Forensic Pharmacology Read online

  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