Chapter 4: Pharmacology

efficacy

The most intense, or peak, level of a drug effect -Efficacy is defined as the peak of the dose-effect curve for a given effect. In Figure 4.5, that peak is where each curve reaches a plateau.

drug potency

The minimum effective dose of a drug.

Drug distribution

-. Some drugs, such as the barbiturates, may bind chemically to certain proteins in the plasma. The more "tightly" bound a drug is, the slower its distribution to sites of action - Its distribution is uneven throughout the body because of selective binding, and the effects achieved by taking the drug are attenuated. Part of the dose does not immediately reach its sites of action

Steps in the drug experience

1. A drug of a specified chemical structure is present. 2. A certain quantity of this drug is measured. 3. This quantity of the drug is administered in one of a number of possible ways. 4. The drug is absorbed into the blood and distributed to site(s) of action. 5. Some pharmacological effect is produced. 6. In humans, a drug's pharmacological effects may be modified depending on characteristics of the person, such as genetic constitution, gender, age, personality, and drug tolerance. 7. The setting or context of drug use may also modify a drug's pharmacological effects

Drugs used for Medical and Nonmedical reasons and their routes of administration

1. Alcohol Oral 2. Amphetamines Oral; intravenous (preferred by chronic high-dose abusers); sniffed by occasional or new users 3. Barbiturates Oral; rectal (through the mucous membrane of the rectum); subcutaneous; intramuscular; intravenous 4. Benzodiazepines Most commonly oral; some intravenous or intramuscular 5. Caffeine Most commonly oral; medically, occasionally by injection for mild stimulant properties; intravenous injection by abusers 6. Cannabis Almost all routes; most commonly smoking (inhalation); injection not efficient because THC is not water-soluble 7. Cocaine Cocaine hydrochloride is taken through nasal or other mucous membranes, such as those of the mouth, vagina, and rectum; also intravenous. Cocaine freebase (crack) is volatile and therefore most often vaporized in a freebase pipe and inhaled into the lungs 8. Heroin Most commonly is dissolved in water and injected subcutaneously, intramuscularly, or intravenously; may be inhaled by smoking, or sniffed 9. Nicotine Inhaled by smoking (cigarettes); nicotine in cigar or pipe smoke mainly absorbed across membranes of the mouth and upper respiratory tract; may be absorbed through membranes of the mouth (chewing tobacco) and nose (snuff) and through the skin 10. LSD (lysergic acid diethylamide-25) Oral; inhalation; the three injection routes; through the skin 11. MDMA (methylenedioxy- methamphetamine) Most commonly oral 12. PCP (phencyclidine) Oral; sniffed; inhalation by smoking (sprinkled on marijuana, parsley, tobacco, or other substance that can be smoked); intravenous injection

drug dose

A drug's dose is computed according to a person's body weight, because heavier people have a greater volume of body fluid than lighter people do. Therefore, a given amount of a drug is less concentrated in the body of a heavier person, and similarly at the site of drug action, than it is in the body of a lighter person - the greater the drug concentration at a site, the greater the drug effect. Therefore, the amount of a drug that is administered has to be adjusted according to body weight to assure that the drug is given in equivalent strength (dose) to people who have different weights.

therapeutic index

A measure of a drug's safety in medical care; it is computed as a ratio: LD 50/ ED 5 -. Here, the ED of interest is the alleviation of the symptoms of some disease or injury. You can see that the higher a drug's therapeutic index, the more useful the drug is in medical treatment. -Another point is that steeper dose-effect curves tend to have smaller therapeutic indices. -The therapeutic index gives health care providers a quick idea of the benefits of prescribing a drug as part of a specific treatment

diffusibility

A more diffusible substance is more easily entered into or "receptive" of another. - The more diffusible tissues receive the drug more rapidly

addiction factors

A series of interrelated factors contributes to a given drug effect. The importance of any one factor, or set of factors, for a given drug-taking occasion depends on the importance of the other factors. This idea sounds complicated, and it is even more complicated to analyze in practice.

Drug absorption

Absorption (of a drug into the bloodstream) also may be defined as the rate and extent to which a drug leaves its site of administration, and it plays a major role in the drug experience.

as a function

A term expressing correlation. In graphs of functional relationships between two variables, changes in one variable (for example, drug effect) associated with changes in another (drug dose) are represented. -the effects of this hypothetical drug are not constant across different doses. Rather, the S shape (sigmoid) of the curve reflects that an accurate description of this drug's effects requires the specification of a dose. - At that point, if the person is having a hard time maintaining con- sciousness, then the possibility of—and the utility of—measuring further slowing of reaction time with a higher dose of alcohol would hover around zero. - The plateau of the dose-effect curve in this instance would be reached at the alcohol dose equivalent of about nine beers. -The example of alcohol and simple reaction time shows that the question is not what effects drug X has but rather what the effect of drug X is at a specified dose.

synergism

Any enhancing drug interaction. -. Here we will use it to denote any enhancing drug interaction. Another word that currently is used in the same way as synergism is potentiation. -When two drugs are synergistic, the effects of taking them together are greater than the effects of taking either drug alone. -In practice, pharmacologists find it difficult to tell for sure whether synergistic effects are a simple result of adding the separate effects of the two drugs together or if somehow one of the drugs is "multiplying" the effects of the other

Drug testing

Drug testing is a term applied to various methods of determining drug use, most commonly by analyzing "biomarkers" such as urine or blood samples. In recent years, drug testing by analysis of sweat, saliva, and hair samples has also been applied with increasing frequency as the technology for such application improves - Much of the discussion and research on drug testing concerns detection of use more remote than the immediate past, which is where the use of urine and other biomarker samples is relevant. -This discussion focuses on analysis of urine samples, because as noted earlier the relevant methods are most commonly used and developed compared to other possibilities, such as hair analysis. - It is notable, however, that hair analysis by far is the method of choice if the goal is to detect drug use from more than the past several days. It is capable of detection of use for up to 90 days ago compared to the typical 1-3 days for detection by urine or saliva

side effects

Effects of a drug other than those of central interest; used most often in reference to the other- than-therapeutic effects of medications, such as the side effect of drowsiness for antihistamines. Note that what are considered a drug's side effects depend on what specifically the drug is being used for

awareness of interaction

In medical practice, knowledge of drug interactions is vital because drugs are often used in combinations for more effective treatment of an illness. -Therefore, drug interactions may be used to improve medical care. -On the other hand, interactions could be a problem, for example, for physicians. -Difficulties may occur if a physician is not aware of all the drugs a patient may be using at a given time. ex./For example, the effects of one drug could cancel the therapeutic effects of another. -Furthermore, prescribed medication could have detrimental or even lethal effects in the presence of other drugs. -Drug interactions also may cause problems with different nonprescribed drugs or combinations of prescribed and nonprescribed drugs. -The most common examples are mixing drugs that depress the central nervous system. ex./ For example, as we said earlier, alcohol and the barbiturates may be lethal in enhancing the sedative effects of each. This drug combination has caused many intentional and accidental deaths.

Routes of administration

In pharmacology, the "route of drug administration" may refer to either the site where a drug is taken or how a drug is taken. -The route of drug administration can strongly influence the effects that a drug has. -The five most common are oral, by injection (includes three ways—subcutaneous, intramuscular, and intravenous), and by inhalation. Three other important routes are intranasal (sniffing), sublingual (under the tongue), and transdermal (through the skin).

Control

In research, to be able to account for variables that may affect the results of a study - To evaluate the impor- tance or contribution of any one factor to a drug effect or experience, researchers must comprehend or at least somehow control the effects of other relevant fact

Feedback

In this context, in a series of events, what happens in a later event alters events that preceded it.

Intranasal

In this route, a drug in powdered form is taken through the nose. The drug is then absorbed through the mucous membranes of the nose and the sinus cavities. -Other terms for intranasal administration that you may have heard are snorting and sniffing. -Examples of drugs commonly absorbed this way are cocaine, heroin, and powdered tobacco snuff. - When a drug is fat soluble, sniffing is a rapid and effective way to absorb it. However, lipid solubility should not be too high, because highly fat-soluble drugs tend to be low in water solubility. ^Drugs administered nasally should be water-soluble as well as fat-soluble, because of the high water content in the nasal cavity. If the drug has poor water solubility, then drug bio-availability will be low. -Another point is that if a sniffed drug is irritating and disrupts blood flow, then it can cause damage. ex./An example that has been cited often is the damage that cocaine sniffing causes to the nasal septum and lining of the

Intravenous

Intravenous means "into the veins," and therefore most absorption problems are avoided. -A common street term for the route is "mainlining." The drug is injected in solution directly into the veins. -The effects can be immediate. As a result, intravenous administration is valuable in emergency medical situations, and doses can be precisely adjusted according to the person's response. ^In addition, irritating drugs as well as irritating vehicles can be taken intravenously (as opposed to, say, subcutaneously or intramuscularly) because blood vessel walls are relatively insensitive and the drug is further diluted by blood -The apparent advantages of intravenous administration raise the question of why this is not the preferred route for prescribed medications. -A major reason is that the intravenous route is the one most highly associated with complications because large quantities of the drug quickly reach the site of action. ^This feature contrasts with oral administration, which is considered safe because drugs reach their sites of action relatively slowly. >Another point to consider is that if a drug is repeatedly administered intravenously, then a healthy vein must be maintained. In general, intravenous injection is associated with such risk that administration must be done slowly and with careful monitoring of a person's response. >Obviously, this care is much more likely in a controlled medical environment than in other settings where drugs are taken. -Those who regularly take drugs like heroin, cocaine, or heroin and cocaine together (called "speedball") intravenously are called "hard-core addicts." -These users take drugs intravenously because they want immediate and powerful drug effects. -However, the risks of taking a drug intravenously, coupled with the assault that such drug taking has on the body, usually take a toll on a person. ^Drug-induced deaths, intentional or not, are an ever-present danger among addicts and other nonmedical drug users who take their drugs intravenously. -Another critical point to consider when drugs are taken by injection is that, to prevent diseases such as AIDS, hepatitis, and tetanus, drugs must be injected using sterile needles and solutions ^ Therefore, dirty needles or nonsterile solutions may carry illness-inducing microorganisms that the body cannot "screen out." This is why, for instance, street drug abusers who share their needles are at high risk for contracting AIDS.

Variations of the does-effect curve

Not all drug effects look like Figure 4.2 when plotted over a range of doses. One variant is a biphasic drug effect. This means that the effect of a drug may go in one direction— say, increase as the dose goes up—but then the effect changes direction (decreases) as the dose continues to go up. -As the dose continues to increase, however, the curve changes direction to represent the decrease in drug effect with higher drug doses. ex./In this example, the size of the effect essentially returns almost to the level at the lowest drug doses. -Heart rate is an effect that has been reported to be biphasic for both alcohol and marijuana - Some dose-effect curves for a given drug could look quite different, however, depending on what effects are being measured. This brings out a major point: The dose-effect curve for a drug depends on the effect being measured. - looks different from the other dose-effect curves we have shown because we have changed how effect is represented (vertical axis) to accommodate a negative drug effect. ^As the figure shows, the college women perceived that their sexual arousal increased with increasing doses of alcohol, at least up to moderate doses (very high doses have not been studied). ^However, physiological measures of the women's sexual arousal showed decreases as the dose increased

Drug elimination

One question that may have occurred to you is whether the drug metabolic by- products themselves have pharmacologic action. If they do, then it is difficult to see how a drug state could ever become deactivated. -The kidney is by far the most important organ for excretion of both drugs and their metabolites, but excretion may occur in other ways as well. ex./ For example, drugs that are taken orally may be excreted directly in the feces. -Drug metabolites may be excreted in liver bile. -Drugs are excreted in mother's milk, which is not critical so much because of the proportion of drug that leaves the body this way but because of the dangers posed to the nursing infant. -Drugs also may be excreted through the lungs, which is why you can smell alcohol on a person's breath after he or she drinks it. Finally, drugs may be excreted in perspiration. -Pharmacologists have discovered that the rate of elimination of drugs from the body obeys two general laws: zero-order kinetics and first-order kinetics -. First-order kinetics, on the other hand, means that the amount of drug that is metabolized in a unit of time depends on how much drug is in the blood. ^Most drugs obey the law of first-order kinetics. Knowledge of these laws is a great help to people who do research on drugs and to physicians when they prescribe medications.

orally

Oral administration, or swallowing, is the route with which you probably are most familiar. -Drugs taken orally are usually in the form of pills, capsules, powders, or liquids. ex./ Examples are the variety of headache medicines, cough syrups, and cold remedies available at any drugstore. Such accessible medications are virtually always prepared for oral administration because it usually is the safest, most convenient, and most economical way to administer a drug -When drugs are swallowed, they pass through the stomach and are absorbed primarily through the small intestine. ^This travel course affects both how fast a drug can register its effect physically and how much effect is registered. ^A major factor in determining the effect is how much food is in the digestive tract when the drug is taken. >The presence of food delays the stomach from emptying and may dilute the concentration of a drug. -The result: delayed absorption and a decrease in the maxi- mum drug level achieved. - Finally, oral administration, even without the complications of food in the stomach, causes the drug to be absorbed into the blood more slowly than with other routes. Therefore, the pluses of oral -Therefore, the pluses of oral administration—relative safety, convenience, and economy—must be balanced against considerations of time to absorption and the maximum drug effect that can be reached with a particular drug dose. ^With some drugs, such as heroin, the stomach acids used in digestion actually break down the drug to some degree before it is absorbed into the blood. >Once in the blood, the chemically altered drug is passed through the liver before it reaches the brain. Because the liver is the major site of the metabolization of most drugs, only a fraction of the drug dose actually reaches the brain. The outcome is a diminished drug effect

Inhalation

Some drugs may be inhaled and then absorbed through the lung's membranes. -For such drugs, inhalation results in a fast and effective absorption. - A drug has to be in one of a few states to be inhaled. If drugs can be changed into gaseous states then their vapors may be inhaled. ex./Three examples of such substances, which typically are ingredients of commercial products and are aptly called inhalants when used for their psychoactive properties, are benzene, toluene, and naphtha. - Lastly, drugs in small particles of matter that are suspended in a gas may be inhaled. ex./ For example, tobacco smoke contains tiny drops of nicotine. Similarly, the smoke from freebase cocaine (crack) contains droplets of cocaine.

half-life

The amount of time that must pass for the amount of drug in the body to be reduced by half - Drug half-life actually is a term that has been given more importance than is warranted. It has been discovered to be a result of other statistics that reflect the body's ability to clear a drug. -These other statistics are directly linked to the kinetics law that the drug is obeying. In any case, you will see the term half-life again in this text and likely in other sources, so it is useful to know i

Pharmacokinetics

The branch of pharmacology that concerns the absorption, distribution, biotransformation, and excretion of drugs - Drug absorption and distribution are essential for determining how much drug reaches its sites of action and therefore for determining its effects. Absorption and distribution are key factors in the drug experience -Once in the body, drugs do not stay forever. The basics of how the body elimi- nates drugs and how that is studied are also covered in this chapter. Knowing about drug excretion or elimination is required for learning the effect a drug will have after it enters the bod

pharmacodynamics

The branch of pharmacology that concerns the biochemical and physiological effects of drugs and their mechanisms of action. - Pharmacodynamics is relevant to the drug experience because this branch of pharmacology concerns the biological bases of observed drug effects. It will be valuable for you to know what standards are followed in describing and represent- ing these effects.

antagonism

The diminished or reduced effect of a drug when another drug is present -. As you might guess, drug antagonism is represented by a shift to the right of a drug's dose-effect curve. For example, the amphetamines, which are CNS stimulant drugs, antagonize alcohol's CNS depressant effects. -However, the amphetamines do not reduce alcohol's impairment of motor skills, like driving

effective dose

The dose at which a given percentage of individuals show a particular effect of a drug. - (ED) is the dose at which a given percentage of individuals show a particular effect of a drug. -The ED is found on a dose-effect curve by extending a horizontal line from the vertical axis at a given percentage to the relevant effect curve and dropping a vertical line to the drug dose axis from there. -That point represents the ED for a given percentage. ED 50 is a standard term that pharmacologists use, and Figure 4.6 shows ED 50 for sedation for the hypothetical drug. ^That means that 50% of the people who receive that amount of the drug will experience sedation. Of course, the ED for any percentage can be found in the same way.

lethal dose

The dose of a drug at which a given percentage of individuals die within a specified time -e (LD) of a drug is a special case of the effective dose. As the name implies, in lethal dose, the effect of interest is death, and the LD is the dose at which a given percentage of nonhumans (human subjects are not used in experiments to determine the lethal doses of drugs) die within a specified time. - A standard referent in pharmacology is a drug's LD 50, which is the dose at which 50% of the animals administered a given dose of a drug died within a stated time. -Determining the LD 50 of a drug in humans is a matter of extrapolating the findings with animal subjects to humans. -A drug's EDs and LDs are of more than casual interest. Of particular importance for a city's health officials, for example, is the difference between a drug's ED and LD. -When the difference is small, much more danger of accidental suicide exists for a person who is using drugs for nonmedical reasons. For some drugs, such as caffeine, the ED-LD difference is large; however, other drugs pose more of a problem - Alcohol is another example. A 160-pound man with average tolerance to alcohol typically would report feeling relaxed after drinking about 3 ounces of whiskey in an hour on an empty stomach. However, that person would reach LD 50 for alcohol if he drank about a fifth (25.3 ounces) of that whiskey in an hour. ^Such drinking occurs more often than you might think and has been responsible for serious injuries and deaths in fraternity hazings (initiation rites).

solubility

The ease with which a com- pound can be dissolved or entered into a solution. - Drugs that are more soluble in lipids penetrate body membranes and therefore reach sites of action more easily than do less lipid-soluble drugs. -The fat solubility of a drug also plays a role in how much of it can reach the brain. This is important to us because we concentrate on drugs that affect the central nervous system (CNS) in this text. -Although the blood flow to the brain makes it a natural repository for drugs (and other chemicals) that enter the body, substances must cross the blood-brain barrier before they can reach the brain.

Slope, efficacy, and Potency

The first feature of the curves is the slope, or steepness. The slope of the curve reflects how much the drug dose changes before the effect gets larger. -Slope can have very practical implications in prescribing drugs therapeutically or in considering potentially life-endangering effects of drugs taken nonmedically. ex./ Examples of the latter are the sedating effect of barbiturates and the effects of taking a benzodiazepine drug and alcohol together. In Figure 4.5, curve A has a steeper slope than curve B, so as the curves rise to a plateau, a given dose of A yields a larger effect.

qualitative

The kind, as opposed to quantity, of effect -Drinkers sometimes consume large amounts of black coffee (containing caffeine) in hopes of antagonizing alcohol's CNS depressant effects. -In truth, however, caffeine seems to do little to counter alcohol's effects on the CNS. -These two examples illustrate drug users' attempts to modify the intensity (quantitative) of drug effects. -However, drugs also may be combined to achieve qualitative interaction effects that could not be achieved by any of the drugs separately. -Users might take a depressant drug, such as one of the benzodiazepines, along with LSD to have a tranquil state while they experience the perceptual alterations that result from LSD

Intramuscular

The name of this route means "within the muscle." Intramuscular injection requires a deeper penetration than the subcutaneous method but is associated with a faster absorption rate when the drug is prepared in a water solution and there is a good rate of blood flow at the site of administration. -Absorption rates may differ depending on the rate of blood flow to the muscle group the drug is injected into; in practice, the most common muscle sites are the deltoid, thigh, and buttocks. -The absorption rate can also be modulated by the solution that the drug is prepared in for administration. -One disadvantage is that intramuscular injection can result in localized pain (at the site of injection). ^Furthermore, when a person who is not formally trained administers drugs intramuscularly, the risk of infection from irritating drugs and tissue damage is high.

Bioavailability

The portion of the original drug dose that reaches its site of action or that reaches a fluid in the body that gives it access to its site of action.

metabolism

The process by which the body breaks down matter into more simple components and waste.

range of elimination

The range of elimination times pertains to elimination of the drug itself (shorter time) and to elimination of the drug's metabo- lites (longer time) from the body. ^Alcohol has no range because its metabolites are used too efficiently in the body to be measured reliably -The validity of drug testing depends on factors such as the dose last taken of the drug, the testing method used, and the laboratory quality control procedures used in testing. -The detectability of drug use is determined by the drug's clearance rates from the body and the clearance rates of the drug's metabolites.

Transdermal

The transdermal route actually is not an effective one for many drugs, because the skin acts as a barrier to some chemicals and thus is relatively impermeable. -For those drugs that more readily penetrate intact skin, absorption is better because the drug is applied to a wider area. -Drugs that penetrate the skin are absorbed better at sites that have a higher rate of cutaneous blood flow. In addition, a drug dose may be modified by mixing it with other substances, such as an oily preparation, to improve penetration at the site of administration - is a patch containing a preparation of nicotine and other substances that is applied to the skin so that nicotine can enter the body. This is one type of pharmacological treatment of nicotine dependence. [0 -Nitroglycerine may be administered by patch, which avoids the problem of metabolizing the drug before it reaches its site of action when it is taken orally. ^ Finally, patches may be used to place a drug at a site of the skin that is advantageous for its increased blood flow.

distribution

The transport of drugs by the blood to their site(s) of action in the body

The dose effect curve

This curve is a representation of some effect according to a dose of the drug. ex./For example, several groups of people may drink different doses of alcohol and be asked to report their degree of -relaxation at a given point. If the average reports of relaxation for each group were then plotted, we would have a dose-effect curve. - The vertical axis of the graph, labeled "Effect size," represents the change we are interested in recording. -The changes that we emphasize in this text are reported in some generally accepted measurement of mood, behavior, or nervous system function. ex./ Examples might include memory task performance, ratings of mood, or some measure of physiological arousal such as heart rate. On the vertical axis, the effect is generally depicted as going from smaller to larger. -The graph's horizontal axis represents the range of doses under investigation, from smaller to larger doses. (Often the logarithm of the drug dose is represented on the horizontal axis.) Typically, a minimum of three doses is studied. -Creating the curve is then simply a matter of plotting the effect, however measured, for the individuals who have received a given dose of the drug under evaluation.

subcutaneous

This route involves injecting the drug under the layers of the skin. It is the easiest of the injection routes to use because the target site of the needle is just below the skin surface. - This route may also be preferred medically for drugs that are not irritating to body tissue because of the route's relatively slow (but faster than oral) and constant absorption rate. - A drug should not be taken subcutaneously when the drug irritates body tissue and when large volumes of solution must be taken to introduce enough of the drug to achieve the desired effect

Injection

Three of the most common routes of drug administration involve injecting drugs into the body using a needle and syringe. -When drugs are taken this way, they typically are dissolved or suspended in some solution ("vehicle") before injection. -The routes for administration when injecting drugs are subcutaneous, intramuscular, and intraveno

dissolved

When a drug changes from solid to liquid by mixing it with a liquid

suspended

When a drug's particles are dispersed in solution but not dissolved in it

Freebase

When a substance is separated, or "freed," from its salt base. The separated form of the substance is thus called "freebase."

absorbed

When drugs have entered the bloodstream.

Interacts

When the effects of one drug are modified by the presence of another drug. -. Two drugs have an interaction if the effect of one modifies or alters the effect of the other. Drug interactions may be analyzed qualitatively or quantitatively; the degree of effect, or quantitative study, is by far better understood in pharmacology

Sublingual

With this route, a drug tablet is placed under the tongue and dissolves in saliva. -The drug is absorbed through the mouth's mucous membranes. Nitroglycerin, which is taken for treatment of angina pectoris (heart pain), is usually taken sublingually. -Nicotine may be taken in the form of chewing tobacco or "dipping" snuff by the sublingual route. -The sublingual route results in faster and more efficient drug absorption than oral administration. -It also is preferred to oral administration for drugs that irritate the stomach and cause vomiting. -Almost any drug with the right chemical properties may be taken in pill form sublingually. -However, this route is used less frequently than might be expected because of the unpleasant taste of many of the drugs that may be taken sublingually