficacy non-selective arterio-
  venous dilators.




                                                 74
• Prognostic benefits of ACE inhibitors have
  been established in mild to moderate CCF as
  well as in patients with asymptomatic systolic
  dysfunction.

• They are thus recommended for all grades of
  CCF, unless contra-indicated or if renal
  function deteriorates

                                                   75
   SEs of ACE inhibitors should be
            remembered
• dry cough,
• low blood pressure,
• worsening kidney function and electrolyte
  imbalances, and
• rarely, true allergic reactions.




                                              76
• For those patients who are unable to tolerate the
  ACE inhibitors, an alternative group of drugs, called
  the angiotensin receptor blockers (ARBs), may be
  used.

• These drugs act on the same hormonal pathway as
  the ACE inhibitors, but instead block the action of
  angiotensin II at its receptor site directly.
                                                    77
• A small, early study of one of these agents
  suggested a greater survival benefit in elderly
  congestive heart failure patients as compared
  to an ACE inhibitor.




                                                    78
                 Beta-blockers
• Certain hormones, such as epinephrine
  (adrenaline), norepinephrine, and other similar
  hormones, act on the beta receptor's of various
  body tissues and produce a stimulative effect.

• The effect of these hormones on the beta receptors
  of the heart is a more forceful contraction of the
  heart muscle.
• Beta-blockers are agents that block the action of
  these stimulating hormones on the beta receptors
  of the body's tissues.                            79
• Since it was assumed that blocking the beta
  receptors further depressed the function of the
  heart, beta-blockers have traditionally not been
  used in patients with congestive heart failure.



• In congestive heart failure, however, the stimulating
  effect of these hormones, while initially useful in
  maintaining heart function, appears to have
  detrimental effects on the heart muscle over time.


                                                     80
• However, studies have demonstrated an impressive clinical
  benefit of beta-blockers in improving heart function and
  survival in congestive heart failure patients who are already
  taking ACE inhibitors.

• It appears that the key to success in using beta-blockers in
  congestive heart failure is to start with a low dose and
  increase the dose very slowly.

• At first, patients may even feel a little worse and other
  medications may need to be adjusted.                        81
SEs of beta blockers which must be
              in mind
•   fluid retention,
•   low blood pressure,
•   low pulse, and
•   general fatigue and lightheadedness.




                                           82
• Beta-blockers should generally not be used in
  people with certain significant diseases of the
  airways (for example, asthma, emphysema) or very
  low resting heart rates.




• While carvedilol (Coreg) has been the most
  thoroughly studied drug in the setting of congestive
  heart failure, studies of other beta-blockers have
  also been promising.
                                                  83
                 Cardiac glycosides
• Digoxin
• Digitoxin
• Ouabain (Strophanthus )
•   Gitoxin
•   Getalin
•   Proscillaridin-A
•   Thevetin
•   Bufotoxin
•   Deslanoside                       84
• Cardiac glycosides are used therapeutically
  mainly in the treatment of cardiac failure, due
  to their anti-arrhythmic effects.

• Theseagents have ability to increase cardiac output
  by increasing force of contraction by prolonging the
  plateau phase of cardiac depolarization thus
  slowing ventricular contraction and allowing more
  time for ventricular filling. (If you increase the pre-
  load, you increase the force of contraction - Frank-
  Starling law).

                                                     85
                          MOA
• Normally, sodium-potassium pumps in the membrane of
  cells (in this case, cardiac myocytes) pump potassium ions
  in and sodium ions out.
• Cardiac glycosides inhibit this pump so that sodium cannot
  be extruded: intracellular sodium concentration therefore
  increases.
• A second membrane ion pump, NCX, is responsible for
  pumping calcium ions out of the cell and sodium ions in
  (3Na/Ca); raised intracellular sodium levels inhibit this
  exchange, so calcium ions are not extruded and will also
  begin to build up inside the cell.
                                                        86
• Increased cytoplasmic calcium concentrations cause
  increased calcium uptake into the sarcoplasmic
  reticulum via the SERCA2 transporter.

• Raised calcium stores in the SR allow for greater
  calcium release on stimulation, so the myocyte can
  achieve faster and more powerful contraction by
  cross-bridge cycling.

• The refractory period of the AV node is increased,
  so cardiac glycosides also function to regulate heart
  rate.
                                                   87
• If SR calcium stores become too high, some ions
  are released spontaneously through SR ryanodine
  receptors.

• Then after-depolarization this effect leads initially
  to bigeminy: regular ectopic beats following each
  ventricular contraction.
• If higher glycoside doses are given, rhythm is lost
  and ventricular tachycardia ensues, followed by
  fibrillation                                       88
89
• The process of membrane depolarization /
  repolarization is controlled by the
  movement of three cations, Na+, Ca+2, and
  K+, in and out of the cell.
• At the resting stage, the concentration of Na+ is
  high on the outside.
• On membrane depolarization sodium fluxes-
  in leading to an immediate elevation of the
  action potential.
• Elevated intracellular Na+ triggers the influx of free Ca++ that
  occurs more slowly.
• The higher intracellular [Ca++] results in
  the efflux of K+.
• The reestablishment of the action potential occurs later
  by the reverse of the Na+-K+ exchange.
                                                             90
• The Na+ / K+ exchange requires
  energy which is provided by an
  enzyme Na+-K+-ATPase.
• Cardiac glycosides are proposed to inhibit this enzyme
  with a net result of reduced sodium exchange with
  potassium that leaves increased intracellular Na+
  >>>>>>>this results in increased intracellular [Ca++].
• Elevated intracellular calcium
  concentration triggers a series of
  intracellular biochemical events that
  ultimately result in an increase in the
  force of the myocardial contraction or
  a positive inotropic effect.
                                                    91
          PK of cardiac glycosides
• In general, cardiac glycosides with more lipophilic
  character are absorbed faster and exhibit longer
  duration of action as a result of slower urinary
  exretion rate.
• Lipophilicity is markely influenced by the number of
  sugar residues and the number of hydroxyl groups
  on the aglycone part of the glycoside.



                                                  92
• Comparison of digitoxin and digoxin structures
  reveals that they differ only by an extra OH
  group in digoxin at C-12, yet their partition
  coefficients differ by as much as 15 % points.




                                               93
             DIGOXIN (C41H64O14)

• Bioavailability >>>>> 60 to 80% (Oral)
• Protein binding >>>>> 25%
• Metabolism >>>> Hepatic (16%)
• Half life>>>>36 to 48 hours (with normal RF). 4 to 5
  days
  (patients with impaired renal function)
• Excretion >>>> renal
• Other routes of adm. >>>>>> IV
                                                   94
• Digoxin also known as digitalis, is a purified cardiac
  glycoside extracted from the foxglove plant,
  Digitalis lanata.
• Its corresponding aglycone is digoxigenin, and its
  acetyl derivative is acetyldigoxin.
• Digoxin is widely used in the treatment of various
  heart conditions, namely atrial fibrillation, atrial
  flutter and sometimes heart failure that cannot be
  controlled by other medication.
                                                    95
• Digoxin preparations are commonly
  marketed under the trade names Lanoxin,
  Digitek, and Lanoxicaps.

• It is also available as a 0.05 mg/mL oral solution
  and 0.25 mg/mL or 0.5 mg/mL injectable solution.



                                                  96
           Pharmacological actions
• The main pharmacological effects are on the heart.
• Extracardiac effects are responsible for many of
  the adverse effects.
• Its main cardiac effects are
• Negatively chronotropic - i.e. slowing the heart
  rate by decreasing conduction of electrical impulses
  through the AV node, making it a commonly used
  antiarrhythmic agent in controlling the heart rate during
  atrial fibrillation or atrial flutter.
• Positively inotropic - i.e. increasing the force of heart
  contraction via inhibition of the Na+/K+ ATPase pump.
                                                      97
                    Clinical uses
• Most common indications for digoxin are atrial
  fibrillation and atrial flutter with rapid ventricular
  response, but beta- or calcium channel- blockers
  should be the first choice.



• High ventricular rate leads to insufficient diastolic
  filling time.

                                                       98
• By slowing down the conduction in the AV node
  and increasing its refractory period, digoxin can
  reduce the ventricular rate.



• The arrhythmia itself is not affected, but the
  pumping function of the heart improves owing to
  improved filling.
                                                      99
• The use of digoxin in heart problems
  during sinus rhythm was once
  standard, but is now controversial.
• In theory the increased force of
  contraction should lead to improved
  pumping function of the heart, but its
  effect on prognosis is disputable and
  other effective treatments are now
  available.
                                      100
• Digoxin is no longer the first choice for
  congestive heart failure, but can still be useful
  in patients who remain symptomatic despite
  proper diuretic and ACE inhibitor treatment.

• It has fallen out of favor because it was proven to
  be ineffective at decreasing morbidity and mortality
  in congestive heart failure.



• It is shown to increase quality of life,
  however.                                        101
• Digoxin is also used as a standard control
  substance to test for p-glycoprotein inhibition.




                                                102
         Drug-drug interaction
• Quinidine, verapamil, and amiodarone
  increases plasma levels of digoxin (by
  displacing tissue binding sites and depressing
  renal digoxin clearance) so plasma digoxin
  must be monitored carefully.




                                               103
                Adverse effects
• The occurrence of adverse drug reactions is
  common, owing to its narrow therapeutic index.

• Adverse effects are concentration-dependent, and
  are rare when plasma digoxin concentration is <0.8
  μg/L.
• They are also more common in patients with
  low potassium levels (hypokalemia), since
  digoxin normally competes with K+ ions for
  the same binding site on the Na+/K+ ATPase
  pump.
                                                 104
                      Common SEs
•   Loss of appetite,
•   Nausea,
•   Vomiting,
•   Diarrhea,
•   Blurred vision,
•   Visual disturbances (yellow-green halos),
•   Confusion,
•   Drowsiness,
•   Dizziness,
•   Nightmares, agitation, and/or depression, as well as a
    higher acute sense of sensual activities.
                                                             105
         Less frequent adverse effects

•   Acute psychosis,
•   Delirium,
•   Amnesia,
•   Shortened QRS complex,
•   Atrial or ventricular extrasystoles,
•   Paroxysmal atrial tachycardia with AV block,
•   Ventricular tachycardia or fibrillation,
•   Heart block                                    106
            DIGITOXIN (C41H64O13)
• Bioavailability >>>>> 95% (Oral)
• Metabolism >>>> Liver

• Half life >>>   5-7 days
• Excretion >>>>> Liver



                                     107
• It has similar structure and effects to digoxin
  (though the effects are longer-lasting).



• Unlike digoxin (which is eliminated from the body
  via the kidneys), it is eliminated via the liver, so
  could be used in patients with poor or erratic
  kidney function.
                                                    108
                       Toxicity

• Digitoxin exhibits similar toxic effects to the more-
  commonly used digoxin, namely:
• anorexia,
• nausea,
• vomiting,
• diarrhea,
• confusion,
• visual disturbances,
• cardiac arrhythmias.                              109
Ouabain OR Strophanthin
      (C29H44O12)




                          110
• poisonous cardiac glycoside
• found in the ripe seeds of African plants
  Strophanthus gratus
• potent sodium pump inhibitor




                                              111
• classical mechanism of action of ouabain involves
  its binding to and inhibition of the plasma
  membrane Na+/K+-ATPase (sodium pump)
  especially at the higher concentrations attainable
  with intravenous dosage.




                                                  112
• Inhibition of the sodium pump and the
  secondary effect on the handling of calcium
  ions by sodium calcium exchanger (NCX) is
  widely believed to underlie the original
  beneficial effect as an inotropic agent following
  intravenous use of ouabain; digoxin is a
  structurally related and more lipophilic cardiac
  glycoside that largely replaced ouabain for
  therapy because of its superior bioavailability
• Digoxin continues to be used therapeutically for
  many of the same indications in which ouabain was
  used (including atrial fibrillation and congestive
  heart failure).
                                                113
• In addition to the classical mechanism of action of
  ouabain, a small number of reports spanning the
  last 30–40 years have observed that low (i.e.,
  subnanomolar) concentrations of ouabain may
  sometimes stimulate the Na-K-ATPase. e.g.,
• This stimulatory effect does not appear to be
  mimicked by digoxin.


                                                  114
   Endogenous ouabain and ouabain
              mimics
• In 1991, a potent sodium pump inhibitor was
  isolated from the human circulation and identified
  as ouabain.
• Several additional observations led to the view that
  the circulating ouabain in humans was an
  endogenous hormone.



                                                  115
• A reinterpretation of a portion of the analytical data
  led to the proposal that endogenous ouabain may
  have been the 11 epimer, i.e., an isomer of plant
  ouabain.

• However, this possibility has been excluded by the
  synthesis of the 11 epimer and the demonstration
  that it has different chromatographic behavior from
  ouabain.                                         116
• There is compelling analytical evidence that
  ouabain is synthesized in the adrenal gland.

• A ouabain-like factor may also be made in the
  hypothalamus and possibly the heart where it
  may be stimulated by oxygen deficiency.



                                                  117
• In the latter instances, analytical data are needed to
  support the identity of the secreted materials.

• Further, secretion is not equivalent to biosynthesis;
  most all tissues sequester ouabain from the circulation.

• When such tissues are removed from the circulation they
  secrete ouabain but this phenomenon, by itself, is not
  proof of biosynthesis.
                                                           118
• The mode of action and significance of physiological levels
  of endogenous ouabain are under active investigation.

• In human plasma from healthy individuals, the circulating
  levels are normally distributed in the population and range
  typically from 30 - 380 pM. Significantly higher levels of
  endogenous ouabain that may approach or even exceed 1
  nM have been observed in many patients with congestive
  heart failure, essential hypertension, renal failure and some
  cancers.

                                                          119
   Dose related effects of ouabain

• It has been suggested that
  physiological concentrations of
  ouabain promote cell growth and in
  some manner stimulate the Na+/K+-
  ATPase activity while the higher
  levels achieved during intravenous
  therapy or in pathophysiological
  disorders may inhibit the Na+/K+-
  ATPase
                                     120
                          Uses
• Ouabain isolated from plants is widely used by
  scientists in in vitro studies to specifically block the
  sodium pump (Na-K-ATPase).

• In many non rodent species, low concentrations of
  this substance (i.e., in the subnanomolar range)
  may stimulate the Na-K-ATPase.

• The mechanism of the stimulatory effect is not
  understood and remains controversial                121
• Ouabain is no longer widely used for the treatment
  of human heart failure.



• However, intravenous ouabain has a long
  history in the treatment of heart failure, and
  some continue to advocate its use
  intravenously and per os (orally) in angina
  pectoris and myocardial infarction.              122
• The parenteral absorption seems to be better.

• There is some evidence for a highly significant
  efficacy of ouabain by several thousand
  patients by several observational studies and
  two double-blind studies with 30-40 patients
  each

• no well controlled research exists that proves or
  disproves the efficacy the per os practice.         123
• Extracts containing ouabain have long been
  used by Somali tribesmen and other groups to
  poison hunting arrows




                                            124
          Other mechanical therapies
• There are several devices available for clinical use
  and many more are actively being developed.
• For instance, there are currently left ventricular
  assist devices that are approved for use as a
  temporary mode of circulatory support in very ill
  patients until a transplant can be performed.




                                                    125
• Studies examining the possible role of these
  mechanical assist devices on a long term basis as
  permanent self-contained implants are ongoing.

• The current major limitation of these devices is the
  risk of infection, especially at the site where the
  device exits the body through the skin to
  communicate with its external power source.
                                                  126

				
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