Chapter 30 Drugs affecting autacoids

Local hormones  Prostaglandins, histamine and serotonin belong to a group of compounds called autacoids. Although differed in structures and pharmacologic activities, they all have the common feature of being formed by the tissues on which they act; thus, they act as local hormones.  In this chapter, we are going to discuss histamine and histamine antagonists mainly.

Section 1 Arachidonic acid and it’s productions Ⅰ、 Prostaglandins (PGs) Alprostadil (PGE 1 ) Epoprostenol (PGI 2 )

Misprostol Enprostil （恩前列素） Ⅱ、 LTs and LTs inhibitors 1 、 LTs 2 、 LTs inhibitors Ⅲ、 PAF and it’s antagonists 1 、 PAF （血小板活化因子） 2 、 PAF receptor antagonists

Section 2 5-HT and antagonists Ⅰ、 5-HT Ⅱ、 5-HT receptor agonists sumatriptan （舒马普坦） buspirone （丁螺环酮） cisapride （西沙必利） dexfenfluramine （右芬氟 拉明）

Ⅲ、 5-HT receptor antagonists Cyproheptadine （赛庚啶） Ondansetron （昂丹司琼） Ergot alkaloids 1.peptide alkaloids Ergotamine （麦角胺） ergotoxine （麦角毒）

2. Amine alkaloids ergonovine （麦角新碱） methylergonovine （甲基麦角 新碱） methysergide （二甲麦角新碱）

Section 4 Polypeptides Ⅰ、 kinins 1 、 bradykinin (BK) 2 、 kinin inhibitors aprotinin （抑酞酶） icatibant （艾替班特） Ⅱ、 endothelins (ETs) 1 、 Ets 2 、 Ets inhibitors Ⅲ、 substance (SP)

Section 5 Nitric oxide (NO) Section 6 Adenosine

Section 3 Histamine and receptor antagonists Ⅰ． Histamine

 Histamine is a chemical messenger that mediates a wide range of cellular response, including: allergic reactions Local inflammatory reactions gastric acid secretion cardiovascular function possibly neuro-transmission in parts of the brain.

Metabolism of histamine (1) Synthesis Histidine histamine (2) Storage and release of histamine stored in mast cell and basophil Histamine methylhistamine methylimidozoleacetic acid

[Mechanism of actions] Three types of histamine receptors: H 1, H 2 and H 3 -R H 1 receptors are important in  producing smooth muscle contraction  increasing capillary permeability  Dilating vascular smooth muscle  Stimulating sensory nerve ending

H2 receptors  mediate gastric acid secretion  Dilating vascular smooth muscle  Increase heart rate and contractility H3 receptors is located in presynaptic membrane and possibly mediate the negative feedback of histamine release.

Action of histamine

pharmacological effects 1. Cardiovascular system: (1)heart: positive inotropism----H1,H2-R positive chronotropism----H2-R (2)vessel: dilation BP↓ In small doses, the cardiovascular effect of histamine is mainly mediated by H 1 - receptors. In large doses, the cardiovascular effect of histamine is mainly mediated by both H1 and H2-receptors.

 ( 3) triple effect on terminal vasculature (itching & pain):  i. reddening at injection site due to vasodilation  ii. wheal or disk of edema within 1 to 2 min  iii. a large, bright crimson flare or halo surrounding the wheal

Pharmacological effects 2. splanchnic smooth muscle: histamine causes bronchiolar and gastrointestinal tract smooth muscle constriction which is mediated by H 1 receptors.

3. Exocrine system: histamine has long been recognized as a powerful stimulant of gastric acid secretion which is caused by activation of H 2 -receptors on gastric parietal cells. secretion of nasal and bronchial mucus are also increased. it enhances salivary and lacrimal gland secretion (minimal unless large doses are given)

Pharmacological effects 4. nervous system: histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itch. This H 1 -receptor-mediated effect is an important component of some allergic reactions.

clinical uses mainly for diagnosis (1) Testing the secretion of gastric acid (2) Diagnosis of pheochromocytoma (3) Pulmonary function testing (4) Tool drugs Betahistine ( 培他司汀，抗眩啶）

Histamine Antagonists H 1 receptor antagonists have a history for over 60 years. The first H 2 receptor antagonist was reported in 1972, while selective H 3 receptor antagonists are not yet available for clinical use.

H 1 receptor antagonists Pharmacological effects 1.H 1 receptor blockade (1) capiliary (2) BP (3) GI SM (4) branchial SM

H 1 receptor antagonists 2.Actions not caused by histamine receptor blockade (1) Sedative and hypnotic effects (2) Antiemetic （止吐） action (3) Anticholinoceptor actions

Therapeutic uses 1. Skin and mucosa allergic conditions ： H 1 blockers are useful in treating allergies caused by antigens acting on IgE-antibody sensitized mast cells, including: Allergic rhinitis( 鼻炎 ), urticaria( 荨麻疹 ), pollen disease, hay fever, atopic dermatitis, contact dermatitis, drug rash low efficacy on asthma ineffective on alergic shock

Therapeutic uses  2. motion sickness and nausea: some H 1 receptor antagonists, such as diphenhydramine (DH) and dimenhydrinate ( 乘晕宁 ) are the most effective agents for the prevention of the symptoms of motion sickness.

 3. insomnia: some of the H 1 receptor antagonists, such as DH and promethazine, have strong sedative properties.  4. other use: promethazine

adverse reactions H 1 receptor antagonists have a low specificity, that is, they interact not only with histamine receptor but also with muscarinic cholinergic receptors, α-adrenergic receptors and serotonin receptors.

 1. CNS reactions: Sedation, somnolence, hypodynamia the most frequently observed reactions, but less common in some new agents for they do not enter the CNS.  2.gestraintestinal reaction: dry mouth, anorexia, constipation, diarrea

H 2 receptor antagonists Effects (1) Reduce the secretion of gastric acid. (2) Other effects related to H 2 receptor blockade 1) Cardiovascular system 2) Immunoregulation effects

uses  The chief clinical use for histamine H 2 receptor antagonists is as inhibitors of gastric acid secretion in the treatment of peptic ulcers. We will discuss it in other chapter.

H 3 receptor blockers Burimamide GT2277