Transcript Histamine and Histamine Antagonists

Histamine and
Histamine Antagonists
GAO Fen-Fei
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.
• 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).
Receptors & Effects
•
Two receptors for histamine, H1 and H2,
mediate most of the well-defined actions;
1. H1 receptor: important in smooth muscle effects,
especially those caused by IgE-mediated responses.
① IP3 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.
2. H2 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. H3 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.
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.
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
H2-R. But H1-R mediates the decrease of
contractility in human atrial muscle.
2) Vascular effects: vasodilator action (H1-R, H2-R).
endothelial cells contraction and increased
permeability (H1-R).
3) Platelet function: aggregation (H1-R)
antiaggregation (H2-R)
3. Smooth muscle: contraction (H1-R) →
bronchoconstriction, abort. histamineinduced 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. (H2-R)
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.
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.
Toxicity & Contraindications
• Like those of histamine release, doserelated.
• Flushing, hypotension, tachycardial(心动过
速), headache, wheals,
bronchoconstriction, and gastrointestinal
upset.
Other Histamine Agonists
• Betahistine(培他司汀；抗眩啶): H1-R
agonists
• Impromidine(英普咪定；甲双咪胍): H2-R
agonists
• (R)α-methylhistamine(Rα-甲基组胺): H3-R
agonists
Subgroups of Histamine
Receptor Blockers
H1 Receptor Antagonists
• Divided into first-generation and secondgeneration 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.
Mechanism & Effects
1. H1-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: atropinelike 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
Clinical Uses
1. Allergic Reaction:
2. Motion Sickness and Vestibular(前庭的)
Disturbances:
Toxicity
• Sedation
• Antimuscarinic effects such as dry mouth
and blurred vision
• α-blocking actions may cause
orthostatic(直立的) hypotension
H2 Receptor Antagonists
• Presently available H2-R antagonists reversibly
compete with histamine at H2-R sites.
• Relatively selective and have no significant
blocking action at H1 or autonomic receptors.
• The only therapeutic effect of clinical importance
is the reduction of gastric acid secretion.
Blockade of cardiovascular H2-R mediated
effects has no clinical significance.
• Immunomodulating effect.