How Drugs Work

Systemic Vascular Resistance and Flow Etiology

Resistance within the arterial system has major implications for HBP. Resistance in an artery is a measurement of how easily fluid is able to flow. Resistance is inversely proportional to flow. Likewise, an increase in resistance correlates to a decrease in flow. As seen in Figure 3, resistance is also inversely related to vessel radius. The smaller the vessel, the more resistance to flow. To understand these implications, imagine yourself drinking red Gatorade through a straw out of a barrel. For this example, Gatorade will represent blood (hence the red color), while the straw, barrel, and your mouth will represent the cardiovascular system. First imagine drinking the Gatorade through a straw the size of a garden hose, with a radius of 2 millimeters, for 30 seconds. Your mouth would have to apply only a small amount of negative pressure (at a resistance of 1/16) to remove a large amount of Gatorade. Next, imagine drinking the Gatorade through a normal "McDonald's size" straw with a radius of 1 millimeter. In order to remove the same amount of Gatorade as was removed from the hose sized straw, you will need to apply more negative pressure (at a resistance of 1) to take out the same amount Gatorade in 30 seconds. Lastly, imagine drinking the Gatorade from a coffee straw with a radius of 0.5 millimeters. As you could guess, it would take an extreme amount of negative pressure (at a resistance of 16) to remove the same amount of Gatorade. In fact, it is doubtful you would be able to remove an amount even close to the normal or hose sized straws by utilizing a coffee straw.

The cardiovascular system works in the same way; however, instead of trying to EXTRACT Gatorade, it has to PUSH blood. The amount of flow through your Gatorade straws is inversely proportional to its resistance. Furthermore, the resistance of the straw is determined by the inverse of the radius to the fourth power, assuming the straws were of the same length. Therefore, a small decrease in radius causes a very large increase in resistance (and likewise inversely proportional decrease in flow). The same physics applies to the cardiovascular system. In the terms of the cardiovascular system there are many things that can cause changes in vessel radius. First, endogenous changes will be discussed (changes due to the body's control), followed by exogenous changes (changes due to external factors).

Endogenous

There are many different ways the body can regulate peripheral resistance. For the purpose of this unit, only those that have direct pharmacological ties will be discussed. These endogenous systems will be divided by the system they impact. Be aware that many of these systems involve many complex steps. Having multiple steps enables the body to accurately/specifically alter its physiology. For example, instead of having one on/off switch for blood pressure there are many different, specific on/off switches. In terms of pharmacology, the presence of multiple control systems allows the body to alter physiology through a variety of mechanisms.

Renin-Angiotensin-Aldosterone System (RAAS)

The body uses the RAAS to regulate normal volume of the cardiovascular system. When blood volume is low, the kidneys realize this and release rennin, which is then secreted into the blood. Renin flows through the blood and converts angiotensinogen into angiotensin I. Angiotensin I is then converted into Angiotensin II by the action of the angiotensin converting enzyme (ACE). The Angiotensin II hormone is an important vasoconstrictor (meaning it decreases the radius of blood vessels). Angiotensin II can also stimulate the production of aldosterone. Aldosterone prevents the kidney from excreting water and sodium into the bladder (which is then released through urination). Likewise, aldosterone allows the body to hold onto its water (and sodium), which helps to maintain blood pressure. ⁵ In summary, the secretion of renin by the kidney leads to vasoconstriction (a decrease in arterial radius) and water retention (an increase in blood volume). Both of these things lead to an increase in blood pressure.

Adrenergic Receptor Systems

The nervous system contains two divisions: parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS). For both of these systems, there are chemicals, enzymes, and hormones that can activate (called agonists) or block activation (called antagonists). These agonists and antagonists are called ligands. Ligands work by interacting with receptors found on cell membranes. This interaction causes a response that is prescribed by each ligand/receptor. For example, the SNS agonist, epinephrine, would increase heart rate, while an antagonist drug, such as a beta–blocker, would slow heart rate. In general, the SNS is used for flight/fight responses. In other words, when a rabid grizzly bear starts running after you, your SNS increases your heart rate, dilates your blood vessels and allows you to either fight the bear (not advisable) or flee (run away). Your PSNS is the "chill" system. In terms of a human, the PSNS controls salivation, lacrimation (crying), urination, defecation, the gastrointestinal tract movement, and emesis (vomiting) (known collectively by the acronym SLUDGE).³ These actions allow for normal bodily functions to occur (once you have dealt with the bear from the SNS example).

Overexposure to certain insecticides, herbicides, or nerve agents causes your body to over activate the PSNS. This causes a massive SLUDGE reaction. The antidote for this poisoning is the PSNS antagonist Atropine. Atropine works by blocking the PSNS receptors in an antagonistic fashion. Federal agencies often carry large quantities of Atropine in preparation for an attack that utilizes the aforementioned agents. ⁶

The receptors that work specifically for the sympathetic nervous system, adrenergic receptors, are found throughout the body, and control a multitude of functions. The adrenergic receptor system is further complicated as it is broken into two divisions: alpha (α), and beta (β). To make things more perplexing, there are subsets of each division: there are α1 and α2, as well as β1, β2, and β3 receptors.³⁵ This complexity allows the body to have very specific control over its physiology: different tissues, expressing different combinations of receptors, can tailor their response to the same ligand (epinephrine).

For the purposes of this unit we will discuss α2, β1, and β2 adrenergic receptors. The α2 adrenergic receptors activate smooth muscle of the arteries. Smooth muscle is muscle that lines much of our internal organs and is used for general internal organ movement, including vessels of the cardiovascular system. Likewise, α2 receptors have implications for blood pressure regulation. The actions of β–adrenergic receptors can be easily remembered by remembering their number. β1 receptors affect our ONE heart, while β2 receptors affect our TWO lungs. The actions of the β1 adrenergic effects are broken down into three functions. Chronotropic refers to the how fast the heart beats (think chronology or time = chronotropic). Dromotropic refers to how well the electrical signal of the heart passes through the heart. When the electrical signal passes more easily through the heart, the HR is affected. Inotropic refers to the contractility of the heart. When the heart contracts more forcefully, this pushes more blood with each beat (i.e. increases SV).³ These three functions are affected in different ways by different medications.

While the complexity of this system allows for specificity of its actions, cross activation of receptors can occur with certain pharmaceuticals. For example, if a patient is having an asthma attack, a paramedic may administer an albuterol nebulizer. One thing the paramedic must monitor during the administration is the patient's heart rate. While the albuterol is an β2 adrenergic agonist (i.e. it relaxes the smooth muscle in the lungs causing the patient to breath more easily), it can also affect β1 adrenergic receptors. Likewise, if β1 adrenergic receptors are activated, the patient's heart rate can increase. Generally, this is not a problem; however, if the patient is elderly, with chronic heart failure, and a history of heart attacks, elevating the heart rate may have detrimental effects. ⁶

Calcium Channels

The contraction of cardiac muscle is dependent on the release of calcium throughout the cells of the myocardium (heart muscle tissue). Teaching the mechanisms of calcium channels, and action potential of muscle cells, is usually saved for advanced physiology classes. For the purposes of this unit, these mechanisms will not be discussed in detail. It is important to understand, however, that calcium is used for muscle contractions. For cardiac muscle, changing the permeability of calcium channels can affect the contractility of the heart muscle. This has implications for both inotropic and chronotropic changes in the heart. In endothelium smooth muscle (as found in arteries), changing the permeability of calcium channel affects its contraction; which in turn can cause changes in the vasodilation/vasoconstriction of these vessels.³

Endothelium–Derived Relaxing Factors (EDRF)

The endothelium of the cardiovascular system has its own regulatory system to control the constriction of its smooth muscle (hence the name). There are two factors that are endothelium–derived that control vasodilation/vasoconstriction: EDRF and Endothelin (ET). It is believed that Endothelin is consistently present in the blood stream, and regulates the vasoconstriction of the vessels. EDRF, on the other hand, is created to block ET's action, and likewise cause vasodilation. In general, EDRF–NO acts as a quick vasodilator that has a relatively short duration of action. ⁷

Kidney Control

Up until now, this unit approached blood pressure as it directly affected by the cardiovascular system. Another important facet to blood pressure control is the amount of fluid in the cardiovascular system. To an extent, more fluid in the cardiovascular system (without change in vascular dilation/constriction) leads to increased blood pressure. Therefore, the work of the kidneys to maintain a balanced blood volume level is imperative for normal blood pressure. The study of the kidneys' ability to filter out water and electrolytes is a very complicated topic. For the purposes of this unit, a general understanding of the nephron is important for understanding pharmacological impacts. When blood enters the kidney it is split into pathways that flow through the approximately one million nephrons. The nephron is the basic structure in the kidney that is responsible for filtration. As blood enters the nephron it travels through a system of corresponding tubules that abut the blood vessel. Through changes in channel permeability in the nephron's structures, salt and water are able to enter/exit the kidneys' vessels. This exchange of salt and water leads to the production of urine, which eventually is excreted into the bladder where it is eliminated during urination. Water leaving the cardiovascular system (by accumulation in urine) causes a decrease in blood pressure due to a decrease in volume. The less volume in the system, the less pressure the system exerts. The body, as well as pharmaceuticals, work to change the amount of water that exits through urination.³

[Fun fact: ethyl alcohol [EtOH] (alcohol that is consumed in recreation), as well as caffeine, work to prevent the secretion of the antidiuretic hormone (ADH). Likewise, while consuming these substances, diuresis (i.e. excessive urination), can occur. This is potentially dangerous when large amounts of EtOH are consumed. Not only do these patients tend to become dehydrated, they also lose key electrolytes (that are usually excreted along with water).⁶ In the hospital, these patients are administered "banana bags." Banana bags are large liter bags of a yellow fluid (hence the name banana) that helps to replenish lost water and electrolytes.]

Exogenous

There are many external factors that can affect the narrowing of blood vessels, and likewise affect blood flow. For the purposes of this unit, two main exogenous factors are most often concurrent with high blood pressure: tobacco use, and high cholesterol (or hypercholesterolemia). Nicotine, an active molecule in tobacco, can activate SNS receptors which causes vasoconstriction. While moving through the bloodstream, nicotine can also interrupt the normal functions of endothelium, and cause them to harden. Cholesterol is a main exogenous cause of increased SVR in hypertensive patients. The common types of circulating cholesterol (often heard in commercials, and physician offices) are high–density lipoprotein (HDL), and low–density lipoprotein (LDL). LDL, also known as "bad" cholesterol, in fact refers to the protein (specifically called a lipoprotein) that surrounds a cholesterol molecule. When LDL associates to a cholesterol molecule it is then called LDL–C. Circulating LDL–C has the potential to cause harm through the build up of plaque in arterial blood vessels. HDL, also known as "good" cholestesterol, is the protein that transports cholesterol molecules throughout the body. The "good" part of HDL is its interactions while holding onto a cholesterol molecules (thus becoming what is known as HDL–C). HDL–C travels through the bloodstream and is used it to clean up LDL.²

The buildup of cholesterol that causes hypertension does not occur within hours of eating a double quarter pounder (with or without cheese), but may take years to develop. Cholesterol starts as "fatty streaks." These one centimeter long yellow streaks occur on the tunica intima of arteries. Also known as foam cells, these streaks cause no disturbance of blood flow, and can regress over time. They are commonly found in individuals by age 20, and can act as precursors to further problems. Fibrous plaque forms off of fattty streaks. This plaque is usually larger, firmer, and is gray in color. While fibrous plaque can occur in many arteries of the body, they are commonly found in walls of the heart's blood supplying (also known as coronary arteries), locations along the aorta (the main artery of the body), carotid arteries (which supply blood to head), and the circle of Willis (a main collection of arteries within the brain). ²

Many problems can incur from the presence of these plaques. The problem most related to this unit is the decrease of blood flow through areas of increased plaque build–up. Decrease of blood flow can occur for two reasons. The first reason is due to the decrease in radius of artery walls due to plaque build–up. Known as atherosclerosis, presence of plaque can cause turbulent blood flow, which can lead to a decrease in downstream perfusion. Arteriosclerosis, or the hardening of artery walls, occurs when fatty plaque builds up and prevents the body's endogenous control over vasoconstriction/vasodilation. Other complications that can arise from fatty plaque include the potential for a lethal thrombus. A thrombus is a piece of plaque that breaks off and causes blockages (called clots) downstream. This is especially dangerous when the clot forms in the lungs (pulmonary embolism). Even more critical is when a clot forms blockages within plaqued arteries and causes loss of perfusion directly downstream. This can occur in the vessels that deliver blood to heart muscle and cause a heart attack (myocardial infarction or MI), or in the brain, causing a stroke. An overall decrease in blood lipid levels, as well as stability of dangerous clot causing plaque can be achieved through drugs, such as statins; however, these will not be discussed in this unit.²