CHAPTER 11 Introduction to Central Nervous System Drugs*
Drugs that alter synaptic function are likely to have considerable impact on neuronal activity. An understanding of these fundamental mechanisms permits appreciation of the therapeutic actions and side-effect profiles of many of the central nervous system (CNS) drugs in the brain and in the spinal cord. The interested student is encouraged to seek several excellent reviews in this area.23,30 The pharmacology of specific CNS drugs is discussed in greater detail in Chapters 12 through 21 and Chapter 23.
Early research on nervous system function involved behavioral studies in whole organisms. Observing the effects of damage to regions of the nervous system provided clues to the function of various nerve and brain structures. The development of the microscope and its use produced an explosion of interest in the cellular anatomy and structure of the normal and diseased brain. Santiago Ramón y Cajal received an early Nobel Prize in Physiology or Medicine (1906) for his use of the microscope to study the brain.
When electronic amplifiers were developed, it became possible to study the collective electrical action of many neurons (e.g., with electroencephalography or stimulus-evoked potential recordings) and individual neurons with extracellular or intracellular electrical recordings. Using these techniques, it became possible to understand the electrical properties of single nerves and synapses and to consider how these actions related to the action of the whole organism engaged in various behaviors. Hodgkin, Huxley, and Eccles shared a Nobel Prize in Physiology or Medicine in 1963 for their work on action potentials and synaptic connections.
Using these techniques, physiologists, chemists, and pharmacologists began to investigate the chemical nature of neurotransmission and brain function. Chemists produced novel agonists that were used by physiologists and pharmacologists to gain additional information about how the brain functions. With such studies, the basis for chemical neurotransmission and its regulation was explored. The biochemistry of the brain has been gradually revealed. The Nobel Prize for Physiology or Medicine in 1970 was awarded to Katz, von Euler, and Axelrod for their discoveries in the area of chemical neurotransmission.
In the last two decades the pace of discovery has accelerated considerably. Experiments that previously took years can often be performed in days. Genomic approaches allow tens of thousands of biochemical reactions to be studied simultaneously. A key development was the polymerase chain reaction by Mullis at Cetus Corp. Mullis shared the Nobel Prize in Chemistry in 1993 for his part in the invention. The invention of the gene microarray is another technology that is important in this respect.32 The data from these experiments are analyzed using computers rather than manually. These techniques are beginning to reveal how networks of genes, amino acids, proteins, lipids, sugars, and other chemicals interact to mediate the various functions of the brain. A genomic study of tissue from a patient with epilepsy revealed that the seizures were associated with excess glutamate release from the astrocytes.27
Future investigations of the brain may reveal that many chronic brain disorders result from tissue inflammation or breakdown, rather than dysregulation of a particular neurotransmitter. This hypothesis seems to be true in the case of schizophrenia and Alzheimer’s disease.32,37 In 2008, the Nobel Prize in Chemistry was awarded to Shimomura, Chalfie, and Tsien for the development of the green fluorescent protein technique, which has facilitated understanding of genetic modifications in dense tissue such as the brain. Other powerful techniques applicable to brain research are continually being developed.
The CNS integrates sensory information from the external and internal environments; maintains homeostasis through visceral and somatic secretory and motor activity; and generates memory, thoughts, and emotions. Many common diseases have their origins in CNS dysfunction, including Alzheimer’s disease, epilepsy, stroke, anxiety, psychoses, movement disorders, mental impairment, and some forms of chronic pain. In addition, the therapeutic effects or side effects of many drugs arise from alterations in CNS activity. Approximately 20% of the most frequently prescribed medications have their principal sites of action within the CNS (e.g., opioid-containing analgesics, benzodiazepines such as alprazolam, antidepressants such as sertraline and fluoxetine, and sleep aids such as zolpidem), and it is virtually certain that every practicing dentist will perform dental treatment on patients taking these drugs. This chapter reviews the anatomic, cellular, and biochemical organization of the CNS from the perspective of drug actions in the CNS. Table 11-1 lists representative drugs that act on the CNS to produce their therapeutic effects.
Several excellent texts are available that provide comprehensive descriptions of the organizational structure and pharmacology of the CNS.13,23,30,31 This section reviews only the key structural elements of the CNS most pertinent to understanding drug actions and effects.
The cerebral cortex consists of two hemispheres with deeply enfolded grooves termed gyri. The extensive folding of the cerebral cortex increases its surface area. The major divisions of the cortex are the motor cortex (which initiates and coordinates somatic muscle activity); somatosensory cortex (which processes sensory information); frontal, parietal, and temporal association/integration areas; and visual and auditory areas. More recent imaging studies have focused additional attention on deeper cortical structures, such as the cingulate, the midline cortex (the face of the cortex between the two hemispheres), the insula, and the opercular cortex (buried behind the lateral sulcus). Several of these areas are important for experiencing pain and pleasure. Together, cortical regions are involved with voluntary movement and integration of sensation, consciousness, abstract thought, memory, and learning.
A primary organizational feature of the cerebral cortex is its arrangement as a series of densely packed columns of interconnected cells. The columnar organization of the cerebral cortex is probably a major factor in the integration of neural activity. Each column is approximately 0.5 mm to 1 mm in diameter and includes 10,000 to 50,000 interconnected neurons. The classic studies by Penfield and Rasmussen40 determined the somatic representation of the human body surface on the sensory cortex (the “sensory homunculus”). These studies indicated that approximately 75% of the sensory cortex processes afferent input from orofacial structures, including the lips, jaws, tongue, and teeth. This predominant cerebral processing of orofacial sensation may contribute to the aversive anxiety that many patients have during the course of dental care.
Drugs that alter cerebral cortical activity include general anesthetics, antianxiety drugs, sedative-hypnotics, anticonvulsants, antidepressants, and antipsychotics. As detailed subsequently (and in later chapters), the sites of action and the precise biochemical mechanisms for many of these drugs are still incompletely understood. The clinical consequence of a reduction in cortical activity is generally sedation or unconsciousness, however. Administration of the inhalation anesthetic halothane reduces cerebral activity in the frontal cortex during the induction of general anesthesia.14 Opioids produce analgesia in part by binding to the cingulate and insular cortex, which play a role in registering the aversive qualities of stimuli.5
Another major organizational component of the CNS is the limbic system. It is composed of the amygdala, septum, hippocampus, hypothalamus, olfactory lobes, basal ganglia, and portions of the thalamus. These interrelated structures act to coordinate affective (i.e., emotional) sensations with motor, visceral, and endocrine functions. Many of these structures are reciprocally connected with the cerebral cortex, and some are arranged in loops. Such loops integrate the functions of different parts of the brain but can also play a role in brain disease when disturbances develop along a loop. These loops may play a role in Parkinson’s disease and drug abuse. In addition, many behavioral functions ascribed to the limbic system are linked functionally to the reticular formation. Hyperexcitation of the amygdala has been associated with panic attacks.41 The hypothalamus is important for endocrine function, but it is also an important regulator of cyclic functions such as waking and sleeping, monthly ovulatory function, and longer cycles such as yearly hibernation in animals. The study of these periodic phenomena is termed chronobiology.
Many drugs act in part by modifying the activity of the limbic system. Benzodiazepines act at several discrete sites within this system to potentiate the effects of the neurotransmitter γ-aminobutyric acid (GABA), resulting in a reduction of anxiety and the development of sedation (see Table 11-1).50 Benzodiazepines also reduce seizure activity. Endogenous ligands for the benzodiazepine receptor may be involved in the pathogenesis of epilepsy because epileptic patients have a significant reduction in benzodiazepine receptors in the cortex and limbic system.46 If administered in excess, local anesthetics such as lidocaine and the antibiotic penicillin may induce seizure activity.
A major hypothesis for some forms of mental dysfunction (e.g., schizophrenia) proposes an excess in dopaminergic activity. Several antipsychotic drugs are dopamine receptor antagonists and are thought to act at various sites in the limbic system and reticular formation. The clinical consequence of dopamine receptor blockade in these patients is the amelioration of psychotic behavior. Parkinson’s disease is associated with a chronic reduction of dopamine activity in the basal ganglia complex.55 This disease is commonly managed by the administration of drugs such as levodopa (l-dihydroxyphenylalanine, the amino acid precursor to dopamine) that increase dopamine activity. Dopamine is an important neurotransmitter in the brain reward circuitry located in the basal ganglia, and it plays a role in the development of drug dependence to cocaine and amphetamines and indirectly to other drugs.12,19
Many drugs have a site of action in the hypothalamus and related structures. The estrogens contained in many birth control formulations act in part by inhibiting release of the hypothalamic gonadotropin-releasing hormone and luteinizing hormone and follicle-stimulating hormone, preventing ovulation. In addition, alcohol-induced diuresis results from inhibition of the release of antidiuretic hormone (also known as vasopressin). Diabetes insipidus is the clinical disease caused by chronically diminished release or activity of antidiuretic hormone.
The midbrain and brainstem regions consist of the mesencephalon, pons, medulla, reticular activating system, and most of the cranial nerve nuclei, including the trigeminal nuclei. This region processes sensory information from the viscera, coordinates visceral (i.e., cardiovascular, pulmonary, and gastrointestinal) systems, and integrates various reflexes (e.g., swallowing and vomiting). In addition, the reticular activating system is implicated in the maintenance of arousal and development of sleep. Damage to small areas of the brainstem can be lethal if they interfere with cardiovascular or respiratory control. The reticular activating system is sensitive to many drugs, including most CNS depressants.7
Several drugs have major sites of action within midbrain and brainstem structures. Opioids such as morphine produce analgesia in part by activating opioid receptors located in the periaqueductal gray region, locus coeruleus, and nucleus raphe magnus. In addition, the antihypertensive drug clonidine is an α2-adrenergic receptor agonist whose therapeutic effect results in part from stimulating α2-adrenergic receptors in the medulla oblongata.
Not all drug effects in the CNS are considered therapeutic. Opioid-induced emesis is caused by activation of receptors located in the chemoreceptor trigger zone of the medulla. This side effect is especially prominent in ambulatory patients, whose walking increases activity in the vestibular system. This interaction between drug effect and neural input is the rationale for instructing patients in acute pain receiving opioid analgesics to avoid excessive motion to minimize nausea and vomiting.
The spinal cord is involved with the processing and modulation of general sensory information (e.g., touch, heat, cold, pressure, and pain), somatic motor activity, and skeletal and visceral reflexes. Numerous drugs are thought to activate spinal cord mechanisms. Opioids produce analgesia in part by stimulating receptors located in the spinal dorsal horn. (An analogous site of action for opioid inhibition of trigeminal pain involves interaction with receptors located in the medullary dorsal horn, as mentioned in Chapter 20.) This site of action is the basis for the administration of opioids through epidural catheters to elicit spinal analgesia. In addition, the epidural administration of local anesthetics such as bupivacaine is commonly used for the production of regional anesthesia in surgical and obstetric procedures. More recent studies suggest that nonsteroidal anti-inflammatory drugs produce analgesia after intrathecal injection, suggesting that these drugs have both central and peripheral sites of action.
The CNS is isolated from the rest of the body by the blood-brain barrier. Endothelial cells of the brain capillary system are modified by numerous tight junctions and are surrounded with extensive perivascular astrocytic processes. These modifications prevent the free diffusion of many substances into the CNS. Lipid solubility is a key factor in dictating the CNS actions of many drugs. Drugs that are highly lipophilic (e.g., thiopental, diazepam, nicotine, and heroin) easily cross the blood-brain barrier and have a rapid onset of action. In contrast, hydrophilic drugs (e.g., dopamine and some antibiotics) are largely excluded by the blood-brain barrier, minimizing their therapeutic effects in the CNS. Many drugs are “relatively” excluded from the brain, meaning that their onset of action may be delayed, but they eventually cause significant CNS effects. Morphine is relatively excluded from the brain and reaches a peak effect about 1 hour after administration.
There are some holes or “windows” in the blood-brain barrier. One such site is near the area postrema. This area is near the vomiting center, and drugs or other chemicals in the blood can quickly pass to the center and produce nausea and vomiting. Other “windows” include the subfornical organ and the organum vasculosum of the lamina terminalis.
Transporter proteins can accelerate the movement of some molecules into or out of the brain. The treatment of Parkinson’s disease provides an example. An amino acid transport through the blood-brain barrier transports hydrophilic levodopa into the brain.
The blood-brain barrier is not completely developed at the time of birth, and many drugs administered to neonates achieve greater concentrations in the CNS than occur in older children or adults.29 Numerous other conditions can produce a temporary breakdown of the blood-brain barrier, which can increase the penetration of drugs such as morphine and antibiotics into the brain. Some of these conditions include hypertension, inflammation, hypercapnia, osmotic stress, multiple sclerosis, and hyperthermia.
Assessment of brain function in health and disease is important for understanding and treatment of various nervous system conditions. Early techniques for assessing brain disorders included x-ray images of the head and monitoring electrical activity on the scalp using electroencephalography. Computer-assisted tomography visualization of the interior of the skull became feasible with the advent of powerful and inexpensive computers. McCormick, who was credited with the development of mathematical algorithms for reconstruction of brain images in the 1960s, shared the 1979 Nobel Prize in Physiology or Medicine with Hounsfield, who developed a working computed tomography (CT) machine, which he used to study the brain. CT allowed the interior of the head to be represented as shades of gray, which basically represent the structures inside the head. Swollen ventricles or hematomas are readily apparent.
Tomographic reconstruction was subsequently extended to other forms of detectable energy. Chemicals labeled with positron emitting isotopes can be visualized based on the geometry of their emitted radiation, which permits back calculation of the point of origin. This technique is referred to as positron emission tomography (PET); a less expensive variant is single-photon emitted computed tomography (SPECT). Most of the energy in the brain is needed for the Na+,K+-ATPase pumps that maintain the membrane potential. Monitoring glucose, oxygen, or adenosine triphosphate (ATP) permits functional assessment of the activity in the brain.49 An early functional PET scan used fluorodeoxyglucose to follow glucose use.4 Labeling compounds that bind selectively to known proteins, such as the dopamine uptake transporter, permitted the visualization of its brain binding sites.55 In Parkinson’s disease, these techniques show a loss of dopamine uptake in the basal ganglia. Although these results were exciting, they also were limited to fuzzy images.
Another kind of radiation, radio waves, can be induced to be transmitted from the brain by placing the brain in a powerful magnet that causes the nuclei of atoms to align. When a probing radiofrequency signal is applied, the nuclei shift to an energized state, and when the radio signal is turned off, the nuclei return to a lower energy state and emit radiofrequency radiation that can be localized with greater precision than with earlier techniques. This imaging technique is known as magnetic resonance imaging (MRI). MRI carries additional information about the environment of the molecule releasing the radiation, and water, oxygen, and fatty tissues can be distinguished with MRI. A further refinement of this technique is known as functional MRI. With functional MRI, the function of the tissue (the neural work) can be represented. One popular functional MRI technique is blood oxygenation level dependent (BOLD) functional MRI. BOLD detects levels of oxygen saturation in regions of the brain that vary with brain activity. A further application of the MRI signal is diffusion tensor imaging (DTI). With DTI, it is possible to map nerve pathways within the living brain. This technique uses the constraints in movement of water molecules in long skinny neurons. This technique can be used to determine if damage has occurred to the nerve tracts.
Functional MRI and DTI are primarily experimental techniques at this time but are likely to move into the clinic.33 One problem with these techniques is temporal resolution; they require a few seconds to get enough information for an image. Magnetoencephalography is a new technique with a temporal resolution of 2 msec and may be useful when faster techniques are needed.
Typically, neurons are composed of three primary regions: the soma, or cell body; the dendrites, which are projections that primarily receive synaptic input from other neurons; and the axon, which transmits information from the cell body to other neurons. Similar to other cells in the body, the soma contains the nucleus and the Golgi apparatus. The various vesicles and proteins that are needed by the cell are primarily synthesized in the cell body and distributed to the other parts of the cell by transport processes. A critical region of the neuron is the axon hillock, the junction between the cell body and the axon. The axon hillock region (initial segment) has enriched numbers of voltage-gated Na+ channels and is typically the site at which the action potential depolarization begins. The terminal end of the axon may contain arborizations of the axon termed the telodendria. This region determines the extent to which the information sent on the axon spreads out (collateralizes) as the signal reaches its target.
Communication within the CNS incorporates digital and analog encoding.13,30 The digital encoding consists of the frequency of action potential depolarizations that are conveyed along the plasma membrane of the axon. Axon potentials are termed all or none, meaning that when the threshold for triggering an action potential is reached, the cell generates a complete action potential, whose maximal voltage is consistent for its travel down the axon. The major pharmacologic intervention for this form of signal encoding is the use of drugs that block ion channels, preventing the initiation and conduction of action potentials. The blockade of Na+ channels by local anesthetics is a primary example. The CNS effect is the basis for many of the toxic effects of local anesthetics (e.g., sedation, convulsions).
Typically, axons contain voltage-gated ion channels. These are needed for a patch of the neuron to carry an action potential, a regenerating electrical signal. Regenerating action potentials enable the neuron to send information over long distances without degradation. The sciatic nerve projects from the spinal cord to the tip of the toes, a distance that is equal to thousands of axon diameters. Axons can be unmyelinated or myelinated. Unmyelinated axons act like a burning fuse; the signal is passed from one region of the membrane to the next by the voltage from an active region exceeding the threshold for “depolarization” of the next region causing it to produce its own action potential. This is a relatively slow conduction process. Myelinated axons have regions of the nerve membrane covered by lipid layers that act as electrical insulators. In between the myelinated patches are nodes of Ranvier, which are short gaps of exposed nerve membranes enriched in voltage-gated ion channels. In myelinated neurons, the action potential “hops” down the axon (saltatory conduction) skipping the myelinated regions but depolarizing the nodes. This movement produces a faster nerve conduction rate and saves energy needed to repolarize the nerve membrane.
In the CNS, dendrites typically do not have the components needed to produce action potentials. These regions of the cell typically conduct information by analog (or passive) potentials. Analog signals are voltages developed on the nerve membrane that spread out on the membrane as though it were a leaky cable following Ohm’s law. Typically, these signals are large near their source but decline exponentially with distance from the source of the electrical stimulus. For dendrites the source of the electrical stimulus is typically synaptic connections. Analog signals in the dendrites can combine additively so that the voltage wave that reaches the initial segment is an integrated value of all of the signals applied to the dendrites.
Active membrane and passive membrane regions of neurons are distributed by functional need, rather than by the structure of the neuron. Typical neurons in the CNS include the pyramidal cells of the cortex or the cerebellum. These neurons have extensive dendritic arborizations that receive axonal input from many other cells. The integrated information on the dendritic tree is conducted by passive potentials to the cell body and axon hillock. When these potentials reach a depolarization threshold, the axon hillock depolarizes, and the action potential rapidly conducts the signal down the long axon to the telodendria inducing the release of neurotransmitter from the presynaptic nerve endings.
In most cases, the dentist will be concerned with sensory primary afferent neurons. Here the structure is quite different. These cells are termed bipolar cells or pseudobipolar cells. The part of the neuron that conducts the information from the innervated tissue to the CNS is the axon; the cell body is displaced from the projecting axon by a short stalk in the trigeminal or dorsal root ganglion and is not essential for integrating information. Instead the information is conducted directly from the periphery to the dorsal horn of the spinal cord. For these sensory nerves, the neuron is specialized for transferring signals from the periphery to the spinal cord with minimal opportunity for integration or crosstalk.
The cell body is the primary source of organelles and transmitter molecules needed by the neurons. Ion channels and other essential molecules need to be transported from the cell body to other parts of the cell by transport processes. The transport process in the neuron is analogous to a toy train. Filaments or microtubules (e.g., tubulin, actin) in the cells act as miniature tracks. Molecules similar to muscle proteins act as tiny locomotives termed Kinesins. Organelles or their subunits are attached to the Kinesins and are pulled along the tracks using ATP for energy. By a similar process, the peripheral part of the nerve can also send cargo back to the nucleus. To return materials from the nerve ending to the nucleus (retrograde transport), a different locomotive is used (dynein proteins).
Uncharacteristic of a pyramidal neuron in the brain, the primary afferent neuron releases biologically active compounds at both ends of the cell—that is, within the brainstem but also at the sites of sensory input.43 In the brainstem, these chemicals (glutamate, substance P, calcitonin gene–related peptide) are considered neurotransmitters. These substances are also transported to the site of an injury, however, and mediate inflammation and chemotaxis of inflammatory cells. Similarly, the transient receptor potential vanilloid 1 receptor, a nonspecific ion channel that mediates the burning pain associated with hot chili peppers,54 is present in the dorsal root ganglia and transported to the peripheral nerve ending and the spinal cord.26
The use of local anesthetics helps to relieve pain by reducing the release of proinflammatory-mediators and hyperalgesia-mediating chemicals. Neurotrophins (e.g., nerve growth factor and brain-derived neurotrophic factor) are synthesized in the skin and macrophages where they bind t/>