Routes of Drug Administration



The Circulatory System and

Routes of Drug Administration

Samuel D. Hodge, Jr., Esq. and

Jack Hubbard, M.D., Ph.D.

This Constitution, and the laws of the United States which shall be made in pursuance thereof; and all treaties made, or which shall be made, under the authority of the United States, shall be the supreme law of the land; and the judges in every state shall be bound thereby, anything in the Constitution or laws of any State to the contrary notwithstanding.

Article VI of the United States Constitution

THIS STATEMENT CONTAINED in the United States Constitution is known as the Supremacy Clause and governs the interaction between federal and state governments. It also serves as the foundation for the preemption doctrine which makes federal law paramount to any conflicting state law.

FEDERAL PREEMPTION ● Over the years, the Supreme Court has been asked to determine if certain state actions violate this important legal mandate. From McCulloch v. Maryland, 17 U.S. 316 (1819), in

which the court held that Maryland could not tax a bank chartered by the federal government, to Riegel v. Medtronic, 128 S. Ct. 999, 169 L.Ed. 2d 892. (2008), where the Medical Device Act was found to preempt common law claims against manufactures whose medical devices had received pre-market FDA approval, the court has issued a number of landmark rulings on the topic. On March 4, 2009, the Supreme Court issued another preemption ruling; this decision has sent shock waves throughout the pharmaceutical industry.

THE SUPREME COURT ● Wyeth v. Levine, 555 U. S. ___, 2009 WL 529172, U.S. Vt., March 04, 2009 (NO. 06-1249) involved negligence and failure to warn claims against a drug manufacturer on the basis that a Food and Drug Administration (FDA) approved label was inadequate under state law. To be more specific, the issues before the court were whether a state-law duty to provide a stronger warning label interferes with Congress’ purpose in entrusting an expert agency with drug labeling decisions and whether state-law claims are preempted because it is impossible for drug manufacturers to comply with both their federal labeling mandates and state-law duties.

The Holding

The Supreme Court resolved both of these questions against the drug manufacturer noting that the question of preemption must be guided by two cornerstones: (1) “the purpose of Congress is the ultimate touchstone in every pre-emption case” and (2) “the historical police powers of the States were not to be superseded by the Federal Act unless that was the clear and manifest purpose of Congress.” While the FDA is given the power to protect the public’s health and assure the safety and reliability of drugs, the court found that subsequent amendments to the Act added a savings clause that indicated state law would only be declared invalid upon a “direct and positive conflict.” Since no such conflict existed, the court found that manufacturers remain responsible for updating their labels after FDA approval based upon safety information that becomes available after the drug’s initial approval. Also, in keeping with Congress’ intent not to specially preempt common law tort suits, the Supreme Court noted that the FDA regarded state law remedies as a complementary form of drug regulation. Therefore, state related failure to warn lawsuits support the premise that manufacturers and not the federal agency bear the primary reasonability for drug labeling at all times.

THE MEDICAL ISSUE ● Whether Congress will try to amend the Food and Drug Act and related legislation to expressly prohibit state court actions in this area remains to be seen. However, Wyeth v. Levine is such an important preemption decision that it will be the subject of future law review articles and commentaries. The balance of the Chapter, therefore, will not discuss the legal implications of this case. Rather, it will focus on the underlying medical issues presented in Wyeth v. Levine, the circulatory system and routes of drug administration. This is a subject that is not well understood in the legal community, even though the circulatory system is vital to survival and pharmacology plays such an important role in the treatment of patients.

The Medical Facts

Wyeth is the manufacturer of the drug, Phenergan, an antihistamine used to treat nausea. Diana Levine, a professional musician, suffered from migraine headaches and resultant nausea. The musician visited a clinic for treatment of a migraine and received an intramuscular injection of Phenergan. Later in the day, Levine retuned to the clinic because she continued to suffer nausea and received a second dose of Phenergan. This time the medication was

administered through an “IV push.” The medication was supposed to be injected into her vein, but somehow it found its way into an artery. The result was that the artery and tissues in her arm were severely damaged and died, leading to gangrene and amputation of her arm. Levine v. Wyeth, 944 A.2d 179 (VT. 2008). The evidence demonstrated that because of the toxic nature of the drug when administered improperly, the medication should not come in contact with an artery; this danger being understood by the manufacturer. It was also known that the “IV push” method of drug administration increased the risk of arterial exposure. In fact, the manufacturer was aware that a number of people over the years had suffered limb amputations from the improper administration of the medication, but the drug’s label was never changed to warn against the dangers of the IV push method.

The Circulatory System ● Many drugs are administered through the circulatory system so it is important to obtain an understanding of this important body system. Primarily, it is the vehicle by which oxygen and nutrients are transported via the blood to the various tissues and

the way that metabolic waste products are removed from the cells. It also acts as a cooling station.

The circulatory system has two loops through the body: pulmonary circulation, a journey by the blood through the lungs where it is infused with oxygen; and systemic circulation, a loop through the rest of the human structure to provide the body with oxygenated blood. (Circulatory System, Wikipedia, Circulatory_system.) This is a continuous and rapid process that is needed to sustain life.

The following are the primary functions of the circulatory system:

• Substance transport to and from the tissues and organs of the body through the blood vessels.

• Removal of metabolic waste such as carbon dioxide, urea, and creatinine.

• Distribution of hormones to the tissues through the blood.

• Immune protection by the distribution of leucocytes or white blood cells.

• Temperature regulation by altering the blood flow through the skin.

• Reproduction by providing a mechanism for penile erection.

(Oprean, Functions of the Circulatory System, , http:// anatomy-physiology/functions-of-the-circulatory-system.html.)

While the heart is the driving force that pumps the blood throughout the body, the lungs and blood vessels play an equally important role. They each perform their jobs independently but are dependant upon each other to accomplish the important tasks of the circulatory system. (See, Circulatory System: The Circle of Blood, The Franklin Institute, circulation. html.)

The Heart

The heart, a muscular pear shaped organ, is slightly bigger than

the size of a fist and weighs between 7 and 15 ounces. Its primary function is to serve as a pump, keeping the blood flowing throughout the body. In fact, during a 24 hour period, the heart will beat about 100,000 times and pump around 2,000 gallons of blood. Anatomically, the heart is nestled between the lungs, and slightly to the left of the sternum. (Heart Anatomy, Texas Heart Institute at St. Luke’s Episcopal Hospital, Anatomy/ anatomy2.cfm.)

This hollow vessel is constructed of thick muscle cells called the myocardium or cardiac muscle which form the bulk of the cardiac wall. It has less connective tissue than skeletal muscle but does contain specially modified fibers that make up the electrical conduction system of the heart that tells it when to beat. These fibers include the sinoatrial node (SA) or natural pacemaker which is located in the right atrium and initiates the heart beat, the atrioventricular (AV) node which serves as the bridge between the atria and ventricles, the AV bundle, and the Purkinje fibers which carries the electrical signals

throughout the ventricles. The primary function of these myocardial fibers is to contract the heart after stimulation. About 60-100 signals

per minute travel these pathways which mean that a person has a heart rate of between 60-100 beats per minute. (Myocardium, The Free Dictionary by Farlex, . com/myocardium, and The Heart's Electrical System, Life Beat Online, Summer 2004, . templatedata/ imports/HTML/lifebeatonline/summer2004/learning.shtml .) It is this systematic stimulation of the myocardium that allows the blood to be distributed throughout the body. (Electrical Conduction System of the Heart, Wikipedia Free Encyclopedia, Electrical_conduction_system_of_the_heart.) An electrocardiogram traces these electrical impulses.

Three forms of electric signals appear on the electrocardiogram and each shows a different part of the heartbeat. The first is the P wave which records the electrical activity of the heart's two atria. The QRS wave is the second and largest wave and represents the electrical activity of the heart's ventricles. The third is the T wave which shows the heart's return to its resting state. By examining the size and shape of the waves, and the rate and regularity of beating and the time

between waves,, a physician is able to ascertain the health of the heart the heart and its rhythm. (How the Heart Works, Heart Information Center, .)

Mechanically, these electrical signals control the heartbeat in two ways. Initially, each signal causes a heartbeat and the number of electrical impulses determines the heart rate. The electrical signals also spread across the heart, triggering the heart muscle to contract in the proper sequence, thus coordinating each heartbeat and assuring that this cardiac muscle works as efficiently as possible. (Fogoros, The Cardiac Electrical System - How the Heart Beats, , http: //heart disease. od/palpitationsarrhythmias/ss/ electricheart.htm.)

When the heart muscle becomes inflamed, the condition is known as myocarditis and a number of medical problems can cause this problem, including:

• Infection

• Diphtheria

• Rheumatic fever

• Toxic drug poisoning

• Tuberculosis

(Myocardium and Myocarditis, American Heart Association, http:// presenter.jhtml?identifier=4729.)

This hollow vessel is then surrounding by a covering, similar to a baggie, dubbed the pericardium (Hirschman, Anatomy of the Heart and Circulatory System—Heart, Medical Proof of Social Security Disability 2d, Section 5.2, 2008.) The outside layer of the pericardium envelops the roots of the heart's major blood vessels and is attached

to the spinal column, diaphragm, and other body parts by ligaments. On the other hand, the inner layer of the pericardium attaches to the

heart muscle itself. These two layers of tissue are then separated by fluid, letting the heart move as it beats, yet remain attached to the body. (Heart Anatomy, Texas Heart Institute at St. Luke’s Episcopal Hospital, supra.)

A dissection of the heart reveals that it has two sets of chambers, the atria and ventricles, which are separated by valves. Therefore, with a right side and a left side, there are a total of four chambers in the heart. In looking at the heart, one would observe that the atria are the two discharging chambers located at the top or superior portion of the heart that push the blood out of the heart. In turn, the ventricles are the two chambers at the bottom or inferior portion of the structure that store the blood returning to this organ, and at the proper moment empting into the right and left ventricles. (Fogoros, The Heart's Chambers and Valves, , http:// heartdisease. cs/starthere/a/chambersvalves.htm.)

More specifically, venous blood returns to the heart from the body into the right atrium, and then flows to the right ventricle. Blood from the right ventricle is pumped to the lungs where the carbon

dioxide waste carried by the red blood cells is exchanged for the incoming oxygen (brought in by the lungs from the outside environment). This oxygenated blood is pumped back to the left side of the heart, entering the left atrium, then the left ventricle, and finally pumped out to the organs and tissues of the body.

With four separate chambers that control the flow of blood, what keeps this important liquid from flowing backwards into the wrong chamber thereby compromising this critical process? Four valves separate the chambers and open and close to let the blood flow in only one direction. These valves and their locations are:

• The tricuspid valve which is located between the right atrium and right ventricle.

• The pulmonary valve which is situated between the right ventricle and the pulmonary artery.

• The mitral valve which is between the left atrium and left ventricle.

• The aortic valve which is between the left ventricle and the large artery known as the aorta.

Each valve also has a set of flaps known as leaflets or cusps. When working properly, these valves open and close fully. A valve, however, can become defective in that it fails to fully open or close. When a heart value cannot open completely so that the blood is pumped

through a smaller-than-normal opening, the value is labeled stenotic. A heart valve may also be unable to close fully thereby leading to

regurgitation, a process in which the blood seeps backwards through

the value when it should be closed. (Heart Valves, American Heart Association, =4598.) Valves that do not work properly generally create murmurs and other abnormal heart sounds that a physician can detect with a stethoscope. However, minor degrees of regurgitation are usually diagnosed only during an echocardiogram. (Introduction: Heart Values Disorders, The Merck Manual Home Edition, http:// merck. com/mmhe/sec03/ch028/ ch028a.html.)

One of the most common valve problems is a mitral valve prolapse (MVP), a condition in which the mitral valve has "floppy" flaps and doesn't close tightly. Most people with MVP have no symptoms and are able to lead active lives. However, mitral valve prolapse can place a person at risk for endocarditis, a form of heart infection. (Mitral Valve Prolapse, Medline Plus, valveprolapse.html.)

A healthy heart beats about 60 to 100 times a minute but may drop below this target rate in people who take medication or who are physical fit. When the heart races and exceeds 100 beats a minute,

the term, tachycardia, is applied. The opposite of this, or a slow heart rate, is bradycardia and an extra heartbeat is dubbed extrasystole. (Heart Palpatations, Medline Plus Medical Encyclopedia, . nlm.MEDLINEPLUS/ency/article/003081.htm.) These abnormal conditions are known as cardiac arrhythmias and physicians generally see five types:

• Premature beats. These common arrhythmias affect a large number of people, especially older Americans and are benign.

• Atrial fibrillation. Found most often in the elderly, they develop when a disturbance in the electrical signals causes the two atrial chambers to quiver rather than pump correctly.

• Bradycardia. A slow heartbeat which can cause a person to feel fatigued, dizzy, and lightheaded.

• Tachycardia. This rapid heartbeat can cause inefficient blood circulation and the person may develop palpitations, rapid heart action, dizziness and lightheadedness.

• Ventricular arrhythmias. This is most serious arrhythmia that affects the beating of the ventricles and occurs when they go out of control, quivering and beating ineffectively therby stopping the pumping action.

Cardiac Arrhythmias, American College of Cardiology, . org/media/patient/chd/cardiac_arrhythmias.htm.)

Physicians routinely take a person’s blood pressure to help asses the condition of the heart. These measurements result from two forces; systolic and diastolic pressure. (Blood Pressure, American Heart Association, ? identifier=4473.) The systolic blood pressure (the first number in a

blood pressure reading, e.g. 120/80 mm/Hg) reflects the pressure

generated by the force of each heartbeat. If the heart stops beating, one can lose consciousness within seconds due to the lack of blood flow to the brain and, if no resuscitation is administered to reverse the problem, the person will die within minutes. The diastolic number, or

lower reading, represents the pressure when the heart relaxes

between beats.

The optimal blood pressure for adults is 120 over 80. A systolic pressure of 120 to 139 mmHg or a diastolic pressure of 80 to 89 mmHg is considered "pre-hypertension" and needs to be monitored by a physician. On the other hand, an elevated reading of 140 over 90 or higher is considered abnormal and will usually result in the issuance of blood pressure medication. (Id.)

In most cases, the cause of hypertension is not known. Certain medical conditions, however, can cause an elevation in blood pressure and are labeled secondary hypertension and include:

• Kidney abnormalities

• A structural abnormality of the aorta

• Narrowing of certain arteries

The difficulty with hypertension is that it increases the workload of the heart and arteries. In other words, the heart pumps harder, and the arteries must transport blood that's moving under greater pressure.

Other organs may also be affected by this elevation causing an increased risk of stroke, congestive heart failure, kidney failure and heart attack. (What Causes High Blood Pressure?, The American Heart Association, =2152.)

The Blood Vessels

This second part of the circulatory system is divided into arteries and veins. Arteries are thick, muscular vessels that carry the oxygenated enriched blood from the left ventricle of the heart out to the periphery of the body. As an artery reaches its destination, such as the arm, it divides and subdivides into smaller and smaller vessels, down to the smallest, termed arterioles. In the target tissues, the

arterioles further subdivide into capillaries, microscopic in size. At the capillary level, oxygen and nutrients are delivered to the tissues. Waste products from the cells and tissues, along with carbon dioxide, are then picked up and transported to the venous side. Blood flows first though the smaller venules, then small veins and finally the larger veins of the body, much like a large river as it increases in size from the tributaries that feed it. The large veins then dump the blood back

into the right atrium and the cycle starts over again.

In addition to the type of oxygenated blood they carry, and the thickness and construction of the vessel wall, arteries and veins differ in how much pressure they carry. Arteries are the high pressure side

of the system; veins are low pressure.

The heart needs oxygenated blood to survive and this muscle has its own vascular system, called coronary circulation. The aorta, the largest blood vessel in the human structure, is the primarily supplier of blood to the body, and divides into two main coronary blood vessels. These coronary arteries then branch off into smaller arteries, which

supply oxygenated enriched blood to the heart muscle. These include the right coronary artery (RCA) which provides blood primarily to that side of the heart or more specifically to the right atrium and right ventricle. This side of the heart is smaller because it sends blood only to the lungs. The left side of the heart receives its blood supply from the left main coronary artery, which subdivides into the left anterior descending artery (LAD) and the circumflex artery. (The Coronary Arteries, Texas Heart Institute Health Information Center, http://

texasheart HIC/ Anatomy/ coroanat.cfm.) The LAD supplies the front and bottom of the left ventricle and the front of the septum while the circumflex artery supplies blood to the left atrium, side and back of the left ventricle. (Your Heart and Blood Vessels, Cleveland Clinic Miller Family Heart & Vascular Institute, . heart/disorders/ cad/cad_arteries.aspx.) The left side of the heart ends up being bigger and more muscular because it must

distribute blood to the rest of the body. (The Coronary Arteries, Texas Heart Institute Health Information Center, supra.)

The heart is connected to two veins, known as the venae cavae, that carry oxygen depleted blood to the right atrium of the heart. The first vessel is the superior vena cava since it is located at the top of the heart and receives blood returning from the brain and upper extremities. The other is located at the bottom of the heart and is labeled the inferior vena cava. Its job is to drain blood from the trunk and lower exteremities. (Venae Cavae, The Free Online Dictionary by Farlex, cavae.) There is one other set of veins in the heart known as ithe pulmonary veins which

extend from the left atrium and consist of four structures known as the right superior, right inferior, left superior, and left inferior pulmonary veins. (Bailey, Heart Anatomy: Pulmonary Veins, -Biology, March 1, 2006, 03/01/heart-anatomy-pulmonary-veins.htm.) Their job is to carry oxygenated blood from the lungs to the left atrium. They also have the distinction of being the only veins in the body that transport oxygenated blood. (Pulmonary Vein, Wikipedia Free Encylopdia, . org/wiki/Pulmonary_vein.)

The Blood

Blood is the critical fluid that courses through the blood vessels supplying the cells with their nutrients and oxygen while helping to eliminate carbon dioxide from the body. A human has approximately 5.3 quarts of blood which makes up about 7 to 8 percent of a person's weight. (Bianco, How Blood Works, How Stuff Works, . blood.htm.)

Whole blood is living tissue that circulates through the heart, arteries, veins, and capillaries and consists of red blood cells, white

blood cells, and platelets suspended in a fluid called plasma. Whole Blood and Blood Components, AABB, /About_Blood/Facts_About_Blood_and_Blood_Banking/Fabloodwhole. htm.)

Red blood cells or erythrocytes (RBCs), are perhaps the most recognizable and numerous component of whole blood. These cells contain hemoglobin, a complex iron-containing protein that carries oxygen throughout the body and gives blood its red color. By way of analogy, they are like a delivery service that transports packages of oxygen to the body. The “percentage of blood volume” consisting of red blood cells is known as the “hematocrit” and makes up about 47% of the blood volume in men. Produced in the bone marrow, red blood cells are continuously produced and live for about 120 days and are eventually discarded by the spleen. Id.

White blood cells or leukocytes (WBCs) are the soldiers in the blood that fight infections. When a germ appears, the white blood cells attack it in several ways. Some will produce protective antibodies that overpower the unwarranted intruder while other white blood cells surround and devour the bacteria. White Blood Cells: Battling Blood

Cells, The Human Heart, The Franklin Institute, learn/heart/ blood/white.html.) White blood cells have a short shelf life and only live a few weeks at the most. Blood contains anywhere from 7,000 to 25,000 white blood cells in a droplet of blood and when confronted with an infection, that number dramatically increase. (Id.)

Because of the importance of blood, it must contain a substance that stops it from leaking out of the vessels. This glue like substance is known as platelets or thrombocytes and they are smaller than the white and red blood cells. When needed, the platelets gather at the site of bleeding and clump together to form a plug that seals the blood vessel and stops the bleeding. (Biology of Blood, The Merck Manual of Medical Information, Home Edition, Chapter 152, page 734, Merck Research Laboratories, 1997.) Calcium, Vitamin K, and a protein known as fibrinogen help the platelets form clots. Basically, a clot starts to form when the blood is exposed to air causing the platelets to break apart. They then react with the fibrinogen to start forming fibrin, a substance which resembles small threads. In turn, these threads form a mesh that traps the blood cells within it causing the blood cells

to harden into clots, or a scab. (Platelets: Sticky Situations, The Human Heart, The Franklin Institute, heart/blood/platelet.html.)

The blood receives most of its volume from plasma, a yellow liquid in which the blood is suspended. Water makes up about 92% of the volume of this substance, and contains dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon dioxide. (Blood plasma, Wikipedia, Free Encylopdia, Blood_ plasma.)

ROUTES OF ADMINSTRATION ● Wyeth v. Levine involves the medical issue as to the differences in the way that drugs may be

administered. For instance, what is the distinction among an intramuscular injection, a peripheral or central line IV, an IV push and transdermal administration of medication?

Pharmaceutical drugs are essential in the treatment of patients, but there are countless ways by which they can be administered. The FDA lists more than 100 different methods in which medication can be

introduced into the body. See: Center for Drug Evaluation and Research, Data Standards Manual, http:// cder/dsm /DRG/drg00301.htm.

The technical term for the dispensing of medicine is the “route of administration” which refers to the starting point for the drug’s introduction into the body up to the place where it acts upon the target organ or system. Russ, Freeman, and McQuade, Attorneys Medical Advisor, MEDADV, section 30:4 (August 2008.

The way that the body handles medication, through absorption, distribution, metabolism and elimination, is known as pharma-cokinetics. Goodman & Gilman, The Pharmacological Basis of Therapeutics, McGraw Hill Companies, 11 Edition, Chapter One. Drugs also vary widely in their individual pharmacokinetic properties.

Therefore, the route that a specific drug is given to a patient depends upon a number of factors, particularly the nature of the drug, its pharmacokinetics, and the nature and urgency of the medical

condition. While multiple variations exist, the main methods of medication administration are: oral, transdermal, transmucosal, inhalation, and parental – which is further divided into subcutaneous, intramuscular, and vascular routes.

1. Oral (enteral). The most common way to give medications is orally, or by mouth, in which the patient swallows a pill or capsule. The enteral route is used primarily for convenience, economy, stability, and patient acceptance. The Merck Manual of Diagnosis and Therapy, 18th ed, Merck Research Laboratories, Chapter 302, Concepts in Pharmacotherapy; 2006. When ordered by a physician, this method of administration is usually written as p.o. (per os). In this route of delivery, the medication must reach the intestine where it is broken down, absorbed across the intestinal wall, picked up in the blood stream, and delivered to its intended target. These steps, however, take time, up to 30 to 45 minutes between the taking of the medication and its effect. Examples of medication given this route include Lipitor for cholesterol, Keppra for epilepsy and Norvasc for blood pressure.

The potencies and therapeutic effects of a number of medications are reduced when taken orally because of the partial degradation and varying absorption rates across the intestine that occur before the drug reaches its intended target. Time-release medications and pharmaceuticals are designed to produce slow, uniform absorption into the body. Vogelosn, Advances in Drug Delivery Systems, Modern Drug Discovery, April 2001, Vol. 4 No. 4, pp 49–50, 52. The variability and certain unpredictability of the oral route, however, have led pharmaceutical researchers to look for other methods of medication administration.

2. Transmucosal. The mucosa is the highly vascular lining of all entry ports to the body such as the mouth, nose, rectum, and vagina. Some medications can be applied directly to the mucosa, thereby causing absorption into the blood vessels directly and on to the target organs of the body. This method by-passes the intestines, resulting in the much quicker onset of action. A major benefit of this application is its simplicity; it requires little preparation, supervision or expertise. The possible disadvantages are localized tissue irritation/ burning and with, oral preparations, a disagreeable taste. Current Topics in Oncology, Routes of Opioid Analgesic Therapy in the

Management of Cancer Pain, , http:// professional/ ccj_pain.aspx?id=23793. Examples of transmucosal medications include nitroglycerine for angina (taken under the tongue), Zomig NS for migraine (as a nasal spray), and rectal Valium for seizure control.

3. Inhalation. Inhalation of medication, a type of transmucosal approach, is usually administered for respiratory problems such as asthma and severe allergies. With this method, the drug is inhaled through a specialized delivery system into the airways leading to the lungs. Medications administered by this method frequently use a device known as a metered dose inhaler, or "MDI." Inhalation provides a better chance of the drug reaching the small airways, thereby increasing the medication's effectiveness. On the other hand, potential problems include large drug particles that could end up in the mouth that are absorbed into the bloodstream, causing increased side effects. Also, smaller particles could move so quickly that they strike the back of the throat, resulting in less of the drug’s ability to reach the airways. Using Inhaled Medications, Cleveland Clinic Health Systems, . health/health-Info/docs/

2400/ 2415.asp ? index =8694&pflag =1. Examples of these medications include Advair Diskus for asthma and Combivent for bronchospasm.

4. Transdermal. Some medication delivery systems are designed to be applied directly to the skin, providing a controlled-release method over several days. In these specifically formulated medications, the drug is slowly absorbed through the skin by the application of a patch imbedded with the drug. Like the transmucosal method, the medication enters the blood stream directly, by-passing the intestinal system. An advantage of this application is that of patient convenience and compliance since the patch usually only needs to be applied once every day or several days rather than taking a pill multiple times during a day. Like the transmucosal route, local skin irritation may occur as a complication. Current Topics in Oncology, Routes of Opioid Analgesic Therapy in the Management of Cancer Pain, supra. Examples of these medications include a Transderm Scopolomine patch (for vertigo and sea-sickness), Fentanyl (a potent narcotic analgesic), and Flector (an anti-inflammatory agent).

5. Parental. Medications that are delivered by injection with a needle are described as being given by the parental route of administration. The three most common categories in this delivery system are subcutaneous, intramuscular and intravascular. Because

all three of these routes bypass the intestinal system and quickly access the vascular system on their way to their target organ, they offer a more rapid onset of action.

Subcutaneous injections (written as s.c. in a doctor’s order) are those in which a small needle is inserted just under the skin and the medication is injected. This method is used because there is little blood flow to fatty tissue, and the injected medication is generally absorbed over a longer period of time. Subcutaneous Injection Guide: Why are subcutaneous injections given?, HGH News, . hghnews.us/p/Subcutaneous_ Injection _Guide_Why_are_ subcutaneous_injections_given_ 175,298,,.html. Examples of pharmaceutical drugs given this route include insulin for diabetes mellitus, Imitrex for migraine, and Copaxone for multiple sclerosis.

Intramuscular injections (written as i.m. in a doctor’s orders) are injected directly into a large muscle of the body. This route has the

added advantage of serving as a storage point for the drug as it is slowly released into the circulatory system. These muscle locations typically are in the upper arm close to the shoulder, the front of the thigh and the buttock. Intramuscular Injection, Encyclopedia of Nursing & Allied Health, . com/ nursing- encyclopedia/intramuscular-injection. Hitting a major nerve lying deep within the muscle is a potential complication of intramuscular injections. Examples of these medications include the antibiotic penicillin G and Sandostatin LAR Depot for acromegaly.

Intravascular administration refers to medication injected directly into the circulatory system. This route is the most immediate and provides the quickest onset of action. The two approaches for this method are injection into a vein (written as i.v.) or into an artery (written in the orders as i.a.). Before discussing this route in more detail, however, it would be helpful to briefly describe the circulatory system of the body.

Intravenous (i.v.) delivery of a drug, therefore, involves the administration of a drug into a vein and the medication is diluted by the blood before it reaches its target organ. Intravenously

administered drugs can be given slowly by infusion or rapidly by syringe. With the slow infusion method, a short catheter or butterfly needle is inserted into a vein and connected by tubing to an IV bag. The bag contains a saline solution with the medication dissolved in the fluid. In another approach, the drug may be “piggy-backed” from a smaller bag into the larger IV bag. Which ever method is used, the drug is then “dripped” slowly into the vein, usually by means of a pump which controls the rate of infusion. This method is most useful with antibiotics or chemotherapy given over hours or days. The IV can be placed in a location distant to the heart such as the hand or arm (even the foot or head if necessary), or close to the heart in the subclavian vein just beneath the collar bone, termed a central line.

Long term IV therapy over days to months is accomplished through a peripherally inserted central catheter (PICC line). With a PICC line, a catheter is inserted in a vein in the arm and threaded centrally to the large veins emptying into the right atrium of the heart.

If a more rapid delivery system is needed, the medication can be administered directly into the vein through a syringe without the IV bag, a procedure known as an intravenous (IV) push. Veins used in

this method can be either those peripherally, located in the hand and arm, or centrally, close to the heart such as the subclavian vein. Which of these venous locations are used depends upon the urgency of the situation and the patient’s cardiovascular stability.

Intra-arterial (written as i.a. in an order) injection is not a usual route of administration for most medications because the drug will be quickly transported in large amounts to a localized area of the body. The potential consequence of this action is vascular and tissue damage and death “downstream” from the injection site, such as that which tragically occurred to Diana Levine. One application of intra-arterial injection is for dissolving a blood clot in an artery with tissue plasminogen activator (t-PA).

The following table compares and contrasts the two major routes of drug administration – oral (enteral) and injection (parenteral).

Comparison of Enteral and Parenteral

Routes of Drug Administration

|ROUTE |Absorption Pattern |Special Utility |Precautions |

|Enteral (oral) |Variable, depend on many factors |Most convenient and economical; |Requires patient compliance, |

| | |usually more safe |bioavailability may be erratic and |

| | | |incomplete |

|Parenteral (injection) | | |

| Subcutaneous |Prompt, use aqueous solutions |Suitable for some poorly soluble |Not suitable for large volumes, |

| | |suspensions and some slow release |possible pain and tissue death from |

| | | |irritating substances |

| Intramuscular |Prompt with aqueous solutions; slow and|Suitable for moderate volumes, |Not with anticoagulant therapy; may |

| |sustained with repository drugs |oily solutions, and some |interfere with some results |

| | |irritating substances | |

| | | | |

| Intravenous |Avoids intestinal absorption; rapid |Useful in emergency, can adjust |Increase risk of adverse effects; |

| |onset; useful for large volumes, |dosage easily and quickly; |must inject solutions slowly as a |

| |irritating substances or complex |required for large molecular drugs|rule; not suitable for oily solutions|

| |mixtures when diluted | |or poorly soluble substances |

modified from Goodman & Gilman’s The Pharmacological Basis of Therapeutics

11th ed.

THE CIRCULATORY SYSTEM - LEGAL ISSUES ● An injury to the circulatory system can have devastating consequences and any part of this system is vulnerable. For example, one can sustain a ruptured aneurysm, a heart attack or damage to a blood vessel and all of these problems have been the subject of litigation.

First of all, an aneurysm is a budge in the wall of a blood vessel, very similar to a budge in a tire. They are dangerous because a rupture can cause a depletion of blood in the circularity system leading to death. (See Aortic Aneurysms, American Heart Association, http:// American presenter.jhtml?identifier=4455.)

The most well known type of aneursyms is an aortic aneurysms which occurs primarily in the abdomen below the level of the kidneys. However, they may also develop in the chest cavity when the wall of the aorta becomes weakened by build ups of fatty deposits known as plaque, a phenomenon is called atherosclerosis. Certain inherited diseases such as Marfan Syndrome can also cause aneurysms. Id. On the other hand, an aneurysm in the brain, also known as a cerebral or

intracranial aneurysm, is an abnormal bulge of one of the arteries in the brain. Unfortunately, these aneurysms are frequently diagnosed only after they have ruptured with a resultant bleed into the brain. They may also rupture into the space surrounding the brain and are known as a subarachnoid hemorrhage which condition can lead to brain damage, a stroke or death. (What is a Brain Aneurysm?, Brain Aneurysm Resources, .)

Aneurysms come in a variety of forms including:

• Common aneurysms which area bulges at the point where the middle wall of the artery has weakened.

• Berry aneurysms or a cerebral aneurysms, which resemble a small, rounded berry at the "V" where cerebral arteries branch.

• Saccular aneurysms, which term refers to a bulge that does not encase the entire circumference of the vessel and frequently appears in the aorta.

• Fusiform aneurysms, which deal with bulges around an entire vessel.

• Dissecting aneurysms, in which the blood enters an opening between the layers of the artery wall.

(Russ, Freeman and McQuade, Aneurysms and Fistulas, 8 Attorneys Medical Advisor § 87:21.)

Failure to Diagnose an Aneurysm

The failure to diagnose an aneurysm has been the subject of a number of medical malpractice cases. For instance, liability has been found when a radiologist failed to diagnose an aneurysm in the abdominal aorta on an arteriogram, Stone v. Williamson, 2007 WL 1135686, Mich. App., 2007; for the failure to timely diagnose an abdominal aortic aneurysm, Bell v. U.S., 854 F.2d 881 (Mich. C.A.6 1988); where an emergency room physician failed to diagnose an

abdominal aneurysm after the patient complained of abdominal bloating, discomfort, weakness and vomiting, Estate of Cangemi v. Cone, 774 A.2d 1262 (Pa. Super. 2001); and where a physician failed to refer a prisoner to a specialist or perform a spinal tap after the inmate complained of worsening headache symptoms for most of the month and then died of from a ruptured berry aneurysm, Larkin v. State, 446 N.Y.S.2d 818 (N.Y. A.D. 1982).

Defense verdicts were rendered where a physician was found not to have departed from the standard of care when he failed to advise the decedent of the possibility that an aneurysm might develop, Delaune v. Davis, 316 So.2d 7 (La. App. 1975); a doctor who performed an examination solely to determine the patient’s eligibility for worker’s compensation benefits was found not to have owed a duty to the claimant when the physician failed to discover an aneurism, Henkemeyer v. Boxall, 465 N.W.2d 437 (Minn. App. 1991); and an emergency room physician was not responsible for failing to evaluate a patient for a cerebral aneurysm which went undiagnosed when the patient suffered from mid-sternal chest pain that radiated to her shoulders and neck, a severe headache, vomiting, diarrhea, and

sweating, Camp v. EMSA Ltd., 518 S.E.2d 482 (Ga. App.1999).

Injury to a Vein or Artery

As noted earlier, many drugs are administered through the circulatory system and a variety of complications can arise that lead to lawsuits. For instance, it was not malpractice when a patient developed a hand infection caused by an intravenous needle that was maintained in place by a Heparin lock where the hospital staff monitored the intravenous fluid on a daily basis and noticed nothing wrong, Simmons v. U.S., 841 F. Supp. 748 (W.D. La.1993); the doctrine of res ipsa loquitur was inapplicable to an arm injury sustained during the withdrawal of blood for a test, Pipers v. Rosenow, 333 N.Y.S.2d 480 (N.Y. A.D. 1972). Contrary results, however, were reached when a physician punctured a lung while perform a subclavian stick, Eichelberger v. Barnes Hospital, 655 S.W.2d 699 (Mo. App. E.D. 1983), and it was not malpractice when the insertion of a Port-A-Cath punctured a patient’s left innominate vein causing the patient to die. MacGuineas v. U.S,738 F. Supp. 566 (D.D.C. 1990).

Heart Attacks

Whether it is labeled a myocardial infarction or heart attack, the Center for Disease Control reports that heart disease is the leading cause of death in both men and women. (Heart Disease Facts and Statistics, Center for Disease Control.) A heart attack occurs when the blood vessels that nourish the heart with blood are blocked thereby preventing oxygen from reaching the heart. Most of these attacks occur because a blood clot obstructs one of the coronary arteries causing the heart cells to die. Sudden stress can also trigger a myocardial infarction. Chest pain is the major symptom of this problem which pain can also radiate into the arm, jaw, neck, shoulder or teeth. (Heart Attack, Medline Plus Medial Encyclopedia, http:// nlm.MEDLINEPLUS/ency/article/000195.htm.)

The average heart attack victim waits more than 3 hours after the symptoms first appear before seeking help. Therefore, more than half of the fatalities happen before the person reaches the hospital. However, just because the patient reaches a physician, is not always a cure because patients are occasionally discharged after an inadequate evaluation or misdiagnosed only to die at another location. Therefore, the failure to diagnose a myocardial infarction is a common issue and the most expensive malpractice claim against emergency rooms.

(Danner, Varn and Mathias, Misdiagnosis of Heart Attack, 5 Medical Malpractice Checklist and Disc. Section 32:1, 2009.

For example, a 38 year old man developed chest pain and was brought to the hospital where the discomfort began to radiate to both shoulders. This discomfort was accompanied by shortness of breath and sweating. The admission sheet also noted that the patient was taking two medicines for high blood pressure, smoked and was overweight. The patent received an electrocardiogram and was

discharged. Upon arrival at home, he suffered a fatal heart attack. At trial, the plaintiff’s expert alleged that there was an eighty-five to ninety percent probability that the patent would have survived the heart attack had he been hospitalized but the expert was unable to state specifically how long the decedent would have lived following his heart attack. The court found that the Estate presented sufficient evidence that the doctor’s failure to admit the patient to the hospital was negligent. Furthermore, the plaintiff did not have the burden of proving the length of time by which decedent's life was shortened and what damages flowed there from. Taylor v. Decker, 514 N.E.2d 754 (Ohio App. 1986).

An interesting case on this topic is Hamil v. Bashline, 307 A.2d 57 (Pa. Super. 1973) where the court ruled that malpractice exists if the physician does something or fails to do something that increases the risk of harm in having a heart attack. The decedent was brought to the emergency room where a doctor ordered an EKG to assess the man’s severe chest pain. The machine did not work so another machine was requested but the physician left the hospital. A second machine could not be located so the patient was taken to a doctor in a

nearby city where he died from an acute myocardial infarction. While the plaintiff’s Estate could not prove that the decedent would have survived even if he had received proper treatment, the defendant’s actions were found to have increased the risk of death by failing to use reasonable care under Section 323(a) of the Restatement of Torts. See also; Sharp v. Kaiser Foundation Health Plan of Colorado, 710 P.2d 1153 (Colo. App. 1985); and McClain v. Metabolife Intern., Inc., 401 F.3d 1233 (C.A.11 (Ala.) 2005).

Angiogram

The coronary arteries can become clogged from such things as a buildup of cholesterol, cells or other substances. This can reduce the blood flow to the heart thereby cause a variety of complications. If a

blood clot blocks the blood from coursing through an artery, a heart attack may occur. A coronary angiogram, therefore, is a specialized X-ray to ascertain if the coronary arteries are clogged, where and by how much. (What is a Coronary Artery Angiogram?, American Heart Association,.) The test is

performed by a physician threading a thin catheter from the leg or arm into the coronary artery on its journey up to the heart. Once the catheter is in place, a dye is injected to illuminate the blood vessels in the area. If a blockage is discovered, it can be treated with medicine, a percutaneous coronary intervention such as a stent, angioplasty or open heart surgery depending upon the severity of the blockage. (Id.)

Needless to say, this invasive procedure has been the subject of malpractice claims. For instance, in Lasley v. Georgetown University

688 A.2d 1381 (D.C. 1997), the court ruled that a plaintiff who sustained a ruptured blood vessel during an angiogram must still present expert testimony premised on the failure to warn of the risks of developing an embolization even though the problem occurred during the procedure. In Macey v. James, 427 A.2d 803 (Vt. 1981), the court found that whether a physician was negligent in the

performance of an angiogram, and whether such negligence caused the patient to develop a fistua, were questions for the jury. On the other hand, a motion for summary judgment was granted in favor of the defense when plaque allegedly dislodged following a cardiac catherization causing a hearing problem dislocation of arterial plaque is a known risk of the procedure and would not establish a deviation from

the standard of care. Applebaum v. Sharma, 801 N.Y.S.2d 776 (N.Y. Supp. 2005).

CONCLUSIONS ● The central medical issue in Levine v. Wyeth concerns the improper way that Phenergan, a medication used for treatment of nausea, was given to a patient, leading to the amputation of her arm. The fact that each pharmaceutical drug requires its own specific route of administration is understood by medical providers, but is not well appreciated in the legal community or by the average person. The specific route required – oral (enteral) or injection (parenteral); subcutaneous or intramuscular; intravenous drip or push; transdermal or transmucosal – depends upon a number of factors. These parameters include the characteristics of the drug, its pharmacokinetics, the medical problem being treated, and the urgency

to get the drug into the patient. This overview describes the most commonly used routes of medication administration to provide counsel with a basis of understanding the routes of administration and for further research on this topic. It also provides a basic explanation of the very complex circulatory system.

PRACTICE CHECKLIST FOR

The Circulatory System and Routes of Drug Administration

● Medications play a vital role in the treatment of patients, but there are countless ways by which they can be administered. The technical term for the administration of medicine is the “route of administration” which refers to the starting point for the drug’s introduction into the body up to the place where it acts upon the target organ or system.

● The route chosen to give a specific drug to a patient depends upon a number of factors, including the nature of the drug, its pharmacokinetics, and the patient with respect to the nature and urgency of the medical condition. While multiple variations exist in the

way that medications are administered, the main methods are: oral, transdermal, transmucosal, inhalation, and parental – further divided into subcutaneous, intramuscular, and vascular routes.

● The oral or enteral route, whereby the patient swallows a pill or capsule, is the most common way to administer medications. Because the oral route requires absorption by the intestine, it is the slowest and least reliable method. This route of administration is used primarily for convenience, economy, stability, and patient acceptance

● The transmucosal and transdermal methods involve applying the medication to the mucosa (the highly vascular lining of all entry ports to the body such as the mouth, nose, rectum, and vagina) or the skin. This route by-passes the intestine, resulting in a more rapid and reliable delivery system.

● Inhalation of medication is usually administered for respiratory problems such as asthma and severe allergies. With this method, the

drug is inhaled through a specialized delivery system into the airways leading to the lungs.

● In parental administration, the medication is delivered by an injection; these methods are subcutaneous, intramuscular, and intravascular:

- Subcutaneous (s.c.) injections are those in which the needle is inserted just under the skin.

- Intramuscular (i.m.) injections are given into large muscles in the arm or leg.

- Intravascular administration refers to the medication injected directly into the circulatory system, providing the route which is most rapid in onset. The drug can be injected into a vein (i.v.) either slowly by IV drip, or rapidly by IV push through a syringe. With the exception of t-PA, injections into an artery (i.a.) are usually not done because of possible resulting tissue damage and death.

• The circulatory system is the vehicle by which oxygen and nutrients are transported via the blood to the various tissues and the way that metabolic waste products are removed from the cells. It also acts as a cooling station.

• The primary function of the heart is to serve as a pump, keeping the blood flowing throughout the body.

-The heart is constructed of thick muscle cells called myocardium or cardiac muscle which form the bulk of the cardiac wall.

- This hollow vessel is then surrounding by a covering, similar to a baggie, dubbed the pericardium.

- The heart has two sets of chambers, the atria and ventricles, which are separated by valves.

• Arteries are thick, muscular vessels that carry the oxygenated enriched blood from the left ventricle of the heart out to the periphery of the body.

• Blood flows first though the smaller venules, then small veins and finally the larger veins of the body, much like a large river as it increases in size from the tributaries that feed it.

• Blood courses through the blood vessels supplying the cells with their nutrients and oxygen while helping to eliminate carbon dioxide from the body.

- Red blood cells contain hemoglobin, a complex iron-containing protein that carries oxygen throughout the body and gives blood its red color.

- White blood cells (WBCs) are the soldiers in the blood that fight infection.

- Platelets stop the blood from leaking out of the vessels when damage occurs.

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