Anti-histamines (Concepts)

Question 1

What is the triple response?

Answer 1

1. Flush (immediate): Redness in area of injury
2. Flare (30-60 seconds): Redness in area surrounding injury
3. Wheal (few minutes): Swelling in area of injury

Question 2

What causes the triple response?

Answer 2

1. Flush: Vasodilation due to release of local mediators such as histamine.
2. Flare: Axon reflex (neurogenic inflammation) from collateral branches of sensory neurones mediating pain sensation.
3. Wheal: Increased vascular permeability as a result of histamine release.

Question 3

What are the substances released by neurones mediating neurogenic inflammation?

Answer 3

1. Calcitonin gene-related peptide (CRGP): Direct vasodilation
2. Substance P: Direct vasodilation & degranulation of mast cells
3. Neurokinin A

Question 4

How do pathogens cause inflammation?

Answer 4

1. Direct release of inflammation-inducing toxins
2. Induction of the innate immune system through PAMPs
3. Lysis of host cells to release DAMPs

Question 5

What is the enzymatic content of the inflammatory exudate?

Answer 5

1. Complement system
2. Coagulation system
3. Fibrinolytic system
4. Kinin system

Question 6

What type of vessels do neutrophils leave the bloodstream from?

Answer 6

Venules

Question 7

What are the different routes taken by neutrophils when leaving the blood vessels?

Answer 7

1. Through endothelial cells (~30 minutes)
2. Between endothelial cells (~15 minutes)

Question 8

What types of receptors are expressed by mast cells?

Answer 8

1. C3a. C5a (G_i-coupled)
2. IgE (FcεR1)
3. TLRs
4. SP (MrgX2, G_q-coupled)

Question 9

What types of cells is histamine synthesised in?

Answer 9

1. Mast cells
2. Basophils
3. Enterochromaffin-like cells (in gut)
4. Some CNS neurones

Question 10

How is histamine stored?

Answer 10

• In acidic granules
• Complexed with macroheparin

Question 11

What is the mechanism of C3a/C5a mediated mast cell degranulation?

Answer 11

G_βγ → PLC_β → IP₃ → ↑[Ca²⁺]_i

Question 12

What is the mechanism of SP mediated mast cell degranulation?

Answer 12

Gα_q → PLCβ → IP₃ → ↑[Ca²⁺]_i

Question 13

What is the mechanism of IgE mediated mast cell degranulation?

Answer 13

Fc_εR1 aggregation → LAT phosphorylation → PLCγ → IP₃ → ↑[Ca²⁺]_i

Question 14

What are the types of histamine receptors?

Answer 14

1. H₁: G_q/11
2. H₂: G_s
3. H₃: G_i
4. H₄: G_i

Question 15

What are functions mediated by H₁?

Answer 15

1. Smooth muscle contraction (ileum, bronchioles, uterus)
2. Vasodilation (via NO)
3. Itching (activation of pruritoreceptors)
4. Inflammation (triple response)
5. Neurotransmission

Question 16

What are functions mediated by H₂?

Answer 16

1. Increased heart rate
2. Gastric acid secretion
3. Neurotransmission

Question 17

What are functions mediated by H₃?

Answer 17

Neurotransmission (pre-synaptic inhibition)

Question 18

How do H₃ receptors mediate pre-synaptic inhibition?

Answer 18

Gi_α → ↓PKA → ↓[Ca²⁺]_i

Gi_βγ → ↓[Ca²⁺]_i

Question 19

How is histamine synthesised?

Answer 19

• From histidine
• Histidine decarboxylase

Question 20

How is histamine metabolised?

Answer 20

1. Histamine → Imidazole acetaldehyde (Histaminase)
2. Histamine → N^T-methylhistamine (Histamine N-methyltransferase)

Question 21

What pathological conditions involve histamine?

Answer 21

• Type 1 hypersensitivity (allergies)
• Urticaria
• Mastocytosis (excess numbers of mast cells)

Question 22

What is the sequence of events leading to histamine-mediated gastric acid secretion?

Answer 22

1. Secretion of gastrin by G-cells
2. Gastrin binds to CCK₂ receptors on ECL cells
3. Increased [Ca²⁺]_i in ECL cells and histamine release
4. Histamine binds to H₂ receptors on parietal cells
5. Activation of PKA and increased phosphorylation of H⁺/K⁺ exchanger
6. Increased trafficking of H⁺/K⁺ exchanger to PM
7. Increased gastric acid secretion