mechanism of inflammation and anti-inflammatory drugs

8/8/2019 Mechanism of inflammation and anti-inflammatory drugs

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InflammationInflammationy Inflammation is the immune systems response to infection, toxins, injury or irritation.

y Inflammation continues beyond the need, or when it response doesnt turn off

appropriately which can cause damage to healthy tissue.y Symptoms- Heat, Pain, Swelling, Redness, loss of Function

Inflammation: Three Phases

y Acute inflammationx initial response to injury

x Autacoids releasex histamine

x serotoninx bradykinin

x prostaglandins

x leukotrienes

x precedes immune response development

y Immune response activation of immune cells and responds to antigenic substances/ organisms

acute or chronic inflammatory responses

y Chronic inflammation ;Mediatorsx IL-1, IL-2, IL-3 (interleukins)

x GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor)

x TNF-a (tumor necrosis factor alpha)

x Interferons

x PDGF (platelet-derived growth factor)

Mediators of

inflammation


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Phospholipase

Arachidonic acid

Cyclooxygenase Lipoxygenases

Steroids-----

NSAIDs -----

Prostaglandins

PGE2PGF2 PGI2

pyrexia vasodilationalgesic

PMNs

Lymphokines

-----Lipoxygenase inhititors

The events of the inflammtory response and mechanisms of anti-flammatory


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Effect of some of mediators in acuteEffect of some of mediators in acute

inflammationinflammationMediator Vasodilation Vascular permeability Chemotaxis Pain

Histamine ++ - -

Serotonin +/- - -

Bradykinin +++ - +++

Prostaglandin +++ +++ +

Leukitrienes-

+++-


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Consequences of inflammationConsequences of inflammation

PID neparthritis psoriasis sarcoidosis

gout gastritis vasculitis atherosclerosis

lupus splenitis laryngitis allergic reactions

asthma sinusitis thyroiditis multiple sclerosis

eczema hepatitis prostatitis some myopathiespleurisy hritis pharyngitis

Autoimmune disorders- An overactive immune response of the body against substances andtissues normally present in the body. The body actually attacks its own cells. The immune system

mistakes some part of the body as a pathogen and attacks itCrohns Disease Graves disease Ulcerative colitis Good pasture

syndrome

Dermato myositis Myasthenia gravis Multiple sclerosis Wegener's

granulomatosis

Diabetes mellitus

type-I

Rheumatoid arthritis Celiac Disease Assitions disease


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Approaches forApproaches for treatementtreatementy Block the mediators

Prostaglandins

Leukotrienes Cytokines

TNF-

y Suppression of immune systemNote- In addition to this antihistaminics, kinin inhibitors, TNF-, INF inhibition shown to be benificial for inflammatory

conditions.

Drug Categories:y Nonsteroidal antiinflammatory drugs COX

y Glucocorticoids - Infammatory genes & decreased transcriptionCytokines

y

Disease modifying antirheumatic drugsy Anti gout drugs

y Leukotriene inhibitors

y TNF--inhibitorsNote: -Slow- acting anti rheumatic drugs, and non-opoid analgesics are some times included in this category as they act against

specific symptom of inflammation


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Non steroidal antiNon steroidal anti--inflammatoryinflammatory

y NSAID indications

Analgesic Anti-inflammatory

Antipyretic

Anti-platelety Choice of different NSAIDS depend on

Selectivity to COX-2

Minimum adverse effects Patient related specifications

Cost effectiveness


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commonly used drugscommonly used drugs

y

Non-steroids Aspirin and other

salicylates

Ibuprofen

Diclofenac sodium Naproxen

Selective cox-2 inhibitor

y

Steroids


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Aspirin and related drugsAspirin and related drugsy Uses

Analgesia/Anti-inflammatory Effects

x Aspirin in combination with opioid analgesics: effective management of some cancer pain.x anti-inflammatory effects of aspirin act to enhance opioid analgesia

x High-dose Salicylates have significant anti-inflammatory properties

x rheumatic fever

x rheumatoid arthritis

x other inflammatory joint diseases

Antipyretic Activity:

Antiplatelet:

May reduce incidents of coronary artery thrombosis

y Adverse effectsx Gastrointestinal Side Effects

x Central Nervous System Effects

x accumulation of salicylic acid derivatives + respiratory depression acidosis

x Leukotriene -mediated hypersensetivity reactions

x Aspirin - Not Effective for management of severe visceral pain, e.g. acute abdomen, pericarditis,myocardial infarction (antiplatelet action may be useful), renal colic.

x Not typically recommended: in pregnant women


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IbuprofenIbuprofeny Uses

For the treatment of pain (muscular and rheumatic),sprains, strains, backache and neuralgia

Treatment of painful menstrual periods.

Temporary relief of fever.

Effective in the treatment of Alzheimer's diseasey Adverse effects

Common Side Effects stomach upset or irritation

Infrequent Side Effects nausea and/or vomiting,constipation, diarrhea

Rare Side Effects skin irritations, drowsiness,gastrointestinal bleeding

Risks liver toxicity, stomach ulcers, allergic reactions


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DiclofenacDiclofenac SodiumSodiumy potent cyclooxygenase inhibitor having

anti-inflammatory analgesic

antipyretic activity

y Clinical Use/characteristics: Chronic inflammatory conditions:

x rheumatoid arthritis

x osteoarthritis

Chronic musculoskeletal pain

Ophthalmic solution: prevention of postoperative ophthalmic inflammation

y Adverse effects (frequency -20%) Gastrointestinal disturbance

Occult GI bleeding Gastric ulceration

Transaminitis (increase serum amino transferase) occurs more frequentlywith diclofenac than with other NSAIDs


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Steroids as antiSteroids as anti--inflammatoryinflammatory

y Inhibit phagocytosisy Inhibit synthesis of IL-1, TNF, PGs LTs.

y Inhibit antigen processing by macrophages

y

Stabilizes lysosomal membranesy Inhibits accumulation of neutrophils and

monocytes at inflammation site.

y Inhibit phospholipase A2.


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Mechanism of glucocorticoid action


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Disease modifying antirheumatic drugs


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y Examples

DM

ARDx Methotrexate

x Antimalarial drug: chloroquine

x Gold

x Penicillamine

x

Steroidsx Acetaminophen

L eukitriene antagonistsx Zafrilukast

x Montelukast

Cytokine inhibitorsx TNF-inhibitor

x Infliximab

x Adalimumabx Etanercept

x

IL-inhibitorx Ankinra


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AntiAnti--gout drugsgout drugsBy increasing uric acid excretion (Uricosuric agents: probenecid,

sulfinpyrazone)

By inhibiting leucocytes migration into the joint: Colchicine)

By a general anti-inflammatory and analgesic effect (NSAIDs).

By inhibiting uric acid synthesis: Allopurinol(this is the main

prophylactic drug)

mechanism of inflammation and anti-inflammatory drugs

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