Download Routes of Drug Administration

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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
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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.
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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.
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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
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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
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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, http://en.wikipedia.org/wiki/
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.
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(Oprean, Functions of the Circulatory System, Heatrzine.com, http://
heartzine.com/anatomy-physiology/functions-of-the-circulatorysystem.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, http://www.fi.edu/learn/heart/systems/ 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, http://www.texasheart.org/HIC/ Anatomy/
anatomy2.cfm.)
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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, http://medical-dictionary.thefreedictionary.
com/myocardium, and The Heart's Electrical System, Life Beat Online,
Summer 2004, http://www. bostonscientific.com/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
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Heart, Wikipedia Free Encyclopedia, http://en.wikipedia.org/wiki/
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, http://your-doctor.com/healthinfocenter/medicalconditions/cardiovascular/conductiontutorial.html.)
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
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that this cardiac muscle works as efficiently as possible. (Fogoros, The
Cardiac Electrical System - How the Heart Beats, About.com, http:
//heart disease. about.com/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://
www.americanheart.org/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
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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, About.com, http://
heartdisease. about.com/cs/starthere/a/chambersvalves.htm.)
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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.
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
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, http://www.americanheart.org/presenter.jhtml?identifier
=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:// www.merck.
com/mmhe/sec03/ch028/ ch028a.html.)
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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,
http://www.nlm.nih.gov/medlineplus/mitral 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,
http://www. nlm.nih.gov/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.
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
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, http://www.acc.
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
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forces; systolic and diastolic pressure. (Blood Pressure, American
Heart Association, http://www.americanheart.org/presenter.jhtml?
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.)
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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, http://www.americanheart.org/presenter.jhtml?Identifier
=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
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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
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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://
www.texasheart institute.org/ 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, http://my.
clevelandclinic.org/heart/disorders/ cad/cad_arteries.aspx.) The left side
of the heart ends up being bigger and more muscular because it must
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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, http://www.thefreedictionary.com/venae+ 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, About.com-Biology,
March 1, 2006, http://biology.about.com/b/2006/ 03/01/heartanatomy-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.
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(Pulmonary Vein, Wikipedia Free Encylopdia, http://en.wikipedia.
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, http://health.
howstuffworks.com/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, http://www.aabb.org/Content
/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
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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, http://www.fi.edu/
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.)
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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, http://www.fi.edu/learn/
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
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the volume of this substance, and contains dissolved proteins, glucose,
clotting factors, mineral ions, hormones and carbon dioxide. (Blood
plasma, Wikipedia, Free Encylopdia, http://en.wikipedia.org/wiki/
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:// www.fda.gov/cder/dsm
/DRG/drg00301.htm.
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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 pharmacokinetics. 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.
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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
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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, CancerConsultants.com, http://
professional/ cancerconsultants.com/ccj_pain.aspx?id=23793.
Examples of transmucosal medications include nitroglycerine for
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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, http://www. cchs.net/health/health-Info/docs/
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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 controlledrelease 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).
30
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, http://www.
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
31
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, http://www.enotes. com/ nursingencyclopedia/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
32
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
33
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; usually
more safe
Requires patient
compliance,
bioavailability may be
erratic and incomplete
Parenteral (injection)
34
Subcutaneous
Prompt, use aqueous
solutions
Suitable for some
poorly soluble
suspensions and
some slow release
Not suitable for large
volumes, possible pain
and tissue death from
irritating substances
Intramuscular
Prompt with aqueous
solutions; slow and
sustained with
repository drugs
Suitable for
moderate volumes,
oily solutions, and
some irritating
substances
Not with anticoagulant
therapy; may interfere
with some results
Intravenous
Avoids intestinal
absorption; rapid onset;
useful for large
volumes, irritating
substances or complex
mixtures when diluted
Useful in
emergency, can
adjust dosage easily
and quickly;
required for large
molecular drugs
Increase risk of
adverse effects; must
inject solutions slowly
as a rule; not suitable
for oily solutions 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.
35
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://
www.American heart.org/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, http://www.brainaneurysm.com.)
36
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
37
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
38
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
39
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://
www.nlm.nih.gov/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.
40
(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).
41
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
42
blood clot blocks the blood from coursing through an artery, a heart
attack may occur. A coronary angiogram, therefore, is a specialized Xray to ascertain if the coronary arteries are clogged, where and by how
much. (What is a Coronary Artery Angiogram?, American Heart
Association,http://www.americanheart.org/downloadable/heart/11961
9923016841%20WhatIsaCoronaryAngiogram_9-07.pdf.) 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
43
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
44
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
45
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
46
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.
47

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.
48

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.