Drugs for inflammation

A. Introduction

• The first line of defense in the body are physical, mechanical, and biochemical barriers.

• Physical barriers include: the tightly associated epithelial cells of skin, GI, genitourinary and respiratory tracts

• Mechanical barriers involve the clearance of pathogens that are sloughed off with dead skin cells,

•

• expelled by coughing or sneezing,

• vomited from the stomach,

• and flushed from urinary tract in urine.

• Biochemical barriers include mucus, perspiration, saliva,

• tears, earwax.

• They all trap potential invaders and contain substances that kill microorganisms

The second line of defense is the inflammatory response.

• There is a large, unrelated group of disorders where abnormalities associated with inflammation are manifested:

• asthma

• systemic lupus erythematosus (SLE)

• glomerulonephritis

• inflammatory bowel disease (IBD)

• vasculitis

• rheumatoid arthritis

• osteoarthritis

B. Response to biochemical mediaors

• There are many different types of cells involved in the inflammatory response: lymphocytes (natural killer cells), monocytes, (macrophages), basophils, neutrophils, eosinophils, and mast cells

• mast cells

• These cells both respond to and secrete biochemical mediators

• Most of these cells are recruited and activated by products of the activation of the plasma protein systems and by biochemicals (released during cell destruction, or produced by microbes)

• The plasma protein systems include the complement system,

• the clotting system,

• and the kinin system

• Cells involved in the inflammatory response secrete biochemical mediators responsible for the vascular changes associated with inflammation and for modulating the activities of other inflammatory cells

• The mediators released include histamine and the prostaglandins.

• These mediators often cause inappropriate or exaggerated inflammatory processes that have detrimental effects.

• Even appropriate inflammation can be painful and harm healthy tissues.

• In such cases, the defense reactions themselves may cause progressive tissue injury

C. Prostaglandins

• Prostaglandins are lipid based substances synthesized from arachidonic acid.

• The source of arachidonic acid are phospholipid molecules imbedded within cell membranes.

• The enzyme phospholipase A2 (PLA2) releases arachidonic acid from the phospholipid.

• Arachidonic acid is converted, by way of the cyclooxygenase enzymes to various families of prostaglandins (i.e. PGD, PGE, PGF, PGI)

• There are 2 major versions of the cyclooxygenase enzyme:

• cyclooxygenase-1 (COX-1)

• cyclooxygenase-2 (COX-2)

• COX-1 is found in all cells, especially in platelets, the kidneys, and the GI tract and plays a role in maintaining homeostasis in these cells.

• COX-2 appears to be manufactured in activated macrophages (in response to injury or damage to local tissues).

2. Functions of prostaglandins

• Prostaglandins coordinate both physiologic and pathologic processes, either in the cells in which they are formed or in closely adjacent cells.

• Prostaglandins are the major lipid molecule involved in the inflammatory response.

• They act like hormones in many ways, except that their range is limited to the cells where they are made, or in nearby cells.

• They are deactivated too easily to be transported very far in the body.

• Under normal physiologic conditions, they have essential homeostatic functions in the cytoprotection of gastric mucosa, renal physiology, and gestation.

• PGI2 (also known as prostacyclin) is produced by the action of one of the cyclooxygenase enzymes, COX-1, which is ubiquitous throughout the human gastrointestinal tract.

• Prostacyclin decreases the secretion of hydrochloric acid from parietal cells, and increases the secretion of mucous.

• Therefore, it has protective effects on the gastrointestinal mucosa.

• Prostaglandins are also implicated in a number of pathological conditions where inflammation is a component of the disease.

• PGD2 is detected in high concentrations in the airways of asthmatic patients.

• PGE2 is involved in the pathology of rheumatoid arthritis.

• The high levels of prostaglandins found in inflammation are presumed to be due to the induction of the COX-2 enzyme.

• In these situations, inflammation itself becomes a disease process and requires treatment with anti-inflammatory drugs, which interrupt the inflammatory response.

D. Antiinflammatory drugs

• 1. Corticosteroids

• a. introduction

• Corticosteroids are also called glucocorticoids. They are the very potent anti-inflammatory agents.

• They function by inhibiting the enzyme phospholipase A2.

• Phospholipase A2 is needed to release arachidonic acid from phospholipid molecules.

• If arachidonic acid is not released from phospholipid molecules, then the entire cascade leading to prostaglandin synthesis is inhibited.

• Corticosteroids are approved by the FDA for use in a wide range of inflammatory disorders where a degenerative process is out of control:

• rheumatoid arthritis

• osteoarthritis

• ulcerative colitis and Crohn’s disease (will be discussed under Drugs for GI disorders)

• severe allergic reactions and asthma (will be discussed under Drugs for respiratory disease)

• In addition, there are other uses that are medically appropriate, although not specifically approved by the FDA (off-label use).

• Such inflammatory conditions include:

• acute mountain sickness

• COPD

• respiratory distress syndrome

• bacterial meningitis

• septic shock

b. Corticosteroids administered topically

• Corticosteroids administered topically for the treatment of inflammation and pruritis (itching) due to eczema, insect bites, poison ivy, detergents, and cosmetics include:

• hydrocortisone (Bactine, Cortaid, Cortizone, Dermacort, Lanacort)

c. Corticosteroids administered systemically in the treatment of

SLE• SLE is a chronic inflammatory disease

characterized by the production of autoantibodies against RBC’s, platelets, and other cellular components.

• This results in the formation of immune complexes which circulate and are deposited in the heart, spleen, lungs, GI tract, skin and the kidneys.

• Symptoms of SLE include: fever, weight loss, hair loss, mouth and nose sores, malaise, and fatigue.

• Ninety percent of patients experience joint inflammation similar to rheumatoid arthritis.

• As there is an increased incidence of SLE in twins, it is believed that there is a genetic predisposition for the disease.

• In these genetically susceptible individuals, some environmental factor (UV light, virus) may trigger the onset or recurrences of the disease.

• There is no cure for SLE, therefore treatment goals involve relieving symptoms by reducing inflammation (and autoimmune activity).

• Oral corticosteroids used here include:

• a. prednisone (Deltasone)

• b. betamethasone (Celestone)

• c. methylprednisolone (Medrol, Depo-Medrol)

d. Corticosteroids administered systemically in the treatment of

glomerulonephritis• Glomerulonephritis is an inflammation of

the capillary loops of the glomerulus.

• It generally has a sudden onset, lasts a short time, and proceeds to either complete recovery or end stage renal disease.

• It most commonly presents after a streptococcal infection.

• Vasculitis, SRE, and hereditary nephritis are other causes.

• Prednisone is the drug of choice for treating this disease (and possibly immune suppressing drugs if vasculitis or SRE are the cause).

e. Corticosteroids administered systemically in the treatment of

rheumatoid arthritis• Rheumatoid arthritis (RA) is less common

but generally more severe than osteoarthritis (OA).

• It differs from OA in that it is a systemic autoimmune disorder which results in symmetrical joint inflammation.

• It affects cartilage, bone, tendon, ligament and synovial membranes that line joint surfaces, especially the small joints of the hand and feet.

• It is almost three times more prevalent in women than in men, with peak onset between 20 and 45 years of age.

• The etiology of RA is not known. Some researchers have postulated a viral trigger.

• Others, Mikuls et. al., 2002 have linked decaffeinated coffee intake with RA onset, in a prospective study of over 31,000 women aged 55-69 years of age.

• Symptoms of RA include pain, inflammation, stiffness, and swelling (from the accumulation of synovial fluid).

• Anemia and the appearance of an abnormal circulating protein, RF (rheumatoid factor) may precede the appearance of symptoms.

• Medical management of RA includes salicylates or NSAIDs, immunosuppresive agents and the corticosteroid prednisone.

• Corticosteroids decrease inflammation more rapidly and to a greater degree than other drugs.

• However, they do not prevent joint destruction, and their clinical benefit often diminishes with time.

• Because of their long-term adverse effects, many doctors recommend that corticosteroids be given to maintain function only until another DMARD (Disease-modifying antirheumatic drug, i.e. methotrexate) has taken effect.

• If systemic steroids have been prescribed for one month or less, the following side effects may arise:

• Weight gain

• increased appetite

• Sleep disturbance

• Almost everyone on systemic steroids for more than a month suffers from some adverse effects. These may include any of the following:

• Osteoporosis, particularly in smokers, postmenopausal women, the elderly, those who are underweight or immobile, and patients with diabetes or lung problems.

• Precipitation or aggravation of diabetes mellitus

• Increase in circulating triglycerides

• Redistribution of body fat: moon face, buffalo hump and truncal obesity.

• Salt retention: leg swelling, raised blood pressure, weight increase and heart failure.

• Psychological effects including insomnia, mood changes, increased energy, excitement, delirium or depression.

• Skin problems such as thinning and acne

f. Corticosteroids administered by injection in the treatment of

osteoarthritis• The most common form of arthritis,

osteoarthritis occurs when cartilage in various joints wears down over time.

• It most commonly affects joints in your hands, hips, knees and spine.

• Disks narrow and spurs form. Where bone surfaces (facets) rub together, cartilage becomes worn and may be painful.

• Hip joint on the left is normal, but the hip joint shown on the right shows deterioration of cartilage due to osteoarthritis.

• It isn't always clear what causes osteoarthritis. Many researchers suspect a combination of factors:

• being overweight

• the aging process

• joint injury or stress

• heredity

• The relief of localized inflammation in a particular body area is more rapid and powerful with corticosteroid injections than with traditional anti-inflammatory medications given by mouth (i.e. aspirin).

• A single injection also can avoid certain side effects, notably irritation of the stomach, that accompany many oral anti-inflammatory medications.

• However, in persons who have diabetes, corticosteroid injections can elevate the blood sugar.

• In addition, in patients with underlying infections, cortisone injections can:

• suppress somewhat the body's ability to fight the infection

• possibly worsen the infection

• mask the infection by suppressing the symptoms and signs of inflammation.

• Generally, corticosteroid injections are used with caution in persons with diabetes and avoided in persons with active infections.

• Injection corticosteroid drugs include:

• Betamethasone (Celestone)

• Dexamethasone (Decadron)

• Methylprednisolone (Medrol)

• Triamcinolone (Kenacort, Kenalog)

• Many physicians prefer a one, long-acting injection of methylprednisolone

Others prefer a “cocktail” of lidocaine,

triamcinolone (intermediate acting), and

dexamethasone (long acting)

2. Nonsteroidal antiinflammatory drugs (NSAIDs)

• a. Introduction

• NSAIDs ease the symptoms associated with inflammation because they inhibit prostaglandin synthesis.

• In particular, the NSAIDs ability to inhibit cyclooxygenase (COX) enzymes has been a focus of drug development.

• Nonselective COX inhibitors block both COX-1 and COX-2 enzymes from producing prostaglandins.

• When COX-1 is blocked, prostacyclin is not synthesized and the protective environment within the stomach is altered, leading to dyspepsia, heartburn and GI bleeding.

• To develop better NSAIDs that relieve pain and inflammation but do not cause gastric problems, drugs were designed that selectively interacted only with COX-2. They are called selective COX-2 inhibitors.

• The 3-dimensional structure of the COX enzymes are strikingly similar to each other

• However, slight amino acid differences in COX-2 result in a "side pocket" that allows COX-2 inhibitors to bind, and block the “active site” of the COX-2 enzyme.

• The arachadonic acid cannot reach the active site, and prostaglandin synthesis is prevented.

• NSAIDs are approved for the relief of mild to moderate pain where opioids are not indicated or warranted, including pain arising from local inflammation.

• Indications for NSAIDs include:• headache• dental extraction• soft tissue injury• musculoskeletal/joint overexertion and

strain• dysmenorrhea• osteo and rheumatoid arthritis

b. NSAIDs:Salicylates (acetylated and nonacetylated)

• Salicylates are indicated for rheumatoid arthritis, osteoarthritis, mild to moderate pain, and fever.

• Adverse effects of salicylates include GI disturbances: dyspepsia, heartburn, bleeding, ulceration.

• All salicylates are nonselective COX inhibitors and include:

• aspirin (ASA, Bayer, Ecotrin, Empirin, Norwich) which is acetylated

• choline salicylate (Arthropan) which is nonacetylated

• magnesium salicylate (Doan’s pills) which is nonacetylated

• sodium salicylate, salicylsalicylate, or salsalate (Disalcid) which is nonacetylated

• Aspirin has been largely replaced by ibuprofen and naproxen as an anti-inflammatory medication, largely due to the 1200-1500 mg three times a day recommended anti-inflammatory dosage.

• However, acetylated salicylates like aspirin have an additional benefit: they inhibit platelet aggregation.

• Nonacetylated salicylates inhibit COX, but less effectively than aspirin. They do NOT inhibit platelet aggregation.

• On the up side, they don’t cause as much GI distress as aspirin. However, these agents are not always readily available due to a lack of marketing.

c. NSAIDs: Propionic acid derivatives

• The propionic acid derivative NSAIDs are indicated for inflammatory disorders including rheumatoid arthritis and osteoarthritis; as well as for the treatment of dysmenorrhea

•

• Dysmenorrhea is characterized by uterine contractions, local vasoconstriction and pain.

• Evidence suggests that women who suffer the discomfort of dysmenorrhea may have higher levels of the uterine prostaglandins PGF2α and PGE2

• Whereas aspirin primarily affects the COX enzymes, the propionic acid derivatives affect the enzyme prostaglandin synthetase, and suppress the release of uterine PGF2α and PGE2

• Adverse effects of the propionic acid derivative NSAIDs include GI disturbances:

• dyspepsia, constipation, flatulence, GI bleeding

• All propionic acid derivatives are nonselective COX inhibitors and include:

• Ibuprofen (Advil, Motrin, Excedrin IB, Nuprin): PO 200-400 mg every 6 hours up to a usual maximum daily dose of 800-1200 mgfor an analgesic effect. PO 600 every 6 hours for an antiinflammatory effect.

• With ibuprofen there is GI irritation and bleeding, but this is less frequent than with aspirin.

• Concomitant use of ibuprofen with aspirin has been found to: decrease the total antiinflammatory effect, counteract the inhibition of platelets induced by aspirin, and therefore limit the cardioprotective effects of aspirin.

• ketoprofen (Orudis): PO 70 mg three times a day

• naproxen (Aleve): PO 375 bid

• Interestingly, naproxen’s free fraction (that not bound to albumin) is significantly higher in women than in men. There is however, a much greater incidence of GI bleeding in naproxen compared to ibuprofen.

d. NSAIDs: COX-2 selective inhibitors

• These are specific inhibitors of the COX-2

enzyme, and their development allowed the circumvention of the negative GI effects associated with the classical COX inhibitors, while still reducing inflammation.

• COX-2 inhibitor drugs include:

• Celebrex (Celecoxib) 100 – 200 mg bid with a ½ life of 11 hours (compare to aspirins ½ life of 15 minutes). Celebrex is as effective as the other NSAIDs in treating both RA and OA.

• Clinical trials have reported fewer ulcers with Celebrex compared to other NSAIDs. Celebrex does not aggregate platelets. Both edema and HT have been reported, but no more than with other NSAIDs. Celebrex may cause rashes (possibly because it is a sulfonamide).

• In July of 2005, the FDA had Pfizer add a "black box”.

• This is the most severe type of warning, and reflects the risk of heart attacks, strokes and gastrointestinal bleeding.

• Vioxx (Rofecoxib) (No longer on market as of September 2004)

• Bextra (Valdecoxib) (No longer on market as of April 2005)

• Celebrex (Pfizer) and Vioxx (Merck) were introduced in 1999 and rapidly became the most frequently prescribed new drugs in the United States.

• Sales of Celebrex reached $3.1 billion in 2001.

• Bextra received FDA approval in 2001

• There was widespread acceptance of Celebrex and Vioxx by physicians due to the publication of two large trials in JAMA, the Celecoxib Long-term Arthritis Safety Study (CLASS) study, and the Vioxx Gastrointestinal Outcomes Research (VIGOR) study.

• Both publications concluded that COX-II specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects.

• However, when the FDA later presented more complete data from the CLASS and VIGOR trials, the results were less certain.

• The CLASS trial omitted data from months 12 and 15. In these time segments of the trial the number of ulcer-related complications for Celebrex caught up to the control NSAID.

• In a similar manner, when the complete VIGOR study data was revealed, and all adverse events, not just gastrointestinal, were evaluated, the patients receiving VIOXX reported a significantly higher incidence of adverse events overall than the control NSAID group.

• The risk of MI, in particular, was greater in the VIOXX patients versus the NSAID control group. In addition, there were more withdrawals in the Vioxx group compared to the NSAID group due to HT, liver problems, edema, and heart failure.

• VIOXX was pulled off the market by Merck in September 2004. Since then, thousands of lawsuits have been filed against Merck.

• The FDA asked Pfizer to take Bextra off the market in April of 2005.

• Prexige (Lumiracoxib) had been approved in the United Kingdom and was slated for approval in the United States in 2007.

• November 2007: Prexige tablets have been withdrawn from the UK market following reports of suspected adverse liver reactions.

• Arcoxia (Etoricoxib) from Merck & Co. Currently is approved in more than 60 countries worldwide but not in the US, where the (FDA) has required additional safety and efficacy data before it will issue approval

• In April 2007, by a vote 20 to one, FDA advisers recommended against approval of Merck's Cox-2 inhibitor etoricoxib (Arcoxia).

• The FDA's Arthritis Drugs Advisory Committee declared that the cardiovascular risks of the drug outweigh its benefits for easing arthritis pain.