DRUGS USED IN INFLAMMATORY DISORDERS

1.         The Inflammatory Response

a.            Inflammation is divided into three phases:

i.          acute inflammation

ii.          the immune response

iii.         chronic inflammation

b.         Acute inflammation is the initial response to tissue injury.

c.         The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response.

d.         Chronic inflammation ensures if the immune response is unable to remove the foreign antigen or organism which triggers the inflammatory process.

e.            Rheumatoid arthritis is caused by chronic inflammation of the joints, resulting in pain and destruction of bone and cartilage that can lead to severe disability and in which systemic changes occur that can result in shortening of life.

2.            Therapeutic Strategies

a.         Goal of treatment of Inflammation:

i.          relief of pain.

ii.          slowing or arrest of the tissue-damaging process.

b.         Classes of drugs used:

i.            corticosteroids

ii.          non-steroid anti-inflammatory drugs (NSAIDs)

iii.         disease modifying antirheumatic drugs (DMARDs)

c.            Considerations:

i.          cost

ii.            therapeutic effects vs side effects

iii.         dosage schedules

iv.         patient compliance

3.            Mechanism of Action of NSAIDs

a.            Arachidonic acid is a polyunsaturated fatty acid present in large amounts in phospholipids of the cell membrane.

b.         Source of free arachidonic acid:    

i.          it is released from membrane phospholipids due to activation of cellular phospholipases by inflammatory stimuli or by other chemical mediators such as C5a.

ii.          during inflammation, lysosomes of neutrophils are an important source of phospholipases and products of arachidonic acid metabolism.

c.         Free arachidonic acid is metabolized mainly by two divergent enzymatic pathways that are invariably distributed among different cells:

i.            cyclooxygenase pathway: forms prostaglandins and thromboxanes.

ii.            lipoxygenase pathway: forms leukotrienes.

d.         Two forms of Cyclooxygenase:

e.            Prostaglandins protect gastric mucosa by increasing thickness of mucous layer, decreasing pH gradient, increasing bicarbonate secretion and mucosal blood flow.

f.          COX in Platelets:

i.            platelets contain COX-1 but not COX-2.

ii.            thromboxane A₂ is predominant COX product.

iii.            thromboxane A₂ promotes platelet aggregation.

iv.         typcial NSAIDs reduce platelet aggregation, resulting in a mild bleeding diathesis.

g.            NSAIDs inhibit cyclooxygenase and thus inhibit prostaglandin synthesis.

4.         Aspirin

a.            Pharmacokinetics:

i.          aspirin is a simple organic acid with a pKa of 3.5.

ii.          it is rapidly absorbed from the stomach and upper small intestine.

iii.         the acid medium in the stomach keeps it in an unionized form, promoting absorption; at high drug levels, gastric mucosal barrier is damaged.

iv.         aspirin is bound to albumin; it is hydrolyzed to acetic acid and salicylate by esterases in tissue and blood.

v.            alkalinization of the urine increases the rate of excretion of free salicylate.

vi.         when aspirin is sued in low doses, elimination is in accordance with first order kinetics and the serum half-life is 3-5 hours.; with higher dosage, zero-order kinetics prevail, the half-life increases to 15 hours.

b.            Mechanism of action:

i.          the effectiveness of aspirin is largely due to its capacity to inhibit prostaglandin biosynthesis.

ii.          it does this by irreversibly blocking the enzyme cyclooxygenase, which catalyzes the conversion of arachidonic acid to endoperoxide compounds.

iii.         at appropriate doses, aspirin decreases the formation of both prostaglandins and thromboxanes.

c.         Anti-inflammatory effects:

i.          aspirin also interferes with the chemical mediators of the kallikrein system.

ii.          as a result, aspirin inhibits granulocyte adherence to damaged vasculature, stabilizes lysosomes, and inhibits the migration of polymorphonuclear leukocytes and macrophages into the site of inflammation.

d.            Analgesic effects:

i.          aspirin is most effective in reducing pain of mild to moderate intensity.

ii.          it alleviates pain of varying causes, such as that of muscular, vascular, and dental origin, postpartum states, arthritis, and bursitis.

iii.         aspirin acts peripherally through its effects on inflammation but also inhibits pain stimuli at a subcortical site.

e.            Antipyretic effects:

i.          aspirin reduces elevated temperatures.

ii.          aspirin blocks both pyrogen-induced production of prostaglandins and the central nervous system response to interleukin-1 and so may reset the ‘temperature control’.

f.          Platelet effects:

i.          aspirin affects hemostasis.

ii.          single doses of aspirin produce a slightly prolonged bleeding time.

iii.         the change is explained by inhibition of platelet aggregation secondary to inhibition of thromboxane synthesis.

g.         Clinical use:

i.          aspirin is most frequently used for relieving mild to moderate pain of varied origins; it is not effective in the treatment of severe visceral pain such as renal colic and pericarditis.

ii.          it is used in high doses as initial therapy for rheumatoid arthritis, rheumatic fever, and other inflammatory joint conditions with the exception of gouty arthritis.

iii.         as an antipyretic.

iv.         aspirin decreases the incidence of transient ischemic attacks and unstable angina in men and is effective in reducing the incidence of thrombosis in coronary artery bypass grafts.

v.         it may reduce cataract formation.

h.            Dosage:

i.          the optimal analgesic or antipyretic dose of aspirin is less than 0.6g oral dose.

ii.          the usual dose may be repeated every 4 hours.

iii.         due to its long half-life, frequent dosing is not necessary when daily doses of 4g or more are required.

5.            Adverse effects of Aspirin

a.            Gastrointestinal effects:

i.          at the usual dosage, the main adverse effect is gastric upset.

ii.            continual use is associated with increased incidence of peptic and duodenal ulcers.

iii.         effect can be minimized with suitable buffering, taking aspirin with meals followed by water or antacids and use of a prostaglandin E derivative, misoprostol to reduce aspirin-induced ulceration.

iv.         aspirin should be avoided or taken with effective buffers or prostaglandins by individuals with peptic ulcer disease.

v.            vomiting may occur as a result of central nervous system stimulation after absorption of large doses of aspirin.

b.         Central nervous system effects:

i.          low toxic doses lead to respiratory alkalosis as a result of increased ventilation in response to increased acid load in system.

ii.          high toxic doses can cause tinnitus, decreased hearing and vertigo.

c.         Aspirin may cause mild, usually asymptomatic hepatitis in patients with underlying disorders such as systemic lupus erythematosus and rheumatoid arthritis.

d.         It may cause reversible decrease of glomerular filtration rate in patients with underlying renal disease.

e.         Toxic amounts affect the cardiovascular system directly and may depress cardiac function and dilate peripheral blood vessels.

f.          Aspirin is contraindicated in patients with hemophilia and in pregnant women.

g.         Use of aspirin in children during or after a viral infection has been associated with an increase in the incidence of Reye’s syndrome.

h.            Overdosage toxicity:

i.          serious intoxications results when the amount ingested exceeds 150-175 mg/kg of body weight.

ii.          gastric lavage is advised in overdosing.

iii.         sodium bicarbonate infusions may be employed to alkalinize the urine, which will increase the amount of drug excreted.

I.          Drug interactions:

i.          drugs that enhance salicylate intoxication are acetazolamide and ammonium chloride.

ii.          alcohol increases gastrointestinal bleeding produced by salicylates.

iii.         aspirin displaces tolbutamide, chlorpropamide, NSAIDs, methotrexate, phenytoin and probenecid from protein binding sites in the blood.

iv.            corticosteroids may decrease concentration.

v.         aspirin reduces activity of spironolactone, competes with penicillin G for renal tubular secretion and inhibits uricosuric effect of sulfinpyrazone and probenecid.

6.         Other NSAIDs

7.         Drugs used in Arthritis

a.            Arthritis: inflammation of the joints.

b.         Types of Arthritis and drugs used in treatment:

c.         Goals of Arthritis Therapy:

i.          relieve pain / inflammation.

ii.            minimize risks of therapy.

iii.         retard disease progression.

iv.         provide patient education.

v.         prevent work disability.

vi.            enhance quality of life and functional independence.

8.            DMARDs

a.         The effects of DMARDs typically take 4 weeks to 1 year to become evident, i.e. they are slow-acting compared with NSAIDs.

b.            Members of the group include:

i.            immunosuppressant agents: methotrexate, azathioprine.

ii.            chelators: penicillamine.

iii.            antimalarials: hydroxychloroquine and chloroquine.

c.            Methotrexate and other immunosuppressants:

i.          their use is restricted to seriously crippling disease with reversible lesions after conventional therapy has failed.

ii.            toxicities include nausea and mucosal ulcers, progressive dose-related hepatotoxicity in the form of enzyme changes, fibrosis and cirrhosis.

d.            Antimalarial drugs:

i.          used in high doses.

ii.          may suppress the T lymphocyte chemotaxis, stabilize lysosomal membranes and inhibit DNA and RNA synthesis.

iii.         long latent period of 4-12 weeks.

iv.         used in NSAID resistant cases, SLE.

v.         adverse effects: retinopathy, myopathy.

e.         Gold compounds:

i.            administered as aurothiomalate and auranofin; poor oral absorption except auranofin.

ii.          very long duration of action as they are taken up by phagocytes.

iii.         alters the morphology and functional capabilities of human macrophages.

iv.         other effects include inhibition of lysosomal enzyme activity, reduction of histamine release from mast cells and suppression of phagocytic activity of neutrophils.

v.         used short term to halt rapidly progressing disease.

vi.         high incidence of adverse effects: rash, stomatitis, renal damage, eosinophilia, hematologic abnormalities.

f.          D-Penicillamine:

i.            decrease level of rheumatoid factor.

ii.            reserved for patients with active, progressive erosive rheumatoid disease not controlled by conservative therapy.

iii.         adverse effects: leukopenia, thrombocytopenia, aplastic anemia, anorexia, inhibition of wound healing; contraindicated in pregnancy.

iv.            impedes absorption of many drugs and prevents them from reaching therapeutic levels.

8.         Drugs used in Gout

a.         Gout and arthritis:

i.          gout is a familial metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage.

ii.            formation of uric acid calculi in the kidneys may also occur.

iii.         gout is associated with high serum levels of uric acid, a poorly soluble substance that is the end product of purine metabolism.

b.         The treatment of gout is aimed at relieving the acute gouty attack and preventing recurrent gouty episodes and urate lithiasis.

c.         Gout cycle:

i.          urate crystals are initially phagocytosed by synoviocytes, which then release prostaglandins, lysosomal enzymes and interleukin-1.

ii.            attracted by these chemotactic mediators, polymorphonuclear leukocytes migrate into the joint space and amplify the ongoing inflammatory process.

iii.         in the later phases of the attack, increased numbers of mononuclear phagocytes appear, ingest the urate crystals and release more inflammatory mediators.

d.            Colchicine:

i.          specific for gouty arthritis.

ii.            dramatically relieves the pain and inflammation of gouty arthritis in 12-24 hours by disrupting the gout cycle.

iii.            produces its anti-inflammatory effects by binding to the intracellular protein tubulin, thereby preventing its polymerization into microtubules and leading to the inhibition of leukocyte migration and phagocytosis.

iv.         it also inhibits the formation of leukotriene B₄.

v.         adverse effects: highly irritant to tissues, GIT, blood dyscrasias, myopathy, diarrhea, vomiting, nausea, abdominal pain.

e.            NSAIDs:

i.            indomethacin may be used as initial treatment of gout or as an alternative drug when colchicine is unsuccessful or cause too much discomfort.

ii.            phenylbutazone is also effective in acute attacks of gout.

iii.            salicylates should not be used as they are anti-uricosuric at low doses.

f.            Uricosuric agents:

i.            probenecid and sulfinpyrazone are uricosuric drugs employed to decrease the body pool of urate in gout.

ii.          they inhibit reabsorption of uric acid in renal tubules.

iii.         adverse effects: allergic dermatitis, nephrotic syndrome, aplastic anemia.

g.            Allopurinol:

i.          reduce synthesis of uric acid by inhibiting xanthine oxidase.

ii.          acute attacks of gouty arthritis occur early in treatment with allopurinol when urate crystals are being withdrawn from the tissues and plasma levels are below normal.

iii.         adverse effects: gastrointestinal intolerance, nausea, vomiting, diarrhea, peripheral neuritis, necrotizing vasculitis.