Drugs that provide pain relief. Analgesics can be subdivided into narcotic and nonnarcotic medications. Narcotic drugs are derivatives of opium, such as morphine and codeine. Nonnarcotic medications are useful in treating pain and inflammation. They also have antipyretic activity.

Anesthetics

Drugs that depress the nervous system. Anesthetics can be divided into local and general anesthetics. General anesthesia causes total loss of consciousness and reflexes, which results in the absence of pain perception. Local anesthetics are applied to a specific site and decrease pain perception at the specific site and do not affect level of consciousness. Both types of anesthetics are often used during surgical procedures.

Antidepressants

Drugs that can alter levels of certain neurotransmitters, in particular, norepinephrine and serotonin, within the brain. Depending on the class of antidepressant, they can either inhibit the reuptake of neurotransmitters or decrease their degradation, ultimately allowing for increased levels of neurotransmitter at the nerve terminal.

Antipsychotics

Drugs used to treat psychotic disorders, such as schizophrenia. Antipsychotics affect primarily the neurotransmitter dopamine.

Anxiolytics

Minor tranquilizers. Anxiolytics are drugs used to treat several conditions, including anxiety disorders and insomnia. The most common class of anxiolytics is the benzodiazepines. They bind to the γ-aminobutyric acid (GABA) receptor to increase the inhibitory actions of this neurotransmitter.

Central nervous system (CNS)

The brain and spinal cord make up the functional components of the CNS. The spinal cord provides nerve fibers that transport signals to and from the brain. The brain largely comprises three components: cortex, midbrain, and brainstem. Together, these provide for all conscious and subconscious functions of the body.

Cholinesterase inhibitors

Drugs that block the activity of cholinesterase, an enzyme that inactivates the neurotransmitter acetylcholine. Acetylcholine is found at nerve terminals in both the CNS and the peripheral nervous system. Cholinesterase inhibitors are used in the treatment of dementia to slow the progression of cognitive decline.

Conscious sedation

Method used during certain invasive procedures. The goals of conscious sedation are to decrease the level of consciousness and relieve anxiety and pain, while allowing the patient to follow verbal commands. Conscious sedation is achieved through the use of several classes of drugs, including benzodiazepines and narcotic analgesics.

Mood stabilizers

Drugs used primarily to treat bipolar disorders.

Neurotransmitter

Chemical substance that allows neurons to transmit electrical impulses throughout the CNS and peripheral nervous system. The action of the electrical impulse is determined by the chemical structure of the neurotransmitter and the receptor to which it binds.

Stimulants

Drugs that increase activity of the brain. Stimulants can be divided into two classes: amphetamines and respiratory stimulants. Amphetamines cause increased wakefulness, improved concentration, and appetite suppression. Respiratory stimulants include doxapram, xanthines, carbonic anhydrase inhibitors, salicylates, and progesterone.

The most widely used drugs, both therapeutic and recreational, are agents affecting the central nervous system. Humans are intrinsically concerned with and perhaps even defined by the processes of thinking and feeling. These processes originate within the brain. Thoughts and feelings, although poorly understood, reside primarily with neurochemical interactions and balance in the brain. Drugs that affect the central nervous system (CNS) are used for their effects on perception and mood. Although the gross anatomy of the brain has been elegantly described, the complex interaction of various brain areas and individual neurons is less well understood.

Generally, the cortex, or outer covering, of the brain is considered to be the location of thought, memory, self-awareness, and personality. Perception of sensation and control of body movement, including speech, are also represented in specific areas of the cortex. The midbrain functions as a relay station for information traveling to and from the cortex. It also integrates and modulates autonomic functions; this function occurs primarily in the hypothalamus. The brainstem, or medulla, contains the control areas for autonomic functions such as breathing and cardiovascular control and the areas responsible for alertness, the reticular activating system. The spinal cord enters the brain at the brainstem, and the cerebellum, immediately behind the brainstem, affects fine motor control and coordinates movement.

Much of our understanding of brain organization and function comes from removing areas of brain and identifying resulting deficits in animals. Some information has been acquired by studying humans who have had strokes or destructive brain surgery. These observations have led to a general understanding of functional neuroanatomy and recognition that the brain can recover significant function after damage to important areas.

Individual neurons have a wide array of connections with many different neurons in diverse areas of the brain; this is more complicated than the gross anatomy would suggest. These patterns are different in different individuals and change with time in the same individual. Many functions apparently are represented in multiple ways, making them resistant to damage. Although the number of individual neurons does not increase in adulthood, the brain is able to change and increase the number of connections and complexity of the neuronal circuitry throughout life. Although each neuron releases only a single neurotransmitter and occasionally a coneurotransmitter, the actual effect of these neurotransmitters on the next neuron is modified by additional presynaptic and postsynaptic neurons, which may inhibit or augment the primary neurotransmitter effect.

Several diseases are apparently related to loss of particular neurons with specific neurotransmitters. Parkinson disease is caused by a loss of dopamine-containing neurons in the substantia nigra area of the midbrain. This condition is characterized by resting tremor; rigidity; bradykinesia, or slowness in initiating movement; gait disturbances; and postural instability. Treatment of Parkinson disease involves increasing the amount of dopamine contained in and released from the remaining neurons.¹^,² Some forms of depression are believed to be caused by reduced activity of norepinephrine neurons in the brain, particularly neurons in the locus caeruleus.³ There seems to be a decrease in the preganglionic augmentation effects of serotonin and in direct stimulatory effects of norepinephrine. Treatment is to restore more normal activity of the norepinephrine neurons by inhibiting the reuptake of serotonin by modulating neurons, enhancing the amount of norepinephrine released, and increasing the duration of its effects in the synapse.

Because of the diversity of neuronal connections and the plasticity of the CNS, drugs used for CNS therapy have widespread and varying effects. This functional and chemical complexity of the brain and peripheral nervous system explains why side effects and toxicities are common with CNS drug therapy.

! KEY POINT

Drugs that affect the central nervous system (CNS) are commonly prescribed. These drugs exert their effects by interacting with neurotransmission; by affecting neurotransmitter release, metabolism, or uptake; or by acting at primary or modifying receptors or transport proteins.

Neurotransmitters

! KEY POINT

Clinical effects of CNS drugs depend on the localization of specific neurotransmitters in specific brain areas.

! KEY POINT

Because the organization of the CNS is complex, the main cause of side effects of CNS drugs is their interaction in diffuse brain areas.

! KEY POINT

CNS drugs may increase or decrease individual neuronal activity. The balance of activity of different types of neurons seems to affect brain function and mood. Restoration of this balance is the goal of treatment of mood disorders.

Each neuron releases predominantly one type of neurotransmitter from its axon to synapse with the next neuron. If enough receptors are activated on the postsynaptic membrane, electrical depolarization occurs, and a signal is passed to the next neuron. The functional anatomy and components of neurotransmission are illustrated in Figures 20-1 and 20-2. Released neurotransmitters are bound to and transported by proteins in the synapse, taken back up by the releasing nerve terminal, repackaged into vesicles, and recycled. Bound neurotransmitters are unavailable for receptor interactions, and alterations in the transport proteins in amount or affinity affect the signal propagation potential. Some of the released neurotransmitter is metabolized by membrane-bound enzymes on the postsynaptic cell membrane. The resulting constituent components are taken up presynaptically and used as precursors for neurotransmitter synthesis. Receptors on both the presynaptic membrane and the postsynaptic membrane specific for the released chemicals and for other chemicals from modulating and neighboring neurons affect the activity of the neuron.

Figure 20-1 Schematic of components of neuron-to-neuron communication. Neurotransmitter is synthesized in the nerve and transported and stored in the nerve terminal. Other components of neurotransmission include transport proteins *(TP)* in the synapse, receptors *(R)* on the postjunctional membrane, receptors *(R)* on the prejunctional membrane, membrane-bound enzymes *(ENZ),* and modifying neurons.

Figure 20-2 Schematic for pathways that neurotransmitters follow after release into the synapse. After axonal depolarization, stored neurotransmitter *(NT)* is released into the synapse *(1),* where it is bound to the transport or carrier protein *(TP)*. NT is transported to and binds with postjunctional receptors *(2),* is metabolized by membrane-bound enzymes *(2),* is actively taken up by the releasing neuron *(3),* or is released and binds to prejunctional receptors. NT substance that is degraded to its component parts is taken up by the releasing neuron to be resynthesized and reused *(4)*.

Chemicals that behave as neurotransmitters are listed in Table 20-1. The effect of the neurotransmitter released is determined by many factors, including the amount of neurotransmitter released, type and quantity of transport proteins, previous release of neurotransmitters, presence of modifying substances, efficiency of reuptake processes, and activities of modulating interneurons. Specifics of this transmission modulation system differ for various brain areas, mental functions, and neurotransmitters. CNS-active drugs may have effects on specific parts of a neurotransmitter system or have generalized effects on brain function. Augmentation or inhibition of neurotransmission can result from drug interaction at any of the sites illustrated in Figures 20-1 and 20-2.

TABLE 20-1

Central Nervous System Chemicals That Function as Neurotransmitters

CHEMICAL CLASS	NEUROTRANSMITTER
Biogenic amines	Norepinephrine Epinephrine Dopamine Acetylcholine Histamine Serotonin (5-hydroxytryptamine)

Amino acids

γ-aminobutyric acid (GABA)

Glutamate

Glycine

Aspartate

Nucleotides and nucleosides

Adenosine triphosphate

Adenosine

Peptides

Thyrotropin-releasing hormone

Luteinizing hormone–releasing factor

Corticotropin-releasing factor

Somatostatin

Secretin

Melanocyte-stimulating hormone

Psychiatric medications

! KEY POINT

Depression is a common mood disorder. Several classes of drugs, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs), are used for this disorder and exhibit a wide range of side effects.

! KEY POINT

Other psychotherapeutic drugs include major tranquilizers and sedative-hypnotic drugs.

Antidepressants

Depression is one of the most common psychiatric disorders and a major cause of worldwide disability. In the United States, the 1-month prevalence of a major depressive episode has been estimated to involve more than 2% of the population.⁴ The Global Burden of Disease Study found unipolar depression to be the fourth leading cause of worldwide disability, even after excluding deaths from suicide.⁵ The prevalence of major depressive disorder may be increasing, and it is predicted that unipolar major depression will be the second leading cause of disability worldwide by 2020.⁶

Depressive disorder has multiple etiologies, including biologic, psychological, and social factors. Serotonin and norepinephrine have been shown to be important neurotransmitters, and their relative deficiency has been linked to depression. For more than a decade, selective serotonin reuptake inhibitors (SSRIs) have been the first line of medical treatment for major depressive disorder. These drugs are preferred because they are safer and more tolerable than older medications such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). In addition, newer drugs target both norepinephrine and serotonin; they are called serotonin norepinephrine reuptake inhibitors. These drugs and their side effects are listed in Tables 20-2 and 20-3.

TABLE 20-2

Drugs Used to Treat Depression

CLASS	GENERIC DRUG	U.S. BRAND NAME
Selective serotonin reuptake inhibitors (SSRIs)	Citalopram	Celexa
	Fluoxetine	Prozac, Prozac Weekly, Sarafem
	Fluvoxamine	Luvox, Luvox CR
	Paroxetine	Paxil, Paxil CR, Pexeva
	Sertraline	Zoloft
	Escitalopram oxalate	Lexapro
Serotonin and norepinephrine reuptake inhibitors	Venlafaxine	Effexor, Effexor XR
	Duloxetine	Cymbalta
	Desvenlafaxine	Pristiq
Serotonin receptor antagonist	Nefazodone	Nefazodone
Dopamine reuptake inhibitor	Bupropion	Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban
Tricyclic antidepressants (TCAs)	Amitriptyline	Amitriptyline
	Amoxapine	Amoxapine
	Clomipramine	Anafranil
	Desipramine	Norpramin
	Doxepin	Sinequan
	Imipramine HCl	Tofranil
	Imipramine pamoate	Tofranil-PM
	Nortriptyline	Aventyl, Pamelor
	Protriptyline	Vivactil
	Trimipramine	Surmontil
Tetracyclic antidepressants	Maprotiline	Maprotiline
	Mirtazapine	Remeron, Remeron SolTab
Monoamine oxidase inhibitors (MAOIs)	Phenelzine	Nardil
	Tranylcypromine	Parnate
	Isocarboxazid	Marplan
Herbal remedy	St. John’s wort (Hypericum perforatum)	St. John’s wort
Miscellaneous drugs	Trazodone	Desyrel

CR, Controlled release; SolTab, orally disintegrating tablet; SR, sustained release (12 hour); XL, extra long (extended release 24 hour); XR, extended release.

TABLE 20-3

Incidence of Side Effects of Commonly Used Antidepressants

MEDICATION	SEDATION	AGITATION	ANTICHOLINERGIC EFFECTS*	POSTURAL HYPOTENSION	GASTROINTESTINAL UPSET	SEXUAL DYSFUNCTION	WEIGHT GAIN	WEIGHT LOSS
Serotonin and Norepinephrine Reuptake Inhibitors
*Tricyclics (Tertiary Amines)*
Amitriptyline	++++	0	++++	+++	+	+	++	0
Doxepin	++++	0	++++	+++	+	+	+	0
Imipramine	++++	0	++++	+++	+	+	+	0
*Tricyclics (Secondary Amines)*
Desipramine	+++	0	+++	++	+	+	+	0
Nortriptyline	+++	0	+++	++	+	+	+	0
*Bicyclic*
Venlafaxine^†	++	+	++	0	+++	++	0	+
Selective Serotonin Reuptake Inhibitors
Citalopram	0	0	+	0	++	+	+	+
Fluoxetine	+	++	+	0	++	++	+	+
Paroxetine	++	0	+	0	++	++	+	+
Sertraline	+	+	+	0	++	++	+	+
Serotonin Norepinephrine Reuptake Inhibitor
Duloxetine	++	+	++	+	++	+	+	+
Norepinephrine Reuptake Inhibitor, Dopamine Reuptake Inhibitor
Bupropion	+	++	++	0	++	0	+	++
Serotonin Antagonists and Reuptake Inhibitors
Nefazodone	++	0	++	+	+	0	0	0
Trazodone	++++	0	++	+	+	0	+	+

0, None; +, minimal (<5% of patients); ++, low frequency (5%-20%); +++, moderate frequency (21%-40%); ++++, high frequency (>40%).

^*Side effects may include dry mouth, dry eyes, blurred vision, constipation, urinary retention, tachycardia, or confusion.

^†Venlafaxine may cause a dose-related elevation in diastolic blood pressure; monitoring of blood pressure is recommended.

From Whooley MA, Simon GE: Managing depression in medical outpatients, N Engl J Med 343:1947, 2000.

Mood stabilizers

Mood stabilizers are used primarily for bipolar disorder. This affective disorder involves alternating episodes of depression and mania or hypomania. Mania is characterized by at least 1 week of elevated or irritable mood and at least three of the following: inflated self-esteem or grandiosity, decreased need for sleep, being more talkative than usual, rapid thoughts or the subjective experience that one’s thoughts are racing, distractibility, an increase in goal-directed behavior, or excessive involvement in pleasurable activities that have a high potential for painful consequences.⁷ Hypomania is similar to mania but less intense and of shorter duration.⁷

Medical treatment of any degree of bipolar disorder must begin with a mood stabilizer. These drugs include lithium; anticonvulsants such as valproic acid, carbamazepine, gabapentin, and lamotrigine; and antipsychotics, which are discussed subsequently. Except for lithium, the main side effect of these drugs is sedation. Lithium has a narrow therapeutic window and consequently must be used judiciously. Lithium can cause tremor, cognitive slowing, hypothyroidism, renal insufficiency, leukocytosis, polyuria, and polydipsia. Lithium toxicity can result in coma.⁸ Table 20-4 lists common mood stabilizers.

TABLE 20-4

Drugs Used as Mood Stabilizers

GENERIC DRUG	BRAND NAME
Carbamazepine	Tegretol, Tegretol-XR, Epitol, Carbatrol, Equetro, Teril
Lamotrigine	Lamictal, Lamictal XR, Lamictal CD, Lamictal ODT
Lithium	Lithobid, Eskalith
Valproic acid	Depakene, Depakote, Depakote ER, Depakote CP, Stavzor

CD, Chewable; CP, delayed release; ER, XR, extended release; ODT, orally disintegrating.

Antipsychotics

Psychotic disorders are characterized by impaired reality testing. They include schizophrenia spectrum disorders and psychosis associated with depression or mania. Pharmacotherapy is generally used to increase dopamine in the brain. These drugs are most efficacious for active psychotic symptoms, such as hallucinations and abnormal thought processes. Older drugs, such as thorazine, thioridazine, and haloperidol, had numerous side effects, which affected compliance. These side effects included extrapyramidal symptoms such as cogwheel rigidity, acute dystonia, oculogyric crisis, and cholinergic side effects. Newer agents, such as risperidone, olanzapine, and quetiapine, are more tolerable. Table 20-5 lists common antipsychotics.

TABLE 20-5

Drugs Used in Management of Psychotic Disorders

CLASS	GENERIC DRUG	BRAND NAME
Phenothiazines	Chlorpromazine	—
	Fluphenazine	—
	Perphenazine	—
	Prochlorperazine	—
	Trifluoperazine	—
Thioxanthene	Thiothixene	Navane
Butyrophenones	Droperidol	Inapsine
	Haloperidol	Haldol
Miscellaneous agents	Clozapine	Clozaril, FazaClo ODT
	Lithium	Lithobid, Eskalith
	Olanzapine	Zyprexa, Zydis
	Pimozide	Orap
	Quetiapine	Seroquel, Seroquel XR
	Risperidone	Risperdal, Consta
	Ziprasidone	Geodon
	Aripiprazole	Abilify
	Paliperidone	Invega
	Iloperidone	Fanapt

ODT, Orally disintegrating; XR, extended release.

Drugs for alzheimer dementia: cholinesterase inhibitors

Alzheimer dementia is associated with cognitive deficits secondary to decreased acetylcholine levels within the brain. Cholinesterase inhibitors improve cognition and function in patients with Alzheimer disease. These drugs include donepezil, tacrine, galantamine, and rivastigmine. The use of these drugs is sometimes limited by gastrointestinal side effects, which include nausea, vomiting, diarrhea, and hepatotoxicity, especially with tacrine.⁹ These drugs are listed in Table 20-6.

TABLE 20-6

Drugs Used in Treatment of Dementia

CLASS	GENERIC DRUG	BRAND NAME
Cholinesterase inhibitors	Donepezil	Aricept, Aricept ODT
	Galantamine	Razadyne, Razadyne ER
	Rivastigmine	Exelon
	Tacrine	Cognex
	Memantine	Namenda