Chapter 3

PSYCHOPHARMACOLOGICAL CONCEPTS

A. ROUTES OF DRUG ENTRY AND EXIT

Drug Administration

Oral administration.

Rectal administration.

Mucous membranes.

Inhalation.

Subcutaneous injection.

Intramuscular injection.

Intravenous injection.

Intraarterial injection.

Intraperitoneal injection.

Transpleural injection.

Intracranial injection.

Intrathecal injection.

Transdermal infusion.

Drug Disposition

Protein binding.

Liver enzymes.

Renal excretion.

Body surface.

Pools.

The Net Effect of Drug Entry and Exit

B. DOSAGE AND BEHAVIOR CONSIDERATIONS

Dose-Response Curves

Law of Initial Values

Drugs Have Multiple Effects

Individual Differences in Drug Effects

Calculating Drug Dosages

C. THE BLOOD BRAIN BARRIER

D. CLASSIFICATION OF DRUGS

Methods of Classification

Behavioral Categories.

Biochemical Categories.

Structural Categories.

Categories are Useful in Understanding Drug Effects

E. SUMMARY

Principles

Terms


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PSYCHOPHARMACOLOGICAL CONCEPTS

A. ROUTES OF DRUG ENTRY AND EXIT

Drug Administration

In order for a drug to have an effect, it is necessary for it to reach some specific tissue of the body. The classification of drugs and the description of drug effects is usually based upon the interaction of the drug with this receptor tissue. In the parlance of traditional pharmacology, this interaction at the cellular level is the drug action, whereas the more complicated consequences of this action are termed the drug effect. These terms, action and effect, are frequently used interchangeably, but it is important to recognize that different issues must be considered in each instance.

The basic question that is being addressed here is, "How does the drug get from the shelf to the receptive tissue?" We know from casual experience with pharmaceuticals that drug effects are neither immediate (the headache does not go away at the instant the pill is taken), nor permanent (repeated dosages must be taken). The full consideration of these issues requires a knowledge of membrane biophysics, acid-base kinetics, and other aspects of cell physiology; all of which are of critical importance in the design of pharmaceutical products and in understanding certain aspects of drug actions. Fortunately, we need only consider some of the more global aspects of these topics at this point.

One of the most important determinants of a drug effect is the concentration of drug molecules in the bloodstream or plasma compartment of the body. The drug concentration is determined by the rate of entry into the blood stream and the rate of exit from the bloodstream. In each case, the compound must cross a membrane barrier.

The various membrane surfaces of the body are very similar in terms of their properties that allow specific types of molecules to pass through them. The membrane can be considered as a double layer of lipid molecules sandwiched between an inner and outer layer of protein molecules (Fig. 3.1). Small membrane pores (about 4-8 Angstroms in diameter) penetrate these layers at intervals along the surface. This physical structure determines the way in which a particular molecule will pass through the membrane:

a. Molecules that are smaller than the diameter of the pores cross the membrane by passive diffusion

b. Molecules that are lipid soluble dissolve in the membrane and diffuse through it according to the concentration gradients.

c. Molecules that are too large and not lipid soluble do not pass through the membrane, except when special metabolic systems called active transport systems carry the molecules through the membrane. Such transport mechanisms are fairly common for endogenous compounds, but do not appear very frequently in the case of pharmaceutical compounds.

There are many different ways in which a drug can be administered, or in terms of the above discussion, different ways to make the drug accessible to the membranes that allow passage into the circulatory system. One way to modify the accessibility of the drug is to change the vehicle, or carrier, of the drug. For example, the drug may be mixed with distilled water, saline, oil, or even solutions of other drugs to systematically change the characteristics of entry into the bloodstream. The rate at which a drug enters the circulatory system varies tremendously, depending upon the route of administration:

Table 3.1

Major Routes of Drug Administration

Oral
Rectal
Mucous membranes
Inhalation
Subcutaneous injection
Transdermal infusion
Intramuscular injection
Intravenous injection
Intraarterial injection
Intraperitoneal injection
Intrathecal injection
Intracranial injection
Each of these routes will be taken up in turn:

Oral administration.

This is certainly the most common method of drug administration, and unless otherwise specified, we assume that taking medication means oral ingestion. This route of administration has the advantage of quickly and easily placing the drug in contact with the relatively large surface membrane of the stomach, which has a rich supply of capillaries for entry into the plasma compartment. The stomach wall is relatively resistant to the irritating properties of most drugs, and the churning action of the stomach will improve the physical distribution of the compound. Finally, the presence or absence of food in the stomach can be manipulated to increase or decrease the rate of absorption, to minimize irritating effects, or to change the chemical environment of the stomach.

There are, however, some special characteristics of the gastric environment that may cause difficulties for the administration of certain drugs. The high acidity of the stomach may alter the structure of the drug, causing it to precipitate and be less easily absorbed. Depending on the acid-base characteristics of the drug, the gastric environment may either increase or decrease the tendency of the drug to split into ionized (or charged) forms. This is a very important consideration for large molecules, because only the non-ionized forms of otherwise lipid soluble compounds will pass through the lipid barrier of the membranes. Because of the differences in pH of the stomach and the intestines, some drugs which are not readily absorbed through the stomach walls because of ionization change their state when they pass from the stomach to the intestine and become lipid soluble. This effectively delays the entry of the drug into the bloodstream. By contrast, other drugs may become ionized and ineffective upon leaving the stomach, so that the amount of the original dosage that actually becomes useful is determined by the length of time it was in the stomach. Modern manufacturing methods now produce several different "time release" formulations that encapsulate the drug into a vehicle that dissolves at some specified rate to release the drug dosage gradually over time.

Rectal administration.

The absorption of drugs administered rectally is essentially the same as that of drugs that reach the intestine via oral administration. This method is most frequently used under direct medical supervision when it is difficult or impossible for the drug to be administered orally. One of the disadvantages of the method is that the drug may be eliminated before complete absorption has occurred.

Mucous membranes.

There are many drugs that readily pass through the mucous membranes of the mouth and nasal passages. The best known examples of these routes of administration are probably the "nitro" capsules that cardiac patients place under the tongue for almost immediate relief of symptoms, and the snorting of cocaine into the nostrils by users of recreational drugs. In both cases, the drugs are quickly absorbed and significant levels of the drugs enter the bloodstream within seconds.

Inhalation.

Drugs that are volatile can enter the bloodstream very rapidly when inhaled. This is, in fact, just an extension of the mucous membrane route discussed above, but the very large surface area and rich blood supply of the lungs make this an exceptionally rapid route of administration. The major disadvantage is the difficulty of controlling dosage levels, and possible harmful effects upon the membranes. Because of these practical difficulties, this route of administration is usually limited to drugs that are used specifically for their local effects (e.g, anti-asthmatic compounds), and medically supervised anesthesia. It should also be kept it mind that this extremely efficient route of administration renders us vulnerable to the accidental administration of toxic levels of volatile compounds that may be airborne in our environment. Each year, physicians see a number of serious if not fatal cases of poisoning due to exposure to solvents, cleaning fluids, and even the burning of poison ivy along with autumn leaves. On the street drug scene, one of the most dangerous forms of cocaine use is the inhalation of the drug known as "crack". Less acute, but perhaps no less dangerous on a global scale, are the effects of voluntary (and involuntary) inhalation of the contents of tobacco smoke.

Subcutaneous injection.

The skin provides a relatively impermeable barrier to most substances (we will see exceptions later), which led to the development of the hypodermic(literally meaning under the skin) syringe for the administration of drugs through this barrier. When administered in this manner, the drug is sequestered in a localized area, being forced into the interstitial fluid that surrounds the local cells and capillaries. The drug will enter the bloodstream via these local capillaries. Because of the limited physical dispersion of the drug dosage, the absorption of drugs administered subcutaneously tends to be slow and uniform. A further advantage is that the rate of absorption can be controlled by varying the conditions under which the drug is administered. For example, the application of heat or mixing the drug with vasodilators will increase the rate of absorption. More commonly, the physician is interested in slowing down the rate of absorption and may administer the drug in combination with a local vasoconstrictor, mix the drug in an oil vehicle, apply ice over the area of injection, or in emergency situations, even apply a tourniquet between the site of injection and the systemic circulation. Although less commonly used, it is also possible to surgically implant a capsule under the skin, where the drug is slowly released, sometimes over a period of weeks or months.

Intramuscular injection.

Some drugs have irritant or caustic effects upon local tissues that will cause the skin to sluff off if administered subcutaneously. If the injection route is still preferable, these problems can be minimized by administering drugs deeply into the muscle mass. Certain forms of penicillin are commonly injected via the intramuscular route.

Intravenous injection.

This is the most direct route for the systemic administration of a drug, because it is placed directly into the circulatory system without having to cross any membranes. The rapidity of effects can actually be a disadvantage with this route of administration, since acute overdosage is possible. The most common usage of the intravenous route is the administration of anesthetics, since the level of anesthesia can be carefully titrated by monitoring vital signs. Additionally, drugs that would otherwise be severe irritants to local tissue can sometimes be administered via this route, owing to the resistant nature of the walls of the bloodstream and the rapid dilution of the drug in the moving fluid environment. The self administration of narcotic drugs by this route (sometimes referred to as mainlining) is exceptionally hazardous because of the likelihood of acute overdosage and infections.

Intraarterial injection.

This method also places the drug directly into the bloodstream, but is usually reserved for experimental purposes to inject a drug directly into the blood supply of a specific organ (e.g., the liver or the brain) to assay the effects of the drug upon that organ. One particularly interesting application of this method is to inject a fast acting anesthetic into one of the carotid arteries (see Wada & Rasmussen, 1960). This results in the brief anesthetization of one side of the brain, which can be useful in diagnosing the location of brain functions (e.g., language areas) or disorders such as tumors.

Intraperitoneal injection.

The intraperitoneal route of administration involves the injection of the substance through the wall of the abdomen into the peritoneal cavity. Absorption of the compound occurs largely through the rich vascular bed of the intestines, though from the outside rather than the inside. It is by far the most common method for administering drugs to small experimental animals, owing to the relative difficulty of the intravascular route and the inconsistency of oral administration in laboratory animals. This technique is rarely used in humans because of the potential (though slight) for damaging internal organs and the greater risk of infection.

Transpleural injection.

This is an interesting procedure that occasionally has been used for experimental purposes, especially in small animals. Procedurally, it is somewhat comparable to the intraperitoneal injection, except that the needle is inserted through the rib cage above the diaphragm so that the drug is injected into the pleural cavity. For some drugs, the effect is almost as rapid as an intravenous injection because of the extremely fast absorption through the rich vascular supply of the lungs (hence, the term transpleural, which means across the lungs).

Intracranial injection.

In some cases, it is advantageous to administer a behaviorally active drug more locally into the brain, rather than indirectly through the systemic circulation. There are actually two subdivisions of this route, which overlap to a considerable extent in both theory and practice. The intracisternal route involves the injection of the drug directly into the cerebrospinal fluid (usually abbreviated, csf) of the brain ventricles. In some cases, this is done via a cannula (tube) that has been permanently positioned, but in other cases it is done (with skilled hands!) by direct injection through the foramen magnum at the back of the skull of experimental rats or mice. The intracerebral route involves the application of a drug directly onto brain tissue. A common experimental procedure for intracerebral injections involves the permanent placement of a cannula into a specific region of the brain. Minute quantities of drugs can then be administered in either liquid or crystal form to determine the response (both neurophysiological and behavioral) of the specific brain region to a specific drug. These techniques have been very useful as experimental procedures for studying drug effects in experimental settings, but have had limited use in human applications.

Intrathecal injection.

The major application for this route of administration has been the use of the so-called "spinal" anesthetics. In this procedure, a needle is inserted between the vertebrae and through the sheath of the spinal cord. Small quantities of drugs can act on the local cell population and produce anesthesia (usually of the lower body and limbs) while having few if any systemic effects.

Transdermal infusion.

The skin surface normally serves as an effective barrier against the entry of foreign substances into the body. There are, however, some substances that will penetrate the skin and enter the bloodstream. There even have been cases of infant intoxication or death resulting from being wrapped in alcohol soaked bandages as an attempt to reduce fever. (This effect is compounded by inhalation due to rapid breathing of the evaporating alcohol (cf., Arditi & Killner, 1987)). Recently, researchers have been studying the transdermal route of administration for drugs that need to be administered in continuous low dosage over long periods of time (e.g., certain hormones). The drug could be applied on a skin patch, which could be changed every few days or weeks as needed, thereby avoiding the necessity (or inconsistency) of frequent oral or hypodermic administration. There are a number of technical problems in developing this procedure, the most important of which are the facts that most drugs do not penetrate the skin readily, and compounds that facilitate their entry also may indiscriminately carry other substances (e.g., household chemicals, insecticides, etc.) through the protective barrier of the skin.

Drug Disposition

Getting the drug into the bloodstream is in some sense the easy part of the problem. Once there, the drug faces a morass of physiology which determines the ultimate fate of the compound. The specific action of the drug with the target tissue must be viewed within the much larger context of the distribution of the drug throughout the body.

Table 3.2
Major Routes of Drug Disposition
Protein binding
Liver Enzymes
Renal excretion
Body surface
Pools




Protein binding.

The most immediate consideration is the possibility that the drug will be bound to proteins of the blood (especially, albumin). This binding effectively inactivates the drug by attaching it to a molecule that is too large to reach the target tissue. This usually represents a dynamic equilibrium in which a portion of the drug is bound and a portion may be in the free form. The strength of this binding determines the availability of drug in the free form.

Liver enzymes.

The principle mechanism of transforming drugs from their original form is through the action of enzymes of the liver. Typically, this mechanism is viewed as the degradation and inactivation of the drug; the drug is transformed into other compounds (usually simpler) that are inactive. These compounds are ultimately excreted from the body. In some cases, however, the transformation of the drug into related compounds results in another compound that may also be effective. This transformed compound may have an action that is similar to the original compound, it may be toxic, or it may have some remotely related effect. In some cases, a knowledge of such transformations allows a drug to be administered in the form of the precursor of the desired compound. In any event, the understanding of a drug action is complicated by the fact that the drug may not stay in its original form.

Renal excretion.

The kidneys form the most common route for the exit of drugs from the body. In some cases, the free form of the drug can be excreted in the urine, while in other cases it is the product of degradation by enzymes. The efficiency of the kidneys in eliminating either the free form of the drug or the active metabolites is an important determinant of drug effects.

Body surface.

In this case, the body surface is considered in a broad sense to include both the skin and the lungs. Detectable quantities of a drug or its metabolites can be found on the skin, especially in the perspiration, but this is rarely a major route of exit. A much more rapid route of exit for some compounds is through the respiratory system. (Despite their location, the lungs are actually a major part of the body's exterior surface.) Significant quantities of some drugs may leave the system along with the water vapor of respiratory exhalation. This forms the basis of the well known breath test for alcoholic intoxication, since the concentration of alcohol in the expired air is closely related to the concentration of alcohol in the bloodstream.

Pools.

The term pools has been applied to the general concept that compounds may exist in several different compartments within the body. For example, some drugs may be distributed in equilibrium throughout the fat stores of the body. The drug that is being stored in this lipid pool is inactive, but serves as a sort of reservoir that can gradually give up its contents to the bloodstream over an extended period of time. Drugs may also be sequestered in the bladder or be chemically bound to certain cellular components. In each case, the amount of drug that is inactivated by the pool, as well as the rate at which the drug can re-enter the plasma compartment (if at all) are important determinants of the overall drug effect.

The Net Effect of Drug Entry and Exit

The existence of multiple routes by which a drug can enter or exit the bloodstream complicates the matter of drug dosage. The attainment of a specific level of drug is not like mixing a solution. It is a dynamic process that involves the entry of the drug into the plasma compartment from several different locations simultaneously and at different rates. No sooner has the drug begun to enter the bloodstream than it begins to leave, again by several simultaneous routes at differing rates. Meanwhile, some of the drug is transformed into other compounds or enters one of several pools from which it may reenter at a later time. A useful analogy may be to consider the number of spectators who actually are in their seats (receptor sites) in a stadium following an injection of people into the ball park via traffic arteries. The time of arrival is uneven, some people may be sequestered at the concession stands, locker rooms, or the parking lot, some may leave early, and others may leave late. Overall, the effect is predictable, but many factors influence the number of seated spectators at any given time.

In most cases, the combination of all of the mechanisms listed in Tables 3.1 and 3.2 leads to a gradually increasing level of drug in the bloodstream, a stable level for a time, followed by a gradual decline. The duration of each of these phases depends upon the drug, the vehicle, the initial dosage, the route of administration, and the organism's current physiology--a moving target in every sense of the word.

We turn now to some considerations of drug dosage as they interact with behavior.

B. DOSAGE AND BEHAVIOR CONSIDERATIONS

Dose-Response Curves

One of the most important principles of behavioral pharmacology is the concept of the dose-response curve. The simplest and most general expectation would be that larger dosages produce larger effects. Indeed, this is almost always true within some range of the drug dosage, but there is usually some level of dosage beyond which this relationship breaks down, and larger dosages produce progressively less of an effect or even an opposite effect.

An example of this type of dose-response relationship can be seen in Figure 3.2, which shows a schematized change in behavior as a function of various dosages of a drug. Using the same behavioral measure, other drugs would show differently shaped curves at different peak plasma levels. The important point is that the effect of a drug on a behavior cannot be stated in a simple manner: A particular drug may enhance the behavior at low dosages, have no observable effect at some higher dosage, and impair the behavior at still higher dosages. Thus, the appropriate answer to the question, "What does Drug X do to Behavior Y?" is "It depends."

This type of noncommittal answer is (or should be) commonplace in the field of behavioral pharmacology. As shown in Figure 3.3, the plasma concentration of a drug changes continuously over time, as discussed in the previous section of this chapter. If one were to transfer sections of this changing concentration curve to the dose response curve in Figure 3.2, the behavioral effect at any given time would be changing in accordance with the changing concentration curve. In fact, with a single large dosage, it would be possible to show a gradual enhancement of behavior as the drug concentration was increasing, a decline and eventual impairment of behavior as the plasma concentration reached very high levels, a return to enhanced behavior as the drug concentration began to lower, and finally a return to baseline levels as the drug was cleared from the plasma compartment completely. Thus, the effect depends not only on the amount of drug administered, but on the amount of time that has elapsed since the administration.

Given the interaction of behavior with drug dosage and the dynamic nature of the drug concentration, about the best one can hope for in terms of a stable effect is that shown in Figure 3.4. Properly spaced multiple dosages of a drug can lead to a more or less sinusoidal variation in plasma concentrations within the range of dosage that has the desired behavioral effect.

Law of Initial Values

The law of initial values was put forth many years ago during the early stages of studying the cardiovascular system. It was noted that certain drugs which reduced a rapid heart rate had no effect on the normal heart or one which was already beating slowly. Likewise, drugs that raised an abnormally low heart rate were ineffective in raising the rate of a normal heart or one which was already beating rapidly. Thus, the effect of a drug depends upon the initial value of the heart rate.

This same principle can be applied in many cases of the behavioral effects of drugs. As shown in Figure 3.5, behaviors that have a moderate baseline respond in the typical dose-dependant manner; an increase at moderate dosages and a progressive decline at higher dosage levels. Behavior that begins at high levels is less effected by low dosages and the first effect that is observed is a decline in the rate. At lower baselines, the drug-induced increase continues into higher dosage ranges before declining.

The law of initial values, as it applies to behavior, is frequently referred to as a rate dependency effect. That is, the effect of a drug depends upon the rate of behavior that is observed at the time the drug is administered. These principles certainly do not apply to all drugs, but the phenomenon is sufficiently common to make it necessary to consider the possibility whenever a new drug and behavior combination is tested.

The law of initial values interacts in a complex fashion with the concept of dose-response effects. In some sense, it is possible to hold the plasma level of a drug constant and vary the "dosage" of behavior (low, moderate, or high) that is used to assay the effects of the drug. Furthermore, there is very likely a dynamic interaction between the baseline behavior and the drug-altered behavior in that a higher rate of behavior (induced by the drug) might be less influenced by the drug.

Drugs Have Multiple Effects

It is almost a truism that every drug has multiple effects. Ideally, a drug would have only one effect, which could be used for a specific therapeutic purpose. More commonly, any given drug may have several major effects and several minor effects. As an example, a particular drug may be given as a muscle relaxant, but have a "side effect" of producing drowsiness. The same compound may be prescribed for another patient for the purpose of producing drowsiness and lowered anxiety, with a side effect of muscle relaxation. Along with these major effects, several minor side-effects might be common to both prescriptions and include cardiovascular problems, gastrointestinal upset, skin rashes, and so forth. In general, the higher the dosage, the greater the number of different drug effects.

Each of these effects and side effects may have a different dose-response curve. As a result, a typical situation might be that shown in Figure 3.6, in which a dosage prescribed for Effect A might have Side-Effect C. A dosage prescribed for Effect B would be would have Side Effects C and D, as well as the tail end of Effect A, which is labeled Side Effect E. This sort of entanglement of desired effects and side effects prevents many drugs from being marketed.

These considerations are especially important in trying to unravel the effects of a drug upon complex behavior. Consider, for example, a situation in which an animal is performing a visual discrimination that enables it to obtain food and avoid shock according to a variable interval schedule. A particular drug would very likely influence each aspect of the task (e.g., visual perception, hunger, pain threshold, memory, etc.) at differing dosages, and the rate of behavior engendered by task parameters would, in turn, interact with the drug dosage. Thus, many different combinations of observations must be made before a complete account can be given.

A specific set of examples may help to understand some of the dynamics of these dose-response curves, multiple effects, and other complications of interpretation (refer to Fig. 3-7).

Low doses of epinephrine produce a slight drop in blood pressure, whereas high doses produce a large increase in blood pressure. This curious reversal of effects can be explained as follows: The molecular structure of epinephrine allows it to interact with both alpha and beta receptors. The beta receptors, although fewer in number, are more sensitive than the alpha receptors. With low dosages of epinephrine, the beta receptors are the only ones effected and they inhibit the smooth muscles of the blood vessels causing a decrease in the pressure through vasodilation. High doses of epinephrine stimulate alpha receptors, which cause the constriction of blood vessels and a corresponding increase in blood pressure. The beta receptors are also stimulated, but their influence is overpowered by the effects of the alpha receptors. (Careful observation will show a brief reduction of blood pressure as the epinephrine first enters the system and as it is finally leaving the system, reflecting the low concentrations of the drug at these times.)

Almost exactly the same type of change in blood pressure can be observed with low and high doses of acetylcholine, but for different reasons. Low doses of acetylcholine reduce the blood pressure by acting on the muscarinic receptors which inhibit the smooth muscles of the blood vessels to cause vasodilation. High doses of acetylcholine produce a large increase in blood pressure by stimulating the nicotinic receptors of the autonomic ganglia (refer also to Fig. 1-9 and Fig. 1-12). These nicotinic receptors are much less sensitive to circulating levels of acetylcholine, but once stimulated, their effects are much more potent than those of the muscarinic stimulation. Under these conditions, the sympathetic ganglia predominate, and the resulting stimulation of the adrenal gland and release of norepinephrine from the sympathetic fibers cause an increase in blood pressure. Thus, the large dose of acetylcholine increases blood pressure indirectly via sympathetic arousal.

In these examples, we see the essence of dos-response interactions. Two completely different drugs (epinephrine and acetylcholine) produce identical profiles of change in blood pressure (a decrease at low doses and an increase at high doses.) In each instance, the reversal occurs because low doses influence one type of receptor while high doses influence a different type of receptor. Furthermore, in the case of acetylcholine, the final effect is actually due to the indirect activation of an opposing system. This particular set of results makes sense because the underlying mechanisms have already been determined. In many cases of drug and behavior interactions we do not yet enjoy this luxury.

Individual Differences in Drug Effects

The effectiveness of specific drugs can also be influenced by a wide range of organismic variables such as species, age, sex, disease status and behavioral history. In many cases, the specific origin of these differences in drug response cannot be identified, but some general comments can be made in relation to the dosage considerations discussed above. The notation of such variables as age, sex, species, and so forth does not describe the underlying cause of differences in drug response, but is rather used as a convenient label for sub-populations that may share some common physiological variable.

One of the most important physiological differences that interacts with the behavioral effects of drugs is the neurochemical status of the brain. There are well documented changes in brain chemistry during the course of development and continuing through senescence. The presence or absence of sex hormones, the environment of the organism, and the behavior that the organism engages in can all modulate these neurochemical changes. Since most of the behaviorally active drugs produce their effects through interaction with these chemical substrates, the variables that alter neurochemistry interact with drug response. It is simply easier and more convenient to specify some external variable such as age or sex, rather than attempting to outline the more directly relevant neurochemical factors.

Differences in drug response can also occur in the absence of any important differences in the neurochemical substrates. All of the ports of entry into and exit from the bloodstream vary as a function of these external variables. For example, liver function is not fully developed in the very young and no longer fully efficient in the very old. Differences in behavioral and dietary history will alter liver function, gastrointestinal function, cardiovascular efficiency and general metabolism. Body fat levels vary in response to a wide range of variables. Each of these changes has the capacity to alter the drug response through a simple shift in the time course of effective drug concentration in the bloodstream. The same relative quantity of drug might produce an increase in the behavior of a young organism, no change in adult females, and an impairment of behavior in aging males. As indicated before, "It depends."

Calculating Drug Dosages

At some point, all of these considerations of the dynamics of drug dosage must yield to a pragmatic decision. A specific dosage must be administered to a specific organism. In some sense, this involves adding enough drug to the organism's system to produce the desired concentration in a volume of liquid, the blood plasma. Since the volume of the plasma compartment is highly correlated with body weight, dosages are usually measured in milligrams of drug per kilogram of body weight (mg/kg). In the case of experimental animals, this is usually done precisely for each animal. In the case of humans who are taking pills or capsules, dosages are commonly based on average size.

Drugs differ markedly in the actual amount that is effective, ranging from millionths of a gram up to several hundred milligrams. Perhaps the most important bit of information about a particular drug is the smallest dosage that will produce a desired effect. This measure has been termed the minimum effective dosage (MED) and is usually determined empirically by administering varying dosages to a test population to calculate the minimum dosage that is effective in 50 percent of the population, the MED-50 (sometimes it is simply referred to as the ED-50). Since most drugs have the potential for lethal effects at high dosages, a second measure is calculated for the lethal dosage for 50 percent of the population, the LD-50. A safe drug is one which has a lethal dosage that is several times larger (preferably 10 or more) than the effective dose. This therapeutic ratio (LD-50/MED-50) represents the clinical safety factor of a drug. This ratio is not specific to a drug, but rather to a drug effect: A drug, for example, might have a safe ratio for use in anxiety reduction, but be dangerous in the dosage required for muscle relaxation.

C. THE BLOOD BRAIN BARRIER

All of the preceding discussion of the dynamics of drug dosage has dealt with the general concepts of the passage of drugs between the bloodstream and the tissues. Although these general principles continue to apply, behaviorally active compounds require special consideration because of some of the unique physiological aspects of the brain. In particular, the vascular system of the brain is both quantitatively and qualitatively unique.

The brain is one of the most richly vascularized organs of the body. The two internal carotids and two vertebral arteries (which supply all the blood to the brain) branch out into an extremely dense system of capillaries. Consequently, the brain is responsible for nearly twenty percent of the body's total oxygen consumption, even though it accounts for less than two percent of the body mass. Neurons are particularly vulnerable to ischemia, and such a lack of blood flow for as little as four to five minutes can lead to serious brain damage.

Ordinarily, organs that are highly vascularized receive a disproportionate share of a circulating drug, because the rate of equilibration of drug levels in the plasma and the adjacent tissue is directly related to the rate of blood flow. However, the dense capillary system of the brain is very selective in terms of the molecules that will pass through into the surrounding tissue space. Water, oxygen, carbon dioxide pass freely through the endothelial walls. Glucose, which supplies virtually all of the nutritive requirements of brain tissue, also passes through relatively freely. Thus, there is an efficient exchange of molecules that are essential for the high metabolic demands of neural tissue.

The story is quite different for other types of molecules. The capillaries of the brain have two special features that tend to prevent the passage of molecules into the adjacent tissue space. The endothelial cells that form the walls of the capillaries are densely packed, such that only small molecules can pass through the junctions. Additionally, glial cells called astrocytes surround about 85% of the surface of the capillaries, adding a lipid barrier to the system. Thus, large molecules and molecules that are not lipid soluble do not easily penetrate the brain. These special features of the cerebral vascular system have been termed the blood-brain barrier.

Another special feature of the central nervous system is the cerebrospinal fluid (csf) which fills the ventricles of the brain and central canal of the spinal cord. The csf is formed by blood vessels within the ventricular system, most notably the concentrated groups in the lateral ventricles which are termed the choroid plexus. The csf excreted by these vessels is similar to blood plasma, except for very low levels of proteins and cholesterol. It is the extracellular fluid of the brain, which is formed continuously and absorbed (by the arachnoid villi) at a rate of about 10% per hour. Thus there is a continual flow of the fluid which bathes the brain cells. The capillary walls of the choroid plexus have the same dense epithelial structure as those within the brain tissue proper, hence provide an extension of the blood-brain barrier.

The blood-brain barrier should not be viewed as a system which isolates the brain, but rather as one which buffers it from the changing conditions of the remainder of the body (see Fig. 3.8). The critically important ions that determine the electrical excitability of neurons (Na+, K+, Ca++, and Cl-) equilibrate with the brain fluids very slowly, requiring as much as 30 times longer than in other tissues. Relatively small molecules such as urea are exchanged rather freely with muscle tissue and other body organs, but enter the brain very slowly over a period of several hours. Larger molecules such as bile salts and circulating catecholamines (from the adrenal glands and peripheral autonomic nervous system) are essentially blocked from entering the brain. (However, the acidic precursors of brain transmitter amines such as L-DOPA and 5-hydroxy tryptophan enter readily.) Thus, the brain is protected from fluctuations of chemicals in the plasma compartment, allowing homeostatic processes a considerable margin of time to correct any deviations while the brain's environment remains relatively constant.

The physiological paradox that arises is that a buffer system between the fluctuating physiology of the organism and the brain also buffers the information that the brain must use to guide the correction of the homeostatic deviations. This paradox has apparently been resolved by the presence of a group of structures called the circumventricular organs. As the name implies, these organs lie adjacent to the ventricular system of the brain and more importantly, lie outside the blood brain barrier. There are five such organs, each of which appears to have specific chemical receptors to monitor changing body conditions and relay the information to other areas of the brain: The subcommissural organ and subfornical organ are responsive to levels of angiotensin and plasma volume, respectively, and are important in the regulation of thirst for the maintenance of body water and electrolyte balance. The posterior pituitary is responsive to a variety of pituitary, adrenal, gonadal and hypothalamic hormones, and helps to regulate the circulating levels of all of these. The pineal gland is involved in circadian rhythms. The functional importance of the supraoptic crest is uncertain.

The nature of the blood brain barrier poses a number of problems in terms of the behavioral response to drugs. In the most extreme cases, some compounds simply do not enter the brain in significant concentrations. In other cases (e.g., dopamine or serotonin), the relevant compound per se does not enter, but the precursor molecules can be administered to facilitate the synthesis of the active form within the brain. The compounds can also be injected directly into the brain or CSF, physically bypassing the barrier, but several compounds have so called paradoxical effects on brain tissue. For example, penicillin produces convulsions, epinephrine in the ventricles leads to somnolence, and curare can lead to seizures. Aside from some general guidelines relating to molecular size and lipid solubility, it is difficult to predict with accuracy how easily a drug will penetrate the brain and what the effect will be. In many cases, it is necessary to make an empirical determination.

A more subtle aspect of the blood brain barrier is that it is differentially effective in different areas of the brain. The white regions of the brain are composed mainly of fibers, which are surrounded by glial cells to form the myelin sheaths. As a result of this additional lipid barrier, these regions of the brain reach equilibrium with certain drugs much more slowly than the cellular regions of grey cortex. To the extent that these different areas serve different behavioral functions or are differentially sensitive to the drug, the overall response to a drug dosage over time will become increasingly complicated.

Finally, the blood brain barrier changes as a function of organismic variables, the most important of which is probably age. The myelinization of fibers appears late in the course of ontogenetic development. Consequently, young organisms are frequently responsive to drugs that are ineffective in adults. Furthermore, the completion of the process of myelinization is not uniform throughout the brain, so that organisms of different ages would have different concentrations of drug in certain brain areas that were not fully myelinated.

On the bright side, the blood brain barrier can be a useful stage for certain types of experiments. One of the best known is that involving drugs that block the acetylcholine receptor. The systemic administration of such compounds (e.g, atropine or scopolamine) influences not only the brain, but also the entire parasympathetic division of the autonomic nervous system. Are the resulting effects due to brain actions or the effect upon the peripheral system? The addition of a methyl group onto the nitrogen of these compounds (methyl atropine or methyl scopolamine) forms a compound that is very similar in terms of its effects in the periphery, but it will not cross the blood brain barrier. Thus, if the centrally active form produces an effect that the methylated form does not, a reasonable conclusion is that the effect is caused by the action of the drug on the brain.

D. CLASSIFICATION OF DRUGS

Methods of Classification

One of the most important contributions of the scientific method is that of classification. Through the process of classification, chaos turns into order and mountains of individual facts turn into simple concepts. As examples, we have the organization of plants and animals into an organized system that defines genera, orders, families and species of animals. We have the periodic table that organizes elements on the basis of their subatomic structure. In each case, the classification results in a system that both facilitates memory and increases our understanding of the interrelationships among the various subcategories--the concepts of mammals and heavy metals provide insights that might not be apparent from the particular examples of llama and lead.

The goal of the field of behavioral pharmacology is to organize and classify behavior and drugs into systems that will enhance our understanding of the relationships between chemistry and behavior. At the present state of development of this discipline, there are numerous schemes for organizing the available information, and none of these is as discrete and well organized as the systems for organizing chemical elements and species. An additional hundred years or so of research will certainly improve this situation, but we already have some useful systems of classification that guide our research efforts and our thinking in this area.

There are three major methods of classifying drugs: (a) behavioral, (b) biochemical, and (c) structural. Table 3.3 shows a few representative selections for each type of classification. This table is by no means exhaustive, but simply shows the types of considerations that go into each scheme of classification.

Table 3.3
Drugs Classified by

Molecular Structure

Drugs Classified by

Biochemical Actions

Drugs Classified by

Behavioral Effects

amino acids receptor blockers stimulants
monoamines mimickers sedatives
benzodiazepines synthesis inhibitors hallucinogens
alcohols false transmitters antidepressants




Behavioral categories.

The classification that we are most interested in is that involving the behavioral effect of the drug. Drugs are administered to produce some alteration in behavior (or physiology) such as increasing arousal level, combating depression, lowering blood pressure, and so on. As information about the effect of each particular compound becomes available, the name of the drug can be added to the list pertaining to each desired effect.

This method of classifying drugs by their behavioral action is probably the oldest method used. As indicated in Chapter 1, early practitioners discovered various herbs and chemical preparations that produced specific effects. This method has limitations, however, in that the categories that define behavioral change may not always be sufficiently specific and any particular compound may have several different effects.

Biochemical categories.

An alternative scheme of classification is to determine the biochemical effects of the drugs. That is, the drug action rather than the drug effect. This is probably the most highly sophisticated scheme of classifying various drugs, and deserves some additional amplification at this point.

The headings in the biochemical scheme of classification are based on the mechanisms of chemical neurotransmission. A typical way or organizing the information is in terms of drugs that either impair or facilitate the action of a particular neurotransmitter system. Let us consider some of the logical possibilities for changing the function of a particular transmitter system (refer to Fig. 3.9):

a. Precursor compounds

In some cases, the amount of transmitter substance that is synthesized and stored for later release may be increased by injecting additional precursor molecules.

b. Synthesis blockade

A drug may interfere with the enzymes of synthesis (Es), reducing the amount of transmitter substance that is available for release.

c. Transmitter depletion

A drug may cause the gradual and continual leakage of transmitter substance from the vesicles, resulting in an exhaustion of the transmitter stores.

d. Prevention of release

A drug may interfere with the release of transmitter that normally occurs when an action potential arrives at the terminal bouton.

e. Receptor inhibition

A drug may have chemical characteristics that allow it to occupy the receptor sites and prevent the normal transmitter substance from acting. This can occur in two separate ways: Some drug molecules occupy the receptors in a reversible manner, and simply compete with the real transmitter molecules for access to the receptors (competitive inhibition). Other drug molecules may alter the physical shape of the receptor so that the real transmitter no longer fits, thereby reducing the total number of functioning receptor sites (noncompetitive inhibition).

f. Mimicking

A drug may have chemical characteristics that allow it to occupy the receptor sites and stimulate the postsynaptic membrane in a manner comparable to that of the naturally occurring transmitter.

g. Inactivation blockade

A drug may interfere with the enzymes that normally degrade the transmitter substance (Ed). In low dosages, this can increase function, but if the accumulation of transmitter is too great, the continuous stimulation can actually block function by preventing repeated action potentials.

h. Reuptake blockade

This is functionally equivalent to item g above, but occurs in those systems in which the transmitter is inactivated by the process of re-uptake rather than enzyme degradation.

i. False transmitters (-)

A drug may be taken up by the cell, stored in the vesicles, and released along with normal transmitter during normal stimulation. To the extent that the drug molecules are less effective, or actually block receptors, the level of function will be reduced.

j. False transmitters (+)

This is identical to item i, except that some drugs may be more effective than the naturally occurring transmitter and increase the level of function upon release.

k. Conduction blockade

Some drugs may prevent the action potential from being conducted down the axon to the terminal bouton. In these cases, the entire synaptic region may be functionally normal, but is rendered nonfunctional because stimulation cannot occur. These drugs are usually not specific to a particular transmitter system, but are more likely to be selective in terms of metabolic properties, as in the case of some local anesthetics that influence primarily fibers of small size.

As indicated in earlier sections, most drugs have multiple behavioral effects which may be due to multiple biochemical actions. Drug dosage would interact in a complex fashion with neuronal function in those cases, for example, in which low levels of the drug blocked re-uptake while higher levels also mimicked the real transmitter. Also, as indicated in items f, g and h above, excessive stimulation can result in a functional blockade.

Structural categories.

The third column in Table 3.3 includes categories that are based strictly on the molecular structure of the drugs. This column by itself provides no information at all about either the biochemical action of the drug or the behavioral (physiological) effect of the drug. As we will see below, it becomes useful only when used in the context of the other two columns.

Categories are Useful in Understanding Drug Effects

Therapeutically, the second and third columns of Table 3.3 are completely irrelevant. It would be possible to list the names (or numbers, for that matter) of compounds that are known to have each desired behavioral effect. The drugs could be prescribed solely on the bases of their effects and nothing more need be known. Indeed, this accounts for a large portion of day-to-day therapeutic decisions. Yet, it is an unsatisfactory (and potentially dangerous) state of affairs if this is done in the absence of an understanding of how the drugs interact with the brain and behavior. We will now examine more carefully the progression from a simple, pragmatic practice of therapeutics to a more fundamental understanding of the drug interactions with the brain and behavior.

The complexity of understanding drug effects arises from the fact that any drug produces multiple changes in behavior and different drugs may produce similar changes in behavior. For example, Drug A may reduce depression and also cause tremor. Drug B may be equally effective in reducing depression, but also cause drowsiness. Why?

The answer to this question must be sought at another level of analysis. Typically, researchers would determine the relationship between the biochemical actions of Drug A and Drug B. If both drugs interfere with the reuptake of Transmitter X, then one can postulate that Transmitter X may be the basis for the mutual effect of combating depression.

A test of this postulation might involve moving over to the third column of Table 3.3 to compare the molecular structure of Drug A and Drug B. If these compounds are similar in structure, then additional compounds (Drug C and Drug D) may be synthesized and administered to determine their behavioral effects on depression and their biochemical actions on Transmitter X.

Figure 3.10 schematizes this procedure of interrelating molecular structure, biochemical activity and behavioral effect. This process forms the basis for all of our research and can sometimes lead to a relatively complete understanding of the chemical bases of behavior. For example, an entire group of compounds may differ only in terms of the length of the carbon chain that is attached to a common triple-ring structure. If the effectiveness of these compounds in blocking the reuptake of Transmitter X is related to the length of this side chain, then something has been learned about the biochemical specificity of this reuptake mechanism.

This type of information is called the structure-activity relationship and has been determined for a number of different systems as will be seen throughout the text. For example if the same compounds that are most effective in blocking reuptake are also most effective in combating depression, then it seems likely that depression may be related to the level of functioning of this particular transmitter system. Additional compounds (e.g., compounds that mimic the transmitter or increase the synthesis) may be studied to further evaluate the hypothesis. The resulting description of the relationship between drug and behavior is far more useful than a simple catalogue of drugs and drug effects.

We have examined some of the basic principles for the organization of the brain and behavior, some of the considerations that go into the study of drug effects, and some of the considerations that go into classifying drugs for purpose of therapeutics and research. The next section of the text will study specific areas in which these principles have been especially useful in furthering our understanding of the chemical bases of behavior.

E. SUMMARY


Principles


1. Drug molecules must reach the appropriate target tissues before they can become effective.

2. The accessibility of the drug molecules to the target tissue is largely determined by the amount of drug in the bloodstream.

3. Drug molecules may be injected directly into the bloodstream, but they are more commonly administered by indirect routes such as oral ingestion.

4. Once the drug has been administered, a host of physiological factors determine the how fast the drug molecules enter and exit the bloodstream.

5. Different dosages of a drug change not only the magnitude of the drug effect, but also the nature of the drug effect.

6. All drugs have multiple effects, and the term side effect is usually applied to an effect that is not desired.

7. Individual differences such as behavior, gender, age and general health status all influence the effectiveness of a drug.

8. The blood brain barrier provides a buffer between the central nervous system and the remainder of the organism's physiology.

9. The classification of drugs according to biochemical actions and molecular structure contributes to the development of new drugs and a better understanding of the chemistry of behavior.

Terms

Active transport

Astrocytes

Blood-brain barrier

Body surface

Cerebrospinal fluid

Choroid plexus

Circumventricular organs

Competitive inhibition

Dose-response curve

Drug action

Drug effect

False transmitter (+/-)

Hypodermic

Inhalation

Interstitial fluid

Intraarterial

Intracerebral

Intracisternal

Intracranial

Intraperitoneal

Intrathecal

Intravenous

Ischemia

Law of initial values

LD-50

Lipid soluble

Liver enzymes

MED-50

Membrane pores

Mucous membranes

Noncompetitive inhibition

Oral

Organismic variables

Pools

Precursor

Protein binding

Rate dependency

Rectal

Renal excretion

Side effects

Structure-activity relationship

Subcutaneous

Therapeutic ratio

Transdermal

transpleural

vehicle