THE RATIONALE USE OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) (ILORIN METROPOLIS AS A CASE STUDY)
CHAPTER ONE
1.1 INTRODUCTION
Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications used to relieve pain, fever and inflammation and they include a large group of anti-inflammatory agents that work by inhibiting the production of prostaglandins. Nonsteroidal anti-inflammatory drugs (NSAIDs) also represent diverse group of drug with analgesic property and most frequently prescribed drug globally. They represent the first choice of drug with well demonstrated efficiency for the pain management primarily musculoskeletal disorder and osteoarthritis to treat mild to moderate pain. Although its serious toxicity related to Gastro intestinal tract its choice in this category of its choice (Gul and Ayub, 2014).
There is overwhelming evidence linking chronic nonselective NSAID (including aspirin) use to a variety of Gastrointestinal (GI) tract injuries. Age is a significant risk factor for NSAID-induced GI events; indeed, patients above 75 years of age carry the highest risk and are similar in this respect to patients with a history of peptic ulcer (Beradi and Welage, 2005)
People desire to take responsibility for their own health care management. Many do so via self‑medication. Self‑medication is defined as the use of over‑the‑counter (OTC) drugs without consulting a professional health care practitioner. Self‑medication involves acquiring medication without a prescription, resubmitting an old prescription to procure medication, sharing medications with others, or utilizing a medication that is already available in the residence. Several governmental organizations developed policies to encourage self‑care for minor illnesses, reclassifying many drugs as nonprescription medications instead of prescription‑only medications, allowing the drugs to be administered by patients without a prescription. (Saeed et al, 2015) and could also be described as Medication that is taken on patient's own initiative or on advice of a pharmacist or lay person(Neha et al, 2013)
The terms ‘misuse’ and ‘abuse’ are often used interchangeably, but they have precise meanings in this context. Misuse is defined as using an OTC product for a legitimate medical reason but in higher doses or for a longer period than recommended. Abuse is the nonmedical use of OTC drugs(Gul and Ayub, 2015)
HISTORIC PERSPECTIVE OF NSAIDS
Aspirin and NSAIDs have a storied history in the treatment of pain and rheumatic diseases. In the 4th century B.C., Hippocrates detailed the use of powder made from the bark and leaves of the willow tree (Salixspp.) for headache, pain, and fever. Ancient Egyptians and Assyrians also used a willow extract to relieve the pain and erythema of inflamed joints( Apebum, 2002)
In 1828, Johann Buchner at the University of Munich extracted and purified salicin from willow, and three decades later, Charles Gerhardt succeeded in synthesizing a “buffered” form of salicylate to reduce dyspepsia, acetylsalicylic acid. This synthetic compound, containing no willow derivatives, was marketed by Felix Hoffmann of the Bayer company in 1899 as aspirin. The U.S. Food and Drug Administration (FDA) approved aspirin for the primary and secondary prevention of cardiovascular disease, and the secondary prevention of stroke and transient ischemic attacks, in 1988.
Additional NSAIDs were developed, such as phenylbutazone in 1949, indomethacin in 1963, and ibuprofen in 1969; however, the mechanism of action of these NSAIDs was unknown. In 1972, John R. Vane demonstrated that aspirin blocks the synthesis of a proinflammatory cytokine, prostaglandin E, for which he was granted the Nobel Prize in 1982 (Vane, 1971)
Prostaglandin synthase (COX), the enzyme inhibited by aspirin, which converts arachidonic acid to prostaglandins, was discovered in 1989, and was found to have two isoforms, COX-1 and COX-2; this discovery paved the way for the development of COX-2 selective inhibitors, which were hypothesized and later proven to have reduced GI toxicity.Babberdia,1999, Goldstain, 2001) .The first COX-2 selective inhibitor, celecoxib (Celebrex), approved by the FDA in 1998 based upon the results of five clinical trials involving more than 5000 patients with degenerative or rheumatoid arthritis, showed comparable analgesia and efficacy to nonselective NSAIDs and placebo with fewer clinical and endoscopic gastroduodenal ulcers.(Emery, 1999; silverstainn et al, 2000;Denson et al 1999; and Bonberdier et al 2000)
Two other COX-2 selective inhibitors, valdecoxib and rofecoxib, were subsequently approved; however, in the wake of concerns of an increased risk of thromboembolic events, and with valdecoxib an additional risk of Stevens–Johnson syndrome, both were withdrawn from the U.S. market in 2005(Bresalier et al, 2005; Solomon et al 2005). Celecoxib remains available for the treatment of pain associated with degenerative joint disease and rheumatoid arthritis, but as of April 2005 carries a “black box” warning alerting consumers to the increased cardiovascular risk associated with this medication.
Over the last few years, professional organizations, including the American College of Rheumatology, the American Pain Society (Emery et al 1999) , and the European League Against Rheumatism (Silverstein et al, 2000), have published treatment guidelines to assist clinicians in achieving effective pain management. Safety is a core concern in all these guidelines, especially for chronic conditions, such as OA, that require long-term treatment. Hence, there is a consensus among recommendations that paracetamol (acetaminophen) should be the first-line analgesic agent due to its favorable side effect and safety profile, despite several meta-analyses having shown that it is less effective in pain relief than anti-inflammatory drugs (Scarpignato et al, 2015).
Concerns have been raised regarding the safety of nonsteroidal antiinflammatory drugs (NSAIDs), which havebeen linked to increased cardiovascular morbidity. This association was first established in large clinical trials investigating the effect of selective cyclooxygenase-2 (COX-2) inhibitors on preventing gastrointestinal ulcers and gastrointestinal polyps. Later, these results have been confirmed in several large-scale observational studies(FitzGerald, 2003).
Pharmacists are usually the custodian of drugs and are charged with the responsibilities of delivering safe and efficacious medicines to the public (Owusu-Ansah, 2009) . In developing countries, traders perceive drugs as items of trade. In Nigeria, a country where the ratio of pharmacist to non-pharmacist in an urban environment and commercial centre, like Lagos is approximately 1:3, NSAIDs are sold or ingested without the required level of caution. These unregistered drug outlets, usually manned by traders, are located virtually in every street of urban centers in Nigeria.
Evaluation of drug use revealed that there was a great deal of drug misuse ranging from sub – therapeutic dosing, wrong indication and irrational combination of drugs, even in high doses (Awofisayo et al, 2008)
DEFINITION
One of the conditions that necessitate the use of NSAIDs is pain. Pain is an unpleasant, subjective sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.
Greater understanding of pain mechanisms and growing appreciation for pain control have, however, caused rheumatologists to consider new approaches in pain management.. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Both selective and nonselective cyclooxygenase (COX) inhibitors have antipyretic, anti-inflammatory and analgesic effects and are widely used in treating many painful conditions, including rheumatic diseases. NSAIDs are effective and widely available in over-the-counter formulations and in prescription products. Examples include ibuprofen, naproxen, diclofenac, and celecoxib. NSAIDs are frequently used without considering the relative contraindications since most NSAIDs are sold over the counter. Conventional NSAIDs are associated with gastrointestinal (GI) side effects. Estimates of the number of deaths from NSAID-related gastrointestinal bleeding vary widely and figures of approx. 3500 to 16.500 per year are quoted for the US in a recent FDA report. Both conventional NSAIDs and COX-2 inhibitors are associated with increased cardiovascular risk. NSAIDs may increase blood pressure, particularly in hypertensive patients. Of all NSAIDs, naproxen seems to pose the least cardiovascular risk, although naproxen is associated with the same risk for myocardial infarction as other NSAIDs. Contrary to some clinical assumptions, gastrointestinal risk is present at first dose with a non-selective NSAID, and co-therapy with a proton pump inhibitor (PPI) does not guarantee complete protection(Well et al, 2006)
Pain could be classified into two main groups: NOCICEPTIVE PAIN and NEUROPATHIC PAIN
THE NOCICEPTIVE PAIN
Nociceptive (acute) pain is either somatic (arising from skin, bone, joint, muscle, or connective tissue) or visceral (arising from internal organs such as the large intestine or pancreas).
Stimulation of free nerve endings known as nociceptors is the first step leading to the sensation of pain. These receptors are found in both somatic and visceral structures and are activated by mechanical, thermal, and chemical impulses. Release of bradykinins, K+, prostaglandins, histamine, leukotrienes, serotonin, and substance P may sensitize and/or activate nociceptors. Receptor activation leads to action potentials that are transmitted along afferent nerve fibers to the spinal cord.
Action potentials continue from the site of noxious stimuli to the dorsal horn of the spinal cord and then ascend to higher centers. The thalamus acts as a relay station and passes the impulses to central structures where pain is processed further.
The body modulates pain through several processes. The endogenous opiate system consists of neurotransmitters (e.g., enkephalins, dynorphins, and beta-endorphins) and receptors that are found throughout the central nervous system (CNS). Endogenous opioids bind to opioid receptors and inhibit the transmission of pain impulses.
The CNS also contains a descending system for control of pain transmission. This system originates in the brain and can inhibit synaptic pain transmission at the dorsal horn. Important neurotransmitters here include endogenous opioids, serotonin, norepinephrine, gama-aminobutyric acid (GABA), and neurotensin.
NEUROPATHIC PAIN
Neuropathic (chronic) pain is sustained by abnormal processing of sensory input by the peripheral or central nervous system. There are a large number of neuropathic pain syndromes that are often difficult to treat (e.g., low back pain, diabetic neuropathy, postherpetic neuralgia, cancer-related pain, spinal cord injury). Nerve damage or persistent stimulation may cause pain circuits to produce spontaneous nerve stimulation, autonomic neuronal pain stimulation, and a progressive increase in discharge of dorsal horn neurons.
The inflammatory process is the response to an injurious stimulus. It can be evoked by a wide variety of noxious agents (e.g., infections, antibodies, or physical injuries). The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury; in some situations and diseases, the inflammatory response may be exaggerated and sustained without apparent benefit and even with severe adverse consequences. No matter what the initiating stimulus, the classic inflammatory response includes calor (warmth), dolor (pain), rubor (redness), and tumor (swelling).
Inflammatory responses occur in three distinct temporal phases, each apparently mediated by different mechanisms:
(1) An acute phase characterized by transient local vasodilation and increased capillary permeability;
(2) A delayed, subacute phase characterized by infiltration of leukocytes and phagocytic cells; and
(3) A chronic proliferative phase, in which tissue degeneration and fibrosis occur.
Many mechanisms are involved in the promotion and resolution of the inflammatory process. Although earlier studies emphasized the promotion of migration of cells out of the microvasculature, recent work has focused on adhesive interactions, including the E-, P-, and L-selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and leukocyte integrins, in the adhesion of leukocytes and platelets to endothelium at sites of inflammation.
Activated endothelial cells play a key role in "targeting" circulating cells to inflammatory sites. Expression of the adhesion molecules varies among cell types involved in the inflammatory response. Cell adhesion occurs by recognition of cell-surface glycoproteins and carbohydrates on circulating cells due to the augmented expression of adhesion molecules on resident cells. Thus, endothelial activation results in leukocyte adhesion as the leukocytes recognize newly expressed L-selectin and P-selectin; other important interactions include those of endothelial-expressed E-selectin with sialylated Lewis X and other glycoproteins on the leukocyte surface and endothelial ICAM-1 with leukocyte integrins. It has been proposed that some, but not all, NSAIDs may interfere with adhesion by inhibiting expression or activity of certain of these cell-adhesion molecules . Novel classes of antiinflammatory drugs directed against cell-adhesion molecules are under active development but have not yet entered the clinical arena.
In addition to the cell-adhesion molecules outlined above, the recruitment of inflammatory cells to sites of injury involves the concerted interactions of several types of soluble mediators. These include the complement factor C5a, platelet-activating factor, and the eicosanoid LTB4. All can act as chemotactic agonists. Several cytokines also play essential roles in orchestrating the inflammatory process, especially interleukin-1 (IL-1) and tumor necrosis factor (TNF) (Dempsey et al., 2003). IL-1 and TNF are considered principal mediators of the biological responses to bacterial lipopolysaccharide (LPS, also called endotoxin). They are secreted by monocytes and macrophages, adipocytes, and other cells. Working in concert with each other and various cytokines and growth factors (including IL-8 and granulocyte-macrophage colony-stimulating factor, they induce gene expression and protein synthesis in a variety of cells to mediate and promote inflammation.
IL-1 comprises two distinct polypeptides (IL-1a and IL-1b) that bind to the same cell-surface receptors and produce similar biological responses. Plasma IL-1 levels are increased in patients with active inflammation. IL-1 can bind to two types of receptors, an 80-kd IL-1 receptor type 1 and a 68-kd IL-1 receptor type 2, which are present on different cell types.
TNF, originally termed "cachectin" because of its ability to produce a wasting syndrome, is composed of two closely related proteins: mature TNF (TNF-a) and lymphotoxin (TNF-b), both of which are recognized by the same cell-surface receptors. There are two types of TNF receptors, a 75-kd type 1 receptor and a 55-kd type 2 receptor. IL-1 and TNF produce many of the same proinflammatory responses.
A naturally occurring IL-1 receptor antagonist (IL-1ra), competes with IL-1 for receptor binding, blocks IL-1 activity in vitro and in vivo, and in experimental animals can prevent death induced by administration of bacteria or LPS. IL-1ra often is found in high levels in patients with various infections or inflammatory conditions. Thus, the balance between IL-1 and IL-1ra may contribute to the extent of an inflammatory response. Preliminary studies suggest that the administration of IL-1ra (designated anakinra)¾by blocking IL-1 action on its receptor¾may be beneficial in rheumatoid arthritis and other inflammatory conditions(Louie et al., 2003; Olson and Stein, 2004).
Other cytokines and growth factors [e.g., IL-2, IL-6, IL-8, and granulocyte/macrophage colony stimulating factor (GM-CSF)] contribute to manifestations of the inflammatory response. The concentrations of many of these factors are increased in the synovia of patients with inflammatory arthritis. Certain relevant peptides, such as substance P, which promotes firing of pain fibers, also are elevated and act in concert with cytokines at the site of inflammation. Other cytokines and growth factors counter the effects and initiate resolution of inflammation. These include transforming growth factor-b1 (TGF-b1), which increases extracellular matrix formation and acts as an immunosuppressant, IL-10, which decreases cytokine and prostaglandin E2 formation by inhibiting monocytes, and interferon gamma, IFN-g, which possesses myelosuppressive activity and inhibits collagen synthesis and collagenase production by macrophages.
Histamine was one of the first identified mediators of the inflammatory process. Although several H1 histamine-receptor antagonists are available, they are useful only for the treatment of vascular events in the early transient phase of inflammation. Bradykinin and 5-hydroxytryptamine (serotonin, 5-HT) also may play a role in mediating inflammation, but their antagonists ameliorate only certain types of inflammatory response. Leukotriene (LT)-receptor antagonists (montelukast and zafirlukast) exert antiinflammatory actions and have been approved for the treatment of asthma. Another lipid autacoid, platelet-activating factor (PAF), has been implicated as an important mediator of inflammation; however, inhibitors of PAF synthesis and PAF-receptor antagonists have proven disappointing in the treatment of inflammation.
Intradermal, intravenous, or intra-arterial injections of small amounts of prostaglandins mimic many components of inflammation. Administration of prostaglandin E2 (PGE2) or prostacyclin (PGI2) causes erythema and an increase in local blood flow. Such effects may persist for up to 10 hours with PGE2 and include the capacity to counteract the vasoconstrictor effects of substances such as norepinephrine and angiotensin II, properties not generally shared by other inflammatory mediators. In contrast to their long-lasting effects on cutaneous vessels and superficial veins, prostaglandin-induced vasodilation in other vascular beds vanishes within a few minutes.
Although PGE1 and PGE2 (but not PGF2a) cause edema when injected into the hind paw of rats, it is not clear if they can increase vascular permeability in the postcapillary and collecting venules without the participation of other inflammatory mediators (e.g., bradykinin, histamine, and leukotriene C4 [LTC4]). Furthermore, PGE1 is not produced in significant quantities in humans in vivo, except under rare circumstances such as essential fatty acid deficiency. Unlike LTs, prostaglandins are unlikely to be involved in chemotactic responses, even though they may promote the migration of leukocytes into an inflamed area by increasing blood flow.
Rheumatoid Arthritis. Although the detailed pathogenesis of rheumatoid arthritis is largely unknown, it appears to be an autoimmune disease driven primarily by activated T cells, giving rise to T cell-derived cytokines, such as IL-1 and TNF-a. Activation of B cells and the humoral response also are evident, although most of the antibodies generated are IgGs of unknown specificity, apparently elicited by polyclonal activation of B cells rather than from a response to a specific antigen.
Many cytokines, including IL-1 and TNF-a, have been found in the rheumatoid synovium. Glucocorticoids interfere with the synthesis and actions of cytokines, such as IL-1 or TNF-a . Although some of the actions of these cytokines are accompanied by the release of prostaglandins and thromboxane A2 (TXA2), COX inhibitors appear to block only their pyrogenic effects. In addition, many of the actions of the prostaglandins are inhibitory to the immune response, including suppression of the function of helper T cells and B cells and inhibition of the production of IL-1. Thus, it has been suggested that COX-independent effects may contribute to the efficacy of NSAIDs in this setting. Besides an impact on adhesive interactions, salicylate and certain NSAIDs can directly inhibit the activation and function of neutrophils, perhaps by blockade of integrin-mediated neutrophil responses by inhibiting downstream Erk signaling.
The availability of a wide variety of drugs coupled with easy access and lack of effective regulatory control has led to problems associated with drug use like self-medication, drug misuse and drug abuse (Amoako et al 2003). Self medication: defined as the act of taking medicines or medical devices especially designed and labeled for use in the treatment of common health problems without the authority or prescription of a physician (Lawan et al, 2013). Drug abuse is the recurrent use of illegal drugs, or the misuse of prescription or over-the-counter drugs with negative consequences. Hence, drug misuse is an aspect of drug abuse. This practice cuts across all age groups, gender, educational backgrounds, marital status, employment and occupation. Pattern of drug misuse varies from place to place and it is known to be affected by socio-economic factors (Kehinde and Ogunnowo, 2013).
Self-medication is the act of taking medicines or medical devices especially designed and labeled for use in the treatment of common health problems without the authority or prescription of a physician and it is one of the rapidly growing areas of concern to medical professionals, government and the general public (Lawan et al, 2013).
There is overwhelming evidence linking chronic nonselective NSAID (including aspirin) use to a variety of Gastrointestinal (GI) tract injuries. Age is a significant risk factor for NSAID-induced GI events; indeed, patients above 75 years of age carry the highest risk and are similar in this respect to patients with a history of peptic ulcer (Berardi and Welage, 2005).
NSAIDs rank second to aminoglycosides as the most common cause of drug induced renal failure (ARF) and also known to cause acute interstitial nephritis with haematuria, proteinuria and flank pain (Welton, 1999).
In a study carried out in Ghana, about 40% of prescribed analgesics were NSAIDs and diclofenac was the most widely prescribed (Owusu-Ansah, 2009).
Aspirin remains the most commonly prescribed NSAIDs in cardiovascular diseases like hypertension and ischemic heart disease where it is used as antiplatelet agent(Aguw and Adibe, 2012).
Exposure of pregnant women to any type of NSAIDs during early pregnancy predispose them to spontaneous abortion (Li et al, 2003)
A high proportion of chronic urticarial patients experience symptom aggravation when exposed to aspirin and NSAIDs known as Aspirin-exacerbated cutaneous disease (Sánchez-Borges, 2013)
MECHANISM OF ACTION OF NSAIDs
Salicylic acid and salicylates, obtained from natural sources, have long been used as medicaments. Salicylic acid was chemically synthesized in 1860 and was used as an antiseptic, an antipyretic, and an antirheumatic. Almost 40 years later, aspirin was developed as a more palatable form of salicylate. Soon after, other drugs having similar actions to aspirin were discovered, and the group was termed the "aspirin-like drugs" (also now termed the nonsteroidal anti-inflammatory drugs [NSAIDs]). Twenty-five years ago, it was proposed that the mechanism of action of NSAIDs was through their inhibition of prostaglandin biosynthesis. Since then, there has been general acceptance of the concept that these drugs work by inhibition of the enzyme cyclo-oxygenase (COX), which we now know to have at least two distinct isoforms: the constitutive isoform, COX-1, and the inducible isoform, COX-2. COX-1 has clear physiologic functions. Its activation leads, for instance, to the production of prostacyclin, which when released by the endothelium is antithrombogenic and when released by the gastric mucosa is cytoprotective. COX-2, discovered 6 years ago, is induced by inflammatory stimuli and cytokines in migratory and other cells. It is therefore attractive to suggest that the anti-inflammatory actions of NSAIDs are due to inhibition of COX-2, whereas the unwanted side-effects, such as irritation of the stomach lining, are due to inhibition of COX-1. Drugs that have the highest COX-2 activity and a more favorable COX-2: COX-1 activity ratio will have a potent anti-inflammatory activity with fewer side-effects than drugs with a less favorable COX-2.(Vane and Botting, 1998)
All NSAIDs, including the subclass of selective COX-2 inhibitors, are antiinflammatory, analgesic, and antipyretic. NSAIDs are a chemically heterogeneous group of compounds, often chemically unrelated (although most of them are organic acids), which nevertheless share certain therapeutic actions and adverse effects. Aspirin also inhibits the COX enzymes but in a manner molecularly distinct from the competitive, reversible, active site inhibitors and is often distinguished from the NSAIDs (Brunton et al, 2008).
Aspirin covalently modifies COX-1 and COX-2, irreversibly inhibiting cyclooxygenase activity. This is an important distinction from all the NSAIDs because the duration of aspirin's effects is related to the turnover rate of cyclooxygenases in different target tissues. The duration of effect of nonaspirin NSAIDs, which competitively inhibit the active sites of the COX enzymes, relates more directly to the time course of drug disposition. The importance of enzyme turnover in relief from aspirin action is most notable in platelets, which, being anucleate, have a markedly limited capacity for protein synthesis. Thus, the consequences of inhibition of platelet COX-1 (COX-2 is expressed only in megakaryocytes) last for the lifetime of the platelet. Inhibition of platelet COX-1-dependent TXA2 formation therefore is cumulative with repeated doses of aspirin (at least as low as 30 mg/day) and takes roughly 8 to 12 days¾the platelet turnover time to recover once therapy has been stopped(Brunton et al, 2008).
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