Учебники / Otolaryngology - Basic Science and Clinical Review

This chapter is designed to present an overview of the pharmacokinetics necessary to understand the processes by which drugs of different varieties enter the human body, exert their effects, and are excreted. The subject of pregnancy as it relates to the pharmacology of drug administration will also be discussed.After this overview, several classes of drugs will be examined; namely, local anesthetics, antireflux medications, steroids, nonsteroidal anti-inflammatory drugs, analgesics, and antibiotics. The topic of antihistamines is covered in Chapter 3 on allergies.

PHARMACOKINETICS

Pharmacokinetics describes the process by which drugs are absorbed into the organism and eventually into the cell, distributed to the various compartments within the body, and ultimately excreted from the body. The activity of a given drug is dictated by the interplay of these processes.

The process of absorption actually begins not at the cell membrane but rather at the point of administration to the organism. Various factors affect this process: the solubility and concentration of the drug, the circulation at the site of absorption, the surface area for absorption and the route of ingestion. The critical step of the process of absorption is the drug’s passage across the cell membrane. The cell membrane is a dynamic arrangement of a bilayer of lipids with protein molecules either embedded in one side or completely traversing the membrane.A drug’s ability to pass through this membrane relates to the intrinsic properties of the drug as well as those of the cell membrane itself.The molecular size and shape of the drug, the solubility of the drug at the site of absorption, and the relative lipid solubility of the drug’s ionized and nonionized forms are all important factors.

Drugs can cross the cell membrane by several routes; some require energy and are therefore active processes. Others do not require energy and are termed passive. Drugs that are electrically charged and have difficulty entering into a cell are transported by carrier-mediated active membrane transport. Their passage across the membrane is linked to the passage of certain anions and cations [usually sodium (Na) and potassium (K)] and requires adenosine triphosphate (ATP). A variant of this type of transport occurs when the charged particles do not have to travel against the established intercellular electrochemical gradient and therefore the process does not require energy. This process of carrier-mediated transport is called facilitated diffusion.

Drugs crossing cell membranes by passive mechanisms do so by passive diffusion along concentration gradients

according to their solubility in the lipid bilayer. This diffusion is proportional to the magnitude of the concentration gradient across the membrane as well as to the lipid/water coefficient of the drug. It follows that the greater the coefficient, the higher the concentration of the drug in the membrane, and therefore the faster the diffusion.

Passive diffusion differs for drugs that are electrolytes from those that are nonelectrolytes. For nonelectrolytes, after steady state is achieved, the concentration of that drug on either side of the membrane is equal. For electrolytes, the concentration of that drug relates to the differences of pH across the membrane as well as to the pKa. This is an important concept because most drugs are either weak acids or bases existing both in ionized and nonionized forms. The Pharmacological Basis of Therapeutics (Hardman et al, 2001) offers an excellent example of a drug that is a weak acid in the stomach where the gastric mucosa acts as a partition between the acidic environment in the stomach and the plasma itself. It is assumed for the purpose of this example that the mucosa acts as a lipid bilayer cell membrane.

In plasma, the ratio of the nonionized to ionized drug is 1:1000, whereas in the gastric contents the ratio is 1:0.001. An opposite result would be seen if the drug were a weak base. Understanding these concepts is extremely important because of the tremendous implications in terms of further absorption, and then upon excretion.

DISTRIBUTION

After a given drug is absorbed into the body, it is distributed to the various compartments within the body. Depending on the solubility and concentration of the drug and on the drug-binding ability of plasma proteins, the drug can either go through the systemic circulation or be trapped by reservoirs such as fat and be released slowly over a period of time. The volume of distribution relates the initial dosage of a particular drug administered and absorbed to the serum concentration of the drug.

BIOTRANSFORMATION

Once the drug has been absorbed and distributed and has exerted its given effect, it must be altered in some fashion to allow the body a means of excreting it, or else it would continue to accumulate until reaching toxic levels. Moreover, some drugs reach their active state only after having been altered in the body. These two needs, of acilitating excretion and promoting an intended action of a given drug, are accomplished by the transformation

of lipophilic drugs to more polar, less lipophilic substances. This is done by enzyme systems found mostly in the smooth endoplasmic reticulum of the liver (named the microsomal system), but also found in the kidney, lung, and gastrointestinal system. Drugs absorbed enterally or rectally are first presented for biotransformation to the liver; this is the so-called firstpass effect. Drugs that are administered sublingually travel directly to the systemic circulation from the superior vena cava and avoid the first-pass effect.

Biotransformation is a process of oxidation/reduction (phase I) reactions, conjugation reactions (phase II), or a combination of the two. The key step for oxidation reaction is the insertion of one atom of molecular oxygen into the substrate. This usually produces an unstable intermediary that will then be broken down further.This process of oxidation is largely controlled by a large family of isoenzymes called cytochrome P-450 that are located in the smooth endoplasmic reticulum of the liver. The most common factors affecting the biotransformation process by the P-450 system are genetically determined polymorphisms. A second factor affecting this process of biotransformation includes the administration of certain drugs such as ethanol and cimetidine that inhibit the P-450 enzymatic process. A third factor that can affect the cytochrome P-450 is hepatic blood flow.

Conjugation is the other means of biotransformation that facilitates excretion. Conjugation requires glucoronyl transferases that are found mainly in the hepatic endoplasmic reticulum but also can be found in the kidney and other tissues. Hyperbilirubinemia of infancy is due to a deficiency of this enzyme. Once conjugated, drugs are excreted into the bile and urine.

EXCRETION

Drugs are excreted mainly from the kidney, but also in the stool. In the case of anesthetic gases, excretion takes place via the pulmonary system. Importantly, drugs can be excreted into breast milk, and this must be remembered to prevent unwanted effects on the infant.

Renal excretion is a process of glomerular filtration, active tubular secretion, and passive tubular reabsorption. It is highly influenced by the pH of the urine.When the urine is made more alkaline, weak acids are excreted more rapidly; weak bases are preferentially excreted when the urine is made more acidic. Some of the protocols for the treatment of drug overdoses and poisoning derive from these tenets.

Many of the products derived from the hepatic first-pass effect are excreted into the feces; others are

reabsorbed in the blood and then excreted in the urine. Alternative, though less consequential, routes of excretion include saliva, sweat, and tears.

By adding all the routes of excretion to achieve a single rate of excretion for the entire organism, one can begin to derive a dosing regimen that will not produce toxic levels. With the given assumption of complete bioavailabilty (a measure of how much of a dose gets into the body and reaches its site of action), at steady state, the rate of drug administration will equal the rate of drug elimination, and a dosing rate can be easily calculated. This concept of measuring the rate of elimination from the human body is called clearance. Clearance can be expressed as a measure of the total body, or it can be individualized for a particular organ system such as the kidney or the liver. Once the clearance and the volume of distribution are known, the half-life of a particular drug can be determined. It follows that as the clearance decreases, the half-life of a particular drug would increase and vice versa.

PHARMACOKINETICS AS IT

RELATES TO PREGNANCY

Placental transfer of drugs depends on several factors: the physiochemical properties of the drug, the rate at which the drug crosses the placenta, the duration of exposure, the pattern of fetal distribution, and the stage of the placenta and fetus at the time of exposure. The general tenets of pharmacokinetics hold that the more lipophilic the drug, the more readily it will pass through the placenta. Of note, though, even polar substances will pass through the placenta given high enough concentration gradients.

Another factor influencing placental transfer is the molecular size of the drug. Drugs with a molecular weight of 250 to 500 readily pass through, whereas drugs with a molecular weight greater than 1000 have difficulty crossing. Protein binding also produces an effect. This is somewhat influenced by maternal blood flow and other factors, including lipid solubility and relative ionization.

Once entering the placenta from the maternal system, two mechanisms are present that help protect the fetus. First, the placenta functions not only as a semipermeable barrier but also as a site of biotransformation. Several different types of oxidation reactions have been demonstrated to occur in the placenta. Second, drugs enter the fetal circulation via the umbilical vein, where 40 to 60% of this blood enters the fetal liver and undergoes some degree of the first-pass effect. In addition, a large proportion of the blood from the umbilical artery is

shunted back through the umbilical vein to the liver for another round of biotransformation. There are obvious limits to the amount of biotransformation possible in the fetal liver. For example, as mentioned earlier in the case of neonates and applying to the fetus as well, a deficiency of glucoronyl transferase in the fetal liver inhibits the process of conjugation. Nevertheless, the fetus is afforded a moderate degree of protection from these mechanisms of biotransformation.

A complete list of medications that can adversely affect the fetus is beyond the scope of this textbook. The reader is referred to the Physicians’ Desk Reference (PDR) for a drug-by-drug accounting of the indications, contraindications, and dosages before prescribing a given drug to the pregnant patient.

SUMMARY OF PHARMACOKINETICS

Armed with the fundamental understanding of how drugs enter the human body, exert their effect, and then are executed, we are now ready to examine certain distinct classes of drugs used in the field of otolaryngology–head and neck surgery.

GASTROESOPHAGEAL REFLUX DISEASE: TREATMENT OF THE OTOLARYNGOLOGICAL MANIFESTATIONS

Approximately 10% of all laryngeal complaints are thought to be secondary to reflux esophagitis.The causative factors precipitating reflux esophagitis include an incompetent lower esophageal sphincter (LES), increased acid production or decreased clearance, alteration of the epithelial resistance to acid injury, and an incompetent upper esophageal sphincter (UES). The signs of laryngeal reflux esophagitis differ from the normal presentation because they are seldom accompanied by the classic esophageal symptoms of heartburn and regurgitation. The classic presentation of laryngeal reflux disease is a patient complaining of hoarseness, chronic cough, cervical dysphagia, or the sensation of a foreign body in the throat (globus sensation). Recent studies demonstrate a strong connection between laryngeal stenosis and reflux disease and hint at an association with laryngeal carcinoma.

The workup of suspected laryngeal reflux disease begins with a proper history and physical exam. The patient should be questioned as to the previously described symptoms. Initial examination should include indirect evaluation of the larynx: signs of edematous, erythematous arytenoids, or heaped up tissue in the

posterior pharyngeal region should be considered highly suspicious for reflux disease. Double-probe pH monitoring is the gold standard diagnostic test, but for the case of suspicious reflux laryngitis in the absence of either stenosis or carcinoma, many treat empirically for the presumptive diagnosis.

The first-line treatment for laryngeal reflux laryngitis is avoidance of substances such as spicy foods, chocolate, tea, and caffeine, as well as smoking. The medical armamentarium to fight reflux disease includes proton pump inhibitors and H2 blockers. Other agents that are used for classic reflux esophagitis that can be used as complementary agents include the classes of prokinetic drugs.

H2 RECEPTOR BLOCKING AGENTS

Cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid) are all examples of the class of drugs that act as H2 receptor antagonists. Acid production is stimulated by a combination of histamine, gastrin, and acetylcholine. The H2 receptors appear to be specific for acid production in the human body. The receptor antagonists act by competitive antagonism and function by preventing acid and pepsid secretion. The major side effects of this class of drug are mostly associated with cimetidine and its interaction with the hepatic cytochrome P-450 system. Cimetidine has been shown to slow down the clearance of drugs using the P-450 system. The other H2 receptor antagonists do not interfere with the P-450 system. Cimetidine also binds to testosterone receptors and thus can cause gynecomastia and decreased libido in males. Ranitidine, for its part, has been shown to reduce renal clearance of triamterene in humans. Overall, this class of drug is safe and is now available in over-the-counter preparations.

PROTON PUMP INHIBITORS

Drugs such as omeprazole (Prilosec) and lansoprazole (Prevacid) function by preventing the parietal cell H+, K+-adenosinetriphosphatase (ATPase) from transporting H+ into the lumen of the stomach.These drugs therefore prevent acid production at the final common pathway and are the most potent antacids available.The potentially serious side effect of significant gastric mucosal hyperplasia has failed to be demonstrated in humans.

PROKINETIC DRUGS

Drugs such as erythromycin (E-Mycin), cisapride (Propulsid), and metoclopramide (Reglan) act by

increasing peristaltic contractions, by increasing LES resting tone, or by combining these two actions. Metoclopramide functions as a dopamine D2 antagonist to increase the tone of the LES and to increase the force of and coordinate peristaltic contractions. It is also an antiemetic. Cisapride acts via the serotonin pathways as a 5-HT agonist, and also functions to increase the LES resting tone and to increase and coordinate contractions. Cisapride can cause diarrhea. It is metabolized by the P-450 system; therefore, its levels can be elevated when used with other drugs that saturate the P-450 system. A rare side effect due to cisapride overdosage is arrythmia.

TREATMENT STRATEGY

The largest prospective study concerning the treatment of laryngeal reflux disorders was performed between 1983 and 1988 by Kaufman (1991) and involved 225 consecutive patients who presented with a history either of laryngeal cancer (31 patients) or laryngeal stenosis (33 patients), or a history suspicious for gastroesophageal reflux disease (GERD, 143 patients); 18 patients were categorized as miscellaneous. Patients were initially treated with lifestyle alteration and medical therapy consisting of H2 receptor antagonists administered for a duration of 6 months. After 6 months, 85% of the patients experienced relief of the symptoms with which they had initially presented. Over a 4-year period of time, 20% of the patients who had experienced relief after the initial treatment with medication had recurrences of the symptoms.The overall failure rate for medical treatment was 35%. Those patients who failed medical treatment went on to undergo Nissen fundoplication. After this landmark study, the advent of the proton pump inhibitors has changed the arsenal such that these agents are now the first-line medication for medical treatment of laryngeal reflux disorders. Large-series prospective studies with long-term statistics from this treatment strategy have yet to be published.

GLUCOCORTICOIDS AND THEIR USE IN OTOLARYNGOLOGY

Glucocorticoids are formed in the adrenal cortex, which uses cholesterol as a precursor substrate. Production of glucocorticoids is highly regulated by the hypothalamic- pituitary-adrenal (HPA) axis. Production is increased during times of physiological stress to the organism. Glucocorticoids exert their effects broadly; they promote gluconeogenesis in the liver and lipolysis in adipose tissue, and they affect protein synthesis and

degradation in striated muscle.They regulate growth and development in fetal tissues and induce the production of surfactant in the fetal lungs. Their most important actions relative to the field of otolaryngology stem from their effect on the body’s immunologic response to foreign insult either by injury or by inflammation from foreign antigen; it is this suppression of the immune system that renders glucocorticoids potent in the treatment of allergic, inflammatory, and autoimmune disorders. Glucocorticoids diminish the ability to adhere to vascular endothelium after injury. They inhibit the antigen processing by macrophages and suppressT-cell helper activity. They inhibit the cytokine response to injury or inflammation.They promote eosinopenia and lymphopenia. Glucocorticoids perform this immunosuppression at the price of decreasing the body’s ability to ward off infection.This potentially disastrous side effect must be remembered each time glucocorticoids are to be prescribed for a length of time.

Glucocorticoids, as mentioned previously, are produced in the adrenal cortex as cortisol and then are released into the circulation.There, most of the cortisol is bound to cortisol-binding globulin, and 5 to 10% is bound to albumin. The free fraction in the circulation exerts the effects already described. Of note, dexamethasone does not bind to cortisol-binding globulin; therefore, almost 100% of it remains in the free, active form.

Cortisol and cortisone are used only for replacement therapy for adrenal insufficiency; they have a greater mineralocorticoid than glucocorticoid activity. Prednisone, prednisolone, and methylprednisolone are the glucocorticoids exogenously administered for their anti-inflammatory properties. They are used to treat allergic reactions (as elaborated in Chapter 3), inflammatory process (such as chronic sinusitis), autoimmune processes (e.g., collagen vascular diseases and acute sensorineural hearing loss), and vasculitic syndromes (e.g.,Wegener’s granulomatosis and giant cell arteritis). Dexamethasone and betamethasone have maximal anti-inflammatory properties and are used for acute inflammatory crises, but their side effects preclude long-term usage.

The side effects of glucocorticoids are as diverse as their range of activity. As already described, their ability to suppress the immune system promotes infection. They also promote osteoporosis by disrupting the regulation of calcium metabolism. Long-term usage is associated with the development of Cushing’s syndrome and diabetes mellitus as well as the development of peptic ulcers. They can produce hypogonadism in men and anovulation and oligomenorrhea in women.Acutely, they

can produce central nervous system (CNS) effects such as arousal and euphoria.

Exogenous glucocorticoid administration produces a host of potential side effects; the withdrawal of this exogenous administration also produces a similar range of side effects because the HPA axis has been downregulated and the body cannot produce enough endogenous glucocorticoid. To prevent the potentially serious morbidity and mortality (tiredness, nausea, vomiting, and hypotension) from too rapid a withdrawal from exogenous glucocorticoid administration, several precautions are taken. Some centers have taken to administering exogenous glucocorticoid on an alternating day regimen in the hopes of maintaining the anti-inflammatory responses while preventing the down-regulation of the HPA axis. Dosage patterns vary greatly; a common antiinflammatory dosage for collagen vascular disorders or allergic reactions is 1 mg/kg/day of prednisone or the equivalent dose of another substance. The common practice is to taper the dosage of glucocorticoids if the equivalent of 5 mg of prednisone has been given for 2 weeks or more (Table 8-1). The short adrenocorticotropic hormone (ACTH) test is used to assess the recovery of the HPA axis. In this test, ACTH is given intravenously, and plasma cortisol levels are measured at 30and 60-minute intervals after this administration. A normal HPA axis will allow for a greater than 20 g/dL increase in the serum cortisol level.

NONSTEROIDAL ANTI-

INFLAMMATORY DRUGS

Nonsteroidal anti-inflammatory drugs (NSAIDs) are weak organic acids that exert their effects by inhibiting the enzyme cyclooxygenase, thereby inhibiting the pathway from arachidonic acid (found in cell membranes) to various prostaglandins.They also exert their effects by interacting with the various other products of arachidonic acid metabolism; namely, leukotrienes. NSAIDs inhibit the many processes regulated by prostaglandins;

they reduce fever by inhibiting prostaglandin-E2 synthesis in the hypothalamic region and by blocking the hypothalamic response to interleukin-1 (IL-1), affect pain control by affecting prostaglandin synthesis at local sites, and also affect vascular permeability, the degree of leukocyte infiltration, and therefore the inflammatory response.

Of the NSAIDs, aspirin (acetylsalicylate) is perhaps the most commonly used. It is absorbed and hydrolyzed to acetic acid and salicylate in the tissue and serum and then is bound to albumin. It is excreted in the urine; this process of excretion is augmented by alkalinizing the urine, which is done in cases of overdosage. It acts by permanently acetylating an active site on the enzyme cyclooxygenase. It is effective as an anti-inflammatory, antipyretic, or analgesic agent. It is also an effective inhibitor of platelet aggregation. Its side effects include allergic reactions, gastrointestinal bleeding, coagulation disorders, renal abnormalities, and “salicylism”—tinnitus, hearing loss, and vertigo.Allergic reactions, especially in the face of nasal polyposis and asthma, can be severe and include bronchoconstriction and shock.The phenomenon of tinnitus derives from effects on the stria vascularis and is reversible upon discontinuation of the agent.The coagulation disorders engendered by aspirin require the regeneration of platelet cyclooxygenase for reversal; this process has a half-life of 7 to 10 days.Aspirin has also been associated with Reye’s syndrome.

Because it has few side effects, acetaminophen is widely used as an NSAID. It is effective for local pain control and as an antipyretic; it has relatively little anti-inflammatory action. Ibuprofen (the active ingredient in Advil and Nuprin) is also superior in attaining pain control but is not an active anti-inflammatory agent. Other NSAIDs such as indomethacin have greater anti-inflammatory properties as compared with their ability to control pain or fever. Indomethacin, however, has a greater number of side effects, including the possibility of developing gastrointestinal hemorrhage and pancreatitis.

THE PHARMACOLOGY

OF ANALGESICS

I esteem it the office of the physician not only to restore health, but to mitigate pain and dolors.

Sir Francis Bacon

Early humans attempted to relieve pain by entreaties to nature, sun or moon, and a variety of deities. Unfortunately, death was often the only effective surcease of pain. Homer, in the Odyssey, notes that Helen, the daughter of Zeus, prepared a drug (possibly opium), dissolved in wine, to ward off pain. In the 12th century Nicolas of Salerno suggested the use of the soporific sponge infused with a melange of possibly active and probably toxic substances whose inhalation not only could relieve pain but also could induce anesthesia. Also, it was reversible, with the judicious application of juice from the root of fennel. As unlikely as this magic sponge was in relieving pain, it does indicate some knowledge of the magnificent pain killer opium. By the 13th century opium, with a few fellow travelers, was used (undoubtedly with some success) to abate pain. Shakespeare, in Romeo and Juliet, Othello, and Antony and Cleopatra, mentions in each play a potent potion able to induce sleep and relieve pain. Knowledge of the beneficial effects of opium thus existed in crude form for many years, but it was not until 1806 that Friedrich Serturner isolated the active component of opium, which he named morphium (later morphine) after the Greek god of dreams, Morpheus. Although morphine has been followed by several effective pain relievers, none has yet to prove of greater value and reliability than the discovery of an early 19th-century Westphalian chemist.

MORPHINE

Opium is obtained from the seedpod of the poppy (Papaver somniferum).The dried juice can be broken down into its important component alkaloids, morphine, codeine, and papaverine. Chemically, morphine and codeine are phenanthrenes, and papaverine is a benzylisoquinoline.The chemical configuration of morphine can be manipulated to produce active compounds such as heroin, hydromorphone, oxymorphone, and codeine. None of these substances has demonstrated clinical superiority to morphine.

Morphine’s pharmacological activity rests in its action as an agonist to receptors in the spinal and supraspinal CNS and bowel. In patients with pain, it produces both profound analgesia and drowsiness. In patients without pain, nausea and vomiting are common, and drowsiness may be exaggerated. In toxic doses

morphine induces severe respiratory depression, which may be fatal.This depressant effect is due to morphine’s ability to diminish markedly the respiratory stimulating action of carbon dioxide (CO2). The obtunded patient will breathe on command but, without command, will simply stop breathing and asphyxiate.

Nausea and vomiting are more common in ambulatory patients than those who are supine. There is direct stimulation of the chemoreceptor trigger zone within the medulla of the brain and an increase in vestibular sensitivity. Although this unpleasant aspect of morphine has received significant attention, it should be understood that all agonists share the unpleasantry and that in equianalgesic doses, morphine is no greater a culprit than other commonly used analgesics.

In the supine patient, morphine has little effect on blood pressure and pulse, and cardiac inotropy is well maintained. However, morphine is a vasodilator, and, on sitting up, the subject may experience marked hypotension. Morphine causes the release of histamine, a potent vasodilator. The hypotensive effect is not due solely to histamine, but probably is an antiadrenergic effect, both centrally and peripherally. Because of its vasodilator effect and hypotensive consequences, morphine should be used with great care (if at all) in a hypovolemic patient.

Morphine also causes an increase in biliary pressure and may precipitate biliary colic. The drug inhibits the urinary voiding reflex and increases sphincter tone. Occasionally, urinary tract catheterization is necessary after the use of morphine.

Because the opioid analgesics are metabolized in the liver, liver disease with consequent decrease in metabolism will increase circulating levels of morphine. Renal disease may increase levels of the active metabolite morphine- 6-glucuronide. Hepatic and renal disease thus demands caution on the part of the clinician when using opioids.

Morphine when injected intramuscularly or subcutaneously in a dose of 10 mg to an average adult is active for 4 to 5 hours and has a plasma half-life of 2 hours. Bioavailability after oral ingestion is very limited.

CODEINE

The major advantage of codeine is its ready bioavailability when taken by mouth due to minimal first-pass metabolism in the liver. The drug has little analgesic ability per se, but is metabolized to morphine, which then exerts its effect. Codeine by mouth is 60% as effective as parenteral codeine. Because codeine is approximately one tenth as potent as morphine, 60 mg of oral codeine would be equal in analgesic potency to 3.5 mg of parenteral

morphine (60 0.6/10). The analgesic effect of the combination of codeine and aspirin exceeds the analgesic effect of either drug alone.

MEPERIDINE

Meperidine is a phenylpiperidine whose chemical structure bears little obvious resemblance to that of morphine. However, its pharmacological properties are similar to those of morphine. Analgesia occurs 10 minutes after parenteral administration and peaks at approximately 1 hour. Meperidine is approximately one tenth as potent as morphine, with 100 mg of meperidine equivalent to 10 mg of morphine. Oral meperidine is approximately 50% as active as parenteral meperidine. The drug is metabolized in the liver to meperidinic acid and normeperidine. Normeperidine increases CNS excitation and can cause convulsions in patients with renal or hepatic insufficiency.

AGONIST-ANTAGONIST ANALGESICS

This group of drugs binds to the receptor and thus competes with other active drugs for the receptor site. Because they have little activity, they are either partial agonists or competitive antagonists.The group includes pentazocine, nalbuphine, butorphanol, and buprenorphine. Advocates of these drugs point to the “ceiling effect” on respiratory depression; that is, these drugs cause respiratory depression, but there is a peak beyond which further drug administration causes no increase in depression. However, respiratory depression is significant and can be hazardous. These drugs also have a capacity to counter the effects of the opioids and induce withdrawal symptoms in addicts or in those whose pain has been relieved by morphine or meperidine.They also have the ability to produce hallucinogenic effects with high doses.

OPIOID ANTAGONISTS

Naloxone is a very effective opioid antagonist and can quickly counter the respiratory depressant effect of these drugs. Small doses (0.2–0.4 mg intravenously) exert an almost immediate action with little undesirable side effects. The sudden antagonism of the analgesic effect can cause marked increases in catecholamine levels, with significant increases in pulse and blood pressure.

ANESTHETIC ANALGESICS

Although morphine and meperidine have long been important components of the anesthesiologist’s

intraoperative armamentarium, these drugs have largely been supplanted in the operating room by a family of synthetic analgesics, including fentanyl, alfentanil, and sufentanil. Major advantages in this class of drugs include little or no histamine release and brief duration of action.

Use of Analgesics

Safe, effective pain relief is available for every patient and must be the clearly defined goal of the surgical and nursing staffs. Too often patients have suffered needlessly because of groundless fears of inducing addiction. Respiration must be monitored, and naloxone must be readily available. Recent advances in patient-controlled analgesia have placed patients in a decision-making role, thus providing them with the comfort of control.

SUMMARY OF ANALGESICS

Potent analgesic drugs are readily available to provide pain relief to surgical patients. Respiratory depression is an urgent consideration with any of these drugs but can be overcome with the administration of safe and effective antagonists. Patients need not, and should not, suffer.

THE PHARMACOLOGY OF

LOCAL ANESTHETICS

Local anesthetics are safe, effective drugs, widely used when general anesthesia is inadvisable or not required by the nature of the operative procedure. The clinician must choose from a variety of available drugs. To make this choice, it is necessary to have knowledge of

•Chemistry of the local anesthetics

•Physiology of nerve transmission

•Pharmacology of local anesthetics

•Individual anesthetic drugs, their advantages and disadvantages

•Toxicity, prevention, recognition, and treatment

CHEMISTRY

The clinically used local anesthetics have three chemical components:

•Lipophilic aromatic residue

•Hydrophilic amino group

•Linkage group, either ester or amide

Figure 8–1 Structural formula of procaine. (From Gotta AW, Donovan R, Sullivan CA. The pharmacology of local anesthetics. Ophthalmol Clin NA 1998;11(1). Reprinted with permission)

An ester is a salt of an organic acid. An amine is a substitution product of ammonia (NH3,), and an amide is a substitution product of NH3, with substitution by an acid or oxidized radical.

Procaine is a typical ester local anesthetic (Fig. 8-1), with its aromatic residue linked by the ester intermediate chain to the terminal diethyl amino group.Tetracaine also has an ester link between aromatic and amino groups.

Lidocaine and bupivacaine differ from procaine and tetracaine in that their linking intermediate chain has an amide configuration (Fig. 8-2).

The local anesthetics may thus be divided into amide or ester anesthetics (Tables 8-2, 8-3) an important distinction because of the different metabolism of the two groups. The esters are metabolized by plasma (pseudo-) cholinesterase that is abundant in normal human blood. Rapid hydrolysis by pseudocholinesterase decreases the potential toxicity of ester-type local anesthetics, giving this class of drugs an inherent safety from the risks of excessive accumulation and toxicity. The amides are metabolized in the liver, a more prolonged process than rapid hydrolysis of the esters, although in blood-borne transit to the liver some of the anesthetic will find its way to the target organs of toxicity, the brain and heart.

TABLE 8-2 COMMONLY USED AMIDE LOCAL ANESTHETICS

Lidocaine (Xylocaine, lignocaine)

Bupivacaine (Marcaine, Sensorcaine)

Mepivacaine (Carbocaine)

Prilocaine (Citanest)

Ropivacaine (Naropin)

Liver disease may limit metabolism of either class of local anesthetic, but it is more likely to be clinically significant for the amides. The presence of an atypical pseudocholinesterase, or the presence of the enzyme in markedly diminished concentration, could cause prolonged metabolism, anesthetic effect, and increased risk of toxicity. Decreased levels of pseudocholinesterase may account for slower metabolism of procaine in newborn infants and in patients with liver disease. The commonly used muscle relaxant succinylcholine is also metabolized by pseudocholinesterase. A prolonged reaction to either local anesthetic or muscle relaxant should alert the clinician to the increased possibility of toxicity in the other class of drug.

The local anesthetics are tertiary amines and thus exist in the uncharged (cationic) or positively charged (protonated) form. The distribution relationship between the two forms is a function of the pH of the solution and the pKa of the anesthetic. The pKa is the pH at which a substance is 50% charged and 50% uncharged.This distribution is important because it is the uncharged form that crosses cell membranes (including neural), but it is the charged form that exerts the anesthetic effect. Nonionized local anesthetics are insoluble in water. They are soluble, however, when acidified (and thus protonated).When the aqueous solution of the protonated anesthetic is injected, it is buffered by tissue fluids, producing an uncharged form that crosses nerve membranes, where the drug molecules are again protonated by the lower pH within the axon. This protonated form is believed to produce neural blockade.

When a local anesthetic is injected into an area of decreased pH, the shift to the nonionized form will be

Figure 8–2 Structural formula of bupivacaine. (From Gotta AW, Donovan R, Sullivan CA. The pharmacology of local anesthetics. Ophthalmol Clin NA 1998;11(1) Reprinted with permission.)

TABLE 8-3 COMMONLY USED ESTER LOCAL ANESTHETICS

Procaine

Chloroprocaine (Nesacaine)

Tetracaine (Pontocaine)

Cocaine

Hexylcaine (Cyclaine)

limited, resulting in a relative increase of the acidic form and thus decreasing the amount of mobile, nonionized form. Clinically, this results in lack of anesthesia. Cellulitis, with increased metabolism and cell breakdown, will produce an acidic environment, decreasing the effectiveness of local anesthetics.

PHYSIOLOGY OF NERVE TRANSMISSION

Potassium is present in high concentrations in the axonal fluid and in low concentrations outside the nerve membrane. The nerve membrane is freely permeable to potassium.The energy expended to maintain the potassium gradient represents the resting membrane potential and is defined mathematically as membrane potential (millivolts) 61 log intracellular K+ concentration extracellular K+ concentration. In contrast to potassium, sodium is present in high concentrations outside the resting nerve membrane but in low concentrations within the axon.The nerve membrane is not permeable to sodium, which can traverse the membrane only through specific lipoprotein pores.

Nerve transmission depends on opening the lipoprotein pores in the nerve membrane and the influx of sodium. To maintain ionic balance, potassium crosses the nerve membrane and becomes extraneural. Sodium is then actively pumped out of the cell, and potassium reenters and the resting state is then reestablished.

There are thus four possible mechanisms that might affect a pharmacological blockade of nerve transmission:

•Blocking the sodium channel at its external opening

•Blocking the sodium channel at its internal opening

•Incorporation of the local anesthetic into the nerve membrane, with consequent expansion of the volume of the membrane and physical compression of the sodium channel

•Blocking the regulator of the “gate” mechanism

The external opening of the sodium pore is blocked by the toxins saxitoxin and tetrodotoxin but is not the mechanism for the local anesthetics. There is no conclusive evidence that alteration in the gate mechanism is important.

Current opinion holds that the second and third mechanisms account for local anesthetic activity. According to this theory, a small part of the anesthetic action is due to incorporation of the uncharged local anesthetic molecule into the nerve with consequent membrane expansion.The majority of local anesthetic molecules pass through the sodium pores in their nonionized form. Within the axon they become protonated and then attach themselves to the axoplasmic opening of the pore, closing it to sodium flux and thus preventing nerve transmission.

COMMONLY USED LOCAL ANESTHETICS

Cocaine

Cocaine is an ester-type drug, chemically similar to atropine and scopolamine. It is notable for its remarkable CNS effects and the marked euphoria it may produce.

Cocaine is a useful topical anesthetic. It is also a potent vasoconstrictor and helps to create a dry, bloodless field, with little edema.Vasoconstriction results from cocaine’s ability to inhibit norepinephrine reuptake at the sympathetic nerve terminus. Although localized increases of norepinephrine occur, systemic levels will also increase and lead to tachycardia and hypertension, and can cause serious, even fatal, cardiac arrhythmias. Arrhythmias may occur at any time but are especially prone to occur with the concurrent use of inhaled anesthetics that sensitize the myocardium to catecholamines (e.g., halothane).Although the toxic concentration of cocaine is generally put at 200 mg in an adult (3 mg/kg), serious arrhythmias have been reported with concentrations as low as 50 mg.

Lidocaine

Lidocaine is an amide local anesthetic, suitable for a variety of clinical applications. It is an effective topical anesthetic at concentrations of 2 to 4%, and may be used for local infiltration at 0.5 to l.0% and for nerve blocks in l.0 to 2.0%. It has a rapid onset of action (usually 15 minutes or less) and is effective for 11⁄2 to 2 hours without epinephrine and 2 to 4 hours when epinephrine (1:200,000) is added to the anesthetic.

Bupivacaine

Bupivacaine is an amide local anesthetic capable of providing prolonged block (up to 24 hours). Onset of block is slow, and it is not unusual to mix a rapidacting local anesthetic (e.g., lidocaine) with bupivacaine to produce rapid onset and prolonged duration. Bupivacaine possesses a unique toxicity in that the premonitory CNS signs are often absent, and the first indication of toxicity is cardiac arrest. Bupivacaine-induced cardiac arrest may be very difficult to reverse, perhaps because the drug binds tightly to myocardial proteins.

Chloroprocaine

Chloroprocaine is an ester drug with rapid onset of action (less than 15 minutes), brief duration of action (30– 45 minutes), and limited toxicity owing to rapid hydrolysis.

Ropivacaine

Ropivacaine is a recently introduced amide local anesthetic, a congener of mepivacaine and bupivacaine.

Ropivacaine and bupivacaine are equally potent, but ropivacaine (0.25–1.0%) appears to have a longer duration of action than bupivacaine and may be a vasoconstrictor over a wide range of concentrations. Studies suggest that ropivacaine has less cardiac toxicity than bupivacaine at equipotent concentrations but is more cardiotoxic than lidocaine.

CLINICAL CONSIDERATIONS

Physicians who use local anesthetics should familiarize themselves with at least one representative of each of three groups. Short-acting local anesthetics (20–45 minutes) include procaine and chloroprocaine. Intermediateacting local anesthetics (60–120 minutes, longer with epinephrine) include lidocaine and mepivacaine. Longacting anesthetics (400–450 minutes) include bupivacaine, etidocaine, and ropivacaine.The clinician can thus choose an anesthetic with a duration of action most closely approximating the duration of surgery.The longer acting local anesthetics may even be used for relatively brief surgical procedures to provide analgesia lasting well into the postoperative period.

The duration of block can be prolonged by the incorporation of a vasoconstrictor into the anesthetic mix. Epinephrine is most useful in a concentration of 1:200,000; stronger concentrations are not indicated. Epinephrine should be used with caution (if at all) in any patient where increased sympathetic activity might be deleterious (e.g., with heart disease, hypertension, or hyperthyroid).The drug should also be avoided in areas of end arterioles (e.g., fingers, nose, subcutaneously).

TOXICITY

Misadventures with local anesthetics occur when the drugs are not effectively localized to the desired site of action but reach the target organs of toxicity, the brain and heart, in toxic concentrations. It is conventional to recommend a maximum dose of a particular local anesthetic, but the practice is arbitrary, unscientific, and misleading. Small doses of local anesthetic can cause a

toxic reaction if they are injected directly into a blood vessel. Although the total amount of drug used plays a role in the development of toxicity, other factors include the location of injection and the incorporation of epinepherine. The vasoconstrictor thus serves to prolong the duration of block and minimize the risk of toxicity. Blood levels of local anesthetics are also a function of plasma protein binding of the drug, binding capacity that is variable and dependent on the patient’s state of health. Alpha 1-acid glycoprotein (AAG) is the most important binding protein, and albumin is second in importance.AAG levels increase in chronic inflammatory illnesses, such as Crohn’s disease, inflammatory arthritis, and chronic renal diseases with superimposed inflammatory disease.Theoretically, these disease processes would decrease the risk of local anesthetic toxicity by increasing AAG levels and decreasing the amount of unbound drug in the blood. Table 8-4 gives the maximum doses but should serve only as a rough guide to the clinician.

Prevention of Toxicity

Appropriate premedication may serve to prevent or modify local anesthetic toxicity. The barbiturates are effective only at unacceptably large (and toxic) doses. However, the benzodiazepines are effective, probably because of the high density of benzodiazepine receptors in the limbic system of the brain, the primary site of toxicity.

Diazepam is water insoluble and will not produce an effective blood level when injected intramuscularly. It is soluble in propylene glycol, a venous irritant, causing pain on intravenous injection. Lorazepam is water miscible and can produce effective blood levels with intramuscular injection. Midazolam is water soluble and produces desired blood levels after either intramuscular or intravenous injection. The benzodiazepines are potent respiratory depressants and, in combination with narcotics, can produce significant hypotension.When benzodiazepines are used either as premedicant or for intraoperative sedation, the antagonist