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12 Vitamins

June 6, 2024

ANTI-INFLAMMATORY AGENTS. ANTIALLERGIC AGENTS. IMMUNOMODULATORS. (Acidum acetylsalicilicum, Acidum mephenamicum, Butadionum, Indometacinum (Metindol), Dyclofenac-natrium, Ibuprophen, Naproxen, Pyroxicam, Meloxicam, Celecoxib, Nimesulid, Dimedrolum, Tavegilum, Fencarolum, Suprastinum, Diazolinum, Loratinum, Diprasinum, Fexofenadinum, Ranitidinum, Famotidinum, Levamisolum, Timalinum, Т-activinum, Prodigiosanum, Natrii Nuclrinas, Methyluracilum, Pentoxilum)

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.

CAZy ~ Carbohydrate-Active enZymes

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 enzymes are found in the …

2-OXOACID-DEPENDENT ENZYMES

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.

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

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, including inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while most non-COXselective NSAIDs are reversible inhibitors. Selectivity for COX-1 versus COX-2 is variable and incomplete for the older members, but highly selective COX-2 inhibitors (celecoxib, rofecoxib, and valdecoxib) are now available and other highly selective coxibs are being developed. The highly selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, indomethacin, piroxicam, and sulindac were somewhat more effective in inhibiting COX-1; ibuprofen and meclofenamate inhibited the two isozymes about equally. The

efficacy of COX-2-selective drugs equals that of the older NSAIDs, while gastrointestinal safety may be improved. On the other hand, highly selective COX-2 inhibitors may increase the incidence of edema and hypertension.

The NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from T lymphocytes, and reverse vasodilation. To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2-selective agents and the nonacetylated salicylates) inhibit platelet aggregation. NSAIDs are all gastric irritants as well, though as a group the newer agents tend to cause less gastric irritation than aspirin. Nephrotoxicity has been observed for all of the drugs for which extensive experience has been reported, and hepatotoxicity can also occur with any NSAID.

Although these drugs effectively inhibit inflammation, there is no evidence that—in contrast to drugs such as methotrexate and gold—they alter the course of an arthritic disorder.

Aspirin

Aspirin’s long use and availability without prescription diminishes its glamour compared to that of the newer NSAIDs. Aspirin is now rarely used as an anti-inflammatory medication; it has been replaced by ibuprofen and naproxen, since they are effective, are also available over the counter, and have good to excellent safety records.

Pharmacokinetics

Salicylic acid is a simple organic acid with a pKa of 3.0. Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 (see Table 1–1). Sodium salicylate and aspirin (Figure 36–2) are equally effective anti-inflammatory drugs, though aspirin may be more effective as an analgesic. The salicylates are rapidly absorbed from the stomach and upper small intestine, yielding a peak plasma salicylate level within 1–2 hours. Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood. Salicylate is bound to albumin, but the binding is saturable so that the unbound fraction increases as total concentration increases. Ingested salicylate and that generated by the hydrolysis of aspirin may be excreted unchanged, but the metabolic pathways for salicylate disposition become saturated when the total body load of salicylate exceeds 600 mg. Beyond this amount, increases in salicylate dosage increase salicylate concentration disproportionately. As doses of aspirin increase, salicylate elimination halflife increases from 3–5 hours (for 600 mg/d dosage) to 12–16 hours (dosage > 3.6 g/d).

Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates.

Figure 36–2.

Mechanisms of Action

Anti-Inflammatory Effects

Aspirin is a nonselective inhibitor of both COX isoforms (Figure 36–3), but salicylate is much less effective in inhibiting either isoform. Nonacetylated salicylates may work as oxygen radical scavengers. Aspirin irreversibly inhibits COX and inhibits platelet aggregation, while nonacetylated salicylates do not.

Figure 36–3.

Aspirin also interferes with the chemical mediators of the kallikrein system, thus inhibiting granulocyte adherence to damaged vasculature, stabilizing lysosomes, and inhibiting the chemotaxis of polymorphonuclear leukocytes and macrophages.

Analgesic Effects

Aspirin is most effective in reducing pain of mild to moderate intensity through its effects on inflammation and because it probably inhibits pain stimuli at a subcortical site.

Antipyretic Effects

Aspirin reduces elevated temperature, whereas normal body temperature is only slightly affected.

Aspirin’s antipyretic effect is probably mediated by both COX inhibition in the central nervous system and inhibition of IL-1 (which is released from macrophages during episodes of inflammation).

Antiplatelet Effects

Single low doses of aspirin (81 mg daily) produce a slightly prolonged bleeding time, which doubles if administration is continued for a week. The change is due to irreversible inhibition of platelet COX, so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet).

Clinical Uses

Analgesia, Antipyresis, and Anti-Inflammatory Effects

Aspirin is employed for mild to moderate pain of varied origin but is not effective for severe visceral pain. Aspirin and other NSAIDs have been combined with opioid analgesics for treatment of cancer pain, where their anti-inflammatory effects act synergistically with the opioids to enhance analgesia. High-dose salicylates are effective for treatment of rheumatic fever, rheumatoid arthritis, and other inflammatory joint conditions.

Other Effects

Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting .

Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects.

Dosage

The optimal analgesic or antipyretic dose of aspirin is less than the 0.6–0.65 g oral dose commonly used. Larger doses may prolong the effect. The usual dose may be repeated every 4 hours. The anti-inflammatory dose for children is 50–75 mg/kg/d in divided doses and the average starting anti-inflammatory dose for adults is 45 mg/kg/d in divided doses (Table 36–1). The relationship of salicylate blood levels to therapeutic effect and toxicity is illustrated in Figure 36–4.

Adverse Effects

At the usual dosage, aspirin’s main adverse effects are gastric upset (intolerance) and gastric and duodenal ulcers, while hepatotoxicity, asthma, rashes, and renal toxicity occur less frequently.

Upper gastrointestinal bleeding associated with aspirin use is usually related to erosive gastritis. A 3 mL increase in fecal blood loss is routinely associated with aspirin administration; the blood loss is greater for higher doses. On the other hand, some mucosal adaptation occurs in many patients, so that blood loss declines back to baseline over 4–6 weeks; ulcers have been shown to heal while aspirin was taken concomitantly.

With higher doses, patients may experience “salicylism”—vomiting, tinnitus, decreased hearing, and vertigo—reversible by reducing the dosage. Still larger doses of salicylates cause hyperpnea through a direct effect on the medulla. At toxic salicylate levels, respiratory alkalosis followed by metabolic acidosis (salicylate accumulation), respiratory depression, and even cardiotoxicity and glucose intolerance can occur (Figure 36–4). Two grams or less of aspirin daily usually increases serum uric acid levels, whereas doses exceeding 4 g daily decrease urate levels. Like other NSAIDs, aspirin can cause elevation of liver enzymes (a frequent but mild effect), hepatitis (rare), decreased renal function, bleeding, rashes, and asthma.

The antiplatelet action of aspirin contraindicates its use by patients with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsiaeclampsia. When overdosing occurs, gastric lavage is advised and an alkaline, high urine output state should be maintained. Hyperthermia and electrolyte abnormalities should be treated. In severe toxic reactions, ventilatory assistance may be required.

Sodium bicarbonate infusions may be employed to alkalinize the urine, which will increase the amount of salicylate excreted.

Nonacetylated Salicylates

These drugs include magnesium choline salicylate, sodium salicylate, and salicylsalicylate. All nonacetylated salicylates are effective anti-inflammatory drugs, though they may be less effective analgesics than aspirin. Because they are much less effective than aspirin as cyclooxygenase inhibitors, they may be preferable when cyclooxygenase inhibition is undesirable, such as in patients with asthma, those with bleeding tendencies, and even (under close supervision) those with renal dysfunction.

The nonacetylated salicylates are administered in the same dosage as aspirin and can be monitored using serum salicylate measurements.

COX-2 Selective Inhibitors

COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostacyclin synthesis by the COX-2 isoenzyme induced at sites of inflammation without affecting the action of the constitutively active “housekeeping” COX-1 isoenzyme found in the gastrointestinal tract, kidneys, and platelets. Coxibs selectively bind to and block the active site of the COX-2 enzyme much more effectively than that of COX-1. COX-2 inhibitors have analgesic, antipyretic, and anti-inflammatory effects similar to those of nonselective NSAIDs but with fewer gastrointestinal side effects. Likewise, COX-2 inhibitors have been shown to have no impact on platelet aggregation, which is mediated by the COX-1 isoenzyme. As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs, which has resulted in some patients taking low-dose aspirin in addition to a coxib regimen to maintain this effect. Unfortunately, because COX-2 is constitutively active within the kidney, recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs. They are not recommended for patients with severe renal insufficiency. Furthermore, some clinical data have suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib, but this issue has not yet been settled. Data from animal studies have also pointed to the role of the COX-2 enzyme in bone repair, resulting in a recommendation for short-term use of different drugs in postoperative patients and those undergoing bone repair. COX-2 inhibitors have been recommended mainly for treatment of osteoarthritis and rheumatoid arthritis, but other indications include primary familial adenomatous polyposis, dysmenorrhea, acute gouty arthritis, acute musculoskeletal pain, and perhaps ankylosing spondylitis.

Celecoxib

Celecoxib is a highly selective COX-2 inhibitor—about 10–20 times more selective for COX-2 thanfor COX-1. Pharmacokinetic and dosage considerations are given in Table 36–1.

Celecoxib is as effective as other NSAIDs in rheumatoid arthritis and osteoarthritis, and in trials it has caused fewer endoscopic ulcers than most other NSAIDs. Because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9.

The coxibs continue to be investigated to determine whether their effect on prostacyclin production could lead to a prothrombotic state. The frequency of other adverse effects approximates that of other NSAIDs. Celecoxib causes no more edema or renal effects than other members of the NSAID group, but edema and hypertension have been documented.

Etoricoxib

Etoricoxib, a bipyridine derivative, is a second-generation COX-2-selective inhibitor with the highest selectivity ratio of any coxib for inhibition of COX-2 relative to COX-1. It is extensively metabolized by hepatic P450 enzymes followed by renal excretion and has an elimination half-life of 22 hours. Etoricoxib is approved in the United Kingdom for acute treatment of the signs and symptoms of osteoarthritis (60 mg once daily) and rheumatoid arthritis (90 mg once daily), for treatment of acute gouty arthritis (120 mg once daily), and for relief of acute musculoskeletal pain (60 mg once daily). Approval in the United States is pending. Clinical data have demonstrated that 90 mg of etoricoxib once daily has superior efficacy compared with 500 mg of naproxen twice daily for treatment of patients with rheumatoid arthritis over 12 weeks. Other studies have shown etoricoxib to have similar efficacy to traditional NSAIDs for treatment of osteoarthritis, acute gouty arthritis, and primary dysmenorrhea and a gastrointestinal safety profile similar to that of other coxibs. Since etoricoxib has structural similarities to diclofenac, it is appropriate to monitor hepatic function carefully in patients using this drug.

Meloxicam

Meloxicam is an enolcarboxamide related to piroxicam that has been shown to preferentially inhibit COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as the other coxibs. The drug is popular in Europe and many other countries for most rheumatic diseases and has recently been approved for treatment of osteoarthritis in the USA. Its efficacy in this condition and rheumatoid arthritis is comparable to that of other NSAIDs. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, it appears that even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result Rofecoxib, a furanose derivative, is a potent, selective COX-2 inhibitor (Table 36–1). In the USA, rofecoxib is approved for osteoarthritis and rheumatoid arthritis, and it also appears to be analgesic and antipyretic—in common with other NSAIDs. This drug does not inhibit platelet aggregation and appears to have little effect on gastric mucosal prostaglandins or lower gastrointestinal tract permeability. At high doses it is associated with occasional edema and hypertension. Other toxicities are similar to those of other coxibs.

Diclofenac

Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a cyclooxygenase inhibitor. Pharmacokinetic and dosage characteristics are set forth in Table 36–1.

Adverse effects occur in approximately 20% of patients and include gastrointestinal distress, occult gastrointestinal bleeding, and gastric ulceration, though ulceration may occur less frequently than with some other NSAIDs. A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. Another combination of diclofenac and omeprazole was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients. Diclofenac at a dosage of 150 mg/d appears to impair renal blood flow and glomerular filtration rate. Elevation of serum aminotransferases may occur more commonly with this drug than with other NSAIDs. A 0.1% ophthalmic preparation is recommended for prevention of postoperative ophthalmic nflammation and can be used after intraocular lens implantation and strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses. Diclofenac in rectal suppository form can be considered a drug of choice for preemptive analgesia and postoperative nausea.

In Europe, diclofenac is also available as an oral mouthwash and for intramuscular administration. Fenoprofen, a propionic acid derivative, is the NSAID most closely associated with the toxic effect of interstitial nephritis. This rare toxicity may be associated with a local T cell response in renal tissue.

Other adverse effects of fenoprofen include nausea, dyspepsia, peripheral edema, rash, pruritus, central nervous system and cardiovascular effects, tinnitus, and drug interactions. However, the latter effects are less common than with aspirin.

Ibuprofen

Ibuprofen is a simple derivative of phenylpropionic acid. In doses of about 2400 mg daily, ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect.

Pharmacokinetic characteristics

are given in table 36–1. Oral ibuprofen is often prescribed in lower doses (< 2400 mg/d), at which it has analgesic but not anti-inflammatory efficacy. It is available over the counter in low-dose forms under several trade names. A topical cream preparation appears to be absorbed into fascia and muscle; an (S)(–) formulation has been tested. Ibuprofen cream was more effective than placebo cream for the

treatment of primary knee osteoarthritis. A liquid gel preparation of ibuprofen 400 mg provided faster relief and superior overall efficacy in postsurgical dental pain. In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention than indomethacin. Ibuprofen has been shown to be effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. Oral ibuprofen is as effective as intravenous administration in this condition.

Gastrointestinal irritation and bleeding occur, though less frequently than with aspirin. The use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect. The drug is relatively contraindicated in individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin. In addition to the gastrointestinal symptoms (which can be modified by ingestion with meals), rash, pruritus, tinnitus, dizziness, headache, aseptic meningitis (particularly in patients with systemic lupus erythematosus), and fluid retention have been reported. Interaction with anticoagulants is uncommon.

The concomitant administration of ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin. Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. Rare hematologic effects include agranulocytosis and aplastic anemia. Effects on the kidney (as with all NSAIDs) include acute renal failure, interstitial nephritis, and nephrotic syndrome, but these occur very rarely. Finally, hepatitis has been reported.

Indomethacin

Indomethacin, introduced in 1963, is an indole derivative (Figure 36–1). It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation. Probenecid prolongs indomethacin’s half-life by inhibiting both renal and biliary clearance.

Clinical Uses

Indomethacin enjoys the usual indications for use in rheumatic conditions and is particularly popular for gout and ankylosing spondylitis. In addition, it has been used to treat patent ductus arteriosus. Indomethacin has been tried in numerous small or uncontrolled trials for many conditions, including Sweet’s syndrome, juvenile rheumatoid arthritis, pleurisy, nephritic syndrome, diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and prophylaxis of heterotopic ossification in arthroplasty, and many others. An ophthalmic preparation seems to be efficacious for conjunctival inflammation (alone and in combination with gentamicin) to reduce pain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indomethacin oral rinse. Epidural injections produce a degree of pain relief similar to that achieved with methylprednisolone in postlaminectomy syndrome.

Adverse Effects

At higher dosages, at least a third of patients have reactions to indomethacin requiring discontinuance. The gastrointestinal effects may include abdominal pain, diarrhea, gastrointestinal hemorrhage, and pancreatitis. Headache is experienced by 15–25% of patients and may be associated with dizziness, confusion, and depression. Rarely, psychosis with hallucinations has been reported. Hepatic abnormalities are rare. Serious hematologic reactions have beeoted, including thrombocytopenia and aplastic anemia. Hyperkalemia has been reported and is related to inhibition of the synthesis of prostaglandins in the kidney. Renal papillary necrosis has also been observed.

Ketoprofen

ketoprofen

Ketoprofen is a propionic acid derivative that inhibits both cyclooxygenase (nonselectively) and lipoxygenase. Its pharmacokinetic characteristics are given in Table 36–1. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.

The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDs in the treatment of rheumatoid arthritis, osteoarthritis, gout, dysmenorrhea, and other painful conditions. In spite of its dual effect on prostaglandins and leukotrienes, ketoprofen is not superior to other NSAIDs. Its major adverse effects are on the gastrointestinal tract and the central nervous system.

Ketorolac

Ketorolac is an NSAID promoted for systemic use mainly as an analgesic, not as an anti-inflammatory drug (though it has typical NSAID properties). Pharmacokinetics are presented in Table 36–1. The drug does appear to have significant analgesic efficacy and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain. It is most often given intramuscularly or intravenously, but an oral dose formulation is available. When used with an opioid, it may decrease the opioid requirement by 25–50%. An ophthalmic preparation is available for anti-inflammatory applications. Toxicities are similar to those of other NSAIDs, although renal toxicity may be more common with chronic use.

Meclofenamate & Mefenamic Acid

Meclofenamate and mefenamic acid (Table 36–1) inhibit both COX and phospholipase A2.

Meclofenamate appears to have adverse effects similar to those of other NSAIDs, though diarrhea and abdominal pain may be more common; it has no advantages over other NSAIDs. This drug enhances the effect of oral anticoagulants. Meclofenamate is contraindicated in pregnancy; its efficacy and safety have not been established for young children.

… suppress the acid in the stomach …

Mefenamic acid is probably less effective than aspirin as an anti-inflammatory agent and is clearly more toxic. It should not be used for longer than 1 week and should not be given to children.

Naproxen

Naproxen is a naphthylpropionic acid derivative. It is the only NSAID presently marketed as a single enantiomer, and it is a nonselective COX inhibitor. Naproxen’s free fraction is 41% higher in women than in men, though albumin binding is very high in both sexes (Table 36–1). Naproxen is effective for the usual rheumatologic indications and is available both in a slow-release formulation and as an oral suspension. A topical preparation and an ophthalmic solution are also available.

The incidence of upper gastrointestinal bleeding in OTC use is low but still double that of OTC ibuprofen (perhaps due to a dose effect). Rare cases of allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria as well as the more common NSAID-associated adverse effects have beeoted.

Piroxicam

Piroxicam, an oxicam (Figure 36–1), is a nonselective COX inhibitor but at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life (Table 36–1) permits once-daily dosing.

Piroxicam can be used for the usual rheumatic indications. Toxicity includes gastrointestinal symptoms (20% of patients), dizziness, tinnitus, headache, and rash. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered.

Clinical Pharmacology of the NSAIDs

All NSAIDs, including aspirin, are about equally efficacious with a few exceptions—tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for ankylosing spondylitis. Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the gastrointestinal and renal side effects of ketorolac limit its use. Fries et al (1993), using a toxicity index, estimated that indomethacin, tolmetin, and meclofenamate were associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen were least toxic. The selective COX-2 inhibitors were not included in this analysis.

For patients with renal insufficiency, nonacetylated salicylates may be best. Fenoprofen is less used because of its rare association with interstitial nephritis. Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs. The relatively expensive and selective COX-2 inhibitors are probably safest for patients at high risk for gastrointestinal bleeding. These drugs or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in those patients at highest risk for gastrointestinal bleeding; in this subpopulation of patients, they are cost-effective despite their high acquisition costs.

The choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (eg, other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no “best” NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person.

Antiallergic agent

1. To understand the mechanism of the anti-inflammatory action of glucocorticoids

2. To understand the mechanism of positive and negative transcriptional regulation by the glucocorticoid receptor.

3. To understand the basic mechanism of action of commonly used non-steroidal anti-inflammatory agents

OUTLINE

1. The Pathophysiology of Asthma

2. Physiological Actions of Glucocorticoids

3. Mechanism of Action of the Glucocorticoid Receptor

4. Pharmacology of Glucocorticoid Use in Asthma Treatment

5. Other Anti-Inflammatory Agents Used to Treat Asthma

REVIEW OF ASTHMA PATHOPHYSIOLOGY

Asthma is a chronic disorder of the airways that is characterized by reversible airflow obstruction and airway inflammation, persistent airway hyper-reactivity (AHR) and airway remodeling. The pathogenesis of asthma involves several processes. Chronic inflammation of the bronchial mucosa is prominent, with infiltration of activated T-lymphocytes and eosinophils. This results in subepithelial fibrosis and the release of chemical mediators that can damage the epithelial lining of the airway. Many of these mediators are released following activation and degranulation of mast cells in the bronchial tree. Some of these mediators act as chemotactic agents for other inflammatory cells. They also produce mucosal edema, which narrows the airway and stimulates smooth muscle contraction, leading to bronchoconstriction. Excessive production of mucus can cause further airway obstruction by plugging the bronchiolar lumen.

Inflammatory mediators in Asthma: Activation of mast cells results in secretion of several mediators that contribute to the pathogenesis of asthma. These mediators produce bronchconstriction and initiate both the acute inflammatory response and attract cells responsible for maintaining chronic inflammation. IL, interleukin; GM-CSF, granulocyte and macrophage colony-stimulating factor; PG, prostaglandin; TNF, tissue necrosis factor; IFN interferon

IMPORTANT CONCEPT 1. Asthma is an inflammatory disease and thus effective treatments for the chronic management of asthma should be directed to reduce the inflammatory response

The available agents for treating asthma can be divided into two general categories: drugs that inhibit smooth muscle contraction, i.e. bronchodilators (beta-adrenergic agonists, methylxanthines, and anticholinergics) and agents that prevent and/or reverse inflammation, i.e., the “long-term control medications” (glucocorticoids, leukotriene inhibitors and receptor antagonists, and mast cell-stabilizing agents or cromones).

GLUCOCORTICOIDS (CORTICOSTEROIDS)

Physiology

Glucocorticoids (i.e. cortisol [hydrocortisone] in humans) are synthesized in the adrenal cortex at a daily rate of 10 mg/day and exhibit a diurnal pattern of secretion (i.e. 16 µg/dL in blood @ 8 a.m. and 4 µg/dL @ 4 p.m.). These hormones have access to all tissues in the body and exert wide-ranging effects on many organ systems. Under conditions of severe stress, glucocorticoid levels can rise at least 10-fold.

The major physiologic effects of glucocorticoids are:

· Regulation of carbohydrate, protein, and lipid metabolism

· Maintenance of fluid and electrolyte balance

· Preservation of normal function of the cardiovascular system, the immune system, the kidneys, skeletal muscle, the endocrine system, and the nervous system

· Preservation of organismal homeostasis

The impact of glucocorticoids on homeostasis is illustrated by the potent anti-inflammatory and immunosuppressive actions of these hormones.

IMPORTANT CONCEPT 2. The anti-inflammatory and immunosuppressive actions of glucocorticoids play an important role in preventing potentially damaging effects of an unopposed inflammatory response and can be exploited therapeutically.

Given the various tissues that are affected by glucocorticoids, systemic treatment with pharmacological doses of glucocorticoids generates many adverse side effects. Since physiological glucocorticoids (i.e. cortisol) bind with reasonably high affinity to the mineralocorticoid receptor, alterations in fluid and electrolyte handling (mediated physiologically by the mineralocorticoid receptor) and ensuing hypertension are important side effects of glucocorticoid therapy.

Table 59–3 Effects of Glucocorticoids on Components of Inflammatory/Immune Responses

CELL TYPE

FACTOR

COMMENTS

Macrophages and monocytes

Arachidonic acid and its metabolites (prostaglandins and leukotrienes)

Mediated by glucocorticoid inhibition of cyclooxygenase–2 and phospholipase A₂.

Cytokines, including: interleukin (IL)-1, IL-6, and tumor necrosis factor- (TNF-)

Production and release are blocked. The cytokines exert multiple effects on inflammation (e.g., activation of T cells, stimulation of fibroblast proliferation).

Acute phase reactants

These include the third component of complement.

Endothelial cells

Endothelial leukocyte adhesion molecule-1 (ELAM-1) and intracellular adhesion molecule-1 (ICAM-1)

ELAM-1 and ICAM-1 are intracellular adhesion molecules that are critical for leukocyte localization.

Acute phase reactants

Same as above, for macrophages and monocytes.

Cytokines (e.g., IL-1)

Same as above, for macrophages and monocytes.

Arachidonic acid derivatives

Same as above, for macrophages and monocytes.

Basophils

Histamine, leukotriene C4

IgE-dependent release inhibited by glucocorticoids.

Fibroblasts

Arachidonic acid metabolites

Same as above for macrophages and monocytes. Glucocorticoids also suppress growth factor–induced DNA synthesis and fibroblast proliferation.

Lymphocytes

Cytokines (IL-1, IL-2, IL-3, IL-6, TNF-, GM-CSF, interferon-)

Same as above for macrophages and monocytes.

Table 27–1 Potential Adverse Effects Associated with Inhaled Glucocorticoids

ADVERSE EFFECT

RISK

Hypothalamic–pituitary–adrenal axis suppression

No significant risk until dosages of budesonide or beclomethasone increased to >1500 g/day in adults or >400 g/day in children

Bone resorption

Modest but significant effects at doses possibly as low as 500 g/day

Carbohydrate and lipid metabolism

Minor, clinically insignificant changes occur with dosages of beclomethasone >1000 g/day

Cataracts

Anecdotal reports, risk unproven

Skin thinning

Dosage-related effect with beclomethasone dipropionate over a range of 400 to 2000 g/day

Purpura

Dosage-related increase in occurrence with beclomethasone over a range of 400 to 2000 g/day

Dysphonia

Usually of little consequence

Candidiasis

Incidence <5%, reduced by use of spacer device

Growth retardation

Difficult to separate effect of disease from effect of treatment, but no discernible effects on growth when all studies are considered

IMPORTANT CONCEPT 3. The beneficial effects of glucocorticoids to limit inflammation is counter-balanced by its many adverse side effects

Mechanism of Action

The Glucocorticoid Receptor

Glucocorticoid effects in target tissues are mediated by a single receptor protein, the glucocorticoid receptor, which is a member of the nuclear receptor (NR) superfamily. The glucocorticoid receptor, like all NRs, is a transcription factor that exerts most of its physiological effects through the positive or negative regulation of specific target genes. Thus, many of the changes in cellular physiology that result from glucocorticoid exposure are not acute and require hours or even days to develop.

Glucocorticoid Regulation of Gene Expression

Each tissue and cell type contains a distinct set of target genes that are regulated by glucocorticoids. Specific sequences within genes are recognized by the hormone-bound glucocorticoid receptor. The binding of the glucocorticoid receptor to target gene sequences can either lead to increased or decreased transcription of that gene. However, many other transcription factors (directly bound to gene sequences) and transcription cofactors (recruited to gene sequences through protein-protein interactions) are required for the glucocorticoid receptor to exert its effects on transcription.

IMPORTANT CONCEPT 4. Tissue- and cell type-specific effects of glucocorticoids are likely to be driven by many factors that influence the gene regulatory activity of the glucocorticoid receptor.

Glucocorticoid Repression of Inflammatory Modulator Gene Expression

The transcription factors Nuclear Factor-kappa B (NF-kB) and AP-1 regulate a number of genes of the immune system and are subject to activation by many external stimuli. When bound to hormone, the glucocorticoid receptor can inhibit the action of NF-kB and AP-1 on many genes and thereby lead to repression of transcription of many genes that are activated in an immune or inflammatory response. These effects of glucocorticoids are observed in many cells of the immune system.

IMPORTANT CONCEPT 5. The broad anti-inflammatory actions of glucocorticoids are due primarily to transcriptional repression of many pro-inflammatory genes in multiple cell types by the glucocorticoid receptor.

Modulation of Chromatin Structure of Target Genes by Glucocorticoid Receptors

DNA within the nucleus is packaged into chromatin due to its association with basic proteins known as histones. In general, the extent of transcription from a given gene is influenced by the tightness of its binding to histones. Actively transcribed genes are generally associated with less condensed chromatin while inactive genes are associated with more condensed chromatin. When associated with its target genes, the glucocorticoid receptor also recruits large protein complexes that function to modify the chromatin structure of target genes. Thus, when activating gene transcription the glucocorticoid receptor recruits enzymes such as Histone Acetyltransferases (HATs) to the gene. Increased histone acetylation by HATs neutralizes some histone basic character and “loosens” their grip on DNA. When repressing gene transcription, the glucocorticoid receptor recruits enzymes such as Histone Deacetylases (HDAC) to the gene. Decreased histone acetylation by HDACs restores histone basic character and “tightens” their grip on DNA.

IMPORTANT CONCEPT 6. The glucocorticoid receptor regulates gene transcription (either positively or negatively) through the gene-selective recruitment of histone modifying enzymes.

Pharmacology

Structure/Activity Relationships

Chemical modification of cortisol can dramatically influence its half-life and efficacy. For example, prednisolone has enhanced glucocorticoid activity with reduced mineralocorticoid activity. Prednisolone is also metabolized much more slowly than cortisol. The fluorinated glucocorticoids dexamethasone and betamethasone have very long half-lives, are potent glucocorticoids, and have no detectable mineralocorticoid action. Cortisone must be enzymatically reduced by 11ß-hydroxysteroid reducatase (typically in liver) to order to be active.

Table 59–2 Relative Potencies and Equivalent Doses of Representative Corticosteroids

COMPOUND

ANTIINFLAMMATORY POTENCY

Na⁺-RETAINING POTENCY

DURATION OF ACTION^*

Cortisol

0.8

0.8

0.8

^*S, short (i.e., 8–12 hour biological half-life); I, intermediate (i.e., 12–36 hour biological half-life); L, long (i.e., 36–72 hour biological half-life).

IMPORTANT CONCEPT 7. Structural modifications of the natural glucocorticoid cortisol generate hormones with enhanced half-life and more potent and efficacious glucocorticoid activity

Glucocorticoid Withdrawal

Since glucocorticoids suppress their own synthesis through a feedback mechanism that operates at the pituitary (i.e. reduced ACTH synthesis) and the brain (reduced CRH synthesis), rapid cessation of glucocorticoid therapy leads to acute adrenal insufficiency, which can be debilitating.

IMPORTANT CONCEPT 8. The cessation of high dose, systemic glucocorticoid treatment must be gradual to limit acute adrenal insufficiency.

Delivery of Glucocorticoids

Systemic glucocorticoids, although not routinely used for asthma treatment given the potential for side effects, are nonetheless still used for acute asthma exacerbations, and chronic, severe asthma. However, the development of aerosol delivery systems for glucocorticoids has led to dramatic increases in the therapeutic index of glucocorticoid treatment for less severe, chronic asthma. Thus, this allows for the generalized anti-inflammatory actions of this hormone to be exploited. Various glucocorticoid formulations are available for aerosol delivery that differ in their affinity for the glucocorticoid receptor. Various factors influence the choice and dose of the drug used including the severity of the disease and the devise used for drug delivery. However, maximal improvement of lung function may not occur until several weeks after treatment.

Several systemic effects of inhaled steroids have been described and include dermal thinning and skin capillary fragility. Inhaled steroids may have local side effects due to the deposition of inhaled steroid in the oropharynx.

The most common problems are hoarseness and dysphonia. Oropharyngeal candidiasis occurs in 5% of patients.

Even with proper use of aerosol devices, typically 10% of inhaled glucocorticoids are deposited in lung with the remainder swallowed and absorbed in the gut. Thus, even inhaled glucocorticoids have the potential to exert systemic effects.

IMPORTANT CONCEPT 9. The aerosol delivery of glucocorticoids to the lungs limits systemic exposure to the hormone and greatly reduces side effects.

Some new analogs of potent glucocorticoids are being used (i.e. fluticasone propionate, the active component of FLONASE) that are subjected to rapid inactivation in liver. The only circulating metabolite of fluticasone propionate detected in man is its 17ß-carboxylic acid derivative, which is formed through the cytochrome P450 3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Thus, the bioavailability of these drugs is negligible outside of the airways. The risk of systemic effects due to improper inhalation and swallowing of the drug is dramatically reduced.

Glucocorticoids can also be combined with long-acting ß-adrenergic receptor agonists in a single inhaler devise. This can lead to an enhancement of the anti-inflammatory action of glucocorticoids at lower doses.

IMPORTANT CONCEPT 10. New generation synthetic glucocorticoids with more rapid metabolism in the liver overcome potential side effects due to ingested hormone upon aerosol delivery.

Another strategy currently being evaluated by many researchers is the development of “dissociated” glucocorticoids. These compounds are expected to unleash the gene repression activity of the glucocorticoid receptor while having little or lessened impact on the gene activation activity of the receptor. Since the anti-inflammatory actions of glucocorticoids are mainly but not exclusively due to gene repression, these compounds should still have anti-inflammatory activity but reduced side effects. The detrimental side effects of glucocorticoids are thought to be due principally to gene activation by the glucocorticoid receptor.

IMPORTANT CONCEPT 11. New generation synthetic glucocorticoids that maintain gene repression but limit gene activation by the glucocorticoid receptor (i.e. dissociated glucocorticoids) may hold promise as anti-inflammatory drugs with reduced side effects.

Glucocorticoid Resistance

Corticosteroid-dependent (CD) asthma, a situation of reduced responsiveness to glucocorticoids, is common and requires high inhaled or oral doses for disease control. In CD patients, asthma conditions worsen if glucocorticoid doses are reduced. A rare form of CD asthma is found in 1/1,000 asthma patients where complete corticosteroid resistance is observed. This rare corticosteroid-resistant (CR) asthma is defined as a failure to improve lung function by more than 15% after treatment with high doses of prednisolone (30-40 mg daily) for 2 weeks. The mechanisms responsible for CR or CD may involve disruptions in glucocorticoid receptor function. These include reduced nuclear translocation of the glucocorticoid receptor or disruptions in histone modifications in chromatin of glucocorticoid receptor regulated genes. Patients with CR asthma can be treated with long-acting inhaled ß2-agonists, as they often have a good bronchodilator response to these agents. Theophylline may also be effective for the treatment of CR asthma, but its effects are not mediated by its inhibition of phosphodiesterease. The effectiveness of theophylline in the treatment of CR asthma may be due to its action at the genome level to decrease the extent of chromatin-associated histone protein acetylation (i.e. through the increased activity of histone deacetylase enzymes).

Anti-Leukotrienes

The generation of cysteinyl leukotrienes (CysLT) (e.g. LTC4, LTD4 and LTE4) from arachadonic acid requires the action of the 5-lipoxygenase enzyme (5-LOX) and is regulated by various stimuli, cell types, genetics of the host, and cytokine stimulation. Expression, distribution, and activation of specific receptors regulate the actions of CysLTs. Their modulation of the immune response, collagen deposition, and recruitment and activation of inflammatory cells increase chronic airway obstruction and bronchial hyper-responsiveness. Several leukotriene-modifying drugs have been developed for clinical use including leukotriene receptor antagonists (Zafirlukast [ACCOLATE], montelukast [SINGULAIR]) and a 5^’-lipoxygenase enzyme inhibitor (Zileuton [ZYFLO]).

Anti-IgE Therapy

Omalizumab (XOLAIR) is a recombinant humanized monoclonal antibody against IgE that is being used for asthma treatment. When bound to Omalizumab, IgE is unable to bind to IgE receptors on mast cells, and this drug thereby blocks the inflammatory process at an early step. Omalizumab also reduces the number of IgE receptors on the surfaces of basophils further enhancing its anti-inflammatory actions.

Antiviral agents

Antiviral Agents: Introduction

Viruses are obligate intracellular parasites; their replication depends primarily on synthetic processes of the host cell.

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inhibitors of virus replication may interfere with host cell function and produce toxicity. The search for chemicals that inhibit virus-specific functions is currently one of the most active areas of pharmacologic investigation. Research in antiviral chemotherapy began in the early 1950s, when the search for anticancer drugs generated several new compounds capable of inhibiting viral DNA synthesis. The two firstgeneration antivirals, 5-iododeoxyuridine and trifluorothymidine, had poor specificity (ie, they inhibited host cellular as well as viral DNA) that rendered them too toxic for systemic use. However, both are effective when used topically for the treatment of herpes keratitis. Recent research has focused on the identification of agents with greater selectivity, in vivo stability, and lack of toxicity. Selective antiretroviral agents that inhibit a critical HIV-1 enzyme such as 3TC: Lamivudine

cella-zoster virus

Agents to Treat Herpes Simplex Virus (HSV) & Varicella Zoster Virus (VZV) Infections Three oral agents are licensed for the treatment of HSV and VZV infections: acyclovir, valacyclovir, and famciclovir. They have similar mechanisms of action and similar indications for clinical use; all are well tolerated.

Acyclovir, licensed first, has been the most extensively studied; in addition, it is the only anti-HSV agent available for intravenous use in the United States. Neither valacyclovir nor famciclovir have been fully evaluated in pediatric patients; thus, they are not indicated for the treatment of varicella infection.

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Acyclovir

Acyclovir is an acyclic guanosine derivative with clinical activity against HSV-1, HSV-2, and VZV. In vitro activity against Epstein-Barr virus, cytomegalovirus, and human herpesvirus-6 is present but comparatively weaker.

Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the di- and triphosphate compounds by the host’s cellular enzymes. Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated and accumulates only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: competitive inhibition with deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex; and chain termination following incorporation into the viral DNA.

Pharmacokinetics

The bioavailability of oral acyclovir is 15–20% and is unaffected by food. Peak serum concentrations of approximately 1 g/mL after a 200 mg oral dose and 1.5–2 g/mL after an 800 mg dose are reached 1.5–2 hours after dosing. Peak serum concentrations are 10 g/mL and 20 g/mL after intravenous infusions (over 1 hour) of 5 mg/kg and 10 mg/kg, respectively. Topical formulations produce local concentrations that may exceed 10 g/mL in herpetic lesions, but systemic concentrations are undetectable.

Acyclovir is cleared primarily by glomerular filtration and tubular secretion. The half-life is approximately 3 hours in patients with normal renal function and 20 hours in patients with anuria.

Acyclovir is readily cleared by hemodialysis but not by peritoneal dialysis. Acyclovir diffuses into most tissues and body fluids to produce concentrations that are 50–100% of those in serum. Cerebrospinal fluid concentrations are 50% of serum values.

Clinical Uses

Oral acyclovir has multiple uses. In primary genital herpes, oral acyclovir shortens by approximately 5 days the duration of symptoms, the time of viral shedding, and the time to resolution of lesions; in recurrent genital herpes, the time course is shortened by 1–2 days.

Treatment of primary genital herpes does not alter the frequency or severity of recurrent outbreaks. Long-term chronic suppression of genital herpes with oral acyclovir decreases the frequency both of symptomatic recurrences and of asymptomatic viral shedding in patients with frequent recurrences, thus decreasing sexual transmission. However, outbreaks may resume upon discontinuation of suppressive acyclovir. In recurrent herpes labialis, oral acyclovir reduces the mean duration of pain but not the time to healing. Oral acyclovir decreases the total number of lesions and duration of varicella (if begun within 24 hours after the onset of rash) and cutaneous zoster (if begun within 72 hours). However, because VZV is less susceptible to acyclovir than HSV, higher doses are required. A meta-analysis suggested that acyclovir was superior to placebo in reducing the duration of “zoster-associated pain,” a continuous variable combining acute and chronic pain. When given prophylactically to patients undergoing organ transplantation, oral acyclovir (200 mg every 8 hours or 800 mg every 12 hours) or intravenous acyclovir (5 mg/kg every 8 hours) prevents reactivation of HSV infection. The benefit of acyclovir for prevention of CMV infections in transplant patients is controversial.

Adverse Reactions

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion may be associated with reversible tremors, delirium, seizures); however, these renal dysfunction due to crystalline nephropathy or neurologic toxicity (eg, are uncommon with adequate hydration and avoidance of rapid infusion rates. Chronic daily suppressive use of acyclovir for more than 10 years has not been associated with untoward effects.

High doses of acyclovir cause testicular atrophy in rats, but there has beeo evidence of teratogenicity to date in a cumulative registry and no effect on sperm production was demonstrated in a placebo-controlled trial of patients receiving daily chronic acyclovir.

Valacyclovir

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Valacyclovir is the L-valyl ester of acyclovir. It is rapidly converted to acyclovir after oral administration, resulting in serum levels three to five times greater than those achieved with oral acyclovir and approximating those resulting from intravenous acyclovir administration. Oral bioavailability is about 48%. As with acyclovir, uses of valacyclovir include treatment of first atacks or recurrences of genital herpes, suppression of frequently recurrent genital herpes, treatment of herpes zoster infection, and, recently, as a 1-day treatment for orolabial herpes.

Valacyclovir has also been shown to be effective in preventing cytomegalovirus disease after organ transplantation when compared with placebo. In general, comparative studies have shown similar or slightly improved efficacy of valacyclovir versus acyclovir for all indications; furthermore, valacyclovir therapy was associated with a shorter duration of zoster-associated pain than acyclovir in one study, as well as a lower frequency of postherpetic neuralgia. Once-daily dosing of valacyclovir (500 mg) as chronic suppression in persons with recurrent genital herpes has recently been shown to markedly decrease the risk of sexual transmission. Valacyclovir is generally well tolerated, although nausea, diarrhea, and headache may occur. AIDS patients receiving high-dosage valacyclovir chronically (ie, 8 g/d) had an increased incidence of gastrointestinal intolerance as well as thrombotic microangiopathies such as thrombotic thrombocytopenic purpura and hemolyticuremic syndrome. In transplant patients receiving valacyclovir (8 g/d), non-dose-limiting confusion and hallucinations were the most frequent side effects.

Famciclovir

Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic guanosine analog (Figure 49–2). After oral administration, famciclovir is rapidly converted by first-pass metabolism to penciclovir, which shares many features with acyclovir. It is active in vitro against HSV-1, HSV- 2, VZV, EBV, and HBV. Activation by phosphorylation is catalyzed by the virus-specified thymidine kinase in infected cells, followed by competitive inhibition of the viral DNA polymerase to block DNA synthesis. Unlike acyclovir, penciclovir does not cause chain termination. Penciclovir triphosphate has lower affinity for the viral DNA polymerase than acyclovir triphosphate, but it achieves higher intracellular concentrations and has a more prolonged intracellular effect in experimental systems. The most commonly encountered clinical mutants of HSV are thymidine kinase-deficient and are cross-resistant to acyclovir and famciclovir.

Pharmacokinetics

The bioavailability of penciclovir from orally administered famciclovir is 70%; less than 20% is plasma protein-bound. A peak serum concentration of 2 g/mL is achieved following a 250 mg oral dose. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-infected cells, 20 hours in HSV-2-infected cells, and 7 hours in VZV-infected cells in vitro. Penciclovir is excreted primarily in the urine.

Clinical Uses

Oral famciclovir is effective for the treatment of first and recurrent genital herpes attacks and for chronic daily suppression. It is also used to treat acute herpes zoster (shingles). In controlled trials in immunocompetent patients with zoster, famciclovir was similar to acyclovir in rates of cutaneous healing but was associated with a shorter duration of postherpetic neuralgia.

Comparison of famciclovir to valacyclovir for treatment of herpes zoster in immunocompetent patients showed similar rates of cutaneous healing and pain resolution. However, neither drug decreased the incidence of postherpetic neuralgia.

Adverse Reactions

Oral famciclovir is generally well tolerated, although headache, diarrhea, and nausea may occur. As with acyclovir, testicular toxicity has been demonstrated in animals receiving repeated doses. However, men receiving daily famciclovir (250 mg every 12 hours) had no changes in sperm morphology or motility. The incidence of mammary adenocarcinoma was also increased in female rats receiving famciclovir for 2 years.

AIDS TREATMENT

A large and increasing number of antiretroviral agents are currently available for treatment of HIV- 1-infected patients. When to initiate therapy is controversial, but it is clear that monotherapy with any one agent should be avoided because of the need for maximal potency to durably inhibit virus replication and to avoid premature development of resistance. A combination of agents (highly active antiretroviral therapy; HAART) is usually effective in reducing plasma HIV RNA levels and in gradually increasing CD4 cell counts, particularly in antiretroviral-naïve patients. Also important in selection of agents is optimization of adherence, tolerability, and convenience. Given that many patients will ultimately experience at least one treatment failure, close monitoring of viral load and CD4 cell counts is critical to trigger appropriate changes in therapy. The judicious use of drug resistance testing should be considered in selecting an alternative regimen for a patient who is not responding to therapy.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and can also be incorporated into the growing viral DNA chain to cause termination. Each requires intracytoplasmic activation as a result of phosphorylation by cellular enzymes to the triphosphate form. Most have activity against HIV-2 as well as HIV-1. Lactic acidemia and severe hepatomegaly with steatosis have been reported with the use of NRTI agents, alone or in combination with other antiretroviral drugs. Obesity, prolonged nucleoside exposure, and risk factors for liver disease have been described as factors that increase risk for lactic acidemia; however, cases have also been reported in patients with no known risk factors.

NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic or lactic acidosis of unknown cause. Given their similar mechanism of action, it is probable that these cautions should be applied to treatment with nucleotide inhibitors as well (see Nucleotide Inhibitors).

Zidovudine

As the first licensed antiretroviral agent, zidovudine has been well studied. Zidovudine has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia. In pregnancy, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation (100 mg five times a day), intravenous zidovudine during labor (2 mg/kg over 1 hour, then 1 mg/kg/h by continuous infusion), and zidovudine syrup to the neonate from As with other NRTI agents, resistance may limit clinical efficacy. High-level zidovudine resistance is generally seen in strains with three or more of the five most common mutations: M41L, D67N, K70R, T215F, and K219Q. However, the emergence of certain mutations that confer decreased susceptibility to one drug (eg, L74V in the case of didanosine and M184V in the case of lamivudine) seems to enhance susceptibility in previously zidovudine-resistant strains.

Withdrawal ofzidovudine exposure may permit the reversion of zidovudine-resistant HIV-1 isolates to the susceptible wild-type phenotype.

The most common adverse effect of zidovudine is myelosuppression, resulting in anemia or neutropenia. Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. Less frequent side effects include thrombocytopenia, hyperpigmentation of the nails, and myopathy. Very high doses can cause anxiety, confusion, and tremulousness. Zidovudine causes vaginal neoplasms in mice; however, no humn cases of genital neoplasms have been reported to date. Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance.

Zidovudine may decrease phenytoin levels, and this warrants monitoring of serum phenytoin levels in epileptic patients taking both agents. Hematologic toxicity may be increased during coadministration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. (See Treatment of HIV-Infected Individuals: Importance of Pharmacokinetic Knowledge.)

Didanosine

Didanosine (ddI) is a synthetic analog of deoxyadenosine. At acid pH, hydrolysis of the glycosidic bond between the sugar and the base moieties of ddI will inactivate the compound.

Resistance to didanosine, due typically to mutation at codon 74 (L74V), may partially restore susceptibility to zidovudine but may confer cross-resistance to abacavir, zalcitabine, and lamivudine. High-level resistance (> 100-fold decreased susceptibility) has not been reported to date.

The major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis (eg, alcoholism, hypertriglyceridemia) are relative contraindications to administration of didanosine, and other drugs with the potential to cause pancreatitis should be avoided. Other reported adverse effects include painful peripheral distal neuropathy, diarrhea, hepatitis, esophageal ulceration, cardiomyopathy, and central nervous system toxicity (headache, irritability, insomnia). Asymptomatic hyperuricemia may precipitate attacks of gout in susceptible individuals. Reports of retinal changes and optic neuritis in patients receiving didanosine— particularly in adults receiving high doses and in children—indicate the utility of periodic retinal examinations.

Fluoroquinolones and tetracyclines should be administered at least 2 hours before or after didanosine in order to avoid decreased antibiotic plasma concentrations due to chelation. Coadministration with ganciclovir results in an increased AUC of didanosine and a decreased AUC of ganciclovir, while coadministration with methadone results in decreased didanosine serum levels.

Lamivudine

Lamivudine (3TC) is a cytosine analog (Figure 49–4) with in vitro activity against HIV-1 that is synergistic with a variety of antiretroviral nucleoside analogs—including zidovudine and stavudine—against both zidovudine-sensitive and zidovudine-resistant HIV-1 strains. Oral bioavailability exceeds 80% and is not food-dependent. Peak serum levels after standard doses are 1.5 ± 0.5 g/mL, and protein binding is less than 36%. In children, the mean CSF:plasma ratio of lamivudine was 0.2. Mean elimination half-life is 2.5 hours, while the intracellular half-life of the active 5′-triphosphate metabolite in HIV-1-infected cell lines is 10.5–15.5 hours. The majority of lamivudine is eliminated unchanged in the urine, and the dose should be reduced in patients with renal insufficiency or low body weight No supplemental doses are required after routine hemodialysis. Lamivudine therapy rapidly selects—both in vitro and in vivo—for M184V-resistant mutants of HIV, which show high-level resistance to lamivudine and a reduction in susceptibility to abacavir, didanosine, and zalcitabine.

Potential side effects are headache, insomnia, fatigue, and gastrointestinal discomfort, though these are typically mild. Lamivudine’s AUC increases when it is coadministered with trimethoprimsulfamethoxazole. Peak levels of zidovudine increase when the drug is administered with lamivudine, though this effect is not felt to have clinical significance.

Stavudine

The thymidine analog stavudine (D4T) (Figure 49–4) has high oral bioavailability (86%) that is not food-dependent. The plasma half-life is 1.22 hours; the intracellular half-life is 3.5 hours; and mean cerebrospinal fluid concentrations are 55% of those of plasma. Plasma protein binding is negligible. Excretion is by active tubular secretion and glomerular filtration. The dosage of stavudine should be reduced in patients with renal insufficiency, in those receiving hemodialysis, and for low bodyweight.

Since zidovudine may reduce the phosphorylation of stavudine, these two drugs should generally not be used together.

Abacavir

In contrast to earlier NRTIs, abacavir is a guanosine analog. It is well absorbed following oral administration (83%), is unaffected by food, and is about 50% bound to plasma proteins. In singledose studies, the elimination half-life was 1.5 hours. Cerebrospinal fluid levels are approximately one-third those of plasma. The drug is metabolized by alcohol dehydrogenase and glucuronosyltransferase to inactive metabolites that are eliminated primarily in the urine. High-level resistance to abacavir appears to require at least two or three concomitant mutations (eg, M184V, L74V), and for that reason it tends to develop slowly. Although cross-resistance to lamivudine, didanosine, and zalcitabine has beeoted in vitro in recombinant strains with abacavir-associated mutations, the clinical significance is unknown.

Hypersensitivity reactions, occasionally fatal, have been reported in 2–5% of patients receiving abacavir. Symptoms, which generally occur within the first 6 weeks of therapy, involve multiple organ systems and include fever, malaise, and gastrointestinal complaints. Skin rash may or may not be present. Laboratory abnormalities such as mildly elevated serum aminotransferase or creatine kinase levels are not specific for this reaction. Although the syndrome tends to resolve quickly with discontinuation of medication, rechallenge with abacavir following discontinuation results in return of symptoms within hours and may be fatal. Other adverse events may include rash, nausea and vomiting, diarrhea, headache, and fatigue. Adverse effects that appear to be infrequent include pancreatitis, hyperglycemia, and hypertriglyceridemia. Clinically significant adverse drug interactions have not been reported to date, though coadministration of alcohol and abacavir may result in an increase in abacavir’s AUC.

Nucleotide Inhibitors

Tenofovir

Tenofovir disoproxilfumarate is a prodrug that is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine. Like the NRTIs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. The oral bioavailability of tenofovir from tenofovir disopoxilfumarate, a water-soluble diester prodrug of the active ingredient tenofovir, in fasted patients is approximately 25%. Oral bioavailability is increased if the drug is ingested following a high-fat meal (increased AUC by

about 40%); therefore, taking the drug along with a meal is recommended. Maximum serum concentrations are achieved in about 1 hour after taking the medication. Elimination occurs by a combination of glomerular filtration and active tubular secretion. However, only 70–80% of the dose is recovered in the urine, allowing for the possibility of hepatic metabolism as well as alteration in hepatic insufficiency; the latter has not been studied.

Tenofovir is indicated for use in combination with other antiretroviral agents. Initial studies demonstrated potent HIV-1 suppression in treatment-experienced adults with evidence of viral replication despite ongoing antiretroviral therapy; similar benefit in antiretroviral-naive patients has yet to be demonstrated. The once-daily dosing regimen of tenofovir lends added convenience.

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

The NNRTIs bind directly to a site on the HIV-1 reverse transcriptase, resulting in blockade of RNA- and DNA-dependent DNA polymerase activities. The binding site is near to but distinct from that of the NRTIs. Unlike the latter group of agents, the NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active. Resistance to an NNRTI is generally rapid with monotherapy and is associated with the K103N mutation as well as the less critical Y181C/I mutation; cross-resistance among this class of agents, although observed in vitro, is of unknown clinical significance. There is no cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors.

A syndrome of drug hypersensitivity has been described in patients receiving NNRTIs as well as in those receiving amprenavir or abacavir. Serious rashes, including Stevens-Johnson syndrome, have occurred.

Nevirapine

The oral bioavailability of nevirapine is excellent (> 90%) and is not food-dependent. The drug is highly lipophilic, approximately 60% protein-bound, and achieves cerebrospinal fluid levels that are 45% of those in plasma. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.

Nevirapine is typically used as a component of a combination antiretroviral regimen. In addition, a single dose of nevirapine (200 mg) has recently been shown to be effective in the prevention of transmission of HIV from mother to newborn when administered to women at the onset of labor and followed by a 2-mg/kg oral dose given to the neonate within 3 days after delivery.

Severe and life-threatening skin rashes have occurred during nevirapine therapy, including Stevens- Johnson syndrome and toxic epidermal necrolysis. Nevirapine therapy should be immediately discontinued in patients with severe rash and in those with rash accompanied by constitutional symptoms. Rash occurs in approximately 17% of patients, most typically in the first 4–8 weeks of therapy, and is dose-limiting in about 7% of patients. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the frequency of rash. Fulminant hepatitis may occur in association with rash and fever, typically within the first 6 weeks of initiation of therapy, or may occur without a concomitant rash. Therefore, serial monitoring of liver function tests is strongly recommended. Other frequently reported adverse effects associated with nevirapine therapy are fever, nausea, headache, and somnolence.

Delavirdine

Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids. It is extensively bound (about 98%) to plasma proteins. Cerebrospinal fluid levels average only 0.4% of the corresponding plasma concentrations, representing about 20% of the fractioot bound to plasma proteins. Caution should be used when administering delavirdine to patients with hepatic insufficiency because clinical experience in this situation is limited. Skin rash occurs in about 18% of patients receiving delavirdine; it typically occurs during the first month of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other adverse effects may include headache, fatigue, nausea, diarrhea, and increased serum aminotransferase levels.

Efavirenz

Efavirenz can be given once daily because of its long half-life (40–55 hours). It is moderately well absorbed following oral administration (45%), and bioavailability is increased to about 65% following a high-fat meal. Peak plasma concentrations are seen 3–5 hours after administration of daily doses; steady state plasma concentrations are reached in 6–10 days. Efavirenz is principally metabolized by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites; the remainder is eliminated in the feces as unchanged drug. It is highly bound to albumin (> 99%).

Cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels; these are approximately three times higher than the free fraction of efavirenz in the plasma. Because there is limited experience to date, caution is advised with use in patients with hepatic impairment.

The principal adverse effects of efavirenz involve the central nervous system (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria); these may occur in up to 50% of patients. They tend to occur during the first days of therapy and may resolve while medication is continued; administration at bedtime may be helpful. However, psychiatric symptoms may be severe. Skin rash has also been reported early in therapy in up to 28% of patients, is usually mild to moderate, and typically resolves despite continuation. Other potential adverse reactions include nausea and vomiting, diarrhea, crystalluria, elevated liver enzymes, and an increase in total serum cholesterol by 10–20%. High rates of fetal abnormalities occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage of 600 mg/d. Therefore, pregnancy should be avoided in women receiving efavirenz.

Protease Inhibitors

During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene products are translated into polyproteins and then become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core.

Saquinavir

In its original formulation as a hard gel capsule (saquinavir-H; Invirase), oral saquinavir was poorly bioavailable (about 4% in the fed state). It was therefore largely replaced in clinical use by a soft gel capsule formulation (saquinavir-S; Fortovase), in which absorption was increased approximately threefold. However, reformulation of saquinavir-H for once-daily dosing in combination with lowdose ritonavir (see Ritonavir) has both improved antiviral efficacy and decreased the gastrointestinal side effects typically associated with saquinavir-S. Moreover, coadministration of saquinavir-H with ritonavir results in blood levels of saquinavir similar to those associated with saquinavir-S, thus capitalizing on the pharmacokinetic interaction of the two agents.

Ritonavir

The most common adverse effects of ritonavir are gastrointestinal disturbances, paresthesias (circumoral and peripheral), elevated serum aminotransferase levels, altered taste, and hypertriglyceridemia. Nausea, vomiting, and abdominal pain typically occur during the first few weeks of therapy, and patients should be told to expect them. Slow dose escalation over 4–5 days is recommended to decrease the frequency of dose-limiting side effects. Liver adenomas and carcinomas have been induced in male mice receiving ritonavir; no similar effects have been observed to date in humans.

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Ease of administration is limited by ritonavir’s numerous drug interactions. Ritonavir is both a substrate and an inhibitor of CYP3A4; as such, coadministration with agents heavily metabolized by CYP3A must be approached with the same precautions discussed above. In addition, since ritonavir is an inhibitor of the CYP3A4 isoenzyme, concurrent administration with other PIs results in increased plasma levels of the latter drugs; these interactions have been exploited to permit more convenient dosing.

1. http://www.youtube.com/watch?v=nudFAzJsTog&feature=related

2. http://www.youtube.com/watch?v=ywdk3BTjK2s&feature=related