HUF 2-80 Pharmacology of autacoids and anti-inflammatory drugs I Flashcards
1
Q
What is inflammation?
A
- universal reaction to tissue damage & pathogen invasion => restore homeostasis - ↑ local immune cells activation - proinflammatory mediators - blood vessel permeability - leukocyte invasion from periphery
2
Q
Events of inflammation
A
1. Vasodilation => ↑ blood flow => redness; local hotness 2. Chemotaxis => inflammatory mediators, cytokines, cytotoxic agents => migration of immune cells (defense) 3. Blood coagulation => platelet plug formation => stop bleeding 4. ↑ capillary permeability => edema (fluid from interstitial space) => swelling 5. Sensitization of nociceptive fibres => pain (also from compression of sensory n. fibres) => temporary loss of function
3
Q
What are autacoids?
A
- locally released chemical mediators (paracrine)
- from: tissue/cells (epithelial cells)
- from: immune cells (neutrophils/monocytes…)
- monoamine: histamine
- membrane lipid-derived: eicosanoid (PG, TX, LT)
- peptide: kinin (bradykinin)
- others: endothelin, NO, serotonin…
4
Q
What is normal inflammatory response?
A
- acute
- resolves after removal of inciting stimulus
5
Q
What are diseases of inflammation?
A
- inappropriate inflammation / chronic inflammation
- long-term inappropriate response to stimulus
- offending agent is not removed
6
Q
Simple outlines of drug treatments of inflammation
A
- Target inflammatory mediators
=> treat symptoms
e.g. NSAID, anti-histamines, anti-pyretics - Target inflammatory responses caused by pathophysiologic stimuli
e. g. anti-inflammation and pain-relief treatments for gout
7
Q
What are eicosanoids?
A
- PG, TX, LT
- polyunsaturated fatty acid; 20 C; 4 C=C
- mediator in inflammation; regulator of coagulation
- synthesized and released upon stimulation
- not stored intracellularly
- PLA2 (Phospholipase A2): enzyme for membrane phospholipid → AA (arachidonic acid)
- PLA2 activated upon stimulation of other signalling molecules e.g. cytokine
8
Q
Reactions of cyclo-oxygenase (COX)
A
- Cyclooxygenase step: AA → PGG2 (COX1/2)
- Peroxidase step: PGG2 → PGH2 (COX1/2)
- PGH2
→ PGE2/PGF2 (altered vascular permeability)
→ TXA2 (vasoconstriction, platelet aggregation)
→ PGI2 (inhibition of platelet aggregation, vasodilation)
9
Q
Classifications of COX
A
- COX1
- constitutively expressed
- regulation of homeostasis
e. g. renal function, gastric mucosal protection, platelet function - COX2
- inducible
- cells at inflammatory sites
=> gene induction
=> ↑ COX2
10
Q
Properties of PGE2
A
- pyrogenic (inducing fever in infection)
- vasodilation
- ↑ pain sensation (↑ effects of pain-producing agents e.g. SP, BK)
11
Q
Properties of TXA2
A
- TXA2 synthase (in platelets)
- vasoconstriction
- TP receptors on platelets (Gq)
=> GPIIb/IIIa receptor activation
=> platelet aggregation
12
Q
Properties of PGI2 (prostacyclin)
A
- PGI2 synthase (endothelial cells)
- vasodilator
- IP receptors => anti-thrombic
13
Q
What are prostanoids?
A
- extracellular messengers which bind to surface prostanoid receptors (GPCR)
- tissue-specific intracellular signalling context
- variations in downstream effectors
- same prostanoids & tissue types => diff. responses
14
Q
Metabolism of prostaglandins
A
- very short t1/2 (< 1 min.)
- rapidly metabolised to inactive products
- lung metabolism:
1. cellular uptake
2. PGDH (e.g. 15-PGDH) OR other reductases
3. resulting metabolites (inactive products) degraded by general fatty acid-oxidising enzymes
15
Q
Alprostadil
A
- clinical name of PGE1
- ↑ blood flow & oxygenation by vessel relaxation
- neonatal defects
