Inflammation and Anti-inflammatory agents

Question 1

What are the Microvascular effects of Inflammation?

What is the Lewis Triple Response?
→ What is the mediator for this response?

Answer 1

• ↑Blood flow (by Histamine, PG) and ↑Endothelial permeability (by Histamine, Bradykinin)
• Erythema (Local redness), Flare (Wider redness), Wheal (Raised skin)
  → Histamine

Question 2

HISTAMINE:
What is it formed from? What enzyme is used?

What is it metabolised by?

Where is it made, stored and released?

What inhibits its release?

What are its 4 types of receptors? Where are they found?

What does stimulation of the H1 receptor cause?

What does stimulation of the H2 receptor cause?

Answer 2

• Histidine - by Histidine Decarboxylase
• Imidazole-N-methyltransferase (INMT) and Diamine Oxidase
• Mast cells, Basophils, Neurons, and Histaminergic cells in Gut (Enterochromaffin cells)
• β-adrenoreceptors
• • H1 (Gq) - ↑DAG/IP3 - SMOOTH MUSCLE, ENDOTHELIUM, CNS, Sensory nerves
  • H2 (Gs) - ↑cAMP - HEART, PARIETAL CELLS, Uterus, Mast cells, Neutrophils
  • H3 (Gi) - ↓cAMP - Synapses
  • H4 (Gi) - ↓cAMP - Basophils, Bone marrow, Gut
• Vasodilation of arterioles (↓TPR), ↑Venule permeability, Bronchoconstriction, ↓Blood volume, Pain, Itching, Sneezing
• Tachycardia, ↑Gastric acid secretion

Question 3

H1 Receptor Antagonists:
What is used for?

Give examples of its 1st Generation drugs?
→ What is their major Side-effect?
→ What can Promethazine be used as?

Give an example of its 2nd and 3rd Generation drug?
→ What can increase it’s levels?
→ How does it relate to Fexofenadine?

What are these drugs ineffective for?

H2 Receptor Antagonists:
What is used for?

What does it do?

What are the 2 common drug examples?

How does it affect Histamine metabolism?

What are the side-effects?

What is a side-effect specific to Cimetidine?

Answer 3

• ACUTE INFLAMMATION
• Mepyramine, Promethazine
  → Drowsiness
  → Anti-emetic as it has anti-muscarinic effects
• Terfenadine
  → Grapefruit juice, which inhibits P450
  → Active, non-toxic metabolite of Terfenadine
• Asthma

• GASTRIC PROBLEMS
• ↓Gastric acid secretion in the treatment of Gastric/Duodenal ulcers, Zollinger-Ellison syndrome (tumours that secrete gastrin)
• Cimetidine, Ranitidine
• ↑INMT activity = ↑Histamine metabolism
• Confusion, Dizziness, Tiredness, Diarrhoea
• Cimetidine decreases P450 activity = Gynecomastia

Question 4

BRADYKININ:
What’s it produced as a result of?

How is it produced in the Kinin-Kallikrein System?

What are its effects?

Answer 4

• • Activation of Hageman factor (FXII) and production of Plasma Kallikrein
  • Production of Lysylbradykinin by tissue Kallikreins
  • Action of cellular Proteases in Kinin formation
• Kallikrein converts High Molecular Weight Kininogen into Bradykinin
• • Pain, Vasodilation, ↑Vessel permeability, Chemotaxis of wbc’s
  • Contraction of smooth muscle of Gut and Bronchi, which causes Dry Cough

Question 5

5-HT/SEROTONIN:
What’s it derived from?

What’s it released from?

What are its inflammatory effects?

Answer 5

• L-Tryptophan
• • Platelets for Platelet aggregation
  • Enterochromaffin cells of Gut to mediate gut motility, causing diarrhoea
  • Brain for Cognition, Pain, Behaviour, Feeding, Sleep, Vomiting
  • Some tumours for more cancer cell proliferation
• • Stimulates Mast cell Adhesion and Migration = ↑Mast cells at site of injury
  • ↑Inflammatory reactions of Skin, Lungs, and Gut
  • May work with TXA2 to stimulate Platelet activity and Vasoconstriction