Forensic Pharmacology
Page 2
in a medical school, at the University of Michigan, in 1891.
Abel is considered the father of American pharmacology,
and played a major role in the organization of the American
Society for Pharmacology and Experimental Therapeutics
(ASPET). Today, pharmacology is part of the educational
programs at medical, nursing, pharmacy, and other health
professional schools.
Some of the earliest forensic toxicologists were Alex-
ander Gettler, Raymond Abernethy, and Rutherford Grad-
wohl. In their time, analytical instruments and procedures
were in their infancy, but they developed many of the tech-
niques used today in chemical analysis. They were founders
of the American Academy of Forensic Sciences (AAFS) in
1948. Today, the AAFS is divided among 10 sections: crimi-
nalistics, engineering sciences, general, jurisprudence,
odontology, pathology/biology, physical anthropology, psy-
chiatry and behavioral sciences, questioned documents,
and toxicology.
Introduction: The Role of the Forensic Pharmacologist
the workplace or in sports. The pharmacologist may be involved
in a broader scope of forensic issues than the toxicologist, with
such diverse cases as adverse drug reactions to medicines, over-
dose of medicines, drug interactions, personal injury following
exposure to medicines, effects from drugs of abuse or industrial
chemicals, and induction of cancer by chemicals.
REAL-LIFE CASES
One of the authors has testified in court as an expert witness
on many drug-related issues, including unexpected reactions to
a medicine, whether a person accused of assault or murder of
an attacker who had high blood levels of drugs of abuse could
reasonably claim self-defense, whether exposure to medicinal
chemicals, industrial chemicals, mercury-containing herbal
preparations, carbon monoxide, or lead paint could have caused
certain injuries or illnesses, whether drugs could have affected
the behavior of people involved in motor vehicle accidents or
accused of murder, and whether the presence of drugs of abuse
in urine can be explained by reasons other than intentional drug
abuse. Examples from these actual forensic pharmacology cases
will be presented in the individual drug chapters.
As an example of an actual criminal case, two defendants
were accused of raping a woman they had invited to their
apartment. They claimed that the victim drank herself into a
stupor within about 30 minutes after arrival, that she imag-
ined the rape occurred, and that she left on her own about
four hours later. The victim testified that she had two beers
and one scotch within a 2.5-hour period. At some point she
excused herself to make a phone call. Shortly after she returned
and finished her drink, she felt dizzy and lost consciousness.
She awoke briefly to find herself being raped but was weak, in
a dreamlike state, and could not speak or move. She was able
0 Forensic Pharmacology
to leave about two hours later with the assistance of family
members. The author’s testimony before the jury explained
that the amount of alcohol consumed by the victim was insuf-
ficient to induce unconsciousness and that if enough alcohol
had been consumed to reach a level of unconsciousness, as the
defendants claimed, given the rate of alcohol metabolism, it is
highly unlikely a person would appear relatively normal sev-
eral hours later. The author’s opinion was that when the victim
left the room to make the phone call, it is likely that drugs were
added to her drink. This testimony, along with other evidence,
helped the jury find the two defendants guilty, and they were
sentenced to up to 25 years in prison.
As an example of an actual civil case not involving drugs of
abuse, an infant developed seizures after being hospitalized for
fever. Analysis of the infant’s bodily fluids revealed the presence
of high levels of theophylline, a drug used to treat asthma that in
high doses can cause seizures. The plaintiff alleged that an error
occurred in the hospital and that the infant was given theophyl-
line instead of an antibiotic. At trial, the hospital countered that
the theophylline in the infant came from the mother’s breast
milk, since the mother was taking theophylline for asthma and
was breast-feeding her child. Theophylline pharmacokinetic
data were presented to the jury indicating that the amount of
theophylline excreted via breast milk could never account for
the levels found in the infant. An error in drug administration
probably occurred. The parties settled the lawsuit.
This book will outline what forensic pharmacology is and
how it is used in similar cases in the real world. Chapter 2 will
describe principles used by forensic pharmacologists to establish
causation, namely pharmacokinetics and pharmacodynamics.
Chapter 3 will describe the tools used by forensic scientists to
identify and quantify chemicals in bodily fluids and tissues.
Chapter 4 will describe current trends in drug abuse, focusing
Introduction: The Role of the Forensic Pharmacologist
on drug abuse by adolescents. Chapters 5 to 12 will describe the
pharmacology of eight major categories of drugs of abuse as well
as interesting forensic issues for many of the drugs. Chapter 13
will discuss the future of forensic pharmacology, and Chapter 14
will test the reader’s knowledge by presenting several cases for
the reader to solve. There are hundreds of street names for many
of the drugs of abuse. We have selected a few names from select
resources for each drug, and the bibliography and further read-
ing list should be consulted for additional references.
2 Pharmacokinetics
and
Pharmacodynamics
The first aspect of pharmacokinetics involves the entry of a
drug into the body. Chemicals, in the form of foods, medicines,
drugs of abuse, or industrial chemicals, can enter the human body
via several routes, including ingestion, inhalation, injection, skin
application, and suppository. Except for cases of injection directly
into the bloodstream, the chemical must pass through complex
living cell membranes before it can enter the bloodstream.
For example, chemicals that enter the digestive tract must be
absorbed by the cells lining the small intestine and then be trans-
ferred through the cells, where the chemical can then be absorbed
by the capillary cells into the bloodstream. Chemicals that are
inhaled must pass through the alveoli, the cells of the lungs, to get to the capillaries and enter the bloodstream.
As chemicals pass into and out of cells, they must cross the
cell membrane that keeps all of the cell contents securely inside,
but which allows some materials to pass (Figure 2.1). Chemicals
can move through the cell membrane through one of several
mechanisms.
One of the mechanisms for moving chemicals through the cell
membrane is passive diffusion, which
is based on the difference
12
Pharmacokinetics and Pharmacodynamics
13
Figure 2.1 The cell membrane consists mainly of lipids (fats),
proteins, and carbohydrates in the form of a lipid bilayer. The two lipid
layers face each other inside the membrane, and the water-soluble
phosphate groups of the membrane face the watery contents inside the
cell (the cytoplasm) and outside the cell (the interstitial fluid).
in concentration of the chemical outside of the cell compared to
inside the cell. The greater the difference, the greater the move-
ment of the chemical to the inside of the cell. Since the membrane
is highly lipid in nature, lipophilic (lipid-loving) chemicals will
diffuse more easily across the membrane. Ionized molecules
that are more water soluble do not diffuse across membranes as
readily as lipophilic molecules and are influenced by the pH of
the fluid surrounding the cell. Water-soluble chemicals can also
14 Forensic Pharmacology
be transported using carrier proteins, and this process is called
facilitated diffusion.
Inorganic ions, such as sodium and potassium, move through
the cell membrane by active transport. Unlike diffusion, energy
is required for active transport as the chemical is moving from a
lower concentration to a higher one. One example is the sodium-
potassium ATPase pump, which transports sodium [Na+] ions
out of the cell and potassium [K+] into the cell.
Chemicals may cross the cell membrane via membrane pores.
This diffusion depends on the size of the pore and the size and
weight of the chemical. The chemical flows through the mem-
brane along with water. Finally, the membrane can actually
engulf the chemical, form a small pouch called a vesicle, and
transport it across the membrane to the inside of the cell. This
process is called pinocytosis.
DISTRIBUTION OF CHEMICALS
Once the chemical is in the bloodstream, it can be distrib-
uted to various organs. Initially its concentration in blood is
greater than in tissues. Because of the difference in concen-
tration, the chemical will leave the blood and enter the sur-
rounding cells.
Sometimes other factors affect the movement of the chemical.
For example, not all chemicals easily enter the brain. The capil-
lary cells in the brain have tight junctions restricting the flow of
materials between cells. One type of cell forms a tight covering
on the capillary and prevents or slows down large molecules from
passing through the cells. This structure is known as the blood-
brain barrier. All of the drugs discussed in this book—drugs of
abuse—affect the central nervous system (CNS), which consists
of the brain and spinal cord. Thus, the drug must pass through
the blood-brain barrier.
Pharmacokinetics and Pharmacodynamics
15
The availability of a chemical to the cells is affected by where
it is stored. First, lipophilic chemicals tend to get absorbed by
and retained in fat cells, from which they are released slowly
back into the bloodstream. Second, some chemicals are strongly
bound to plasma proteins and are released to the cells more
slowly over time. For example, acetaminophen (Tylenol®) does
not bind strongly to plasma proteins, while diazepam (Valium®)
does. Thus, diazepam will persist in the body for longer periods
of time than will acetaminophen. Finally, some elements, such
as fluorine, lead, and strontium, are bound up in bone for long
periods of time. As bone slowly renews itself or is broken down
under special circumstances such as pregnancy, the chemicals
are released and can affect the mother and fetus.
METABOLISM OF CHEMICALS
Many xenobiotics, or chemicals that are foreign to the body,
undergo metabolism. This type of metabolism is different from
the metabolism of food nutrients necessary for production of
energy to drive bodily functions. The purpose of xenobiotic
metabolism is to convert active chemicals into inactive forms
or convert inactive chemicals into active ones, and to transform
chemicals into more water-soluble forms so that they can be
more easily excreted via the urine and bile. To understand drug
action, it is important to know whether the original chemical
or the product of its metabolism (its metabolites), or both, is
responsible for the pharmacological effects.
While many tissues can metabolize foreign chemicals, metab-
olism of xenobiotics primarily occurs in the liver. It is important
to note that everything that is ingested and passes into the intes-
tine first passes through the liver before entering the general
circulation. Thus, you can think of the liver as the filter for the
entire body.
16 Forensic Pharmacology
Metabolism of xenobiotics proceeds via a two-stage process.
Phase I consists of oxidation, reduction, or hydrolysis to form
polar groups such as hydroxyl (OH) or carboxyl (COOH). Phase
II consists of conjugation, whereby enzymes add to the polar
groups glucuronic acid, sulfate, acetate, or glutathione, making
the chemical more water soluble. Sometimes, the new metabo-
lite is as active or more active than the parent chemical. Such
an example is morphine-6-glucuronide, which is as active as
morphine.
Phase I enzymes, located in the endoplasmic reticulum,
include cytochrome P450-dependent monooxygenases. There
are many genes for the different cytochrome P450 (CYP)
enzymes, each acting on different sets of chemicals. Another
Phase I enzyme, monoamine oxidase (MAO), can be found in
mitochondria. The enzymes involved in Phase II metabolism
are found mainly in the cytoplasm. Also in the cytoplasm is
the enzyme alcohol dehydrogenase that metabolizes ethanol
(drinking alcohol) to acetaldehyde which is then metabolized
to acetic acid. Interestingly, exposure to the xenobiotic chemical
sometimes increases the amount of the enzyme used for its own
metabolism.
Since one particular enzyme system can metabolize many
different chemicals, there is great potential for drug interaction.
If one drug can increase the level of a specific enzyme, a second
drug metabolized by that enzyme would also be more quickly
metabolized. This may result in enhanced activity or a lowering
of the drug’s blood level and decreased effectiveness of one or both
drugs. Also, if two drugs compete for an enzyme’s activity, each
drug might be metabolized more slowly, thereby prolonging their
effects. Such information may be important in legal cases involv-
ing toxic effects of chemicals as a result of drug interaction.
Some people are rapid metabolizers of drugs and some are
slow metabolizers. Factors that can affect the response to drugs
Pharmacokinetics and Pharmacodynamics
17
include age, gender, and genetics. Very young children and older
people metabolize drugs more slowly. There are some differences
seen betw
een men and women, as well as between races, in the
metabolism of certain drugs. A new field of pharmacogenomics
studies the role of genes in drug action and will someday allow
for study of an individual’s genes to determine in advance the
response to drug therapy.
It is important to know how much of the chemical is destroyed
as it passes through the liver to enter the general circulation. If,
for example, someone ingests 100 milligrams of drug A and only
50 milligrams exits from the liver, then 50% of the drug was
lost. This is known as the first-pass effect. Using this example,
if 200 milligrams is required for a therapeutic effect, then a
pharmaceutical manufacturer must incorporate 400 milligrams
into each tablet. First-pass metabolism influences the effects of
several drugs of abuse.
EXCRETION OF CHEMICALS
Chemicals and/or their metabolites are eventually eliminated.
The three organs predominantly involved in elimination are
the liver, the lungs, and the kidneys. Other routes of excretion
include bile, feces, sweat, saliva, breast milk, nails, and hair.
As blood passes through the lungs for exchange of carbon
dioxide and oxygen, volatile chemicals such as alcohol exit from
the blood and are exhaled. Drugs that are eliminated via the bile
are excreted into the small intestine and then eliminated via the
feces, though some drugs are partly reabsorbed. This pattern of
circulation, called enterohepatic circulation, from bile to intes-
tine and back to liver, continues until the drug is completely
eliminated. Blood is filtered as it passes through the kidney, and
chemicals can leave the blood to become part of the urine form-
ing in the renal tubules.
18 Forensic Pharmacology
As a result of metabolism and excretion, drugs leave the body
at certain rates. The rate of elimination may vary widely with
different drugs, which explains why some medications must be
taken four times daily, while others are taken only once a day.
The half-life of a drug is the time in which the concentration of
drug, generally in blood or plasma, decreases by 50%. Thus, if
drug X has a half-life of three hours, and after absorption of drug
X the blood concentration is 100 units, then three hours later the
concentration would be 50 units, and three hours after that the
blood concentration would be 25 units. After five half-lives, the