Chapter 9 - More Interesting Version

Inflammation Introduction

• Inflammation is a complex response to cell injury in vascularized connective tissue.
• Inflammatory mediators eliminate the cause of injury and clear debris for tissue repair.
• Noxious agents, infections, or injuries activate the response by releasing damage and pathogen-associated molecules.
• Immune system cells recognize these molecules.
• The intensity and duration of inflammatory responses can become inappropriate, leading to chronic conditions.
• Anti-inflammatory drugs manage these conditions.
• Pharmacological interventions control the inflammatory process and minimize inflammatory pain.
• The two main classes of anti-inflammatory medications are corticosteroids (glucocorticoids) and nonsteroidal anti-inflammatory drugs (NSAIDs).

Inflammatory Process

• Acute phase response or inflammation is a physiological response to tissue injury and infection, but not interchangeable with infection.
• Vascular changes lead to clinical signs of inflammation: redness, heat, pain, and swelling.
• Vasodilation and increased blood vessel wall permeability are consistent vascular responses.
• Vasodilation increases blood flow (hyperemia), producing redness and heat.
• Increased permeability of vascular endothelium allows exudation of plasma, causing swelling and pain.
• Local chemical mediators or cytokines cause vascular changes released by damaged cells or synthesized in the injured tissue.
• Examples include histamine, bradykinin, prostaglandins, and other complex agents.
• Some of these substances sensitize sensory nerve endings and enhance nociception and pain transmission.

Acute Inflammation

• Three major phases of acute inflammation:
  • Vascular Phase: Vasoactive mediators (cytokines) dilate arterioles and cause endothelial cells to shrink, increasing permeability of capillaries and venules, which leads to extravasation of plasma, swelling, and pain.
  • Cellular Phase: Chemotactic mediators target leukocytes, which adhere to endothelium (margination), squeeze through openings (diapedesis), and migrate into tissues (emigration); chemokines attract macrophages to the inflammation site.
  • Tissue Healing Phase: Macrophages arrive at the damaged tissue within 6 hours. Activated macrophages secrete significant proinflammatory cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), which induce coagulation, increase vascular permeability, and promote the acute-phase response.
• Acute inflammation has a rapid onset following tissue injury and resolves relatively quickly.
• The resulting tissue pathology is mild and localized.
• The acute inflammatory response occurs similarly whether due to tissue injury or the body’s attempt to limit invading pathogens.

Chronic Inflammation

• Chronic inflammation results from continuous or repeated exposure to the offending element or process.
• Causes include continued tissue damage, persistence of pathogens, autoimmune diseases, and cancers.
• Macrophage and lymphocyte accumulation and activation, as well as fibroblasts replacing damaged or necrotic tissue, are hallmarks.
• Soluble factors released by macrophages and lymphocytes play a role in the development of chronic inflammation.
• Fibroblast replacement of damaged tissue leads to fibrosis, an excessive deposition of fibrous tissue, interfering with normal tissue function due to excessive growth factors (platelet-derived growth factor, fibrogenic cytokines [IL-1 and TNF-α], and angiogenic factors (fibroblast growth factor, vascular endothelial growth factor).
• Chronic inflammation can also lead to granuloma formation, consisting of activated macrophages surrounded by activated lymphocytes.

Controlling Inflammation

• Drugs are available to decrease joint pain, swelling, inflammation, and minimize the progression of the inflammatory response.
• The two major categories of anti-inflammatory drugs:
  • Corticosteroids (e.g., prednisone or hydrocortisone).
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, or naproxen).
• NSAIDs inhibit the vascular phase of inflammation.
• Corticosteroids primarily inhibit the cellular phase of inflammation.
• Corticosteroids alter the immune responses of lymphocytes, making them anti-inflammatory and immunosuppressive.
• Corticosteroids do not address the underlying cause of the disease or condition; suppressing inflammation has enormous clinical utility, making these drugs frequently prescribed.
• Anti-inflammatory medications inhibit parts of the arachidonic acid cascade.
• Nonselective NSAIDs target cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin production.
• Corticosteroids prevent the liberation of arachidonic acid from plasma-membrane phospholipids, reducing the synthesis of eicosanoids (e.g., prostaglandins, thromboxanes, and leukotrienes).
• NSAIDs are widely used for their anti-inflammatory and analgesic effects
• NSAIDs are a necessary choice because of the integrated role of the COX pathway in the generation of inflammation and the biochemical recognition of pain.

Corticosteroids

• Corticosteroids (glucocorticoids or steroids) are endogenous hormones, like cortisol, secreted by the adrenal glands.
• Corticosteroid medications are a synthetic version of cortisol, such as cortisone, prednisone, or hydrocortisone, effective at reducing inflammation and suppressing the immune system.
• Corticosteroids historically have been used for pain relief in inflammatory conditions.
• The use of corticosteroids to treat inflammatory and autoimmune diseases makes them among the most frequently prescribed classes of drugs.
• Extended administration and rapid withdrawal may cause serious side effects because corticosteroids exert effects on almost every organ system.
• The decision to institute therapy with systemic corticosteroids requires careful consideration of the relative risks and benefits in each patient.
• Most generic names end in -one.
• Cortisol is released in response to stress and has numerous effects on the body that are essential for life.

Corticosteroids - Therapeutic Effects

• Corticosteroids inhibit the inflammatory response to tissue injury.
• Endogenous corticosteroids suppress manifestations of allergic disease due to histamine release from mast cells and basophils.
• High levels of circulating corticosteroids are required for anti-inflammatory effects and cannot be produced by administering exogenous corticosteroids without producing excess manifestations.
• The hypothalamic-pituitary-adrenal (HPA) axis is suppressed in patients receiving corticosteroids for prolonged periods.
• Large doses of exogenous corticosteroids inhibit adrenocorticotropic hormone (ACTH) release from the pituitary gland.
• ACTH stimulates the release of cortisol from the adrenal cortex.
• ACTH secretion to the point of severe adrenal insufficiency can be a dangerous problem when therapy is stopped abruptly.
• Local administration of corticosteroids produces a high local concentration of the steroid, often without enough systemic absorption to cause serious side effects.
• Main differences among corticosteroids lie in their potency (dose), half-life, and propensity for fluid retention due to effects on sodium retention.

Steroid Hormones

• Steroids used to treat inflammation specifically, corticosteroids, are different than the anabolic steroids that some athletes use to gain muscle.
• Steroids are a large group with many different functions.

Corticosteroids - Mechanism of Action

• The primary mechanism of action of the corticosteroids includes both anti-inflammatory and immunosuppressive actions.
• These drugs function to decrease inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.
• Multiple mechanisms involved in the suppression of inflammation by corticosteroids include:
  • Inhibition of the production of factors critical for generating the inflammatory response.
  • Decreased release of vasoactive and chemoattractive factors.
  • Diminished secretion of lipolytic and proteolytic enzymes.
  • Decreased extravasation of leukocytes to areas of injury.
  • Decreased fibroblast activity at the site of injury.
• Anti-inflammatory effects of corticosteroids are due to a reduction in the synthesis or release of inflammatory mediators, including prostaglandins.
• The sum of these actions results in suppression of the vascular changes responsible for the cardinal signs of inflammation.
• Corticosteroids also inhibit certain aspects of leukocyte function, accounting for their immunosuppressant effect.

Corticosteroids - Routes of Administration

• Corticosteroids treat a variety of inflammatory conditions and can be administered:
  • Intravenously
  • Orally
  • Intra-articularly
  • Topically
  • Intralesionally
  • Transcutaneously
• Corticosteroids marketed as anti-inflammatories are often topical formulations, such as nasal sprays for rhinitis or inhalers for asthma.
• Prednisone is one of the most commonly used corticosteroids because of its low cost and is available only in oral form.
• These medications should be administered with food to decrease GI upset.
• Generic oral formulations of prednisone, methylprednisolone, and triamcinolone typically last for 12 to 36 hours in the body, whereas dexamethasone and betamethasone last for 32 to 72 hours.
• Some corticosteroids are formulated in a way that extends their duration of action.
• Depot preparations of methylprednisolone provide anti-inflammatory effects for 1 to 4 weeks.
• Long-acting repository (depot) formulations are intended for intramuscular or intra-articular injection.

Corticosteroids - Pharmacodynamics and Pharmacokinetics

• Corticosteroids are strikingly similar in their molecular structures and clinical effects.
• All oral corticosteroids undergo first-pass metabolism during absorption.
• When dosed equivalently, the various corticosteroids are equivalent in anti-inflammatory efficacy and have similar side-effect profiles, except for fluid retention.
• Preparations are readily interchangeable if equipotent doses are prescribed.
• Prednisone is a prototypical corticosteroid drug.

Corticosteroids - Dosing Guidelines

• Dosing of corticosteroids depends on the condition being treated and the patient's response.
• For people who are taking corticosteroids long term, the provider may prescribe extra doses during times of acute stress, such as severe infection or surgery.
• Corticosteroids mimic the cortisol surge that is normally produced by the body during stressful events.
• Discontinuation of therapy that has lasted longer than 7 days may require tapering of the drug to prevent adrenal crisis.
• Standard formulations of prednisone, methylprednisolone, and triamcinolone last for around 12 to 36 hours in the body, whereas dexamethasone and betamethasone last for 32 to 72 hours.
• Dose requirements are variable, and individualized doses are based on disease and patient response.
• A methylprednisolone (Medrol Dosepak) is a low-dose oral corticosteroid treatment course used to treat lower back injuries and other musculoskeletal conditions and contains 21 tablets of methylprednisolone 4 mg that are taken over a 6-day period.
• When corticosteroids are administered at recommended dosages for short durations of time, these potent anti-inflammatories are considered safe.
• More regular or extended dosing has been associated with several severe adverse effects.
• Long-term use of high-dose corticosteroids can cause avascular necrosis, especially of the head of the femur and humerus.
• The reason is unknown, but one hypothesis is that corticosteroids can increase lipid levels in the blood, thereby reducing blood flow.
• If untreated, avascular necrosis worsens with time, and eventually the bone can collapse.
• Avascular necrosis also causes bone to lose its smooth shape, potentially leading to severe arthritis.

Potential Consequences of Corticosteroid Use

• Corticosteroids treat spinal disc herniation, chronic tendinopathy, and autoimmune/inflammatory diseases like systemic lupus erythematosus.
• Studies link osteonecrosis of the hip to corticosteroid use.
• High-dose corticosteroid use is the most frequently associated independent factor with the development of osteonecrosis, especially of the femoral head.
• Little evidence exists linking a single course of MTP to osteonecrosis.
• Osteonecrosis is responsible for >10% of all hip arthroplasties in the United States and Europe and is the most common reason that many physicians do not routinely prescribe corticosteroids.

Corticosteroids - Indications and Precautions

• Short-term administration of corticosteroids may be prescribed for acute and subacute bursitis, acute nonspecific tenosynovitis, ankylosing spondylitis, epicondylitis, posttraumatic osteoarthritis, and several types of arthritis.
• During an exacerbation or as maintenance therapy, the prescriber may consider corticosteroids for select cases of acute rheumatic carditis, systemic dermatomyositis, and systemic lupus erythematosus.
• Prolonged use of corticosteroids may cause immunosuppression that increases secondary infection, masks acute infection, prolongs or exacerbates viral infections, or limits response to certain vaccines.
• Certain viral infections, such as chicken pox or measles, may have a more severe course in people taking corticosteroids.
• Prescription doses of exogenous corticosteroids can cause higher than normal levels of cortisol in the blood.
• High levels of exogenous corticosteroids for a prolonged time cause the hypothalamus to secrete less corticotropin-releasing hormone (CRH), which reduces ACTH, thereby causing the adrenal glands to stop making cortisol.
• This condition is a concern if the medication is stopped suddenly because the adrenal cortex will not immediately begin producing corticosteroids again.
• Acute adrenal insufficiency or Addison’s disease symptoms include irritability, nausea, joint pain, dizziness, and low blood pressure.
• To avoid this condition, steroid medication should be withdrawn slowly over several days or weeks to allow the adrenal cortex to fully resume its functioning capacity again.

Corticosteroid Injections and Pregnancy

• Corticosteroid use is preferred for pregnant women with musculoskeletal inflammation late in pregnancy
• NSAIDs are contraindicated during the third trimester.
• Corticosteroids are used during pregnancy to treat an autoimmune disorder of the mother that could be more harmful to fetal health than high doses of the medication.
• A historical link was found between corticosteroids and cleft lip births, but contemporary evidence indicates this incidence is modest.
• Other corticosteroid risks during pregnancy include preeclampsia, low birth weight, preterm birth, and potential hyperglycemia and ketoacidosis for the patient with gestational diabetes.
• Corticosteroid use following birth can disturb normal lactation, but this is reversible after stopping use of the medication.

Corticosteroids - Adverse Effects

• Suppression of the HPA axis occurs in cases of adrenal insufficiency in patients receiving high doses of corticosteroids for prolonged periods.
• Adrenal glands atrophy and can take months to recover full function after discontinuation of the exogenous corticosteroid.
• Overuse of steroid joint injections may also result in adrenal suppression after their discontinuation.
• HPA axis suppression may lead to acute adrenal crisis, a potentially life-threatening medical condition requiring immediate emergency treatment.
• Withdrawal and discontinuation of a corticosteroid should be conducted slowly and carefully.
• Adult patients receiving >20 mg per day of prednisone (or equivalent) may be most susceptible.
• Any patient prescribed corticosteroids must follow the precise instructions of the daily schedule without deviation.
• Anaphylactoid reactions are rare but have been observed in patients receiving corticosteroids.
• Corticosteroids have been associated with many side effects:
  • Agitation and irritability
  • Blurred vision
  • Difficulty concentrating
  • Dizziness
  • Facial hair growth in female patients
  • Fast or irregular heartbeat
  • Fluid retention
  • Headache
  • High blood pressure
  • Increased blood sugar, cholesterol, or triglycerides
  • Increased risk of gastric ulcers or gastritis
  • Loss of potassium
  • Shortness of breath
  • Sleeplessness
  • Weight gain
• Long-term use of exogenous corticosteroid therapy may cause abnormally high cortisol levels and lead to Cushing’s syndrome (hypercortisolism).
• Symptoms include a fatty (buffalo) hump between the shoulders, a round face, weight gain, irregular menstrual cycles, fatigue, and depression.

Nonsteroidal Anti-Inflammatory Drugs

• Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used groups of drugs.
• Over 20 different NSAIDs are available commercially and are used worldwide.
• All the NSAIDs (including aspirin) have analgesic, antipyretic, and anti-inflammatory effects.
• Traditional (nonselective) NSAIDs also have antithrombotic effects.
• These medications relieve pain by blocking the production of pain-signaling molecules.
• NSAIDs relieve pain in joints, muscles, and other soft tissues by inhibiting the COX enzymes.
• NSAIDs are a choice in pain management because of the integral role of the COX pathway in the generation of inflammation and the biochemical recognition of pain.
• The agents differ with respect to their side effects, duration of action, degree of platelet antagonism (bleeding), and gastrointestinal (GI) toxicity.
• Traditional nonselective COX inhibitor NSAIDs and the selective cyclooxygenase COX-2 inhibitors are widely used for their anti-inflammatory and analgesic effects.
• NSAIDs are grouped by their chemical similarity, leading to functional similarity.
• This chemical diversity yields a broad range of pharmacokinetic characteristics.
• There are two major categories of NSAIDs:
  • Nonselective COX inhibitor NSAIDs vary in their potency, analgesic and anti-inflammatory effectiveness, and duration of action.
  • Selective cyclooxygenase-2 (COX-2) inhibitor NSAIDs (all named with the ending -coxib) produce analgesia equivalent to that of the nonselective NSAIDs while decreasing the adverse effects, specifically the GI toxicity associated with chronic NSAID use.
• Postclinical experience involving some of the highly selective COX-2 inhibitors has shown a higher incidence of cardiovascular thrombotic events than with the nonselective drugs.
• Rofecoxib (Vioxx) and valdecoxib (Bextra) have been withdrawn from the market because of an increased risk of adverse cardiovascular events at high doses in the elderly and skin reactions.
• Only celecoxib (Celebrex) is currently available for use in the United States despite having similar risks.

Cardiovascular Risk Associated With NSAIDs

• Some drugs used to treat noncardiovascular conditions may adversely affect the cardiovascular status of patients both with and without known cardiovascular disease.
• The cardiovascular safety of NSAIDs, including celecoxib, valdecoxib (withdrawn), and rofecoxib (withdrawn) revealed an increase in the incidence of myocardial infarction, stroke, and vascular death.
• Major vascular events were increased by about a third by a coxib.
• Diclofenac, a nonselective COX inhibitor, is primarily prescribed topically due to an increase in major coronary events

NSAIDs - Therapeutic Effects

• The NSAIDs are antipyretic, analgesic, and anti-inflammatory medications.
• NSAIDs provide mostly symptomatic relief from pain and inflammation associated with musculoskeletal disorders, such as strains, sprains, and various symptoms associated with rheumatoid arthritis and osteoarthritis.
• Patients with debilitating disease may not respond adequately to full therapeutic doses of NSAIDs and may require aggressive therapy.
• Genomic variation may affect a person’s success rate with a particular NSAID; thus, there are >20 treatment options.
• NSAIDs are effective against inflammatory pain of low to moderate intensity.
• Maximal efficacy is generally less than that of opioids, however NSAIDs lack the unwanted adverse effects of opiates in the central nervous system (CNS), including respiratory depression and the potential for the development of physical dependence.
• Coadministration of NSAIDs can reduce the opioid dose needed for sufficient pain control and thus, reduce the likelihood of adverse opioid effects.
• NSAIDs are particularly effective when inflammation has caused sensitization of pain perception, postoperative pain or pain arising from inflammation, such as arthritic pain, is controlled well by NSAIDs, whereas pain arising from the hollow viscera usually is not relieved.
• NSAIDs are commonly used to treat migraine attacks and can be combined with antiemetics to aid relief of the associated nausea.
• NSAIDs generally lack efficacy in neuropathic pain, such as diabetic neuralgia or pain associated with shingles (postherpetic neuralgia).
• Ketorolac (Toradol) 60 mg administered intramuscularly (IM) produces analgesia equivalent to morphine 10 mg IM for this type of pain

NSAIDs - Mechanisms of Action

• Classic COX inhibitors inhibit all types of COX enzyme activity, impairing the transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes.
• The inhibition of prostaglandin and thromboxane synthesis results in reduced inflammation, as well as antipyretic, antithrombotic, and analgesic effects.
• NSAIDs affect pain pathways in at least 3 ways:
  • Prostaglandins reduce the activation threshold at the peripheral terminals of primary afferent nociceptor neurons. By reducing prostaglandin synthesis, NSAIDs decrease inflammatory hyperalgesia and allodynia.
  • NSAIDs decrease the recruitment of leukocytes and, thereby, the production of leukocyte-derived inflammatory mediators.
  • NSAIDs that cross the blood-brain barrier prevent the generation of prostaglandins that act as pain-producing neuromodulators in the spinal cord dorsal horn.

NSAIDs - Routes of Administration

• NSAIDs are used for the treatment of mild to moderate pain, especially pain associated with musculoskeletal inflammation, such as in arthritis and gout.
• The primary route of NSAID administration is oral for both prescription and over-the-counter (OTC) medicines.
• Ketorolac (Toradol) is the only NSAID routinely administered via the parenteral route.
• Topical NSAIDs have decreased systemic exposure compared to the oral and intravenous formulations; therefore, they are expected to cause less serious side effects.
• Diclofenac gel, ketoprofen gel, piroxicam gel, and diclofenac plaster work reasonably well for strains and sprains.
• For hand and knee osteoarthritis, topical diclofenac and topical ketoprofen rubbed on the skin for ≥6 weeks helped reduce pain by at least half in a modest number of people.
• Methods that enhance transdermal delivery, such as iontophoresis or chemical penetration enhancers, continue to be investigated.
• Topical NSAIDs reported fewer GI side effects compared with those using oral formulations.
• The cardiovascular and renal safety profile of topical NSAIDs remains to be assessed, and the possibility of skin rashes due to topical application of NSAIDs should be kept in mind.
• Lower systemic exposure that is expected from topical usage may result in a better overall safety profile for these routes of administration.

NSAIDs - Pharmacokinetics

• The major differences between NSAIDs are their therapeutic half-lives and safety profiles.
• NSAIDs are systemic drugs that are distributed throughout the body and readily penetrate synovial joints, making these drugs ideal for reducing musculoskeletal inflammation.

NSAIDs - Absorption and Distribution

• Most NSAIDs are acidic compounds with a relatively high bioavailability.
• After oral administration, the absorption of NSAIDs is generally rapid, peak plasma concentrations are reached within 3 hours.
• Oral NSAIDs undergo hepatic first-pass metabolism, resulting in reduced bioavailability.
• Food intake may delay absorption and systemic availability.
• Antacids, commonly prescribed to patients on NSAID therapy, variably delay absorption.
• Aspirin begins to acetylate platelets within minutes of reaching the presystemic circulation.
• For distribution, NSAIDs bind to plasma proteins, are usually metabolized in the liver, and are excreted in the urine.
• Most NSAIDs are extensively bound (95% to 99%) to plasma proteins, usually albumin, and achieve sufficient concentrations in the CNS to have a central analgesic effect.
• Most NSAIDs are distributed widely throughout the body and readily penetrate synovial joints, yielding synovial fluid concentrations in the range of half the plasma concentration.
• The volume of distribution of NSAIDs is low, ranging from 0.1 to 0.3 L/kg, suggesting minimal tissue binding.
• NSAID binding in plasma can be saturated when the concentration of the NSAID exceeds that of albumin.

NSAIDs - Metabolism and Excretion

• Hepatic biotransformation and renal excretion are the principal routes of metabolism and elimination of the majority of NSAIDs.
• Common NSAIDs have a variable half-life (t½).
• Aspirin has a t½ of 0.25 to 0.3 hours.
• Ibuprofen has a t½ of about 2 hours, is relatively safe, and is the least expensive of the traditional nonselective NSAIDs.
• Naproxen has a comparatively long but highly variable t½ ranging from 12 to 17 hours.
• Genetic variation in the major metabolizing enzymes and variation in the composition of the intestinal microbiome may contribute to variability in metabolism and elimination.
• NSAIDs are not recommended in patients with advanced hepatic or renal disease due to the drugs’ potential altered pharmacokinetic effects, which can potentiate increased adverse pharmacodynamic effects, including risk of bleeding and acute kidney injury.
• NSAID elimination is dependent on the free (unbound) fraction of the drug within the plasma and the intrinsic enzyme activities of the liver to metabolize the drug to an excretable metabolite.

NSAIDs - Dosing Guidelines

• Most patients take therapeutic doses of NSAIDs for short durations of time and usually tolerate them well.
• NSAIDs have a dose-dependent relationship between concentration and therapeutic effects.
• All NSAIDs pose dose- and age-related risks of gastropathy and renal impairment.
• Because most NSAIDs block COX-1, they all increase the risk of stomach ulcers and GI bleeding.
• Naproxen is the only NSAID with a neutral-positive cardiac profile.
• Some selective NSAIDs, along with some of the nonselective COX-inhibitor NSAIDs, were found to increase the risk of heart attacks.

NSAIDs - Precautions

• Safety concerns exist for NSAID use in patients with, or at elevated risk for, cardiovascular disease, diabetes, or thrombotic events.
• NSAIDs should be avoided in patients with renal insufficiency.