Liver and Gastrointestinal Pharmacology

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Liver and Gastrointestinal Pharmacology JENNIFER NGUYEN-LEE, CHRISTINE T. NGUYEN-BUCKLEY, AND ANI BAGDASARJANA

CHAPTER OUTLINE Liver Pharmacology Cytochrome P450 Enzymes Hepatic Extraction Plasma Protein Binding Anesthetic Drugs and the Liver Anesthetic Agents and Hepatic Blood Flow Metabolism of Volatile Anesthetics and Hepatotoxicity Metabolism of Intravenous Anesthetic Agents Hepatobiliary Metabolism and Elimination of Neuromuscular Blockers Gastrointestinal Pharmacology Basic Principles Gastric Acid–Suppressing Medications Drugs to Reduce Portal Venous Pressure Opioids and the Gastrointestinal System Sphincter of Oddi Spasm Statins Other Treatments for Dyslipidemia Hepatitis C Treatment Emerging Developments Suppression of Gastric Acid Secretion Direct-Acting Antivirals for Hepatitis C Treatment PCSK9 Inhibitors for Dyslipidemia Obeticholic Acid

Liver Pharmacology Cytochrome P450 Enzymes The bulk of liver drug metabolism is carried out by the cytochrome P450 (CYP 450) enzyme system (Tables 32.1 and 32.2) (see Chapter 4). CYP 450 enzymes in the endoplasmic reticulum oxidate lipidsoluble compounds in phase I and phase II reactions.1 Drug response varies from 25% to 60% among patients because of environmental, genetic, and disease influences.2 Phase I reactions transform lipophilic molecules into hydrophilic molecules.3–6 Phase II reactions then conjugate drugs and metabolites to highly polar compounds that are more readily excreted.7,8 The CYP1, CYP2 and CYP3 families perform almost 80% of oxidative drug metabolism and 50% of drug elimination. Although the liver is the major site of CYP 450–mediated metabolism, small intestine enterocytes are a secondary site. More than 65 commonly used drugs are metabolized by CYP 2D6. Genetic variability in CYP 2D6 metabolism can thereby lead to subtherapeutic or supratherapeutic drug levels and effects. This variability is usually unanticipated because CYP 450 genotyping is not widely available.9 Slow metabolism by CYP 2D6 is a major factor in warfarin toxicity, for example.10 The CYP 3A family also metabolizes a wide variety of drugs.11 Drug-drug interactions expand variability up to 400-fold. CYP 5 catalyzes the isomerization of prostaglandin endoperoxide to thromboxane A, a reaction that leads to platelet aggregation and potentially thrombosis.12

Hepatic Extraction

O

ne of the main functions of the liver is to protect against toxins. The endoplasmic reticulum of hepatocytes contains families of enzymes that protect the organism against an accumulation of lipid-soluble exogenous and endogenous compounds. This is done by transforming compounds to water-soluble metabolites, which are more readily excreted by the kidneys. Gastrointestinal absorption of orally administered drugs and the pharmacology of the gastrointestinal tract are critical to pharmacotherapy and to perioperative medicine.

The fraction of drug presented to the liver that is eliminated during a single pass is called the hepatic extraction ratio. The hepatic extraction ratio becomes equal to 1 (unity) when the drug that reaches the liver is completely eliminated. When no drug is eliminated by the liver, the extraction ratio is zero.13 For oral drugs that are completely absorbed into the portal circulation, bioavailability depends on the extraction ratio. Bioavailability for high– extraction ratio drugs is much less than for low–extraction ratio drugs (Table 32.3). Hepatic clearance reflects the removal of the drug as it passes through the liver and is the product of hepatic blood flow multiplied by the extraction ratio (Fig. 32.1). If the liver is very efficient in 645



CHAPTER 32  Liver and Gastrointestinal Pharmacology 645.e1

Abstract

Keywords

One of the main functions of the liver is to protect the organism against intoxication. The endoplasmic reticulum of liver cells contains enzymes that protect the organism against an accumulation of lipid-soluble exogenous and endogenous compounds. This is done by transforming the compounds to water-soluble metabolites, which are then easily excreted by the kidney. Gastrointestinal absorption of orally administered drugs and pharmacology of the gastrointestinal tract is an equally complex system mediated by neuronal and hormonal influences.

liver gastrointestinal pharmacology first pass hepatic extraction bioavailability

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TABLE Human Cytochrome P450 Enzymes Involved in 32.1  Metabolism of Xenobiotics Located in

TABLE 32.3  Hepatic Extraction Ratios of Important Drugs

Extrahepatic Tissues

CYP Enzyme

Tissue

Low Ratio (<0.3)

Intermediate Ratio (0.3–0.7)

High Ratio (>0.7)

1A1a

Lung, kidney, gastrointestinal tract, skin, placenta, lymphocytes, and others

Carbamazepine

Aspirin

Alprenolol

Diazepam

Quinidine

Cocaine

1B1

Skin, kidney, mammary, prostate, uterus, fetus

Indomethacin

Codeine

Desipramine

2A6

Lung, nasal membrane, and possibly others

Naproxen

Nifedipine

Lidocaine

2B6

Gastrointestinal tract, lung

Nitrazepam

Nortriptyline

Meperidine

2C

Gastrointestinal tract (small intestine mucosa), larynx, lung

2D6

Gastrointestinal tract

2E1

Lung, placenta, and others

2F1

Lung, placenta

2J2

Heart

3A

Gastrointestinal tract, placenta, fetus, uterus, kidney, lung

4B1

Lung, placenta

4A11

Kidney

Phenobarbital

Morphine

Phenytoin

Nicotine

Procainamide

Nitroglycerin

Salicylic acid

Pentazocine

Theophylline

Propoxyphene

Valproic acid

Propranolol

Warfarin

Verapamil

From references 102–105.

CYP, Cytochrome P450. a After induction. From Rendic S, Carlo FJ Di. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997;29:1–2.

TABLE 32.2  Examples of Clinical Substrates, Inhibitors, and Inducers for Cytochrome P450–Mediated Metabolism

CYP Enzyme

Sensitive Substrates

Moderately Sensitive Substrates

Strong Inhibitors

Moderate Inhibitors

Strong Inducers

Moderate Inducers

1A2

Alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, theophylline, tizanidine

Clozapine, pirfenidone, ramosetron

Ciprofloxacin, enoxacin, fluvoxamine, zafirlukast

Methoxsalen, mexiletine, oral contraceptives

—

Phenytoin, rifampin, ritonavir, smoking, teriflunomide

2B6

Bupropion

Efavirenz

—

—

Carbamazepine

Efavirenz, rifampin, ritonavir

2C8

Repaglinide

Montelukast, pioglitazone, rosiglitazone

Clopidogrel, gemfibrozil

Deferasirox, teriflunomide

—

Rifampin

2C9

Celecoxib

Glimepiride, phenytoin, tolbutamide, warfarin

—

Amiodarone, felbamate, fluconazole, miconazole, piperine

—

Aprepitant, carbamazepine, enzalutamide, rifampin, ritonavir

2C19

S-mephenytoin, omeprazole

Diazepam, lansoprazole, rabeprazole, voriconazole

Fluconazole, fluoxetine, fluvoxamine, ticlopidine

—

Rifampin, ritonavir

Efavirenz, enzalutamide, phenytoin

2D6

Atomoxetine, desipramine, dextromethorphan, nebivolol, nortriptyline, perphenazine, tolterodine, venlafaxine

Amitriptyline, encainide, imipramine, metoprolol, propafenone, propranolol, tramadol, trimipramine

Bupropion, fluoxetine, paroxetine, quinidine, terbinafine

Cimetidine, cinacalcet, duloxetine, fluvoxamine, mirabegron

CYP, Cytochrome P450. From Isoherranen N, Lutz JD, Chung SP, et al. Importance of multi-P450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude, and prediction from in vitro data. Chem Res Toxicol. 2012;25:2285–2300.

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removing a drug (extraction ratio ~1) but blood flow is low, clearance will also be low. At the same time, if the liver is extremely inefficient in removing a drug, clearance will be low even if blood flow is high.14,15

Plasma Protein Binding Only unbound drug is able to cross membranes and be eliminated. In patients with low plasma proteins, such as those with endstage liver disease, the proportion of unbound drug increases. If a drug has a low extraction ratio, an increase in the fraction of unbound drug will proportionally increase clearance. Therefore the unbound drug concentration remains constant and no dose adjustment is required. On the other hand, if a drug has a high extraction ratio, as the fraction of unbound drug increases the clearance remains constant. As the unbound concentration increases, toxicity can ensue.16

Anesthetic Drugs and the Liver Anesthetic Agents and Hepatic Blood Flow Maintaining hepatic perfusion is important, particularly in patients with compromised hepatic function. The hepatic arterial buffer response, which increases hepatic artery flow when portal vein flow is reduced, is impaired with inhaled anesthetics.17 Table 32.4 summarizes the effects of various anesthetic agents on hepatic blood flow. Halothane and nitrous oxide decrease hepatic blood flow in a dose-dependent fashion.18–20 Hepatic blood flow is maintained at 1 minimum alveolar concentration (MAC) of isoflurane and sevoflurane.17–19 Whereas desflurane decreases hepatic blood flow in

Clearance

=

Hepatic blood flow

×

Extraction ratio

• Fig. 32.1  Hepatic clearance = hepatic blood flow multiplied by hepatic extraction ratio. TABLE Volatile Anesthetic Effects on Hepatic 32.4  Blood Flow

Halothane Isoflurane Sevoflurane Desflurane Decreased Maintained Maintained

Nitrous Oxide

Decreased in Decreased animals, possibly increased in humans

From references 17–19, 21, 22, 25.

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animals, a single-center human study showed increased hepatic blood flow at 1 MAC desflurane compared with isoflurane.21,22 Intravenous (IV) and neuraxial anesthetic agents also affect hepatic blood flow. Propofol and opioids increase hepatic blood flow23–26 (Table 32.5). Ketamine does not affect hepatic flow, but oxygen delivery is reduced, possibly owing to increased oxygen consumption by other organs.20 Etomidate, barbiturates, dexmedetomidine, and benzodiazepines decrease hepatic blood flow.27–29 Thoracic epidural anesthesia decreases hepatic blood flow, consistent with previous studies of lumbar epidurals.30,31

Metabolism of Volatile Anesthetics and Hepatotoxicity Many volatile anesthetics are oxidized to variable extents by CPY 2E1 in the liver (see Chapter 3).32 Halothane use has fallen out of favor because of concerns about hepatotoxicity, which involves two different mechanisms. The first reaction is a transient benign postoperative transaminase elevation. The second reaction, halothane hepatitis, is a rare autoimmune reaction leading to centrilobular necrosis and acute liver failure with a high mortality rate.33 Halothane is oxidized, leading to trifluoroacetyl adduct formation, which leads to antibody production in susceptible patients. Repeat exposure to halothane leads to hepatocyte necrosis. Desflurane, isoflurane, and enflurane also undergo oxidation to trifluoroacetyl, with rare reports of autoimmune liver failure. Sevoflurane does not form reactive trifluoroacetyl intermediates and therefore presents a lower concern for immune-mediated hepatitis.33

Metabolism of Intravenous Anesthetic Agents The majority of IV hypnotic agents undergo hepatic metabolism (see Chapter 2). Their pharmacokinetics depend on hepatic blood flow, degree of hepatic extraction, and plasma protein binding. Patients with hepatic dysfunction have greater susceptibility to pharmacologic effects owing to decreased hepatic metabolism, decreased hepatobiliary clearance, and low serum protein and albumin concentrations.34 The liver oxidizes propofol with a very high extraction ratio; therefore elimination depends largely on hepatic blood flow. Barbiturates are potent CYP 450 inducers. Patients with deficiencies in heme synthesis pathways receiving barbiturates are at risk of inducing aminolevulinic acid synthase, precipitating an attack of acute intermittent porphyria.35 The liver is centrally involved in the pathogenesis of this disorder, as aminolevulinic acid synthase induction leads to increased demand for hepatic heme and consumption of hepatic CYP 450 enzymes.36 Furthermore, liver transplantation has been used for treatment of refractory acute porphyria. The liver oxidizes midazolam to 1-hydroxymethylmidazolam, an active central nervous system depressant metabolite that can accumulate in patients with hepatic or renal dysfunction.37 By

TABLE 32.5  Intravenous and Neuraxial Anesthetic Effects on Hepatic Blood Flow

Propofol

Ketamine

Etomidate

Barbiturates

Dexmedetomidine

Benzodiazepines

Opioids

Increased

Maintained

Decreased

Decreased

Decreased

Decreased

Increased

From references 23, 24, 26, 28, 29, 31.

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contrast, lorazepam undergoes glucuronidation to inactive metabolites. Most opioids are metabolized in the liver.34 Patients with cirrhosis have decreased clearance of opioids, leading to increased accumulation, which can precipitate hepatic encephalopathy. Lower opioid doses and longer intervals between doses are advocated in these patients.34

Hepatobiliary Metabolism and Elimination of Neuromuscular Blockers The hepatobiliary system metabolizes selected neuromuscular blockers. For aminosteroid nondepolarizing agents (rocuronium, vecuronium and pancuronium), prolonged blockade becomes apparent after redosing or continuous infusion, because redistribution is responsible for recovery from a single bolus dose.38 A higher initial dose of a nondepolarizing neuromuscular blocker may be needed in patients with cirrhosis owing to an increased volume of distribution.38 Cisatracurium and atracurium undergo chemical degradation independent of the liver and are useful in redosing when rapid recovery is desired.39 Succinylcholine is metabolized by plasma cholinesterase, a product of the liver; patients with liver disease can have prolonged blockade.40 Current reversal agents, including suggamadex, do not undergo hepatic metabolism or excretion.41

Gastrointestinal Pharmacology Basic Principles Gastrointestinal function is controlled by a variety of influences, including extrinsic autonomic innervation, a complicated intrinsic neural system, and multiple hormones such as gastrin, glucagon, and somatostatin. Gastrointestinal motility is a function of nerve inputs, and slow electrical waves generated in the longitudinal layer located in the smooth muscle are required for peristalsis.42 Drugs targeting the gastrointestinal system tend to focus on decreasing gastric acid secretion, treating nausea and vomiting, and diminishing side effects of slowed motility causing constipation. Because of convenience, oral drug administration is the preferred route of delivery for many medications, particularly in the outpatient setting. After oral administration of a drug, CYP 450 enzymes can reduce the portion of the dose that reaches the systemic circulation, influencing the drug’s effects, which is known as first-pass metabolism.43 Oral administration is highly dependent on drug bioavailability, which is determined by the quantity of drug absorbed from the gastrointestinal tract and hindered by first-pass elimination in the gastrointestinal wall, liver, and lung. Gastrointestinal absorption depends on the stability of the drug in gastrointestinal fluids, absorption time, solubility, and how readily the drug permeates the gastrointestinal epithelium (Fig. 32.2).44 The primary site of drug absorption is the small intestine, followed by the stomach and colon.45 For about 40% of commonly used drugs, less than half of the administered oral dose is bioavailable because of limited absorption, first-pass metabolism, or both. Oral bioavailability can be altered by drug interactions that result in either inhibition or induction of the involved enzymes. Drug metabolism differences in the intestine and liver between patients are common and are major contributors to differences in drug response, including adverse effects.11 When an orally administered drug undergoes extensive first-pass metabolism, its bioavailability in the setting of CYP 3A inhibition

Drug

Liver metabolism

Stomach

Small intestine metabolism

Drug metabolites Bioactive e drug

Kidney Excretion

Large intestine

Systemic circulation

Urine

Feces

• Fig. 32.2  Transit of drug through gastrointestinal tract and drug metabolism leading to bioactive drug in systemic circulation.

can increase severalfold, whereas the rate of elimination can be reduced43 (Table 32.6). When a drug is administered orally, intestinal CYP 3A enzymes are exposed to higher concentrations of the drug and are inhibited to a greater degree than are unaffected hepatic CYP 3A enzymes. An example of this is an interaction between grapefruit juice and CYP 3A substrates.46,47 Grapefruit juice is contraindicated in patients receiving drugs that are extensively metabolized by CYP 3A, including calcium channel blockers and statins, as a single glass can cause CYP 3A inhibition for 24 to 48 hours.11 There are many recognized potent inhibitors of CYP 3A that result in increased plasma concentrations of drugs even when administered at recommended doses. These situations are sometimes used to therapeutic advantage. CYP 3A inhibition is typically reversible, normally within 2 to 3 days once the interacting drug is discontinued. In some cases, CYP 3A is destroyed and new CYP 3A enzyme must be synthesized, leading to a prolonged drug effect.48 Treatment with drugs such as the rifamycin and some anticonvulsants predictably results in a major decrease in the plasma concentrations of certain drugs administered concurrently. CYP 3A activity is especially sensitive to such drug interactions involving upregulation of several proteins critical to drug disposition, and CYP 3A substrate metabolism is acutely affected by treatment with these inducing agents.49 In this situation, drug dosages that were previously effective become ineffective.50 New protein must be synthesized; thus the consequences of CYP 3A induction are not immediate. Steady-state levels generally are reached in 2 to 3 weeks. Similarly, the induction effect after discontinuing the inducing agent takes several weeks to wash out. Adequate drug therapy is still achievable by creating stepwise increases or decreases in the medication regimen while monitoring plasma levels.51

Gastric Acid–Suppressing Medications The two classes of gastric acid suppressing medications in common use are proton pump inhibitors (PPIs) and H2-histamine receptor antagonists (H2RAs). They are used to decrease peptic ulcers, treat

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TABLE Common Drug Substrates, Inhibitors, and 32.6  Inducers of CYP 3A According to Drug Class

CYP 3A Substrates

CYP 3A Inhibitors

CYP 3A Inducers

Calcium Channel Blockers

Calcium Channel Blockers

Rifamycins

Diltiazem Felodipine Nifedipine Verapamil

Diltiazem Verapamil

Rifabutin Rifampin Rifapentine

Immunosuppressant Agents

Azole Antifungal Agents

Anticonvulsant Agents

Cyclosporine Tacrolimus

Itraconazole Ketoconazole

Carbamazepine Phenobarbital Phenytoin

Benzodiazepines

Macrolide Antibiotics

Anti-HIV Agents

Alprazolam Midazolam Triazolam

Clarithromycin Erythromycin (Not azithromycin)

Efavirenz Nevirapine

Statins

Anti-HIV Agents

Others

Atorvastatin Lovastatin (Not pravastatin)

Delavirdine Indinavir Ritonavir Saquinavir

St. John’s wort

Macrolide Antibiotics Clarithromycin Erythromycin

Anti-HIV Agents Indinavir Nelfinavir Ritonavir Saquinavir

Others Losartan Sildenafil CYP, Cytochrome P450; HIV, human immunodeficiency virus. From Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–2221.

gastroesophageal reflux, and for stress ulcer prevention. In anesthesia practice, these medications are used to reduce stomach acidity and thereby reduce the risk of lung injury in the event of aspiration of stomach contents into the trachea. PPIs are benzimidazole derivatives that decrease gastric acid production through inhibition of the parietal cell hydrogenpotassium adenosine triphosphatase (Fig. 32.3). Available PPIs include omeprazole, lansoprazole, pantoprazole, and esomeprazole. Because proton pumps are stimulated by ingested food, oral PPIs should be given 30 to 60 minutes before a meal to ensure high serum concentration when proton pumps are active. A single dose is effective for up to 15 hours, but several days of administration can be necessary to reach maximal efficacy.52 Multiple PPIs, including lansoprazole, pantoprazole, and esomeprazole, are available as intravenous (IV) formulations. IV

649

PPIs have the advantage of rapid onset within 1 hour with effects lasting up to 12 hours.53 Oral and IV pantoprazole have demonstrated similar efficacy in reducing gastric acidity.54 Long-term side effects of PPI use include malabsorption of key electrolytes and vitamins, particularly calcium, magnesium, and vitamin B12, and a predisposition toward infections including Clostridium difficile and pneumonia.55,56 Concerns exist for risk of osteoporosis, renal insufficiency, and dementia with long-term PPI use, although randomized controlled trial evidence is limited.56 Results of observational studies have raised concerns about decreased efficacy of clopidogrel when given with PPIs. However, there was no apparent cardiovascular interaction in a large randomized trial.57 Observational studies show a consistent association of long-term PPI use with gastric polyps, although there is not a clear clinical association with gastric or colon cancer.56 Histamine receptor antagonists, including famotidine, cimetidine, and ranitidine, suppress gastric acid through competitive antagonism of histamine binding on stomach parietal cells (see Fig. 32.3). Famotidine is more potent than cimetidine and ranitidine and has a longer duration of action.58 Oral H2RAs have rapid onset with time to peak serum concentration 1 to 3 hours after ingestion, but they undergo extensive first-pass metabolism, with bioavailability of 43% to 60%.59 IV onset is less than 1 hour.60 Drug half-life is increased and clearance is reduced in renal failure and advanced and neonatal age; therefore the dose should be reduced in these patients.59 The most common side effects reported with H2RAs are diarrhea, headache, drowsiness, fatigue, and muscular pain. Other possible side effects include gynecomastia, bone marrow suppression, druginduced hepatitis, increased creatinine levels, and cardiac arrhythmias including bradycardia associated with rapid infusion. Doses should be reduced in elderly patients and those with renal and hepatic dysfunction owing to the risk of altered mental status.59 Compared with PPIs, H2RAs are less effective at preventing gastrointestinal bleeding in patients in intensive care units but are associated with a lower risk of pneumonia.60 H2RAs can interact with a number of other drugs. Cimetidine interacts with CYP 450, potentially leading to increased plasma levels of warfarin, theophylline or phenytoin. This interaction is also possible with ranitidine, but it binds less avidly to CYP 450.59 Several randomized trials have examined the effects of gastric acid–suppressing medications in reducing gastric volumes and pH in perioperative settings. In adults undergoing elective surgery, IV pantoprazole and ranitidine reduced gastric pH and gastric volume within 1 hour.53,61 Based on the lack of conclusive evidence regarding reduction of pulmonary aspiration, a task force of the American Society of Anesthesiologists recommended against routine perioperative administration of gastric acid–suppressing medications in patients with no apparent increased risk for pulmonary aspiration.62

Drugs to Reduce Portal Venous Pressure Standard therapy for upper variceal bleeding is a combination of a vasoconstrictor, a PPI, and endoscopic therapy to obtain effective acute control of bleeding and prevent early rebleeding.63 Vasoconstrictors include somatostatin, its analog octreotide, and terlipressin (see Chapter 25). Somatostatin interacts with cells through G-protein–coupled receptors, leading to modulation of intracellular signaling pathways including adenylyl cyclase, phosphotyrosine phosphatase, and mitogen-activated protein kinase.64 These vasoconstrictors decrease portal venous pressures, although the

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Acetylcholine

Histamine H2receptor antagonists

Muscarinic M3 receptor

Muscarinic antagonists Gastrin

Histamine Histamine H2-receptor

CCK2 receptor Ca2+dependent pathway

cAMPdependent pathway +

+ K+

H+

Parietal cell

H+K+-ATPase

Proton pump inhibitors

Cl–

Acid (HCl)

Gastric gland lumen

• Fig. 32.3

  A cartoon summarizing the mechanisms of selected acid-lowering therapies. Gastric acid is secreted by parietal cells of the stomach in response to stimuli, such as the presence of food in the stomach or intestine, and the taste, smell, sight, or thought of food. Such stimuli result in the activation of histamine, acetylcholine or gastrin receptors (the H2, M3 and CCK2 receptors, respectively) located in the basolateral membrane of the parietal cell, which initiates signal transduction pathways that converge on the activation of the H+,K+-ATPase—the final step of acid secretion. Inhibition of this proton pump has the advantage that it will reduce acid secretion independently of how secretion is stimulated, in contrast to other pharmacologic approaches to the regulation of acid secretion. For example, the inhibition of acid secretion by H2-receptor antagonists can be overcome by food-induced stimulation of acid secretion via gastrin or acetylcholine receptors. Ca2+, Calcium ion; cAMP, cyclic adenosine monophosphate; CCK2, cholecystokinin 2 receptor; Cl−, chloride ion; H+, hydrogen ion; H+,K+-ATPase, hydrogen potassium adenosine triphosphatase; HCl, hydrochloric acid; K+, potassium ion; M3, muscarinic acetylcholine receptor 3. (Adapted with permission from Olbe L, Carlsson E, Lindberg P. A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat Rev Drug Discov. 2003;2:132–139.)

mechanism is uncertain; possible mechanisms are inhibition of glucagon and insulin-like growth factor 1 or reducing hepatic metabolism and portal inflow. It has been hypothesized that octreotide infusions may be able to lower the need for red blood cell transfusion during orthotopic liver transplantation through portal vasoconstriction. In a small underpowered study of 50 patients, red blood cell transfusion was reduced from 20 to 18 units, although there was no statistically significant difference.65

Opioids and the Gastrointestinal System Coordination of peristalsis depends on the central nervous system and enteric nervous system that control smooth muscle contraction, blood flow, and secretions. Opioids interfere with gastrointestinal function, delaying recovery, particularly after abdominal surgery. Opioid-related gastrointestinal effects include decreased gastric

motility and enzyme secretion, inhibition of intestinal propulsion, and increased anal sphincter tone mediated primarily through the mu-opioid receptor (see Chapter 17).66 New treatments for opioid-induced constipation have been developed based on nonabsorbable opioid receptor antagonists. Methylnaltrexone is a charged molecule resulting from N-methylation of naltrexone, an opioid antagonist. This charged derivative cannot cross the blood-brain barrier and has been shown to conserve analgesic effects of opioids while maintaining normal gastrointestinal function.67 Alvimopan is a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine peripheral mu-opioid receptor antagonist used to reduce postoperative ileus. Side effects of alvimopan include anemia, dyspepsia, and urinary retention. When studied as a twice-daily dosing regimen for long-term use as a treatment of chronic opioidinduced constipation, a higher incidence of myocardial infarction was seen; alvimopan is only approved by the U.S. Food and Drug



Administration (FDA) for short-term in-hospital use (maximum of 15 doses per patient).68

Sphincter of Oddi Spasm The smooth muscle sphincter of Oddi controls biliary and pancreatic secretions into the duodenum under the influence of cholecystokinin.69 Spasm can be provoked by opioids, manipulation of the common bile duct, or injection of contrast.70 Meperidine might be less likely to induce spasm compared with other opioids, notably morphine. Pharmacologic treatments for sphincter of Oddi spasm include somatostatin, glucagon, nitroglycerin, calcium channel blockers, nalbuphine, and naloxone.71

Statins Statins, used to treat dyslipidemia and to prevent and treat coronary artery disease and cerebrovascular disease, lower plasma low-density lipoprotein (LDL) cholesterol by competitively inhibiting HMG-CoA reductase, a precursor of cholesterol (Fig. 32.4). With long- term therapy, upregulation of LDL receptors occurs.72 Statins have a complex hydrophobic ring structure, and bioavailablity decreases with increasing hydrophobicity. Chronic statin use is associated with stabilization of atherosclerotic plaques.73 Adverse drug reactions include myopathy, rhabdomyolysis, and renal failure.72 Although transient transaminase elevations can occur with initiation of therapy, hepatotoxicity is rare and acute liver failure is extremely rare.74 Although concern exists for a serious interaction between statins and succinylcholine leading to rhabdomyolysis and hyperkalemia, there is limited evidence from clinical trials and observational studies to support this interaction.75,76 One study showed patients using statins who

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were given IV succinylcholine in doses of 1.5 mg/kg had greater myoglobinemia and fasciculations, but the level of myoglobin reached was not sufficient to cause renal toxicity.76

Other Treatments for Dyslipidemia Bile acid sequestrants (cholestyramine, colesevelam, colestipol) are positively charged molecules that bind negatively charged intestinal bile acids to block cholesterol absorption. They also inhibit bile acid reabsorption, leading to increased bile acid synthesis and competitive inhibition of cholesterol synthesis. Bile acid resins are associated with mild transaminase elevations but no clinically apparent acute liver injury.77 Ezetimibe is a synthetic azetidinone that inhibits intestinal cholesterol absorption and is associated with a low rate of transaminase elevations and clinically apparent liver injury.78 Fibrates (gemfibrozil, fenofibrate, clofibrate) are fibric acid derivatives that lower plasma lipids and triglyceride levels. Chronic therapy has been associated with mild elevations in transaminases and rare acute liver injury.79 Omega-3 fatty acids are essential polyunsaturated fatty acids used for the treatment of hypertriglyceridemia that are well tolerated and have not been implicated in liver injury.80 Niacin (nicotinic acid, vitamin B3) is a water-soluble, essential B vitamin that in high doses lowers LDL cholesterol and raises high-density lipoprotein cholesterol. Niacin can raise transaminases. High doses and certain formulations have been linked to acute liver injury.78

Hepatitis C Treatment Alpha interferons are immune-regulating signaling proteins with antiviral and antiproliferative activity. Treatment with interferon alfa (IFN-α) alone can occasionally completely eradicate hepatitis C infection, but sustained virologic response is seen in less than 20% of patients.81,82 Pegylated interferon is a synthetic interferon to which polyethylene glycol has been attached, prolonging duration of action. Treatment with pegylated INF-α leads to increased and sustained virologic response compared with standard IFN-α, especially when combined with the antiviral drug ribavirin.82 Ursodeoxycholic acid (ursodiol) is a bile acid that is used in chronic hepatitis C treatment for its immunomodulatory effects and to decrease clinical symptoms of liver disease such as pruritus.83,84

Emerging Developments Suppression of Gastric Acid Secretion

• Fig. 32.4

  A diagram summarizing the mechanisms of selected cholesterol-lowering therapies. Statins, exetimibe, and PCSK9 inhibitors all increase the expression of low-density lipoprotein (LDL) receptors and reduce LDL cholesterol levels (by percentages shown). Statins inhibit cholesterol synthesis in the liver, ezetimibe blocks cholesterol absorption in the intestine, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors block the PCSK9-mediated degradation of LDL receptors. (Adapted with permission from Grundy SM. Dyslipidaemia in 2015: advances in treatment of dyslipidaemia. Nat Rev Cardiol. 2016;13:74–75).

A novel class of potassium-competitive gastric acid blocker, vonoprazan fumarate, has been on the market in Japan since 2015. It is used as an oral medication prescribed once daily for both treatment of gastric ulcers and secondary prevention of gastric acid reflux. Vonoprazan reversibly inhibits hydrogen potassium adenosine triphosphatase (H+,K+-ATPase) activity, resulting in a decrease in gastric acid secretion 350 times greater than standard PPIs.85 In a study of healthy adults, vonoprazan showed inhibition of gastric acid secretion (pH > 6) lasting for almost 24 hours. Other benefits over PPIs include its stability in acidic environments, improved solubility in the stomach, and stronger inhibition of H+,K+-ATPase activity overall, leading to more effective lowering

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of gastric acid secretion.86 Additional clinical trials are underway, but vonoprazan has not been approved for use in the United States. If approved, vonoprazan could replace PPI use for treatment of gastroesophageal reflux disease, erosive esophagitis, peptic ulcer disease, prevention of nonsteroidal antiinflammatory drug–associated gastrointestinal events, and, used in combination with antibiotics, for treatment of Helicobacter pylori infection.87

Direct-Acting Antivirals for Hepatitis C Treatment Prior treatment of hepatitis C virus (HCV) was based on pegylated IFN-α plus ribavirin therapy, which was associated with a multitude of negative side effects, including anemia, fatigue, and malaise. Since 2011 a new generation of HCV treatments classified as oral direct-acting antivirals has been released, including boceprevir, telaprevir, and simeprevir. The most commonly used is a combination of ledipasvir 90 mg and sofosbuvir 400 mg approved by the FDA in 2014 for genotype 1 HCV infection.88 In a phase III clinical trial, this combination showed a 97% to 99% sustained virologic response (defined as undetectable HCV ribonucleic acid [RNA] at 12 weeks after treatment) in patients receiving once-daily treatment in combination or without concurrent ribavirin treatment with treatment for either 12 or 24 weeks.89 Direct-acting antivirals target the life cycle of the HCV RNA virus to inhibit replication. Ledipasvir targets one of the nonstructural HCV proteins called nonstructural protein 5A (NS5A) used in viral replication and absent in human cells.90 Common side effects include fatigue, headache, nausea, and diarrhea.91 Ledipasvir is used in combination with sofosbuvir, an NS5B polymerase inhibitor owing to its high rate of resistance.90 The ledipasvirsofosbuvir combination is indicated for use in adults with HCV genotype 1, 4, 5, or 6 without cirrhosis or with compensated cirrhosis. In combination with ribavirin, it can be used in patients with HCV genotype 1 with decompensated cirrhosis or liver transplant recipients without cirrhosis. It is also FDA approved in children older than 12 years or weighing more than 35 kg. The usual course of treatment is 12 weeks but can be extended to 24 weeks in patients who have received previous treatment with compensated cirrhosis.92

PCSK9 Inhibitors for Dyslipidemia Previous standard treatments for hypercholesterolemia relied on diet modification and use of statins. A novel class of medications— monoclonal antibodies that inhibit proprotein convertase subtilisinkexin type 9 (PCSK9)—includes evolocumab and alirocumab; similar to statins, these agents increase LDL receptor activity in the liver (see Fig. 32.4).93 In phase II and III clinical trials (Open Label Study of Long Term Evaluation Against LDL-C [OSLER-1 and OSLER-2], respectively) common adverse reactions to

evolocumab include injection site reactions, arthralgias, headache, and muscle pain leading to discontinuation of the medication in 2.4% of study patients. When compared with standard therapy, evolocumab decreased LDL cholesterol by 52%, decreased total cholesterol by 36%, and raised high-density lipoprotein cholesterol by 7%.94 Although evolocumab was successful at lowering LDL cholesterol, a follow-up study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Patients with Elevated Risk [FOURIER]) was performed to evaluate effects on reducing cardiovascular endpoints, such as myocardial infarction, stroke, unstable angina, or need for coronary revascularization. The combination of evolocumab plus standard statin therapy significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke by 20%, which correlated with decreases in LDL levels.95 Evolocumab is currently FDA approved for treatment of hypercholesterolemia in combination with other lipid-lowering medications (e.g., statins, ezetimibe), and is only recommended as single-agent therapy in patients diagnosed with primary hyperlipidemia, which is typically an inherited disease. It is given as a 140-mg subcutaneous injection once every 2 weeks or 420 mg monthly.96

Obeticholic Acid Nonalcoholic steatohepatitis (NASH) is associated with obesity, diabetes mellitus, and insulin resistance. Behind hepatitis and alcoholic cirrhosis, is the third most common indication for liver transplantation in the United States. In 2009, 9.7% of liver transplant recipients were performed for NASH cirrhosis.97 An emerging treatment for NASH is obeticholic acid, a variant of the naturally produced bile acid chenode oxycholic acid, which activates the farnesoid X nuclear receptor, activation of which promotes insulin sensitivity and decreases hepatic lipid synthesis.98 In the FLINT (Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis) trial of patients with biopsy-proven NASH, 45% of patients treated with obeticholic acid had histologic improvement (decreased fibrosis, hepatocellular ballooning, and steatosis) on liver biopsy compared with 21% in the placebo group. The obeticholic treatment group also showed elevations in total serum cholesterol and LDL cholesterol, particularly within the first 12 weeks of initiating treatment.99 Obeticholic acid was also studied as treatment for primary biliary cholangitis in a randomized phase III clinical trial comparing obeticholic acid in combination with standard of care ursodiol. In the obeticholic acid group, 77% of patients had a reduction of at least 15% in alkaline phosphatase compared with placebo (29%). Other markers, including total bilirubin, conjugated bilirubin, gamma-glutamyl transferase; alanine aminotransferase, and aspartate aminotransferase, also showed decreases in the treatment group. Despite improvement in laboratory values, patient symptoms showed no change on questionnaire.100

Key Points • Hepatic drug metabolism takes place primarily by cytochrome P450 enzymes, where genetic variability in metabolism can affect drug plasma concentrations. • Volatile anesthetics undergo oxidative metabolism in the liver and have variable effects on hepatic blood flow.

• Individual differences in drug metabolism in the intestine and liver are common and are major contributors to differences in drug response, including adverse effects. • Proton pump inhibitors and H2-histamine receptor antagonists are effective in decreasing gastric acid secretion but have

CHAPTER 32  Liver and Gastrointestinal Pharmacology



long-term side effects, including vitamin and electrolyte malabsorption, and possible predisposition toward infections, such as C. difficile and pneumonia. • New treatments for opioid-induced constipation include methylnaltrexone and almivopan. • Statins lower plasma low-density lipoprotein cholesterol and contribute to stabilization of atherosclerotic plaque. Adverse reactions include myopathy, transient transaminase elevations, and rare hepatoxicity, rhabdomyolysis, and renal failure.

Key References Alhazzani W, Alshamsi F, Belley-Cote E, et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. Intensive Care Med. 2018;44:1–11. Large metaanalysis of 57 trials with 7293 patients comparing proton pump inhibitors, H2-histamine receptor antagonists, and sucralfate for stress ulcer prophylaxis. (Ref. 61). American Society of Anesthesiologists Committee. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: an updated report by the Society of Anesthesiologists Committee on Standards and Practice Parameters. Anesthesiology. 2011;114:495–511. Most recent practice guidelines by the American Society of Anesthesiologists with recommended fasting times and concurrent use of medications to prevent aspiration. (Ref. 62). Beard TL, Leslie JB, Nemeth J. The opioid component of delayed gastrointestinal recovery after bowel resection. J Gastrointest Surg. 2011;15:1259–1268. Elucidates the role of opiates and postoperative ileus, and describes current recommendations for prevention and treatment. (Ref. 66). Freedberg DE, Kim LS, Yang Y-X. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152:706–715. Current recommendations from the American Gastroenterological Association regarding best practice for long-term proton pump inhibitor use. (Ref. 55). Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med. 2010;362:823–832. Primary prophylaxis, treatment, and secondary prophylaxis of variceal bleeding in cirrhotic patients. (Ref. 63). Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879–1888. Phase III open-label study dividing 647 patients into 3 treatment groups: ledipasvir-sofosbuvir for 8 weeks, ledipasvirsofosbuvir plus ribavirin for 8 weeks, and ledipasvir-sofosbuvir for 12 weeks, evaluating for sustained virologic response in the treatment of hepatitis C. (Ref. 91). Li H-C, Lo S-Y. Hepatitis C virus: virology, diagnosis and treatment. World J Hepatol. 2015;7:1377–1389. Explains the life cycle of the hepatitis C virus and how new direct-activing antivirals target certain parts of the virus. (Ref. 88). Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722. Randomized, double-blind, placebo-controlled trial with 27,564 patients showing the efficacy of evolocumab in reducing LDL cholesterol levels and reducing risk of cardiovascular events. (Ref. 95). Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. Br J Haematol. 2017;176:527–538. A recent review of acute porphyrias including clinical presentation, triggers and late complications. (Ref. 36)

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CHAPTER 32  Liver and Gastrointestinal Pharmacology

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