Cardiovascular Drugs

• Drugs Covered
  • Spironolactone
  • Prazosin
  • Hydralazine hydrochloride
  • Amlodipine
  • Nitroglycerin
  • Isosorbide dinitrate
  • Isosorbide mononitrate
  • Sildenafil
  • Carvedilol
  • Furosemide
  • Torsemide
  • Bumetanide
  • Atropine
  • Propantheline bromide
  • Isoproterenol
  • Digoxin
  • Diltiazem
  • Verapamil
  • Atenolol
  • Esmolol
  • Sotalol
  • Propranolol
  • Metoprolol
  • Lidocaine
  • Mexiletine

Mineralocorticoid Receptor Blockers (MRB): Spironolactone

• Functions as an antagonist of aldosterone receptors in the kidney's late distal convoluted tubule (DCT) and collecting ducts (CDs)
• Increases water and sodium excretion while decreasing potassium excretion
• Potassium-sparing diuretic
• Rapidly absorbed via the GI tract and converted to active metabolites
• Bioavailability is highest (80-90%) when given with food in dogs
• Recommended as adjunctive therapy for dogs with myxomatous mitral valve disease (MMVD) in ACVIM stages B2 to D
• Effective dosage of 2 mg/kg once daily and can restore the urinary Na⁺/K⁺ ratio in dogs
• Part of quadruple therapy for congestive heart failure (CHF) in dogs (ACEIs + pimobendane + furosemide + spironolactone)
• Extra-label use in cats with asymptomatic hypertrophic cardiomyopathy (HCM) showed no reduction in left ventricular mass or improvement in diastolic function
• Monitor serum electrolytes and renal values (BUN, serum creatinine) in patients

Vasodilators

• Cause relaxation of blood vessels, leading to decreased blood pressure and reduced afterload on the heart

Prazosin (α₁ antagonist)

• Produces vasodilation by adrenergic blocking on vascular smooth muscle
• Limited current use to short-term treatment of acute heart failure when other agents are ineffective or contraindicated

Hydralazine hydrochloride (Apresoline®)

• Relaxes arteriolar smooth muscle; acts as an afterload reducer
• Primarily used as an afterload reducer for adjunctive treatment in CHF and as an antihypertensive agent in dogs and cats
• Mainly used in cases of refractory heart failure associated with mitral regurgitation
• Initial dosage is 0.5 mg/Kg PO q 12, which can be adjusted upward but should not exceed 3 mg/Kg

Calcium Channel Blocking Drugs

• Suppress calcium (Ca++) ion influx through plasma membrane (PM) channels
• Located in cardiac tissues (myocardial cells), vascular smooth muscle, and other excitable cell types
• Reduction in intracellular Ca++ leads to:
  • Reduction in myocardial contractility (- inotropic effect)
  • Vasodilation in peripheral arterial beds
  • Reduced myocardial oxygen demand
  • Slowed AV impulse conduction

Amlodipine (Dihydropyridine)

• Primarily used as therapy for systemic hypertension, especially in cats and dogs
• Vasodilator actions can also benefit hemodynamics by decreasing cardiac workload
• Adverse effects: hypotension, lassitude, anorexia, and collapse

Nitrovasodilators

• Act as an exogenous source of nitric oxide (NO)
• Activate guanylate cyclase (GC), leading to the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP)
• cGMP inhibits the contraction of vascular smooth muscle (VSM)
• Decrease myocardial O₂ requirements
• Reduce the workload of the heart and decrease the availability of Ca++ in VSM
• Interfere with myosin-actin interaction
• Available Formulations: Ointments, creams, sublingual tablets, and lingual sprays
• Metabolized quickly with a half-life of a few minutes and have significant first-pass effects
• Usually used in the short-term management of acute heart failure
• Development of nitrate tolerance limits continuous use (more than 36 hours)

Nitroglycerin

• Topical ointments (2%)
• Dosage ranges from 4-15 mg q 6-12h for dogs and 3-4 mg q 6-12h for cats
• Topical formulations should be applied to hairless areas (groin, axillary area, ear pinna, or shaved portion of the body)
• Owners should wear exam gloves during application and wash hands afterward

Isosorbide dinitrate (Isordil®)

• Available as an oral tablet, topical ointment, and lingual spray (2.5 – 5.0 mg/dog)

Isosorbide mononitrate (Ismo®)

• Has better oral absorption (bioavailability ~70%)
• Available as a 2% cream, 2% ointment, and 0.2, 0.4, 0.6, and 0.8 mg/h patch

Phosphodiesterase Type 5 Inhibitor (PDE V): Sildenafil (Viagra®)

• Prevents the degradation of cyclic guanosine monophosphate (cGMP)
• Leads to relaxation of smooth muscle in the pulmonary vasculature and, to a lesser degree, systemic vessels
• PDE V is found in high concentrations in the lung
• Levels are elevated in humans with pulmonary hypertension (PHT)
• PHT is clinically important in dogs (associated with high mortality) and is often a sequelae of other diseases like chronic obstructive pulmonary disease and heartworm disease
• Use: Dogs with naturally occurring pulmonary hypertension with concurrent myxomatous mitral valve disease (MMVD)
• Dosage:0.5 – 1 mg/kg PO two or three times a day
• Decreases systolic pulmonary arterial pressure and increases exercise capacity and quality of life
• Often used in combination with other conventional heart failure therapeutics

Carvedilol: β-Adrenergic Receptor Antagonist (Nonselective)

• Receptor Affinity: β₁ = β₂ ≥ α₁ > α₂ with a β₁/β₂ to α₁-receptor antagonist potency ratio of 10:1
• Reduces myocardial workload by lowering heart rate and peripheral vascular resistance
• Blunts sympathetic nervous system (SNS) activity
• Should be initiated at a low dose (less than 0.2 mg/kg) and titrated up to 0.4 mg/kg twice a day in dogs with heart failure
• The target dose in dilated cardiomyopathy (DCM) is gradually increased until 0.5 – 1 mg/Kg twice daily is reached

Additional Therapy in Congestive Heart Failure: Diuretics

• Potent loop-acting diuretics are a key part of CHF management
• Mechanism of Action (Loop Diuretics like Furosemide, Torsemide, Bumetanide): reversible inhibition of the sodium/potassium/chloride (NKCC) cotransporter
• Chronic Oral Administration of Furosemide (Lasix®, Salix®): Dogs: 1 to 2 mg/Kg PO two to four times a day; Cats: 1 to 2 mg/Kg PO twice a day
• Parenteral Administration of Furosemide (IM or IV): Dogs: 2 to 8 mg/Kg as needed to control edema; Cats: 1 to 2 mg/Kg as needed to control edema
• Often used in combination with ACE inhibitors and pimobendane (triple therapy) or with the addition of spironolactone (quadruple therapy)
• Patients receiving diuretics should be monitored for serum electrolytes, renal values (BUN, serum creatinine), body weight, and state of hydration

Antiarrhythmic Drugs

• Arrhythmia: An abnormality in the rate, regularity, or site of origin of the electrical impulse or a disruption in impulse conduction
• Often associated with an imbalance of the parasympathetic and sympathetic branches
• Associations: changes in serum electrolyte concentrations (K⁺ and Ca⁺⁺), excessive stretch of cardiac tissue, and mechanical trauma

Classification (Vaughn Williams, 1984)

• Class I: Local anesthetics (e.g., Lidocaine, Mexiletine)
• Class II: β-adrenergic blockers (e.g., Atenolol, Esmolol, Sotalol, Propranolol, Metoprolol, Carvedilol)
• Class III: Potassium channel blockers (e.g., Sotalol)
• Class IV: Calcium channel blockers (e.g., Diltiazem, Verapamil)

Bradyarrhythmia

• Heart rates below the normal range
• May be responsive to drugs that increase heart rate by decreasing vagal tone (vagolytic) or increasing sympathetic tone

Vagolytic Drugs

• Atropine: 0.4 mg/Kg SC
• Propantheline bromide (Pro-Banthine®): Antimuscarinic agent

Increase Sympathetic Tone

• Isoproterenol (ISO): β₁ = β₂ > > > > α, increases heart rate by stimulating adrenergic receptors in the sinus and atrioventricular node

Tachyarrhythmias

• Sinus tachycardia is often a response to low blood pressure, pain, sepsis, fever, low cardiac output, or CHF
• If secondary to heart disease, treating the underlying condition with cardiac drugs like pimobendan and ACE inhibitors is indicated

Supraventricular Tachyarrhythmias (SVTA)

• Often caused by primary cardiac disease and secondary atrial enlargement
• Treatment aims to slow rapid conduction through the AV node
• Digitalis (Digoxin): Slows conduction through the AV node and reduces ventricular response rate
• Calcium Channel Blockers (Class IV): Diltiazem and Verapamil
• β-Adrenergic Receptor Blockers (Class II): Atenolol, Esmolol, Sotalol, Propranolol, Metoprolol, Carvedilol
  • Atenolol: Specific β₁-blocking drug
  • Esmolol: Ultrashort-acting blocker (half-life < 10 min), given IV (CRI) for acute termination of very fast SVTA
  • Sotalol: Non-selective β-blocker and potassium channel blocker (Class II and III)

Ventricular Tachyarrhythmias (VTA)

• Goal of treatment is to decrease the number of abnormal ventricular complexes
• Local Anesthetics (Class IB): Lidocaine
• Local Anesthetics (Class IB): Mexiletine