Positive Inotropes (Cardiovascular Therapeutics)

Cardiac Glycosides

Mechanism(s) of Action

Electrolyte changes occur with each heart beat (action potential)

• At rest
  • Sodium is high outside
  • Potassium is High inside
  • FREE Calcium is Low inside
• After the action potential goes through:
  • Sodium is higher inside
  • Potassium is Lower inside
  • FREE Calcium is higher inside

SOMETHING has to put things back where they belong AFTER the action potential. That SOMETHING is the Na/K ATPase (actually many copies of this tiny pump per cell).

Positive Inotropic Effect

• Increases [Na]_i
• Increases [Ca]_i (positive inotropic result)
• Decreases [K]_i
• lowers resting membrane potential (less negative)
• EKG changes depend on patient factors
  • [K]_o
  • [Ca]_o
  • heart rate (toxicity easier at higher rate)
  • resting sympathetic and parasympathetic tone

Effect of positive inotropic action on Cardiac Performance

Negative Chronotropic Effect of Digoxin

• Stimulates vagus centrally
  
  Increases refractoriness of AV node
  • Decreases ventricular response to atrial rate
  • Controls heart rate in atrial fibrillation
  Slows depolarization rate of SA node
  • Decreases sinus rate
  • Decreases heart rate in Sinus Tachycardia
  
  
  
• Decreases Sympathetic Tone
  
  If Contractility and Stroke Volume Increase

Pharmacokinetics (Digoxin, Digitoxin)

HIGHLY variable kinetics + VERY narrow therapeutic index = need to individualize, modify regimes

Relatively long half-lives of elimination

• Accumulation to steady state
• Loading doses employed (less often now)
• Delays following changes in therapy

100 mg Elixer dose gives 80 mg of Digoxin in the bloodstream
133 mg Tablet dose gives 80 mg of Digoxin in the bloodstream.

Plasma Concentration Determinations

Effective range = 1.0 - 2.5 ng/ml
Toxic range = 1.5 - and up

Rarely essential to a diagnosis of toxicity
Estimate of degree of overdose
Can be used to calculate dose adjustments

Toxicity

Gastrointestinal (relate to vagal effects)

• anorexia
• abdominal discomfort / pain
• vomiting
• diarrhea

Cardiac - any arrhythmia ever described (alterations in resting [electrolytes] AND vagal effects)

• Premature ventricular depolarizations
• nodal rhythms
• AV dissociation

Treatment of Toxicity

• Stop giving the drug (for a time)
• antiarrhythmics (lidocaine, procainamide, propranolol, phenytoin) IF the arrhythmias appear to be life-threatening in their own right (multi-focal pvcs, high rate ventricular tachycardia) or if the arrhythmias severely compromise cardiac output.
• Potassium (if hypokalemic)
• Cholestyramine, activated charcoal etc. to bind digoxin in GI tract and shorten half-life
• Digoxin Antibodies (therapeutic monitoring becomes irrelevant).

Drug Interactions

Changes in plasma electrolyte composition

• Adrenocorticoids
• Amphotericin B
  
• Diuretics
  
• Salts (especially calcium and potassium)

Changes in digoxin absorption

• Antacids (decrease)
• Antidiarrheal adsorbants (decrease)
• Cholesterol modifying agents (decrease)
• Laxatives (decrease)
• Sulfasalazine (decrease)

Changes in cardiac cell activity

• Sympathomimetics
• Succinylcholine

Increased plasma concentrations (probable binding interactions)

• Ca channel blockers (verapamil, diltiazem)
• Captopril
• Quinidine
• Spironolactone

Decreased plasma concentrations

• Phenylbutazone
• Thyroid hormones

Additive depression of AV conduction

• Ca channel blockers
• Parasympathomimetics

Clinical Uses

Increase contractility - all patients
Decrease heart rate - most patients but especially atrial fibrillation

Pimobendan (Vetmedin ^®)

Mechanism(s) of action:

Phosphodiesterase III inhibitor and "Calcium sensitizer" - this is a mixed action that may result in Increased force of contraction and vasodilation. The occurrence of these two outcomes (and the ratio of one to the other) is likely dose dependent.

Specific Therapeutic Objective(s):

As an inotrope:

1. Continuous inotropic support
2. Supplement with Digoxin for rate control

1. May reduce afterload
2. May reduce preload
3. May reduce pulmonary hypertension (unusual and not part of typical heart failure)

Approval:

See AnimalDrugs@fda

Evidence:

European studies compare it to Benazepril
• Lombard CW, Jons O, Bussadori CM. Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J Am Anim Hosp Assoc. 42(4): 249-61, 2006.
• Fuentes VL, Corcoran B, French A, Schober KE, Kleemann R, Justus C. A double-blind, randomized, placebo-controlled study of pimobendan in dogs with dilated cardiomyopathy. J Vet Intern Med. 16(3):255-61, 2002. This study showed a difference in survival times between cocker spaniels (no difference) and dobermans (pronounced improvement) produced by pemobendan therapy.
US studies compare it to enalapril FDA Freedom of Information Summary (this was a "non-inferiority" study): FOI

Conclusion: Promising new addition to our heart failure armamentarium. Does not eliminate need to consider digoxin, ace inhibitors, furosemide. Furosemide still needed for most dogs with advanced heart failure. Inadequate if cardiac rate control is critical. Chewable tablet dose form makes it a VERY attractive drug to use in dogs with heart failure. There is still much to learn about exactly where this drug fits in heart failure therapy.

Sympathomimetic Amines

Mechanism(s) of Action

β-1 Stimulation

• Increased force of contraction
• Increased heart rate (SA node effect by changing the slope of spontaneous depolarization)
• Increased heart rate (AV effect by increasing conduction velocity and decreasing refractory period)
• Lipolysis

β-2 Stimulation

• Bronchodilation
• Vasodilation - skeletal muscle (decreases vascular resistance and diastolic pressure)
• Decreased GI tone

α-1 Stimulation

• Vasoconstriction increases peripheral resistance and systemic blood pressure
  
• Contraction of urinary and gi sphincters

Pharmacokinetics

Absorption

• IV route (usually)
• Respiratory mucosa (for Bronchodilation, Cardiac Arrest) absorption of moderate bronchodilator doses is minimal, high doses are reasonably well absorbed

Elimination

• IV - half-lives are all 2 - 10 minutes, effects terminate rapidly when discontinued
• Respiratory mucosa, some evidence of effects can last 1 - 4 hours (usually)

Toxicity

• Cardiovascular
  • arrhythmias (supraventricular and ventricular ectopic depolarizations)
    
  • hypokalemia
  • excessive peripheral resistance
• Gastrointestinal
  • stasis
• Urinary
  • dysuria
• CNS
  • nervousness, restlessness

Drug Interactions

• Increased risk of arrhythmias
• Halogenated hydrocarbon anesthetics (halothane, methoxyflurane, enflurane, etc.)
• Cardiac Glycosides
• Electrolyte disturbances
• Reduced sympathetic effects
• α blockers
• β blockers
• Enhanced sympathetic effects
• anticholinergics
• phosphodiesterase inhibitors, theophylline
• thyroid supplementation

Clinical Uses

Epinephrine - β-1, β-2, α-1

• Cardiac arrest
• Anaphylaxis
• Emergency Bronchdilation

Norepinephrine - β-1, α-1

• Cardiac arrest
• Anaphylaxis

Isoproterenol - β-1, β-2

• Emergency support of heart rate
• Emergency support of contractility (definitely not preferred)
• Bronchodilator

Dopamine - β-1,β-2, α-1, Peripheral Dopaminergic

• Renal (Blood Flow) Shut down
• usually secondary to prolonged anesthesia
• not appropriate for decompensated chronic renal failure

Dobutamine - β-1

• Congestive Heart Failure
  
  • improving cardiac contractility
    
  • lowest potential for arrhythmias (of this class)
    
  • BENEFICIAL EFFECT MAY PERSIST FOR WEEKS to MONTHS (DOCUMENTED!)

Phosphodiesterase inhibitors

Pimobendan

Mechanism(s) of Action

• Increased force of contraction
  Phosphodiesterase inhibition
  increased cyclic AMP in myocardial cell (same biochemical effect as β-1,-2 stimulation)
  
• Reduced preload and afterload
  Direct inhibition of smooth muscle
  arterial and venous>

Clinical Uses

• management of mild, moderate or severe CHF in dogs (NYHA Class II, III or IV)
• management of signs of CHF due to atrioventricular valvular insufficiency or dilated cardiomyopathy.
• clinical experience is limited

Topic Summary (Positive Inotropes)

1. Cardiac glycosides are definitely indicated for control of tachycardia associated with congestive heart failure. The heart rate effects can be monitored (contractility effects cannot).
2. Cardiac glycoside therapy is inherently risky and difficult. You will produce some toxicity in some patients or you are not treating aggressively enough.
3. Digoxin dosage must be individualized for each patient.
4. Bioavailability of digoxin dose forms varies considerably (relative to the therapeutic index). Patient monitoring should be increased when a change is made.
5. Non-glycoside inotropes are available for emergency treatment. Some evidence exists to suggest that a short course of dobutamine may have lasting (weeks) effects on patient performance.