Introduction+to+Cardiovascular+Pharmacology

= = =HHP621= = = =Introduction to Cardiovascular Pharmacology=

Before going on, why not [|review the Cardiac Cycle]
 * . Notice that many of the drugs are used for a variety of cardiovascular disorders. Thus remembering what they do (i.e. //Pharmacodynamics or Mechanisms of Action)// will tell you what they are used for therapeutically. For examples b antagonists (both non-selective and b1 selective) reduce heart rate. If they reduce heart rate they must alter the electrical activity of the heart (useful for treating arrhythmia), the amount of work the heart must do and the oxygen required for this work (important in treating angina and hypertension). ||

**Heart Failure** occurs when decreases in contractility prevent the heart from contracting forcefully enough to deliver blood to meet the demands of the body. Decreases in C.O. activate reflex responses in the SNS which attempt to compensate for the reduced C.O.: These **//reflex responses//** include //1//. **//increases in heart rate//** (tachycardia), **//2.// //increased preload//** (salt and water retention increase blood volume through activation of the **renin-angiotensin-aldosterone pathway (see fig below from //Scientific American//, 1999)** -this leads to //peripheral and pulmonary edema//. Since the volume returned is greater than the ability of the heart to pump, blood remains in the heart with each stroke leading to //enlargement of the heart)//, and **//3. increased afterload//** (through vasoconstriction via a receptors as well as through the production of angiotensin II) resulting in compensated heart failure. Ultimately, SNS activation can no longer compensate, and the heart fails. Drug treatment is directed towards **1) enhancing cardiac output** with //+ inotropic drugs//**,** **2) decreasing preload** with //diuretics// and //__A__ngiotensin __C__onverting __E__nzyme (ACE) inhibitors//, and/or **3) decreasing afterload** with //vasodilators like organic nitrates// and //ACE inhibitors//**.** We have already discussed [|diuretics] and [|b1 agonists] in previous lectures.
 * Cardiac Performance is determined by 4 functions (see figure above)**
 * **Preload** - the volume of blood returned to the heart through the vena cavae and in the heart before it beats
 * **Afterload** - resistance to blood flow including opening of aortic valves and pushing blood through the arteries (peripheral vascular resistance of PVR)
 * **Contractility** - the forcefulness with which the heart contracts
 * **Heart Rate** - the major determinant of cardiac output |||||| ||
 * **[|The Autonomic Nervous System]**
 * Sympathetic Nervous System
 * Parasympathetic Nervous System**The Heart**
 * Cardiac Anatomy
 * The Cardiac Cycle
 * Factors Influencing Cardiac Performance
 * Factors Affecting Pumping Efficiency
 * Factors Affecting Myocardial Oxygen Consumption**The Vasculature**
 * The Circulatory System
 * Vessels Controlling Blood Pressure**Regulation|Regulation of Blood Pressure**
 * Short-Term Regulation
 * Long-Term Regulation**Cardiovascular Diseases****Useful Equations** --Glossary= = **Introduction**The cardiovascular system consists of three anatomical components: the autonomic nervous system, the heart, and the vasculature. These three components interact in a complex manner to control blood flow to organs throughout the body. A clear understanding of the basic principles of cardiovascular physiology and is needed to appreciate the complex effects of many cardiovascular drugs.

The Autonomic Nervous System
The autonomic nervous system is widely distributed throughout the body and controls a variety of bodily functions, including blood pressure and heart rate. The efferent peripheral autonomic nervous system is composed of two opposing subsystems, the sympathetic nervous system and the parasympathetic nervous system.**Sympathetic Nervous System**
 * Vascular smooth muscle (increased contraction of skin, renal, splanchnic, skeletal muscle blood vessels via alpha-adrenergic receptors; increased relaxation of skeletal muscle blood vessels via beta2-adrenergic receptors)
 * Heart (increased contractility via beta1-adrenergic and beta2-adrenergic; increased heart rate via beta1-adreneregic)
 * Kidney (increased renin release -- beta1-adrenergic)
 * Bronchiolar smooth muscle (increased relaxation -- beta2-adrenergic)**Parasympathetic Nervous System**The parasympathetic nervous system innervation of the cardiovascular system is essentially just the innervation of the heart by the vagus nerve. This innervation is relatively discrete, being limited to the sino-atrial (SA) node (pacemaker) and the atrioventricular (AV) junction. There is little or no innervation of the cardiac ventricles or blood vessels, although acetylcholine released by the parasympathetic nervous system can bind to receptors in the endothelium (the cells that line blood vessels) causing the release of EDRF (Endothelium Derived Relaxing Factor) which relaxes vascular smooth muscle. The postganglionic neurotransmitter of the parasympathetic nervous system is acetylcholine. Acetylcholine released by the parasympathetic nervous system binds to muscarinic cholinergic receptors on target tissues. Below is a list of cardiovascular targets of the parasympathetic nervous system, the effects of parasympathetic stimulation on these targets, and the major cholinergic muscarinic (M) receptor subtypes on each target tissue.


 * Heart-sinus (SA) node and AV junction (decreased heart rate -- cholinergic M2)
 * Endothelium- (releases EDRF in response to circulating acetylcholine -- cholinergic M3 which relaxes vascular smooth muscle) ||

The Heart
The heart is responsible for pumping blood through the circulatory system. A brief description of the anatomy of the heart, the cardiac cycle, and factors affecting cardiac pumping efficiency and performance are described below.

Cardiac Anatomy The Cardiac Cycle
 * The heart muscle (the 2 atria pump blood into the ventricles and the 2 ventricles pump blood out of the heart)
 * The valves of the heart which maximize the pumping action of the heart (2 atrioventricular valves: the tricuspid and mitral; 2 semilunar valves: the pulmonic and aortic)
 * The electrical pacemaker and conduction system which sets the normal rhythym of the heart and coordinates the contraction of the heart (sinoatrial (SA) node, atrioventricular (AV) junction, His bundle, Purkinje fibers)
 * The coronary circulation which distributes blood to the heart itself
 * The autonomic nervous system innervation of the heart which regulates heart rate and contractility (sympathetic nerve endings in muscle of atria and ventricles, SA node, and AV junction; parasympathetic nerve endings mainly in atrial muscle, pacemaker, and the AV junction)
 * The proper functioning of the cardiac conduction system, with the consequent coordination of contraction and valve opening and closing in each region of the heart, is critical for efficient pumping of blood. Each phase of the cardiac cycle is described below:**

Factors Influencing Cardiac Performance
 * An impulse arising from the SA node results in depolarization and contraction of the atria (the right atrium contracts slightly before the left atrium)
 * The atrioventricular valves open and the ventricles are filled with blood
 * There is a short delay of the electrical impulse in the AV junction that allows the ventricles to fill completely
 * The electrical impulse is then propagated through the His bundle and Purkinje system to allow the ventricles to contract from the apex of the heart towards the base
 * As the ventricles contract and the pressure in the ventricles exceeds that in the atria, the atrioventricular valves close and the atria begin to relax and refill with blood
 * When the pressure in the ventricles exceed the pressure in the pulmonary artery and aorta, the pulmonic and aortic valves open, and blood is pumped into the pulmonary and systemic circulations, respectively
 * As the ventricles begin to relax after systole, the pulmonic and aortic valves close and diastole begins
 * A number of factors influence the force, speed, and extent of contraction of the heart:**


 * Resting muscle fiber length (preload or end-diastolic pressure/volume). The relationship between resting muscle fiber length and the tension generated during contraction is referred to as Starling's Law of the Heart.
 * Degree of afterloading (pulmonary artery pressure, mean arterial pressure). This is the load against which the heart must pump.
 * Inotropic state (contractility). Drugs and hormones can profoundly affect cardiac performance by altering (positively or negatively) the inotropic state of the heart.
 * Frequency of contraction. Increased heart rate is a postive inotropic stimulus

A number factors can effect the efficiency of the heart (the amount of energy required to pump a given volume of blood):**
 * Factors Affecting Pumping Efficiency**

Factors Affecting Oxygen Consumption
 * Conduction system abnormalities (incomplete filling and/or emptying can decrease efficiency)
 * Anatomical abnormalities and pathologies (valvular leakage or stenosis can decrease efficiency)
 * Compromised myocardium (ischemia, hypertrophy, myocardial disease)
 * Afterload and preload (increased load can decrease efficiency)
 * Contractility (increased contractility can decrease efficiency).
 * The pumping activity of the ventricles accounts for about 10% ofthe total basal oxygen consumption of the body. Moreover, an imbalance of oxygen consumption of the heart relative to oxygen supplied by the coronary circulation can result in myocardial ischemia and angina. Factors affecting myocardial comsumption include:**
 * Heart rate. Oxygen consumption is greater at higher heart rates.
 * Blood pressure. Oxygen consumption is higher with higher afterload (pressure work = systolic pressure x heart rate).
 * Stroke volume (the volume of blood pumped with each beat of the heart). Oxygen consumption is greater with larger stroke volumes (volume work = stroke volume x systolic pressure).
 * Inotropic state. Increasing contractility increases oxygen consumption.

The Vasculature
The vasculature consists of the blood vessels responsible for distributing blood to various tissues of the body.

The Circulatory System Blood Vessels
 * The pulmonary circulation (low pressure, low resistance). The right heart pumps blood into the pulmonary circulation.
 * The systemic circulation (high pressure, high resistance). The left heart pumps blood into the systemic circulation.
 * Blood vessels can be classified according to size, location and function:**
 * Arteries are large diameter, thick-walled vessels that carry blood away from the heart.
 * Arterioles are small, thick-walled vessels that represent the major part of vascular resistance. These resistance vessels serve as "circulatory stopcocks" and control the distribution of blood to various organs.
 * Capillaries are extremely small, extremely thin-walled vessels (one cell thick) that allow exchange of gases, nutrients, and other small molecules between the blood stream and tissues. Increases in capillary hydrostatic pressure or capillary permeability can lead to edema.
 * Venules are small thin-walled vessels that serve to bring blood back to the heart. These vessels are highly distensible and (along with veins) contain a large fraction of the blood volume.
 * Veins are large diameter thin-walled vessels that bring blood back to heart. They are distensible and (in addition to venules) contain a large fraction of the blood volume.

Blood Vessels Controlling Blood Pressure
 * The major blood vessels controlling blood pressure are are referred to as the resistance vessels and the capacitance vessels:**
 * Resistance vessels. Arterioles are the primary resistance vessels and control mean arterial blood pressure and blood flow to specific tissues. Vascular smooth muscle tone in these vessels is controlled by the sympathetic nervous system and local factors (metabolic need)
 * Capacitance vessels. Systemic venules and veins serve as a volume reservoir for the circulatory system (approx. 50% of total blood volume is contained in these vessels). Sympathetic and humoral regulation of these vessels can significantly alter venous return (preload) and fluid exchange in the associated capillary beds.

Regulation of Blood Pressure
Blood pressure is closely regulated on a short-term (seconds-to-minutes) and long-term (days-to-weeks) basis. An understanding of the physiological mechanisms involved in blood pressure control is essential to understanding how many cardiovascular drugs act. Mean arterial pressure is monitored by baroreceptors primarily in the aortic arch and carotid artery and is regulated by two temporally different (but integrated) reflex pathways. Because the response of both reflexes are monitored by the baroreceptors, both reflex pathways are feedback loops.

Short-Term Regulation
 * Changes in mean arterial pressure are sensed by the baroreceptors and processed by the vasomotor centers in the medulla which differentially regulate sympathetic and parasympathetic nervous system output.
 * If a drop in blood pressure is seen by the baroreceptors, neuronal activity to the vasomotor centers is decreased, resulting in an increase in sympathetic tone and a decrease in parasympathetic (vagal) tone.
 * A rise in mean arterial pressure causes an increase in baroreceptor neuronal activity and gives rise to an increase in vagal tone (activity of the vagus nerve) and a decrease in sympathetic tone.
 * Increases in sympathetic tone result in increased peripheral vascular resistance, increeased venous tone, increased heart rate, and increased contractility of the myocardium.
 * Increases in vagal tone lead to lowering of heart rate.

Long-Term Regulation** Long-term changes in blood pressure (hours to days) are primarily mediated by humoral factors that control blood volume by regulating Na+ and water retention. The reflex pathways are described below:
 * Changes in renal blood flow and pressure, which are directly related to mean arterial pressure, result in changes in renin secretion. A drop in renal blood flow or pressure results in an increase in renin release from the kidney. High sympathetic outflow also causes an increase in renin secretion
 * An increase in renin release leads to an increase in circulating angiotensin II. The primary actions of angiotensin II are:
 * To stimulate the synthesis and secretion of aldosterone.
 * To raise blood pressure by direct vasoconstrictor effects (angiotensin II is one of the most potent vasoconstrictors known).
 * Aldosterone acts on the kidney to retain Na+ (and therefore water), leading to an increase in blood volume.

Cardiovascular Diseases
Cardiovascular disease accounts for nearly half of all deaths in the U.S. The following is a list of cardiovascular diseases that contribute to most of the deaths:
 * Congenital defects and inherited disorders
 * Hypertension
 * Coronary insufficiency (Atherosclerosis, angina pectoris, myocardial infarction)
 * Peripheral vascular disease (Stroke, pulmonary embolism, thrombosis, diabetes)
 * Cardiac dysrhythmias (also commonly referred to as arrhythmias)
 * Cardiomyopathy (Chemical toxicity, infectious, congenital)
 * Valvular disease
 * Effects of aging on the cardiovascular system
 * Congestive heart failure

Useful Equations
Many cardiovascular terms are quantifiable such as blood pressure, cardiac output, stroke volume, etc. The following equations describe the mathematical relationships between many commonly used cardiovascular terms:
 * Ohm's law (V =I x R): Blood pressure= Cardiac output x Peripheral vascular resistance (BP = CO x PVR)
 * Cardiac output =Heart rate x Stroke volume (CO= HR x SV)
 * Cardiac index: Cardiac output corrected for body surface area (~3 liter/min/M2)
 * Stroke work =Mean pressure x Stroke volume (SW= P x SV)
 * Ejection fraction =Stroke volume / End-diastolic volume (EF= SV / EDV)
 * Laplace equation: Tension = Pressure x Radius
 * Compliance = Change in Volume / Change in Pressure (Change in Length / Change in Tension)
 * Stiffness = Inverse of compliance (1 / Compliance)