Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

excreted in the urine as the glucuronide, and about 25% in feces.

Mechanism of Action

These agents function primarily as ligands for the nuclear transcription receptor, peroxisome proliferator-activated receptor-alpha (PPAR-). They increase lipo-lysis of lipoprotein triglyceride via LPL. Intracellular lipolysis in adipose tissue is decreased. Levels of VLDL decrease, in part as a result of decreased secretion by the liver. Only modest reductions of LDL occur in most patients. In others, especially those with combined hyperlipidemia, LDL often increases as triglycerides are reduced. HDL cholesterol increases moderately. Part of this apparent increase is a consequence of decreasing triglycerides in plasma, with reduction in exchange of triglycerides into HDL in place of cholesteryl esters. Some increase in HDL protein has been reported.

Therapeutic Uses & Dosage

These drugs are useful in hypertriglyceridemias in which VLDL predominate and in dysbetalipoproteinemia. They also may be of benefit in treating the hypertriglyceridemia that results from treatment with viral protease inhibitors. The usual dose of gemfibrozil is 600 mg orally once or twice daily. The dosage of fenofibrate is one to three 54 mg tablets (or a single 160 mg tablet) daily. Absorption of both drugs is improved when they are taken with food.

Toxicity

Rare adverse effects include rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase. A few patients show decreases in white blood count or hematocrit. Both agents potentiate the action of coumarin and indanedione anticoagulants, and doses of these agents should be adjusted. Rhabdomyolysis has occurred rarely. Risk of myopathy increases when fibrates are given with reductase inhibitors. These drugs should be avoided in patients with hepatic or renal dysfunction. There appears to be a modest increase in the risk of cholesterol gallstones, reflecting an increase in the cholesterol content of bile. Therefore, fibrates should be used with caution in patients with biliary tract disease or in those at high risk such as women, obese patients, and Native Americans.

Bile Acid-Binding Resins

Colestipol, cholestyramine, and colesevelam are useful only for isolated increases in LDL. In patients who also have hypertriglyceridemia, VLDL levels may be further increased during treatment with resins.

Chemistry & Pharmacokinetics

These agents are large polymeric cationic exchange resins that are insoluble in water. They bind bile acids in the intestinal lumen and prevent their reabsorption. The resin itself is not absorbed.

Mechanism of Action

The bile acids, metabolites of cholesterol, are normally efficiently reabsorbed in the jejunum and ileum (Figure 35–2). Excretion is increased up to tenfold when resins are given, resulting in enhanced conversion of cholesterol to bile acids in liver via 7-hydroxylation, normally controlled by negative feedback by bile acids. Increased uptake of LDL and IDL from plasma results from upregulation of LDL receptors, particularly in liver. Therefore, the resins are without effect in patients with homozygous familial hypercholesterolemia who have no functioning receptors but may be useful in patients with receptor-defective combined heterozygous states.

Therapeutic Uses & Dosage

The resins are used in treatment of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage. If resins are used to treat LDL elevations in persons with combined hyperlipidemia, they may cause an increase in VLDL requiring the addition of a second agent such as niacin. Resins are also used in combination with other drugs to achieve further hypocholesterolemic effect (see below). They may be helpful in relieving pruritus in patients who have cholestasis and bile salt accumulation. Because they bind digitalis glycosides, the resins may be useful in digitalis toxicity.

Colestipol and cholestyramine are available as granular preparations. Colestipol is also available in 1 g tablets that must be swallowed whole. The maximum dose is 16 g daily. A gradual increase of dosage of granules from 4 or 5 g/d to 20 g/d is recommended. Total dosages of 30–32 g/d may be needed for maximum effect. The usual dosage for a child is 10–20 g/d. Granular resins are mixed with juice or water and allowed to hydrate for 1 minute. Colesevelam is available in 625 mg tablets. The maximum dose is six tablets daily. Resins should be taken in two or three doses with meals, and they lack effect when taken between meals.

Toxicity

Common complaints are constipation and bloating, usually relieved by increasing dietary fiber or mixing psyllium seed with the resin. Resins should be avoided in patients with diverticulitis. Heartburn and diarrhea are occasionally reported. In patients who have preexisting bowel disease or cholestasis, steatorrhea may occur. Malabsorption of vitamin K occurs rarely, leading to hypoprothrombinemia. Prothrombin time should be measured frequently in patients who are taking resins and anticoagulants. Malabsorption of folic acid has been reported rarely. Increased formation of gallstones, particularly in obese persons, was an anticipated adverse effect but has rarely occurred in practice. An occasional problem is dry flaking skin, relieved by application of lanolin.

Absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, and ascorbic acid.

Any additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorption. Colesevelam does not bind digoxin, warfarin, or reductase inhibitors.

Inhibitors of Intestinal Sterol Absorption

Ezetimibe is the first member of a new group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels.

Chemistry & Pharmacokinetics

Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12–14 hours. It undergoes enterohepatic circulation. Its half-life is 22 hours. Approximately 80% of the drug is excreted in feces. Plasma ezetimibe concentrations are substantially increased when it is administered with fibrates and reduced when it is given with cholestyramine. Other resins may also decrease its absorption. There are no significant interactions with warfarin or digoxin.

Mechanism of Action

Ezetimibe is a selective inhibitor of intestinal absorption of cholesterol and phytosterols. It is effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile.

Therapeutic Uses & Dosage

The effect on cholesterol absorption is constant over the dosage range of 5–20 mg/d. Therefore, a single daily dose of 10 mg is used. Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol. It is also effective in patients with phytosterolemia. Ezetimibe is apparently synergistic with reductase inhibitors, producing decrements as great as 25% in LDL cholesterol beyond that achieved with the reductase inhibitor alone.

Toxicity

Ezetimibe does not appear to be a substrate for cytochrome P450 enzymes. Preliminary data reveal a low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor. Liver function tests should be done before starting the drug and then at intervals of 2–4 months.

Treatment with Drug Combinations

Combined drug therapy is useful (1) when VLDL levels are significantly increased during treatment of hyper-cholesterolemia with a resin; (2) when LDL and VLDL levels are both elevated initially;

(3) when LDL or VLDL levels are not normalized with a single agent, or (4) when elevated levels of Lp(a) or HDL deficiency coexist with other hyperlipidemias.

Fibric Acid Derivatives & Bile Acid-Binding Resins

This combination is sometimes useful in treating patients with familial combined hyperlipidemia who are intolerant of niacin. However, it may increase the risk of cholelithiasis.

HMG-CoA Reductase Inhibitors & Bile Acid-Binding Resins

This highly synergistic combination is useful for treatment of familial hypercholesterolemia but may not control levels of VLDL in some patients with familial combined hyperlipoproteinemia. Pravastatin, atorvastatin, and fluvastatin should be given at least 1 hour before or 4 hours after the resin to ensure their absorption.

Niacin & Bile Acid-Binding Resins

This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disorders involving both increased VLDL and LDL levels. When VLDL and LDL levels are both initially increased, doses of niacin as low as 1–3 g/d may be sufficient in combination with a resin. The niacin-resin combination is effective for treating heterozygous familial hypercholesterolemia. Niacin also significantly elevates levels of HDL cholesterol and frequently decreases levels of Lp(a).

Quantitative evidence of reversal of coronary disease was demonstrated with this regimen in three major clinical trials. Effects on lipoprotein levels are sustained, and no additional adverse effects have developed other than those encountered when the drugs are used singly. The drugs may be taken together, because niacin does not bind to the resins. LDL levels in patients with heterozygous familial hypercholesterolemia are usually normalized with daily doses of up to 6.5 g of niacin with 24–30 g of resin.

Niacin & Reductase Inhibitors

This regimen is more effective than either agent alone in treating familial hypercholesterolemia. Experience indicates that it is the most efficacious and practical combination for treatment of familial combined hyperlipoproteinemia.

Reductase Inhibitors & Ezetimibe

This combination is synergistic in treating primary hypercholesterolemia and has some use in the treatment of homozygous familial hypercholesterolemia.

Ternary Combination of Resins, Niacin, & Reductase Inhibitors

These agents act in a complementary fashion to normalize cholesterol in patients with severe disorders involving elevated LDL. The effects are sustained, and little compound toxicity has been observed. Effective doses of the individual drugs may be lower than when each is used alone—eg,

as little as 1–2 g of niacin may substantially increase the effects of the other agents.

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Preparations Available

Atorvastatin (Lipitor)

Oral: 10, 20, 40, 80 mg tablets

Cholestyramine (generic, Questran, Questran Light)

Oral: 4 g packets anhydrous granules cholestyramine resin; 210 g (Questran Light), 378 g (Questran) cans

Colesevelam (Welchol)

Oral: 625 mg tablets

Colestipol (Colestid)

Oral: 5 g packets granules; 300, 500 g bottles; 1 g tablets

Ezetimibe (Zetia)

Oral: 10 mg tablets

Fenofibrate (Tricor)

Oral: 54, 160 mg tablets

Fluvastatin (Lescol)

Oral: 20, 40 mg capsules; extended release (Lescol XL): 80 mg capsules

Gemfibrozil (generic, Lopid)

Oral: 600 mg tablets

Lovastatin (generic, Mevacor)

Oral: 10, 20, 40, 80 mg tablets; extended release tablets (Altocar) 10, 20, 40, 60 mg

Niacin, nicotinic acid, vitamin B3 (generic, others)

Oral: 100, 250, 500, 1000 mg tablets

Pravastatin (Pravachol)

Oral: 10, 20, 40, 80 mg tablets

Rosuvastatin (Crestor)

Oral: 5, 10, 20, 40 mg tablets

Simvastatin (Zocor)

Oral: 5, 10, 20, 40, 80 mg tablets

Chapter 36. Nonsteroidal Anti-Inflammatory Drugs, DiseaseModifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout

Katzung PHARMACOLOGY, 9e > Section VI. Drugs Used to Treat Disease of the Blood, Inflammation, & Gout > Chapter 36. Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout >

The Immune Response

The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be beneficial, as when it causes invading organisms to be phagocytosed or neutralized. On the other hand, the outcome may be deleterious if it leads to chronic inflammation without resolution of the underlying injurious process (see Chapter 56: Immunopharmacology). Chronic inflammation involves the release of a number of mediators that are not prominent in the acute response. One of the most important conditions involving these mediators is rheumatoid arthritis, in which chronic inflammation results in pain and destruction of bone and cartilage that can lead to severe disability and in which systemic changes occur that can result in shortening of life.

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. As discussed in Chapter 18: The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds, the cyclooxygenase pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. The discovery of cyclooxygenase (COX) isoforms (COX-1 and COX-2) led to the concepts that the constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy. The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability.

Kinins, neuropeptides, and histamine are also released at the site of tissue injury, as are complement components, cytokines, and other products of leukocytes and platelets. Stimulation of the neutrophil

membranes produces oxygen-derived free radicals. Superoxide anion is formed by the reduction of molecular oxygen, which may stimulate the production of other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process.

Katzung PHARMACOLOGY, 9e > Section VI. Drugs Used to Treat Disease of the Blood, Inflammation, & Gout > Chapter 36. Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout >

Therapeutic Strategies

The treatment of patients with inflammation involves two primary goals: first, the relief of pain, which is often the presenting symptom and the major continuing complaint of the patient; and second, the slowing or—in theory—arrest of the tissue-damaging process. In rheumatoid arthritis, response to therapy can be quantitated by means of the American College of Rheumatology scoring system values ACR20, ACR50, and ACR70, which denote the percentage of patients showing an improvement of 20%, 50%, or 70% in a global assessment of signs and symptoms.

Reduction of inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs) often results in relief of pain for significant periods. Furthermore, most of the nonopioid analgesics (aspirin, etc) also have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions.

The glucocorticoids also have powerful anti-inflammatory effects and when first introduced were considered to be the ultimate answer to the treatment of inflammatory arthritis. Unfortunately, the toxicity associated with chronic corticosteroid therapy limits their use except in the control of acute flare-ups of joint disease. Therefore, the nonsteroidal anti-inflammatory drugs have assumed a major role in the long-term treatment of arthritis.

Another important group of agents are characterized as slow-acting antirheumatic drugs (SAARDs) or disease-modifying antirheumatic drugs (DMARDs). They may slow the bone damage associated with rheumatoid arthritis and are thought to affect more basic inflammatory mechanisms than do the NSAIDs. Unfortunately, they may also be more toxic than the nonsteroidal anti-inflammatory agents.

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Nonsteroidal Anti-Inflammatory Drugs

Salicylates and other similar agents used to treat rheumatic disease share the capacity to suppress the signs and symptoms of inflammation. These drugs also exert antipyretic and analgesic effects, but it is their anti-inflammatory properties that make them most useful in the management of disorders in which pain is related to the intensity of the inflammatory process.

Although all NSAIDs are not FDA-approved for the whole range of rheumatic diseases, all are probably effective in rheumatoid arthritis, seronegative spondyloarthropathies (eg, psoriatic arthritis and arthritis associated with inflammatory bowel disease), osteoarthritis, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be

ineffective in gout). Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed in attempts to improve upon aspirin's efficacy and decrease its toxicity.

Chemistry & Pharmacokinetics

The NSAIDs are grouped in several chemical classes, some of which are shown in Figure 36–1. This chemical diversity yields a broad range of pharmacokinetic characteristics (Table 36–1). Although there are many differences in the kinetics of NSAIDs, they have some general properties in common. All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug. Most of these drugs are well absorbed, and food does not substantially change their bioavailability. Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. Metabolism of most NSAIDs proceeds, in part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver. While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of lower gastrointestinal tract irritation correlates with the amount of enterohepatic circulation. Most of the NSAIDs are highly proteinbound ( 98%), usually to albumin. Some of the NSAIDs (eg, ibuprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac).

Figure 36–1.

Chemical structures of some NSAIDs.

Table 36–1. Properties of Aspirin and Some Nonsteroidal Anti-Inflammatory Drugs.

1Major anti-inflammatory metabolite of aspirin.

2Salicylate is usually given in the form of aspirin.

3Total urinary excretion including metabolites.

4Recommended for treatment of acute (eg, surgical) pain only.

5Nabumetone is a prodrug; the half-life and urinary excretion are for its active metabolite.

6A single daily dose is sufficient because of the long half-life.

All NSAIDs can be found in synovial fluid after repeated dosing. Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives.

Pharmacodynamics

The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins. Various NSAIDs have additional possible mechanisms of action,