Histamine Flashcards
To rock the heck out of histamine!
From what essential amino acid does histamine come from?
L-histidine
What alteration can account for histamine intolerance in approximately 1% of the population?
Alteration in histamine degrading enzymes (DAO or HNMT)
What three roles does Histamine have?
- Mediator of immediate allergic inflammatory reactions
- Role in gastric acid secretion
- Neurotransmitter and neuromodulator
Where are the highest amounts of Histamine located? (3 locations)
- Lungs
- Skin
- GI tract
Where are “pools” of histamine stored in tissues & blood?
Tissues - Mast cells
Blood - Basophils
How are the “pools” of histamine managed in basophils?
Synthesized and stored in secretory granules in an inactive form
Histamine is bound to a proteoglycan intracellularly. What is this glycan in mast cells? in basophils?
Heparin-sulfate and ATP in mast cells
Chondroitin-sulfate in basophils
Is the turnover of Histamine in mast cells and basophils fast or slow?
Slow turnover
How is histamine handled differently in non-mast cells (gastric mucosa, epidermis, neurons)? (4 points)
- There are no granules
- Histamine is continuously synthesized and released
- There is a rapid turnover
- Histidine decarboxylase levels correlate with activity
What are the immediate effects of histamine release? (5 items)
- Burning/itching sensation
- Intense warmth
- Skin reddens
- BP decreases
- HR increases
What are the effects of histamine release within minutes (different than immediate)? (2 items)
- BP recovers
2. Hives appear
Describe the process of histamine release when there has been prior exposure to the antigen. (3 steps)
Binding of IgE to FceRI on mast cells
Antigen binding to IgE
Activation of mast cell with release of mediators
Describe the process of first exposure to an allergen in relation to histamine release.
Antigen activation of TH2 cells
Stimulation of IgE class switching in B cells
IgE secreted antibodies engage in future encounters
How is drug/peptide/venom release of histamine different that allergic release? (2 points)
It is not antigen-antibody mediated
Results in direct stimulation without prior exposure
What drugs cause direct stimulation of histamine release? (5 items)
Succinylcholine
Morphine
Curare
Plasma expanders (dextran, PVP)
Vancomycin ("red-man syndrome")What peptides can cause direct stimulation of histamine release? (3 items)
Bradykinin
Complement
Substance P (release during tissue injury)
What venom can cause direct stimulation of histamine release?
Wasp venom
What is the mechanism for direct stimulation of histamine release?
Increase in intracellular calcium
What is the clinical picture of Red-man syndrome? (2 items)
Rash to face, neck, upper torso
Hypotension
What is the name for the inhaled anti-inflammatory, anti-histamine agent used in asthma?
Cromolyn Sodium
What is the mechanism for Cromolyn Sodium? (2 points)
Stabilizes mast cell membrane to prevent release of histamine
Prevents mast cell degranulation
What is the primary route of admin for Cromolyn sodium?
What are the alternatives?
Inhalation
Oral, Nasal, Ophthalmic
What is the therapeutic utility of Cromolyn sodium? (3 points)
Chronic asthma control
Prophylaxis of bronchospasm (allergen- or exercise-induced)
Not a rescue medication!
What are the major uses for the Nasal, Ophthalmic, and Oral preparations of Cromolyn sodium?
Nasal - Allergic rhinitis
Ophthalmic - Conjunctivitis
Oral - Systemic mastocytosis
What is the mechanism of action for Omalizumab? (2 points)
Decreases amount of antigen specific IgE
Binds tightly to free IgE to prevent FceRI binding
What is the route of administration for Omalizumab?
SQ
What adverse effects should one look for with Omalizumab? (2 points)
Injection site reaction
Anaphylaxis after first dose
What are the H1 histamine receptors primarily located?
What does activation of these affect?
Endothelial cells
Vasodilation
How does H1 & H2 receptor combined activation contribute to vascular dilation? (3 points)
H1 system coupled to increase in calcium
H1 receptors activate NO synthase
H2 receptors couples to increase in cAMP
What effect does H1 receptor activation have on large vessels?
vasoconstriction
What effect does activation of H1 and H2 have on BP overall?
decrease
Activation of H1 receptors have what effect on vascular permeability?
Why?
Increased
Located on post-capillary venules-endothelial cells
Contraction of these cells causes exposure of basement membrane
What effect do H2 receptors have on cardiac myocytes? (2 points)
Increased contractility
Increased electrical conduction
What effects do H1 and H2 receptors have on bronchioles? (2 points)
H1 - contraction
H2 - relaxtion (minor)
Which histamine receptor causes intestinal smooth muscle contraction?
H1
Which histamine receptor causes gastric acid secretion?
H2
Which histamine receptor causes pain & itching in peripheral nerve endings?
H1
Which H receptor is responsible for increased arousal/wakefulness?
H1
What are the 4 first generation H1 receptor blockers for this course?
Diphenhydramine
Dimenhydrinate
Chlorpheniramine
Promethazine
Which first generation H1 blocker also blocks dopamine receptors?
Promethazine
What are the 4 second generation H1 blockers for this course?
Fexofenadine
Loratadine
Cetirizine
Desloratidine
What is the difference between first and second generation H1 receptor blockers?(2 points)
Second generation have little to no CNS effects
First generation also have mild/moderate muscarinic antagonism in CNS
What type of activity are H1 receptor blockers classified as having?
Inverse agonism
What are the major therapeutic effects of H1 antagonists?
Inhibition of vascular permeability
Suppressed itching
No effect on blood pressure
No effect on bronchoconstriction
What effect do 1st generation H1 blockers have on CNS? (2 points)
Is it different in children?
Sedation and Anti-cholinergic reduction in motion sickness
Yes, can cause stimulation in children
Can anti-cholinergic effects be seen with H1 blockers?
What kinds?
Which generation?
Yes
Dry mucus membranes, Urinary retention, “anti-cholinergic syndrome”
1st generation only.
What are the oral pharmacokinetics of H1 blockers? (2 points)
Rapid absorption
Peak conc. 1-2 hours
How are 2nd generation H1 blockers metabolized?
Liver P450 (CYP3A4/CYP2D6)
What is the metabolite of Terfenadine?
Fexofenadine
What is the metabolite of Loratadine?
Desloratadine
Hydroxyzine is metabolized to what active agent?
Cetirizine
How does a 1st generation H1 blocker cause sedation?
Central H1 effect and central anti-cholinergic effect
Which 2nd generation H1 blocker has the most sedative effect?
Cetirizine
Have there been any adverse effects seen of loratadine on QT interval?
No
Which H1 blockers exhibit a noticeable anti-cholinergic effect useful for motion sickness?
dimenhydrinate (dramamine)
promethazine (phenergan)
diphenhydramine (benadryl)
Off-label uses and the used (4 points)
Sleeping aid - Diphenhydramine
Vestibular disturbance - Dimenhydrinate
Nausea/Vomiting - Promethazine
Early stage Parkinson’s - Diphenhydramine
What are the indications for H2 receptor antagonists? (4 points)
Relief of symptoms peptic ulcer disease
Gastroesophageal reflux disease
Peptic ulcer secondary to H. pylori
Gastric injury from NSAIDS
What is the mechanism of action for H2 receptor antagonists?
H2 receptor stimulation on parietal cells increases adenylyl cyclase, cAMP, and PKA –> this increases acid production.
H2 blockers stop this activity.
Is H2 stimulation the terminal step in acid production?
No, Gastrin and ACH also have direct effect on parietal cells. Proton pump is terminal step.
What type of inhibitor are H2 antagonists?
Reversible competitive inhibitor (can act as inverse agonist)
What is the importance of the inverse agonism of H2 antagonists?
Inhibition of fasting acid secretion and inhibition of nocturnal gastric acid secretion is a big determinant in the healing of ulcers.
What common side effects are seen with H2 blockers?
Diarrhea, headache, drowsiness
What are less common effects seen mostly with IV administration in elderly patients?
confusion
delirium
slurred speech
What is the significance of Cimetidine that is not present with other H2 blockers?
Inhibition of P450 metabolism
What are the three H2 blockers for this course?
Cimetidine
Famotidine
Ranitidine
Long term use of high doses of Cimetidine can lead to what undesirable effects in men?
Decreased testosterone binding
Gynecomastia due to inhibition of estradiol hydroxylation
What is the order of potency of H2 blockers?
Famotidine (Pepcid) > Ranitidine (Zantac) > Cimetidine (Tagamet)
