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Pharmacology_Katzung. C. Cardiovascular System 1. Cardiomyopathy and heart failure—Alcohol has complex effects on the cardiovascular system. Heavy alcohol consumption of long duration is associated with a dilated cardiomyopathy with ventricular hypertrophy and fibrosis. In animals and humans, alcohol causes cardiac membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of phospholipids and fatty acids, and up-regulation of voltage-gated calcium channels. There is evidence that patients with alcohol-induced dilated cardiomyopathy do significantly worse than patients with idiopathic dilated cardiomyopathy, even though cessation of drinking is associated with a reduction in cardiac size and improved function. The poorer prognosis for patients who continue to drink appears to be due in part to interference by ethanol with the beneficial effects of β blockers and angiotensin-converting enzyme (ACE) inhibitors. 2.


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Pharmacology_Katzung. 2. Arrhythmias—Heavy drinking—and especially “binge” drinking—are associated with both atrial and ventricular arrhythmias. Patients undergoing alcohol withdrawal syndrome can develop severe arrhythmias that may reflect abnormalities of potassium or magnesium metabolism as well as enhanced release of catecholamines. Seizures, syncope, and sudden death during alcohol withdrawal may be due to these arrhythmias. 3. Hypertension—A link between heavier alcohol consumption (more than three drinks per day) and hypertension has been firmly established in epidemiologic studies. Alcohol is estimated to be responsible for approximately 5% of cases of hypertension, independent of obesity, salt intake, coffee drinking, and cigarette smoking. A reduction in alcohol intake appears to be effective in lowering blood pressure in hypertensive individuals who are also heavy drinkers; the hypertension seen in this population is also responsive to standard blood pressure medications. 4.


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Pharmacology_Katzung. Coronary heart disease—Although the deleterious effects of excessive alcohol use on the cardiovascular system are well established, there is strong epidemiologic evidence that moderate alcohol consumption actually prevents coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. This type of relationship between mortality and the dose of a drug is called a “J-shaped” relationship. Results of these clinical studies are supported by ethanol’s ability to raise serum levels of high-density lipoprotein (HDL) cholesterol (the form of cholesterol that appears to protect against atherosclerosis; see Chapter 35), by its ability to inhibit some of the inflammatory processes that underlie atherosclerosis while also increasing production of the endogenous anticoagulant tissue plasminogen activator (t-PA, see Chapter 34), and by the presence in alcoholic beverages (especially red wine) of antioxidants and other substances that may protect against atherosclerosis. These


Pharmacology_Katzung

Pharmacology_Katzung. plasminogen activator (t-PA, see Chapter 34), and by the presence in alcoholic beverages (especially red wine) of antioxidants and other substances that may protect against atherosclerosis. These observational studies are intriguing, but randomized clinical trials examining the possible benefit of moderate alcohol consumption in prevention of CHD have not been carried out.


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Pharmacology_Katzung. D. Blood Alcohol indirectly affects hematopoiesis through metabolic and nutritional effects and may also directly inhibit the proliferation of all cellular elements in bone marrow. The most common hematologic disorder seen in chronic drinkers is mild anemia resulting from alcohol-related folic acid deficiency. Iron deficiency anemia may result from gastrointestinal bleeding. Alcohol has also been implicated as a cause of several hemolytic syndromes, some of which are associated with hyperlipidemia and severe liver disease. E. Endocrine System and Electrolyte Balance Chronic alcohol use has important effects on the endocrine system and on fluid and electrolyte balance. Clinical reports of gynecomastia and testicular atrophy in alcoholics with or without cirrhosis suggest a derangement in steroid hormone balance.


Pharmacology_Katzung

Pharmacology_Katzung. Individuals with chronic liver disease may have disorders of fluid and electrolyte balance, including ascites, edema, and effusions. Alterations of whole body potassium induced by vomiting and diarrhea, as well as severe secondary aldosteronism, may contribute to muscle weakness and can be worsened by diuretic therapy. The metabolic derangements caused by metabolism of large amounts of ethanol can result in hypoglycemia, as a result of impaired hepatic gluconeogenesis, and in ketosis, caused by excessive lipolytic factors, especially increased cortisol and growth hormone. F. Fetal Alcohol Syndrome


Pharmacology_Katzung

Pharmacology_Katzung. F. Fetal Alcohol Syndrome Chronic maternal alcohol abuse during pregnancy is associated with teratogenic effects, and alcohol is a leading cause of mental retardation and congenital malformation. The abnormalities that have been characterized as fetal alcohol syndrome include (1) intrauterine growth retardation, (2) microcephaly, (3) poor coordination, (4) underdevelopment of midfacial region (appearing as a flattened face), and (5) minor joint anomalies. More severe cases may include congenital heart defects and mental retardation. Although the level of alcohol intake required to cause serious neurologic deficits appears quite high, the threshold for more subtle neurologic deficits is uncertain.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanisms that underlie ethanol’s teratogenic effects are unknown. Ethanol rapidly crosses the placenta and reaches concentrations in the fetus that are similar to those in maternal blood. The fetal liver has little or no alcohol dehydrogenase activity, so the fetus must rely on maternal and placental enzymes for elimination of alcohol. The neuropathologic abnormalities seen in humans and in animal models of fetal alcohol syndrome indicate that ethanol triggers apoptotic neurodegeneration and also causes aberrant neuronal and glial migration in the developing nervous system. In tissue culture systems, ethanol causes a striking reduction in neurite outgrowth. G. Immune System


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Pharmacology_Katzung. G. Immune System The effects of alcohol on the immune system are complex; immune function in some tissues is inhibited (eg, the lung), whereas pathologic, hyperactive immune function in other tissues is triggered (eg, liver, pancreas). In addition, acute and chronic exposure to alcohol have widely different effects on immune function. The types of immunologic changes reported for the lung include suppression of the function of alveolar macrophages, inhibition of chemotaxis of granulocytes, and reduced number and function of T cells. In the liver, there is enhanced function of key cells of the innate immune system (eg, Kupffer cells, hepatic stellate cells) and increased cytokine production. In addition to the inflammatory damage that chronic heavy alcohol use precipitates in the liver and pancreas, it predisposes to infections, especially of the lung, and worsens the morbidity and increases the mortality risk of patients with pneumonia. H. Increased Risk of Cancer


Pharmacology_Katzung

Pharmacology_Katzung. H. Increased Risk of Cancer Chronic alcohol use increases the risk for cancer of the mouth, pharynx, larynx, esophagus, and liver. Evidence also points to a small increase in the risk of breast cancer in women. A threshold level for alcohol consumption as it relates to cancer has not been determined. Alcohol itself does not appear to be a carcinogen in most test systems. However, its primary metabolite, acetaldehyde, can damage DNA, as can the reactive oxygen species produced by increased cytochrome P450 activity. Other factors implicated in the link between alcohol and cancer include changes in folate metabolism and the growth-promoting effects of chronic inflammation. Interactions between ethanol and other drugs can have important clinical effects resulting from alterations in the pharmacokinetics or pharmacodynamics of the second drug.


Pharmacology_Katzung

Pharmacology_Katzung. The most common pharmacokinetic alcohol-drug interactions stem from alcohol-induced increases of drug-metabolizing enzymes, as described in Chapter 4. Thus, prolonged intake of alcohol without damage to the liver can enhance the metabolic biotransformation of other drugs. Ethanol-mediated induction of hepatic cytochrome P450 enzymes is particularly important with regard to acetaminophen. Chronic consumption of three or more drinks per day increases the risk of hepatotoxicity due to toxic or even high therapeutic levels of acetaminophen as a result of increased P450-mediated conversion of acetaminophen to reactive hepatotoxic metabolites (see Figure 4–5). Current US Food and Drug Administration (FDA) regulations require that over-the-counter products containing acetaminophen carry a warning about the relation between ethanol consumption and acetaminophen-induced hepatotoxicity.


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Pharmacology_Katzung. In contrast, acute alcohol use can inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow. Phenothiazines, tricyclic antidepressants, and sedative-hypnotic drugs are the most important drugs that interact with alcohol by this pharmacokinetic mechanism. Pharmacodynamic interactions are also of great clinical significance. The additive CNS depression that occurs when alcohol is combined with other CNS depressants, particularly sedative-hypnotics, is most important. Alcohol also potentiates the pharmacologic effects of many nonsedative drugs, including vasodilators and oral hypoglycemic agents.


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Pharmacology_Katzung. Alcohol is the cause of more preventable morbidity and mortality than all other drugs combined with the exception of tobacco. Epidemiologic studies indicate that for men under 65, risk is increased by consumption of more than four drinks on any single day or more than 14 drinks per average week; for women and for men over 65, risk is increased by consumption of more than three drinks on a single day or seven drinks per week. The search for specific etiologic factors or the identification of significant predisposing variables for alcohol abuse has led to disappointing results. Personality type, severe life stresses, psychiatric disorders, and parental role models are not reliable predictors of alcohol abuse. Although environmental factors clearly play a role, evidence suggests that there is a large genetic contribution to the development of alcoholism. Not surprisingly, polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase that lead to increased aldehyde accumulation and


Pharmacology_Katzung

Pharmacology_Katzung. is a large genetic contribution to the development of alcoholism. Not surprisingly, polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase that lead to increased aldehyde accumulation and its associated facial flushing, nausea, and hypotension appear to protect against alcoholism. Much attention in genetic mapping experiments has focused on membrane-signaling proteins known to be affected by ethanol and on protein constituents of reward pathways in the brain. Polymorphisms associated with a relative insensitivity to alcohol and presumably thereby a greater risk of alcohol abuse have been identified in genes encoding an α subunit of the GABAA receptor, an M2 muscarinic receptor, a serotonin transporter, adenylyl cyclase, and a potassium channel. The link between a polymorphism in an opioid receptor gene and a blunted response to naltrexone raises the possibility of genotype-guided pharmacotherapy for alcohol dependence.


Pharmacology_Katzung

Pharmacology_Katzung. Nontolerant individuals who consume alcohol in large quantities develop typical effects of acute sedative-hypnotic drug overdose along with the cardiovascular effects previously described (vasodilation, tachycardia) and gastrointestinal irritation. Since tolerance is not absolute, even individuals with chronic alcohol dependence may become severely intoxicated if sufficient alcohol is consumed. The most important goals in the treatment of acute alcohol intoxication are to prevent severe respiratory depression and aspiration of vomitus. Even with very high blood ethanol levels, survival is probable as long as the respiratory and cardiovascular systems can be supported. The average blood alcohol concentration in fatal cases is above 400 mg/dL; however, the lethal dose of alcohol varies because of varying degrees of tolerance.


Pharmacology_Katzung

Pharmacology_Katzung. Electrolyte imbalances often need to be corrected, and metabolic alterations may require treatment of hypoglycemia and ketoacidosis by administration of glucose. Thiamine is given to protect against Wernicke-Korsakoff syndrome. Patients who are dehydrated and vomiting should also receive electrolyte solutions. If vomiting is severe, large amounts of potassium may be required as long as renal function is normal.


Pharmacology_Katzung

Pharmacology_Katzung. Abrupt alcohol discontinuation in an individual with alcohol dependence leads to a characteristic syndrome of motor agitation, anxiety, insomnia, and reduction of seizure threshold. The severity of the syndrome is usually proportionate to the degree and duration of alcohol abuse. However, this can be greatly modified by the use of other sedatives as well as by associated factors (eg, diabetes, injury). In its mildest form, the alcohol withdrawal syndrome of increased pulse and blood pressure, tremor, anxiety, and insomnia occurs 6–8 hours after alcohol consumption is stopped (Figure 23–2). These effects usually lessen in 1–2 days, although some, such as anxiety and sleep disturbances, can be seen at decreasing levels for several months. In some patients, more severe acute reactions occur, with withdrawal seizures or alcoholic hallucinations during the first 1–5 days of withdrawal. Alcohol withdrawal is one of the most common causes of seizures in adults. Several days later,


Pharmacology_Katzung

Pharmacology_Katzung. occur, with withdrawal seizures or alcoholic hallucinations during the first 1–5 days of withdrawal. Alcohol withdrawal is one of the most common causes of seizures in adults. Several days later, individuals can develop the syndrome of delirium tremens, which is characterized by delirium, agitation, autonomic nervous system instability, low-grade fever, and diaphoresis.


Pharmacology_Katzung

Pharmacology_Katzung. The major objective of drug therapy in the alcohol withdrawal period is prevention of seizures, delirium, and arrhythmias. Potassium, magnesium, and phosphate balance should be restored as rapidly as is consistent with renal function. Thiamine therapy is initiated in all cases. Individuals in mild alcohol withdrawal do not need any other pharmacologic assistance.


Pharmacology_Katzung

Pharmacology_Katzung. Specific drug treatment for detoxification in more severe cases involves two basic principles: substituting a long-acting sedative-hypnotic drug for alcohol and then gradually reducing (“tapering”) the dose of the long-acting drug. Because of their wide margin of safety, benzodiazepines are preferred. Long-acting benzodiazepines, including chlordiazepoxide and diazepam, have the advantage of requiring less frequent dosing. Since their pharmacologically active metabolites are eliminated slowly, the long-acting drugs provide a built-in tapering effect. A disadvantage of the long-acting drugs is that they and their active metabolites may accumulate, especially in patients with compromised liver function. Shorter-acting drugs such as lorazepam and oxazepam are rapidly converted to inactive water-soluble metabolites that will not accumulate, and for this reason the short-acting drugs are especially useful in alcoholic patients with liver disease. Benzodiazepines can be administered orally


Pharmacology_Katzung

Pharmacology_Katzung. metabolites that will not accumulate, and for this reason the short-acting drugs are especially useful in alcoholic patients with liver disease. Benzodiazepines can be administered orally in mild or moderate cases, or parenterally for patients with more severe withdrawal reactions.


Pharmacology_Katzung

Pharmacology_Katzung. After the alcohol withdrawal syndrome has been treated acutely, sedative-hypnotic medications must be tapered slowly over several weeks. Complete detoxification is not achieved with just a few days of alcohol abstinence. Several months may be required for restoration of normal nervous system function, especially sleep. 0 1 2 3 4 5 6 7 8 Delirium tremens (tachycardia, hypertension, low-grade fever, tremor, diaphoresis, delirium, agitation) Anxiety, insomnia, tremor, palpitations, nausea, anorexia Withdrawal seizures Alcoholic hallucinations 30-909


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Pharmacology_Katzung. FIGURE 23–2 Time course of events during the alcohol withdrawal syndrome. The signs and symptoms that manifest earliest are anxiety, insomnia, tremor, palpitations, nausea, and anorexia as well as (in severe syndromes) hallucinations and seizures. Delirium tremens typically develops 48–72 hours after alcohol discontinuation. The earliest symptoms (anxiety, insomnia, etc) can persist, in a milder form, for several months after alcohol discontinuation. After detoxification, psychosocial therapy either in intensive inpatient or in outpatient rehabilitation programs serves as the primary treatment for alcohol dependence. Other psychiatric problems, most commonly depressive or anxiety disorders, often coexist with alcoholism and, if untreated, can contribute to the tendency of detoxified alcoholics to relapse. Treatment for these associated disorders with counseling and drugs can help decrease the rate of relapse for alcoholic patients.


Pharmacology_Katzung

Pharmacology_Katzung. Three drugs—disulfiram, naltrexone, and acamprosate—have FDA approval for adjunctive treatment of alcohol dependence. Naltrexone, a relatively long-acting opioid antagonist, blocks μ-opioid receptors (see Chapter 31). Alone and in combination with behavioral counseling, naltrexone has been shown in a number of short-term (12to 16-week), placebo-controlled trials to reduce the rate of relapse to either drinking or alcohol dependence and to reduce craving for alcohol, especially in patients with high rates of naltrexone adherence. Naltrexone is approved by the FDA for treatment of alcohol dependence. Nalmefene, another opioid antagonist, appears to have similar effects in alcohol-use disorder but is not yet approved by the FDA for this indication.


Pharmacology_Katzung

Pharmacology_Katzung. Naltrexone is generally taken once a day in an oral dose of 50 mg for treatment of alcoholism. An extended-release formulation administered as an intramuscular injection once every 4 weeks is also effective. The drug can cause dose-dependent hepatotoxicity and should be used with caution in patients with evidence of abnormalities in serum aminotransferase activity. The combination of naltrexone plus disulfiram should be avoided, since both drugs are potential hepatotoxins. Administration of naltrexone to patients who are physically dependent on opioids precipitates an acute withdrawal syndrome, so patients must be opioid-free before initiating naltrexone therapy. Naltrexone also blocks the therapeutic analgesic effects of usual doses of opioids.


Pharmacology_Katzung

Pharmacology_Katzung. Acamprosate has been used in Europe for a number of years to treat alcohol dependence and is approved for this use by the FDA. Like ethanol, acamprosate has many molecular effects including actions on GABA, glutamate, serotonergic, noradrenergic, and dopaminergic receptors. Probably its best-characterized actions are as a weak NMDA-receptor antagonist and a GABAA-receptor activator. In European clinical trials, acamprosate reduced short-term and long-term (more than 6 months) relapse rates when combined with psychotherapy. However, in a large American trial that compared acamprosate with naltrexone and with combined acamprosate and naltrexone therapy (the COMBINE study), acamprosate did not show a statistically significant effect alone or in combination with naltrexone.


Pharmacology_Katzung

Pharmacology_Katzung. Acamprosate is administered as one or two enteric-coated 333-mg tablets three times daily. It is poorly absorbed, and food reduces its absorption even further. Acamprosate is widely distributed and is eliminated renally. It does not appear to participate in drug-drug interactions. The most common adverse effects are gastrointestinal (nausea, vomiting, diarrhea) and rash. It should not be used in patients with severe renal impairment.


Pharmacology_Katzung

Pharmacology_Katzung. Disulfiram acts by inhibiting aldehyde dehydrogenase. Alcohol is metabolized as usual, but acetaldehyde accumulates. Thus, disulfiram causes extreme discomfort in patients who drink alcoholic beverages. Disulfiram alone has little effect; however, flushing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion occur within a few minutes after an individual taking disulfiram drinks alcohol. The effects may last 30 minutes in mild cases or several hours in severe ones. Because adherence to disulfiram therapy is low and because evidence from clinical trials for its effectiveness is weak, disulfiram is no longer commonly used.


Pharmacology_Katzung

Pharmacology_Katzung. Disulfiram is rapidly and completely absorbed from the gastrointestinal tract; however, a period of 12 hours is required for its full action. Its elimination is slow, and its action may persist for several days after the last dose. The drug inhibits the metabolism of many other therapeutic agents, including phenytoin, oral anticoagulants, and isoniazid. It should not be administered with medications that contain alcohol, including nonprescription medications such as those listed in Table 63–3. Disulfiram can cause small increases in hepatic transaminases. Its safety in pregnancy has not been demonstrated.


Pharmacology_Katzung

Pharmacology_Katzung. Several other drugs have shown efficacy in maintaining abstinence and reducing craving in chronic alcoholism, although none has FDA approval yet for this use. Such drugs include antiseizure agents (topiramate, gabapentin, and valproate, see Chapter 24); and baclofen, a GABA receptor antagonist used as a spasmolytic (see Chapter 27). Studies of varenicline (see Chapter 7) indicate that this nicotinic agonist drug can reduce binge drinking in mice. Clinical trials of selective serotonin reuptake inhibitors (SSRIs, see Chapter 30) and ondansetron, a 5-HT3 antagonist (see Chapter 62) yielded negative results overall, but suggested that these agents may have benefits in certain subgroups of patients. Based on evidence from model systems, efforts are under way to explore agents that modulate cannabinoid CB1 receptors, corticotropin-releasing factor receptors, and GABA receptor systems, as well as several other possible targets. Rimonabant, a CB1 receptor antagonist, has been shown to


Pharmacology_Katzung

Pharmacology_Katzung. cannabinoid CB1 receptors, corticotropin-releasing factor receptors, and GABA receptor systems, as well as several other possible targets. Rimonabant, a CB1 receptor antagonist, has been shown to suppress alcohol-related behaviors in animal models and is being tested in clinical trials of alcoholism.


Pharmacology_Katzung

Pharmacology_Katzung. Other alcohols related to ethanol have wide applications as industrial solvents and occasionally cause severe poisoning. Of these, methanol and ethylene glycol are two of the most common causes of intoxication. Isopropyl alcohol (isopropanol, rubbing alcohol) is another alcohol that is sometimes ingested when ethanol is not available. It produces coma and gastrointestinal irritation, nausea, and vomiting, but is not usually associated with retinal or renal injury. Methanol (methyl alcohol, wood alcohol) is widely used in the industrial production of synthetic organic compounds and as a constituent of many commercial solvents. In the home, methanol is most frequently found in the form of “canned heat” or in windshield-washing products. Poisonings occur from accidental ingestion of methanol-containing products or when it is misguidedly ingested as an ethanol substitute.


Pharmacology_Katzung

Pharmacology_Katzung. Methanol can be absorbed through the skin or from the respiratory or gastrointestinal tract and is then distributed in body water. The primary mechanism of elimination of methanol in humans is by oxidation to formaldehyde, formic acid, and CO2 (Figure 23–3). Animal species show great variability in mean lethal doses of methanol. The special susceptibility of humans to methanol toxicity is due to metabolism to formate and formaldehyde, not due to methanol itself. Since the conversion of methanol to its toxic metabolites is relatively slow, there is often a delay of 6–30 hours before the appearance of severe toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Physical findings in early methanol poisoning are generally nonspecific, such as inebriation and gastritis, and possibly an elevated osmolar gap (see Chapter 58). In severe cases, the odor of formaldehyde may be present on the breath or in the urine. After a delay, the most characteristic symptom in methanol poisoning— visual disturbance—occurs along with anion gap metabolic acidosis. The visual disturbance is frequently described as “like being in a snowstorm” and can progress to blindness. Changes in the retina FIGURE 23–3 Methanol is converted to the toxic metabolites formaldehyde and formate by alcohol dehydrogenase and aldehyde dehydrogenase. By inhibiting alcohol dehydrogenase, fomepizole and ethanol reduce the formation of toxic metabolites.


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 23 The Alcohols 405 may sometimes be detected on examination, but these are usually late. The development of bradycardia, prolonged coma, seizures, and resistant acidosis all imply a poor prognosis. The cause of death in fatal cases is sudden cessation of respiration. A serum methanol concentration higher than 20 mg/dL warrants treatment, and a concentration higher than 50 mg/dL is considered serious enough to require hemodialysis. Serum formate levels are a better indication of clinical pathology but are not widely available. The first treatment for methanol poisoning, as in all critical poisoning situations, is support of respiration. There are three specific modalities of treatment for severe methanol poisoning: suppression of metabolism by alcohol dehydrogenase to toxic products, hemodialysis to enhance removal of methanol and its toxic products, and alkalinization to counteract metabolic acidosis.


Pharmacology_Katzung

Pharmacology_Katzung. The enzyme chiefly responsible for methanol oxidation in the liver is alcohol dehydrogenase (Figure 23–3). Fomepizole, an alcohol dehydrogenase inhibitor, is approved for the treatment of methanol and ethylene glycol poisoning. It is administered intravenously in a loading dose of 15 mg/kg followed by 10 mg/kg every 12 hours for 48 hours and then 15 mg/kg every 12 hours thereafter until the serum methanol level falls below 20–30 mg/dL. The dosage increase after 48 hours is based on evidence that fomepizole rapidly induces its own metabolism by the cytochrome P450 system. Patients undergoing hemodialysis are given fomepizole more frequently (6 hours after the loading dose and every 4 hours thereafter). Fomepizole appears to be safe during the short time it is administered for treatment of methanol or ethylene glycol poisoning. The most common adverse effects are burning at the infusion site, headache, nausea, and dizziness. Intravenous ethanol is an alternative to fomepizole. It has a


Pharmacology_Katzung

Pharmacology_Katzung. methanol or ethylene glycol poisoning. The most common adverse effects are burning at the infusion site, headache, nausea, and dizziness. Intravenous ethanol is an alternative to fomepizole. It has a higher affinity than methanol for alcohol dehydrogenase; thus, saturation of the enzyme with ethanol reduces formate production. Ethanol is used intravenously as treatment for methanol and ethylene glycol poisoning. The dose-dependent characteristics of ethanol metabolism and the variability of ethanol metabolism require frequent monitoring of blood ethanol levels to ensure appropriate alcohol concentration.


Pharmacology_Katzung

Pharmacology_Katzung. In cases of severe poisoning, hemodialysis (discussed in Chapter 58) can be used to eliminate both methanol and formate from the blood. Two other measures are commonly taken. Because of profound metabolic acidosis in methanol poisoning, treatment with bicarbonate often is necessary. Since folate-dependent systems are responsible for the oxidation of formic acid to CO2 in humans (Figure 23–3), folinic and folic acid are often administered to patients poisoned with methanol, although this has never been fully tested in clinical studies.


Pharmacology_Katzung

Pharmacology_Katzung. Polyhydric alcohols such as ethylene glycol (CH2OHCH2OH) are used as heat exchangers, in antifreeze formulations, and as industrial solvents. Young children and animals are sometimes attracted by the sweet taste of ethylene glycol and, rarely, it is ingested intentionally as an ethanol substitute or in attempted suicide. Although ethylene glycol itself is relatively harmless and eliminated by the kidney, it is metabolized to toxic aldehydes and oxalate.


Pharmacology_Katzung

Pharmacology_Katzung. Three stages of ethylene glycol overdose occur. Within the first few hours after ingestion, there is transient excitation followed by CNS depression. After a delay of 4–12 hours, severe metabolic acidosis develops from accumulation of acid metabolites and lactate. Finally, deposition of oxalate crystals in renal tubules occurs, followed by delayed renal insufficiency. The key to the diagnosis of ethylene glycol poisoning is recognition of anion gap acidosis, osmolar gap, and oxalate crystals in the urine in a patient without visual symptoms.


Pharmacology_Katzung

Pharmacology_Katzung. As with methanol poisoning, early fomepizole is the standard treatment for ethylene glycol poisoning. Intravenous treatment with fomepizole is initiated immediately, as described above for methanol poisoning, and continued until the patient’s serum ethylene glycol concentration drops below a toxic threshold (20–30 mg/dL). Intravenous ethanol is an alternative to fomepizole in ethylene glycol poisoning. Hemodialysis effectively removes ethylene glycol and its toxic metabolites and is recommended for patients with a serum ethylene glycol concentration above 50 mg/dL, significant metabolic acidosis, and significant renal impairment. Fomepizole has reduced the need for hemodialysis, especially in patients with less severe acidosis and intact renal function. • Ethanol Multiple effects on neurotransmitter receptors, ion channels, and signaling pathways Zero-order metabolism • duration depends on dose • Toxicity:


Pharmacology_Katzung

Pharmacology_Katzung. • Ethanol Multiple effects on neurotransmitter receptors, ion channels, and signaling pathways Zero-order metabolism • duration depends on dose • Toxicity: Acutely, central nervous system depression and respiratory failure • chronically, damage to many systems, including liver, pancreas, gastrointestinal tract, and central and peripheral nervous systems • Interactions: Induces CYP2E1 • increased conversion of acetaminophen to toxic metabolite Methanol: Poisonings result in toxic levels of formate, which causes characteristic visual disturbance plus coma, seizures, acidosis, and death due to respiratory failure


Pharmacology_Katzung

Pharmacology_Katzung. Ethylene glycol: Poisoning creates toxic aldehydes and oxalate, which causes kidney damage and severe acidosis •Benzodiazepines(eg, chlordiazepoxide, diazepam, lorazepam) BDZ receptor agonists that facilitate GABA-mediated activation of GABAA receptors Prevention and treatment of acute ethanol withdrawal syndrome See Chapter 22 •Thiamine(vitaminB1) Essential vitamin required for synthesis of the coenzyme thiamine pyrophosphate Administered to patients suspected of having alcoholism (those exhibiting acute alcohol intoxication or alcohol withdrawal syndrome) to prevent Wernicke-Korsakoff syndrome Administeredparenterally•Toxicity: None•Interactions: None DRUGS USED IN ACUTE ETHANOL WITHDRAWAL • Ethanol: Higher affinity than methanol or ethylene glycol for alcohol dehydrogenase; used to reduce metabolism of methanol and ethylene glycol to toxic products Disulfiram Generic, Antabuse Chlordiazepoxide HCl Generic, Librium


Pharmacology_Katzung

Pharmacology_Katzung. Disulfiram Generic, Antabuse Chlordiazepoxide HCl Generic, Librium DRUGS FOR THE PREVENTION OF ALCOHOL ABUSE Acamprosate calcium Generic, Campral Diazepam Generic, Valium Naltrexone HCl Generic, Vivitrol, ReVia Lorazepam Generic, Ativan Oxazepam Generic, Serax Thiamine HCl Generic Ethanol Generic Fomepizole Generic, Antizol Anton RF: Naltrexone for the management of alcohol dependence. N Engl J Med 2008;359:715. Anton RF et al: Combined pharmacotherapies and behavioral interventions for alcohol dependence: The COMBINE study: A randomized controlled trial. JAMA 2006;295:2003. Brent J: Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med 2009;360:2216. Brodie MS et al: Ethanol interactions with calcium-dependent potassium channels. Alcohol Clin Exp Res 2007;31:1625. Centers for Disease Control and Prevention: Fetal alcohol spectrum disorder. https://www.cdc.gov/ncbddd/fasd/


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Pharmacology_Katzung. Centers for Disease Control and Prevention: Fetal alcohol spectrum disorder. https://www.cdc.gov/ncbddd/fasd/ Chan LN, Anderson GD: Pharmacokinetic and pharmacodynamics interactions with ethanol (alcohol). Clin Pharmacokinet 2014;53:1115. Chen YC et al: Polymorphism of ethanol-metabolism genes and alcoholism: Correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences. Chem Biol Interact 2009;178:2. Colombo G et al: The cannabinoid CB1 receptor antagonist, rimonabant, as a promising pharmacotherapy for alcohol dependence: Preclinical evidence. Mol Neurobiol 2007;36:102. Crabbe JC et al: Alcohol-related genes: Contributions from studies with genetically engineered mice. Addict Biol 2006;11:195. Das SK, Vasudevan DM: Alcohol-induced oxidative stress. Life Sci 2007;81:177. Edenberg HJ: The genetics of alcohol metabolism: Role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 2007;30:5.


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Pharmacology_Katzung. Edenberg HJ: The genetics of alcohol metabolism: Role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 2007;30:5. Heffernan TM: The impact of excessive alcohol use on prospective memory: A brief review. Curr Drug Abuse Rev 2008;1:36. Hendricson AW et al: Aberrant synaptic activation of N-methyl-D-aspartate receptors underlies ethanol withdrawal hyperexcitability. J Pharmacol Exp Ther 2007;321:60. Johnson BA: Pharmacotherapy for alcohol use disorder. In: Saitz R (editor): UpToDate. Waltham, MA. http://www.uptodate.com/contents/ pharmacotherapy-for-alcohol-use-disorder Johnson BA: Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings. Biochem Pharmacol 2008;75:34. Jonas DE et al: Pharmacotherapy for adults with alcohol use disorders in outpatient settings. A systematic review and meta-analysis. JAMA 2014;311:1889. Klatsky AL: Alcohol and cardiovascular diseases. Expert Rev Cardiovasc Ther 2009;7:499.


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Pharmacology_Katzung. Klatsky AL: Alcohol and cardiovascular diseases. Expert Rev Cardiovasc Ther 2009;7:499. Lepik KJ et al: Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: A comparison of ethanol and fomepizole. Ann Emerg Med 2009;53:439. Lobo IA, Harris RA: GABA(A) receptors and alcohol. Pharmacol Biochem Behav 2008;90:90. Mann K et al: Acamprosate: Recent findings and future research directions. Alcohol Clin Exp Res 2008;32:1105. Mayfield RD, Harris RA, Schuckit MA: Genetic factors influencing alcohol dependence. Br J Pharmacol 2008;154:275. Mitchell JM: Varenicline decreases alcohol consumption in heavy-drinking smokers. Psychopharmacology (Berl) 2012;223:299. National Institutes of Health: National Institute on Alcohol Abuse and Alcoholism. http://www.niaaa.nih.gov/ O’Keefe JH, Bybee KA, Lavie CJ: Alcohol and cardiovascular health: The razor-sharp double-edged sword. J Am Coll Cardiol 2007:50:1009.


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Pharmacology_Katzung. O’Keefe JH, Bybee KA, Lavie CJ: Alcohol and cardiovascular health: The razor-sharp double-edged sword. J Am Coll Cardiol 2007:50:1009. Olson KR et al (editors): Poisoning and Drug Overdose, 7th ed. McGraw-Hill, 2017. Patkar OL et al: The effect of varenicline on binge-like ethanol consumption in mice is β4 nicotinic acetylcholine receptor-independent. Neurosci Lett 2016;633:235. Qiang M, Denny AD, Ticku MK: Chronic intermittent ethanol treatment selectively alters N-methyl-D-aspartate receptor subunit surface expression in cultured cortical neurons. Mol Pharmacol 2007;72:95. Seitz HK, Stickel F: Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 2007;7:599. Srisurapanont M, Jarusuraisin N: Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 2005;1:CD001867. Wolf FW, Heberlein U: Invertebrate models of drug abuse. J Neurobiol 2003;54:161.


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Pharmacology_Katzung. This young man exhibited classic signs and symptoms of acute alcohol poisoning, which is confirmed by the blood alcohol concentration. We do not know from the case whether the patient was tolerant to the effects of alcohol but note that his blood alcohol concentration was in the lethal range for a nontolerant individual. Death most likely resulted from respi-ratory and cardiovascular collapse prior to medical treatment, complicated by a chemical pneumonitis secondary to aspira-tion of vomitus. The treatment of acute alcohol poisoning includes standard supportive care of airway, breathing, and circulation (“ABCs,” see Chapter 58). Most importantly, the trachea would be intubated, vomitus removed, and mechani-cal ventilation begun. Intravenous access would be obtained and used to administer dextrose and thiamine, as well as elec-trolytes and vitamins. If a young, previously healthy individual receives medical care in time, supportive care will most likely be highly effective. As the


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Pharmacology_Katzung. dextrose and thiamine, as well as elec-trolytes and vitamins. If a young, previously healthy individual receives medical care in time, supportive care will most likely be highly effective. As the patient recovers, it is important to be vigilant for signs and symptoms of the alcohol withdrawal syndrome. (For a case involving chronic alcoholism and withdrawal management, see Nejad SH et al: Case 39-2012: A 55-year old man with alcoholism, recurrent seizures, and agitation. N Engl J Med 2012;367:2428.)


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Pharmacology_Katzung. Roger J. Porter, MD, & Michael A. Rogawski, MD, PhD was unchanged, and levetiracetam was gradually increased to 1000 mg bid. The patient had no significant adverse effects from this dosage. At age 21, she had a second tonic-clonic seizure while in college; further discussion with her room-mate at that time revealed a history of two recent episodes of 1–2 minutes of altered consciousness with lip smacking (focal impaired awareness seizure, formerly complex partial seizure). A repeat EEG showed occasional right temporal spikes. What is one possible strategy for controlling her present symptoms? A 23-year-old woman presents to the office for consultation regarding her antiseizure medications. Seven years ago, this otherwise healthy young woman had a tonic-clonic seizure at home. She was rushed to the emergency department, at which time she was alert but complained of headache. A consulting neurologist placed her on levetiracetam, 500 mg bid. Four days later, electroencephalography (EEG)


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Pharmacology_Katzung. to the emergency department, at which time she was alert but complained of headache. A consulting neurologist placed her on levetiracetam, 500 mg bid. Four days later, electroencephalography (EEG) showed rare right temporal sharp waves. Magnetic resonance imaging (MRI) was normal. One year after this episode, a repeat EEG


Pharmacology_Katzung

Pharmacology_Katzung. Epilepsy is a chronic disorder of brain function characterized by the recurrent and unpredictable occurrence of seizures. Approximately 1% of the world’s population has epilepsy, which is the fourth most common neurologic disorder after migraine, stroke, and Alzheimer’s disease. Seizures that occur in people with epilepsy are transitory alterations in behavior, sensation, or consciousness caused by an abnormal, synchronized electrical discharge in the brain. Many cases of epilepsy are the result of damage to the brain, as occurs in traumatic brain injury, stroke, or infections, whereas in other cases, the epilepsy is caused by a brain tumor or developmental lesion such as a cortical or vascular malformation; these epilepsies are referred to as “symptomatic.” In other cases, genetic factors are believed to be the root cause. Genetic epilepsies are often called idiopathic. In most cases, the inheritance is complex (polygenic). Rarely, a single gene defect can be identified. A wide


Pharmacology_Katzung

Pharmacology_Katzung. are believed to be the root cause. Genetic epilepsies are often called idiopathic. In most cases, the inheritance is complex (polygenic). Rarely, a single gene defect can be identified. A wide diversity of genes may be affected, including (1) those encoding voltage-gated ion channels and synaptic receptors such as GABAA receptors, (2) components of the neurotransmitter release machinery including syntaxin binding protein (STXBP1), (3) neural adhesion molecules such as PCDH19, and (4) proteins involved in synapse development such as leucine-rich glioma inactivated-1 (LGI1).


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Pharmacology_Katzung. The antiseizure drugs described in this chapter are usually used chronically to prevent the occurrence of seizures in people with epilepsy. These drugs are also, on occasion, used in people who do not have epilepsy—to prevent seizures that may occur as part of an acute illness such as meningitis or in the early period following either neurosurgery or traumatic brain injury. In addition, certain antiseizure drugs are used to terminate ongoing seizures such as in status epilepticus or prolonged febrile seizures or following exposure to seizure-inducing nerve toxins. Seizures are occasionally caused by an acute underlying toxic or metabolic disorder, such as hypocalcemia, in which case appropriate therapy should be directed toward correcting the specific abnormality.


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Pharmacology_Katzung. Most antiseizure drugs have been identified by tests in rodent (rat or mouse) models. The maximal electroshock (MES) test, in which animals receive an electrical stimulus, with tonic hindlimb extension as the end point, has been the most productive model. The MES test led to the identification of many of the sodium channel-blocking antiseizure drugs. Another model, the pentylenetetrazol (PTZ) test, in which animals receive a dose of the chemical convulsant PTZ (an antagonist of GABAA receptors) sufficient to cause clonic seizures, has also been widely used. Animals with a genetic susceptibility to absence-like episodes are useful in identifying drugs for the treatment of absence seizures. In the kindling model, mice or rats repeatedly receive a mild electrical stimulus in the amygdala or hippocampus over the course of a number of days, causing them to develop a permanent propensity for limbic seizures when they later are stimulated. The kindling model can be used to assess the ability


Pharmacology_Katzung

Pharmacology_Katzung. over the course of a number of days, causing them to develop a permanent propensity for limbic seizures when they later are stimulated. The kindling model can be used to assess the ability of a chemical compound to protect against focal seizures. In addition to empirical screening of chemical compounds in such animal models, a few antiseizure drugs have been identified by in vitro screening against a molecular target. Examples of targets that have been used to identify approved antiseizure drugs include γ-aminobutyric acid (GABA) transaminase (vigabatrin), GAT-1 GABA transporter (tiagabine), AMPA receptors (perampanel), or the synaptic vesicle protein SV2A (brivaracetam).


Pharmacology_Katzung

Pharmacology_Katzung. Epileptic seizures are classified into two main categories: (1) focal onset seizures (in the past called “partial” or “partial onset” seizures), which begin in a local cortical site, and (2) generalized onset seizures, which involve both brain hemispheres from the onset (Table 24–1). Focal seizures can transition to bilateral tonic-clonic seizures (formerly called “secondarily generalized”). Focal aware seizures (previously “simple partial seizures”) have preservation of consciousness; focal impaired awareness seizures (formerly “complex partial seizures”) have impaired consciousness. Tonic-clonic convulsions (previously termed “grand mal”) are what most people typically think of as a seizure: the person TABLE 24–1 International League Against Epilepsy classification of seizure types. Generalized absence seizure (formerly petit mal seizure; occurs, for example, in absence epilepsy) Myoclonic seizure (occurs, for example, in juvenile myoclonic epilepsy and Dravet’s syndrome)


Pharmacology_Katzung

Pharmacology_Katzung. Generalized absence seizure (formerly petit mal seizure; occurs, for example, in absence epilepsy) Myoclonic seizure (occurs, for example, in juvenile myoclonic epilepsy and Dravet’s syndrome) Atonic seizure (drop seizure or astatic seizure; occurs, for example, in the Lennox-Gastaut syndrome) Epileptic spasms (as in infantile spasms also known as West’s syndrome) Lennox-Gastaut syndrome, Dravet’s syndrome, and juvenile myoclonic epilepsy are epilepsy syndromes in which there are multiple different seizure types.


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Pharmacology_Katzung. loses consciousness, falls, stiffens (the tonic phase), and jerks (clonic phase). Tonic-clonic convulsions usually last for less than 3 minutes but are followed by confusion and tiredness of variable duration (“postictal period”). Generalized tonic-clonic seizures involve both hemispheres from the onset; they occur in patients with idiopathic generalized epilepsies, in some classifications referred to as genetic generalized epilepsies, and have been referred to as primary generalized tonic-clonic seizures. Generalized absence seizures (formerly called “petit mal”) are brief episodes of unconsciousness (4–20 seconds, usually <10 seconds) with no warning and immediate resumption of consciousness (no postictal abnormality). Generalized absence seizures most commonly occur in children with childhood absence epilepsy, a specific idiopathic generalized epilepsy syndrome beginning between 4 and 10 years (usually 5–7 years); most remit by age 12. Other important epilepsy syndromes are


Pharmacology_Katzung

Pharmacology_Katzung. with childhood absence epilepsy, a specific idiopathic generalized epilepsy syndrome beginning between 4 and 10 years (usually 5–7 years); most remit by age 12. Other important epilepsy syndromes are infantile spasms (West’s syndrome), Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, and Dravet’s syndrome. The major seizure type in infantile spasms is the epileptic spasm, which consists of a sudden flexion, extension, or mixed extension-flexion of predominantly proximal and truncal muscles. Limited forms, such as grimacing, head nodding, or subtle eye movements, can occur. Myoclonic seizures are sudden, brief (<100 milliseconds), involuntary, single or multiple contractions of muscles or muscle groups of variable topography (axial, proximal limb, distal limb). Myoclonus is less regularly repetitive and less sustained than is clonus.


Pharmacology_Katzung

Pharmacology_Katzung. Antiseizure drugs used in the chronic treatment of epilepsy are administered orally; the objective is to prevent the occurrence of seizures. The choice of medication depends either on the type of seizures that the patient exhibits or on the patient’s syndromic classification. Appropriately chosen antiseizure drugs provide adequate seizure control in about two-thirds of patients. In designing a therapeutic strategy, the use of a single drug is preferred, especially in patients who are not severely affected; such patients can benefit from the advantage of fewer adverse effects using monotherapy. For patients with hard-to-control seizures, multiple drugs are usually used simultaneously. Patients who do not achieve seizure control following adequate trials with two or more appropriate drugs are considered “pharmacoresistant.” The basis for pharmacoresistance is not well understood. In children, some severe seizure syndromes (catastrophic childhood epilepsies) associated with progressive


Pharmacology_Katzung

Pharmacology_Katzung. are considered “pharmacoresistant.” The basis for pharmacoresistance is not well understood. In children, some severe seizure syndromes (catastrophic childhood epilepsies) associated with progressive brain damage are very difficult to treat. Focal seizures may also be refractory to medications. In some cases, the epilepsy can be cured by surgical resection of the affected brain region. The most commonly performed epilepsy surgery is temporal lobe resection for mesial temporal lobe epilepsy; extratemporal cortical resection, when indicated, is less successful. When seizures arise from cortical injury, malformation, tumor, or a vascular lesion, lesionectomy may be curative. In addition to medications and surgery, several electrical stimulation devices are used in the treatment of epilepsy. The vagus nerve stimulator (VNS) is an implanted programmable pulse generator with a helical electrode that is wrapped around the left vagus nerve in the neck. The device, which continuously delivers


Pharmacology_Katzung

Pharmacology_Katzung. The vagus nerve stimulator (VNS) is an implanted programmable pulse generator with a helical electrode that is wrapped around the left vagus nerve in the neck. The device, which continuously delivers open-loop stimulation according to a duty cycle, is approved for the treatment of drug-refractory focal seizures but may also be a good option for symptomatic (or cryptogenic) generalized epilepsies of the Lennox-Gastaut type, including those with intractable atonic seizures. Another device for the treatment of medically refractory focal epilepsy is the responsive neurostimulator (RNS). The RNS is a closed-loop system that detects a pattern of abnormal electrical activity in the seizure focus and then delivers electrical stimulation to prevent seizure occurrence. Other devices, using various paradigms of electrical stimulation, are in clinical development. One of these, a deep brain stimulation device, has been approved in Canada and Europe but not in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Antiseizure drugs protect against seizures by interacting with one or more molecular targets in the brain. The ultimate effect of these interactions is to inhibit the local generation of seizure discharges, both by reducing the ability of neurons to fire action potentials at high rate as well as reducing neuronal synchronization. In addition, antiseizure drugs inhibit the spread of epileptic activity to nearby and distant sites, either by strengthening the inhibitory surround mediated by GABAergic interneurons or by reducing glutamate-mediated excitatory neurotransmission (the means through which a presynaptic neuron depolarizes and excites a postsynaptic follower neuron). The specific actions of antiseizure drugs on their targets are broadly described as: (1) modulation of voltage-gated sodium, calcium, or potassium channels; enhancement of fast GABA-mediated synaptic inhibition; modification of synaptic release processes; and (4) diminution of fast glutamate-mediated excitation.


Pharmacology_Katzung

Pharmacology_Katzung. sodium, calcium, or potassium channels; enhancement of fast GABA-mediated synaptic inhibition; modification of synaptic release processes; and (4) diminution of fast glutamate-mediated excitation. These actions can be viewed in the context of the balance between excitation mediated by glutamatergic neurons and inhibition mediated by GABAergic neurons. A propensity for seizure generation occurs when there is an imbalance favoring excitation over inhibition, which can result from either excessive excitation or diminished inhibition or both. Treatments, therefore, that either inhibit excitation or enhance inhibition have antiseizure actions to reduce seizure generation. Inhibition of excitation can be produced by effects on intrinsic excitability mechanisms in excitatory neurons (eg, sodium channel blockers) or on excitatory synaptic transmission (eg, modification of release of the excitatory neurotransmitter glutamate; AMPA receptor antagonists). Enhancement of inhibition is produced by


Pharmacology_Katzung

Pharmacology_Katzung. blockers) or on excitatory synaptic transmission (eg, modification of release of the excitatory neurotransmitter glutamate; AMPA receptor antagonists). Enhancement of inhibition is produced by increased activation of GABAA receptors, the mediators of inhibition in cortical areas relevant to seizures. Some drug treatments (eg, benzodiazepines, phenobarbital) act as positive allosteric modulators of GABAA receptors, whereas others (eg, tiagabine, vigabatrin) lead to increased availability of neurotransmitter GABA. Voltage-gated potassium channels of the Kv7 type also serve as an inhibitory influence on epileptiform activity. Retigabine (ezogabine), a positive allosteric modulator of Kv7 channels, exerts a unique antiseizure action by virtue of its ability to enhance the natural inhibitory influence of these channels. The specific sites at excitatory and inhibitory neurons and synapses where currently available antiseizure drugs act to exert these diverse actions are illustrated in


Pharmacology_Katzung

Pharmacology_Katzung. influence of these channels. The specific sites at excitatory and inhibitory neurons and synapses where currently available antiseizure drugs act to exert these diverse actions are illustrated in Figure 24–1. Table 24–2 lists the various targets at which currently available antiseizure drugs are thought to act and the drugs that act on those targets. For some drugs, there is no consensus as to the specific molecular target (eg, valproate, zonisamide, rufinamide) or there may be multiple targets (eg, topiramate, felbamate).


Pharmacology_Katzung

Pharmacology_Katzung. Chronic antiseizure drug administration prevents the occurrence of seizures, which can, on occasion, be life threatening. Therefore, adequate drug exposure must be continuously maintained. However, many antiseizure drugs also have a narrow therapeutic window; dosing must therefore avoid excessive, toxic exposure. An understanding of the pharmacokinetic properties of the drugs is essential. It is also necessary for the clinician to be cognizant of special factors that affect dosing; these factors include nonlinear relationships between dose and drug exposure and the influence of hepatic or renal impairment on clearance (see Chapters 3 and 4). Further, drug-drug interactions occur with many of the agents—a special issue since the drugs are often used in combination. For some antiseizure drugs, drug-drug interactions are complex (see Chapter 66). For example, addition of a new drug may affect the clearance of the current medication such that the dose of the current medication must be


Pharmacology_Katzung

Pharmacology_Katzung. drugs, drug-drug interactions are complex (see Chapter 66). For example, addition of a new drug may affect the clearance of the current medication such that the dose of the current medication must be modified. Further, the current medication may necessitate a different dosing of the new drug—different from dosing in a drug-naïve subject. Many antiseizure drugs are metabolized by hepatic enzymes, and some, such as carbamazepine, oxcarbazepine, eslicarbazepine acetate, phenobarbital, phenytoin, and primidone, are strong inducers of hepatic cytochrome P450 and glucuronyl transferase enzymes. A new antiseizure drug may increase the concentration of an existing drug by inhibiting its metabolism; alternatively, the new drug may reduce the concentration by inducing the metabolism of the existing drug. Other antiseizure drugs are excreted in the kidney and are less susceptible to drug-drug interactions. Some antiseizure drugs have active metabolites. The extent of conversion to the active


Pharmacology_Katzung

Pharmacology_Katzung. drug. Other antiseizure drugs are excreted in the kidney and are less susceptible to drug-drug interactions. Some antiseizure drugs have active metabolites. The extent of conversion to the active forms can be affected by the presence of other drugs. Some antiseizure drugs, such as phenytoin, tiagabine, valproate, diazepam, and perampanel, are highly (>90%) bound to plasma proteins. These drugs can be displaced from plasma proteins by other protein-bound drugs, resulting in a temporary rise in the free fraction. Since the free (unbound) drug is active, there can be transient toxicity. However, systemic clearance increases along with the increased free fraction, so the elevation in free concentration is eventually corrected. Some antiseizure drugs, notably levetiracetam, gabapentin, and pregabalin, are not known to have drug interactions. Antiseizure drugs can also interact with other medications. Importantly, oral contraceptive levels may be reduced by strong inducers, resulting in


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Pharmacology_Katzung. pregabalin, are not known to have drug interactions. Antiseizure drugs can also interact with other medications. Importantly, oral contraceptive levels may be reduced by strong inducers, resulting in failure of birth control.


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Pharmacology_Katzung. Presynaptic terminal Phenytoin, carbamazepine, of glutamate neuron lamotrigine, lacosamide, zonisamide, oxcarbazepine Gabapentin, ˜2° subunit of P/Q-type Ca2+ channel Na+, Ca2+ Na+, (Ca2+) Presynaptic terminal of GABA neuron Astrocyte


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 24–1 Molecular targets for antiseizure drugs at the excitatory glutamatergic synapse (A) and the inhibitory GABAergic synapse (B). Presynaptic targets diminishing glutamate release include Nav1.6 voltage-gated sodium channels (carbamazepine, monohydroxy derivative [MHD], phenytoin, lamotrigine, and lacosamide), Kv7 voltage-gated potassium channels (retigabine [ezogabine]), and α2δ (gabapentin and pregabalin). Postsynaptic targets at excitatory synapses are AMPA receptors (perampanel), T-type Cav voltage-gated calcium channels (ethosuximide, dimethadione), and Kv7 voltage-gated potassium channels (retigabine [ezogabine]). At inhibitory synapses and in astrocytes, vigabatrin inhibits GABA-transaminase (GABA-T) and tiagabine blocks GABA transporter 1 (GAT-1). Phenobarbital, primidone (via metabolism to phenobarbital), and benzodiazepines are positive allosteric modulators of synaptic GABAA receptors; high GABA levels resulting from blockade of GABA-T may act on extrasynaptic GABAA


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Pharmacology_Katzung. metabolism to phenobarbital), and benzodiazepines are positive allosteric modulators of synaptic GABAA receptors; high GABA levels resulting from blockade of GABA-T may act on extrasynaptic GABAA receptors.


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Pharmacology_Katzung. TABLE 24–2 Molecular targets of antiseizure drugs. 1Fosphenytoin is a prodrug for phenytoin. 2Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine. 3Eslicarbazepine acetate is a prodrug for S-licarbazepine. 4Gabapentin enacarbil is a prodrug for gabapentin. 5There is no consensus as to the mechanism of valproate; felbamate, topiramate, zonisamide, and rufinamide may have actions on as yet unidentified targets in addition to those shown in the table. Modified from Rogawski MA, Löscher W, Rho JM: Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med 2016;6:a022780.


Pharmacology_Katzung

Pharmacology_Katzung. Antiseizure drugs must have reasonable oral bioavailability and must enter the central nervous system. These drugs are predominantly distributed into total body water. Plasma clearance is relatively slow; many antiseizure drugs are therefore considered to be medium to long acting, such that they are administered twice or three times a day. Some have half-lives longer than 12 hours. A few, such as zonisamide and perampanel, can often be administered once daily. For some drugs with short half-lives, extended-release preparations are now available; as a result, compliance is better. In the remainder of the chapter, the most widely used anti-seizure drugs, as well as some that are used only in special circumstances, are reviewed. The focal (partial onset) seizure medications are described first, followed by medications for generalized onset seizures and certain epileptic syndromes.


Pharmacology_Katzung

Pharmacology_Katzung. Carbamazepine is a prototype of the antiseizure drugs primarily used in the treatment of focal onset seizures. In addition to being effective in the treatment of focal seizures, carbamazepine is indicated for the treatment of tonic-clonic (grand mal) seizures. This indication derives from studies in patients whose focal onset seizures progressed to bilateral tonic-clonic seizures (previously called “secondarily generalized tonic-clonic seizures”). Drugs like carbamazepine exacerbate certain seizure types in idiopathic generalized epilepsies, including myoclonic and absence seizures, and are generally avoided in patients with such a diagnosis. There is evidence from anecdotal reports and small studies indicating that carbamazepine, phenytoin, and lacosamide may be effective and safe in the treatment of generalized tonic-clonic seizures in idiopathic generalized epilepsies. The most popular drugs for the treatment of focal seizures are carbamazepine, lamotrigine, phenytoin, and


Pharmacology_Katzung

Pharmacology_Katzung. in the treatment of generalized tonic-clonic seizures in idiopathic generalized epilepsies. The most popular drugs for the treatment of focal seizures are carbamazepine, lamotrigine, phenytoin, and lacosamide; levetiracetam is also commonly used. Phenobarbital is useful if cost is an issue. Vigabatrin and felbamate are third-line drugs because of risk of toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Carbamazepine is one of the most widely used antiseizure drugs despite its limited range of activity as a treatment for focal (partial onset) and focal-to-bilateral tonic-clonic seizures. It was initially marketed for the treatment of trigeminal neuralgia, for which it is highly effective; it is usually the drug of first choice for this condition. In addition, carbamazepine is a mood stabilizer used to treat bipolar disorder. Structurally, carbamazepine is an iminostilbene (dibenzazepine)— a tricyclic compound consisting of two benzene rings fused to an azepine group. The structure of carbamazepine is similar to that of tricyclic antidepressants such as imipramine, but unlike the tricyclic antidepressants, carbamazepine does not inhibit monoamine (serotonin and norepinephrine) transporters with high affinity; therefore, carbamazepine is not used as an antidepressant despite its ability to treat bipolar disorder. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Carbamazepine is a prototypical sodium channel-blocking antiseizure drug that is thought to protect against seizures by interacting with the voltage-gated sodium channels (Nav1) responsible for the rising phase of neuronal action potentials (see Chapters 14 and 21). In the normal state, when neurons are depolarized to action potential threshold, the sodium channel protein senses the depolarization and, within a few hundred microseconds, undergoes a conformational change (gating) that converts the channel from its closed (resting) nonconducting state to the open conducting state that permits sodium flux (Figure 24–2). Then, within less than a millisecond, the channel enters the inactivated state, terminating the flow of sodium ions. The channel must then be repolarized before it can be activated again by a subsequent depolarization. Brain sodium channels can rapidly cycle through the resting, open, and inactivated states, allowing neurons to fire high-frequency trains of action


Pharmacology_Katzung

Pharmacology_Katzung. be activated again by a subsequent depolarization. Brain sodium channels can rapidly cycle through the resting, open, and inactivated states, allowing neurons to fire high-frequency trains of action potentials.


Pharmacology_Katzung

Pharmacology_Katzung. Sodium channels are multimeric protein complexes, composed of (1) a large α subunit that forms four subunit-like homologous domains (designated I–IV) and (2) one or more smaller β subunits. The ion-conducting pore is contained within the α subunit, as are the elements of the channel that undergo conformational changes in response to membrane depolarization. Carbamazepine and other sodium channel-blocking antiseizure drugs such as phenytoin and lamotrigine bind preferentially to the channel when it is in the inactivated state, causing it to be stabilized in this state. During high-frequency firing, sodium channels cycle rapidly through the inactivated state, allowing the block to accumulate. This leads to a characteristic use-dependent blocking action in which high-frequency trains of action potentials are more effectively inhibited than are either individual action potentials or the firing at low frequencies (see Chapter 14, Figures 14–9 and 14–10). In addition, sodium


Pharmacology_Katzung

Pharmacology_Katzung. trains of action potentials are more effectively inhibited than are either individual action potentials or the firing at low frequencies (see Chapter 14, Figures 14–9 and 14–10). In addition, sodium channel-blocking antiseizure drugs exhibit a voltage dependence to their blocking action because a greater fraction of sodium channels exist in the inactivated state at depolarized potentials. Thus, action potentials, which are superimposed on a depolarized plateau potential as characteristically occurs with seizures, are effectively inhibited. The use dependence and voltage dependence of the blocking action of drugs like carbamazepine provide the ability to preferentially inhibit action potentials during seizure discharges and to less effectively interfere with ordinary ongoing action potential firing (Figure 24–3). Such action is thought to allow such drugs to prevent the occurrence of seizures without causing unacceptable neurologic impairment. It is noteworthy that sodium


Pharmacology_Katzung

Pharmacology_Katzung. potential firing (Figure 24–3). Such action is thought to allow such drugs to prevent the occurrence of seizures without causing unacceptable neurologic impairment. It is noteworthy that sodium channel-blocking antiseizure agents act mainly on action potential firing; the drugs do not directly alter excitatory or inhibitory synaptic responses. However, the effect on action potentials translates into reduced transmitter output at synapses.


Pharmacology_Katzung

Pharmacology_Katzung. Carbamazepine is effective for the treatment of focal and focalto-bilateral tonic-clonic seizures. As noted earlier, there is anecdotal evidence that carbamazepine may be effective in the treatment of generalized tonic-clonic seizures in idiopathic generalized epilepsies but must be used with caution as it can exacerbate absence and myoclonic seizures. Carbamazepine is also effective for the treatment of trigeminal and glossopharyngeal neuralgia, and mania in bipolar disorder. Carbamazepine has nearly 100% oral bioavailability, but the rate of absorption varies widely among patients. Peak levels are usually achieved 6–8 hours after administration. Slowing absorption by giving the drug after meals causes a reduction in peak levels and helps the patient tolerate larger total daily doses. Extended-release formulations may also decrease the incidence of adverse effects.


Pharmacology_Katzung

Pharmacology_Katzung. Distribution is slow, and the volume of distribution is approximately 1 L/kg. Plasma protein binding is approximately 70%. Carbamazepine has a very low systemic clearance of approximately 1 L/kg/d at the start of therapy. The drug has a notable ability to induce its own metabolism, often causing serum concentrations to fall after a few weeks of treatment. Typically, the half-life of 36 hours observed in subjects after an initial single dose decreases to as little as 8–12 hours in subjects receiving continuous therapy. Considerable dosage adjustments are thus to be expected during the first weeks of therapy. Carbamazepine is metabolized in the liver, and only about 5% of the drug is excreted unchanged. The major route of metabolism is conversion to carbamazepine-10,11-epoxide, which has Closed (resting) Open (activated) Inactivated –80 mV –10 mV 10 mV Fast inactivation of Na+ channelsOpening of Na+ channels 10 ms 0.5 nA 2 ms


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 24–2 (A1) Voltage-gated sodium channels mediate the upstroke of action potentials in brain neurons. Fast inactivation of sodium channels (along with the activation of potassium channels) terminates the action potential. (A2) Voltage-clamp recording of sodium channel current following depolarization, illustrating the time course of sodium channel gating. (B) Schematic illustration of the voltage-dependent gating of sodium channels between closed, open, and inactivated states. (C1) Primary structures of the subunits of sodium channels. The main α subunit, consisting of four homologous repeats (I–IV), is shown flanked by the two auxiliary β subunits. Cylinders represent α-helical transmembrane segments. Blue α-helical segments (S5, S6) form the pore region. +, S4 voltage sensors; grey circles, inactivation particle in inactivation gate loop; III-S6 and IV-S6 (red) are regions of antiseizure drug binding. (C2) Schematic illustration of the sodium channel pore composed of the


Pharmacology_Katzung

Pharmacology_Katzung. grey circles, inactivation particle in inactivation gate loop; III-S6 and IV-S6 (red) are regions of antiseizure drug binding. (C2) Schematic illustration of the sodium channel pore composed of the homologous repeats arrayed around the central channel pore through which sodium flows into the neuron. The S5 and S6 transmembrane α-helical segments from each homologous repeat (I–IV) form the four walls of the pore. The outer pore mouth and ion selectivity filter are formed by re-entrant P-loops. The key α-helical S6 segments in repeat III and IV, which contain the antiseizure drug binding sites, are highlighted. A lamotrigine molecule is illustrated in association with its binding site.


Pharmacology_Katzung

Pharmacology_Katzung. B Voltage Dependence of Block Use Dependence of Block 100Percent of ControlNormalized Current 50 –90 mV –60 mV 0 –90 mV –60 mV 0 mV 1 ms 1 nA 1.0 0.5 0.0 1.0 0.5 0.0 0 5 10 Control 0.7 ms pulse duration 20 ms pulse duration Lamotrigine 15 20 55 60 FIGURE 24–3 (A) Selective effect of a clinically relevant concentration of lamotrigine (50 μM) on action potentials and epileptic-like discharges in rat hippocampal neurons as assessed with intracellular recording. In normal recording conditions, lamotrigine has no effect on action potentials or on the evoked excitatory postsynaptic potentials (EPSPs) that elicit the action potential. In epileptic-like conditions (low magnesium), activation elicits initial spikes followed by repetitive epileptiform spike firing (afterdischarge). Lamotrigine inhibits the pathologic discharge but not the initial spikes. EPSPs were elicited by stimulation of the Schaffer collateral/commissural fibers (triangles).


Pharmacology_Katzung

Pharmacology_Katzung. (B) Voltage and use dependence of block of human Nav1.2 voltage-activated sodium channels. Sodium currents elicited by depolarization from a holding potential of –90 mV (where there is little inactivation) are minimally affected by 100 μM of lamotrigine, whereas there is strong block of current elicited from –60 mV (where there is more substantial inactivation). Trains of 0.7-millisecond (ms) duration pulses from –90 mV (minimal inactivation) are minimally blocked in a use-dependent fashion by 100 μM of lamotrigine, whereas 20-ms pulses (marked inactivation) show substantial use dependence. (Adapted, with permission, from Xie X, Hagan RM: Cellular and molecular actions of lamotrigine: Possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998;38:119.) been shown to have antiseizure activity. This reaction is primarily catalyzed by CYP3A4, although CYP2C8 also plays a role and CYP3A5 may be involved. The contribution of this and other metabolites to the clinical


Pharmacology_Katzung

Pharmacology_Katzung. have antiseizure activity. This reaction is primarily catalyzed by CYP3A4, although CYP2C8 also plays a role and CYP3A5 may be involved. The contribution of this and other metabolites to the clinical activity of carbamazepine is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. Carbamazepine is available in oral forms (tablets and suspensions), and an intravenous formulation is available for temporary replacement of oral therapy. The drug is effective in children, in whom a dosage of 15–25 mg/kg/d is appropriate. In adults, the typical daily maintenance dose is 800–1200 mg/d, and the maximum recommended dose is 1600 mg/d, but rarely patients have required doses up to 2400 mg/d. Higher dosage is achieved by giving multiple divided doses daily. Extended-release preparations permit twice-daily dosing for most patients. In patients in whom the blood is drawn just before the morning dose (trough level), therapeutic concentrations are usually 4–8 mcg/mL. Although many patients complain of diplopia at drug levels above 7 mcg/mL, others can tolerate levels above 10 mcg/mL, especially with monotherapy. Drug initiation should be slow, with gradual increases in dose.


Pharmacology_Katzung

Pharmacology_Katzung. Carbamazepine stimulates the transcriptional up-regulation of CYP3A4 and CYP2B6. This autoinduction leads not only to a reduction in steady-state carbamazepine concentrations but also to an increased rate of metabolism of concomitant antiseizure drugs including primidone, phenytoin, ethosuximide, valproic acid, and clonazepam. Some antiseizure drugs such as valproic acid may inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels. Other antiseizure drugs, notably phenytoin and phenobarbital, may decrease steady-state concentrations of carbamazepine through enzyme induction. These interactions may require dosing changes. No clinically significant protein-binding interactions have been reported.


Pharmacology_Katzung

Pharmacology_Katzung. Carbamazepine may cause dose-dependent mild gastrointestinal discomfort, dizziness, blurred vision, diplopia, or ataxia; sedation occurs only at high doses, and rarely, weight gain can occur. The diplopia often occurs first and may last less than an hour during a particular time of day. Rearrangement of the divided daily dose can often remedy this complaint. A benign leukopenia occurs in many patients, but there is usually no need for intervention unless neutrophil count falls below 1000/mm3. Rash and hyponatremia are the most common reasons for discontinuation. Stevens-Johnson syndrome is rare, but the risk is significantly higher in patients with the HLA-B*1502 allele. It is recommended that Asians, who have a 10-fold higher incidence of carbamazepineinduced Stevens-Johnson syndrome compared to other ethnic groups, be tested before starting the drug.


Pharmacology_Katzung

Pharmacology_Katzung. Oxcarbazepine is the 10-keto analog of carbamazepine. Unlike carbamazepine, it cannot form an epoxide metabolite. Although it has been hypothesized that the epoxide is associated with carbamazepine’s adverse effects, little evidence is available to document the claim that oxcarbazepine is better tolerated. Oxcarbazepine is thought to protect against seizures by blocking voltage-gated sodium channels in the same way as carbamazepine. Oxcarbazepine itself has a half-life of only 1–2 hours; its antiseizure activity resides almost exclusively in the active 10-hydroxy metabolites, S(+)and R(–)-licarbazepine (also referred to as monohydroxy derivatives or MHDs), to which oxcarbazepine is rapidly converted and both of which have half-lives similar to that of carbamazepine (8–12 hours). The bulk (80%) of oxcarbazepine is converted to the S(+) form. The drug is mostly excreted as the glucuronide of the 10-hydroxy metabolite.


Pharmacology_Katzung

Pharmacology_Katzung. Oxcarbazepine is less potent than carbamazepine, both in animal tests and in patients; clinical doses of oxcarbazepine may need to be 50% higher than those of carbamazepine to obtain equivalent seizure control. Some studies report fewer hypersensitivity reactions to oxcarbazepine, and cross-reactivity with carbamazepine does not always occur. Furthermore, the drug appears to induce hepatic enzymes to a lesser extent than carbamazepine, minimizing drug interactions. Although hyponatremia may occur more commonly with oxcarbazepine than with carbamazepine, most adverse effects of oxcarbazepine are similar to those of carbamazepine.


Pharmacology_Katzung

Pharmacology_Katzung. Eslicarbazepine acetate, a prodrug of S(+)-licarbazepine, provides an alternative to oxcarbazepine, with some minor differences. Like oxcarbazepine, eslicarbazepine acetate is converted to eslicarbazepine but the conversion occurs more rapidly and it is nearly completely to the S(+) form, with only a small amount of the R(−) isomer (5%) formed by chiral inversion. Whether there is a benefit to the more selective conversion to S(+)-licarbazepine is uncertain, especially since both enantiomers act similarly on voltage-gated sodium channels. The effective half-life of S(+)licarbazepine following oral administration of eslicarbazepine acetate is 20–24 hours so the prodrug can be administered once daily, which is a potential advantage. The drug is administered at a dosage of 400–1600 mg/d; titration is typically required for the higher doses. S(+)-Licarbazepine is eliminated primarily by renal excretion; dose adjustment is therefore required for patients with renal impairment. Minimal


Pharmacology_Katzung

Pharmacology_Katzung. titration is typically required for the higher doses. S(+)-Licarbazepine is eliminated primarily by renal excretion; dose adjustment is therefore required for patients with renal impairment. Minimal pharmacokinetic effects are observed with coadministration of carbamazepine, levetiracetam, lamotrigine, topiramate, and valproate. The dose of phenytoin may need to be decreased if used concomitantly with eslicarbazepine acetate. Oral contraceptives may be less effective with concomitant eslicarbazepine acetate administration.


Pharmacology_Katzung

Pharmacology_Katzung. Lacosamide is a sodium channel-blocking antiseizure drug approved for the treatment of focal seizures. It has favorable pharmacokinetic properties and good tolerability. The drug is widely prescribed. Mechanism of Action Early studies suggested that lacosamide enhances a poorly understood type of sodium channel inactivation called slow inactivation. Recent studies, however, contradict this view and indicate that the drug binds selectively to the fast inactivated state of sodium channels—as is the case for other sodium channel-blocking antiseizure drugs, except that the binding is much slower.


Pharmacology_Katzung

Pharmacology_Katzung. Lacosamide is approved for the treatment of focal onset seizures in patients age 17 years and older. In clinical trials with more than 1300 patients, lacosamide was effective at doses of 200 mg/d and had greater and roughly similar overall efficacy at 400 and 600 mg/d, respectively. Although the overall efficacy was similar at 400 and 600 mg/d, the higher dose may provide better control of focal-to-bilateral tonic-clonic (secondarily generalized) seizures; however, this dose is associated with a greater incidence of adverse effects. Adverse effects include dizziness, headache, nausea, and diplopia. The drug is typically administered twice daily, beginning with 50-mg doses and increasing by 100-mg increments weekly. An intravenous formulation provides short-term replacement for the oral drug. The oral solution contains aspartame, which is a source of phenylalanine and could be harmful in people with phenylketonuria.


Pharmacology_Katzung

Pharmacology_Katzung. Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. Bioavailability is nearly 100%. The plasma concentrations are proportional to oral dosage up to 800 mg. Peak concentrations occur from 1 to 4 hours after oral dosing, with an elimination half-life of 13 hours. There are no active metabolites, and protein binding is minimal. Lacosamide does not induce or inhibit cytochrome P450 isoenzymes, so drug interactions are minimal. Phenytoin, first identified to have antiseizure activity in 1938, is the oldest nonsedating drug used in the treatment of epilepsy. It is prescribed for the prevention of focal seizures and generalized tonic-clonic seizures and for the acute treatment of status epilepticus. Phenytoin was identified by testing in laboratory animals in a search for better tolerated barbiturates.


Pharmacology_Katzung

Pharmacology_Katzung. Phenytoin, sometimes referred to as diphenylhydantoin, is the 5,5-diphenyl-substituted analog of hydantoin. Hydantoin is a five-membered ring molecule similar structurally to barbiturates, which are based on a six-member ring. Phenytoin free base (pKa = 8.06–8.33) is poorly water soluble, but phenytoin sodium does dissolve in water (17 mg/mL). Phenytoin is most commonly prescribed in an extended-release capsule containing phenytoin sodium and other excipients to provide a slow and extended rate of absorption with peak blood concentrations from 4 to 12 hours. This form differs from the prompt phenytoin sodium capsule form that provides rapid rate of absorption with peak blood concentration from 1.5 to 3 hours. In addition, the free base is available as an immediate-release suspension and chewable tablets. Phenytoin is available as an intravenous solution containing propylene glycol and alcohol adjusted to a pH of 12. Absorption after intramuscular injection is unpredictable, and some


Pharmacology_Katzung

Pharmacology_Katzung. chewable tablets. Phenytoin is available as an intravenous solution containing propylene glycol and alcohol adjusted to a pH of 12. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended.


Pharmacology_Katzung

Pharmacology_Katzung. With intravenous administration, there is a risk of the potentially serious “purple glove syndrome” in which a purplish-black discoloration accompanied by edema and pain occurs distal to the site of injection. Fosphenytoin is a water-soluble prodrug of phenytoin that may have a lower incidence of purple glove syndrome. This phosphate ester compound is rapidly converted to phenytoin in the plasma and is used for intravenous administration and treatment of status epilepticus. Fosphenytoin is well absorbed after intramuscular administration, but this route is rarely appropriate for the treatment of status epilepticus. Mechanism of Action Phenytoin is a sodium channel-blocking antiseizure drug that acts in a similar fashion to carbamazepine and other agents in the class.


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Phenytoin is a sodium channel-blocking antiseizure drug that acts in a similar fashion to carbamazepine and other agents in the class. Phenytoin is effective in preventing focal onset seizures and also tonic-clonic seizures, whether they are focal-to-bilateral tonicclonic (secondarily generalized) or occurring in the setting of an idiopathic generalized epilepsy syndrome. Phenytoin may worsen other seizure types in primary generalized epilepsies, including absence epilepsy, juvenile myoclonic epilepsy, and Dravet’s syndrome.


Pharmacology_Katzung

Pharmacology_Katzung. Absorption of phenytoin is highly dependent on the formulation. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Therefore, while absorption from the gastrointestinal tract is nearly complete in most patients, the time to peak may range from 3 to 12 hours. Phenytoin is extensively (~90%) bound to serum albumin and is prone to displacement in response to a variety of factors (eg, hyperbilirubinemia or drugs such as warfarin or valproic acid), which can lead to toxicity. Also, low plasma albumin (such as in liver disease or nephrotic syndrome) can result in abnormally high free concentrations and toxicity. Small changes in the bound fraction dramatically affect the amount of free (active) drug. Increased proportions of free drug are also present in the neonate and in the elderly. Some agents such as valproic acid, phenylbutazone, and sulfonamides can compete with phenytoin for binding to plasma proteins. Valproic acid also inhibits phenytoin


Pharmacology_Katzung

Pharmacology_Katzung. in the neonate and in the elderly. Some agents such as valproic acid, phenylbutazone, and sulfonamides can compete with phenytoin for binding to plasma proteins. Valproic acid also inhibits phenytoin metabolism. The combined effect can result in marked increases in free phenytoin. In all of these situations, patients may exhibit signs of toxicity when total drug levels are within the therapeutic range. Because of its high protein binding, phenytoin has a low volume of distribution (0.6–0.7 L/kg in adults).


Pharmacology_Katzung

Pharmacology_Katzung. Phenytoin is metabolized by CYP2C9 and CYP2C19 to inactive metabolites that are excreted in the urine. Only a small proportion of the dose is excreted unchanged. The elimination of phenytoin depends on the dose. At low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize the drug is approached (saturation kinetics). Even small increases in dose may be associated with large changes


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 24–4 Relationship between dose and exposure for antiseizure drugs (ASDs). Most antiseizure drugs follow linear (firstorder) kinetics, in which a constant fraction per unit time of the drug is eliminated (elimination is proportional to drug concentration). In the case of phenytoin, as the dose increases, there is saturation of metabolism and a shift from first-order to zero-order kinetics, in which a constant quantity per unit time is metabolized. A small increase in dose can result in a large increase in concentration. Orally administered gabapentin also exhibits zero-order kinetics, but in contrast to phenytoin where metabolism can be saturated, in the case of gabapentin, gut absorption, which is mediated by the large neutral amino acid system L transporter, is susceptible to saturation. The bioavailability of gabapentin falls at high doses as the transporter is saturated so that increases in blood levels do not keep pace with increases in dose.


Pharmacology_Katzung

Pharmacology_Katzung. in phenytoin serum concentrations (Figure 24–4). In such cases, the half-life of the drug increases markedly, steady state is not achieved in routine fashion (since the plasma level continues to rise), and patients quickly develop symptoms of toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. The half-life of phenytoin in most patients varies from 12 to 36 hours, with an average of 24 hours in the low to mid therapeutic range. Much longer half-lives are observed at higher concentrations. At low blood levels, 5–7 days are needed to reach steady-state blood levels after every dosage change; at higher levels, it may be 4–6 weeks before blood levels are stable. Phenytoin— like carbamazepine, phenobarbital, and primidone—is a major enzyme-inducing antiseizure drug that stimulates the rate of metabolism of many coadministered antiseizure drugs, including valproic acid, tiagabine, ethosuximide, lamotrigine, topiramate, oxcarbazepine and MHDs, zonisamide, felbamate, many benzodiazepines, and perampanel. Autoinduction of its own metabolism, however, is insignificant.


Pharmacology_Katzung

Pharmacology_Katzung. The therapeutic plasma level of phenytoin for most patients is between 10 and 20 mcg/mL. A loading dose can be given either orally or intravenously, with either fosphenytoin sodium injection (preferred) or phenytoin sodium injection. When oral therapy is started, it is common to begin adults at a dosage of 300 mg/d, regardless of body weight. This may be acceptable in some patients, but it frequently yields steady-state blood levels below 10 μg/mL, which is the minimum therapeutic level for most patients. If seizures continue, higher doses are usually necessary to achieve plasma levels in the upper therapeutic range. Because of the kinetic factors discussed earlier, toxic levels may occur with only small increments in dosage. The phenytoin dosage should be increased in increments of no more than 25–30 mg/d in adults, and ample time should be allowed for the new steady state to be achieved before further increasing the dosage. A common clinical error is to increase the dosage directly


Pharmacology_Katzung

Pharmacology_Katzung. than 25–30 mg/d in adults, and ample time should be allowed for the new steady state to be achieved before further increasing the dosage. A common clinical error is to increase the dosage directly from 300 mg/d to 400 mg/d; toxicity frequently occurs at a variable time thereafter. In children, a dosage of 5 mg/kg/d should be followed by readjustment after steady-state plasma levels are obtained.


Pharmacology_Katzung

Pharmacology_Katzung. Two types of oral phenytoin are currently available in the USA, differing in their respective rates of dissolution. The predominant form is the sodium salt in an extended-release pill intended for onceor twice-a-day use. In addition, the free acid is available as an immediate-release suspension and chewable tablets. Although a few patients being given phenytoin on a long-term basis have been proved to have low blood levels from poor absorption or rapid metabolism, the most common cause of low levels is poor compliance. As noted, fosphenytoin sodium is available for intravenous or intramuscular use and usually replaces intravenous phenytoin sodium, a much less soluble form of the drug.


Pharmacology_Katzung

Pharmacology_Katzung. Early signs of phenytoin administration include nystagmus and loss of smooth extraocular pursuit movements; neither is an indication for decreasing the dose. Diplopia and ataxia are the most common dose-related adverse effects requiring dosage adjustment; sedation usually occurs only at considerably higher levels. Gingival hyperplasia and hirsutism occur to some degree in most patients; the latter can be especially unpleasant in women. Long-term use is associated in some patients with coarsening of facial features and with mild peripheral neuropathy, usually manifested by diminished deep tendon reflexes in the lower extremities. Long-term use may also result in abnormalities of vitamin D metabolism, leading to osteomalacia. Low folate levels and megaloblastic anemia have been reported, but the clinical importance of these observations is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. Idiosyncratic reactions to phenytoin are relatively rare. A skin rash may indicate hypersensitivity of the patient to the drug. Fever may also occur, and in rare cases, the skin lesions may be severe and exfoliative. Lymphadenopathy may rarely occur; this must be distinguished from malignant lymphoma. Hematologic complications are exceedingly rare, although agranulocytosis has been reported in combination with fever and rash. MEPHENYTOIN, ETHOTOIN, & PHENACEMIDE


Pharmacology_Katzung

Pharmacology_Katzung. MEPHENYTOIN, ETHOTOIN, & PHENACEMIDE Many congeners of phenytoin have been synthesized, but only three have been marketed in the USA, and one of these (phenacemide) has been withdrawn. The other two congeners, mephenytoin and ethotoin, like phenytoin, appear to be most effective against focal and generalized tonic-clonic seizures. No well-controlled clinical trials have documented their effectiveness, and the drugs are rarely used. The incidence of severe reactions such as dermatitis, agranulocytosis, or hepatitis is higher for mephenytoin than for phenytoin. Mephenytoin is metabolized to 5-ethyl5-phenyl-hydantoin (nirvanol) via demethylation; nirvanol contributes most of the antiseizure activity of mephenytoin.


Pharmacology_Katzung

Pharmacology_Katzung. Gabapentin and pregabalin, known as “gabapentinoids,” are amino acid-like molecules that were originally synthesized as analogs of GABA but are now known not to act through GABA mechanisms. They are used in the treatment of focal seizures and various nonepilepsy indications, such as neuropathic pain, restless legs syndrome, and anxiety disorders. Mechanism of Action Despite their close structural resemblance to GABA, gabapentin and pregabalin do not act through effects on GABA receptors or any other mechanism related to GABA-mediated neurotransmission. Rather, gabapentinoids bind avidly to α2δ, a protein that serves as an auxiliary subunit of voltage-gated calcium channels but may also have other functions. The precise way in which binding of gabapentinoids to α2δ protects against seizures is not known but may relate to a decrease in glutamate release at excitatory synapses.


Pharmacology_Katzung

Pharmacology_Katzung. Gabapentin and pregabalin are effective in the treatment of focal seizures; there is no evidence that they are efficacious in generalized epilepsies. Indeed, gabapentin may aggravate absence seizures and myoclonic seizures. Gabapentin is usually started at a dose of 900 mg/d (in three divided doses), but starting doses as high as 3600 mg/d can be used if a rapid response is required. Some clinicians have found that even higher dosages are needed to achieve improvement in seizure control. The recommended starting dose of pregabalin is 150 mg/d, but a lower starting dose (50–75 mg/d) may avoid adverse effects that can occur on drug initiation; the effective maintenance dose range is 150 to 600 mg/d. Although comparative studies are lacking, gabapentinoids are generally considered less effective than other antiseizure drugs for the treatment of focal seizures. Gabapentinoids are frequently used in the treatment of neuropathic pain conditions, including postherpetic neuralgia and painful


Pharmacology_Katzung

Pharmacology_Katzung. than other antiseizure drugs for the treatment of focal seizures. Gabapentinoids are frequently used in the treatment of neuropathic pain conditions, including postherpetic neuralgia and painful diabetic neuropathy, and in the treatment of anxiety disorders. Pregabalin is also approved for the treatment of fibromyalgia. Gabapentin and pregabalin are generally well tolerated. The most common adverse effects are somnolence, dizziness, ataxia, headache, and tremor. These adverse effects are most troublesome at initiation of therapy and often resolve with continued dosing. Both gabapentinoids can cause weight gain and peripheral edema.


Pharmacology_Katzung

Pharmacology_Katzung. Gabapentin and pregabalin are not metabolized and do not induce hepatic enzymes; they are eliminated unchanged in the urine. Both drugs are absorbed by the l-amino acid transport system, which is found only in the upper small intestine. The oral bioavailability of gabapentin decreases with increasing dose because of saturation of this transport system. In contrast, pregabalin exhibits linear absorption within the therapeutic dose range. This is explained, in part, by the fact that pregabalin is used at much lower doses than gabapentin so it does not saturate the transport system. Also, pregabalin may be absorbed by mechanisms other than the l-amino acid transport system. Because of dependence on the transport system, absorption of gabapentin shows patient-to-patient variability and dosing requires individualization. Pregabalin bioavailability exceeds 90% and is independent of dose so that it may produce a more predictable patient response. Gabapentinoids are not bound to plasma


Pharmacology_Katzung

Pharmacology_Katzung. dosing requires individualization. Pregabalin bioavailability exceeds 90% and is independent of dose so that it may produce a more predictable patient response. Gabapentinoids are not bound to plasma proteins. Drug-drug interactions are negligible. The half-life of both drugs is relatively short (ranging from 5 to 8 hours for gabapentin and 4.5 to 7.0 hours for pregabalin); they are typically administered two or three times per day. Sustained-release, once-a-day preparations of gabapentin are available. The gabapentin prodrug gabapentin enacarbil is also available in an extended-release formulation. This prodrug is actively absorbed by high-capacity nutrient transporters, which are abundant throughout the intestinal tract, and then converted to gabapentin presumably within the intestine, so there is dose-proportional systemic gabapentin exposure over a wide dose range.


Pharmacology_Katzung

Pharmacology_Katzung. Tiagabine, a selective inhibitor of the GAT-1 GABA transporter, is a second-line treatment for focal seizures. It is contraindicated in generalized onset epilepsies. Mechanism of Action