week 10 Flashcards
5 signs of inflammation
heat, redness, swelling, pain, loss of function
what are two key pro-inflammatory mediators
prostaglandins & leukotrienes = produce inflammation
list the five major groups of anti-flammatory drugs
- cyclo-oxygenase inhibitors (NSAIDs)
- glucocorticoids
- antirheumatic drugs (DMARDs) - arthritis
- cytokines modulators & other biological agents (bDMARDs)
- others that do not fit in the above groups (antihistamines & other drugs used to control gout)
why inflammatory drugs used so extensively
because inflammation is involved in almost all diseases and in some cases can be the cause
steroidal define and examples
- relates to steroidal hormones and their effects
- steroidal hormones comes from cholesterol
- sex hormones, glucocorticoids, mineralocorticoid
are cyclo-oxygenase (COX) inhibitors steroidal?
no they are non-sterodial anti-inflammatory drugs (NSAIDS)
what are NSAIDs used to treat & are they chemically related
minor aches & pains
they are chemically unrelated
what 3 properties do NSAIDs carry
analgesic (decrease pain), antipyretic (decrease fever) & anti-inflammatory properties
examples of NSAIDs
e.g., diclofenac (voltaren) & naproxen & ibuprofen & celecoxiib & melocicam, aspirin (irreversible)
what is the NSAIDs target
an enzyme COX1 = homodimer (two together)
the usual product of COX1 & the action it leads to
= this is without the drug interference so normal bodily functions
arachidonic is the endogenous substrate
prostaglandin (product) –> toboxon A2 –> platelet activation/aggregation = blood clot/thickening (inflammation)
endogenous substrate of COX1 enzyme
arachidonic acid
affect of the NSAIDs drug e.g., aspirin
- aspirin causes irreversible inhibition = cause a covalent bond in the enzyme COX1 preventing the production of prostaglandins = decrease platelet aggregation = thins the blood
difference between COX-1 & COX-2
- both produce prostaglandins from arachidonic acid
- COX-2 has a side pocket = were able to make drugs cox-2 selective = those drugs have an ending ‘coxib’ & are bulkier
mechanism of action of NSAIDs
= inhibit synthesis of prostaglandins by inhibiting COX enzymes
what is the target of prostaglandins & what specific superfamily
G protein-coupled receptors = then the second messengers etc
the analgesic effect of NSAIDs
= decreased production of prostaglandin: less sensitisation of nocieceptive nerve ending to inflammatory mediators such as bradykinin & 5-hydroxytryptamine (5-HT, serotonin)
the anti-inflammatory action due to NSAIDs
reduces vasodilation and, indirectly, oedema by decreasing prostaglandin E2 and prostacyclin synthesis
the antipyretic effect due to NSAIDs
NSAIDs prevents the release of prostaglandins by interleukin-1 in the CNS, where prostaglandins elevate the hypothalamic set point for temperature control. therefore preventing fever
difference between COX-1 & COX-2 inhibition in terms of effect
1 - impaired gastric protection, antiplatelet effects = gastrointestinal tract
2- more anti-inflammatory action, analgesic action = reduce the risk of gastrointestinal ulceration & upper gastrointestinal bleeding
both - reduction in glomerular filtration & reduction in renal flow
route of administration of NSAIDs
topical (cream), enteral (via gastrointestinal tract through tube) & parenteral (injection)
site of absorption of NSAIDs
stomach & small intestine (presence of food & antacids (neutralises stomach acid) delays absorption)
distribution of NSAIDs
highly bound to plasma protein. wide spread including breast milk & cross placenta
metabolism
liver
distribution of NSAIDs
highly bound to plasma protein (doesn’t necessarily mean low VD) . wide spread including breast milk & cross placenta
metabolism of NSAIDs
liver
excretion NSAIDs
kidney
define topical route
application of medication to the surface of the skin or mucous membrane of the eye, ear, nose, mouth, vagina, etc
e.g., gels, lotions
define enteral route
administration involves the GIT. methods of administration include oral, sublingual (dissolving the drug under the tongue) & rectal
define parenteral administration
introduce drugs to the body by a different route from enteral (GIT). the most frequently used parenteral routes are intravenous route (IV), intramuscular route (IM), and subcutaneous route
is body concentration the same as plasma concentration
no
what are the two steroid hormones
glucocorticoids & mineralocorticoids
what are glucocorticoids synthesised from
cholesterol
main effects of glucocorticoids
- resistance to stress
- metabolic effects
- anti-inflammatory
- immunosuppressant
where are glucocorticoids made
zona fasciculate in the adrenal gland
what controls the release of glucocorticoids
hypothalamic and pituitary control = negative feedback
the two rhythms influence glucocorticoid release
- circadian rhythm (dark-light sleep)
- ultradian rhythm (CRH & ACTH)
what are the effects of glucocorticoids
anti-inflammatory, immunosuppressant & metabolic effects
glucocorticoids effect in inflammation
they are highly effective in controlling inflammation, but largely limited by their adverse effects
examples of glucocorticoids
hydrocortisone (cortisol) dexamethasone betamethasone triamcinolone fludrocortisone
- short-acting
- intermediate acting
- long acting
= eliminated quite quickly for the most time
mechanism of action of glucocorticoids
nuclear effect: they make our bodies synthese more of the protein annexin-1 = inhibits phospholipaseA2 = inhibits the cascade from the top and the arachidonic acid is not synthesised
in what ways does glucocorticoids modulate gene transcription
gene active hormones:
- promotes or inhibits synthesis of specific mRNA
- initiation of new protein synthesis (transactivation)
- blocking of protein production (transrepression)
= alters the required time to produce an effect
non genomic rapid actions = vasorelaxation & maybe PGE2 release inhibition
what is the target for glucocorticoids
nuclear receptors
some examples of NSAIDs adverse effects & understanding why (off or on target??)
- nausea, diarrhoea, headache REMEMBER THIS ONE - dyspepsia, GI ulceration & bleeding (inhibit COX1, e.g., inhibit platlete aggregation) - raised liver enzymes (Diclofenac) - salt & fluid retention - hypertension
some examples of corticosteroids adverse effects & understanding why (off or on target??)
- adrenal suppression (if the drug is removed at once so forgets how to signal cortisol it self) = low blood pressure etc
- dyspepsia (indigestion)
- hypokalaemia, hyperglycemia (effects processing of carbs)
- myopathy, msucle weakness & wasting (protein synthesis)
- sodium & water retention, oedema
- hypertension
- fat distribution
- skin atrophy, bruising (due to increase bleed), acne, hirsutism
- diabetes, osteoporosis, fractures
what two agonists decrease acid secretion
Prostaglandins E2 and I2 & somatostatin
absolute compared to relative conditions
absolute condition is where if u have that condition you should no take the drug, relative is where the doctor is to balance out the risks and benefits
