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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)