Drugs act on cardiovascular system

Learning objectives: Learn about the drugs that act on cardiovascular system, their classification and mechanism of action

Introduction

Cardiovascular system is a vital network consisting of the heart, blood vessels, and blood that continuously circulates blood throughout the body to deliver oxygen and nutrients while removing cellular waste. It is also known as the circulatory system or blood-vascular system.

Note: Defibrillation does not jump-start a completely flatlined heart (asystole). This demonstration for teaching purpose, please do not try by yourself. Automated External Defibrillator (AED) are designed specifically for everyday people, including untrained bystanders, to operate simply and quickly during a sudden cardiac arrest. 

Adrenaline is another critical life-saving interventions used during a cardiac arrest, however, adrenaline and external defibrillator work in completely different ways to help the heart. Adrenaline is injected into the body during resuscitation.

• The Purpose: It stimulates the cardiovascular system to keep blood flowing to vital organs.

• How it Works: It constricts (narrows) the blood vessels. This action increases blood pressure and redirects the remaining blood flow toward the brain and the heart muscle itself. It can also increase the heart rate and the strength of heart contractions.

• Note: Adrenaline can be used for all types of cardiac arrest, including a flatline.

Heart physiology

Heart works as a mechanical and electrical pump to circulate blood and maintain oxygen delivery throughout the body.

A typical human heart has four separate chambers that work together to pump blood through your body.

Upper Chambers (Atria) [remember: blood arrives through atria]

• Right Atrium: This chamber receives oxygen-poor blood from the body and sends it to the right ventricle.

• Left Atrium: This chamber receives oxygen-rich blood from the lungs and sends it to the left ventricle.

Lower Chambers (Ventricles)[remember: blood vacates through ventricle]

• Right Ventricle: This muscular chamber pumps oxygen-poor blood to the lungs.

• Left Ventricle: This is the largest and strongest chamber. It pumps oxygen-rich blood out to the rest of the body.

Dividing Walls (Septa)

• Atrial Septum: A wall of tissue that separates the right and left atria.

• Ventricular Septum: A thick wall that separates the right and left ventricles.

• These walls stop oxygen-rich and oxygen-poor blood from mixing

See video illustration at medmovie.com.

Heart valves 

Heart valves are one-way tissue flaps that keep blood flowing in the correct direction through heart's four chambers.

The Four Heart Valves

• Tricuspid Valve: Sits between the right atrium and right ventricle, controlling blood flow into the lower right chamber from the right atrium.

• Pulmonary Valve: Sits between the right ventricle and the pulmonary artery, sending blood to the lungs for oxygen.

• Mitral Valve (Bicuspid): Sits between the left atrium and left ventricle, passing oxygen-rich blood into the main pumping chamber.

• Aortic Valve: Sits between the left ventricle and the aorta, sending oxygen-rich blood out to the rest of the body.

How They Work

• They open to let blood pass forward during a heartbeat.

• They close tightly to stop blood from flowing backward.

• Their snapping shut creates the distinct "lub-dub" sounds of eartbeat.

To remember the order of Heart Valves (Blood Flow), use Try Pulling My Aorta to recall the sequential path blood takes through the four heart valves:

• T – Tricuspid valve (right atrium to right ventricle)

• P – Pulmonary (or pulmonic) valve (right ventricle to lungs)

• M – Mitral (bicuspid) valve (left atrium to left ventricle)

• A – Aortic valve (left ventricle to body)

[Watch: Human Heart Anatomy: Structure and Function Explained 3D Animation; Heart Valves Explained]

Inotropy and inotropic effect

Inotropy [Greek Inos=fiber; trepein=to influence] is the strength of heart contraction. It is often termed as Left Ventricular End-Diastolic Pressure (LVEDP ). It is the pressure in the heart's main pumping chamber (left ventricle) right before it contracts. It is a primary marker of preload (the stretch on the heart walls). Chronically high LVEDP points to heart failure or a stiff heart muscle. The normal range in adult is 4 – 12 mmHg.

Inotropic effects is the effect of a drug that change the strength of heart muscle contractions when it pumps blood. 

Positive Inotropic Effect

A positive inotropic effect increases the force of heart's contractions. This helps a weak heart pump more blood through the body with each beat.

• How it works: These agents raise calcium levels inside the heart muscle cells, which makes the muscle squeeze harder.

• Medical uses: Positive inotropic drugs are used in critical conditions like severe heart failure, cardiogenic shock, or sepsis.

• Common examples:

• Calcium [Calcium ions enter cardiac muscle cells through voltage-gated L-type calcium channels during an action potential>This entry triggers a much larger release of calcium from the internal storage site called the sarcoplasmic reticulum> Free calcium binds to troponin C, allowing myosin heads to bind to actin, which shortens the muscle fibers and creates a stronger contraction.

• Digoxin [Digoxin blocks the Na+/K+ ATPase pump in cardiac cell membranes>This action raises internal sodium levels, lower the sodium-calcium exchange outside cell, which then increases calcium availability inside the cell> More calcium leads to a stronger and more forceful contraction of the heart muscle. Additionally, increases vagal tone, slows heart rate and atrioventricular conduction (parasympathetic effect)]

• Milrinone (Phosphodiesterase-3 (PDE3) Inhibitior) [blocks the PDE3 enzyme in cardiac and vascular tissue>this prevents the breakdown of cyclic adenosine monophosphate (cAMP)>Higher cAMP levels cause more calcium to enter heart muscle cells, which increases contractility (positive inotropy)>It also relaxes vascular smooth muscle, leading to peripheral and pulmonary vasodilation (afterload reduction).]

• Dobutamine [Dobutamine mainly targets beta-1 adrenergic receptors in the heart muscle> This stimulation increases the force of myocardial (heart muscle) contraction, which is the definition of a positive inotropic effect>By making each heartbeat stronger (improved cardiac output), it increases stroke volume and overall blood flow from the heart.]

• Dopamine [Dopamine's exerts dose-dependent response. At intermediate doses (3 to 10 mcg/kg/min), it stimulates beta-1 (β₁) adrenergic receptors directly and causes the release of norepinephrine (noradrenaline) from nerve endings. This increases heart contractility (inotropic effect) and heart rate (chronotropic effect). At low doses (1 to 2 mcg/kg/min), it mainly stimulates dopamine (D₁) receptors, leading to blood vessel dilation in the kidneys and brain without major changes to heart contractility. At high doses (above 10 mcg/kg/min): Alpha (α) receptor stimulation takes over, causing blood vessel constriction and raising blood pressure.]

• Adrenaline (Epinephrine) [Adrenaline binds to beta-1 (β1) adrenergic receptors on the heart> this binding activates cyclic AMP (cAMP) as a second messenger> it increases calcium entry into heart cells, which causes a more forceful squeeze of the heart muscle.]

• Noradrenaline [Noradrenaline binds to β₁ adrenergic receptors in the heart muscle> This binding increases myocardial contractility (inotropy), causing the heart muscle to squeeze harder and pump blood more effectively> exerts a powerful alpha-1 (α₁) vasoconstriction (raising blood pressure), its concurrent β₁ activity provides mild-to-moderate inotropic support.]

• Isoprenaline (non-selective β-adrenergic agonist) [Isoprenaline binds to β1 receptors in the heart> increases intracellular calcium inside cardiac muscle cells> this influx of calcium raises cardiac contractility (the positive inotropic effect) and speeds up the heart rate (the positive chronotropic effect)> Together, these actions increase overall cardiac output.]

Mnemonic: "Positive Inotropic Drugs Can Dig Million Double Decker without Adding NormAl Insurance" for the above order.

Negative Inotropic Effect

A negative inotropic effect decreases the force of the heart's contractions. This lowers the heart's workload and reduces its need for oxygen.

• How it works: These agents block certain stress signals or lower the flow of calcium into heart cells, making the muscle relax and beat with less force.

• Medical uses: Negative inotropic drugs are prescribed for long-term control of high blood pressure, chest pain (angina), and fast or irregular heart rhythms.

• Common examples:

• Amiodarone [Amiodarone is an antiarrhythmic drug that controls these signals by acting on multiple cellular "channels": blocking all the Potassium, Sodium and Calcium Channels. Potassium Channel blocking is its main action (Class III antiarrhythmic). It delays how fast heart cells reset after a beat, making the resting period (refractory period) longer. This prevents cells from firing too early or out of control. It slows down the speed of Sodium and Calcium Channels at which electrical signals travel through the heart tissue. In addition it blockis Beta Receptors, calms the heart's response to adrenaline, which helps lower a fast heart rate.]

• Beta-blockers like atenolol, metprolol and propranolol

• Calcium channel blockers, specificly, non-dihydropyridine calcium channel blockers like verapamil, diltiazem

• Digoxin (digoxine at high dose exerts negative inotropic effect, increase vagus stimulation)

Chnotropy 

Chnotropy [Greek Chrono=time; trepein=to influence] is the rate of heart beat with time. 

Afterload or Systemic Vascular Resistance (SVR)

Afterload is the total resistance the left ventricle must overcome to push blood throughout the rest of the body. It represents afterload—how constricted or dilated your blood vessels are. High SVR means the heart has to work much harder to pump.

The normal range of afterload in adult is 800 – 1200 dyn·s/cm⁵.

How They Connect: The Pressure-Volume (PV) Loop

In cardiology, these values are mapped on a graph to evaluate cardiac performance:

• The Curve Relationships:

• EDPVR (End-Diastolic Pressure-Volume Relationship): Describes the baseline "stiffness" or compliance of the relaxed heart. If your heart muscle is scarred or thick, the EDPVR slope increases, meaning even a small amount of blood volume causes a spike in EDP/LVEDP, leading to fluid backing up into the lungs (pulmonary congestion).

• ESPVR (End-Systolic Pressure-Volume Relationship): Measures inotropy (the heart's structural contractility or pumping strength). A steeper ESPVR line means a strong, highly contractile heart that can achieve high ESP with less leftover blood volume.

• The Interplay with SVR: If SVR (vessel resistance) spikes—such as during severe hypertension—the heart must generate a higher ESP just to open the aortic valve. Because it is harder to push the blood out, the heart empties less completely (higher end-systolic volume). To compensate on the next beat, the heart fills more, which increases the stretch and elevates the LVEDP.

Heart conduction system

•Sinoatrial (SA) Node:

Located in the right atrium, the SA node is the heart's natural pacemaker. It generates electrical impulses that initiate each heartbeat.

•Atrioventricular (AV) Node:

Located between the atria and ventricles, the AV node acts as a gatekeeper, briefly delaying the electrical signal before it passes to the ventricles. This delay allows the atria to fully contract and push blood into the ventricles.

•Bundle of His:

A pathway that transmits electrical impulses from the AV node to the ventricles.

Bundle Branches:

The bundle of His splits into right and left bundle branches, which conduct electrical signals to the ventricles.

•Purkinje Fibers:

These fibers extend through the ventricular walls, ensuring coordinated contraction of the ventricles. 

Reference: Medicalmania007

Heart-s-Conduction-System-Explained-heart-from@dailycardiology

Clonidine (and Guanfacine)

Clonidine is a prescription medication classified as a centrally acting alpha-2 adrenergic agonist and  used to treat hypertensive urgency and ADHD. Stopping clonidine quickly may cause rebound hypertension.

Indications

• High blood pressure (hypertension) including hypertensive urgency: Lowers blood pressure by decreasing heart rate and relaxing blood vessels.

• Attention Deficit Hyperactivity Disorder (ADHD): Clonidine is used in the second-line treatment in Attention Deficit Hyperactivity Disorder (ADHD) after stimulants (e.g. methylphenidate). It is used often as extended-release tablets or oral suspension for children ages 6 and older and adults to help control attention and impulsivity. 

• Tourette Syndrome: Specifically for intractable tics associated with TS.

• Off-label and other uses: Sometimes prescribed for substance withdrawal (alcohol, opioids, nicotine), menopausal hot flushes, migraine prevention, sleep disturbances, and anxiety or PTSD-related hyperarousal.

Mechanism of action

Clonidine is a centrally-acting alpha-2 receptor agonists and it stimulates alpha-2 receptors in the brain stem. This reduces sympathetic nervous system outflow [Sympatholytic (inhibits fight-or-flight response)], reduces  central adrenergic outflow lowering neuronal norepinephrine release to the heart and systemic circulation, which slows the heart rate, relaxes peripheral blood vessels, and lowers blood pressure.

Common Side Effects

• Rebound hypertension with abrupt cessation

• Dizziness or lightheadedness

• Dry mouth

• Constipation, nausea, or fatigue

• CNS depression

• Bradycardia, hypotension, respiratory depression, miosis

• Impotence

Does not decrease renal blood flow (MB)

Important Safety Warnings

• Do not stop abruptly: Stopping clonidine suddenly can cause severe withdrawal symptoms and rebound hypertension (a dangerous, rapid spike in blood pressure accompanied by nervousness, headaches, or agitation). It must be tapered down slowly under a doctor's supervision.

• Forms: Available as immediate-release tablets, extended-release tablets, transdermal skin patches, and injections. Extended-release tablets must be swallowed whole and never crushed or chewed.

Reference: Clonidine (and Guanfacine)

Further reading

• Cardiovascular physiology with clinical correlation 

•  Basics of ECG

•  Stroke volume

Memory tricks

• Learn seven common drug endings

•  Do not mix Calcium Channel Blockers

•  Stroke volume