Histamine Flashcards
Histamine
-Mediator of immediate allergic and
inflammatory reactions
-
-neurotransmitter and neuomodulator
synthesis/metabolism of histamine
- histidine decarboxylase (an inducible enzyme) creates histamine from histidine
- alterations in histamine degrading enzymes can account for histamine intolerance (1% of population)
- genetic or acquired
Where is most histamine found
-lungs, skin, GI tract
Describe histamine in mast cells
- it is synthesized and stored in secretory granules
- there is a slow turnover bc it is stored here
Yes storage granules!!
Describe histamine is in non-mast cells (gastric mucosa cells, epidermins, neurons)
when histamine is in non-mast cells there are no granules. it is continuously synthesized and released so there is a rapid turnover
no storage granules!
effects of histamine release
- within seconds:
- burning, itching,
- **intense warmth
- **skin reddens
- **BP decreases: increase vascular permeability
- HR increases
within minutes;
- BP recovers
- hives appear
mechanism of release of mast cell histamine
- Antigen-antibody reaction (IgE)
- requires prior exposure to an antigen
- Ca dependent
- also other mediators are released as well not just histamine but histamine is the main one
Is the only way to get histamine released from a mast cell via an Antibody-Antigen response
NO!!!
histamine can be released via direct stimulation/ without prior exposure
-but this is of clinical concern bc it causes and inflammatory response and it is kind of scary that drugs and toxins can directly cause this on first exposure
What is the mechanism of release of direct stimulation causing histmaine release from mast cells
an increase in intracellular Calcium
What are some other stimuli that release histamine
- cold urticaria- cold hives
- Cholinergic urticaria
- Solar urticari a
- non-specific cell damamge
Cholinergic urticaria
-increased sympathetic nevous activity (seen with exercise and stress) stimulate cholinergic fibers innervating sweat glands to release acetylcholine, leading to mast cell degranulation
Cromolyn
- anti-inflammatory agent that stabilizes mast cell membrane to prevent the release of histamine
- it prevents mast cell degranulation
- therapeutic use: prohylaxis of bronchospasm (allergen or exercise-induced)
Omalizumab
-decreases the amount of antigen specific IgE that normally binds to and sensitizes mast cells
-an IgG antibody for which the antigen is the Fc region of the IgE antibody (basically Omalizumab is antibody that binds to the IgE antibody)
-adverse effects: anaphylaxis
therapeutic use: patients with severe asthma that is poorly controlled or patients with severe concomitant allergic rhinitis
Does Omalizumab only work on IgE that is bound to mast cells
NO! it activate high affinity receptors (FcERI) on mast cells and low affinity receptors (FcERII, CD23) on toher inflammatory cells
-so although we use it to stope IgE on mast cells so that less histamine is release Omalizumab can also inpact other inflammatory/immune cells
What are the four subtypes of receptors for Histamine
H1
H2
H3
H4
but there are only drugs for H1 and H2 that we are going to talk about
What is the main effect of histamine on the CV system
Vasodialtion
-H1 (endothelial cells)
H2 (vascular smooth muscle cells)
Where is H1 found
Endothelial cells
Where is H2 found
Vascular smooth muscle
Properties of H1 receptor
Gq which increases Ca and also then NO
Properties of H2
Gs which increases cAMP
H1 effector system is coupled to
increase Ca (endothelial cells which then increases NO and leads to vasodilation)
H2 effector system is coupled to
increase cAMP
How do the H1 receptors lead to vasodilation
H1 receptors located on endothelial cells results in increase in calcium and activation
of nitric oxide synthase
NO is a vasodilator in VSM
How do H2 receptors lead to vasodilation
H2 receptors located on vascular smooth muscle cells results in increase in cAMP
- decreasing intracellular calcium
- decreasing the rate of myosin phosphorylation.
- Inhibit constriction = vasodilation
hypothetical question: If there were H1 receptors on vascular smooth muscle what would happen
constriction bc H1 causes an increase in Ca. so good thing it is in the endothelial cells and can cause the increase in NO and therefore vasodilation
How does histamine impact blood pressure
-in general, histamine dilated resistance vessels and causes an overall fall in BP
How does histamine impact BP
it causes an increase in vascular permeability by acting on H1 receptors
-located on post-capillary venules-endothelial cells, when histamine binds to the H1 receptor is increases Ca which causes the endothelial cells to contract and expose the basement membrane.
this makes the m=basement membrane freely permeable to plasma proteins and fluid.
increase the vascular permeability which decreases BP
What does histamine do to the bronchioles
stimulates the H1 receptor which increases Ca and leads to contraction
What does histamine do to the exocrine glands
- GI secretory tissue (parietal cell)
- H2 receptor leads to gastric acid secretion
- this is where H2 antagonists work
What does histamine do to the peripheral nerve endings
it binds to the H1 receptor and causes pain and itching
Describe the neuroendocrine (Central) Effects of histamine
-it binds to the H1 receptor and causes increased arousal/ wakefulness
List the first generation H1 receptor blockers
-Diphenhydramine
-Dimenhydrinate:Contains both diphenhydramine and
chlorotheophylline
- Chlorpheniramine
- Promethazine: Also dopamine blocker
List the Second generation H1 receptor blockers
- Fexofenadine
- Loratadine
- Cetirizine
- Desloratidine
Describe the pharmacology of the H1 blockers
- specifically reversible antagonists of the H1 receptors located in both the periphery and the brain (therefore can lead to CNS effects like drowsiness)-considered and inverse agonist bc reduce constitutive activity at the receptor and compete with histamine
- First generation drugs have other non-specific effects unrelated to the H1 receptor blockade
- second generation have little to no CNS effects
histamine released during an allergic reaction casues
blood vessels to dilate and causes redness, swelling itching, and changes in the secretions of nasal tissue (ie vascular permeability)
Major pharmacological effect of H1 antagonists
-reduce the symptoms associated with allergic responses/inflammation
- inhibition of vascular permeability
- suppress itching
CNS side effects of H1 antagonists
- specifically mostly the first generations
- most common is slowed reaction times, decreased alertness
Pharmacokinetics of H1 antagonist
- oral administration
- rapid absorption: peak concentration 1-2 hours
-widely distributed: however 2nd generation (fexofenadine, loratadine, desloratadine, cetirizine) less likely to enter the brain
Metabolism of the H1 antagonists
-Extensive liver metabolism
-2nd generation:
some are metabolized by P450 enzymes
terfenadine is metabolized to
fexofenadine
Loratadine si metabolized to
desloratadine
Cetirizine
is active metabolite of hydroxyzine
Sedation is most common with which generation of H1 anatagnists
1st generation
- due to inhibition of central H1 effect
- central anticholinergic effect
What are the reasons for why first generation antihistmines have a sedative effect
- enters CNS
- blocks h1 receptors that mediate arousal (in CNS)
- Are nonspecific and also have structures that allow them to block cholinergic receptors in CNS
other anti-muscarinic (anticholinergic) side effects
seen only with some first generation drugs
-dry mouth, dryness of respiratory passages, urinary retention
which second generation drugs are no longer marketed in the US
Terfenadine and Astemizole
prolong QT interval
When are H1 antagonists less effective for allergies
- Allergens abundant -Exposure prolonged
- Nasal congestion prominent
What is the most potent first generation drug
chlorpheniramine also causes less sedation in some patients
What is the first generation drug with the most sedativeeffects
Diphenhydramine
What is the second generation drug with the most sedative effects
-cetirizine
Tell me about motion sickness
-it involves muscarinic cholinergic transmission
Which drugs have an anti-cholinergic effect
- dimenhydrinate (dramamine)
- promethazine (phenergan)
- diphenhydramine ( benadryl)
What do H2 receptor antagonists cause
relief of symptoms peptic ulcer disease
and gastroesophageal reflux disease (GERD)
how do the H2 histamine receptors lead to increase in stomach acidity
stimulation of H2 receptors on parietal cells increases adenyl cyclase which increases cAMP which activate PKA which increases acid!!!
Pharmacological profile for H2 antagonist
- reversible competitive inhibitors specific for the H2 receptor on the basolateral membrane of parietal cells
- inhibit nocturnal gastric acid secretion which is a big determinant in healing of ulcers
- also reduced volume of gastric acid and H+ concentration
Pharmacokinetics of H2 anatagonists
oral administration rapid
adverse effects for H2 antagonists
incidence is really low!! except for cimetidine (bc cimetidine is metabolized by P450s)
-any drug that inhibits gastric acid secretion or pH can alter bioavailability of other drugs bc it can change their absorption
Side effects of cimetidine
inhibits P450 metabolism and therefore prolongs the half life of other drugs
MAJOR USE OF H2 ANATGONISTS
Uncomplicated GERD
