Chapter 30Drugs 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 (PGE1)

Epoprostenol (PGI2)

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 antagonistsⅠ 、 5-HTⅡ 、 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 PolypeptidesⅠ 、 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 secretioncardiovascular functionpossibly 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:

H1, H2 and H3-R

H1 receptors are important in

producing smooth muscle contraction increasing capillary permeabilityDilating vascular smooth muscleStimulating sensory nerve ending

H2 receptors mediate gastric acid secretionDilating vascular smooth muscleIncrease 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 H1-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 surroundi

ng the wheal

Pharmacological effects

2. splanchnic smooth muscle: histamine causes bronchiolar and gastrointestinal tract smooth muscle constriction which is mediated by H1 receptors.

3. Exocrine system:

histamine has long been recognized as a powerful stimulant of gastric acid secretion which is caused by activation of H2-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 H1-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

H1 receptor antagonists have a history for over 60 years. The first H2 receptor antagonist was reported in 1972, while selective H3 receptor antagonists are not yet available for clinical use.

H1 receptor antagonists

Pharmacological effects

1.H1 receptor blockade

(1) capiliary

(2) BP

(3) GI SM

(4) branchial SM

H1 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 ： H1 blockers are useful in treating allergies c

aused 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 H1 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 H1 receptor antagonists, such as DH and promethazine, have strong sedative properties.

4. other use: promethazine

adverse reactions

H1 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

H2 receptor antagonists

Effects (1) Reduce the secretion of gastric acid. (2) Other effects related to H2 receptor blockade 1) Cardiovascular system 2) Immunoregulation effects

uses The chief clinical use for histamine H2

receptor antagonists is as inhibitors of gastric acid secretion in the treatment of peptic ulcers. We will discuss it in other chapter.

H3 receptor blockers

Burimamide

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