Cardiovascular Pharmacology

1. Pulmonary and Systemic Circulation

• Veins transport blood to the heart; arteries transport blood from the heart.
• Pulmonary circulation (small circulation):
  1. Right ventricle (RV) → 2. Pulmonary valve → 3. Pulmonary arteries → 4. Lungs (O₂ exchange) → 5. Left atrium (LA) → 6. Mitral valve.
• Systemic circulation (big circulation):
  7. Left ventricle (LV) → 8. Aortic valve → 9. Aorta → 10. Body tissues (CO₂ exchange) → 11. Cava veins → 12. Right atrium (RA) → 13. Tricuspid valve.

2. Cardiac Electrical Activity and Pacemakers

• Sinoatrial (SA) node: Primary pacemaker, initiates impulse → atrial contraction → impulse to AV node.
• Atrioventricular (AV) node: Delays and spreads impulse to ventricles → initial ventricular contraction.
• AV bundle (Bundle of His): Conducts impulse to right and left bundle branches → Purkinje fibers → ventricular contraction.

3. Electrophysiology of Pacemaker Cells (SA and AV Nodes)

4. Electrophysiology of Cardiac Muscle Cells

5. Intracellular Calcium and Contraction

• Action potential propagates into cardiac muscle via T-tubules.
• Voltage-dependent Ca²⁺ channels open → Ca²⁺ influx triggers release of Ca²⁺ from sarcoplasmic reticulum.
• Ca²⁺ is essential for cardiac muscle contraction.

6. Key Physiological Parameters

• Cardiac output is regulated by neurohormonal mechanisms involving pressure sensors, CNS, sympathetic and parasympathetic nervous systems, and the renin-angiotensin-aldosterone system (RAAS).
• These regulatory systems are critical targets for cardiovascular pharmacology.

Cardiac output ($CO$) is the product of heart rate ($HR$) and stroke volume ($SV$):
$CO = HR \times SV$

1. Basic Aspects of Cardiac Function

• Preload: Degree of stretch of cardiac myocytes at end of ventricular filling (diastole), influenced by venous return volume.
• Afterload: Pressure the heart must overcome to eject blood during systole.
• Peripheral Vascular Resistance (PVR): Total resistance to blood flow in systemic vessels (excluding lungs), influenced by:
  • Vessel diameter (vasoconstriction increases resistance, vasodilation decreases it)
  • Blood viscosity (thicker blood increases resistance)
• Blood Pressure (BP): Force exerted by blood on arterial walls (mmHg), depends on cardiac output (CO) and PVR.
  • Hypertension: ↑BP mainly due to ↑PVR (vasoconstriction), CO usually normal.
  • Hemorrhage/dehydration: ↓BP mainly due to ↓CO; PVR may be normal or increased in critical organs as a defense mechanism.

2. Frank-Starling Mechanism

• Intrinsic autoregulation of CO: heart matches output to venous return without autonomic nervous system (ANS) input.
• Sequence: Venous return → Preload → Myocardial fiber stretch → Force of contraction → Stroke volume.
• More ventricular filling during diastole → stronger systolic contraction (within physiological limits).

3. Autonomic System Regulation of Cardiac Function

4. Cardiac Diseases in Veterinary Medicine

• Common in dogs and cats (~10% dogs, 15% cats).
• Most frequent:
  • Hypertrophic cardiomyopathy (HCM)
  • Myxomatous mitral valve disease (MMVD) in small breeds
  • Dilated cardiomyopathy (DCM) in large breeds
• 94% acquired, ~6% congenital.
• Mean diagnosis age: 9 years (dogs), 8 years (cats).

5. Drug Therapy Objectives in Heart Failure

• Improve cardiac output (CO).
• Maintain blood pressure (BP) and tissue perfusion.
• Minimize cardiac workload.
• Alleviate clinical signs.
• Optimize quality of life (QoL).

6. Classification of Cardiovascular Drugs

The main goal of cardiovascular drug therapy is to block harmful compensatory mechanisms in heart diseases that often progress to heart failure.

1. Sympathomimetic Inotropic Drugs

Dobutamine

• Used mainly for emergency management of heart failure, especially dilated cardiomyopathy without atrial fibrillation.
• Mechanism: activates myocardial β₁ receptors → increases cAMP → raises intracellular Ca²⁺ → positive inotropic effect (increased contractility and stroke volume).
• Minimal effect on heart rate (HR).
• Very short half-life (1–2 min), requiring continuous rate infusion (CRI).

Dopamine

• Positive inotrope increasing cardiac contractility and stroke volume, with additional chronotropic effects and vasodilation at low doses.
• At higher doses, causes vasoconstriction via α₁ receptors → increases peripheral vascular resistance and blood pressure.
• Used mainly for hypotension during anesthesia and noncardiogenic shock (IV CRI).
• Dose-dependent cardiovascular effects.

2. Cardiac Glycosides: Digoxin

• Derived from Digitalis purpurea; digoxin is the clinically relevant compound.
• Mechanism: inhibits Na⁺/K⁺ ATPase → increases intracellular Na⁺ → reduces Ca²⁺ extrusion → raises intracellular Ca²⁺ → positive inotropic effect.
• Effects:
  • Improves myocardial contractility and ejection fraction → increases cardiac output (CO).
  • Prolongs AV node refractory period → slows AV conduction → reduces HR; useful in supraventricular tachyarrhythmias.
  • Promotes neurohormonal normalization by reducing sympathetic activity.
  • Mild diuretic effect.

Pharmacokinetics

• Good oral absorption (75–90%), peak plasma concentration at ~90 min.
• Half-life varies (15–50 h), requiring individualized dosing and careful monitoring due to narrow therapeutic window.
• Undergoes enterohepatic circulation and urinary excretion.

Clinical Uses

• Congestive heart failure (CHF), especially systolic failure (though newer drugs are preferred).
• Atrial fibrillation management.

Adverse Effects and Contraindications

• Side effects: anorexia, depression, mild GI symptoms (nausea, vomiting, diarrhea), neurological signs, ECG abnormalities, potential fatal arrhythmias.
• Contraindicated in hypokalemia and hypercalcemia due to increased arrhythmogenic risk.
• Avoid in ventricular fibrillation.

Toxicity Management

• Discontinue digoxin and measure serum concentration.
• Use antiarrhythmic therapy if needed.
• Antidigoxin antibodies can be used for rapid recovery but are expensive.

3. Inodilators: Pimobendan

• Combines positive inotropic and vasodilatory effects.
• Widely used in heart disease treatment, especially CHF.
• Demonstrates improved survival and a favorable safety profile.

Key point: Positive inotropic drugs like dobutamine, dopamine, digoxin, and pimobendan improve cardiac contractility through different mechanisms, but their clinical use depends on specific cardiovascular conditions, pharmacokinetics, and safety profiles.

1. Antiarrhythmic Drugs: Overview

Arrhythmias are disturbances in cardiac rhythm characterized by abnormalities in rate, regularity, origin, or conduction of electrical impulses. They can result from heart diseases or drug effects and may cause cardiac output compromise.

2. Classification of Arrhythmias

Common causes:

• AV node blocks (1st, 2nd, 3rd degree)
• Ectopic pacemaker activity
• Autonomic nervous system imbalance (sympathetic vs parasympathetic)

3. Mechanism of Antiarrhythmic Drugs

• Modify impulse formation and/or conduction to restore or maintain normal rhythm.
• Mainly act by:
  • Blocking ion channels: Na⁺, K⁺, or Ca²⁺ channels
  • Inhibiting sympathetic β-adrenergic activity (β-blockers)

Each drug class targets specific ion channels or receptors, affecting distinct phases of the cardiac action potential (AP).

4. Class I Antiarrhythmic Drugs: Na⁺ Channel Blockers

Mechanism: Bind to α-subunit of Na⁺ channels → reduce phase 0 depolarization → decrease conduction velocity and modify refractory period.

5. Key Drugs in Class I

a) Procainamide (Class IA)

• Acts on SA node, AV node, and Purkinje fibers.
• Clinical use: ventricular and supraventricular arrhythmias.
• Adverse effects: gastrointestinal signs (vomiting, diarrhea), hypotension.
• Not first-line due to side effects.

b) Quinidine (Class IA)

• Prolongs refractory period of atrial muscle.
• Clinical use: management of certain arrhythmias.
• Rarely used due to side effects and availability of better alternatives.

c) Lidocaine (Class IB)

• Preferentially affects abnormal ventricular tissue.
• Rapid onset, commonly used for ventricular arrhythmias.
• Minimal effect on SA and AV nodes.

6. Summary Table: Class I Antiarrhythmics

Key point: Antiarrhythmic drugs act by modifying ion channel activity or sympathetic tone to restore normal cardiac rhythm; Class I drugs block Na⁺ channels with subclass-specific tissue selectivity and clinical applications.

1. RAAS Inhibitors and Indirect Cardiac Function Modulation

The Renin-Angiotensin-Aldosterone System (RAAS) plays a crucial role in regulating blood pressure (BP) and fluid balance. In conditions with decreased cardiac output (CO) or renal perfusion, RAAS activation acts as a compensatory mechanism to restore BP and volume, but chronic activation contributes to cardiovascular pathology.

a) RAAS Inhibitors: Mechanism and Effects

• ACE Inhibitors (ACEIs) block the conversion of angiotensin I to angiotensin II, reducing vasoconstriction and aldosterone secretion.
• This leads to vasodilation, decreased sodium and water retention, and ultimately lower BP.
• RAAS inhibition reduces cardiac remodeling and improves outcomes in heart failure and hypertension.

b) Clinical Implications of RAAS Inhibition

c) Adverse Effects and Cautions

• Common adverse effects include hypotension, impaired contractility, and gastrointestinal (GI) signs.
• RAAS inhibitors can inhibit P-glycoprotein, leading to significant drug interactions.
• Careful monitoring is required in patients with renal impairment or electrolyte imbalances.

d) Summary of Indirect Cardiac Modulation

• RAAS inhibitors do not act directly on myocardial cells but improve cardiac function by modulating systemic vascular resistance and fluid balance.
• They are essential in managing heart failure, hypertension, and conditions with maladaptive RAAS activation.
• Their use complements direct antiarrhythmic and inotropic therapies by addressing underlying pathophysiology.

Key point: RAAS inhibitors improve cardiac function indirectly by reducing afterload and preventing maladaptive remodeling through inhibition of angiotensin II and aldosterone effects.

1. RAAS Inhibitors

ACE Inhibitors (ACEIs)

• Mechanism of Action (MoA): Inhibit angiotensin-converting enzyme → ↓ angiotensin II and aldosterone production.
• Main effects:
  • Mixed vasodilation (arterial + venous) → ↓ afterload and preload.
  • Increased Na⁺ and H₂O excretion → ↓ plasma volume → ↓ preload.
  • Protect renal, cardiac, and vascular tissues from angiotensin II and aldosterone damage.
• Clinical relevance:
  • Cornerstone in chronic heart failure management; slows pathological remodeling of heart, vessels, kidneys.
  • Common veterinary ACEIs: captopril, enalapril, benazepril.
• Pharmacokinetics (Pk):
  • Administered orally as prodrugs; converted in liver to active forms (enalaprilat, benazeprilat).
  • Benazeprilat eliminated via renal and enterohepatic routes; others mainly renal.
• Adverse effects (AEs):
  • Symptomatic hypotension (vasodilation).
  • Risk of acute renal injury (ARI) in dehydrated animals.
  • Hyperkalemia if K⁺ supplements given (can be beneficial chronically, even with renal failure).

Angiotensin II Receptor Blockers (ARBs)

• MoA: Directly block angiotensin II type 1 (AT-1) receptor → more effective blockade of angiotensin II effects than ACEIs.
• Example: Telmisartan (high affinity and selectivity for AT-1 receptor).
• Pharmacokinetics:
  • Half-life: 5 h (dogs), 8 h (cats).
  • Oral absorption enhanced with food.
• Clinical uses:
  • Systemic hypertension.
  • Proteinuria in chronic kidney disease.
  • Alternative to ACEIs if ineffective or not tolerated.
• AEs: Mild, transient hypotension.

Aldosterone Receptor Antagonists (Mineralocorticoid Receptor Blockers)

• Example: Spironolactone.
• MoA:
  • Increases urinary Na⁺ and H₂O excretion, decreases K⁺ excretion → reduces preload.
  • Blocks aldosterone-mediated pathological cardiac remodeling (inflammation, hypertrophy, fibrosis).
• Pharmacokinetics:
  • Rapid GI absorption; converted to active metabolites.
  • Bioavailability highest (80–90%) when given with food.
• Clinical use: Adjunctive therapy in stage C and D heart failure, especially secondary to myxomatous mitral valve disease (MMVD).

2. Vasodilators

Rationale: Vasodilation → ↓ peripheral vascular resistance (PVR) → ↓ preload, afterload, or both → reduces cardiac workload.

3. Calcium (Ca²⁺) Antagonists and Other Vasodilatory Drugs

Calcium Channel Blockers (CCBs)

• Primarily arteriolar dilators → reduce afterload.
• Example: Amlodipine.
• Used to treat hypertension and reduce cardiac workload by decreasing systemic vascular resistance.

Nitrovasodilators

• Example: Nitroglycerin.
• Venous dilators → reduce preload by venous pooling.
• Useful in acute heart failure to decrease cardiac filling pressures.

Key point: Vasodilators reduce cardiac workload by lowering preload, afterload, or both, thus improving heart failure symptoms and outcomes.

1. Antihypertensive Therapy

Hypertension is defined as a sustained, abnormal increase in systemic arterial blood pressure (BP) that raises the risk of damage to vital organs such as the kidneys, heart, CNS, arteries, and eyes.

2. Goals of Antihypertensive Therapy

• Achieve a progressive and gradual reduction in BP to normal or near-normal values.
• Three main mechanisms of action (MoA) for antihypertensive drugs:
  1. Reducing cardiac output (CO) – less convenient.
  2. Reducing circulating blood volume (e.g., diuretics) – not first choice.
  3. Vasodilation – best and first-line option to lower BP.

3. Vasodilators in Antihypertensive Therapy

a) Organic Nitrates (Nitrovasodilators)

• Examples: Nitroglycerin (topical), Nitroprusside sodium (IV continuous rate infusion).
• MoA: Act as exogenous sources of nitric oxide (NO), which activates guanylate cyclase → increases intracellular cyclic GMP → vascular smooth muscle relaxation.
• May also stimulate synthesis of vasodilatory prostaglandins PGI2 and PGE.
• Mainly reduce preload by venous dilation.
• Pharmacokinetics: Very short half-life (1–3 minutes), significant first-pass metabolism.
• Adverse effects: Hypotension.
• Veterinary use limited due to inconvenient dosage forms and brief duration.

b) Hydralazine Hydrochloride

• Selective arteriolar vasodilator → reduces peripheral and pulmonary vascular resistance (VR), decreases afterload → improves stroke volume (SV) and cardiac output (CO).
• Clinical use: Management of congestive heart failure (CHF), especially secondary to mitral valve disease (MMVD).
• Pharmacokinetics: Rapid oral absorption, onset in 1 hour, peak effect at 3–5 hours.
• Adverse effects: Tachycardia (common), hypotension.

c) Calcium Channel Blockers (Ca²⁺ Antagonists)

• Antihypertensive effect of amlodipine appears after 4–5 days of treatment.

d) Other Vasodilators

• Sildenafil: Oral phosphodiesterase V (PDE5) inhibitor → prevents cGMP degradation → vasodilation in systemic and pulmonary vasculature. Used for pulmonary hypertension.
• Carvedilol: Nonselective β₁ and β₂ antagonist and α₁ antagonist → used for hypertension and heart failure; limited veterinary data.

Key point: Vasodilation is the preferred mechanism for antihypertensive therapy, aiming to reduce vascular resistance and lower blood pressure effectively and safely.