2004B03 List the effects of histamine.
Write a brief outline on the pharmacology of the H1 blocking drugs.

Structure

·  Basic amine derived from histidine

Location

·  Mostly in tissue mast cells

·  Also circulating basophils

Cellular

·  H₁: G_q G-protein coupled receptor (GPCR) -> ↑IP₃/Ca²⁺, ↑DAG

·  H_2A: G_s GPCR -> ↑cAMP

Heart

·  H₁: ↓AV node conduction, coronary vasoconstriction

·  H_2A: ↑inotropy, coronary vasodilatation

Vasculature

·  H₁: vasodilatation, capillary leak, angioedema

·  ↓SVR, ↓mAP, cardiac arrest

Skin

·  H₁: urticaria

Respiratory

·  H₁: angioedema -> airway obstruction

·  H₁: bronchoconstriction

·  H_2A: bronchodilatation

GIT

·  H_2A: ↑gastrin and HCl secretion (?) (e.g. ranitidine)

Brain

·  H₁: ARAS wakefulness, nausea/vomiting CTZ and vestibular

First generation

·  Not H₁ specific, crosses blood-brain barrier (BBB), often has other receptor effects

·  e.g. promethazine anti-H and anti-DA₂

·  Use: anti-emetic (especially vestibular), sedation or pre-med

·  H₁ side effects: drowsiness

·  DA₂ side effects: extra-pyramidal (e.g. Parkinsonism)

Second generation

·  Peripheral H_1R specific, doesn’t cross BBB

·  e.g. cetirizine

·  Use: ↓allergy symptoms (especially allergic rhinitis)

·  Side effects: headache, anti-muscarinic e.g. dry mouth

Third generation

·  H₁ specific, doesn’t cross BBB, ↑potency, ↓side effects, often enantiopure

·  e.g. L-cetirizine

·  Use: hypoallergenic effect