histamine
molecule synthesized from amino acid histidine through decarboxylation reaction. No
carboxyl acid in final produce. Recycled to start the process over or excreted out of the
body. Stored in tissues via mast cells or other (epidermis, gastric mucosa, neurons, etc)
and in the blood (basophils).
other tissues (gastric mucosa and neurons)
histamine is released slowly from these and rapidly replenished.
mast cells and basophils
histamine is rapidly released from these and replenished slowly.
H1 receptor
GPCR that is in bronchial smooth muscle cells, vascular endothelial cells, CNS,
epithelial cells, hepatocytes, chondrocytes, DCs, monocytes, neutrophils, T/B cells.
Binding to this causes cutaneous itching and pain, wakefulness and emesis (via CTZ in
medulla oblongata).
H2 receptor
GPCR found in smooth muscle cells, gastric mucosa (parietal cells), cardiac muscle,
mast cells, CNS, T/B cells, DCs. Binding to this causes cutaneous itching and pain.
H3 receptor
GPCR found in presynaptic CNS. Brain myenteric plexus, other neurons, monocytes,
eosinophils, DCs. Binding to this inhibits histamine synthesis and release and causes
regulation of DA, GABA, ACh, 5-HT, and NE. Don't need to know this.
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effects of histamine
cause erythema (increased blood flow to capillaries), uticaria (increased permeability
leading to hives/wheals), and pruritis (itchy skin).
triple response of Lewis
localized red spot within seconds (via vasodilation H1); brighter red flush/flare
developing more slowly (histamine stimulation of axon reflexes causing indirect
vasodilation); wheal within minutes occupies same area as red spot (histamine's ability
to increase capillary permeability leading to edema). These are reactions to the allergy
skin test if actually allergic. More severe the farther away the flare is from the wheal.
manifestations of histamine
include asthma-like symptoms - bronchoconstriction due to H1 in bronchial smooth
muscle. Also includes edema/wheal response - leading to contraction and separation of
endothelial cells leading to vascular permeability due to H1 in vascular endothelium.
Also includes itchiness/pain - sensitization of afferent nerve terminals due to H1 in
peripheral nerves. Also includes peptic ulcer disease/heartburn - increase gastric acid
secretion due to H2 in stomach.
mild to moderate symptoms of histamine
skin reactions, tachycardia, dysrhythmias, hypotension, mild respiratory distress.
severe anaphylactic symptoms
include hypotension, ventricular fibrillations, cardiac arrest, bronchospasms, respiratory
arrest.
inverse agonists
these stabilize the receptor into an inactive position. they do the exact opposite of an
agonist. So if a receptor causes wakefulness, it causes sleepiness.
clinical uses of antihistamines
for immediate hypersensitivity reactions like rhinitis, conjunctivitis, urticaria, pruritis. Also
for motion sickness, N/V (chemotherapy, pregnancy), and insomnia.
good to use during pregnancy
include promethazine, diphenhydramine, cetrizine, loratidine
BAD to use during pregnancy
include azelastine, hydroxyzine, fexofenadine.
first generation H1 antagonist
include diphenhydramine, hyroxyzine, chlorpheniramine. Those have indications for
allergy. Also include cyclizine, dimenhydrinate, and meclizine. Those are primarily for
motion sickness. Also includes promethazine for nausea. These are reversible,
competitive antagonists of H1 receptors. Mildly anticholinergic (anti-SLUDE). Used for
relief of allergy symptoms, sedation/sleep aid, prevention of motion sickness, vertigo,
nausea, vomiting. Adjuvant to epinephrine in anaphylaxis. Local anesthetic (for lidocaine
allergy. Cough suppressant. All these will cross both the BBB and placenta!*
first generation H1 antagonist adverse effects
include sedation (paradoxical stimulation in some) - dizziness, fatigue, additive with
classical antimuscarinics and CNS depressants (alcohol). Tachycardia/dysrhythmias
with OD. Allergic reactions with topical use. Antimuscarinic effects. Chlorpheniramine's
effects can be increased with MAOIs. But in general, well tolerated!
second generation H1 antagonists
include fexofenadine, loratadine (claritin), cetirizine (zyrtec), desloratadine (active
metabolite of loratadine). Useful as non sedating anti allergy therapeutics. Adverse
effects - cetirizine induces more CNS actions than other in this categories so not
recommended for use by pilots. All except desloratadine are excreted mainly in
unmetabolized form in urine/feces. Others are metabolized by cytochrome P450s. So
keep in mind drug interactions. Well absorbed in Gi tract, BBB, placenta. Allergy to
topical application. Hepatic transportation, renal elimination (so bad in liver disease).
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H2 receptor antagonist
include cimetidine, famotidine, ranitidine. These reduce stomach acid production by
parietal cells. Adjuvant to epinephrine in anaphylaxis. Administered orally. 1-3 hours in
plasma, duration 4-6 hours, 12-24 hours. Side effects are unusual but can include
dizziness, headaches, somnolence, mild and brief diarrhea, some hematology changes,
rash, impotence, mild gynecomastia, muscle pain, and fever. Drug interactions include
inhibitors of cytochrome p450-mediated drug metabolism since metabolized that way.
mast cell stabilizers
include cromolyn sodium and nedocromil. Prevent release of histamine from mast cells.
Used in treatment of allergic rhinitis, conjunctivitis, and asthma. Adverse effects include
cough and bitter taste making patient compliance an issue. Prevent degranulation!
Allergen can still bind, just no histamine will be released. Usually these are inhaled or
squirted into nasal cavity.
hypersensitivity
undesirable (damaging, discomfort producing, sometimes fatal) reactions produced by
the immune system to an otherwise innocuous antigen. Leads to vascular permeability,
vasodilation, smooth muscle contraction, and local inflammation. Include type I, II, III,
and IV.
type I hypersensitivity
IgE mediated. IgE is bound to mast cells via its Fc portion. When allergen binds to these
antibodies, cross-linking of IgE induces degranulation. Causes localized and systemic
anaphylaxis, seasonal allergies including hay fever, food allergies such as those to
shellfish and peanuts, hives, and eczema. Treated with cromolyns, leukotriene
modifiers, B agonists, methylxanthines, anti-IgE, desensitization (immunotherapy), and
*histamines!
type II hypersensitivity
IgG-mediated cytotoxic. Cells are destroyed by bound antibody, either by activation of
complement or by cytotoxic T cell with an Tc receptor for the antibody. Red blood cells
destroyed by complement and antibody during transfusion or mismatched blood type or
during eythroblastosis fetalis. Treated with immunotherapy, anti-inflammatory agents,
and immunosuppressants. Antihistamines are NOT a treatment option!
desensitization
method of switching one hypersensitivity reaction to a different one so it can be treated
with different methods or medications. Not getting rid of the allergy necessarily, but just
switching it to a different one.
type III hypersensitivity
immune complex-mediated. antigen-antibody complexes are deposited in tissues,
causing activation of complement, which attracts neutrophils to the site. Most common
forms of immune complex disease are seen in glomerulonephritis, RA, and lupus. Also
being bit by a venomous snake is also this kind of reaction. Treated with anti-
inflammatory agents and immunosuppressants NOT antihistamines.
type IV hypersensitivity
cell-mediated. Th1 cells secrete cytokines, which activate macrophages and cytotoxic T
cells and can cause macrophage accumulation at the site. Most common forms are
contact dermatitis, tuberculin reaction, autoimmune disease such as diabetes mellitus I,
MS, and RA. This will take several days to develop. Also reaction to poison ivy is
considered this. Treated with corticosteroids.
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