06 Histamine Flashcards
How is histamine synthesized?
Essential AA L-histadine => Histamine
Histidine decarboxylase using pyridoxal 5-phosphate as cofactor
Inhibited by methylhistidine
What co-factor is needed to synthesize histamine?
pyridoxal 5-phosphate
What inhibits histamine synthesis?
Methylhistidine inhibits histidine decarboxylase
Inhibition or impairment of what enzymes lead to increased histamine?
Diamine oxidase or Histamine N-Methyl Transferase (HNMT)
What is histamine and its functions?
Mediator of immediate allergic and inflammatory reactions
Role in gastric acid secretion
NT and neuromodulator
Where is histamine localized?
It is ubiquitous
Highest: lung, skin, stomach
Pools of histamine:
Synthesized and stored in secretory granules–slow turnover:
- heparin-sulfate and ATP (mast cells–in tissue)
- chondroitin-sulfate (basophils–in blood)
Non-mast cell stores (e.g., epidermal cells, gastric mucosa cells, brain neurons, regenerative and tumor cells)
- Rapid turnover, no granules, continuously released
- histidine decarboxylase levels correlate with activity
Histamine found in secretary granule in the blood vs tissue
Blood: basophil
Tissue: mast cell
Slow turnover
Difference in turnover and synthesis between histamine stored in granules and non-mast cells
Granules: synthesized and stored. Slow turn over
Non-mast cells: continuously synthesized and released–rapid turnover
Defects in what contributes to the flushing seen during alcohol intake (certain Asian populations) and some cases of food poisoning?
Defects in the metabolism of histamine by the diamine oxidase (DAO) or acetaldehyde dehydrogenase
What happens within seconds of histamine release? minutes?
Seconds:
- -burning, itching
- -intense warmth
- -skin reddens
- -BP dec
- -HR inc
Mins:
- -BP recovers
- -Hives
Antigen-Antibody reaction
Release of mast cell histamine (vasoactive amine)
Prior exposure:
- induction of IgE-mediated allergic sensitivity to drugs and other allergens
- response of IgE-sensitized cells to subsequent exposure to allergens
Ca2+ dependent
Release of other mediators (Cytokines)
What is the concern with drugs, peptides, and venoms that promote release of histamine?
Stimulate release of histamine directly without prior sensitization– unexpected anaphylactoid reactions
Drugs: succinylcholine, morphine, curare, some antibiotics,
radio contrast media, certain carbohydrate plasma expanders
Vancomycin-induced “red-man syndrome”
Peptides: Bradykinin, complement, substance P (tissue injury)
Venoms: wasp venom
Mech: increase intracellular Ca2+ via number of different pathways
What is the mechanism of direct histamine release without prior sensitization?
Drug, peptide, or venom increase intracellular Ca2+ via number of different pathways
Red-Man Syndrome
Vancomycin (for serious G+ infections)
Following rapid IV infusion
Rash in face, neck, upper torso
Hypotension
Due to mast cell degranulation (not allergic reaction to vancomycin)
What causes Red-Man syndrome?
Vancomycin (for serious G+ infections)
After rapid IV infusion, mast cell degranulation causes rash in face, neck, and upper torso and hypotension
Not an allergic reaction
Is Red-Man syndrome due to an allergic reaction?
Due to mast cell degranulation following rapid IV infusion of vancomycin (not allergic reaction)
What other stimuli release histamine (non-Ag-Ab or Drug)?
cold urticaria, cholinergic urticaria, solar urticaria, nonspecific cell damage
Cholinergic urticaria–inc sympathetic nervous activity (seen with exercise, stress) stimulates cholinergic fibers innervating sweat glands to release ACh, leading to mast cell degranulation
Cromolyn sodium
Inhibit Histamine release
Inhaled anti-inflammatory agent
Mech: stabilizes most mast cell membranes and prevents release of histamine
AEs: safe drug/few side effects
Tx:
- preventive management of asthma (chronic control)–not rescue
- allergic rhinitis, conjunctivitis
- food allergies
What drug stabilizes most mast cell membranes and prevents histamine release for bronchospasm prophylaxis (chronic asthma control)?
Cromolyn sodium
What does Cromolyn sodium treat?
Tx:
- preventive management of asthma (chronic control)–not rescue
- allergic rhinitis, conjunctivitis
- food allergies
Omalizumab
Inhibits histamine release
Monoclonal antibody
Mech: dec amount of Ag specific IgE that normally binds to and sensitizes mast cells
– binds tightly to free IgE in circulation so no affinity for FcRI
SubQ admin
AE: life-threatening anaphylaxis and bleeding
Tx: Allergic asthma
What drug is a monoclonal antibody that binds tightly to free IgE in circulation that normally bind to and sensitize mast cells?
Omalizumab
What is a major adverse effect with an omalizumab subQ injection?
Life threatening anaphylaxis
What are the histamine receptors?
All are GPCRs:
- H1, H2, H3, H4
H1: G protein second messenger and distribution
Gq (inc Ca2+, inc NO and inc cGMP)
Smooth muscle, endothelial cells, CNS
H2: G protein second messenger and distribution
Gs (inc cAMP)
Gastric parietal cells, cardiac muscle, mast cells, CNS
Effect of histamine-receptor activation of the Cardiovascular system?
In general, histamine dilates resistance vessels, increases capillary permeability and causes an overall fall in BP.
In some vascular beds, histamine constricts veins, contributing to edema formation (increased permeability)
H1 and H2 activation
Histamine activation in endothelial cells
H1 activation results in increase in intracellular Ca2+ and activation of NO Synthase
Histamine activation in vascular smooth muscles
H2 activation coupled to increase in cAMP
- decreases intracellular Ca2_
- decreases rate of myosin phosphorylation
H1 receptor on vascular smooth muscles
Vasoconstriction of large vessels (less important for effects on BP)
H1 receptors located on vascular smooth muscle cells results in increase in intracellular calcium
What histamine receptors are activated for blood pressure control?
blood pressure (intravenous injection of histamine or released during systemic anaphylaxis)
Both H1 and H2 receptors
In general, histamine dilates resistance vessels and causes an overall fall in BP
What histamine receptor is activated to increase vascular permeability and where is it located?
H1 receptors located on post-capillary venules
Inc in Ca2+ causes endothelial cells to contract and expose basement membrane
Freely permeable to plasma proteins and fluid
What histamine receptor is located on post-capillary venules and its action?
H1 receptors located on post-capillary venules
Inc in Ca2+ causes endothelial cells to contract and expose basement membrane
Freely permeable to plasma proteins and fluid
What histamine receptors are on the heart and its actions?
Predominantly H2
Increases both cardiac contractility and electrical conduction directly
H2 receptors on the heart cause?
Increase both cardiac contractility and electrical conduction direction
What histamine receptors are located on the bronchioles?
H1–contraction
H2–relaxation (minor)
What histamine receptors are located on intestinal smooth muscle?
H1–contraction
What histamine receptors are on GI secretory tissue (parietal cell)?
H2–gastric acid secretion
What histamine receptors are located on peripheral nerve endings?
H1–pain and itching
What are the effects of histamine as a neurotransmitter?
H1–arousal/wakefullness
H1–decrease appetite
H1 and H2–CV, Thermo, Pain
What is the difference between First and Second generation antihistamines?
Second generation (Nonsedating antihistamine) drugs have little to no anticholinergic side-effects
Do not easily cross BBB to CNS
First Generation H1 Receptor Blockers
Ethanolamines:
- Diphenhydramine
- Dimenhydrinate
Alkylamines:
– Chlorpheniramine
Phenothiazines:
– Promethazine
Second Generation H1 Receptor Blockers
Non sedating Antihistamines
Piperidines:
- Fexofenadine
- Loratadine
- Desloratadine
Piperazines:
– Cetirizine
H1 Receptor Blockers
Specific reversible competitive antagonists of the H1 receptors located in both periphery and CNS
– inverse agonist because reduce constitutive activity at receptor and compete with histamine
Pharmacology
1. inhibit capillary permeability
- suppress immediate hypersensitivity reactions in anaphylaxis and allergy (itching)
- no effect on blood pressure
- no effect on bronchoconstriction
- CNS effects:
- - First gen can stimulate (children) and depress (most common) CNS
- - some prevent motion sickness via CNS anti-cholinergic effect - Peripheral and central anticholinergic effect
- - Atropine like (inhibit response to ACh)
- - dry mucus membranes, urinary retention - Local anesthetic effect:
- - block nerve conduction (Promethazine)
Pharmacokinetics
1. Admin: Oral (rapid absorption), topical, nasal
- Distributed widely
- - 2nd generation less likely to enter brain - Extensive liver metabolism
- - 2nd generation:- CTP3A4/CYP2D6
- Active metabolites:
- Fexofenadine
- Desloratadine
- Cetirizine
Major Side effects:
- Sedation
- - most common with 1st gen due to inhibition of central H1 (mediates arousal) AND central cholinergic effect
- - Cetirizine (2nd gen) most sedative
- - 1st gen paradoxical CNS stimulation (children) - GI (minor)
- - loss of appetite, n/v
- - rare: inc appetite and weight gain - Anti-muscarinic 1st gen
- - dry mouth, dryness of respiratory passages - CV Toxicity
- - Early 2nd gen (no longer in US): prolongation of QT interval and polymorphic ventricular contractions
- - due to inc dosage and in combination with drugs that inhibit P450 metab
- - no toxicity seen with Loratadine
Tx:
- Allergies (acute): rhinitis, urticaria, conjunctivitis
- - less effective for seasonal allergies - Motion sickness–due to anticholinergic effects
- Nonprescription sleeping tablets
- Other:
- - Vestibular disturbances
- - Chemo induced n/v
- - Early stage Parkinson’s
What antihistamine is the most potent in treating acute allergies with symptoms of rhinitis, urticaria, and conjunctivitis as well as less prone to cause drowsiness?
Chlorpheniramine
H1 receptor blocker First gen: Alkylamine
What antihistamine is used to treat acute allergies with symptoms of rhinitis, urticaria, and conjunctivitis but causes profound sedation?
Diphenhydramine
H1 receptor blocker First gen: Ethanolamine
What 2nd generation antihistamines are used to treat acute allergies with symptoms of rhinitis, urticaria, and conjunctivitis?
Loratadine
Desloratadine
Fexofenadine
Cetirizine (higher incidence of sedation)
What antihistamines are used to treat motion sickness?
Due to anticholinergic effects
H1 receptor blocker First gen:
Promethazine
Dimenhydrinate
Diphenhydramine
Scopolamine (muscarinic receptor antagonist)
What antihistamine is used as a nonprescription sleeping tablet?
Diphenhydramine
What antihistamine is used to treat vestibular disturbances?
Dimenhydrinate
What antihistamine is used to treat chemotherapy induced n/v?
Promethazine
What antihistamine is used to treat early stage Parkinson’s?
Diphenhydramine
What does chlorpheniramine treat?
Acute allergies–most potent and less prone to cause drowsiness
What does diphenhydramine treat?
- Acute allergies–profound sedation
- Motion sickness
- Nonprescription sleeping tablet
- Early stage Parkinson’s
What does loratadine treat?
Acute allergies
What does desloratadine treat?
Acute allergies
What does fexofenadine treat?
Acute allergies
What does cetirizine treat?
Acute allergies–higher incidence of sedation compared to other 2nd gen H1 receptor blockers
What does promethazine treat?
Motion sickness
Chemotherapy induced n/v
What does dimenhydrinate treat?
Motion sickness
Vestibular disturbances
H2 Receptor Antagonists
- Relief of symptoms peptic ulcer disease
- Gastroesophageal reflux disease
- Peptic ulcer secondary to H. pylori infection
- gastric injury by NSAIDs
Physio:
- histamine released from mast cells and enterochromaffin-like cells stimulated by vagus nerve and gastrin
- stimulation of H2 on parietal cells:
- inc adenylyl cyclase, cAMP, PKA
- Increased H+ (gastric acid)
- ACh and gastrin also directly increase gastric acid secretion
Pharm:
- reversible competitive H2 inhibitors on basolateral membrane of parietal cell (inverse agonist)
- inhibit (basal/fasting/nocturnal) gastric acid secretion from parietal cells
- reduce volume of gastric acid and its H+ conc
Pharmacokinetics:
- rapidly absorbed following oral admin
- small amounts of drugs undergo liver metab
- excreted by kidneys
Side effects (low incidence except cimetidine):
- diarrhea, headache, drowsiness
- Less common: confusion, delirium, slurred speech–IV admin or in elderly
- alter bioavailability bc inhibit gastric acid secretion
AEs:
- Cimetidine inhibits P450 (ranitidine to less extent): prolong half-life of other drugs that are substrates for P450
- long term use at high dose: decreased testosterone binding and inhibits CYP that hydroxylates estradiol
- in men: gynecomastia, reduced sperm count, and impotence)
Tx:
- uncomplicated Gastro-Esophageal Reflux Disease (GERD)***
- promote healing of gastric and duodenal ulcers
- prevent occurrence of stress ulcers
- Zollinger-Ellison Syndrome: overproduction of gastrin (PPIs now preferred)
Comparison: - same mech of action - minimal side effects except cimetidine - Potency: Famotidine > Ranitidine > Cimetidine
What treats GERD?
H2 antagonists
- famotidine
- ranitidine
- cimetidine
What does famotidine treat?
Tx:
- uncomplicated Gastro-Esophageal Reflux Disease (GERD)***
- promote healing of gastric and duodenal ulcers
- prevent occurrence of stress ulcers
- Zollinger-Ellison Syndrome: overproduction of gastrin (PPIs now preferred)
What does ranitidine treat?
Tx:
- uncomplicated Gastro-Esophageal Reflux Disease (GERD)***
- promote healing of gastric and duodenal ulcers
- prevent occurrence of stress ulcers
- Zollinger-Ellison Syndrome: overproduction of gastrin (PPIs now preferred)
What does cimetidine treat?
Tx:
- uncomplicated Gastro-Esophageal Reflux Disease (GERD)***
- promote healing of gastric and duodenal ulcers
- prevent occurrence of stress ulcers
- Zollinger-Ellison Syndrome: overproduction of gastrin (PPIs now preferred)
Inhibits CYP450 = side efects
