From textbook

1.1: What Is a Drug?

Most people understand what is meant by the term drug. Even so, providing a precise definition of this term is surprisingly difficult. Traditionally, a drug is defined as any substance that alters the physiology of the body. Although food and nutrients alter the physiology of the body, we do not usually think of these as drugs. Consequently, a drug is sometimes defined as a substance that alters the physiology of the body but is not a food or nutrient. While this narrower definition is often sufficient, it still lacks a sense of accuracy in capturing a universal meaning of the term drug (and highlights just how difficult it can be to formulate an exact definition for all cases).

One factor that complicates our ability to define a drug is the intention of the user. If a substance is consumed recreationally to get “high,” or as a pharmaceutical to treat a disorder or medical condition, it is commonly thought of as a drug. But if that same substance is consumed accidentally or for taste or sustenance, it may not be useful to think of it as a drug. For instance, vitamin C alters physiology but is it a drug? If consumed in the form of an orange, it is clearly food, but if taken as a tablet to prevent or treat a cold, it could be thought of as a drug. A similar debate has also been waged about caffeine. As you will learn in Chapter 9, caffeine alters human physiology, but it is also used as a flavoring agent in products such as soft drinks. If consumers prefer a soft drink that contains caffeine because they like the drink’s taste, perhaps caffeine should not be thought of as a drug in that instance. If the soft drink is consumed as a means of stimulating wakefulness and energy, then in that context it is appropriate to think of caffeine as a drug. Substances that impact the nervous system to alter a person’s mood, perceptions, or level of consciousness (as caffeine does) are often referred to as psychoactive drugs. Likewise, some substances that alter the physiology of the body may best be thought of as toxins or poisons rather than as drugs. Gasoline and solvent vapors are examples. If they are huffed (inhaled deliberately to get high) they may be thought of as drugs. When inhaled unintentionally in the workplace, however, they may be identified as environmental toxins.

Fortunately, it is not necessary for us to form an absolute definition of the term drug—intuitive and working definitions will serve our purposes. However, we should never lose sight of the fact that any one definition may not be appropriate in all circumstances.

1.2: Naming Drugs

One source of confusion when learning about drugs is their myriad of names. Pharmaceutical drugs have at least three names—a chemical name, a generic name, and a trade name—and it may not always be apparent which name is being used at any given time. In addition, when used recreationally, these drugs have an assortment of street names that vary across time and place.

1.2.1: Chemical Name

All drugs have a chemical name stated in formal, technical jargon such as this:

7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one

A chemist can tell what the drug molecule looks like by its name. The chemical terminology, letters, and numbers indicate the drug’s composition and refer to places where different parts of the drug molecule are joined. To make things more complicated, there are different conventions for numbering these parts of molecules. As a result, the same drug will have different chemical names if different conventions are used.

1.2.2: Generic Name

When a drug becomes established, its chemical name is too clumsy to be useful and a new, shorter generic name or nonproprietary name is created. The generic name for the drug whose chemical name we just struggled through is diazepam, an anxiety-reducing medication you will learn more about in Chapter 7. The conventions for making up generic names are handy to know because they are clues to the nature of the drug. Initially, the generic name was derived by combining parts of the chemical name, and these names are still in use. More recently, a system has been adopted that uses a stem to indicate the class or function of the drug. The stem is usually the last part of the generic name, although it could be at the beginning or in the middle. For example, oxetine is a stem that indicates an antidepressant drug. Thus, if you see the name fluoxetine or duloxetine, you know what type of drug it is, even though you may never have heard of it before. Table 1-1 shows stems for some behaviorally active drugs.

Table 1-1 Generic Name Stems of Behaviorally Active Drugs

Generic Drug Name Stem Definition Examples

-azenil Benzodiazepine receptor agonists/antagonists bretazenil; flumazenil

-azepam Antianxiety agents (diazepam type) lorazepam

-barb-; -barb Barbituric acid derivatives phenobarbital; secobarbital; eterobarb

-caine Local anaesthetics dibucaine

-clidine Muscarinic agonist (various indications) vedaclidine; talsaclidine

-clone Hypnotics/tranquilizers (zopiclone type) pagoclone

-dopa Dopamine receptor agonists levodopa

-erg- Ergot alkaloid derivatives pergolide

-eridine Analgesics (meperidine type) anileridine

-fentanil Narcotic analgesics (fentanyl derivatives) alfentanil; mirfentanil; brifentanil

-fylline Theophylline derivatives enprofylline; bamifylline; cipamfylline

-giline MAO inhibitors, type B selegiline

nab-; -nab- Cannabinol derivatives nabazenil; dronabinol

nal- Narcotic agonists/antagonists (normorphine type) nalmefene

-nicline Nicotinic acetylcholine receptor partial agonists/agonists altinicline

-orphan Narcotic antagonists/agonists dextro-(morphinan derivatives) methorphan; dextrorphan

-oxetine Antidepressants (fluoxetine type) dapoxetine; seproxetine

-peridol Antipsychotics (haloperidol type) haloperidol

-peridone Antipsychotics (risperidone type) risperidone; iloperidone; ocaperidone

-pidem Hypnotics/sedatives (zolpidem type) zolpidem; alpidem

-plon Nonbenzodiazepine anxiolytics, sedatives, hypnotics ocinaplon; zaleplon

-pramine Antidepressants (imipramine type) lofepramine

-spirone Anxiolytics (buspirone type) zalospirone; tiospirone

-stigmine Cholinesterase inhibitors (physostigmine type) quilostigmine; teserstigmine

-tidine H2-receptor antagonists (cimetidine type) lupitidine; ranitidine; donetidine

-triptyline Antidepressants (dibenzo[a,d]cycloheptane derivatives) amitriptyline

Prefixes are shown as “stem-,” middle syllable as “-stem-,” and suffixes as “-stem.”

Source: Adapted from United States National Library of Medicine, National Institutes of Health (2015), http://druginfo.nlm.nih.gov/drugportal/jsp/drugportal/DrugNameGenericStems.jsp, accessed June 30, 2015.

Generic names are established in the United States by the United States Adopted Names Council (USANC) and are called United States Adopted Names (USAN). Similarly, British Approved Names (BAN) are established by the British Pharmacopoeia. Internationally, the World Health Organization establishes International Nonproprietary Names (INN). Despite attempts to harmonize the creation and adoption of generic names throughout the world, there are still cases where different names are used for the same drug. For example, the USAN amphetamine is still widely used in Britain and the United States, but many other parts of the world are now using amfetamine, the INN. Most scientific journals and textbooks published in North America (including this book) use USANC generic names.

Because establishing a generic name is a costly and time-consuming process, newly discovered drugs may be investigated extensively before generic names are officially awarded by the official naming agencies. But instead of using their clumsy chemical names, these drugs are sometimes referred to by an unofficial generic name—a code using letters and numbers established by the company. For example, you may see a name like SKF 10,047. The letters refer to the drug company (in this case, Smith, Kline, and French), and the numbers are a unique code for the drug. SKF 10,047 has now been assigned the generic name alazocine.

1.2.3: Trade Name

Drug research and development is a lengthy and costly process for pharmaceutical companies (Box 1-1 describes the rigorous, standard process of psychotherapeutic drug development). During development and marketing of a new drug, the company can patent that drug for a certain time so that no other company can sell it. Drug patents are typically granted for about a 20-year period from the initial application date. By the time the drug is fully developed and granted approval for sale, about 7 to 12 years of patent remain while the drug is on the market. Even though it must use the generic name somewhere in its advertising and documentation, the drug company does not sell the drug under its generic name. Instead, it creates a new name called the trade name, proprietary name, or brand name. Whereas a generic (nonproprietary) name can be used by anyone, a trade (proprietary) name is the property of the company selling the drug and no other company can use that name. The trade name for diazepam is Valium. Once the patent expires, other companies can sell the drug or they can make it under license from the owner of the patent, but they frequently sell it under a different trade name. Therefore, one drug can have many different trade names.

BOX 1-1 The Process of Pharmaceutical Drug Development

Preclinical Testing

When a new chemical entity is discovered or synthesized by researchers, it must be tested extensively before it can be developed into a useful drug. The chemical’s composition, stability, solubility, toxicity, safety, pharmacokinetics, and formulation must be determined. Some of this research is conducted in vitro (in cells in a test tube or culture dish) and some in vivo (in experimental animals, usually rats or mice). If the research results show promise, a report and request to conduct further studies is submitted to the country’s drug licensing authority (in the United States, an Investigational New Drug application is made to the U.S. Federal Drug Administration [FDA]; in Canada, a Clinical Trial application is submitted to Health Canada; and in Europe, a Clinical Trial Authorization Application is assessed by the European Medicines Agency [EMA]). If the application is approved, testing can proceed to clinical trials involving humans. The preclinical testing phase of drug development lasts, on average, 5 to 6 years at a cost upwards of hundreds of millions of dollars and with an estimated success rate of about 0.05% to 0.2% of chemicals tested.

Clinical Testing

Clinical tests on humans are conducted in phases over a number of years and with increasingly large samples of individuals. Phases I and II each last, on average, 2 years at costs upwards of tens of millions of dollars. Phases III and IV last, on average, 2–4 and 15 years, respectively, at costs of hundreds of millions of dollars. Only a fraction of chemicals tested at each Phase will, based on outcome, proceed to the next.

Phase I: Pharmacokinetic and Safety Testing. Between 20 and 100 healthy volunteers are paid to participate in determining the investigational drug’s absorption, distribution, metabolism, and elimination from the body, as well as its dosing ranges, side effects, and safety.

Phase II: Small-Scale Effectiveness Testing. Between 100 and 300 patient volunteers participate in a closely supervised examination of the investigational drug’s effectiveness and possible adverse effects.

Phase III: Large-Scale Effectiveness Testing. Clinical trials are expanded to include between 1,000 and 3,000 patient volunteers who help researchers determine drug efficacy, safety, and any adverse outcomes resulting from longer-term drug use. This testing is often carried out in university-teaching hospitals using the three-groups design described in Chapter 2. With promising outcomes, a New Drug Application or Marketing Authorization Application is filed with the country’s drug licensing authority. If approved, this allows for widespread sale of the drug under its newly created trade name.

Phase IV: Postmarketing Studies. The new drug is available for prescription to any individual who might benefit from it. The pharmaceutical company must continue postmarketing surveillance of users and report to the country’s licensing authority on the drug’s safety, efficacy, and manufacturing processes.

Off-Label Use

When new pharmaceuticals are approved for market, the licensing authority specifies the medical condition for which the drug was tested and developed to treat. Physicians may determine, however, that the drug has other potential benefits and prescribe it to treat other disorders. This is called off-label use. Examples of off-label use include antipsychotics to treat depression, anticonvulsants to treat pain, and antidepressants to treat sexual dysfunction in men. It sometimes happens that a drug works surprisingly well for its off-label prescription. An example of this is the drug bupropion. It was developed originally as an antidepressant and given the trade name Wellbutrin. Later, it was coincidently discovered that bupropion reduced smoking in people who took it. Clinical trials were conducted, and its effectiveness in helping people quit smoking was confirmed. Now, in addition to being marketed as an antidepressant, bupropion is marketed as Zyban, a smoking-cessation aid.

Because drug companies sell their products under trade names, those are the names that people in the medical profession are most familiar with and likely to use. If a physician writes you a prescription, you may not be able to find that drug name listed in this or any other text that uses generic names. Trade names can be distinguished from generic names because their first letter is capitalized.

Because drug companies sell their products under trade names, those are the names that people in the medical profession are most familiar with and likely to use. If a physician writes you a prescription, you may not be able to find that drug name listed in this or any other text that uses generic names. Trade names can be distinguished from generic names because their first letter is capitalized.

Strictly speaking, the trade name refers to more than just the active ingredient in the medicine. The active ingredient may be marketed in the form of a pill, powder, aerosol, or liquid that may contain a number of other ingredients—fillers, coloring agents, binding agents, flavors, preservatives, and coatings—collectively referred to as excipients. The excipients and the active ingredient are combined in a particular way, and this is known as the drug’s formulation. Different pharmaceutical companies may market the same drug under different trade names using different formulations. It cannot be assumed that all formulations with the same active ingredient are equal. For example, different formulations may be released immediately or slowly into the body or may dissolve at different rates in different parts of the gastrointestinal tract and, consequently, may not be equally effective.

1.2.4: Street Name

Drugs that are sold on the street for recreational use generally have a street name, which can change with time and differ geographically. Usually, though, a particular drug has one street name that is widely recognized. For example, the club drug MDMA (3,4-methylenedioxymethamphetamine) is commonly referred to by the street name ecstasy. Many drugs used recreationally are not manufactured by drug companies and prescribed by physicians to treat disease or illness. However, sometimes pharmaceutical drugs are diverted from medical use and sold on the street. Street names for diazepam (Valium) include tranks, downers, blue Vs, old joes, and drunk pills. Select examples of recreationally used pharmaceutical drugs’ chemical, generic, trade, and street names are provided in Table 1-2.

Table 1-2 Chemical, Generic, Trade, and Street Name Examples

Anxiolytics and Sedative-Hypnotics (Chapter 7)

Chemical Name Generic Name Trade Names Street Names

8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine alprazolam Xanax benzos; bicycle parts; blue footballs; handlebars; school bus; totem poles; Upjohn; xanbars; xannies

5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione phenobarbital Luminal; Nembutal abbots; barbs; goofballs; Mexican yellows; nembies; phennies; purple hearts; red birds; tooies; yellow jackets

Psychomotor Stimulants (Chapter 10)

Chemical Name Generic Name Trade Names Street Names

methyl[(2S)-1-phenylpropan-2-yl]amine methamphetamine Desoxyn chaulk; crank; crystal; glass; ice; meth; speed; yaba

1-phenylpropan-2-amine amphetamine Dexedrine; Adderall ampes; bennies; black beauties; blue Mollies; Christmas trees; dexies; eye poppers; lightening; pep pills; uppers

methyl 2-phenyl-2-(piperidin-2-yl)acetate methylphenidate Ritalin; Concerta; Metadate; Methylin, Focalin crackers; kibbles and bits; kiddy coke; pineapple; poor man’s cocaine; R-ball; skippy; skittles; smarties; study buddies; vitamin R; west coast

Opioids (Chapter 11)

Chemical Name Generic Name Trade Names Street Names

4,5a-epoxy-3,14-dihydroxy- 17-methylmorphinan-6-one oxymorphone Opana; Numorphan blue heaven; Mrs. O; octagons; oranges; pink lady; stop signs; the O bomb

N-(1-(2-phenylethyl)-4-piperidinyl)- N-phenylpropanamide fentanyl Sublimaze; Actiq; Fantora; Duragesic Apache; China white; dance fever; friend; goodfella; jackpot; murder 8; Tango and Cash; TNT

6-(dimethylamino)-4,4-diphenylheptan- 3-one methadone Dolophine; Methadose amidone; chocolate chip cookies; dollies; fizzies; jungle juice; junk; metho; wafer

Hallucinogens, Psychedelics, and Club Drugs (Chapter 15)

Chemical Name Generic Name Trade Names Street Names

4-hydroxybutanoate gamma-hydroxybutyrate (GHB) Xyrem easy lay; G; Georgia home boy; goop; grievous bodily harm; liquid ecstasy; liquid X; scoop

2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one ketamine Ketalar cat Valium; jet; K; purple; special LA coke; special K, super acid; vitamin K

1.3: Describing Dosages

All of modern science uses the metric system and drug doses are nearly always stated in milligrams (mg). A milligram is 1/1,000 of a gram (there are a little over 28 grams in an ounce). It is generally true that the behavioral and physiological effects of a drug are related to its concentration in the body rather than the absolute amount of drug administered. If the same amount of a drug is given to individuals of different weights, it will reach different concentrations in the body and brain of each individual. To ensure that the drug is present in the same concentration in all experimental participants or patients, different doses are frequently given according to body weight. For this reason, in research papers, doses are usually reported in terms of milligrams per kilogram (kg) of body weight—for example, 6.5 mg/kg (a kilogram is equal to 2.2 pounds).

Reporting doses in this manner also helps when comparing research on different species. If you account for such factors as metabolic rate and body composition, a dose of 1 mg/kg in a monkey will be roughly equivalent to a dose of 1 mg/kg in a human. Interspecies comparisons, however, can be tricky. Generally, smaller organisms have higher metabolic rates than larger animals. As we shall see later, many drugs are broken down by the body’s metabolism. This means that drugs are metabolized faster in smaller animals, so it is often necessary to give them a higher dose if they are to reach an exposure equivalent to that of a human. Thus, a dose of 1.0 mg/kg in a human may be equivalent to a dose of 10.0 mg/kg in a mouse or rat. For this reason, research done with rats and mice often uses doses that appear excessive in human terms.

1.3.1: Dose–Response Curves

To establish a true picture of the physiological and behavioral effects of a drug, it is usually necessary to give a wide range of drug doses. The range should include a dose so low that there is no detectable effect, a dose so high that increases in dose have no further effect, and a number of doses in between. The effect of this range of doses is plotted on a graph, with the dose indicated on the horizontal axis and the effect on the vertical axis. This type of figure is called a dose–effect curve (DEC) or a dose–response curve (DRC). It is generally found that a small change in low doses can have a big effect, but an equally small change in a large dose has no effect. Plotting doses so that the scale on the horizontal axis is graduated logarithmically allows a wide range of doses to be reported and permits greater precision at the low end of the dosage range.

Oftentimes, the vertical axis will represent a continuous measure, such as response rate, latency to respond, or percentage performance compared to a control group. But there are other types of DRCs in which the effect is a discrete binary variable rather than a continuous one. For example, we could not use a continuous scale if we wanted to report a DRC for the effectiveness of a drug as an anesthetic. Either subjects are anesthetized or they are not! If the vertical axis simply read Yes or No, we would not have any sort of a curve. When a binary variable is used, DRCs are constructed differently.

Binary drug effects are handled by working with groups of subjects. Each group is given a different dose of the drug, and the percentage of subjects in each group that shows the effect is then plotted. An example of this type of DRC is given in Figure 1-1. This hypothetical experiment is designed to establish the DRC for loss of consciousness and the lethal effects (another clearly binary variable) of a fictitious new drug: endital. In this experiment, there are 12 groups of rats. Each group is given a different dose of endital—from 0 mg/kg (a placebo) to 110 mg/kg—represented on the graph’s horizontal axis. The graph’s vertical axis represents the percentage of rats in each group that showed the effect. The curve on the left shows how many rats lost consciousness, and the curve on the right shows the percentage of rats in each group that died. These curves inform us of endital’s effectiveness and lethality.

Figure 1-1 

Results of a hypothetical experiment using 12 groups of rats. Each group was given a different dose of enditol, ranging from 0.0 (a placebo) to 110 mg/kg. One curve shows the percentage of animals in each group that lost consciousness; the other curve shows the percentage that died at each dose. The ED50 and the LD50 are also indicated.

Figure 1-1  Full Alternative Text

ED50 and LD50

A common way of describing dose– response curves and comparing the effectiveness of different drugs is by using the ED50, the median effective dose, or the dose that is effective in 50% of the individuals tested. Figure 1-1 indicates that the ED50 for losing consciousness from endital is 35 mg/kg. By checking the next curve, you can see that the dose of endital that killed 50% of the rats was 84 mg/kg. This is known as the median lethal dose, or the LD50.

It is also common to use this shorthand to refer to lethal and effective doses that are not at the median. For example, the LD50 is the dose at which 50% of subjects die, the LD1 is the dose that kills 1% of subjects, and the ED99 is the dose that is effective in 99% of all cases. In DRCs constructed from continuous rather than binary measures, the ED50 refers to the dose that produces an effect that is 50% of the drug’s maximally effective dose.

1.3.2: Drug Safety

When a new drug is being developed and tested, it is common to establish the LD50 and the ED50 to give an idea of its safety. The farther the lethal dose is from the effective dose, the safer the drug. The therapeutic index (TI; also known as the therapeutic ratio) is sometimes used to describe the safety of a drug. This is the ratio of the LD50 to the ED50; TI = LD50/ED50. The higher the TI, the safer the drug. The TI of endital calculated from Figure 1-1 would be 84/35 = 2.4. Drug safety may also be described as a ratio of the ED99 and the LD1.

1.4: Potency and Effectiveness

Potency and effectiveness (or efficacy) are terms that are sometimes used to describe the extent of a drug’s effect. The two terms do not mean the same thing. When you are comparing two drugs that have the same effect, potency refers to differences in the ED50 of the drugs. The drug with the lower ED50 is more potent. For example, if you constructed two DRCs for lysergic acid diethylamide (LSD) and lysergic acid amide (LSA; a related compound found in morning glory seeds) for the ability to cause hallucinations, you would find that the ED50 of LSA is 10 times higher than that of LSD. In other words, the nature and extent of the effect of LSA would be the same as that of LSD if you increased the dose of LSA by a factor of 10—LSD is 10 times more potent than LSA.

Effectiveness refers to a drug’s ability to produce a maximum, biologically functional response at its molecular target, regardless of dose. Both acetylsalicylic acid (Aspirin) and morphine are analgesics or painkillers. When dealing with severe pain, Aspirin at its most effective dose is not as effective as morphine. To compare these two drugs in terms of potency would not be appropriate. They might both produce analgesia at the same dose and, thus, be equally potent, but the extent of the analgesia would be vastly different. The difference between potency and effectiveness is shown in Figure 1-2.

Figure 1-2 

Left: Drugs A and B are equally effective, but the potency of Drug A is greater than that of Drug B. Right: Drugs C and D are equally potent, but the effectiveness of Drug C is greater than that of Drug D.

1.5: Drug Interactions

When two drugs are mixed together their effects can interact in several ways. If one drug diminishes the effect of another, this interaction is called antagonism. Drug antagonism is established by plotting two DRCs: one for the drug alone, and a second for the drug in the presence of the other drug. If the DRC for the first drug is shifted to the right (i.e., the ED50 increases) by adding the new drug, this result indicates antagonism between the drugs.

If adding the new drug shifts the DRC to the left (i.e., the ED50 decreases), the drugs are said to have an additive effect. If, together, drugs have an effect that is greater than might be expected simply by combining their individual effects, a superadditive effect, or potentiation, exists. This can be particularly dangerous if the drugs’ effects include respiratory depression, as is the case with alcohol and tranquilizing drugs (barbiturates). It is not always obvious whether a drug interaction is additive or superadditive, but in one situation the distinction is clear: if one drug has no effect alone but increases the effect of a second drug, potentiation is clearly occurring.

In these examples, drug interaction is defined in terms of changes in potency—shifts in the DRC indicated by changes in the ED50. Interactions between drugs can also change their effectiveness. That is, the ED50 may not change, but the maximum effect may increase or decrease (see Figure 1-3).

Figure 1-3 

Drug interactions. The curve labeled A is the dose–response curve (DRC) for a drug, against which the effects of the addition of other drugs will be compared. The curve labeled B shows the DRC after the administration of a second drug. Note that the DRC has been shifted to the left and the ED50 has decreased. This indicates potentiation or an additive effect. Curve C is the DRC after another drug has been given. This drug has shifted the DRC to the right, increasing the ED50. This indicates antagonism. Curve D shows the effect of another drug on the DRC. In this case the DRC has been shifted to the right, showing a decrease of potency, and the maximum effect has also been reduced showing a decrease in effectiveness.

1.6: Primary Effects and Side Effects

It is generally accepted that no drug has only one effect, though in most cases only one effect is wanted. It is common to call the effect for which a drug is taken the primary or main effect and any other effect, harmful or otherwise, is a side effect. Often, the distinction between main and side effects is a matter of intention. Aspirin, for example, has several physiological effects: it brings down fever, it reduces swelling and inflammation, and it slows the blood’s ability to clot. If you take Aspirin to reduce a fever, the temperature-lowering effect is the primary effect, and the other two are side effects. The inhibition of blood clotting is a potentially harmful effect because it can cause bleeding into the stomach, which can have serious consequences. But this anticlotting effect can be useful. Strokes are caused by a clot of blood getting caught in the brain. Taking low-dose Aspirin every day can reduce the chance of stroke in people at risk. In this case, the anticlotting effect would be the primary effect, and any other effects that the Aspirin might be having would be the side effects. When new behaviorally active drugs are developed to treat diseases, the ability of a drug to be abused or to create an addiction is considered a dangerous side effect. To a drug user, however, this psychological effect of the drug is vitally important, and any other effects the drug may have on the body are considered unimportant or undesirable side effects.

1.7: Pharmacokinetics

The study of how a drug moves around the body is called pharmacokinetics. Pharmacokinetics includes three processes: absorption—how a drug gets into the blood; distribution—where it goes in the body; and elimination—how the drug is broken down and leaves the body. Drugs do not have an effect on all body tissues. As a matter of fact, most drugs influence the operation of the body only at specific and limited places, called sites of action. A drug may get into the body, but it will have no effect unless it gets to its site of action where it will interact with a cell to change the cell’s biochemical processes. It is, therefore, important to understand how drugs get from their place of administration to the place where they act.

1.8: Routes of Administration

Some foods and medications may contain large amounts of valuable nourishment and medicine, but simply swallowing them or otherwise putting them into the body is no guarantee that they will get to their site of action to exert their desired effect. It is also true that the way a substance is administered can determine its bioavailability—that is, not only whether it gets to its site of action, but also how fast it gets there and how much of it gets there.

A route of administration refers to the method used to get a drug from outside the body to some place under the skin. Some substances can be directly absorbed through the skin, but most cannot. Getting drugs into the body can be accomplished by taking advantage of the body’s natural mechanisms for taking substances inside itself (such as digestion, breathing, or absorption through mucous membranes), or the drug can be artificially placed under the skin by means of injection.

1.8.1: Parenteral Routes of Administration

Parenteral routes of administration involve injection through the skin into various parts of the body, using a hollow needle and syringe. Parenteral routes are further subdivided, depending on where in the body the drug is injected.

Vehicle

Before a drug can be injected, it must be in a form that can pass through a syringe and needle—that is, it must be liquid. Because most drugs are in a dry powder or crystalline form (the word drug is derived from the French drogue, meaning dry powder), it is necessary to dissolve or suspend a drug in some liquid before it can be injected. This liquid is called a vehicle. Most behaviorally active drugs tend to dissolve well in water and remain stable for long periods of time in water solution. Pure water is not totally inert with respect to the physiology of the body, so a weak salt solution is used instead. Because body fluids contain dissolved salts, the most common vehicle is normal or physiological saline, a solution of 0.9% sodium chloride (ordinary table salt), which matches body fluids in concentration and does not irritate the tissues when it is injected, as pure water would.

In some cases, the drug to be injected does not dissolve in water. The primary psychoactive ingredient in marijuana, tetrahydrocannabinol (THC), is an example of such a drug; it requires a different vehicle, such as vegetable oil (see Chapter 14). Administering lipid-soluble drugs in an oil vehicle slows the rate of absorption, prolonging the drug’s effects over several days.

When a drug is in liquid form and the syringe is filled, the needle can be inserted into various places in the body, and the drug and vehicle are then injected to form a small bubble, or bolus. There are four common parenteral routes, depending on the site where the bolus containing the drug is to be placed: (a) subcutaneous, (b) intramuscular, (c) intraperitoneal, and (d) intravenous.

Subcutaneous

In published material, the term subcutaneous is frequently abbreviated s.c. In jargon, it is called sub-q. As the name suggests, in this route of administration, the drug is injected to form a bolus just under the skin or cutaneous tissue. In most laboratory animals, the injection is usually made into the loose skin on the back, between the shoulders. For medical purposes in humans, s.c. injections are usually done under the skin of the arm or thigh, but the hand or wrist is sometimes used to self-administer recreational drugs such as heroin, a procedure referred to as skin popping. Some drugs, including contraceptives, may be manufactured as pellets for s.c. implantation, which prolongs absorption, sometimes for years.

Intramuscular

In the intramuscular (i.m.) route, the needle is inserted into a muscle, and a bolus is left there. Depot injections (discussed below) are administered intramuscularly. In humans, the most common muscle used for this purpose is the deltoid muscle of the upper arm or the gluteus maximus muscle of the buttock. To receive such an injection, the muscle must be fairly large, so i.m. injections are seldom given to rats and mice. They are more frequently given to monkeys. This route of administration is common for pigeons as well; the injection is given into the large breast muscle. Drugs administered i.m. are typically absorbed through the muscle’s capillaries within roughly an hour.

Intraperitoneal

The abbreviation for the intraperitoneal route is i.p., and, as the name suggests, the needle is inserted directly into the peritoneal cavity. The peritoneum is the sack containing the visceral organs, such as the intestines, liver, and spleen. The aim of an i.p. injection is to insert the needle through the stomach muscle and inject the drug into the cavity that surrounds the viscera. It is not desirable to inject the drug directly into the stomach or any of the other organs. Doing so could be harmful and cause hemorrhaging and death. At the very least, injection into an organ is likely to alter the reaction to the drug.

Intraperitoneal injections are commonly used with rats and mice because they are easy and safe and cause the animals very little discomfort. They are much less convenient in larger animals and are almost never given to humans. At one time, rabies vaccine was commonly given to humans via this route, but this is no longer the case.

Intravenous

In an intravenous (i.v.) injection, the needle is inserted into a vein and the drug is injected directly into the bloodstream. Colloquially, this is referred to as mainlining. Before an i.v. injection can be given, it is necessary to find a vein that comes close enough to the surface of the skin that it can be pierced with a needle. In humans, this is usually the vein on the inside of the elbow. The most common procedure is to wrap a tourniquet around the upper arm between the injection site and the heart. Because veins carry blood toward the heart, the tourniquet will dilate or enlarge the vein at the injection site and make injection easier.

When the end of the needle is inserted into the vein, the tourniquet is removed, and the drug is injected when normal blood flow has resumed. This is essentially the reverse of the procedure used when blood is removed for a blood test. When a drug is administered i.v., it gets distributed throughout the body very quickly, reaching the brain in a matter of seconds and producing rapid effects. One difficulty with i.v. injections, however, is that a vein cannot be used too frequently or it will collapse and simply stop carrying blood. When veins have collapsed in the arms, other veins in the wrists, hands, and feet may be used, but they are more difficult to strike accurately with a needle. Another problem is that recreational drugs may contain contaminants that are insoluble (do not dissolve) and, once in the bloodstream, become lodged in and cause damage to small blood vessels in organs such as the lungs or eyes.

In laboratory animals, i.v. injections are not commonly used by behavioral pharmacologists because veins close to the surface of the skin are unusual in rats, mice, and pigeons, and the procedure is not easy in unrestrained animals. Fur and feathers also make veins difficult to locate. When i.v. injections are necessary, they are usually accomplished by means of a permanently implanted tube called a catheter. In rodents and monkeys, venous (in a vein) catheters are usually inserted in the jugular vein in the neck, and the free end of the tube emerges from the animal’s back. When an intravenous injection is required, the syringe is attached to the end of the catheter outside the body, and the drug is injected. Researchers frequently use this type of preparation to study self-administration of drugs by animals (the catheter may be attached to a motor-driven pump that the animal can control by pressing a lever). Intravenous catheters are fairly per­manent and may last for months before they have to be replaced.

Other Parenteral Routes

Experimental research with laboratory animals sometimes involves injections directly into the central nervous system (the brain and spinal cord; see Chapter 4). In intrathecal injections, for example, the needle is inserted into the nervous system between the base of the skull and the first vertebra. The drug is left in the cerebrospinal fluid (CSF; the fluid that bathes the nervous system) and quickly diffuses throughout the nervous system. A drug may also reach the CSF through an intracerebroventricular injection directly into one of the brain’s ventricles, which are chambers filled with CSF. To more precisely determine drug effects on specific areas of the brain, intracerebral injections may be used in which a drug is administered directly into brain tissue. These forms of drug administration are often done through a cannula. A cannula is like a catheter, except it is a rigid tube resembling a hypodermic needle. Cannulae are often attached to the skull using dental cement and can remain permanently implanted.

Absorption From Parenteral Sites

With intravenous injections, the drug is put directly into the bloodstream. But when injected at other sites, the drug must be absorbed into the circulatory system. The rate at which a drug gets from an injection site into the blood is determined by a number of factors associated with blood flow to the area. Generally, the volume of blood flow is greater to the peritoneal cavity than to the muscles, and it is greater to the muscles than under the skin. As a result, next to an i.v. injection, absorption is fastest from an i.p. injection and is slowest from an s.c. injection.

Heat and exercise can speed absorption from i.m. and s.c. sites because such factors increase blood flow to muscles and skin. Thus, an i.m. injection will be absorbed faster if the muscle is exercised after the injection, and the drug from a subcutaneous site will get into the blood faster if heat is applied to the area and more slowly if the area is chilled.

To be absorbed into the bloodstream, a drug must pass through the walls of the capillaries. A capillary is a tiny vessel through which blood flows. Capillaries permeate most body tissues. They are so small in diameter that red blood cells can barely pass through. It is through the walls of capillaries that nutrients and oxygen pass out of the blood into body tissues, and it is also through these capillary walls that waste products and carbon dioxide pass into the blood and are removed. Blood leaves the heart and is distributed around the body in arteries. The arteries divide into smaller and smaller branches until they become capillaries. The blood in capillaries is eventually collected in veins, which carry the blood back to the heart and the lungs (see Figure 1-4).

Figure 1-4 

The circulatory system.

Figure 1-4  Full Alternative Text

The walls of the capillaries are made up of a single layer of cells. Between these cells are small openings, or pores, through which nutrients, waste products, and drugs may pass freely. The only substances in the blood that cannot move in and out of the capillaries through these pores are red blood cells and large protein molecules, which are trapped inside because they are larger than the pores.

Injected drugs pass into capillaries and the bloodstream through these pores by simple diffusion. Diffusion is the process by which a substance tends to move from an area of high concentration to an area of low concentration until the concentrations are equal in both areas. If a drop of food coloring is placed in the corner of a tub of still water, it will remain as a highly colored drop for only a short period of time. The force of diffusion will soon distribute the coloring evenly throughout the tub of water. The same principle determines that a drug injected into a muscle or under the skin will move from the area of high concentration (the bolus at the site of the injection) into the blood, an area of low concentration, until the concentrations in the two places are equal. The drug from an injection site will move through the pores into the blood in the capillaries surrounding the injection site. Because this blood is constantly circulating and being replaced by new blood with a low concentration of drug, more will be absorbed as the blood circulates through the area.

Areas that are serviced by many capillaries will absorb drugs faster than areas that have few capillaries. Because muscles use more oxygen, they have a richer capillary supply than the skin; for this reason, absorption into the blood is faster from i.m. injections than from s.c. injections. Drugs injected into the peritoneum have access to an even greater number of capillaries; consequently, i.p. injections are absorbed even more rapidly.

Absorption through capillary walls is not a factor in intravenous injections because the drug is placed directly into the blood. Blood in the veins is transported to the heart and then redistributed around the body after a short detour through the lungs (see Figure 1-4). The body has about 6 liters of blood, and the heart pumps these 6 liters once a minute, so the drug in most i.v. injections is distributed around the body within a minute after injection.

Depot Injections

Some drugs need to be taken chronically to prevent the symptoms of a disease or disorder from reappearing; antipsychotics are examples of such drugs (see Chapter 12). For a number of reasons, compliance with antipsychotics can be low; people may not continue to take them after release from a hospital. As a result, they may be readmitted regularly with recurring psychotic symptoms. It is possible to give these people depot injections—the drug is dissolved in a high concentration in a viscous oil (often sesame oil) which is then injected into a muscle, usually in the buttock. The drug then slowly diffuses from the oil into the body fluids over a long period of time. A single depot injection of an antipsychotic drug can be effective as long as 4 weeks. This technique usually works only with drugs that are highly lipid soluble or lipophilic (to be discussed shortly); otherwise, they would be released too quickly. Fortunately, antipsychotic drugs have this property (Lemberger, Schildcrout, & Cuff, 1987). Newer formulations use more advanced techniques to generate synthetic polymer beads that have no physiological effect, but degrade slowly in the body and release constant levels of a drug over an extended period of time (Fleischhacker, 2009).

1.8.2: Inhalation

Gases

Every cell in the body requires oxygen and gives off carbon dioxide as a waste product. The lungs are an extremely efficient gas absorption and exchange system. Their inside surface is convoluted and contains many pockets of air so that the total surface area exposed to the air is very large. This entire area is richly supplied with blood by capillaries, which are close to the surface. When drugs in the form of gases, aerosols, or fine mists are inhaled, they are very quickly absorbed through the capillary walls and enter the bloodstream to circulate around the body. The colloquial term huffing refers to the inhalation of volatile substances (substances that evaporate rapidly, such as solvents) for the purpose of achieving a high.

Figure 1-4 shows the circulation to and from the lungs. After blood returns to the heart through the veins, it is pumped directly to the lungs. Here the carbon dioxide is released from the blood into the air, and oxygen in the lungs is absorbed into the blood. The blood then returns directly to the heart and is pumped around the body. One of the main arteries from the heart goes directly to the brain. Consequently, drugs dissolved in the blood in the lungs are delivered very quickly to the brain without having to pass through the liver first, where some metabolism takes place.

The principle that governs the movement of gases from inhaled air into the blood and from the blood into the air within the lungs is diffusion. If the concentration of drug in the inhaled air is higher than that in the blood, the drug will move from the air into the blood, but the reverse is also true; the drug passes out of the blood into the air and is exhaled so that the concentration of the gas in the blood reflects the concentration in the gas that is breathed. Thus, the inhalation of gases provides a means of controlling drug levels in the blood with considerable precision. This principle is one reason gases are used widely as general anesthetics, and inhalation is the favored route of administration for anesthesia. Volatile substances can also be exhaled from the lungs, although the rate is determined by how rapidly the substance evaporates.

Smoke and Solids

Gases and solvent vapors are not the only substances administered through the lungs. Drugs that occur naturally in some plants may be administered by burning the dried plant material and inhaling the smoke. Tobacco, opium, and marijuana are traditionally taken in this manner. When the dried plant material is burned, the active ingredient remains either in the smoke as a vapor or in tiny particles of ash that are inhaled into the lungs. When contact is made with the moist surface of the lungs, the drug dissolves and diffuses into the blood. The major difference between smoke and gases is that the drug in the smoke particles will not revaporize after it is dissolved in the blood and, consequently, cannot be exhaled. These drugs must stay in the body until they are eliminated by other means.

The problem with administration of solids and smoke by inhalation is the susceptibility to damage of all the tissues in the respiratory system. Smoke from burning marijuana and tobacco contains many substances in addition to the active drug; there are tars, hydrocarbons, and other chemicals created by the burning process. In time, these substances may cause respiratory diseases such as emphysema, asthma, and lung cancer, and they may decrease the ability of the lungs to absorb oxygen and eliminate carbon dioxide from the blood. Other drug byproducts with unknown toxicity may also be created by the burning process. In addition, when most substances burn in air, carbon monoxide gas is given off. Carbon monoxide is a very toxic gas because it blocks the ability of the blood to carry oxygen.

Sometimes, refined drugs like cocaine, heroin, methamphetamine, and oxycodone are administered by heating them and inhaling the vapors. Inhaling a vapor works the same way as inhaling smoke, but without the burning of material and consequent production of hydrocarbons and carbon monoxide. Battery-powered e-cigarettes, which heat a nicotine-containing liquid to create an aerosolized vapor, have become hugely popular in part because consumers believe that inhaling nicotine vapor is safer than inhaling cigarette smoke.

In the experimental laboratory, drugs are seldom administered by inhalation to nonhuman animals. The major difficulty is that in order to make an animal inhale a gas or smoke, it is usually necessary to confine it in a closed environment filled with gas or smoke, or the experimenter must make it wear some kind of helmet or face mask. The uncertainty about total dose and the technical problems of administration make this a cumbersome and unpopular route of administration in behavioral pharmacology. However, some researchers have had success in training monkeys to draw smoke or vaporized drugs from a spout inserted into their cage.

Powdered drugs such as cocaine, heroin, and tobacco snuff are sometimes sniffed into the nostrils. This practice is known as intranasal administration or insufflation. On the street, this form of administration is called snorting. What happens to the drug when taken in this manner is unclear. It appears that most of the drug sniffed into the nose is dissolved in the moist mucous membranes of the nasal cavities and is then absorbed into the blood. However, some amount of the drug enters the lungs, while more runs down the throat into the stomach and digestive tract where it may be absorbed. Although the nasal cavity is not as richly supplied with blood as the lungs and although the area is not designed to transport substances into the blood, it is a reasonably efficient system for getting a drug into circulation.

1.8.3: Oral Administration

Drugs absorbed into the body through the gastrointestinal tract of the digestive system are taken into the mouth and swallowed—hence the term per oral (p.o.) or per os. Sometimes substances can get into the digestive system by other means. As just explained, snuff from the nostrils can get down the throat and be swallowed.

A drug may also be taken into the mouth but not swallowed, as with chewing tobacco or sublingual pain medications. Although this is technically a form of oral administration, the absorption into the body is through the buccal membranes, or mucous membranes of the mouth, not the gastrointestinal tract.

The gastrointestinal tract may also be entered via its other end (intrarectal administration). Suppositories placed in the rectum also cause the drug to be absorbed into the blood. Such absorption is not as reliable as oral administration, but it can be a useful method of administering a medication when it is impossible to give it orally, such as when a patient or animal is unconscious or vomiting.

The Digestive System

After a drug is swallowed, it goes directly to the stomach. The stomach churns and secretes strong acids and digestive enzymes to break down food pieces and turn them into a liquid. The liquid is then released slowly into the intestines where nutrients are absorbed. Drugs that are soluble in gastric fluids and resistant to destruction by digestive enzymes may be absorbed from the stomach, but absorption is most efficient in the intestines. The walls of the intestines are lined with capillaries to absorb nutrients from food, and these capillaries also absorb drugs. To get to the capillaries and be absorbed into the blood through the pores in the capillary walls, the drug must first pass through the membrane of the intestinal wall, which does not have any pores. The rate at which a swallowed drug will be absorbed may be determined by the speed with which it gets through the stomach to the intestines. Because solid food tends to be held in the stomach, taking a drug with a meal generally slows its absorption. When a drug is taken on an empty stomach, it will pass quickly into the intestines and be absorbed rapidly.

All body tissue is made of cells that form membranes. Figure 1-5 shows the cross section of a typical membrane in the body, made up primarily of what is called a lipid bilayer. Lipid is another name for fat, and the membrane consists of two layers of fat molecules held tightly together. Each lipid molecule has a clump of atoms at one end (the head region) and two chains of atoms at the other (the tail region). The lipid molecules in a membrane are organized so that, in each of the two layers, the heads point outward, toward the intracellular fluid for one layer and toward the extracellular fluid for the other. The tails of each layer point inward, toward each other. Large molecules of protein are also embedded in the lipid bilayer and they have specific functions that will be described later in this chapter and in Chapter 4. The lipid heads are hydrophilic (water loving) whereas the tails are hydrophobic (water repelling), thereby preventing the passage of water-soluble substances through the membrane. As a result, the extent to which a drug can get through the lining of the intestine to the blood will depend on its ability to dissolve in lipids. Highly lipophilic drug molecules easily diffuse through membranes.

Figure 1-5 

A cross section of a typical membrane. It is made up of two layers of lipid molecules with their hydrophilic heads pointing out and their lipophilic tails pointing inward. Embedded in this lipid bilayer are large molecules of protein that serve special functions such as protein channels, ion pumps, and transporters.

Figure 1-5  Full Alternative Text

Lipid Solubility

Different drugs have different degrees of lipid solubility that are usually expressed in terms of the olive oil partition coefficient. To test lipid solubility, equal amounts of olive oil and water are placed in a beaker, and a fixed amount of drug is mixed into the emulsion. Later the oil and water are separated, and the amount of drug dissolved in each one is measured. Drugs that are highly lipid soluble are more highly concentrated in the oil. Poorly lipid-soluble drugs mostly end up in the water. This test, although not perfectly accurate, predicts reasonably well the degree to which a drug will dissolve in fat tissue in the body.

All drug molecules vary in their degree of lipid solubility in their normal state, but when a molecule of a drug carries an electric charge, it loses its ability to dissolve in lipids. Such a charged molecule is called an ion. Ions are unable to pass through membranes. When a drug is dissolved in a liquid, some or all of its molecules become ionized. The percentage of ionized molecules in a solution is determined by (a) whether the drug is a weak acid or a weak base, (b) whether it is dissolved in an acid or a base, and (c) its pKa. The pKa of a drug is the pH at which half its molecules are ionized.

The easiest way to understand pKa is to imagine the following experiment with a fictional drug called damital. A fixed amount of damital is dissolved in each of 15 bottles; each bottle contains a liquid with a different pH, ranging from 0 to 14. A solution’s pH is a number that describes the degree to which it is either an acid or a base. On this scale, 7 is completely neutral. Numbers less than 7 indicate increasing acidity, and numbers greater than 7 indicate increasing alkalinity. After we dissolve the damital in each bottle, we determine the percentage of damital molecules that are ionized and plot the results. As shown in Figure 1-6, the pH at which half the damital molecules are ionized is 5.

Figure 1-6 

The percentage of ionized molecules in two fictional drugs dissolved in solutions with different pHs. Damital, a weak acid, becomes more highly ionized as the pH becomes more basic (higher numbers). Endital is a weak base, and it becomes more highly ionized at acid pHs. By drawing a horizontal line at the 50% ionization level, we can determine the pKa of each drug: damital, 5.0, and endital, 8.0. Caffeine is a weak base with a pKa of 0.5. Try to envision what its curve would look like on the graph. There is no significant ionization of caffeine at any of the physiological pHs in the body.

Figure 1-6  Full Alternative Text

Most drugs are either weak acids or weak bases. Damital is a weak acid. If we do this experiment again with a drug that is a weak base, we see something different. One line in Figure 1-6 is a plot for an imaginary base, endital. The curve for the acid damital starts with 0% ionization at the acid end of the scale, and ionization increases as it moves toward the base end. Just the opposite is true for endital, the base. It starts with 100% ionization in the acids, but its percentage of ionization decreases as the solution gets more basic. The pKa for endital is calculated in the same way as that for damital. In this case, the pKa for endital is 8. By knowing whether a drug is an acid or a base and by knowing its pKa, it is possible to predict the degree to which it is likely to be ionized in a solution of known pH. The pH at the lining of the intestine is about 3.5. In Figure 1-6, we can see that damital is about 5% ionized at this pH, and endital is completely ionized. Because ionized molecules are not lipid soluble and do not pass through membranes, we can conclude that endital will not be very effective when taken orally, whereas damital will be readily absorbed.

Morphine is an example of a base; its pKa is about 8. Bases are highly ionized in solutions with a low pH (acids), and the curve drops in solutions with higher pHs, so we can predict (correctly) that morphine will be poorly absorbed from the gastrointestinal tract. In general, most bases like morphine are poorly absorbed when taken orally, but their absorption depends on their pKa. For example, caffeine is a base, but it has a pKa of 0.5. Its ionization curve drops off quickly at very low pHs; consequently, it is almost entirely nonionized at pHs encountered in the digestive tract. Caffeine, therefore, is readily absorbed when taken orally.

It is important to understand that significant absorption will take place even if only a small percentage of molecules is not ionized. For example, if 97% of a drug is ionized at digestive system pHs, only 3% will be lipid soluble, but as soon as that percentage diffuses through the membrane and is removed by the blood, 3% of the remaining drug loses its charge, so the 97% ionization figure will stay constant for the drug remaining in the digestive system. The newly nonionized 3% now diffuses into the blood, and 3% more can lose its ionization. This process will continue until equilibrium is reached—that is, the concentration of nonionized molecules is the same on either side of the membrane. For this reason, it is not accurate to think that the percentage of nonionized drug is all that is absorbed. Rather, the percentage of nonionized molecules determines the number of molecules available for absorption at any period of time and, therefore, determines the rate of absorption. If 50% of the molecules are not ionized, absorption will be rapid, but if 3% are not ionized, absorption will be much slower.

1.8.4: Transdermal Administration

Some drugs can be absorbed through the skin. This is called transdermal administration. The skin is composed of several layers, but the main barrier to absorption is the epidermis, the outer layer of skin. It is made up of a continuous sheet of flattened cells that are densely packed with keratin. This layer is virtually impermeable to water and can be penetrated only by lipid-soluble substances. Even then, absorption is very slow. The layer just under the epidermis, however, is made up of connective tissue served by capillaries; therefore, drugs applied to areas where there is a break in the epidermis (as occurs when there is a cut or a wound) can be more readily absorbed.

Considerable research has been aimed at developing ways to make transdermal administration more effective. Traditionally, a drug has been applied in ointments or salves. In this form, absorption of the drug is determined entirely by the lipid solubility of the drug. In some cases, an absorption enhancer may be added to increase the rate of absorption or the drug may be fixed in a special substance that releases it slowly for absorption. Development of patch technology in the early 1980s greatly enhanced the efficiency and reliability of transdermal administration. The transdermal patch separates the drug from the skin by a special membrane that limits the rate of absorption. Patches may be single- or multilayered, depending on the intended immediacy and duration of drug delivery, or they may contain a drug reservoir system that controls delivery. Using patch technology, it is possible to administer a drug at a strictly controlled rate and maintain a consistent blood level for several hours or several months. Nicotine patches were first developed in the 1980s for the treatment of tobacco addiction (see Chapter 8), but now skin patches are used for the controlled delivery of many drugs including opioid analgesics such as fentanyl (see Chapter 11), methylphenidate for treating symptoms of Attention Deficit Hyperactivity Disorder (ADHD; see Chapter 10), and hormones including the contraceptive patch Ortho Evra.

1.9: Distribution of Drugs

Even though most drugs get transported widely around the body by the blood, they tend to become concentrated in particular places and segregated from others. This process is called the distribution of a drug.

1.9.1: Lipid Solubility

It has been stressed that lipid-soluble substances can pass through membranes easily, but as the olive oil partition coefficient test shows, this capacity also means that highly lipid-soluble drugs tend to stay in lipids wherever they are encountered. Consequently, highly lipid-soluble drugs tend to concentrate in body fat outside the central nervous system. Because few drugs have any effect in body fat, all of a drug dissolved in fat is, in effect, inactive. Body fat often acts like a sponge, absorbing a lipid-soluble drug, preventing it from reaching its site of action, and diminishing its effect. Later, the drug is slowly released back into the blood from the fat over a long period of time.

1.9.2: Ion Trapping

The pKa of a drug can also influence where it becomes concentrated in the body. As described earlier in the discussion of lipid solubility, drugs that are weak bases tend to ionize in acidic solutions and drugs that are weak acids tend to ionize in basic solutions. Since ionized molecules are not lipid soluble, the pKa of a drug can hasten or retard its absorption and excretion. The same process operates anyplace where body fluids with different pHs are separated by a membrane; drugs can get trapped on one side of the membrane. Drugs that are weak acids will be concentrated in the fluid on the side of a membrane that is more basic, and weak bases will be concentrated in the fluids on the more acidic side of a membrane. The imbalance can be quite dramatic because a difference in pH of 1.0 on either side of a membrane can cause a drug to be ten times more concentrated on one side than the other. The change in concentration is logarithmically related to the concentration difference so that a difference in pH of 2.0 means that there will be a 100-fold difference in concentration, and a difference of 3.0 will create a 1,000-fold difference in concentration.

1.9.3: Distribution to the Central Nervous System

Many years ago, it was discovered that when certain types of dyes were injected into the blood, they would be distributed to all extracellular fluids except those in the brain and the spinal cord. At that time, it was hypothesized that a special barrier between the blood and the brain protected the central nervous system from free diffusion of many materials carried in the blood. This became known as the blood–brain barrier. It has now been established that the blood–brain barrier is a result of special cells in the central nervous system that wrap themselves around the capillaries and block the pores through which substances normally diffuse. These cells provide a solid lipid barrier so that non-lipid-soluble substances have great difficulty getting into the brain. If not for the blood–brain barrier, the delicate balance of chemicals inside and outside brain cells would be disrupted, even by the food we eat, altering the cells’ ability to function.

The blood–brain barrier is incomplete or weak in some areas of the brain and will permit some non-lipid-soluble molecules to enter. For example, the area postrema of the medulla oblongata (see Chapter 4) contains specialized cells that play an important role in detecting impurities or toxins in the blood and elicits vomiting in an attempt to rid the body of these substances. When opioid drugs such as heroin are first used, they activate the vomiting center in this way. Also, the subfornical organ in the brain plays an important role in detecting hormone levels in the blood, especially those hormones involved in regulating the balance of bodily fluids.

1.9.4: Active and Passive Transport Across Membranes

It is important for the body to carry some non-lipid- soluble substances across membranes. Special transport mechanisms serve this purpose. Transport is carried out by large protein molecules that span the cell membrane (visible in Figure 1-5) and may involve either active or passive mechanisms.

In the passive transport mechanism, the large protein molecule may create a channel that allows the non-lipid-soluble molecule to pass through in response to diffusion. In another variation it appears that the non-lipid-soluble molecule attaches itself to a carrier protein or specialized molecule that permits it to diffuse across the membrane and releases it on the other side. In this way, a substance can move from areas of high to low concentration on either side of a membrane as though it were lipid soluble without the expenditure of energy. The protein molecules illustrated in Figure 1-5 are examples of passive transport mechanisms.

An active transport mechanism is similar to a passive mechanism except that it can work against normal diffusion by concentrating a substance on one side of a membrane. This is an active process that requires an expenditure of energy and takes place only in living membranes. Mechanisms such as ion pumps, which maintain electrical potentials of nerve cells, are examples of active transport systems. The sodium–potassium transporter protein, illustrated in Figure 4-2 of Chapter 4, is one example of an active transport system. The blood–brain barrier has a number of such systems, many of which actively remove undesirable substances, like toxic waste products, from the brain and some of which selectively concentrate substances, like glucose (blood sugar) and some amino acids, in the brain.

1.9.5: Protein Binding

The blood contains a number of large protein molecules that, because of their size, cannot diffuse out of the pores of the capillaries. Some drug molecules become bound (attached) to these protein molecules so strongly that they remain attached and, consequently, never reach their site of action. Other times, protein binding is reversible and bound drug molecules may act like depot injections, becoming slowly unbound (released) as the blood concentration of the drug declines. These released drug molecules reach their sites of action and exert pharmacologic effects before eventually being broken down and excreted. There is a proportional relationship between the ratio of bound:unbound drug molecules and the drug’s lipid solubility (lipophilicity). More lipophilic drugs tend to have a higher percentage of their molecules bound to blood proteins (Láznícek & Láznícková, 1995).

1.9.6: The Placental Barrier

The blood of the fetus and the blood of the mother are not continuous. Nutrients are transferred to (and waste products from) the blood of the fetus through a membrane similar to the blood–brain barrier. This transfer takes place in the placenta, the intermediary organ between the fetus and the wall of the uterus. Most behaviorally active drugs can be transferred from the mother’s blood through the placenta to the fetus. Highly lipid-soluble substances cross more easily than drugs with low lipid solubility. Drug concentration in the blood of the fetus usually reaches 75% to 100% of that of the mother within 5 minutes of administration.

1.10: Elimination

1.10.1: Metabolism and Excretion

There are some substances—for example, heavy metals such as lead and mercury—that the body has difficulty removing. Levels of these substances can build up over time and accumulate to high and toxic concentrations. However, the body has fairly efficient systems to rid itself of most unwanted substances, including drugs, which would continue to exert their effects if not metabolized and excreted. It has already been described how gases and volatile solvent vapors can be eliminated in exhaled breath. Small amounts of many drugs are eliminated in sweat, saliva, and feces, but the major job of elimination is done by the liver and the kidneys, the “dynamic duo” of excretion (the location of these organs can be seen in Figure 1-7).

Figure 1-7 

The location of the liver and kidneys within the body. The close-up is of a nephron, showing the capillaries of the glomerulus that filter fluid out of the blood into the nephron, and the capillary bed that reabsorbs water, nutrients, and lipid-soluble drugs into the blood. All material that is not reabsorbed is excreted in the urine.

Vectomart/Shutterstock

Figure 1-7  Full Alternative Text

1.10.2: The Liver

The liver is a large organ located high in the abdomen, under the diaphragm. Its function may best be compared to that of a chemical factory where molecules are modified to form new substances useful to the body and where toxic molecules are changed into less harmful substances to be filtered out of the blood by the kidneys. These molecular changes are achieved by molecules called enzymes. An enzyme is a catalyst, a substance that controls a certain chemical reaction. The enzyme takes part in the reaction, but when the reaction is finished, the enzyme is released unchanged and is free to participate in another similar reaction. Without the involvement of an enzyme, many reactions would proceed very slowly or would not take place at all. The body controls chemical reactions by controlling the amount of enzyme available to act as a catalyst. Not all enzymes that metabolize drugs are located in the liver. Some may be found in the blood and brain or, as we will soon see, in the digestive tract.

An example of an enzyme is alcohol dehydrogenase. Most enzymes end in the suffix ase, and someone with a background in chemistry can usually tell from its name what an enzyme does. The enzyme alcohol dehydrogenase removes hydrogen from a molecule of alcohol, converting it to acetaldehyde. This process of biotransformation or the restructuring of molecules to rid them from the body is referred to as metabolism, and the products of metabolism are called metabolites. In general, metabolites are either more useful to the body or less toxic than the original substance. Where drugs are concerned, the metabolic process is sometimes called detoxification. Although this term is appropriate some of the time, metabolites are not always less active or less toxic than the original drug. Chloral hydrate, psilocybin, and THC, are good examples of substances whose metabolites can be more active than the original drugs from which they are formed. Drugs with active metabolites typically show a prolonged action in the body, but these metabolites are eventually changed into inactive water-soluble substances and excreted from the body by the kidneys.

Another general rule is that metabolites are usually more likely to ionize. This tendency is very important for the functioning of the kidneys because ionized molecules cannot be reabsorbed into the blood through the nephron wall and, consequently, can be excreted more easily. In this way, the liver and kidneys work together to rid the body of unwanted substances.

1.10.3: First-Pass Metabolism

With oral administration, some metabolism of drug molecules takes place even before the drug gets distributed throughout the body. Drugs that are absorbed into the bloodstream from the digestive system reach the liver before arriving at the heart. This means that any drug absorbed from the digestive system will be subjected to a certain amount of metabolism by liver enzymes before going anywhere else in the body. This is known as first-pass metabolism, and it may be responsible for a significant amount of the metabolism of some drugs. Drugs administered by other routes of administration, including drugs absorbed from the nasal cavities and the membranes of the mouth and rectum, are not subjected to first-pass metabolism by the liver and may reach higher levels in the body. For a drug such as alcohol, some metabolism takes place in the stomach and intestines even before it is absorbed. This is also referred to as first-pass metabolism.

1.10.4: The Kidneys

The kidneys are two organs, each about the size of a fist, located on either side of the spine. Their primary function is to maintain the correct balance between water and salt in body fluids. Along with the excretion of excess water in the form of urine, the kidneys can also excrete molecules of unwanted substances, the by-products of metabolism by liver enzymes. They function as a complex filtering system that physically removes certain substances from the blood. The close-up portion of Figure 1-7 shows the nephron, the functional unit of the kidney. Each kidney has millions of nephrons, all of which work in more or less the same way.

The nephron is essentially a long tube. At one end of the tube is a cuplike structure called Bowman's capsule, and inside Bowman’s capsule is a clump of capillaries called the glomerulus. The other end of the nephron empties into collecting tubes which, in turn, empty into the urinary bladder. The capillaries in the glomerulus have pores in their membranes, and most of the fluid in the blood that flows through these capillaries passes into Bowman’s capsule and down the nephron. The remaining blood, which contains red and white cells and large protein molecules that are too large to pass out of the pores, continues out of the glomerulus and then moves through another bed of capillaries that surround the nephron along most of its length. At this point, most of the fluid and other substances are absorbed through the nephron wall back into the blood. Whatever is not reabsorbed passes through the length of the nephron and is excreted from the body in the urine.

The kidney works not by filtering impurities out but by filtering everything out of the blood and then allowing selective reabsorption of what is required. Reabsorption in the nephron is accomplished by the mechanisms previously described: diffusion, lipid solubility, and active and passive transport. All lipid-soluble substances diffuse through the nephron wall into the blood, unless a selective transport mechanism is working against this diffusion. Desirable substances that are not lipid soluble, such as glucose, have a transport mechanism that successfully reclaims them into the blood. Unless they are reabsorbed by special transport systems, ionized or non-lipid-soluble substances will be excreted.

As with the digestive system, pH influences the degree of ionization and, as a consequence, can influence reabsorption. Urine tends to be acidic (pH = 6.0), and blood is basic (pH = 7.5), so, much like in the digestive system, acids tend to pass through and concentrate on the blood side of the nephron wall, and bases tend to be retained in the urine and excreted.

1.10.5: Rate of Elimination

In most cases there are more than enough enzymes in the liver to handle a drug so that when the drug arrives in the liver in high concentrations, a lot of the drug will be metabolized at once. At low concentrations, the rate of metabolism will be lower. Thus, as drug levels fall, the rate of metabolism slows. The curve that plots the level of a drug in the blood over time is therefore not a straight line but tends to level off to an asymptote. Because of this trailing off, the rate of excretion for most drugs can be described in terms of a half-life. This is the time taken for the body to eliminate half of a given blood level of a drug. In the example given in the top (A) panel of Figure 1-8, half of the original blood level is eliminated in 30 minutes. Thirty minutes later, the level has fallen to 25% of the original level, and 30 minutes after that, it is down to 12.5%. Every 30 minutes, the body gets rid of half of the drug circulating in the blood, so the half-life of the drug in this example is 30 minutes. When the elimination of a drug changes with concentration in this manner, it is said to have first-order elimination kinetics.

Figure 1-8 

The top panel (A) shows a typical elimination curve for a drug with a very short half-life of about 30 minutes. This is an example of first-order elimination kinetics. The bottom panel (B) shows the elimination function for alcohol, which is metabolized at a constant rate (about 15 mg of alcohol/100 ml of blood/hour). Because the elimination function for alcohol is a straight line, the concept of half-life does not apply. This is an example of zero-order elimination kinetics.

Figure 1-8  Full Alternative Text

The excretion of most drugs can be described in terms of half-life, but there is an important exception: alcohol. The excretion curve for alcohol is a straight line, as shown in the bottom (B) panel of Figure 1-8. It is not appropriate therefore to describe the excretion of alcohol in terms of half-life; an absolute rate of excretion is usually given, that is, about 15 mg of alcohol/100 ml blood/hour. When the rate of elimination of a drug is a straight line, it is said to have zero-order elimination kinetics.

1.11: Factors that Alter Drug Metabolism

A number of factors can influence the rate of metabolism of drugs in the liver and, consequently, the intensity and duration of a drug’s effect. Many individual differences in response to drugs can be explained in terms of variations in drug metabolism and enzyme systems that vary according to such factors as age, gender, species, past experience with drugs, and genetics.

1.11.1: Stimulation of Enzyme Systems

To illustrate how enzymes work, we will use the metabolism of alcohol as an example. The steps in alcohol metabolism are shown in Figure 1-9. In the first two steps, alcohol is converted to acetaldehyde by the enzyme mentioned earlier: alcohol dehydrogenase. Then the acetaldehyde is converted to acetate by another enzyme called aldehyde dehydrogenase. Levels of a given enzyme can be increased by previous exposure to a specific drug that uses that enzyme or some other enzyme system. This process, known as enzyme induction, is responsible for the development of metabolic tolerance (discussed in Chapter 3). A good example of such a process is an increase in levels of alcohol dehydrogenase in the livers of heavy drinkers. Those who drink a great deal are able to metabolize alcohol slightly faster than nondrinkers, and this is one reason why they are more resistant to its effects. Box 1-2 gives another example of enzyme induction caused by the herbal antidepressant St. John’s wort.

Figure 1-9 

Steps in the metabolism of alcohol. The enzyme that controls each step is shown to the right of each arrow. Note that disulfiram (Antabuse) blocks the enzyme aldehyde dehydrogenase which leads to a buildup of acetaldehyde.

Figure 1-9  Full Alternative Text

BOX 1-2 Enzyme Induction Caused by St. John’s Wort

St. John’s wort (Hypericum perforatum) is a plant-based alternative therapy whose medical use dates back 2,500 years to ancient Greece. It is one of the most widely sold herbaceutical products, used principally as a treatment for mild to moderate depression (see Chapter 13). Clinical studies have documented a level of efficacy for St. John’s wort similar to that of pharmaceutical antidepressants including Ludiomil, Tofranil, Elavil, and Prozac. Its popularity is due at least in part to users’ belief that it has fewer unwanted sleep, sexual, and cognitive side effects compared to pharmaceutical antidepressant drugs. But it turns out that St. John’s wort has some potentially serious side effects that may not be readily apparent, adverse effects great enough to prompt France to ban its use and Canada, Japan, and the United Kingdom to place warning labels on products containing St. John’s wort. The danger of St. John’s wort stems from its ability to induce production of enzymes that break down many other drugs, reducing their effectiveness.

St. John’s wort has many biologically active ingredients, including hyperforin which is thought to mediate the plant’s antidepressant effects. Hyperforin is a potent activator of a nuclear receptor called pregnane X receptor (PXR). PXR is a ligand-activated transcription factor that stimulates genes in the liver and intestine to produce a large number of metabolizing enzymes and transporters responsible for the destruction of many drugs and toxins (Choudhuri & Valerio, 2005). One such enzyme stimulated by PXR is CYP3A4—a member of the cytochrome P450 superfamily of enzymes that, together, are responsible for ~75% of all drug metabolism (Guengerich, 2008). CYP3A4 alone metabolizes more than 50% of all clinically relevant drugs (Smith, H. S., 2009).

Taking St. John’s wort in the recommended doses can stimulate the enzymes that destroy many important drugs that a person may be taking concurrently. One such drug is the immunosuppressant cyclosporine, which prevents tissue rejection in organ transplant patients. Other drugs include: atorvastatin, a cholesterol-lowering drug; indinavir, a drug used in the treatment of HIV; irinotecan, a cancer-fighting drug; warfarin, an anticoagulant; theophylline, a respiratory stimulant; and the tranquilizers alprazolam, triazolam, and phenobarbital. St. John’s wort can also increase the likelihood of unplanned pregnancy by increasing the breakdown of estrogen, thereby reducing the effectiveness of oral contraceptives. Thus, while St. John’s wort may be an effective antidepressant with apparently few side effects, the overall picture is not that simple. It presents an example of how use of a “natural medicine” can have significant but unforeseen health consequences.

1.11.2: Depression of Enzyme Systems

When two drugs that use the same enzyme are introduced into the body at the same time, the metabolism of each will be depressed because both will be competing for the enzyme. In other cases, the activity of an enzyme can be blocked by another drug. Once again, let’s use the metabolism of alcohol as an example. Acetaldehyde is converted into acetate by aldehyde dehydrogenase. Administration of the drug disulfiram (Antabuse) blocks aldehyde dehydrogenase, causing a rise in acetaldehyde levels in the body because the enzyme required to metabolize it is not readily available (refer back to Figure 1-9). Acetaldehyde is toxic and causes sickness and discomfort, so people who take disulfiram and then drink alcohol will get sick because of the buildup of high acetaldehyde levels. Disulfiram is sometimes used to discourage alcoholics from drinking; alcoholics will feel well and stay that way if they refrain from ingesting alcohol, but as soon as they take a drink, they will feel ill.

Even foods can alter drug metabolism. Substances in grapefruit juice, for instance, can block activity of CYP3A4 in the intestine. Since this important enzyme is responsible for the first-pass metabolism of many drugs, drinking grapefruit juice can significantly increase blood levels of those drugs. As a result, people should avoid drinking grapefruit juice if they are taking any of a number of medications. These include the antianxiety drug buspirone (Buspar), the cholesterol-lowering drugs lovastatin (Mevacor) and simvastatin (Zocor), and the erectile dysfunction drug sildenafil (Viagra).

1.11.3: Age

Enzyme systems are not fully functional at birth and may take time to develop completely. For this reason, immature members of a species may metabolize drugs differently from adults or may not metabolize them at all. For example, the liver of a newborn human first converts theophylline to caffeine and then metabolizes caffeine very slowly. In adults, theophylline is metabolized directly without this intermediate stage. Theophylline is similar to caffeine and is found in tea but is sometimes given to newborn babies to stimulate breathing. In infants, the effects of theophylline are greatly enhanced because of the intermediate stage of metabolism involving caffeine. For this reason, doses must be small and closely monitored to avoid overdose. There can also be impairments in metabolism at the other end of the life span. Liver functioning is less efficient in elderly people, so physicians prescribing for elderly patients often reduce drug doses accordingly. Drugs given to a woman during childbirth are also a concern given that they cross the placental barrier and circulate in the blood of the fetus. While the child’s circulatory system is connected to the mother, the mother’s liver can metabolize the drug. But if the baby is born and the umbilical cord is cut before all the drug is broken down, the drug remains in the infant’s body and is dependent solely on the baby’s immature liver for metabolism, a process that may take many days.

1.11.4: Species

The vast majority of research in behavioral pharmacology uses species other than human beings. Studies are usually done with rats, mice, pigeons, or primates. It is important to understand how differences in drug metabolism can alter the intensity and duration of a similar dose in different species. As an example, the levels of alcohol dehydrogenase are quite different in different species. The liver of a rat or mouse contains about 60% of the alcohol dehydrogenase per gram of that found in a human liver, but the liver of a guinea pig contains 160% of the human level. The liver of a rhesus monkey has a concentration of alcohol dehydrogenase similar to that of a human liver. As such, performing the same experiment with a guinea pig, rat, mouse, rhesus monkey, or human might lead to quite different conclusions.

1.12: Combining Absorption and Excretion Functions

The effects of a drug change over time during a single administration. This change reflects increasing and decreasing drug levels after administration. When these varying effects are plotted on a graph, the result is usually called a time course (the drug effect is usually represented on the vertical axis, and time on the horizontal axis). Figure 1-10 is a time course for the concentration of a drug in the blood after administration. Note that there are three curves. One shows the time course of absorption of a drug from the site of administration. This curve is hypothetical because it assumes that while the drug is being absorbed, the liver and kidneys are not working and no excretion is taking place. The second curve is a hypothetical elimination curve; it shows the rate of elimination of a drug, but assumes instantaneous absorption. In reality, neither of these curves exist. What is actually seen is a combination of the first two curves, shown as a third curve that has both an ascending phase corresponding to the time when absorption is more rapid than elimination and a descending phase when elimination is more rapid than absorption. The rate of excretion of any drug (i.e., its half-life) remains constant, but the absorption rate of any given drug can change depending on the route of administration. Thus, the shape of this curve will vary depending on the route of administration.

Figure 1-10 

The graph presents a theoretical absorption curve, assuming no elimination; a theoretical elimination curve, assuming instantaneous absorption and distribution; and a third line showing the result of these two theoretical processes. The resultant curve is typical of the time course for blood level of most drugs.

Figure 1-11 shows typical curves for various routes of administration. When drugs are inhaled or given intravenously, the absorption phase is very steep; the drug achieves high levels in the blood and brain, and is metabolized and excreted quickly. This combination of effects correlates with a more intense subjective experience, greater reinforcement, and an increased capacity for addiction. When drugs are given orally, the absorption is slow and blood levels do not reach the same high concentrations seen after i.v. administration, but the drug lasts much longer in the body. Intramuscular and subcutaneous routes are intermediate between i.v. and oral routes. The route of administration can determine whether a drug reaches high levels for a short period or lasts a long time at low levels. If the function of a drug depends on maintaining constant blood levels, as with antibiotics, oral administration is preferred. If it is necessary to achieve very high levels for brief periods, the drug is best given intravenously.

Figure 1-11 

The time courses for blood levels of a drug typically seen after different routes of administration. After i.v. administration, absorption is very rapid with a high peak and the drug leaves the body relatively quickly. When the drug is given orally, absorption is slow; the peak level is relatively low; and the drug stays in the body a longer time. The other routes have the same shape curve between these two. The faster the absorption, the higher the peak and the shorter the duration of action.

1.13: The Therapeutic Window

When drugs are administered for therapeutic purposes, it is often important that the right level of the drug be maintained in the blood for an extended period of time. If the drug reaches too high a level, there will be an increase in unwanted side effects and no increase in the therapeutic effect. If the drug falls below a certain level, it will not have a therapeutic effect at all. This range, called the therapeutic window, is illustrated in Figure 1-12. To keep its concentration within this range, a drug must be taken at the correct dose at regular intervals.

Figure 1-12 

The therapeutic window is the range of blood concentrations of a medicine between a level that is minimally effective (therapeutic level) and a level that has adverse side effects (toxic level). When drugs are taken chronically, it is important that the drug be given in the right dose and at the right frequency so that blood levels remain within the therapeutic window.

Figure 1-12  Full Alternative Text

For drugs that are absorbed and excreted slowly, it is usually not difficult to achieve a dosing regimen that keeps the blood level within this window, but the task is more complicated for drugs that are absorbed and excreted rapidly. One such drug is lithium carbonate, which is prescribed to people with bipolar disorder. Lithium has a rather narrow therapeutic window (the effective dose and a dose that causes side effects are very close). Lithium is also absorbed and excreted rapidly, so it must be given in small doses (as many as four times a day). To help solve this problem, pills have been developed in which the lithium is embedded in a material that dissolves slowly to delay the drug’s absorption and, hence, its peak blood level. Using this type of medication makes it easier to keep the blood level within the therapeutic window and reduce the frequency of dosing to twice a day.

With repeated use, individuals may build tolerance to some drugs (this will be discussed further in Chapter 3). Tolerance for some drug effects may build more quickly than tolerance for others. For example, tolerance to the analgesic effects of opioids like morphine builds rapidly, requiring a larger dose of the drug in order for it to be effective in relieving pain. Tolerance to the toxic effects of morphine builds more slowly, moving the curve for the effective dose closer to the curve for the toxic dose, increasing the risk of overdose and narrowing the therapeutic window.

Chapter 3 How We Adapt to Drugs—Tolerance, Sensitization, and Expectation

3.1: Tolerance

In the year 63 bce, Mithridates VI, King of Pontus, tried to commit suicide by poisoning himself. Mithridates was a great leader and great warrior; he had defeated the Roman legions and spread his influence over Asia Minor. But in 63 bce, he had been defeated by the Roman general Pompey, and his son had just led a successful revolt against him. To end his life, the King took a large dose of poison, but it had no effect on him. He was finally forced to have one of his Gallic mercenaries dispatch him with a sword.

What was the source of the King’s resistance to the poison? King Mithridates was also a good pharmacologist. Throughout his life, he lived in great fear of being poisoned, so, to protect himself, he repeatedly took increasing doses of poison until he could tolerate large amounts without illness. This effect has been called mithridatism (Lankester, 1889) after the King; today, we know it as tolerance.

Drug tolerance is defined either as the decreased effectiveness (or potency) of a drug that results with repeated administrations, or as the necessity of increasing the dose of a drug in order to maintain its effectiveness after repeated administrations. The term “tolerance” is frequently used in a way that suggests that all of the effects of a drug diminish at the same rate, but this is usually not the case. Some effects of a drug may develop tolerance very quickly, some others may show tolerance slowly, and some effects may never show tolerance, no matter how often the drug is given. Among the effects of morphine, for example, are nausea and vomiting. These effects show rapid tolerance. Morphine also constricts the pupils of the eyes. This effect shows no tolerance at all, even with long-term use. Because tolerance to different effects of a drug develops at different rates, it is apparent that many mechanisms must be responsible (Young & Goudie, 1995). For this reason, it is more appropriate to think of tolerance developing to the various effects of a drug rather than to the drug itself (Stewart & Badiani, 1993).

Tolerance to one drug may well diminish the effect of another drug. This phenomenon, called cross-tolerance, is usually seen between members of the same class of drugs. For example, all opioid drugs, which include morphine, heroin, and oxycodone (see Chapter 11), will show cross-tolerance. Cross-tolerance is sometimes taken as evidence that the drugs may be producing their effect by common mechanisms.

When tolerance develops, it may not last indefinitely—it may disappear over time, after the use of a drug has been discontinued. During the development of tolerance, the reduction or disappearance of different drug effects may take place at different rates and may depend on the circumstances or environmental setting in which the drug is administered.

3.1.1: Acute Tolerance

Although tolerance most commonly develops following repeated administrations of a drug, it can also occur during a single drug administration. As we learned in Chapter 1, after a drug is taken into the body, its level in the blood rises during the absorption phase and then falls during the elimination phase. With some drugs, and depending on the effect being measured, the drug effect can be greater at a specific blood level during absorption than it is at that same blood level during elimination. This is acute tolerance—tolerance that has developed during a single administration.

Figure 3-1 illustrates acute tolerance. The solid line shows the time course of the blood level of a drug after administration. The dotted line shows the time course for an effect of the drug if acute tolerance is developing. The effect will peak before the blood level peaks, and the effect will be gone before the drug is entirely eliminated from the body. Thus, if you measure the effect of the drug at time A as its level in the blood is rising, and again at time B when its level in the blood is exactly the same but falling, you will see that the effect at time B is much less. A good example of acute tolerance is the subjective effect of alcohol. As blood alcohol level rises, a person feels increasingly intoxicated. But the subjective effect of intoxication peaks before blood alcohol level does, and the subjective effect of intoxication disappears before all of the alcohol leaves the person’s body. This makes it very difficult for the person to estimate his or her own blood alcohol level or the effect alcohol may be having on him or her (Cromer, Cromer, Maruff, & Snyder, 2010).

Figure 3-1 

An illustration of the time course for the level of a drug in the blood (solid line) and an effect of that drug (dashed line). Point A indicates a particular blood level on the ascending limb of the curve, and point B indicates exactly the same blood level on the descending limb of the curve. You can see that the drug effect at time A is greater than it is at time B, even though there is the same drug blood-level. This indicates acute tolerance.

3.2: Mechanisms of Tolerance

3.2.1: Pharmacokinetic Tolerance

The term pharmacokinetic means “drug movement” and refers to the body’s effects on a drug, including its absorption, distribution, and elimination. Pharmacokinetic tolerance (also called metabolic tolerance or dispositional tolerance) arises from an increase in the rate or ability of the body to metabolize a drug, resulting in fewer drug molecules reaching their sites of action. For the most part, this is a result of enzyme induction—an increase in the level of an enzyme the body uses to break down the drug (see Chapter 1). When a drug is given repeatedly, it may induce or increase the action of the metabolizing enzyme. With increases in the rate of metabolism, a given amount of a drug will not reach the same peak levels at its site of action and will not last as long, so that more and more of the drug will be needed to produce the same effect. When pharmacokinetic tolerance takes place, all effects of the drug will be diminished because of the diminished concentration of the drug at the site of action. This will also create cross-tolerance with drugs that are metabolized by the same enzyme.

3.2.2: Pharmacodynamic Tolerance

The term pharmacodynamic means “drug change” and refers to a drug’s effects on the body, including various physiological processes. Pharmacodynamic tolerance (also called physiological tolerance or cellular tolerance) arises from adjustments made by the body to compensate for an effect caused by the continued presence of a drug. It is generally believed that such adjustments are a result of a process called homeostasis. Many of the body’s physiological processes are controlled by feedback loops, in much the same way a thermostat controls the temperature in a room. The thermostat is set to a specific temperature, called a set point. It detects the temperature and, when the temperature falls below the set point, it turns on the heat. When the room temperature rises to the set point, it turns off the heat, thus maintaining an even temperature at the set point. Homeostasis provides a flexible system for maintaining a set point in circumstances in which environmental conditions change. For example, if someone were to leave open a window on a cold day, the thermostat would keep the heat on longer in an attempt to maintain the temperature at the set point.

Homeostatic processes work inside the body to control nearly all of its operations. When drug intake alters some aspect of bodily functioning, the body’s response is controlled by a homeostatic mechanism. The disruption or disturbance created by the drug is detected, and this information is sent to the mechanism that controls the disrupted function. The control center responds by compensating for the effect of the drug, thus working to restore normal functioning; that is, it tries to return the function to its set point. If the drug is administered repeatedly, the body gets better and better at restoring normal functioning and diminishes the disruptive effect of the drug. This means the drug will have a smaller and smaller effect the more it is administered. Some of these compensatory processes begin quickly, but others take longer to develop or do not develop at all. Thus, tolerance may appear rapidly to some drug effects and very slowly to others.

When drug administration is stopped and the drug’s disruptive effect is removed, the compensatory process weakens because it is no longer being employed. Again, some compensatory effects may disappear rapidly, but others may go away slowly. It may take weeks or months for normal functioning to return.

One example of pharmacodynamic tolerance is upregulation and downregulation of neurotransmitter receptors. As described in Chapter 4, nerve cells communicate with one another by releasing a substance called a neurotransmitter, which interacts with specialized molecules called receptor sites on the membrane of a neighboring nerve cell. Some drugs work by blocking these receptor sites and reducing the effect of the neurotransmitter. There is a homeostatic mechanism that detects when this happens and the cell can respond in a number of ways, such as by manufacturing more receptor sites, increasing receptor-site sensitivity to the neurotransmitter, or by increasing the synthesis and release of the neurotransmitter. This is called upregulation. If the drug stimulates the receptor sites rather than blocking them, an opposite compensatory effect called downregulation can occur. Upregulation and downregulation may take a week or longer to take effect.

3.2.3: Functional Disturbances

Constantine Poulos and Howard Cappell (1991) have pointed out that physiological disruptions alone are not always sufficient to cause tolerance. The drug-induced change usually needs to be of some significance to the animal. For example, we know that: (a) amphetamine causes anorexia (a loss of appetite) in rats, and (b) this effect will show tolerance when the drug is repeatedly administered to hungry rats in the presence of food. This is not surprising because food intake is controlled by complex homeostatic mechanisms that attempt to overcome the anorexia so that the rat will consume a sufficient amount of food to stay healthy. But what happens if you give rats repeated doses of amphetamine when no food is present? Anorexia will still occur, but it will have no significance to the rat since the animal cannot eat. It turns out that rats do not develop tolerance to the anorectic effects of amphetamine if the drug is given in the absence of food. In this case, the amphetamine has no opportunity to interfere with the functioning of the organism (that is, with eating), there is no feedback to the feeding control mechanism, and tolerance does not develop. Similarly, tolerance to the hypothermic (body-cooling) effect of alcohol does not develop in rats in a very warm environment where alcohol does not have a hypothermic effect, and tolerance to the analgesic (pain-relieving) effect of morphine develops faster in rats that are subjected to painful stimuli after being given the drug (Poulos & Cappell, 1991). In other words, tolerance will develop (or will develop much more quickly) only in a circumstance where a drug places a demand on an organism’s homeostatic mechanisms. Tolerance to drug effects that are not detected or that do not disrupt functioning does not develop.

3.2.4: Behavioral Tolerance

Tolerance can be influenced by learning—through experience with a drug, an organism can learn to decrease the effect that the drug is having. This is called behavioral tolerance. This type of tolerance, which can involve both operant and classical conditioning processes, is further discussed later in this chapter.

3.3: Withdrawal

Withdrawal symptoms are physiological changes that occur when the use of a drug is stopped or the dosage is decreased. Different drugs produce different withdrawal symptoms, but drugs of the same family generally produce similar withdrawal. Withdrawal can be halted almost instantly by giving the drug that has been discontinued, or by giving another drug of the same family. This phenomenon is known as cross dependence.

Withdrawal symptoms vary in intensity from one drug to another. With some drugs, withdrawal symptoms may be so slight that they can be detected only using sensitive instruments, and the individual might not notice them. With other drugs, withdrawal can be so severe as to cause death. The extent of withdrawal may also depend on the drug dose and administration schedule.

Withdrawal symptoms usually begin some hours after the use of a drug has ceased, but they can be produced much more quickly by giving an antagonist drug. Naloxone, a powerful antagonist to morphine, rapidly blocks all morphine effects soon after it is given by blocking the receptor used by morphine. When naloxone is given to morphine-dependent humans or laboratory animals, severe withdrawal can be seen within minutes.

3.3.1: Dependence

The word dependence can be confusing because over time it has come to mean different things. For many years, the word was used in two ways: (a) to describe a state in which discontinuation of a drug causes withdrawal symptoms, and (b) to describe a state in which a person compulsively takes a drug—this state is often described as addiction. Thus, saying that a person was dependent meant that he or she would experience withdrawal when a drug was discontinued and that he or she used the drug in a compulsive, addicted manner. This is because at one point, it was believed that the two states (dependence and addiction) were exactly the same. It was assumed that if you took a drug to the point where withdrawal symptoms would occur when you stopped, you were dependent. You would then be driven to seek out and consume the drug in a compulsive manner in order to avoid those withdrawal symptoms, and so you were addicted. We now know that this is not the case. People who experience withdrawal symptoms when a drug is discontinued do not necessarily take that drug compulsively, and people may take a drug compulsively even though they will not experience withdrawal symptoms when they stop. The relationship between withdrawal symptoms and addiction or compulsive use and drug craving will be discussed in great detail in Chapter 5. In this text, we will use the terms dependence, physical dependence, and physiological dependence interchangeably to indicate a state in which withdrawal symptoms will occur when drug use stops. These terms will not imply anything about compulsive drug use, abuse, or addiction.

3.3.2: Opponent Process Theory

Tolerance and dependence are believed to be closely related. Withdrawal symptoms are usually thought of as expressions of the compensatory adjustment that homeostatic mechanisms have made to the repeated effects of a drug. As described earlier, with repeated drug administration, the body changes its functioning and, through homeostatic feedback, compensates for the physiological changes the drug produces. Later, when the drug is discontinued and its effects disappear, it takes some time for the body to readjust to the drug’s absence. During this readjustment, the compensatory responses are what cause withdrawal symptoms.

The dynamics of this process were first formulated by Solomon and Corbit (1974) who were proposing a theory of acquired motivations, a theory that also applies to drug use. They proposed that abused drugs stimulate an A process that creates a euphoric (pleasant) a state, but that soon after, a compensatory B process is evoked that creates a dysphoric (unpleasant) b state. This is shown in the top panel of Figure 3-2. During a single administration of a drug, at first the A process dominates, but once the B process kicks in, it very quickly cancels out some of the a effect (euphoria). As the drug wears off, so too does the A process, but the B process endures for a while. This net experience (the overall affective state) is shown in the middle panel of Figure 3-2. When the drug is first administered, the person experiences pleasure, but this decreases as the B process becomes active. When the drug activity terminates, the A process stops and so does the a effect (pleasure), but the continuation of the B process for a brief time causes the person to experience the b effect (dysphoria).

Figure 3-2 

The upper panel shows the effect of a single drug administration on both the A (drug) process and the B (opposing) process. When a drug is given, the A process increases, but shortly thereafter, the opposite B process begins. When the drug wears off, the A process diminishes, but the B process continues for a while before disappearing. The middle panel shows the result of combining the a (euphoric) and b (dysphoric) effects. It shows that the a state will be strongest right after the drug is taken, and then diminish. This decreased effect is due to acute tolerance. The b state dominates for a time after the drug has worn off. The b effect would be experienced as withdrawal. Solomon and Corbit originally proposed this mechanism to explain changes in pleasure (hedonic state) caused by a drug, but the idea can be used to explain many different effects of a drug on the mind and body. (Adapted from Solomon & Corbit, 1974

Figure 3-2  Full Alternative Text

When we think of withdrawal symptoms, we normally think of what happens when a person takes a drug repeatedly for an extended period. But as you can see from the opponent process theory, we can expect withdrawal after each administration. When this happens, we might use the word hangover to describe the effects, but we must be careful because hangover implies something more than a compensatory response. Hangover is a term that usually refers to the aftermath of the acute effects of a drug, such as when you go out drinking at night and then feel sick the next day. Many of the symptoms of an alcohol hangover are the direct result of toxic effects of alcohol, such as dehydration or stomach irritation which remain after the intoxication. But some effects, like sensitivity to lights and noise, can be thought of as brief withdrawal symptoms that are compensatory responses to the effects of alcohol. An example of a hangover that is mostly a compensatory response occurs after taking cocaine. Once the euphoric effects of a dose of cocaine wear off, users often experience letdown or a period of depression that can be thought of as a compensatory response to the high caused by the drug, although this is not usually referred to as a hangover.

Box 3-1 provides an example of the opponent process effect within a single administration of the tranquilizer chlordiazepoxide. The A process creates a tranquilizing (anxiolytic or anxiety-relieving) effect of chlordiazepoxide, and the compensatory B process creates the opposite effect: anxiety.

BOX 3-1 Anxiety as a Conditioned Compensatory Response to a Tranquilizer

Using a two-lever drug discrimination procedure, Barrett and Smith (2005) of Vanderbilt University trained rats to discriminate between a dose of chlordiazepoxide (CDP) and a dose of pentylenetetrazol (PTZ). Chlordiazepoxide is a benzodiazepine tranquilizer that relieves anxiety and has a calming effect (it is an anxiolytic). It works by enhancing the actions of the inhibitory neurotransmitter GABA. Pentylenetetrazol has exactly the opposite effect: it reduces GABA activity and causes tension and anxiety (it is an anxiogenic). Barrett and Smith trained rats to press one lever after being injected with CDP—that is, when they were calm and relaxed—and to press the other lever after being injected with PTZ—that is, when they were tense and anxious. After being injected with saline, the rats did not discriminate—they distributed their responding equally between the two levers.

Following training, Barrett and Smith gave the rats a dose of chlordiazepoxide and recorded discriminative lever pressing at various times after the injection. As can be seen in the following graph, 8 hours after the CDP injection, rats made 90% of their responses on the CDP lever. But by 16 hours after the injection, rats made most of their responses on the PTZ lever. Responding slowly approached the 50% level over a number of days.

These results suggest that 8 hours after the CDP injection, the rats still felt calm and relaxed and therefore responded on the CDP lever. But during this time, a compensatory response had been building that was opposite to the CDP effect. After the drug had left the system, the compensatory response remained. This made the rats feel anxious and tense, a feeling similar to that produced by a dose of PTZ, so they pressed the PTZ lever at the 16-hour test. Eventually, this compensatory response diminished, and by 48 hours the rats were moving closer to drug-free response levels of 50% on each lever. This experiment illustrates Solomon and Corbit’s opponent process theory—the A process creates the tranquilizing a effect of the CDP, and the B process creates the compensatory b state of anxiety. This sort of process appears responsible for the development of a hangover and the experience of symptoms opposite of intoxication once the drug has worn off.

3.3-3 Full Alternative Text

Opponent process theory can also explain acute tolerance. When you take a drug, its effect will be greatest before the B processes build up. As the B processes get stronger, the strength of the A process will diminish. This explains why a drug effect could be greater at a particular blood level as the drug levels are rising than at the same point as the blood levels of a drug are falling.

If you take a drug continuously for weeks or months and maintain a fixed level of the drug in the body so that withdrawal symptoms never occur, the compensatory response builds up. When you stop taking the drug, this compensatory response is expressed as withdrawal symptoms. These can be very unpleasant and, depending on the nature of the drug, intense and severe. Withdrawal symptoms are often exaggerated effects opposite those of the drug, indicating that they are compensatory responses. Figure 3-3 is an extension of Figure 3-2. It shows that, as a drug is repeatedly administered, the compensatory B process gets stronger and begins sooner so that the a state almost disappears entirely (i.e., this is increased tolerance) and the b state (i.e., the withdrawal effect) is more intense and longer lasting. This change, along with other adaptations in the nervous system, has important implications for the development of addiction, as described in Chapter 5.

Figure 3-3 

The upper panel shows the drug effect on both the A process and the opposing B process after chronic administration of a drug. When the drug is taken repeatedly, the A process remains unchanged, but the compensatory B process gets stronger and begins sooner. The overall affective state (illustrated in the middle panel) is such that the a effect almost disappears entirely (i.e., this is increased tolerance) and the b effect (i.e., the withdrawal effect) is more intense and longer lasting. (Adapted from Solomon & Corbit, 1974.)

Figure 3-3  Full Alternative Text

If withdrawal is an expression of compensatory effects that cause tolerance to drugs, you might expect there to be a strong correlation between tolerance and withdrawal symptoms. However, this does not seem to be the case; it is not unusual for a person to show considerable tolerance to the effects of a drug but to have no withdrawal symptoms when the drug is discontinued. Alcohol is a good example. Many long-time casual drinkers have a considerable tolerance for some of the effects of alcohol, but do not show any signs of withdrawal when they stop drinking. There are a number of reasons why this happens. To begin with, there may be some tolerance, like behavioral tolerance (described in Section 3.4), that is not created by a physiological compensatory effect, and so there would be no physiological withdrawal. In addition, withdrawal symptoms may not be experienced if the rate of elimination of the drug from the body is very slow, as is the case with THC, an active ingredient in marijuana (see Chapter 14). With slow elimination, the body may be able to readjust at the pace of the drug’s elimination, and withdrawal symptoms may not be expressed.