PHARM Y1 S2: Anti-Inflammatory Agents Flashcards
inflammatory mediators which induce and potentiate pain
- induce: histamine, bradykinin, 5-HT (serotonin)
- potentiate (amplify): eicosanoids (e.g. prostaglandins)
prostacyclin (PGI2)
- where is it made
- what are its functions
- made in endothelium
- function: vasodilation, hyperalgesic, decreased platelet aggregation
location and function of PGD2
- mast cells
- vasodilation
- decreased platelet aggregation
- GIT relaxation
location and function of PGE2
- GIT
- vasodilator
- decreased gastric acid secretion
- fever
- hyperalgesia
location and functions of PGF2a
- myometrium and lungs
- bronchoconstrictor
- myometrial contraction
thromboxane (Txa2) location and function
- generated in platelets
- promotes thrombosis
- vasoconstriction
what do NSAIDs target?
- inhibit cyclo-oxygenases which convert arachidonic acid into prostaglandins
- decreased prostaglandins = decreased inflammation
function of COX-1 and what eicosanoids does it generate?
- “constitutive”, involved in housekeeping and homeostasis
- generates PGD2, PGE2, PGI2, thromboxane (TxA2), PGF2a,
function of COX-2 and what eicosanoids does it generate?
- induced in inflammatory cells when activated = “inducible”
- generates PGD2, PGE2, PGI2 (NOT TxA2 or PGF2a - these are COX-1)
side effects of non-selective COX inhibitors (i.e. target both COX-1 and COX-2)
- increased bleeding time b/c decreased TxA2 (COX-1) = decreased clotting
- peptic ulcers b/c decreased PGE2 (COX-1 and 2) = increased gastric acid secretion = GIT irritation
- exacerbation of asthma b/c arachidonic acid is instead converted into leukotrienes by lipoxygenase > bronchoconstrictors
how are NSAIDs metabolised?
- by CYP-450 enzymes in liver
aspirin: MOA and function
- @ low doses: selective IRREVERSIBLE COX-1 inhibitor > anti-clotting
- @ higher doses: non-selective COX inhibitor > anti-inflammatory, analgesic, antipyretic
why is aspirin more readily absorbed in the stomach?
- aspirin is a weak acid
- therefore in acidic environments it becomes unionised and therefore more lipid soluble
how does aspirin overdose work?
- Sx and Tx
- too much aspirin = saturate the enzymes that break it down into salicylic acid
- Sx: tinnitus, deafness, confusion, convulsions, coma, death
- Tx: CVS and resp support, then correct acid-base balance
how to correct acid-base balance re: aspirin overdose
- activated charcoal: porous and binds to aspirin > prevent further absorption and promote excretion
- rid body of salicylic acid: forced alkaline diuresis using IV bicarbonate or haemodialysis (severe)
ibuprofen AND diclofenac (voltaren)
- MOA
- functions
- side effects
- inhibits both COX-1 and COX-2
- anti-inflammatory, analgesic, antipyretic
- increased bleeding, peptic ulcers, renal effects
celecoxib AND meloxicam
- MOA
- functions
- risks
- selective COX-2 inhibitor
- decreases inflammation w/ LESS GI effects
- analgesic, anti-inflammatory, antipyretic
- increase risk of AMI due to inhibition of PGI2 (anti-clot), allowing TxA2 (pro-clot) to dominate
- more sodium retained since PGE2 is inhibited = increased BP = risk of AMI
paracetamol
- MOA
- function
- simple analgesic + antipyretic, unknown MOA
- no anti-inflammatory effect and avoids GI side effects b/c not impacting COX-1 and 2
- useful when aspirin is contraindicated e.g. peptic ulcer, coagulation disorder
paracetamol overdose
- what happens?
- why might this occur?
- lots of paracetamol = saturate enzymes which make it water soluble in liver = instead converted to toxic metabolite NAPQI = liver damage
- can occur due to deliberate poisoning, accidental paediatric exposure, inadvertent repeated subtherapeutic ingestions
treatment for paracetamol overdose
- N-acetylcysteine
- inactivates toxic metabolite NAPQI so it can be excreted
breakdown of membrane phospholipid > prostaglandin production pathway
analgesic ladder
- start w/ simple analgesics (paracetamol)
- then NSAIDs if inflammation present
- then weak opioids +/- simple analgesics
- then strong opioids +/- simple analgesics
function of adrenal cortex
- zona glomerulosa (outermost layer): mineralocorticoids
- zona fasciculata: glucocorticoids
- zona reticularis: androgens (sex hormones)
- all have cholesterol as a precursor
glucocorticoids function
- slow onset of action
- regulate CHO and protein metabolism (stress response)
- anti-inflammatory (can also address loss of function) and immunosuppressive
mineralocorticoids function
- regulate water and electrolyte (Na/K) balance
Addison’s disease, Sx, Tx
- deficiency in synthesis of endogenous hydrocortisone due to sudden withdrawal of glucocorticoids
- Sx: weakness, lethargy, dehydration, hypotension
- Tx: hydrocortisone replacement therapy
MOA of glucocorticoids
- enter cell and bind to glucocorticoid receptor in cytosol
- moves to nucleus (NUCLEAR RECEPTORS) and decreases transcription of inflammatory cytokines OR increases anti-inflammatory proteins e.g. lipocortin-1
- this inhibits phospholipase A2 which converts membrane phospholipids into arachidonic acid (prevents synthesis of leukotrienes = prevent bronchoconstriction)
endogenous vs synthetic glucocorticoids
- endogenous glucocorticoids possess mineralocorticoid activity which can lead to side effects
- exogenous: no mineralocorticoid activity
drug interactions w/ glucocorticoids
- increase activity of CYP3A4 enzyme in liver > increased metabolism of other drugs
- more likely to have interactions if administered IV/IM compared to topical
why are glucocorticoids useful in life threatening situations?
- can give a massive ‘one-off’ dose (harmless) b/c side effects like immunosuppression come from prolonged use
- h/w sudden withdrawal can result in adrenal insufficiency (takes time to start producing endogenous glucocorticoids again) > Addison’s disease
what conditions can we use glucocorticoids for?
- eye inflammation
- rheumatoid arthritis
- allergies e.g. hayfever, dermatitis, bee stings, asthma
2 stages of asthma and which stage do glucocorticoids target?
- immediate: bronchospasm
- late: inflammatory reaction + mucus plug
- glucocorticoids prevent late phase, NOT bronchospasm
best way to administer glucocorticoids for asthma
- inhaled: goes straight to site of action
- B agonists increase penetration and cause bronchodilation
- can also give oral in short term but leads to systemic side effects
side effects of glucocorticoids
- increased susceptibility to hyperglycaemia
- growth suppression and muscle wasting in kids
- osteoporosis (decreased Ca2+ absorption and increased renal excretion)
- HTN
- increased risk of infection (hidden symptoms)
Cushing’s syndrome
- opposite to Addison’s syndrome, due to long-term corticosteroid exposure
- Sx: easy bruising (purpura), increased abdominal fat, poor wound healing, thinning of skin, HTN, diabetes, thin bones, moon-shaped face
examples of glucocorticoids
- prednisolone
- dexamethasone: eye inflammation, fever
- fluticasone: prevents asthma
what do the new generation NSAIDs primarily target
- COX-2 only
