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Introduction to Central Nervous System Pharmacology
Jacqueline Rosenjack Burchum DNSc, FNP-BC, CNE
Central nervous system (CNS) drugs—agents that act on the brain and spinal cord—are used for medical and nonmedical purposes. Medical applications include relief of pain, suppression of seizures, production of anesthesia, and treatment of psychiatric disorders. CNS drugs are used nonmedically for their stimulant, depressant, euphoriant, and other “mind-altering” abilities.
Despite the widespread use of CNS drugs, knowledge of these agents is limited. Much of our ignorance stems from the anatomic and neurochemical complexity of the brain and spinal cord. (There are more than 50 billion neurons in the cerebral hemispheres alone.) We are a long way from fully understanding both the CNS and the drugs used to affect it.
Transmitters of the Central Nervous System
In contrast to the peripheral nervous system, in which only 3 compounds—acetylcholine, norepinephrine, and epinephrine—serve as neurotransmitters, the CNS contains at least 21 compounds that serve as neurotransmitters (Box 16.1). Furthermore, there are numerous sites within the CNS for which no transmitter has been identified, so it is clear that additional compounds, yet to be discovered, also mediate central neurotransmission.
None of the compounds believed to be CNS neurotransmitters has actually been proved to serve this function. The reason for uncertainty lies with the technical difficulties involved in CNS research. However, although absolute proof may be lacking, the evidence supporting a neurotransmitter role for several compounds (e.g., dopamine, norepinephrine, enkephalins) is completely convincing.
Although much is known about the actions of CNS transmitters at various sites in the brain and spinal cord, it is not usually possible to precisely relate these known actions to behavioral or psychological processes. For example, we know the locations of specific CNS sites at which norepinephrine appears to act as a transmitter, and we know the effect of norepinephrine at most of these sites (suppression of neuronal excitability), but we do not know the precise relationship between suppression of neuronal excitability at each of these sites and the effect of that suppression on the overt function of the organism. This example shows the state of our knowledge of CNS transmitter function: we have a great deal of detailed information about the biochemistry and electrophysiology of CNS transmitters, but we are as yet unable to assemble those details into a completely meaningful picture.
The Blood-Brain Barrier
The blood-brain barrier impedes the entry of drugs into the brain. Passage across the barrier is limited to lipid-soluble agents and to drugs that cross by way of specific transport systems. Protein-bound drugs and highly ionized drugs cannot cross.
From a therapeutic perspective, the blood-brain barrier is a mixed blessing. The barrier protects the brain from injury by potentially toxic substances, but it can also be a significant obstacle to entry of therapeutic agents.
The blood-brain barrier is not fully developed at birth. Accordingly, infants are much more sensitive to CNS drugs than are older children and adults.
How Do Central Nervous System Drugs Produce Therapeutic Effects?
Although much is known about the biochemical and electrophysiologic effects of CNS drugs, in most cases we cannot state with certainty the relationship between these effects and production of beneficial responses. Why? To fully understand how a drug alters symptoms, we need to understand, at a biochemical and physiologic level, the pathophysiology of the disorder being treated. In the case of most CNS disorders, our knowledge is limited: we do not fully understand the brain in either health or disease. Therefore we must exercise caution when attempting to assign a precise mechanism for a drug’s therapeutic effects.
Although we can’t state with certainty how CNS drugs act, we do have sufficient data to permit formulation of plausible hypotheses. Consequently, as we study CNS drugs, proposed mechanisms of action are presented. Keep in mind, however, that these mechanisms are tentative, representing our best guess based on available data. As we learn more, it is almost certain that these concepts will be modified, if not discarded.
Adaptation of the Central Nervous System to Prolonged Drug Exposure
When CNS drugs are taken chronically, their effects may differ from those produced during initial use. These altered effects are the result of adaptive changes that occur in the brain in response to prolonged drug exposure. The brain’s ability to adapt to drugs can produce alterations in therapeutic effects and side effects. Adaptive changes are often beneficial, although they can also be detrimental.
Increased Therapeutic Effects
Certain drugs used in psychiatry—antipsychotics and antidepressants—must be taken for several weeks before full therapeutic effects develop. Beneficial responses may be delayed because they result from adaptive changes, not from direct effects of drugs on synaptic function. Hence full therapeutic effects are not seen until the CNS has had time to modify in response to prolonged drug exposure.
Decreased Side Effects
When CNS drugs are taken chronically, the intensity of side effects may decrease (while therapeutic effects remain undiminished). For example, phenobarbital (an antiseizure drug) produces sedation during the initial phase of therapy; however, with continued treatment, sedation declines while full protection from seizures is retained. Adaptations within the brain are believed to underlie this phenomenon.
Tolerance and Physical Dependence
Tolerance and physical dependence are special manifestations of CNS adaptation. Tolerance is a decreased response occurring in the course of prolonged drug use. Physical dependence is a state in which abrupt discontinuation of drug use will precipitate a withdrawal syndrome. The kinds of adaptive changes that underlie tolerance and dependence are such that, after they have taken place, continued drug use is required for the brain to function “normally.” If drug use is stopped, the drug-adapted brain can no longer function properly, and withdrawal syndrome ensues. The withdrawal reaction continues until the adaptive changes have had time to revert, restoring the CNS to its pretreatment state.
Development of New Psychotherapeutic Drugs
Because of deficiencies in our knowledge of the neurochemical and physiologic changes that underlie mental disease, it is impossible to take a rational approach to the development of truly new (nonderivative) psychotherapeutic agents. History bears this out: virtually all of the major advances in psychopharmacology have been serendipitous.
In addition to our relative ignorance about the neurochemical and physiologic correlates of mental illness, two other factors contribute to the difficulty in generating truly new psychotherapeutic agents. First, in contrast to many other diseases, we lack adequate animal models of mental illness. Accordingly, animal research is not likely to reveal new types of psychotherapeutic agents. Second, mentally healthy individuals cannot be used as subjects to assess potential psychotherapeutic agents because most psychotherapeutic drugs either have no effect on healthy individuals or produce paradoxical effects.
After a new drug has been found, variations on that agent can be developed systematically: (1) structural analogs of the new agent are synthesized; (2) these analogs are run through biochemical and physiologic screening tests to determine whether they possess activity similar to that of the parent compound; and (3) after serious toxicity has been ruled out, promising agents are tested in humans for possible psychotherapeutic activity. Using this procedure, it is possible to develop drugs that have fewer side effects than the original drug and perhaps even superior therapeutic effects. However, although this procedure may produce small advances, it is not likely to yield a major therapeutic breakthrough.
Approaching the Study of Central Nervous System Drugs
Because our understanding of the CNS is less complete than our understanding of the peripheral nervous system, our approach to studying CNS drugs differs from the approach we took with peripheral nervous system agents. When we studied the pharmacology of the peripheral nervous system, we emphasized the importance of understanding transmitters and their receptors before embarking on a study of drugs. Because our knowledge of CNS transmitters is insufficient to allow this approach, rather than making a detailed examination of CNS transmitters before we study CNS drugs, we will discuss drugs and transmitters concurrently. Hence, for now, all that you need to know about CNS transmitters is that (1) there are a lot of them, (2) their precise functional roles are not clear, and (3) their complexity makes it difficult for us to know with certainty just how CNS drugs produce their beneficial effects.
