1. Histamine and Histamine Antagonists GAO Fen-Fei

2. Histamine Histamine is one of the most important autacoids ( 自泌物 ), and is formed from the amino acid histidine ( 组氨酸 ) and is stored in high concentrations in mast cells, and basophils ( 嗜碱 细胞 ). Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. It may play a role in many brain functions such as neuroendocrine control, cardiovascular regulation, thermoregulation, and arousal.

3. A second important nonneuronal site of histamine storage and release is the enterochromaffin ( 肠嗜铬 ) -like (ECL) cell of the fundus of the stomach.——the primary acid secretagogues ( 促分泌的 ).

4. Receptors & Effects Two receptors for histamine, H 1 and H 2, mediate most of the well-defined actions; 1.H 1 receptor: important in smooth muscle effects, especially those caused by IgE-mediated responses. ① IP 3 and DAG are released. ② Bronchoconstriction and vasodilation. ③ Vasodilation by release of endothelium-derived relaxing factor (EDRF), are typical responses of smooth muscle. ④ Capillary endothelium, in addition to releaseing EDRF, also contracts, opening gaps in the permeability barrier and resulting in the formation of local edema.

5. 2.H 2 receptor: activation of adenylyl cyclase → cAMP↑ ① Mediates gastric acid secretion by parietal cells in the stomach. ② Cardiac stimulant ( 强心剂 ) effect. ③ Reduce histamine release from mast cells——a negative feedback effect. 3.H 3 receptor: ① involved mainly in presynaptic modulation of histaminergic neurotransmission in the central nervous system. ② In the periphery, it appears to be a presynaptic heteroreceptor with modulatory effects on the release of other transmitters.

8. Tissues and Organ System Effects of Histamine Exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, and on the secretory cells of the stomach. Sensitivity to histamine varies greatly among species. Humans, guinea pigs, dogs, and cats are quite sensitive, while mice and rats are much less so.

9. 1.Nervous system: histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching ( 搔痒 ). 2.Cardiovascular system: 1)Cardiac effects: increased contractility and increased pacemaker rate.——mediated chiefly by H 2 -R. But H 1 -R mediates the decrease of contractility in human atrial muscle. 2)Vascular effects: vasodilator action (H 1 -R, H 2 -R). endothelial cells contraction and increased permeability (H 1 -R). 3)Platelet function : aggregation (H 1 -R) anti- aggregation (H 2 -R)

10. 3.Smooth muscle: contraction (H 1 -R) → bronchoconstriction, abort. histamine- induced contraction of guinea pig ileum ( 回肠 ) is a standard bioassay for this amine. 4.Secretory tissues: stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. (H 2 -R)

11. 5.The “triple response”: Intradermal injection of histamine causes a characteristic wheal ( 风团 ) -and-flare ( 红肿 ) response. At the site of injection, ① a reddening appears owing to dilation of small vessels; ② followed soon by an edematous wheal; ③ At last, a red irregular flare surrounding the wheal.——caused by an axon reflex.

12. Clinical Uses A.Pulmonary Function Testing: Histamine aerosol is sometimes used as a provocative test of bronchial hyperreactivity. B.Tesing Gastric Acid Secretion: However, pentagastrin is currently used for this purpose, with a much lower incidence of adverse effests. C.Diagnosis of Pheochromocytoma ( 嗜铬细胞瘤 ) : Histamine can cause release of catecholamine ( 儿茶酚胺 ) from adrenal medullary cells. This hazardous provocative test is now obsolete.

13. Toxicity & Contraindications Like those of histamine release, dose- related. Flushing, hypotension, tachycardial ( 心动过 速 ), headache, wheals, bronchoconstriction, and gastrointestinal upset.

14. Other Histamine Agonists Betahistine ( 培他司汀；抗眩啶 ) : H 1 -R agonists Impromidine ( 英普咪定；甲双咪胍 ) : H 2 -R agonists (R)α-methylhistamine (Rα- 甲基组胺 ) : H 3 -R agonists

15. Subgroups of Histamine Receptor Blockers

16. H 1 Receptor Antagonists Divided into first-generation and second- generation agents. The first-generation drugs are distinguished by the relatively strong sedative effects and more likely to block autonomic receptors. The second-generation drugs are less sedating characteristic owing to less lipid-soluble to enter the CNS with difficulty or not at all. They are longer-acting.

17. Mechanism & Effects 1.H 1 -R Blockade: 2.Sedation: 3.Antinausea and antiemetic ( 止吐的 ) actions: preventing motion sickness. 4.Antiparkinsonism effects: 5.Anticholinoceptor ( 抗胆碱能受体 ) action: atropine- like effects on peripheral muscarinic receptors. 6.Adrenoceptor-blocking actions: 7.Serotonin ( 血清素, 5- 羟色胺 ) -blocking actions: 8.Local anesthesia: block Na + -channel

18. Clinical Uses 1.Allergic Reaction: 2.Motion Sickness and Vestibular ( 前庭的 ) Disturbances:

19. Toxicity Sedation Antimuscarinic effects such as dry mouth and blurred vision α-blocking actions may cause orthostatic ( 直立的 ) hypotension

22. H 2 Receptor Antagonists Presently available H 2 -R antagonists reversibly compete with histamine at H 2 -R sites. Relatively selective and have no significant blocking action at H 1 or autonomic receptors. The only therapeutic effect of clinical importance is the reduction of gastric acid secretion. Blockade of cardiovascular H 2 -R mediated effects has no clinical significance. Immunomodulating effect.