Histamine, Serotonin and Bradykinin
Class
Prototype
Autoacoid
Histamine
H1 receptor
antagonists
Diphenhydramine
(Benadryl)
Mechanism
Mediated by 3 membrane receptors. H1 and H2 in periphery, H3
in CNS. Activation of H1 receptors on endothelial and smooth
muscle cells increases IP3 hydrolysis and increase in intracellular
Ca++. Activation of H2 receptors in gastric mucosa, cardiac,
smooth muscle and some immune cells leads to increase in
intracellular cAMP. H3 activation in CNS leads to decreased
histamine release.
Overall, principal cells that store histamine (blood basophils and
tissue mast cells) are involved in Type I immediate
hypersensitivity reactions
Competitive inhibitor of histamine at H1 receptors. Prevents
inflammatory and bronchoconstrictor effects of histamine (do not
reverse effects).
Terfenadine
(Seldane--no
longer in use)
H2 receptor
antagonists
Cimetidine
Ranitidine
Reversible competitive inhibitors of histamine at H2 receptors (no
H1 inhibiting activity)--mostly, inhibit acid secretion in GI
Tox/Side Effects
Use
Major mediator of
anaphylactic reactions
-↑ HR, ↓ BP
-vasodilation
-bronchoconstrictor
-stimulates gastric acid
secretion
-causes pain and itching
no current clinical
use
-Sedation
-Excitement in young
children
-Blurred vision, constipation
and urination retention
-with Terfenadine-life
threatening arrythmias
-Diarrhea, dizziness,
somnolence and headance
-in high doses in men,
gynecomastia, impotence
and reduced sperm count
-may interfere with hepatic
drug metabolism of other
drugs
Relief of
respiratory tract an
skin irritation due
to allergic reaction
(sneezing, itching,
oocular symptoms)
Gastric and peptic
ulcers
Esophageal reflux
1
Protein Pump Omeprazole
Inhibitor
Autoacoid
Serotonin
Serotonin
agonist
Serotonin
antagonist
Sumatriptan
Decreases gastric acid production by inhibiting the gastric proton
pump of parietal cells
Multiple subtypes of receptors:
-5-HT1a and 5-HT1d=in CNS, act to decrease cAMP intracellularly
-5-HT2=platelets, smooth muscle cells, endothelial cells, and
CNS, act to increase IP3
Overall: constricts most vessels, but vessels in skeletal muscle
and heart are dilated. Can elicit Bezold-Jarisch reflex
(bradycardia) and triphasic blood pressure response. Contributes
to platelet activation and 2° platelet aggregation.
5-HT1d agonist
Ondansetron
5-HT3 antagonist
Autoacoid
Bradykinin
Bradykinin
Receptor
antagonists
none noted
Is the principal kinin in plasma. Two types of receptors B1 = limited distribution, play role in inflammation and collagen
synthesis
B2 = mediate contraction of venous smooth muscle (Bradykinin
induces profound vasodilation)
Overall: produce marked vasodilation in heart, kidney, intestine,
skeletal muscle and liver. 10x more potent than histamine in
relaxing vascular smooth muscle. In veins, primary effect is
contraction. Are also potent stimulators of pain fibers in skin and
viscera.
Have been shown to have neuroprotective effect in severely
brain-injured patients by preventing elevation in intracranial
pressure. Studies in progress.
-inhibits activity of P-450
enzymes
-Possibly involved in
pathophysiology of
migraines and headaches
Peptic ulcers
Reflux esophagitis
No clinical use
Acute migraine an
cluster headaches
Prevents nausea
and vomiting in
chemotherapy.
No clinical use
2