Lecture 4- Therapeutics for inflammation Flashcards
what are H1 receptor antagonists commonly known as?
Anti-histamines
what do histamines do?
- increase vascular permeability
- release pro-inflammatory mediators- eosinophils, adhesion molecules etc.
how many classes of histamine receptor are there?
2 (H1 and H2)
how many generations of anti-histamines have there been?
3
what was a major side-effect of anti-histamine generation 1?
sedation (drowsy)
what changed from generation 1 to generation 2 of anti-histamine side-effects?
no sedating effects but could react with other chemical such as grapefruit juice to give cardiotoxic effects
what changed from generation 2 to generation 3 of anti-histamines?
non sedating and non-cardio toxic
however they still bind to muscarinic receptors which can cause blurred vision and dry mouth
what are the 3 actions of NSAIDs?
1) anti-inflammatory
2) analgesic
3) anti-pyretic (reduce fever)
how do NSAIDs have an anti-inflammatory effect?
decrease in PGE2 and PGI1 to inhibit oedema
how do NSAIDs have an analgesic effect?
decrease prostaglandin sythesis, less sensitisation of nociceptors to bradykinin and 5-HT
how do NSAIDs have an anti-pyretic effect?
prevents IL-1 from releasing prostaglandins in te CNS so doesn’t elevate the hypothalamic set point for body temp
what’s the worst anti-inflammatory NSAID?
salicylic acid
what’s the best anti-inflammatory NSAID?
flurbiprofen
is paracetamol anti-inflammatory?
unknown/ contraversial subject
what 2 important enzyme families do NSAIDs have an effect on to cause side-effects?
COX-1
COX-2
by what mechanism do NSAIDs inhibit COX enzymes?
they prevent the binding of arachidenate to the active site of the COX enzyme
how are NSAIDs distinguished?
by their Cox selectivity, rather than chemical class
what are the 4 classes of NSAIDs with examples?
Selective COX-1 inhibitor- low dose aspirin
Non- selective COX inhibitors- ibuprofen and high dose aspirin
Selective COX-2 inhibitors- meloxicam
Highly selective COX-2 inhibitors- celeboxib
where does most of the knowledge about steroidal anti-inflammatory drugs come from?
observation of naturally produced steroids in the body
is natural cortisol produced at a steady speed or does it fluctuate?
it fluctuates throughout the day
however, it increases in stressful situations like illness
what chemical to anti-inflammatory steroids mimic?
cortisol
show the natural glucocorticoid production and feedback
CRH (corticotropin releasing hormone)–>anterior pituitary –> releases ACTH (adrenocorticotropic hormone) –> adrenal glands (on kidney) –> circulating glucocorticoids –> stops CRH poduction from hypothalamus
what type of feedback is there in natural glucocorticoid production?
negative
what are the 3 actions of exogenous glucocorticoids (steroid anti-inflammatories)?
- suppress immune system (intended, therefore not side effect)
- increase blood glucose
- reduce bone formation
give 2 examples of exogenous glucocorticoids
- hydrocortisol (external)- excema
- prednisolone
what’s the mechanism of actions of steroid anti-inflammatories on cells?
- they’re lipophilic, so can enter cells
- bind to cytoplasmic receptors
- causes dimerisation
- receptor-steroid dimer moves into nucleus
- it interacts with HRE (hormone response element)
- will lead to either up or down- regulation of mRNA production to either increase anti-inflammatory agents or decrease pro-inflammatory agents
what effects do anti-inflammatory drugs have on immune cells?
- reduced migration of neutrophils into tissue from BVs
- reduced activation of WBCs
- reduced T-helper proliferation and fibroblasts e.g. collagen
what effects do anti-inflammatory drugs have on immune chemical mediators?
reduced production of mediatiors such as- cytokines, TNF, cell-adhesion molecules, histamine, NO synthase, complement proteins
increased synthesis of IL-10 and annexin-1 which are anti-inflammatory chemicals
give some side-effects of steroid anti-inflammatories:
candidas bruising weight changes/ fat redistibution osteoporosis adrenal suppression
what effect do steroid hormones have on HPA axis?
negative effect
why can’t patients come straight off most steroid drugs?
takes a while before the HPA axis returns to normal so need to come of slowly to prevent dangerous withdrawal symptoms
what’s the difference between NSAIDs and DMARDs?
NSAIDs only reduce symptoms caused by inflammation, whereas DMARDs can affect the progression of an inflammatory disease over several months
what type of drugs do DMARDs include?
immunosuppressants
antimalarials
gold salts
what’s an important example of an immunosuppressant DMARD?
Methotrexate
what does methotrexate do to cells?
pauses them in S-phase
overall, what negative thing is happening in gout?
increased plasma urate/uric acid which deposits as crystals in synovial joints to cause pain and stiffness
what, immune-system wise is uric acid?
a DAMP which stimulates the production of IL-1
what’s the acute treatment for gout?
- NSAIDs
- corticosteroids
- colchicine- reduces neutrophil mobility
what’s the long-term treatment for gout?
- uricosuric agents- act on kidney to increase uric acid secretion
- xanthine oxidase inhibitors- increase uric acid levels in urine, therefore less in plasma
what are anti-cytokine drugs used to treat?
rheumatoid arthiritis/ other inflammatory arthritis’
what do anti-cytokine drugs target?
TNF and ILs (cytokines)
why are anti-cytokine drugs expensive?
they are biologics (come from a living organism)
what’s a negative long-term effect of anti-cytokine drugs?
increased risk of infection
what does PPAR stand for?
Peroxisome Proliferator Activated Receptor (agonist)
give 2 examples of PPARs
- fibrates
- thiazolidinediones
what do PPARs do?
reduce expression of cytokines, chemokines, cell adhesion molecules, TLRs etc.
what are the 3 subtypes of PPARs?
alpha
beta/delta
gamma
what’s a major pathology PPARs are used to treat?
atherosclerosis
what is it important to balance when treating inflammatory diseases?
the anti-inflammatory effects of drugs with the host’s need for inflammation for immune system function
