Flashcards in Anti inflammatory drugs Deck (64):
Broad reasons for using anti inflammatory drugs
1. anaphylaxis is life threatening
2. autoimmune damage e.g. RA
3. pain, especially chronic
What's the major molecule involved in producing inflammatory mediators?
What functions are eicosanoids involved in?
platelet aggregation, uterine motility, vasoconstriction/vasodilation, bronchodilation/bronchoconstriction, inflammation, gastric function, allergic response
What are the clinical indications for use of NSAIDs?
- mild-moderate pain due to tissue injury
- fever (antipyretic)
- platelet aggregation
What drug group does aspirin belong to?
non-steroidal anti-inflammatory drugs
What is the action of NSAIDs?
What are the COX groups, found in which cells?
COX-1: house keeping (platelet aggregation, vascular flow, renal function), found in most cells
COX-2: induced in activated inflammatory cells
In terms of COX inhibition, what is the effect of aspirin at different doses?
- low dose aspirin = selective for COX-1
e.g. prevent platelet aggregation and thrombosis, prevent heart attack and stroke
- high dose aspirin = non selective, (platelets)
(most other NSAIDs are non selective)
What are the adverse effects of NSAIDs?
GIT peptic ulcers due to lack of prostaglandin inhibition of gastric acid secretion, leading to enhanced mucosal blood flow and increased secretion of mucus
Platelet aggregation inhibited = increased bleeding time, GIT blood loss
allergic = bronchospasm, rhinitis due to increased synthesis of leukotrienes
What is one way to reduce mucosal damage?
An enteric NSAID has a
What does an enteric form mean re NSAID?
Coating over the drug allows it to bypass the stomach and be released in the duodenum
How can foecal blood loss be reduced in using NSAIDs?
Reduce 3-8ml faecal blood loss by 50% by using a soluble rather than compressed formulation
What is a selective COX-2 inhibitor?
Advantage of selective COX-2 inhibitors
Lower risk of GIT effects, but at higher doses there is a higher risk of cardiovascular events
How is the structures of COX-1 and COX-2 different?
COX-2 has a side pocket, shape of COX-2 enzyme channels allows for larger molecules to bind: size and shape of the molecule depends on whether it is a COX-1 or COX-2 inhibitor
How do NSAIDs bind to COX?
NSAIDs enter hydrophobic channel forming reversible hydrogen bonds (@ arginine 120), preventing fatty acids from entering
How is aspirin/ acetyl salicylic acid metabolised?
aspirin is a prodrug that is converted to salicylic acid in the liver: 30% of the prodrug is lost to first pass metabolism
Pharmacokinetics of salicylic acid?
pKa of 3.5 (weak acid)
dose-dependent kinetics - is saturable
t 1/2 = 2-4hours in low doses
t 1/2 = 15-30 hours in high doses
How does aspirin irreversibly inhibit COX?
Enters active site with -OH, irreversibly acetylates a serine @ position 530
Doses for aspirin?
0.5-1mg/kg = low dose, e.g. anti-platelet
5-10mg/kg = moderate dose, e.g. analgesic, antipyretic
>30mg/kg = high dose, e.g. anti-inflammatory
normal tablet has 300mg
What are symptoms of salicylism/aspirin toxicity?
Tinnitus, deafness, headache, mental confusion, convulsions, coma and death
- requires CV and respiratory support, correct acid-base abnormalities and eliminate salicylate/prevent further absorption
What are the three groups of corticosteroids?
Mineralocorticoids, androgens, glucocorticoids - antiinflammation
Where are the corticosteroids synthesised and secreted?
Corticosteroids and cholesterol?
All three groups of corticosteroids are derived from cholesterol
What do mineralocorticoids do?
affect water and electrolyte balance (Na+/K+)
Example of a mineralocorticoid?
What do glucocorticoids do?
affect carbohydrate and protein metabolism
Example of a glucocorticoid?
Glucocorticoid effect as a drug?
Anti-inflammatory activity in doses above normal levels
indications for glucocorticoids?
- adrenal insufficiency (Addison's disease)
- inflammatory/allergic conditions
What is Addison's disease, what are the symptoms?
adrenal insufficiency. lethargy, weakness, hypotension, dehydration
How are glucocorticoids used to treat Addison's disease?
as replacement therapy: glucocorticoid in conjunction with a synthetic mineralocorticoid that mimics aldosterone effects
How do glucocorticoids treat inflammatory and allergic conditions?
inhibit early + late manifestations of inflammation
reverse inflammatory reaction irrespective of causative factor
What are interactions for glucocorticoids?
generally induce CYP3A4
How might glucocorticoids be administered?
systemic = oral, intramuscular, intravenous
topical = creams, eye drops, metered dose inhaler (MDI)
Mode of action of glucocorticoids?
Have nuclear receptors, binding leads to gene transcription
Action of steroidal anti-inflammatory drugs?
interact with protein 'annexin-1' that inhibits phospholipase A2. So no arachidonic acid is produced and no leukotrienes are produced
Why are steroidal anti-inflammatory drugs more potent than NSAIDs?
work at an earlier stage of mediator (leukotriene, prostaglandin, and thromboxane) production: steroidal anti-inflammatory drugs prevent arachidonic acid and leukotriene production, NSAIDs prevent thromboxane and prostaglandin production
What are anti-inflammatory actions?
Decreased oedema, leucocyte activity, fibroblast function, eicosanoid production, cytokines production, NO synthesis, histamine release from basophils
Side effects of glucocorticoids?
- increased susceptibility to hyperglycaemia/diabetes
- growth suppression in children/muscle wasting
- increased risk of infection
What is Cushing's syndrome caused by?
Excess production/administration of glucocorticosteroids.
Symptoms of Cushing's syndrome?
- (redistribution of body fat from extremities to neck, face and abdomen): buffalo hump, thin arms and legs, increased abdominal fat, moon face
- other symptoms: euphoria/emotional instability, hypertension, thinning of skin, poor wound healing, easy bruising, avascular necrosis of femoral head, cataracts, benign intracranial hypertension, red plethoric cheeks
- osteoporosis, tendency to hyperglycaemia, negative nitrogen balance, increased appetite, increased susceptibility to infection, obesity
Relative potency of prednisolone and dexamethasone relative to hydrocortisone (natural glucocorticoid)? Therefore in what type of situation would they be used?
prednisolone 4x as potent
dexamethasone 30x as potent
life threatening situations
What happens in sudden withdrawal of glucocorticoids?
adrenal insufficiency (Addison's disease), due to suppression of endogenous steroids
Effect of a single large dose of glucocorticoids?
Effect of prolonged glucocorticoid therapy (weeks/months)?
usually associated with problems - need to use lowest effective dose for shortest period of time
How long until glucocorticoids take effect?
4-6hours (gene transcriptional changes)
Advantages of NSAIDs therapy?
- control of inflammation and pain
- reduced swelling
- improved mobility, flexibility and range of motion
- improved quality of life
- relatively low-cost
Disadvantages of NSAIDs therapy?
- does not affect disease progression
- GI toxicity common
- renal complications
- hepatic dysfunction
- CV complications e.g. through COX 2
*treat symptoms not the cause
What are DMARDs?
unrelated to each other, different chemical structures and different modes of action
How are DMARDs' potency and toxicity?
potent, often toxic
How long until DMARDs take effect?
6-8 weeks, some up to 6 months
What do DMARDs do?
retard progression of disease process
How are DMARDs managed today?
- earlier and more aggressive intervention with DMARDs
- combination DMARD therapy
- introduction of biologic therapy if DMARDs fail
Time until Methotrexate takes effect?
1-3 months, first line drug in treating arthritis
Mechanism of action of DMARDs?
affect antigen presenting cells, cytokines (less synovial inflammation, production of ECM programs, destructive symptoms, effect on bone)
methotrexate affects T and B cells
Advantages of DMARDs
slow progression of disease
improve functional disability
interfere with anti-inflammatory processes
retard joint erosion
Disadvantages of old DMARDs
- lacking adequate safety profile
- unable to control disease activity in large groups of patients, variable effects
*newer biologic agents could address this by acting on cytokines
Features of cytokines: what, released by what, bind to what and type of action
LMW proteins (30KDa) acting on immune cells
released by immune cells during inflammation to promote proliferation and growth of those immune cells
bind to TRK ("track") receptors to alter gene expression
actions are local (para/autocrine) and synergistic
Examples of cytokines
ILs, chemines, interferons, colony stimulating factors, growth factors, tumour necrosis factor (TNF)
Effects of IL-1?
- activates monocytes/macrophages, (inflammation)
- induce fibroblast proliferation (synovial pannus formation -new granular tissue in cartilage space)
- activates chondrocytes (cartilage breakdown)
- activates osteoclasts (bone resorption)
Effects of TNF-alpha?
interferes with synovial producing cells/synoviocytes (pain, joint swelling)
interferes with osteoclasts (bone erosion)
interferes with chondrocytes, increasing cartilage degradation (narrowing of joint space)
3 examples of Anti-TNF agents? Common mechanism of action?
*infliximab*, etanercept, adalimumab
binds to TNF-alpha, prevents binding of TNF-alpha to TNF receptors on inflammatory cells, results in suppression of downstream cytokines and suppression of leucocyte migration and activation