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.

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.

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.

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.

Anxiolytics

Benzodiazepines are agents that have been used to reduce anxiety under a variety of circumstances. Anxiolytics are also used as amnestics, preventing conversion of short-term experience into permanent memory. By themselves, they cause no change in respiration; however, these agents may augment the respiratory depression induced by opioids. They have little effect on cardiac function and are very safe agents from this standpoint. Benzodiazepines are excellent induction agents when providing general anesthesia and are useful in preventing unpleasant recall during uncomfortable interventions. They may be used as somnifics. These agents are used to terminate seizures, and they elevate seizure threshold. Benzodiazepines exert their effects by binding to benzodiazepine receptors in the γ-aminobutyric acid (GABA) receptor complex on neurons, increasing the GABA chloride channel permeability, which hyperpolarizes the neuron, making depolarization less likely (Figure 20-3). A specific antagonist, flumazenil (Romazicon), can reverse the sedative effects of the benzodiazepines.

Several other drugs are used to treat anxiety and insomnia. Some of these are listed with the benzodiazepines in Table 20-7. Their mechanisms of action are not related to interactions with the benzodiazepine receptor or the GABA system. Some of the drugs listed in Table 20-7 are used to promote sleep; these and other nonrelated sleep-inducing agents are listed in Table 20-8. Although they induce sleep, benzodiazepines and other drug classes interfere with the normal sleep cycles by reducing the amount of time spent in rapid eye movement (REM) sleep.

Barbiturates

The barbiturates, one of the oldest groups of sedative drugs, are derived from barbituric acid. Because of their toxic potential and rapid development of tolerance, barbiturates have largely been replaced by benzodiazepines except for a few specialized uses. Ultra-short-acting barbiturates are used for anesthetic induction (thiopental, thiamylal, and methohexital), as hypnotics (pentobarbital and secobarbital), and for seizure control and prophylaxis (phenobarbital). Use of barbiturates as hypnotics is limited by rapid development of tolerance and reduction in the quality of sleep (decreased amount of REM sleep). They are potent inducers of the cytochrome P450 (CYP450) drug-metabolizing system that can alter the levels of many other drugs. Although many of the therapeutic effects of barbiturates are mediated by a specific receptor at the GABA-mediated inhibitory receptor, they have widespread depressive effects on neuron activity. Intentional or accidental overdose results in respiratory arrest and cardiovascular collapse because of depression of the brain control center. This drug class also carries a high risk of addiction and abuse. Severe withdrawal symptoms, including seizures, occur after abruptly stopping long-term use of barbiturates.

Other hypnotics

Difficulty sleeping is a common clinical complaint that frequently results in the prescription of a hypnotic. In addition to the short-acting benzodiazepines and barbiturates mentioned earlier, several other sedatives are used for inducing sleep. All of these agents disrupt sleep patterns and may not improve overall well-being. Hypnotics to induce sleep are generally recommended for brief periods (1 or 2 weeks). However, some patients continue to take these medications for years. A new drug, eszopiclone, is approved for long-term use. Medications used for sleep enhancement are listed in Table 20-8.

Nonsteroidal antiinflammatory drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) are analgesics frequently used to treat moderate pain (Table 20-9). NSAIDs work by affecting the hypothalamus and by inhibiting the production of inflammatory mediators, primarily prostaglandins, at the peripheral site of the painful stimulus. The salicylates are the oldest member of this class and have been known for more than 100 years for their effects as antipyretics. Aspirin is a common component of over-the-counter (OTC) analgesics and cold remedies. Aspirin decreases the synthesis of prostaglandin by irreversibly inhibiting two enzymes: cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2). COX-1 is located primarily on tissues, including blood vessels, kidney, and gastric mucosa, and COX-2 is associated primarily with inflammation. In contrast to aspirin, others in this group reversibly inhibit these enzymes. Although selective COX-2 inhibitors are thought to cause fewer gastrointestinal side effects, there are no clinical trials clearly showing this.²⁰

Gastric irritation and ulceration are major problems with administering NSAIDs. Renal injury can result from prolonged use and high doses of these medications. NSAIDs also inhibit platelet aggregation, and this compounds the problem of gastrointestinal bleeding. The antiplatelet effects are used therapeutically either after or to prevent cardiac thrombosis. Aspirin use in childhood febrile illness has been associated with an increased incidence of Reye syndrome, an often fatal increase in intracranial pressure associated with massive hepatic dysfunction.^21,22 Allergic reactions to NSAIDs are common. Rashes, urticaria, angioneurotic edema, asthma, and anaphylaxis have been reported.

Acetaminophen (Tylenol), although a weak inhibitor of the cyclooxygenase system, has no significant antiinflammatory effects but is effective in relieving mild to moderate pain. It does not inhibit platelets or cause gastric ulcers. In large doses, acetaminophen can cause lethal hepatic necrosis. Because it is used in many nonprescription cold preparations, accidental overdose from combined dosing during self-medication occasionally occurs. An overdose of acetaminophen can be treated with oral acetylcysteine as described on Chapter 9.

COX-2 inhibitors have been reevaluated for their potential to cause adverse cardiovascular events. Rofecoxib (Vioxx) and valdecoxib (Bextra) have been withdrawn from the market. Other COX-2 inhibitors are currently undergoing trials to assess their potential to increase cardiovascular risk.

Opioid analgesics

Opioids or narcotic analgesics are derivatives of the naturally occurring drug mixture opium, derived from the poppy, Papaver somniferum. These agents are used for the treatment of moderate to severe pain. They act by binding to opioid receptors in the brain and spinal cord. They modify pain pathways at the spinal level and profoundly influence the subjective response to pain at the cortical level. Endogenously occurring opioids, the endorphins and enkephalins, are neuromodulators affecting pain perception and mood. Opioids exert their effects and side effects by binding to receptors for these naturally occurring agents.

There are at least three distinct opioid receptors, mu (μ), kappa (κ), and delta (δ), and several subtypes. Agonist drugs may bind at one or more of these receptors, accounting for some of the differences seen in their effects. Besides pain relief, high enough doses of opioids can result in loss of consciousness and, because of a profound dose-dependent depression of respiratory drive, respiratory arrest. Opioids produce a euphoric effect on mood, making them popular drugs of abuse. Tolerance develops rapidly, and withdrawal is very painful and unpleasant. These factors contribute to the highly addictive potential of the opioids.

The μ receptor is responsible for the analgesic effects in the CNS and spinal cord. It also accounts for respiratory depression, constipation, nausea and vomiting (from the chemotactic trigger zone receptors), and antitussive effects. κ receptors located in the spinal cord and, to a lesser extent, in the CNS mediate analgesia. They may be the receptors responsible for the analgesic effects of the mixed agonist-antagonist drugs. The δ receptor is the receptor for the naturally occurring mediator enkephalin; its role in analgesia is unclear. It may be important in the spinal mediation of pain perception. This is just the outline of the opioid receptor system; there are other types and subtypes of receptors. Their actual function in human health is not understood. The effect of various opioids can be explained by their actions at one or more of these receptors.

Opioids are listed in Table 20-10. Some have pure agonist effects, acting as the endogenous mediators at the receptors, and others antagonize the endogenous mediators but have a small agonist effect (mixed drugs or agonist-antagonist drugs). There are several strictly antagonist agents. These drugs are used to reverse the analgesic and respiratory depressive effects of the opioids. The most serious side effect of opioid antagonists is respiratory depression, which is mediated by decreased sensitivity of the respiratory center to elevations in arterial carbon dioxide pressure (Paco₂). Miosis (small pupils) is pathognomonic for opioid drug administration and is a consequence of effects on the sympathetic nervous system. Constipation results from opioid depression of motility of the stomach and intestines. Nausea and vomiting are a direct effect on the brainstem effectors. Cough suppression results from a direct central effect of the opioid.

Because of their effects on pain perception, narcotics are often used as part of a balanced anesthetic. Doses that cause profound depression of respiration have minimal or no effect on cardiac function; because of this, opioids are the basis for anesthesia for patients with serious cardiovascular compromise. By themselves, opioids have no effect on consciousness or memory. Combined with small doses of benzodiazepines or gaseous anesthetics, they can be used to provide surgical anesthesia.

Strong opioid drugs are often referred to as narcotics, from the Greek word for stupor. The word narcotic has significant legal overtones. For this reason, its use has been avoided in this section. Opiates are compounds derived from opium and represent a small number of the drugs discussed in this section. The term opioids, as used in this section, implies simply that the agents interact with one or more of the opioid receptors.

Local anesthetics

Pain treatment can be achieved by blocking transmission of the pain impulse from the damaged area. Local anesthetics are used to interrupt these nervous signals. Local anesthetics produce nerve conduction block by blocking sodium channels. These are located all along the cell, including the axon. When depolarization occurs, the impulse is propagated down the axon by an abrupt increase in the membrane sodium permeability. When the drug binds to and occludes the channel pore, sodium is unable to enter the cell, and propagation of the electrical impulse is stopped. All local anesthetics consist of a lipophilic part and a hydrophilic, amine part connected by either an amide or ester linkage; this is illustrated in Figure 20-4. Table 20-11 lists several common agents. Sodium channel blockade makes some of these drugs useful in terminating cardiac conduction abnormalities in addition to providing analgesia. Some evidence suggests that systemic administration or inhalation may also enhance bronchodilation in asthma and suppress irritant tracheal cough responses. At toxic levels, CNS excitation occurs, and frank seizures may result. Epinephrine is often added to a local anesthetic for vasoconstriction to delay its absorption, prolonging its effect and decreasing blood levels and potential toxicity. Bupivacaine is very cardiotoxic, and a toxic dose may result in profound and prolonged cardiac depression or arrest.

Epidural analgesia

Continuing epidural infusions for analgesia have improved postoperative pain therapy. There is evidence that patient outcome may also be improved with epidural infusions of local anesthetics, opioids, or both^24,25; this is especially true for very ill patients.^26–29 The quality of analgesia and the ability to eliminate pain in many body areas are superior with local anesthetic infusion compared with systemic analgesics. Epidural infusions are common in some surgical procedures, especially in the delivery of newborns by cesarean section. Minimal effects on normal sensory and motor function can be achieved with very dilute local anesthetics. Addition of opioids to the mixture permits even less local anesthetic to be infused. If sympathetic blockade produces unacceptable hypotension, local anesthetics can be eliminated completely, with significant analgesia obtained with opioid infusion alone. Pain modulation from epidural opioids occurs at receptors at the spinal cord segmental level. The major side effects of epidural analgesia using local and opioid infusions are listed in Box 20-1.

Combinations of analgesic classes

Another strategy to improve analgesia and to reduce the likelihood of opioid overdose is to combine several different classes of analgesics. Prescription combinations of NSAIDs and opioids are widely available (Table 20-12). The concept of attacking pain at several places is useful, but the fixed combinations of drugs with different effects, toxicities, and half-lives make titration to an individual patient’s needs difficult with these agents. Use of the separate agents, independently titrated, may improve this problem, but it is more difficult for patients to take numerous medications.

Conscious sedation

Fear and pain are frequent side effects of many clinical interventions. Besides general anesthesia, many approaches are available to modify the unpleasant experience of diagnostic and therapeutic procedures. Patient preparation, education, relaxation exercises, hypnosis, and drugs may be useful. Conscious sedation is the term applied to pharmacologic modification of painful and frightening experiences during medical procedures. As implied by this term, sedated patients should remain conscious and able to communicate, protect their own airway, and breathe adequately. Improved patient comfort and outcome are the goals of sedation. However, because of variations in patient responses, consciousness and the patient’s ability to maintain an unobstructed airway may be lost during sedation.

Institutional standards for safe and effective provision of conscious sedation are required by the Joint Commission on Accreditation of Healthcare Organizations and other regulatory agencies. These standards must be adhered to throughout the institution, whether sedation is provided by a nurse, respiratory therapist (RT), anesthesiologist, or other health care provider. Many concerned groups have developed guidelines for providing safe conscious sedation. RTs should understand sedative and analgesic pharmacology and may actively participate in provision of conscious sedation.31–33 Because most of the serious complications of conscious sedation relate to airway compromise, RTs are uniquely qualified to safeguard patients and improve outcomes during conscious sedation.

Standards for providing conscious sedation

Most guidelines for conscious sedation and many clinical reports differentiate several levels of sedation. Often a clear distinction is drawn between conscious and deep sedation.³⁴ However, the progression from conscious sedation to deep sedation to general anesthesia is difficult to control clinically, and each deeper level implies increased risks and mandates more intensive monitoring and an increased level of support. The definitions of these states and suggested requirements for monitoring are given in Table 20-15.