NSAIDs

Dr Niyazi Burhan Aldin PhD Clinical Pharmacy

Inflammation The classical signs of inflammation are redness, swelling, heat, pain & loss of function. The actual expression of these processes depend on the site of inflammation for e.g skin abscess may result in the appearance of all of these features. In contrast, pneumonia, bec. of inaccessibility of the lung to examination, may manifest only as loss of function [ shortness of breath & hypoxia ].Inflammation is characterized by the occurrence of several processes.Initiation of the event by a foreign subs. or physical injury, recruitment & chemoattraction of inflammatory mediators capable of damaging or killing an invading microbe or tumor.Inflammation can also result from an auto-immune response to the host’s own tissue, as occurs in rheumatoid arthritis.


Chemical mediators Are compounds released by one cell type that attach to the receptor of a second cell type to affect the response by that second cell The chemicals originate primarily from blood plasma, white blood cells (basophils, neutrophils, monocytes, and macrophages), platelets, mast cells, endothelial cells lining the blood vessels, and damaged tissue cell Examples: Histamine- increases vascular permeability, increases blood flow to injured area Leukotrienes and prostaglandins- pain response, vascular permeability, and chemotaxis.


Mechanism of action The antiinflammatory actions of the NSAIDs are most likely explained by their inhibition of PG syn. by COX2 .The COX2 isoform is the predominant COX involved in production of PGs during inflammatory processes .PGs of the E & F series evoke some of the local & systemic manifestation of inflammation, such as vasodilation, increased vascular permeability, swelling, pain, & increased leukocyte migration. They intensify the effect of inflammatory mediators such as histamine, bradykinin, & 5HTAll NSAIDs [except the COX2 – selective agents] inhibit both Cox isoform & the degree of inhibition of COX1 varies from drug to drug.

Functions of Cox

Cox-1 Constitutive: housekeeping functions present in every organ stomach, intestine, kidney platelets, vascular endothelium
Cox-2 Induced: inflammatory and neoplastic sites also present in kidney, uterus, ovary brain, small intestine

Treatment of inflammation 1-Relief the pain which is the main symptoms. 2-Slow or arresting of the tissue – damaging process. So antiinflammatory drugs are divided into :- 1- NSAIDs which have an antiinflammatory, analgesic & antipyretic effects & useful for treatment of both acute & chronic inflammation. 2- Steroids which have a powerful antiinflammatory effect but long or chronic use of steroid associated with many side effects or toxic effects. 3- Disease – modifying anti rheumatic drugs (DMARDs)They slow the bone damage associated with the rhumatoid arithritis & they are more toxic than NSAIDS.

NSAIDs - Most frequently prescribed and frequently used OTC drug -Weak acids, PH 3-5, well absorbed from stomach and intestinal mucosa -Protein-bound in plasma ( albumin), metabolised in the liver -Have a variety of clinical uses as antipyretic, analgesic, & antiinflammatory effect. -They reduce body temp. in febrile states & thus are effective as antipyretics. -They are useful as analgesic, relieving mild to moderate pain such as myalgia, dental pain, dysmenorrhea & headache. -They are also used to treat the chronic pain & inflammation such as rhumatoid arithritis, osteoartritis & ankylosing spondylitis.


NSAIDs inhibits: Cyclooxygenase enzymes Lipoxygenase enzymes Superoxide generation Lysosomal enzyme release Neutrophil activity Lymphocyte function Cytokine release Cartilage metabolism

Pharmacokinetics Absorption All NSAIDs are absorbed rapidly from the gastrointestinal tract, and thus almost all NSAIDs are available as oral preparations, some of them effective parentally. Gastrointestinal upset can occur, so it should be taken with food or milk, or at least a glass of water Enteric-coated aspirin can reduce stomach upset but it delays absorption Distribution NSAIDs distribute into the central nervous system, in breast milk, and across the placenta Extensively bound to plasma protein (especially some COX-2 inhibitors) Ibuprofen, fenoprofen, naproxen, and tolmetin are 99% bound to plasma protein. Metabolism and Excretion Metabolized by the liver and excreted through urine


Adverse effects -The ability of NSAIDs to increase gastric acid secretion & inhibit blood clotting can lead to GI toxicity -They can impair renal function, cause fluid retention & provoke hypersensitivity reactions, including :- Bronchospasm, aggravation of asthma, urticaria, nasal polyps & rarely anaphylactic reactions. -Developed drugs selectivity inhibit COX2 & there for do not elicit the GI & antiplatelet side effects common to drug that inhibit COX1. Other side effects not related to PG syn. :- Hepatic necrosis, Cholestatic jaundice, Photosensitivities, Headache, Dizziness, Tinnitus, Confusion & Nervousness

CI In patient with history of ulcer disease In patient with renal impairment, heart failure, hypertension, & edema [ used with caution] Hypersensitivity to salicylate or any other NSAIDs (like asthmatic patients)

Drug Interactions withNSAIDsA significant number of drug interactions are common to most of the NSAIDs.GI toxicity increased by concomitant treatment with corticosteroids.NSAIDs can decrease the clearance of methotrexate, resulting in severe hematological and GI toxicity.Because NSAIDs, decrease PG synthesis in the kidney, these drug can increase the nephrotoxicity of agents such as aminoglycosides, amphotericin B, cisplatin, ganciclovir and vancomycin.Certain NSAIDs can also compete for protein binding sites with warfarin.�� Aspirin must be used with caution with warfarin�� COX-2 inhibitors may also affect warfarin response because of plasma protein binding or inhibition of CYP450 enzyme metabolism�� Acetaminophen does not have these anticoagulant effects�� NSAIDs diminish effect of antihypertensive drugs: like diuretics, angiotensin-converting enzyme inhibitors, B-blockers

NSAID Therapy Guidelines The lowest dose for the shortest duration of therapy that accomplishes the therapeutic goal should be used. Most NSAIDs are not used in children, however ibuprofen is an exception


Specific NSAIDs Aspirin and other salicylic acid derivatives Salicylates -Is a weak organic acid that is unique among the NSAIDs, in irreversibly acetylating & [ thus inactivating ] cyclooxygenase. -It decreases inflammation & pain by inhibiting COX2, however when COX1 decreased, the stomach lining is not protected, thus stomach ulcer & bleeding may occur. -The anti-inflammatory and antipyretic effects of salicylates are due to blockade of PG synthesis in the thermoregulatory centers in the hypothalamus and at peripheral target sites. -Salicylates prevents the sensitization of pain receptors to both mechanical and chemical stimuli.

Pharmacological effects of aspirin 1- Antiinflammatory effect In addition to reducing the syn. of PG, aspirin also interferes with the chemical mediators of Kallikren system as a result :- A- inhibit granulocyte to damaged vasculature. B- stabilizes lysosomes. C- inhibits the migration of polymorphonuclear leukocyte & macrophages into the site of inflammation. 2- Analgesic effect Its effective in reducing mild to moderate pain of somatic type but not useful in visceral pain . It alleviates pain of muscular, vascular & dental origin & arthritis. aspirin acts peripherally through it is effect on inflammation but also inhibits pain stimuli at subcortical site

3- Antipyretic effect Aspirin reduces the elevated body temp. by impeding PGE2 synthesis and release & also related to increase heat loss by vasodilation of superficial blood vessels & increased sweating. 4- Effect on platelets [ effect on homeostasis ] Single low doses of aspirin [ about 80 mg ] produce a slight increase in the bleeding time & this occur due to inhibition of platelets aggregation secondary to inhibition of thromboxane syn.



Side effects 1- gastric & intestinal mucosal damage2- prolongation of bleeding time3- skin allergy [ rashes ] & other allergic reaction 4- Raye’s syndrom5- nephrotoxicity C.I In asthmatic patients In children under 12 yearsIn bleeding disorder In gouty patients

Other NSAIDs A- Propionic acid derivatives Ibuprofen, Fenoprofen, Flurbiprofen, Ketoprofen, & Naproxen - Equal selectivity for COX1 & COX2 -Well absorbed orally, totally bound to serum albumin & inactivated by metabolism. -All of these drugs posses antiinflammatory, analgesic, & antipyretic activity Useful in treatment of chronic rheumatoid & osteoarthritis & preferable on aspirin bec. GI effects less intense than aspirin. -The common S.E of this groups are: 1-GI disorder ranging from dyspepsia to bleeding 2-CNS S.E like headache, tinnitus & dizziness.

B-Acetic-acid derivatives Indomethacin, Sulindac, Tolmetin Indomethacin moderate selective for COX1, more potent than aspirin as an antiinflammatory agent & used in the following condition: 1-More selective in relieving inflammation with acute gouty arthritis, ankylosing spondylitis & osteoarthritis of the hip. 2-Effective in treating patent ductus arteriosus Side effects -GIT,nausea, vomiting, diarrhea, & abdominal pain -Frontal headache, dizziness, & vertigo -Hypersensitivity like rash, urticaria, itching & acute attack of asthma.

Sulindac Chemically related to be indomethacin & is generally used for the same indication. It is pro drug that is metabolized to an active sulphide metabolite & an inactive metabolite. The most frequently reported S/E are GI pain, nausea, diarrhea & constipation. The incidence of those effects is lower than for indomethacin because sulindac is pro drug & thus the active metabolite is not highly concentrated at gastric mucosa.


D-Oxicam derivatives Piroxicam, Meloxicam The oxicams are as effective as indomethacin, & their long half-life allows for once-daily dosing. Piroxicam is a non specific cox inhibitor that has a much higher affinity for COX-1 than COX-2. Piroxicam is indicated for the treatment of rheumatoid arthritis & osteoarthritis. Adverse GI reactions have been the most frequently reported side effect, but edema, dizziness, headache, rash, & changes in haematological parameters have also occurred in 1 to 6 % of patients. can cause serious GI bleeding, ulceration & perforation, particularly in the elderly, if the recommended dosage is exceeded or if aspirin is being taken concurrently.

Paracetamol (Acetaminophen) -Inhibit PG synthesis in CNS explain their antipyretic & analgesic properties. -Less effects on peripheral COX weak antiinflammatory activity -No effect on platelet function Clinical uses 1-Analgesic & antipyretic, specially for those whose suffer from gastric irritation 2-Drug of choice as analgesic & antipyretic for children with viral infection 3-Drug of choice for gouty patients bec. it dose not antagonize the uricosuric agents like probenecid.

Paracetamol (Acetaminophen) Pharmacokinetics rapidly absorbed from the GIT under go significant first-pass metabolism conjugated in the liver to form inactive metabolites A portion of acetaminophen is hydroxylated to form N-acetyl-benzoiminoquinone, a highly reactive and potentially dangerous metabolite that react with sulfhydryl groupes and cause liver damage. Acetaminophen & its metabolites are excreted in urine. Side effects With normal therapeutic doses paracetamol is free of significant S.E Skin rash, minor allergic reaction, minor alteration in leukocyte count may be occur. Prolonged & large dose therapy 1- hepatic necrosis 2- renal tubular necrosis

Disease modifying antirhaumatic drugs Rhaumatic diseases A chronic inflammatory disease with frequent acute attacks. The immune system is involved in attacking the joints and surrounding structure such as muscle tendons and most other connective tissue. There is inflammation of the synovial membrane. The majority of patients with rhaumatoid arthritis have a slow onset of diseases over several weeks to months RA presents as a gradual onset of joint pain, stiffness and swelling affecting multiple joints associated with loss of function. RA can be sudden in onset, involving one or more joints and evolving over time. General fatigue, loss of appetite, weight loss and even low-grade fever can predominate in some patients.

Disease modifying antirhaumatic drugs

DMARDs are chemically diverse class of agents, all of which have varying capacity to slow the progression of disease Their action manifest over the course of week to months; they are usually employed in combination with NSAIDs some time other DMARDs They reduce joint swelling and pain, decrease acute phase markers, limit progression joint damage, and improve function.


Disease modifying antirhaumatic drugs 1-Cytotoxics : Azothioprine and Methotrexate 2-Gold peparations : Auranofin3-Biological response modifiers : Etanercept, Rituximab & Infliximab4-Other DMARDs : Cyclosporine, Hydroxychloroquine, Penicillamine and SulfasalazineMethotrexate is the most frequently used DMARDs in RA and it’s the cornerstone in most synthetic and biologic combination, since it’s more efficacious in reducing signs and symptoms, disability and structural damage than other synthetic DMARDs, also because of it’s relatively rapid onset, high rate of response, mild side effect, relatively low cost, and long sustained efficacy.

Disease modifying antirhaumatic drugs Biological response modifiers have improved the currently available treatment due to greater efficacy, fast action and greater tolerability. It should be started as soon as a diagnosis of RA has been made. They can be used alone or as combination of two to three different agents.