Histamine and Histamine Antagonists

1
Histamine and Histamine Antagonists

• GAO Fen-Fei

2
Histamine

• Histamine is one of the most important
  autacoids(???), and is formed from the amino acid
  histidine(???) and is stored in high
  concentrations in mast cells, and
  basophils(????).
• 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(???)-l
  ike (ECL) cell of the fundus of the stomach.the
  primary acid secretagogues(????).

4
Receptors Effects

• Two receptors for histamine, H1 and H2, mediate
  most of the well-defined actions
• H1 receptor important in smooth muscle effects,
  especially those caused by IgE-mediated
  responses.
• IP3 and DAG are released.
• Bronchoconstriction and vasodilation.
• Vasodilation by release of endothelium-derived
  relaxing factor (EDRF), are typical responses of
  smooth muscle.
• Capillary endothelium, in addition to releaseing
  EDRF, also contracts, opening gaps in the
  permeability barrier and resulting in the
  formation of local edema.

5

• H2 receptor activation of adenylyl cyclase ?
  cAMP?
• Mediates gastric acid secretion by parietal cells
  in the stomach.
• Cardiac stimulant(???) effect.
• Reduce histamine release from mast cellsa
  negative feedback effect.
• H3 receptor
• involved mainly in presynaptic modulation of
  histaminergic neurotransmission in the central
  nervous system.
• In the periphery, it appears to be a presynaptic
  heteroreceptor with modulatory effects on the
  release of other transmitters.

6
(No Transcript)
7
(No Transcript)
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

• Nervous system histamine is a powerful stimulant
  of sensory nerve endings, especially those
  mediating pain and itching(??).
• Cardiovascular system
• 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.
• Vascular effects vasodilator action (H1-R,
  H2-R). endothelial cells contraction and
  increased permeability (H1-R).
• Platelet function aggregation (H1-R)
  anti-aggregation (H2-R)

10

1. Smooth muscle contraction (H1-R) ?
   bronchoconstriction, abort. histamine-induced
   contraction of guinea pig ileum(??) is a standard
   bioassay for this amine.
2. Secretory tissues stimulant of gastric acid
   secretion and, to a lesser extent, of gastric
   pepsin and intrinsic factor production. (H2-R)

11

• The triple response Intradermal injection of
  histamine causes a characteristic
  wheal(??)-and-flare(??) response. At the site of
  injection,
• a reddening appears owing to dilation of small
  vessels
• followed soon by an edematous wheal
• At last, a red irregular flare surrounding the
  wheal.caused by an axon reflex.

12
Clinical Uses

1. Pulmonary Function Testing Histamine aerosol is
   sometimes used as a provocative test of bronchial
   hyperreactivity.
2. Tesing Gastric Acid Secretion However,
   pentagastrin is currently used for this purpose,
   with a much lower incidence of adverse effests.
3. Diagnosis of Pheochromocytoma(?????) Histamine
   can cause release of catecholamine(????) from
   adrenal medullary cells. This hazardous
   provocative test is now obsolete.

13
Toxicity Contraindications

• Like those of histamine release, dose-related.
• Flushing, hypotension, tachycardial(????),
  headache, wheals, bronchoconstriction, and
  gastrointestinal upset.

14
Other Histamine Agonists

• Betahistine(???????) H1-R agonists
• Impromidine(????????) H2-R agonists
• (R)a-methylhistamine(Ra-????) H3-R agonists

15
Subgroups of Histamine Receptor Blockers
16
H1 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. H1-R Blockade
2. Sedation
3. Antinausea and antiemetic(???) actions
   preventing motion sickness.
4. Antiparkinsonism effects
5. Anticholinoceptor(??????) action atropine-like
   effects on peripheral muscarinic receptors.
6. Adrenoceptor-blocking actions
7. Serotonin(???, 5-???)-blocking actions
8. Local anesthesia block Na-channel

18
Clinical Uses

1. Allergic Reaction
2. Motion Sickness and Vestibular(???) Disturbances

19
Toxicity

• Sedation
• Antimuscarinic effects such as dry mouth and
  blurred vision
• a-blocking actions may cause orthostatic(???)
  hypotension

20
(No Transcript)
21
(No Transcript)
22
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.

23
(No Transcript)