HUF 2-81 Pharmacology of autacoids and anti-inflammatory drugs II

Question 1

Full events of acute inflammation

Answer 1

• tissue damage / pathogen invasion
  => local cytokine cascade
  => ↑ COX2
  => ↑ proinflammatory, vasoactive eicosanoids
  => ↑ [PGE2], [LT]
  => ↑ blood flow & vascular permeability
  => accumulation & infiltration of inflammatory cells; edema (fluid leak & filtration)

Question 2

LT Pathway

Answer 2

5HPETE (hydroperoxyeicosatetraenoic acid)
↓ (5-lipoxygenase)
LT 
↓
LTB4 OR LTC4/D4/E4

Question 3

LTB4

Answer 3

• produced mainly by neutrophils
• chemotaxis of neutrophils & macrophages
• ↑ cytokine release & lymphocyte proliferation
• GPCR: BLT1, BLT2

Question 4

LTC4/D4/E4

Answer 4

• cysteinyl LT
• produced by eosinophils, basophils, mast cells…
• C4 & D4: potent spasmogens
• E4: less potent; long-lasting spasmogen
• asthma: potent bronchial smooth muscle contraction
• GPCR: CysLT1, CysLT2

Drugs for asthma:

1. Zileuton (5-lipoxygenase inhibitor)
2. Montelukast (CysLT1 antagonist)

Question 5

Platelet Activating Factor (PAF)

Answer 5

Photphatidylcholine → AA (PLA2)
↓
Lyso-glycerylphosphorylcholine
↓ (acetyl transferase)
PAF

• degranulation of platelets
• platelet aggregation
• ↑ TXA2 production (platelets)
• vasodilation
• chemotaxis of leukocytes

Question 6

Histamine Triple Response

Answer 6

1. Histamine from mast cells
   => redenning (vasodilation)
2. Wheal (↑ permeability)
3. Flare by axon reflex
   - antidromic impulse
   => sensory n. fibres release vasodilatory peptides (e.g. CGRP, SP)
   => activate mast cells
   => arteriolar dilatation

(sensory n. fibres stimulated => pain)

Question 7

Histamine

Answer 7

• basic amine in many tissues esp. exposed to outside world (e.g. lung, skin, GI tract)
• stored inside intracellular granules in mast cells and basophils
• asthma, allergy, anaphylaxis

Question 8

Histamine receptors

Answer 8

1. H1 (Gq)
   - wakefulness
   - sm. ms. contraction except vascular sm. ms
   - motion-induced emesis (CNS)
2. H2 (Gs)
   - gastric secretion
   - cardiac stimulation
3. H3
   - regulate histamine & other NT release in CNS
4. H4
   - bone marrow & WBC, many tissues
   - regulate WBC actions (e.g. mast cells, eosinophils)

Question 9

Histamine receptor antagonists

Answer 9

• block H1R in CNS
• weakly block muscarinic receptors
  => sedation, blurred vision, dry mouth…

Opioid-induced emesis

• Cyclizine
• Cinnarizine
• Dimenhyrinate

Pregnancy-induced emesis

• Promethazine
• Meclizine

(All can be used for motion-induced emesis)

Question 10

H2R antagonists

Answer 10

• Cimetidine
• Ranitidine
• Famotidine
• competitive antagonists
• ↑ ulcer healing
• ↓ food- and gastric-stimulated gastric acid secretion
• gastroesophageal reflux

Question 11

Antihistamines (H1R antagonists)

Answer 11

• relieving symptoms of cold & seasonal allergy (rhinorrhea, allergic rhinitis, allergic conjunctivitis)

e.g. diphenhydramine (1st gen.)
- potent muscarinic receptor antagonists
=> sleepiness, drowsiness
- α / 5-HT receptor antagonists
- lack of receptor selectivity => X tolerable

e. g. loratadine (2nd gen.)
- most selective for peripheral H1R
- cannot cross BBB => mainly act outside CNS

• OTC sleep aids
• treat skin rash & hives (e.g. mepyramine)