Inotropic Agents & Cardiovascular Physiology

Cardiac Cycle Overview

• Encompasses all events in a single heartbeat, including diastole (relaxation) and systole (contraction)
• Divided into Atrial Systole, Isovolumetric Contraction, Ventricular Ejection, Isovolumetric Relaxation, and Ventricular Filling

Atrial Systole

• Structures Involved: Atria (left and right), atrioventricular (AV) valves (mitral and tricuspid)
• Atria contract, pushing blood into ventricles through open AV valves
• Right atrium pumps blood into the right ventricle, and left atrium pumps blood into the left ventricle

Isovolumetric Contraction

• Structures Involved: Ventricles (left and right), AV valves, semilunar valves (aortic and pulmonary)
• Ventricular contraction begins, increasing pressure inside the ventricles
• AV valves close to prevent backflow into atria, but semilunar valves remain closed initially
• No volume change occurs as ventricles contract with all valves closed

Ventricular Ejection

• Structures Involved: Ventricles, semilunar valves, arteries (aorta and pulmonary artery)
• Ventricular pressure exceeds arterial pressure, and semilunar valves open
• Blood is ejected from right ventricle into pulmonary artery and from left ventricle into aorta
• Delivers oxygenated blood to the body and deoxygenated blood to the lungs

Isovolumetric Relaxation

• Structures Involved: Ventricles, semilunar valves
• Following ejection, the ventricles begin to relax
• Semilunar valves close to prevent backflow from arteries into the ventricles
• All valves are closed, and the ventricular volume remains constant as pressure falls

Ventricular Filling

• Structures Involved: Atria, ventricles, AV valves
• Ventricular pressure drops below atrial pressure, and AV valves open
• Blood flows passively from atria into ventricles, leading to ventricular filling
• Most ventricular filling occurs during this phase, assisted by atrial contraction later

Importance of Heart Structures

• Valves: Ensure unidirectional blood flow and prevent backflow
• Chambers: Receive and pump blood effectively, with atria as primer pumps and ventricles as main pumps
• Myocardium: Thick ventricular wall facilitates strong contractions for blood ejection

Cardiac Action Potential Phases

• Series of electrical potential changes across heart muscle cell membranes, critical for initiating and propagating impulses for heart contractions

Phase 0 (Depolarization)

• Initiated when voltage-gated sodium (Na+) channels open
• Rapid influx of Na+ ions leads to sharp membrane potential rise
• Corresponds to QRS complex on ECG and represents ventricular depolarization

Phase 1 (Initial Repolarization)

• Na+ channels close, and transient outward potassium (K+) currents occur
• Results in a slight decrease in membrane potential

Phase 2 (Plateau Phase)

• Opening of voltage-gated calcium (Ca2+) channels occurs
• Balance between Ca2+ influx and K+ efflux maintains a plateau
• Corresponds to ST segment on ECG, representing sustained depolarization of ventricles

Phase 3 (Repolarization)

• Calcium channels close; continued efflux of K+ occurs
• Results in return of membrane potential to its resting state
• Corresponds to the T wave on an ECG, which represents ventricular repolarization

Phase 4 (Resting Membrane Potential)

• The cell returns to its baseline electrical state
• Maintained by Na+/K+ ATPase and ion exchange mechanisms
• Prepares cell for next action potential

Conduction System of the Heart

• Ensures action potential propagation for coordinated contraction

Sinoatrial (SA) Node

• The heart's natural pacemaker
• Initiates action potential that spreads through atria

Atrioventricular (AV) Node

• Receives impulse from atria and delays allowing ventricular filling
• Transmits impulse to ventricles through His-Purkinje system

Bundle of His and Purkinje Fibers

• Conduct action potential to ventricles, ensuring rapid and coordinated contraction

Relation to Electrocardiographic Tracing

• P Wave: Represents atrial depolarization, initiated by SA node, precedes atrial contraction
• QRS Complex: Represents ventricular depolarization, the rapid upstroke (Phase 0) of action potential
• T Wave: Represents ventricular repolarization, corresponds to Phase 3 of action potential
• PR Interval: Reflects time for electrical impulse travel from atria to ventricles, includes delay at AV node
• QT Interval: Represents total time of ventricular depolarization and repolarization

Preload

• Degree of cardiac muscle fiber stretch at the end of diastole, just before contraction
• Primarily determined by ventricular end-diastolic volume (EDV)

Preload Determinants

• Venous Return: Amount of blood returning to the heart
• Circulating Blood Volume: More blood volume increases preload
• Venous Tone: Constriction of veins impacts preload
• Atrial Contraction: Efficiency of atrial contraction affects preload

Preload Effects

• Frank-Starling Law: Increased preload leads to increased stroke volume, up to a physiological limit

Afterload

• Pressure heart must work against to eject blood during systole equates to systemic vascular resistance

Afterload Determinants

• Arterial Pressure: Higher systemic arterial blood pressure increases afterload
• Aortic Valve Condition: Aortic stenosis increases afterload
• Peripheral Vascular Resistance: Increased resistance in blood vessels augments afterload

Afterload Effects

• Cardiac Output: Higher afterload reduces stroke volume, increasing force to open aortic valve and eject blood
• Ventricular Hypertrophy: Persistent high afterload leads to thickening of ventricular walls

Preload vs Afterload

• Preload is about volume filling the heart and fiber stretch; afterload is the resistance to eject blood
• Increase in preload enhances output; increase in afterload can decrease stroke volume
• Clinical relevance arises in conditions like heart failure, managed with diuretics and vasodilators

Positive Inotropic Agents

• Enhance heart's contraction force

Positive Inotropic Agents - Effects on Heart Contractility

• Increase calcium availability in cardiac muscle cells

Positive Inotropic Agents - Mechanisms

• Stimulate β-adrenergic receptors (adrenaline, dobutamine) or inhibit cyclic AMP breakdown (milrinone)
• Digitalis increases intracellular calcium by inhibiting sodium-potassium ATPase pump

Positive Inotropic Agents - Effects on Stroke Volume

• Positive inotropic agents increase stroke volume, benefiting compromised hearts

Negative Inotropic Agents

• Reduce heart's contractile force

Negative Inotropic Agents - Effects on Heart Contractility

• Decrease calcium influx or block adrenaline effects

Negative Inotropic Agents - Mechanisms

• Common examples are beta-blockers (propranolol, metoprolol) and calcium channel blockers (verapamil, diltiazem)

Negative Inotropic Agents - Effects on Stroke Volume

• Decrease SV, which is useful in conditions like hypertension or arrhythmias

Inotropic Agents - Comparison

• Positive enhances contractility; negative reduces it
• Positive increases stroke volume; negative decreases it
• Positive helps in conditions of heart failure, negative helps to reduce workload on heart

Epinephrine

• Origin: Adrenal glands produce this adrenaline
• Effect: Increases blood pressure
• Mechanism: Vasoconstriction, increased heart rate, and contractility

Antidiuretic Hormone (ADH)

• Origin: Hypothalamus produces, pituitary gland releases
• Effect: Increases blood pressure
• Mechanism: Water reabsorption in kidneys and vasoconstriction

Natriuretic Peptides

• Types: Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP)
• Origin: ANP produced by atria, BNP by ventricles
• Effect: Decreases blood pressure
• Mechanism: Vasodilation, diuresis, natriuresis, RAAS inhibition

Renin

• Origin: Juxtaglomerular cells of kidneys release
• Effect: Indirectly increases blood pressure
• Mechanism: Converts angiotensinogen to angiotensin I, then to angiotensin II via ACE

Angiotensin II Functions

• Vasoconstriction
• Stimulates aldosterone and ADHRelease

Aneurysm

• Abnormal bulge or ballooning in blood vessel wall due to weakening

Aneurysm Types

• Abdominal Aortic Aneurysm (AAA): In the abdomen
• Thoracic Aortic Aneurysm: In the chest
• Cerebral Aneurysm: In brain vessels
• Peripheral Aneurysms: In arteries of legs, neck, or arms
• Symptoms include pain, pulsating mass, or sudden headache

Thrombus Formation

• Blood clot formation regulated by conditions and factors

Endothelial Injury

• Damage to vessel lining initiates clot formation

Abnormal Blood Flow

• Turbulent or stagnant flow contributes to thrombus formation, damaging the endothelium

Hypercoagulability

• Increased tendency for blood to clot

Thromboangiitis Obliterans (Buerger Disease)

• Mechanism*
• Inflammatory condition affecting small and medium-sized arteries and veins, predominantly in the arms and legs.
  • It is strongly associated with tobacco use, and the exact pathogenesis is related to an immune response triggered by smoking, leading to vasculitis and thrombosis.
  • The inflammation can lead to occlusion of the vessels, impairing blood flow.
• Manifestations of Ischemia*
  • Ischemic pain in the limbs, particularly during physical activity (claudication).
  • Rest pain i severe cases, especially affecting the fingers and toes.
  • Ulcerations and, in some cases, gangrene

Raynaud Phenomenon

• Mechanism*
  • a condition often secondary to other diseases (such as scleroderma, lupus, or rheumatoid arthritis) and characterized by excessive vasoconstriction of the small arteries and arterioles.
  • This vasopastic reacion ypically occurs in response to cold temperatures or stress
• Manifestations of Ischemia*
  • Episodes of color changes in the skin of the fingers and toes (pallor, cyanosis, then erythema) due to spasms of the blood vessels.
  • Numbness, tingling, or pain in the affected areas during episodes.
  • The skin can become brittle, leading to ulcerats or sores in severe cases.

Raynaud Disease

• Mechanism*
  • Similar to Raynaud phenomenon, but is a primary condition not secondary to another disease.
  • Thought to be due to a hypeacvity of the sympathetic nervous system causing vasospasic attacks.
• Manifestations of ischemia*
  • Similar to Raynaud phenomenon, wth episodes triggered by cold
  • occurs widthout associated systemic illness

Varicose Veins - Causes

• Valve Malfunction
• Genetic Predisposition
• Age
• Prolonged Standing or Sitting
• Obesity
• Hormonal Changes

Varicose Veins - Manifestation

• Bulky veins, heavy or painful legs, swelling, itching, skin discoloration

Deep Vein Thrombosis (DVT) - Causes

• Immobility
• Surgery or Injury
• Increased Blood Clotting
• Obesity
• Pregnancy
• Age

Deep Vein Thrombosis (DVT) - Manifestation

• Swelling, pain, red or discolored skin, warmth

Superior Vena Cava Syndrome - Causes

• Tumors
• Thrombosis
• Infections
• Fibrosis or Scarring

Superior Vena Cava Syndrome - Manifestation

• Swelling of face, neck, upper limbs, chest, shortness of breath, distended veins, headache, cyanosis

Myocardial Ischema Treatments

Myocardial ischemia is a condition that occurs when blood flow to the heart muscle is reduced, typically due to a partial or complete blockage of the heart's arteries which leads to chest pain and potentially a heart attack.

• Nitrates
  • Effects: primarily work by dilating blood vessels.
  • Mechanism: They increase levels of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle, leadin to relaxation and vasodilation.
• Beta-Adrenergic Blocking Agents (Beta Blockers
  • Effects: reduce heart rate, decrease blood pressure.
  • Mechanism: They block effects of adrenaline on beta adrenergic receptors in the heart
• Calcium Channel Blockers
  • Effects: These medicaitons relax and dilate arteries, reducing blood pressure and myocardial oxygen demand. They can also decrase the heart rate and reduce contraction.
  • Mechanism: by inhibiting calcium ions from entering caardiac and arterial smooth muscle the cause vasodilation
• Antiplatelet Agents
  • Effects: Antiplatelet help prevent the formation of new clots and reduce the growth of existing clots.
  • Mechanism: They inhibit cyclooxygenase enzyme and reduce thromboxane production which decrease platelet aggretation.
• Percutaneous Coronary Intervention (PCI)
  • Effects: is commonly known as angioplasty, it it a nonsurgical proedure to open narrowed cornary areaeries. by placing a stent in the artery this procedure helps restore blood flow and relief of ischemic symptoms.
  • Mechanism: A ballon is inflated at the site of narrowing to widen the artery and a sent may need to be places to keep the artety widr.
• Coronary Artery Byass Gradt (CABG)
  • Effects: is a surgical procedure used to improve blood flow in the heart it involves taking a blood vessel from another part of the body and grafting it onto the conary artery to bypass the blocked or narrowed portion.
  • Mechanism: This provides and alternative route for blood to reach heart tissus to increase tissue oxygen.. The chice of treatment depends on the severity of ischemia, the patient's over all health and other chinical considertions

Acute Pericarditis - Pathophysiology

• Inflammation of the pericardium

Acute Pericarditis - Cause

• Due to infection, autoimmune disorders, myocardial infarction, trauma, or radiation

Constrictive Pericarditis - Pathophysiology

• Thickened pericardium restricts diastolic filling

Constrictive Pericarditis - Cause

• Develops from acute pericarditis, chronic inflammatory conditions, surgery, or radiation

Pericardial Effusion- Pathophysiology

• Fluid accumulation in the pericardial cavity

Pericardial Effusion- Cause

• Inflammation, trauma, malignancy, uremia, or hypothyroidism
• Comparison:
• Inflammation vs. Mechanical Restriction:
  • Acute Pericarditis: Primarily invovles inflammation
  • Constrictive Pericarditis and Pericardial Effusion: invovles mechanical Resfriction
• Time Course: Acute pericarditis (more suddent) constricitive percorditis ( takes months or years), pericardial effusion (both)
• Symptoms and signs: Acute Pericarditis: Chest pain, Constricitive Percarditis: Right sided heart failur or Kussamails sign, Pericardial Effusions: can come with with heart sounds and hypotention.

Rheumatic Heart Disease - Cause

• Untreated streptococcal throat infection

Rheumatic Heart Disease -

Pathophysiologic Mechanism:

• Autoimmune Reaction: Bacteria and heart tissue lead to an auteoomune response against strep
• Inflammation: Affects the heart valves
• Sccarring and fibrosis: Chronic inflammation resultes in Scars, valves and damages that lead to failure or stroke

Infective Endocarditis - Cause

• Bacterial infection, such as Streptococcus viridans, Staphylococcus aureus, and Enterococcus species

Infective Endocarditis - Pathophysiologic Mechanism

• Bacteremia: Bacteria or other enters bloodstream
• Pathogens: Adhere to damaged heart valves creatin vegetation
• Vegetation formation: the bacateria prolerate within avegetation, creating more issues.
• Embolizism and immmune complex: part of the vegetation can break and led to a blockage or stroke.

Right-Sided Heart Failure (Cor Pulmonale) - Pathophysiology

• Primarily results from pulmonary hypertension, leading to increased right ventricle pressure
• Often results from various lung diseases

Right-Sided Heart Failure (Cor Pulmonale) - Manifestation

• Causes peripheral edema, ascites, enlarged liver/spleen, jugular venous distension, fatigue

Left-Sided Heart Failure (Congestive Heart Failure) - Pathophysiology

• Occurs when the left ventricle can't pump blood effectively, causing backup in the lungs
• Can be systolic (reduced ejection fraction) or diastolic (impaired filling)

Left-Sided Heart Failure (Congestive Heart Failure) - Manifestation

• Causes pulmonary congestion, cough, fatigue, dyspnea, crackles in the lungs

Surfactant- Source

• Produced by type II alveolar cells (pneumocytes) in lungs

Surfactant - Composition

• Dipalmitoylphosphatidylcholine (DPPC), neutral lipids, and surfactant proteins SP-A, SP-B, SP-C, SP-D

Surfactant- Function

• Reduces surface tension, enhances lung compliance, prevents alveolar collapse (atelectasis), supports host defense, and maintains fluid balance

Oxygen Transport in the Blood

• Oxygen is either dissolved in the blood or bound to hemoglobin

Oxygen Transport in the Blood- Dissolved

• The amount of oxygen in Plasma is very small the total amount of oxygen is 1.5 %.
• Oxygen bound to hemoglobin

Oxygen Transport in the Blood - Hemoglobin

• Role of: the majority of oxygen in the blood is transported boung to this.
• Four sub units can bind a molecule of oxygen
• oxyhemoglobation: When oxygen binds it forms the this and this relation is reversible

Factors Influencing Oxygen Binding

• Bohr Effect: The presence of high levels of carbon dioxide and hydrogen ions (low pH) in tissues reduces hemoglobin's affinity for oxygen, promoting oxygen release.
• Temperature and and 2,4 Bisosphoglycerate (BPG

Explore the mechanisms of inotropic agents and cardiovascular physiology. Positive inotropic agents such as digitalis increase heart contractility. Understand the effects of prolonged standing or sitting on varicose veins.