Drugs Affecting Cardiac Function

Introduction

This lecture focuses on drugs affecting cardiac function and vasculature. The key learning point is understanding the drug targets and drug classes rather than memorizing individual drug names. Students should understand how different drug classes affect heart rate, rhythm, and contractility. This lecture emphasizes that the aim is not to learn specific drug treatments for particular conditions at this stage but to understand the mechanisms of action of various drugs and their potential effects. This knowledge will form a foundational "toolbox" for future clinical applications.

Reassurance Regarding Drug Names

It is unnecessary to memorize specific drug names. Focus on understanding classes of drugs, such as beta-blockers, and their mechanisms of action.

Clinical Application

In clinical practice (Year 3 onwards), therapeutic decisions involve choosing specific drugs, considering administration methods, and understanding potential drug interactions. Knowing drug metabolism (how the body processes and eliminates drugs) and pharmacokinetics (how drugs move through the body) is also crucial for optimizing treatment and minimizing adverse effects.

Lecture Objectives

Understand drug targets.
Learn about drug classes affecting heart rate and rhythm.
Learn about drug classes affecting contractility.

Targets for Cardiac Drugs

The lecture refers to previous physiology lectures about the effects of prolonged sympathetic stimulation on the heart, which can lead to detrimental overcompensation. Therapies aim to:

Improve the patient's quality of life.
Slow disease progression.

Therapeutic Targets

Reducing the effects of nervous or hormonal inputs (e.g., enhanced sympathetic drive). This includes understanding the role of the autonomic nervous system and the renin-angiotensin-aldosterone system (RAAS) in cardiac function.
Improving systolic function (if muscle contraction is weak). This can involve enhancing calcium cycling within cardiac myocytes or increasing the sensitivity of contractile proteins to calcium.
Improving diastolic function (if filling is inadequate). This can be achieved by promoting myocardial relaxation and reducing stiffness of the heart muscle.
Correcting abnormal heart rates. Understanding the mechanisms underlying tachycardia (fast heart rate) and bradycardia (slow heart rate) is essential for selecting appropriate drugs.
Correcting abnormal heart rhythms. This involves identifying the type of arrhythmia (e.g., atrial fibrillation, ventricular tachycardia) and using drugs that target specific ion channels or receptors involved in the arrhythmia.
Modifying preload (if elevated) or afterload (in hypotensive cases). Understanding the Frank-Starling mechanism and the factors that determine preload and afterload is important for optimizing cardiac function.

Multiple drugs may be used to target different areas simultaneously. Combination therapy is common in managing heart failure and hypertension.

Target Organs

Vasculature (covered in the second lecture). Drugs targeting the vasculature can affect blood pressure and blood flow to the heart and other organs.
Kidney (briefly mentioned, detailed in renal teaching). The kidneys play a crucial role in regulating blood volume and electrolyte balance, which can impact cardiac function. Diuretics are often used to reduce preload in heart failure patients.
Respiratory system (covered in a separate lecture). The respiratory system provides oxygen to the heart and other tissues, and respiratory diseases can exacerbate cardiac problems. Some cardiac drugs can also affect respiratory function.

Drugs can alter heart rate, rhythm, and contractility.

Cellular Targets

Targets include ion channels, cyclic AMP levels, pumps, and phosphodiesterases. Phosphodiesterases are enzymes that break down cyclic AMP, and inhibiting these enzymes can increase cyclic AMP levels within the cell. Cyclic AMP is a second messenger that plays a critical role in regulating cardiac function.

The parasympathetic system also presents targets, including muscarinic receptors, which slow heart rate. These receptors are activated by acetylcholine released from the vagus nerve.

Calcium Handling

Calcium regulation is closely related to sodium regulation in myocytes. Calcium entry affects sodium efflux via the calcium-sodium exchanger, while sodium levels are controlled by the sodium-potassium ATPase exchange mechanism. Altering sodium levels can affect calcium levels and contractility.

Specific Drug Targets

Receptors:
- Beta-adrenergic receptors (mainly beta-1 in cardiac muscle cells). Activation of beta-1 receptors increases heart rate and contractility.
- Muscarinic receptors (highly expressed in nodal cells). Activation of muscarinic receptors slows heart rate.
Ion Channels:
- Fast sodium channels (responsible for rapid action potential upstroke). These channels are important for the rapid conduction of electrical signals in the heart.
- Slow calcium channels (allow calcium entry for contraction; also in nodal regions for slow depolarization). These channels are important for both contraction and the generation of action potentials in the sinoatrial (SA) and atrioventricular (AV) nodes.
Enzymes:
- Sodium-potassium ATPase (regulates sodium levels). This enzyme is essential for maintaining the proper ionic balance in cardiac myocytes.
- Phosphodiesterases (regulate cyclic AMP levels). Inhibition of phosphodiesterases increases cyclic AMP levels, leading to increased heart rate and contractility.

Cyclic AMP is critical for driving normal cardiac function, and its regulation can be a target for pharmacological intervention, especially in failing hearts with excessive sympathetic drive. Excessive sympathetic drive can lead to downregulation of beta-adrenergic receptors and decreased responsiveness to sympathetic stimulation.

Manipulating Heart Rate

Sustained increases in heart rate can strain the system, increase oxygen demand, and reduce diastolic filling time. This can lead to ischemia (reduced blood flow) and heart failure.

Negative Chronotropic Drugs (Decrease Heart Rate)

Muscarinic Receptor Agonists: Mimic vagus nerve stimulation to slow heart rate. Examples include atropine (side effect). These drugs are rarely used clinically to reduce heart rate due to their potential for side effects.
Cardiac Glycosides (e.g., Digoxin): Increase parasympathetic input to the heart, acting as negative chronotropic drugs. Digoxin is also a positive inotrope, meaning it increases contractility. Useful in some cases of heart failure but have a narrow therapeutic window.
Beta-Blockers (Beta-Adrenergic Receptor Antagonists): Come in various forms (beta-1 selective, non-selective). Useful in cases of tachycardia (e.g., hyperthyroidism in cats). Beta-blockers reduce heart rate and blood pressure by blocking the effects of adrenaline and noradrenaline.

It's important to note that reducing heart rate with beta-blockers also affects contractility, which may not always be desirable. Cardioselective beta-blockers (e.g., metoprolol, atenolol) primarily block beta-1 receptors in the heart and have fewer effects on beta-2 receptors in the lungs and blood vessels.

Positive Chronotropic Drugs (Increase Heart Rate)

Muscarinic Receptor Antagonists (e.g., Atropine): Block parasympathetic influence, increasing heart rate. Used to treat bradycardia (slow heart rate).
Beta-Adrenergic Receptor Agonists (e.g., Isoproterenol): Mimic sympathetic stimulation, increasing heart rate. Used in emergencies. These drugs can have significant side effects, including arrhythmias and increased oxygen demand.

Targeting Heart Rhythm (Antiarrhythmic Drugs)

Arrhythmias often occur in enlarged hearts exposed to neurohormonal mediators. Antiarrhythmic drugs target mechanisms controlling action potential generation and propagation in the muscle. Understanding the specific mechanisms underlying different types of arrhythmias is crucial for selecting the appropriate antiarrhythmic drug.

Classes of antiarrhythmic drugs interact with ion channels:

Class 1: Block fast voltage-sensitive sodium channels, decreasing the rate of signal propagation. Examples include lidocaine. These drugs are often used to treat ventricular arrhythmias.
Class 2: Beta-Blockers, reducing the risk of arrhythmias by dampening sympathetic stimulation. Effective in treating supraventricular arrhythmias.
Class 3: Inhibit potassium channels, prolonging the repolarization phase of the action potential. Example: amiodarone. Amiodarone is a broad-spectrum antiarrhythmic drug used to treat a variety of arrhythmias but can have significant side effects.
Class 4: Calcium channel antagonists. Slow conduction rate, particularly from atria to ventricles. Verapamil and diltiazem are examples of Class 4 antiarrhythmic drugs. Useful to treat supraventricular tachycardias like atrial fibrillation.

Cardiac Muscle Contractility

Positive inotropic drugs enhance the force of contraction. Several approaches can be used:

Using drugs that are positive inotropes without affecting heart rate. This is often desirable to improve cardiac output without increasing oxygen demand.
Bypassing the receptor system to improve the situation. This can be useful when beta-adrenergic receptors are downregulated or desensitized.
Improving contraction without elevating calcium further inside the cell. Excessive intracellular calcium can lead to arrhythmias and cell damage.
Cutting down the overstimulation by noradrenaline. Chronic exposure to noradrenaline can lead to downregulation of beta-adrenergic receptors and decreased responsiveness to sympathetic stimulation.

Ways to Improve Cardiac Contractility

Cardiac Glycosides (e.g., Digoxin): Inhibit sodium-potassium ATPase, increasing intracellular sodium and calcium, thereby improving contractility. Also have a central effect to reduce heart rate through increased vagal tone. Digoxin has a narrow therapeutic index, and toxicity can cause arrhythmias.
Phosphodiesterase Inhibitors: Inhibit the breakdown of cyclic AMP, prolonging its effects on contractility. Useful when beta-adrenergic receptors are downregulated in heart failure. Milrinone and inamrinone are examples of phosphodiesterase inhibitors.
Calcium Sensitizers (e.g., Levosimendan): Increase calcium sensitivity in the myocardium, improving force generation without increasing intracellular calcium. Levosimendan can improve cardiac function without increasing the risk of arrhythmias.
Sympathomimetic Drugs (Beta Agonists): Increase contractility by mimicking beta-adrenergic pathways, but may be less effective in cases where beta-adrenergic receptors are downregulated. Dobutamine and dopamine are examples of beta-agonists. Can increase heart rate and blood pressure, also increase the risk of arrhythmias.

Drugs that Decrease Contractility (Negative Inotropes)

Beta-Adrenergic Receptor Antagonists: Decrease contractility. Can be useful in patients with hypertrophic cardiomyopathy or other conditions where excessive contractility contributes to symptoms.
Sodium Channel Blockers (Class 1 and 2 Antiarrhythmic Drugs): Affect calcium handling, reducing calcium-induced calcium release and force of contraction. Can be used to treat arrhythmias but may also reduce cardiac output.
Calcium Channel Blockers: Reduce calcium entry, decreasing the force of contraction. Verapamil and diltiazem are examples of calcium channel blockers. Useful in treating hypertension and angina.

Conclusion

There are numerous ways to modulate contractility, either increasing it (positive inotropes)