Dr Khulood Alsaraf

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 hosts own tissue, as occurs in rheumatoid arthritis.

The inflammatory process:

Inflammation begins when a stimulus, such as infection, Physical stress, or chemical stress, produces cellular damage. This damage initiates the activation of transcription factors that control the expression of many inflammatory mediators.
Among the more important inflammatory mediators are: eicosanoids, biological oxidants, cytokines, adhesion factors, and digestive enzyme (proteases, hyaluronidase, collagenase, and elastase)

The inflammatory response changes with time & can be divided into phases :The rapid phase occurs with in seconds to min. & consist of :-Vasodilation -Increased blood flow -Edema -Pain The acute phase is charac. by induction of inflammatory genes by NF-kB & other transcription factors, during this phase, moderate amounts of inflammatory mediators are produced The chronic phase occurs over months to years & is marked by dramatically increased production of inflammatory mediators. The secondary chronic phase occurs after years of oxidative damage has degraded blood vessels & tissues Such chronic inflammation appear to play a role in many disease state, such as arteriosclerosis & cancer.

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 They slow the bone damage associated with the Rhumatoid arithritis & they are more toxic than NSAIDS.

NSAIDs
-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 Rhumatoid arithritis, osteoartritis & ankylosing spondylitis.

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, & 5HT -All NSAIDs [except the COX2 selective agents] inhibit both Cox isoform & the degree of inhibition of COX1 varies from drug to drug.

Prostaglandins What is ------prostaglandins Role of PGs as local mediators Synthesis of PGs Types of PGs Actions of PGs Therapeutic uses of PGs

Home work

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

-In patient with history of ulcer disease -In patient with renal impairment, heart failure, hypertension, & patients)

CI

edema [ used with caution] -Hypersensitivity to salicylate or any other NSAIDs (like asthmatic

A significant number of drug interactions are common to most of the NSAIDs. GI toxicity increased by concomitant treatment with corticosteroids. Certain NSAIDs can also compete for protein binding sites with warfarin. 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.

Classification of NSAIDs
NSAIDs are classified according to their selectivity to COX1 or COX2 into :-

1- Less selective for COX1 :Ibuprofen & Paracetamol

2- Equipotent on both enzymes :- Naproxen & Diclofenac 3- Relative selective for COX1 :- Aspirin & Indomethacin 4- More selective for COX2 :- Meloxicam, Celecoxib

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 senistization 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.

Clinical uses
Analgesic and antipyretic External application: salicylic acid used topically to treat corns and epidermaphytosis (eruption caused by fungi). Cardiovascular application: due to inhibition of platelet aggregation and low doses of Aspirin used prophylactically to decrease the incidence of transient Ischemic attack, unstable angina and coronary artery thrombosis.

12345-In -In -In -In

gastric & intestinal mucosal damage prolongation of bleeding time skin allergy [ rashes ] & other allergic reaction Rayes syndrom nephrotoxicity asthmatic patients children under 12 years bleeding disorder gouty patients

Side effects

C.I

Mild to sever toxicity occur with Aspirin if administered in high doses. Mild one (also called salicylism) characterized by: Nausea and vomiting, Hyperventilation, Mental confusion, Headache, Dizziness, Tinnitus (ringing in the ear) Sever toxicity occur when large doses of Aspirin are administered and characterize by: Restlessness, Delirium , Hallucination, Convulsion, Coma Respiratory and metabolic acidosis and death from respiratory failure.

In mild cases, symptomatic treatment are sufficient and sometime increasing urinary PH enhances the elimination of salicylate. In serious cases, fluid I-V administration, dialysis and correction of acid-base and electrolyte balanced.

Treatment

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

Indomethacin, Sulindac, Tolmetin

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

metabolite

prodrug, metabolized to an active sulfide

Not highly concentrated at gastric mucosa, so that the incidence of GI S.E is lower than for Indomethacin

C-Fenamates derivatives
Mefenamic acid

Mefenamic acid & Meclofenamate

indicated for analgesic & primary dysmenorrhea when therapy will not exceed 1 week. Meclofenamate sodium osteoarthritis for rheumatoid arthritis&

D-Oxicam derivatives

Piroxicam, Meloxicam
Meloxicam & Piroxicam
once-daily dosing

long half-life allows for indicated for rheumatoid arthritis &

Piroxicam

osteoarthritis Meloxicam also indicated for rheumatoid arthritis& osteoarthritis & certain acute condition More selective to COX-2 frequency of GI S.E is lower than Piroxicam and other NSAIDs

E-Heteroaryl acetic derivatives

Diclofenac

rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, dysmenorrhea & topically for the treatment of ocular inflammation & actinic keratosis

F-Selective COX-2 inhibitors (sulfonyl phenyl derivatives)

Celecoxib

-Highly COX-2 inhibitors less erosion of the GI mucosa & cause less inhibition of platelet aggregation than do the nonselective COX inhibitors -Indicated for the treatment of rheumatoid arthritis, osteoarthritis, and acute to moderate pain. -Headache, dyspepsia, diarrhea, and abdominal pain are the most common adverse effects

Paracetamol (Acetaminophen)
-Inhibit PG synthesis in CNS analgesic properties. -Less effects on peripheral COX activity -No effect on platelet function explain their antipyretic &
weak antiinflammatory

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.

Clinical uses

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

Side effects

Disease modifying antirhaumatic drugs

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.
-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

Rhaumatic diseases

Disease modifying antirhaumatic drugs

1-Cytotoxics : Azothioprine and Methotrexate 2-Gold peparations : Auranofin 3-Biological response modifiers : Etanercept, Rituximab & Infliximab 4-Other DMARDs : Cyclosporine, Hydroxychloroquine, Penicillamine and Sulfasalazine

Gout

Drugs employed in the treatment of Gout

Hereditary metabolic disease that is a form of acute arthritis and is marked by inflammation of joints. Gout associated with increased body stored of uric acid. Acute attacks involve joint inflammation caused by precipitation of uric acid crystals. hyperuricemia urate crystal in joints inflammatory response
Most therapeutic strategies for Gout involve lowering the uric acid level below the saturation point (below 6mg/dl), thus preventing the deposition of urate crystals. This can accomplished by:

Allopurinol 2- increasing uric acid excretion with Probenecid 3- inhibiting leukocyte entry into affected joint with Colchicine 4- administration of NSAIDs
1- interfering with uric acid synthesis with