Musculoskeletal System

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Chapter 19 Musculoskeletal System

Bisphosphonates (BPs)

Description

Bisphosphonates are agents that prevent the breakdown of bone.

prototypes and common drugs

Aminobisphosphonates

image Prototype: alendronate
image Others: risedronate, pamidronate

Non-Aminobisphosphonates

image Prototype: etidronate
image Others: clodronate, tiludronate, zoledronate

MOA (Mechanism of Action)

image The structural integrity of bone is determined to a large extent by the balance between the activity of osteoclasts, which break down bone (resorptive), and the activity of osteoblasts, which build bone.
image Bisphosphonates (BPs) inhibit osteoclast activity through a variety of mechanisms, some better understood than others (Figure 19-1).
image Inside the osteoclast the aminobisphosphonates disrupt the mevalonate pathway, a pathway involved in the posttranslational modification of proteins that are involved in cellular signaling. Disruption of the mevalonate pathway interrupts osteoclast function and leads to apoptosis of the osteoclast.
image The non-aminobisphosphonates work by increasing the accumulation of cytotoxic metabolites within osteoclasts, interfering with their function and possibly leading to osteoclast cell death.
image The clawlike chemical structure of BPs facilitates their attachment to bone. The multiple oxygen atoms around the perimeter of the BP molecule bind to divalent cations such as Ca2+ within bone matrix. The BPs remain within the matrix until the acids released by the osteoclasts break down the matrix and liberate the BPs. Ironically, the activity of the osteoclasts seals their own fate!
image Osteoclasts contribute further to their demise by devouring the BP molecules after liberating them.
image BPs have a variety of other cellular effects, inhibiting vitamin D production, intestinal Ca2+ transport, cell growth, metabolic changes in bone cells, and changes in acid and alkaline phosphatases.
image

Figure 19-1

Pharmacokinetics

image BPs have very low oral bioavailability (<10%), and their absorption is further reduced by food and by divalent cations such as calcium. It is therefore recommended that BPs be taken on an empty stomach, with plain water.
image The BPs that are absorbed are highly bound to bone, and are not metabolized, nor do they inhibit or induce metabolizing enzymes. They are eliminated by the kidney.
image The oral BPs are typically administered once daily. A higher dose of alendronate is also available as a once weekly formulation.

Indications

image Osteoporosis
image Paget’s disease of the bone (results in enlarged, deformed bones)
image Hypercalcemia:

image Malignancy
image Primary hyperparathyroidism (continuous parathyroid hormone [PTH] release causes bone demineralization)

image Bone metastasis causing osteolysis:

image Multiple myeloma
image Bone metastases of malignant tumors

Contraindications

image Hypocalcemia: BPs have exhibited decreases in serum calcium, so it is recommended that any deficiencies in calcium be addressed before initiation of therapy.
image Poor renal function: BPs are eliminated renally, so patients with creatinine clearance <30 mL/min may experience accumulation of these agents. Patients with poor renal function who begin to take BPs should be monitored closely.

Side Effects

All

image Gastrointestinal: nausea, dyspepsia

Serious

image Esophagitis or esophageal erosion is more commonly seen with the aminobisphosphonates. It may result from a direct irritant effect from tablets lodged in the esophagus or from reflux of gastric acid including the acidic form of the BP. Patients are advised to avoid reclining for at least 30 minutes after taking a BP, reducing the chance of tablet staying in the esophagus or reflux.
image Osteonecrosis of the jaw is typically only seen at higher doses. The mechanism has not been established; however, the fact that BPs alter bone turnover is thought to play a role. Jaw bone may have a higher rate of turnover than other areas of the body, perhaps explaining why this side effect is localized to this area.

Aminobisphosphonates

image Fever, flulike symptoms are a transient, typically first-dose phenomenon seen with intravenous administration. They are believed to be caused by release of proinflammatory cytokines.

Important Notes

image The non-aminobisphosphonates were the original members of this drug class, whereas the aminobisphosphonates are newer, more potent agents.
image BPs have an established history as adjuncts in cancer therapy. They have demonstrated ability to reduce bone pain secondary to metastases and prevent treatment-induced bone loss.
image Etidronate can cause bone demineralization; therefore unlike the other BPs, which are typically taken once daily, etidronate is typically administered in 90-day cycles, with 14 days on treatment and 76 days off treatment. During the off-treatment period, calcium tablets are typically administered, and this 90-day treatment cycle (etidronate followed by calcium) is marketed in one kit.
image Estrogens appear to have a role in decreasing bone resorption; therefore one of the benefits of hormone replacement therapy in postmenopausal women is to maintain integrity of bone, hopefully leading to fewer fractures.
image Nonpharmacologic strategies for preventing osteoporosis include smoking cessation and weight-bearing exercise. Smoking is known to reduce bone mineral density (BMD), and weight-bearing exercise has been shown to substantially reduce fracture risk.

Advanced

Pregnancy

image The use of BPs in pregnancy has not been well studied, but they are believed to cross the placenta, based on animal studies. Given their effects on bone, a very careful assessment of risk versus benefit should be performed before these agents are used.

Evidence

Risedronate versus Placebo or Calcium and Vitamin D or Both in Postmenopausal Osteoporosis

image A 2008 Cochrane review (7 trials, N = 14,049 females) found no statistically significant effects for risedronate with respect to primary prevention of vertebral and nonvertebral fractures. For secondary prevention, risedronate demonstrated statistically significant relative risk reductions (RRRs) of vertebral fractures (39%), nonvertebral fractures (20%), and hip fractures (26%). The corresponding absolute risk reductions were small: 5%, 2%, and 1%, respectively. No statistically significant differences were found for adverse events.

Etidronate versus Placebo and/or Calcium and Vitamin D in Postmenopausal Osteoporosis

image A 2008 Cochrane review (11 trials, N = 1248 females) found no statistically significant effects of etidronate with respect to primary prevention of any fractures. A statistically significant RRR of 47% was found for secondary prevention of vertebral fractures but not for nonvertebral, hip, or wrist fractures. No statistically significant differences were found for adverse events.

BPs versus Placebo or No Treatment in Myeloma

image A 2002 Cochrane review (11 trials, N = 2183 patients) found that BPs prevented pathologic vertebral fractures (number needed to treat [NNT] = 10) and relieved pain (NNT = 11). BPs did not affect mortality, nonvertebral fractures, or hypercalcemia. No significant adverse events were associated with the BPs.

FYI

image One of the earliest indications that the BPs had potential in the treatment of bone diseases was the observation that they inhibit the dissolution of hydroxyapatite crystals.
image Because of their ability to localize in bone, one of the early uses for BPs was as bone scanning agents, used in the detection of malignancies and other skeletal lesions.
image The bisphosphonates are so named because of the two phosphate (P) groups that form the backbone of these molecules.
image The BPs have a clawlike chemical structure. This is a good way to remember that they attach themselves to bone matrix for long periods of time.
image The aminobisphosphonates such as alendronate have an amino (NH2-) group.

Vitamin D Replacement

Description

Vitamin D replacement consists of vitamin D and its derivatives.

Prototype and Common Drugs

image Prototype: calcitriol
image Others: ergocalciferol (vitamin D2), calcipotriene, doxercalciferol, paricalcitol

MOA (Mechanism of Action)

image The two major forms of vitamin D replacements are vitamin D2 and vitamin D3.
image Vitamin D is an important regulator of calcium and phosphate homeostasis and bone metabolism. It works in conjunction with PTH. The overall effect of vitamin D is to increase serum calcium concentrations. These effects are mediated via the following:

image Increased calcium absorption from the intestine
image Regulation of bone resorption and formation

• This occurs via stimulation of both osteoblastic and osteoclastic processes. Osteoblasts form bone, and osteoclasts dissolve bone.

image Increased calcium reabsorption in the distal renal tubules (Figure 19-2)

image Vitamin D results in a negative feedback loop and decreases transcription and secretion of PTH.

image The overall effect of PTH is to increase serum calcium levels, so increased vitamin D inhibits the actions of PTH so that both mechanisms do not drive up calcium levels too high.

image Vitamin D is lipophilic (it is one of the fat-soluble vitamins—A, D, E, and K) and thus freely crosses the cytoplasmic membrane.
image Intracellularly, it binds vitamin D receptors (VDRs) and binds DNA, where it regulates transcription of genes in the intestine, bone, kidney, and parathyroid gland.
image Vitamin D also has actions in macrophages and T cells and in proliferation and differentiation of a large number of cells, including cancer cells. Through these actions, it has immunomodulating and potentially, anticancer actions. Also, these actions are the basis of the mechanism whereby it is effective in psoriasis.
image

Figure 19-2

Pharmacokinetics

image Calcitriol is available in oral and intravenous formulations. It is a lipid-soluble vitamin and therefore can accumulate and cause toxicity (see later).

Indications

image Osteoporosis
image Hyperparathyroidism
image Osteomalacia
image Rickets

Contraindications

image None

Side Effects

image Side effects are related to long-term overadministration of vitamin D supplementation. Symptoms are primarily induced by hypercalcemia, which include gastrointestinal pain, renal stones, and psychiatric disturbances.

Important Notes

image Vitamin D is synthesized in the skin, liver, and kidney. Vitamin D supplementation is therefore frequently required in patients with renal failure.
image Rickets is a childhood disease characterized by impeded growth and deformity (curvature) of the long bones caused by vitamin D deficiency. The fortification of milk with vitamin D has dramatically reduced the incidence of rickets in developed countries.
image Osteomalacia is a condition of bone softening resulting from abnormality in the mineralization of the organic portion of the bone matrix called osteoid. It can be caused by vitamin D deficiency and is like an adult form of rickets. It is characterized by proximal muscle weakness, pain, and bone fragility.
image Osteoporosis is characterized by reduced bone mineral density (BMD) and increased bone fragility. It is caused by abnormal osteoblastic and osteoclastic activity. The bone is porous, hence the name of the disease.

Advanced

image Vitamin D supplements are sometimes used in the treatment of psoriasis, a common skin condition involving rapid turnover and inflammation of the skin. The evidence for this use, however, is not strongly conclusive.
image The various forms of vitamin D are referred to by several different names, summarized in Table 19-1.

TABLE 19-1 Various Forms of Vitamin D

Common Name Drug Name Abbreviation
Vitamin D2 Ergocalciferol D2
1-Hydroxyvitamin D2 Doxercalciferol 1(OH)D2
Vitamin D3 Cholecalciferol D3
25-Hydroxyvitamin D3 Calcifediol 25(OH)D3
1,25-Dihydroxyvitamin D3 Calcitriol 1,25(OH)2D3
24,25-Dihydroxyvitamin D3 Secalcifediol 24,25(OH)2D3

Evidence

Vitamin D Alone and Bone Fractures in the Elderly

image A meta-analysis in 2008 showed that vitamin D alone in the elderly was unlikely to be effective in preventing hip fractures (9 trials, N = 24,749 participants), vertebral fractures (5 trials, N = 9138 participants), or any new fracture (10 trials, N = 25,016 participants).

Vitamin D Plus Calcium and Bone Fractures in the Elderly

image The same meta-analysis in 2008 showed that vitamin D plus calcium supplements do reduce hip fractures in the elderly (8 trials, N = 46,658 participants, relative risk [RR] 0.84). Hypercalcemia is significantly more common in people receiving vitamin D or an analogue, with or without calcium (18 trials, N = 11,346 participants, RR 2.35). There is a significant but modest increase in gastrointestinal symptoms (RR 1.04) and a small but significant increase in renal disease (RR 1.16).

FYI

image The concept that vitamin D comes from the sun is inaccurate; the inert precursor (7-dehydrocholesterol) is present in the skin, and exposure to ultraviolet light converts it to cholecalciferol, which is then isomerized to vitamin D3. Reduced exposure to sunlight is one cause of vitamin D deficiency.
image Calcitonin is another hormone secreted by the thyroid gland. It has the opposing action of PTH: it “tones down” (lowers) the serum calcium levels.
image Vitamin D is a secosteroid: this is a steroid with one of the rings (the B ring) broken. Vitamin D2 is from ergosterol, whereas vitamin D3 is from cholesterol. Ergosterol is not produced in vertebrates, and therefore vitamin D2 is not produced in humans.

Parathyroid Hormone

Description

This agent (teriparatide) is a recombinant form of naturally occurring PTH.

Prototype

image Prototype: teriparatide

MOA (Mechanism of Action)

image PTH is released from the parathyroid gland. It regulates calcium and phosphate flux across cell membranes in bone and kidney. The key effects of PTH are as follows:

image Increased serum calcium
image Decreased serum phosphate
image Increased osteoclast activity in bone

image The effects on osteoclasts are indirect. PTH increases activity of the RANK (receptor activator of nuclear factor κ) ligand (RANKL). RANKL regulates osteoclast activity (see the discussion of RANKL inhibitors in this chapter). Increasing the activity of RANKL in turn stimulates an increase in the activity and number of osteoclasts.
image The stimulation of osteoclasts increases bone remodeling. PTH increases both bone resorption and formation; however, the net effect of excess PTH is to increase bone resorption (Figure 19-3).
image Low levels of intermittent PTH, however, can enhance bone formation. The actions of PTH are largely mediated through the PTH-1 receptor. The anabolic effects are mediated by direct effects of PTH on osteoblasts, increasing their number and inhibiting their apoptosis. PTH also stimulates insulin-like growth factor (IGF-1) in osteoblasts, and IGF-1 also has anabolic effects on bone.
image It is still not clear why high, sustained PTH has a catabolic effect, whereas low, intermittent administration has an anabolic effect on bone.
image In addition to these factors, PTH has several effects on the kidney:

image Increased reabsorption of Ca2+ and Mg2+
image Decreased reabsorption of phosphate, amino acids, bicarbonate, Na+, Cl−, and sulfate
image Stimulation of production of 1,25 dihydroxyvitamin D

image

Figure 19-3

Pharmacokinetics

image Teriparatide is administered as a subcutaneous injection once daily.
image It is both rapidly absorbed and rapidly eliminated, with plasma concentrations reaching their peak at 30 minutes postinjection and falling to undetectable levels after 3 hours.
image The metabolism of teriparatide is poorly understood, but enzymes are thought to be involved.

Indications

image Osteoporosis

image Typically reserved for severe osteoporosis and/or patients in whom previous therapies, including the BPs, have failed

image Osteoporosis secondary to corticosteroid use

Contraindications

image Children or young adults with open epiphysis: The safety and efficacy of teriparatide has not been studied in pediatrics, and its significant impact on bone remodeling is a concern in this population
image Hypercalcemia: PTH already raises Ca2+ levels.
image Active Paget’s disease of bone.
image Skeletal metastases or skeletal malignant conditions: risk of osteosarcoma (see Important Notes).
image History of radiation to the skeleton: risk of osteosarcoma (see Important Notes).
image Pregnancy and lactation: The effects of teriparatide have not been studied in pregnancy. Given its significant effects on bone remodeling, deleterious effects on fetal bone development are possible.

Side Effects

image Hypercalcemia (mild): PTH increases serum calcium. This can be managed by reducing Ca2+ and vitamin D intake or by adjusting teriparatide dose from daily to every other day.
image Leg cramps may occur.
image Nausea may occur.
image Orthostatic hypotension: PTH infusions have a vasodilatory effect in animals. Hypotension has been observed within 4 hours of infusion in clinical trials.

Important Notes

image The greatest safety concern associated with teriparatide is osteosarcoma (malignant bone cancer). However, this concern is based on observations in rodents exposed to prolonged high doses and on the ability of teriparatide to stimulate osteoblasts. So far, there does not appear to be an elevated risk of osteosarcoma with teriparatide use in humans.
image Because of the concerns over osteosarcoma, use of teriparatide is limited to 1.5 to 2 years. The reason for this cutoff is that the safety of teriparatide has not been assessed beyond 2 years in clinical trials.
image Most of the agents used to manage osteoporosis are antiresorptive and work by inhibiting bone turnover. Teriparatide works by promoting bone turnover; thus there is concern that patients switching from antiresorptive agents, particularly potent agents such as BPs, might experience reduced efficacy with teriparatide. Therefore some clinicians suggest that there should be a washout period when switching from the BPs to teriparatide. The benefits of a washout should be balanced against the risk of no treatment, particularly in patients with severe disease.

Evidence

Bisphosphonates or Teriparatide in Postmenopausal Women

image A 2005 systematic review (90 trials) compared all BPs and teriparatide with calcium, calcium plus vitamin D, calcitriol, hormone replacement therapy, exercise, and placebo or no treatment. They found that only teriparatide and risedronate reduced the risk of nonvertebral fracture in women with severe osteoporosis and adequate calcium intake.

FYI

image Teriparatide is supplied as prefilled injectable pens, which make it easier for patients to self-administer subcutaneous injections.

RANKL Inhibitors

Description

RANKL inhibitors regulate osteoclast activity and modify bone structure.

Prototype

image Denosumab

MOA (Mechanism of Action)

image RANK stands for receptor activator of nuclear factor kappa; RANKL stands for RANK ligand.
image RANKL is a cytokine member of the tumor necrosis factor (TNF) superfamily and is an important regulator of osteoclast activity.
image The primary function of osteoclasts is to break down bone; their counterparts are osteoblasts, which function to build up bone.
image The binding of RANKL to RANK results in increased bone resorption through the differentiation, activation, and prolonged survival of osteoclasts.
image Osteoclast activity is an important factor in the development of osteoporosis and is also strongly implicated in bone destruction associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, and sex hormone deprivation (menopause, aromatase inhibitor therapy, and androgen deprivation therapy).
image Denosumab is a new fully humanized monoclonal antibody that binds RANKL and through binding causes inhibition of RANKL and thus inhibits osteoclast activity.

Pharmacokinetics

image Denosumab has a very long half-life and is administered once every 6 months via subcutaneous injection. The time to maximum concentration is 26 days.

Indication

image Osteoporosis

Contraindications

image None of significance

Side Effects

image Eczema (small increase in risk)

Important Notes

image Osteoporosis can be evaluated through plain x-ray films of bones, but the gold standard is dual-energy x-ray absorptiometry (DXA).

image DXA fires two different x-ray beams and through advanced calculation techniques subtracts the signal from soft tissue and then compares the absorption of the two different beams through the bone.

image From the imaging studies, bone mineral density (BMD) scores are calculated.
image Bones with decreased BMD are at increased risk for fracture. A score of less than 2.5 (standard deviations below normal) is the diagnostic criterion for osteoporosis.

Fractures in Osteoporosis

image A double-blind randomized controlled trial (RCT) in 2009 (N = 7868) compared denosumab with placebo with regard to fractures over a 3-year period in women with mild to moderate osteoporosis aged 60 to 90 years and found an incidence of the following:

image Vertebral fractures: 2.3% (denosumab) versus 7.2% (placebo)
image Risk of hip fracture: 0.7% (denosumab) versus 1.2% (placebo)
image Nonvertebral fracture: 6.5% (denosumab) versus 8.0% (placebo)

FYI

image As per naming convention for monoclonal antibodies (mAbs), the –os– refers to bone and the –u– refers to fully humanized.
image Densoumab has recently been approved (June 2010) with the U.S. Food and Drug Administration (FDA).
image Osteopenia is the term for a mild reduction in BMD. Osteoporosis is the term for a more advanced reduction in BMD. The suffix -penia usually refers to a low cell count (e.g., thrombocytopenia means a low thrombocyte or platelet count); therefore osteopenia is somewhat of a misnomer when used in this setting when referring to BMD.

Colchicine

Description

Colchicine is used to treat crystal-associated arthritis, most commonly gout (a disease caused by uric acid crystal deposition in joints).

Prototype

image Colchicine

MOA (Mechanism of Action)

image Most of the pharmacologic effects of colchicine result from colchicine binding to tubulin (Figure 19-4). Tubulin is required for microtubule assembly, and colchicine prevents microtubule assembly. Microtubules are important components of the cytoskeleton and are involved with the following cellular functions:

image Cellular structural support
image Mitosis (the spindle apparatus composed of tubulin pulls the chromosomes into each new half of the dividing cell)
image Vesicular transport
image Gout is a disease that occurs when uric acid levels in the blood are elevated and uric acid crystals precipitate in joints; the crystals induce an intense inflammatory response resulting in arthritis, a condition referred to as crystal-induced arthritis.
image Colchicine is also known to suppress many immune functions in the setting of crystal-induced arthritis:

image Decreased neutrophil chemotaxis
image Decreased neutrophil adhesion
image Decreased release of multiple inflammatory mediators
image Decreased phagocytosis of urate crystals by neutrophils

image

Figure 19-4

Pharmacokinetics

image The half-life of the tubulin-colchicine complex is 20 to 30 hours. The long half-life increases the risk of drug accumulation.
image Although clearance is primarily via the liver, renal clearance accounts for about 20%, and renal insufficiency is a very strong risk factor for toxicity. Doses must be reduced in patients with renal insufficiency.

Indications

image Gout

image Acute attacks
image Long-term prevention of recurrent attacks as an adjuvant to uric acid–lowering therapies

Contraindication

image Renal failure: increased risk of toxicity

Side Effects

image Colchicine has a narrow therapeutic index.
image Gastrointestinal: Diarrhea is virtually a guaranteed side effect when colchicine is given in doses suitable for acute attacks of gout and occurs in many patients treated for prevention (preventative doses are lower than those for acute attacks).
image Bone marrow suppression: Antimitotics preferentially target rapidly dividing cells, such as those found in the bone marrow. This explains why bone marrow function, which relies on rapid cell turnover, is suppressed.
image Myopathy may occur.
image Neuropathy may occur.

Important Notes

image Gout is a common disorder of uric acid metabolism whereby uric acid levels in the blood are elevated, which results in uric acid crystals being deposited into joints, causing inflammation and intense pain. The great toe is the joint most commonly affected.
image Colchicine, because of its high risk of toxicity, is not a first-line therapy for gout. It should be reserved for situations in which first-line therapy (nonsteroidal antiinflammatory drugs [NSAIDs]) is contraindicated or ineffective. Other drugs used to treat gout include uricosurics (drugs that increase elimination of renal uric acid) and xanthine oxidase inhibitors (which decrease uric acid formation).
image Although doses are not routinely described in this textbook, overdose of colchicine can be fatal, and therefore it is important to highlight that there are maximum dose recommendations.
image Multisystem failure and death: One study showed that eight of nine overdoses over a 15-year period resulted in death.
image The FDA reported 33 deaths associated with intravenous colchicine from 1985 to 1997. The manufacture of intravenous colchicine in the United States was halted in February 2008.

Advanced

Drug Interactions

image Because of the risk of toxicity, it is important to recognize drug interactions that could increase colchicine levels in the body. Metabolism is via CYP3A4, and therefore drugs that inhibit CYP3A4 will increase colchicine levels.
image P-glycoprotein (Pgp) influences absorption, distribution, and elimination, and therefore coadministered drugs that modulate or inhibit Pgp function carry risk of increasing toxicity also.

Evidence

Acute Gout Pain

image A Cochrane review in 2006 (one RCT, N = 43), compared with placebo, colchicine demonstrated an absolute reduction of 34% for pain scales and a 30% reduction for tenderness, swelling, redness, and pain. The NNT to reduce pain was three. All participants treated with colchicine experienced gastrointestinal side effects (diarrhea and/or vomiting), and the number needed to harm (NNH) with colchicine versus placebo was one. Note: The sample size was very small, and only one study met inclusion criteria in this review.

FYI

image Colchicine is an alkaloid isolated from Colchicum autumnale, also called autumn crocus or meadow saffron.
image Hippocrates advocated the use of a plant extract (containing colchicine) for gout and concluded that “the best natural relief for [arthritis] is an attack of dysentery.”

Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Description

NSAIDs are antiinflammatory drugs that do not possess a steroidal structure (nonsteroidal).

Prototype and Common Drugs

Nonselective

image Prototype: ibuprofen
image Others:

image Propionic acid derivatives: naproxen, fenoprofen, ketoprofen, flurbiprofen
image Acetic acid derivatives: diclofenac, ketorolac, indomethacin, etodolac, sulindac, piroxicam, meloxicam, nabumetone, tolmetin, mefenamic acid, meclofenamate, flufenamic acid

Cyclooxygenase (COX)-2 selective

image Prototype: celecoxib
image Others: rofecoxib, valdecoxib

MOA (Mechanism of Action)

image Cyclooxygenase (COX) is an enzyme that catalyzes the conversion of arachidonic acid to prostaglandin (PG) G (PGG) and PGH. These intermediaries are then converted to a variety of important PGs as well as thromboxane A2 (TXA2).
image Each of these eicosanoids binds to its respective receptor, mediating the physiologic effects summarized in Figure 19-5.
image There are actually two major isoforms of the COX enzyme: COX-1 and COX-2. COX-1 is a constitutive enzyme, meaning that its levels remain relatively constant, and it is distributed widely throughout the body. COX-1 is thus believed to play a maintenance or protective role, responsible for production of cytoprotective mucus in the stomach and for platelet aggregation (clotting).
image COX-2 is an inducible enzyme, meaning that its levels and activity can increase rapidly and significantly in response to a stimulus. The main stimuli for COX-2 induction are inflammatory mediators, and thus COX-2 is typically associated with inflammation.
image The theory behind selective inhibition of COX-2 enzymes is therefore to preserve the gastric cytoprotective effects mediated through COX-1 while maximizing the antiinflammatory effects mediated through COX-2.
image An unanticipated consequence of selective COX-2 inhibition is a pro-platelet effect. TXA2 and prostacyclin (PGI2) have opposite effects on platelets: TXA2 activates platelets, and PGI2 inhibits platelet activation. Of the two enzymes, COX-1 is primarily responsible for generating TXA2, whereas COX-2 is responsible for generating PGI2. Therefore, selective COX-2 inhibition removes this “check” on the platelet-activating actions of TXA2.
image

Figure 19-5

Pharmacokinetics

image Most NSAIDs are well absorbed, and food has little effect on their bioavailability.
image Most NSAIDs undergo extensive hepatic metabolism, many through either the CYP3A or CYP2C families.
image Many nonselective COX inhibitors have short to intermediate half-lives (2 to 12 hours), requiring frequent administration. The newer COX-2 selective inhibitors typically have longer half-lives and are administered once daily. One exception is celecoxib, which is administered twice daily.
image Many NSAIDs are available in topical dosage forms, including ophthalmic preparations of diclofenac, flurbiprofen, ketorolac, suprofen.
image Indomethacin is also available as a rectal suppository.

Indications

image Pain
image Inflammation
image Fever

Contraindication

image Active peptic ulcer

Side Effects

Nonselective

image Gastrointestinal effects occur because of the inhibition of COX-1–mediated production of cytoprotective mucus in the stomach.
image Edema: PGs inhibit the reabsorption of Na+ and the activity of ADH, so PG inhibition leads to salt and water retention. This can lead to edema and can be problematic in patients with conditions such as congestive heart failure.
image Acute renal failure: Renal PGs often play a protective role in high-risk patients by counteracting the effects of vasoconstrictors such as angiotensin 2 and vasopressin. When PGs are reduced, glomerular afferent vasoconstriction activity is unopposed, reducing renal blood flow and function.

COX-2 Selective

image Cardiovascular: The mechanism is not confirmed, but cardiovascular effects are thought to be a result of disruption of the balance between the platelet-activating effects of COX-1 and the platelet-inhibiting effects of COX-2.

All

image Central nervous system (CNS): Confusion, dizziness, depression, and hallucinations may occur. The mechanism is not confirmed, but COX-2 is the most abundant COX isoform in the CNS, and COX-2 may play a role in neurotransmission. The frequency of CNS side effects appears to be higher with COX-2–selective inhibitors and possibly with indomethacin. These reactions are uncommon.

Important Notes

image Indomethacin is considered to be a particularly potent COX inhibitor with very strong antiinflammatory effects. However, this enhanced efficacy is balanced with an increased severity of adverse effects, particularly gastrointestinal effects. Indomethacin is therefore typically reserved for use in more severe inflammatory conditions rather than everyday analgesia.
image Diclofenac is marketed in a fixed-dose combination with the PGE analogue misoprostol. The theory is that adding a PGE analogue helps to replace the PGE that is lost through COX inhibition.
image The extent of selectivity of COX-2 inhibitors varies significantly, and the distinction between COX-2 selective and nonselective inhibitors is not as clear as one would expect. Rofecoxib is by far the most COX-2 selective among currently marketed agents, with approximately 10 times the selectivity of celecoxib. Diclofenac and etodolac are also relatively selective for COX-2, whereas ketorolac is a relatively selective COX-1 inhibitor.
image Acetylsalicylic acid (ASA; aspirin) is a nonselective COX inhibitor with all the key features of other NSAIDs (antipyretic, analgesic, antiinflammatory activity), but it is often classified separately. Reasons include the fact that it irreversibly inhibits the COX enzyme and as a result has prolonged antiplatelet activity.
image The antiplatelet effects of ASA are observed at doses much lower than required for antiinflammatory or other activities. This is thought to be the case because the antiplatelet effects are mediated by the irreversible inhibition of COX-1 by the parent ASA. Salicylic acid, the metabolite of ASA, is a reversible inhibitor of COX, just like the other NSAIDs. Because the antiplatelet effects of ASA are not affected by first pass, a much lower dose can be used to achieve platelet inhibition.

Advanced

image A potential role for COX inhibitors in the treatment of cancer has been under investigation for many years. The COX-2 enzyme, which may stimulate cell division, has been selectively targeted in indications such as colon cancer. Inhibition of COX-2 may promote apoptosis, inhibit angiogenesis, and inhibit cell growth.

Evidence

Alone or in Combination with Opiates for Treatment of Cancer Pain

image A 2005 Cochrane review (42 trials, N = 3084 patients) found that NSAIDs were more effective than placebo for cancer pain. No conclusions could be drawn about the efficacy of NSAIDs relative to one another. The combination of opiates and NSAIDs was slightly and statistically better than either agent alone in 9 of 14 trials and was no different in 4 of 14 trials. The authors noted that the generalizability of the findings was limited by the short term of the studies.

Versus Opiates for Treatment of Acute Renal Colic

image A 2006 Cochrane review (20 trials, N = 1613 patients) compared NSAIDs with opiates for treatment of renal colic. Results of the trials were too heterogeneous to perform a meta-analysis. The authors concluded that both NSAIDs and opiates can significantly relieve pain in acute renal colic. Opiates appeared to cause more adverse effects, particularly vomiting, and particularly pethidine.

FYI

image Ibuprofen and naproxen are available without a prescription in many jurisdictions.
image The antiplatelet effects of aspirin were first identified in the 1940s, after a physician noted increased bleeding in children who chewed aspirin gum after tonsillectomy. Speculating that a “blood-thinning” effect could reduce cardiovascular risk, he began giving aspirin to high-risk patients. Despite claims of success, the FDA did not accept the antiplatelet effects of aspirin until 1980.
image The use of COX-2 inhibitors in cancer led to one of the largest drug withdrawals in the history of pharmaceutical development. During a very large trial in cancer prevention, it was discovered that there was a higher incidence of cardiovascular events in the rofecoxib-treated group versus placebo. The study was halted, the news hit the media, and this top-selling drug was withdrawn from the market.

Uricosurics

Description

Uricosurics lower uric acid levels in blood as a treatment for gout.

Prototype and Common Drugs

image Prototype: Probenecid
image Others: Sulfinpyrazone

MOA (Mechanism of Action)

image Gout is a condition whereby uric acid crystals precipitate in joints and the crystals induce an intense inflammatory reaction within the synovial space, leading to severe pain. Uric acid is an organic acid and a byproduct of purine metabolism.
image Uric acid levels in the blood are elevated in gout, and one treatment strategy is to lower uric acid levels by enhancing uric acid excretion, which is what uricosurics do.
image Uric acid is freely filtered at the glomerulus and is also both reabsorbed and secreted in the proximal tubule. The amount excreted usually is about 10% of that filtered.
image In the proximal tubule, a transporter that exchanges urate for either an organic or an inorganic anion is the channel responsible for uric acid reabsorption; uricosuric drugs compete with urate for this brush-border transporter, thereby inhibiting its reabsorption. Probenecid is completely reabsorbed by the proximal tubule (Figure 19-6).
image As the urinary excretion of uric acid increases, the amount of urate in the body decreases, although the plasma concentration may not be greatly reduced.
image With the increase in uric acid excretion, a predisposition to renal stone (urate stone) formation is increased. Therefore the urine volume should be maintained at a high level to help reduce urate concentrations in the urine and to promote flow, both acting to minimize precipitation within the renal system.
image Logically, patients with renal failure will be unresponsive to uricosurics.
image

Figure 19-6

Pharmacokinetics

image One uricosuric drug may either add to or inhibit the action of another. The biphasic effect may be seen within the normal dosage range with some drugs such as salicylates.
image Twice-a-day and up to four-times-a-day administration has resulted in probenecid being used by fewer patients compared with another class of gout therapies, the xanthine oxidase inhibitors, which decrease uric acid synthesis.

Indications

image Gout

Contraindications

image Renal insufficiency (creatinine clearance <50 mL/min) is a contraindication.
image Urolithiasis (renal stones or calculi) is a contraindication because increased uric acid is excreted into the urine, where it can then precipitate and cause calculi.
image Peptic ulcer is a contraindication, because uricosurics could exacerbate preexisting lesions.

Side Effects

image Probenecid is well tolerated.
image Gastrointestinal irritation is usually mild.
image Allergic reactions usually are mild and occur in 2% to 4% of patients. Serious hypersensitivity is extremely rare.

Important Notes

image Alcohol and high protein intake will increase uric acid levels in the blood. Therapy for gout must include dietary modification.
image Paradoxically, an acute attack can occur in up to 20% of gouty patients treated with probenecid alone. Therefore concomitant NSAIDs are indicated early in the course of therapy to avoid precipitating an attack of gout.
image Low-dose aspirin causes net retention of uric acid. It should not be used for analgesia in patients with gout.
image Fenofibrate (lipid-lowering agent) and losartan (angiotensin receptor blocker) both have uricosuric properties.
image Transport across the urate transporter is bidirectional, and depending on dose, a uricosuric drug may either decrease or increase the excretion of uric acid. Decreased excretion usually occurs at a low dose, whereas increased excretion is observed at a higher dose.
image In 2006 fewer than 5% of patients treated for gout were treated with probenecid in the United States. The low rate of use of this drug was speculated to be a result of the availability of other medications for gout, the lack of efficacy in patients with renal dysfunction, and the propensity for renal calculi.

Advanced

image Drug interactions: Probenecid inhibits the tubular secretion of a number of drugs and increases their serum concentrations; these drugs include the following:

image NSAIDs
image Methotrexate
image Clofibrate
image Rifampin
image Penicillin and cephalosporins (probenecid was originally developed to prolong penicillin blood levels)

FYI

image Tophaceous means stonelike. Tophaceous gout is a condition in which large stony deposits of uric acid accumulate around the joint.
image Benzbromarone, a potent uricosuric drug, was introduced in the 1970s. It was registered in many jurisdictions throughout Asia, South America, and Europe. In 2003 the drug was withdrawn after reports of serious hepatotoxicity, but it is still marketed in several countries by other drug companies.
image Probenecid is given with penicillin to reduce penicillin excretion and to prolong its half-life.

Xanthine Oxidase Inhibitors

Description

Xanthine oxidase inhibitors decrease uric acid synthesis and are used in gout.

Prototype and Common Drugs

image Prototype: Allopurinol
image Others: Febuxostat

MOA (Mechanism of Action)

image Allopurinol is a purine analogue of hypoxanthine and is a substrate for, and inhibitor of, the enzyme xanthine oxidase.
image Xanthine oxidase converts hypoxanthine to xanthine to uric acid; inhibition therefore reduces the production of uric acid (Figure 19-7).
image Allopurinol’s primary metabolite, oxypurinol, also inhibits xanthine oxidase. Oxypurinol has a long half-life in tissues and is responsible for much of the pharmacologic activity of allopurinol.
image Allopurinol competitively inhibits xanthine oxidase at low concentrations and is a noncompetitive inhibitor at high concentrations.
image Allopurinol also results in the accumulation of xanthine and hypoxanthine; these molecules can cause feedback inhibition of purine synthesis.
image The net effect of xanthine oxidase inhibition is a lower production of uric acid and a decrease of total body uric acid (including dissolved and precipitated uric acid).
image Xanthine oxidase inhibitors facilitate the dissolution of tophi (nodular crystal deposits) and prevent the development or progression of chronic gouty arthritis by lowering the uric acid concentration in plasma below the limit of its solubility.
image Febuxostat is a new nonpurine inhibitor of xanthine oxidase. A significant difference from allopurinol is that being a nonpurine, it does not inhibit purine or pyrimidine synthesis, while allopurinol does.
image

Figure 19-7

Pharmacokinetics

image Allopurinol increases the half-life of probenecid and enhances its uricosuric effect, whereas probenecid increases the clearance of oxypurinol, thereby increasing dose requirements of allopurinol. The clinical relevance of this interaction is that both drugs are used to treat gout and therefore are potentially coadministered.
image Mercaptopurine, azathioprine, and theophylline are metabolized by xanthine oxidase, and coadministration with allopurinol will dramatically increase levels of these drugs. Coadministration should be avoided or should be performed with great caution and should include large dose reductions (down to 25% of the normal dose). Clinical relevance of this interaction is in the treatment of transplant patients because they are treated with immunosuppressants such as mercaptopurine and azathioprine.

Indications

image Gout:

image Recurrent gout attacks not prevented by or amenable to treatment with uricosuric agents
image Tophaceous gout (tophaceous refers to nodular masses of crystal deposition)

image Renal stones composed of uric acid
image Complicated hyperuricemia secondary to:

image Increased cell turnover from increased blood cell production:

• Polycythemia vera, myeloid metaplasia, other blood dyscrasias

image Acute tumor lysis syndrome (occurs when treated cancer cells break open and release contents, which are metabolized to uric acid)
image Inborn errors of uric acid metabolism:

• Lesch-Nyhan syndrome (rare)

image Because of its possible serious side effects, allopurinol is not indicated in the treatment of asymptomatic hyperuricemia.

Contraindication

image Previous hypersensitivity reactions to allopurinol

Side Effects

Allopurinol

image Skin reactions: Both mild and severe reactions can occur.

image The rash is predominantly a pruritic, erythematous, or maculopapular eruption (itchy, red, flat or slightly raised).
image Rarely, toxic epidermal necrolysis or Stevens-Johnson syndrome occurs, which can be fatal. These are very severe skin reactions. The risk for Stevens-Johnson syndrome is probably limited to within the first 2 months of treatment.
image Because the rash may precede severe hypersensitivity reactions, patients who develop a rash should discontinue allopurinol.
image Incidence of rash is increased in patients receiving concurrent allopurinol and ampicillin.

image Liver reactions: Severe hepatic reactions including elevations of liver enzymes, fever, eosinophilia, and rash may occur. Allopurinol should be stopped immediately if a hypersensitivity reaction is suspected.
image Renal insufficiency: Decreased renal function has been seen after initiation of allopurinol, but the mechanism of this side effect has not been established.
image The risk of severe reactions (skin or liver reactions) from allopurinol is estimated to be 1 in 1000 to 1 in 5000.

Febuxostat

image Febuxostat appears to not produce the hypersensitivity reactions that occur with allopurinol.
image Compared with allopurinol, there is a small increase in the risk of myocardial infarction, stroke, and cardiovascular death with febuxostat.

Important Notes

image Paradoxically, urate-lowering therapy can cause a flare-up of gout in the early months of treatment. Therefore:

image Allopurinol is started at a low dose (below the typical maintenance dose) and slowly increased weekly, titrated to serum uric acid levels.
image Colchicine and NSAIDs are coadministered to help suppress acute attacks. Once excess tissue stores of uric acid are reduced, the incidence of acute attacks decreases and colchicine can be discontinued (usually at around 6 months).

image Because allopurinol has no antiinflammatory effects, it has no role in the treatment of acute gouty arthritis.
image Complete blood counts, liver function test results, and renal function test results should be assessed periodically, especially during the first few months of treatment, to monitor for liver and renal injury.
image The development of a skin rash mandates immediate assessment by a physician; a mild rash can be a precursor to a severe skin reaction.
image Lack of effectiveness of allopurinol is generally attributed to inadequate dose or duration of treatment, meaning that patients are treated with a dose that is too small or for too short a time to be effective. Precipitation of acute gout attacks early in the course of therapy is a common cause of discontinuation.

FYI

image Allopurinol initially was synthesized as a candidate antineoplastic agent but was found to lack antineoplastic activity. Subsequent testing showed it to be an inhibitor of xanthine oxidase that was useful clinically for the treatment of gout.
image Eosinophilia (increased eosinophil count in the blood) is a common marker of allergic reactions and is a hallmark of hypersensitivity-mediated drug-induced organ injury. It also occurs in parasitic infections.
image Febuxostat was approved by the FDA in February 2009. It is the first new drug for gout in many decades. It is far more expensive than allopurinol.

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