Antihistamines Flashcards
name the cells that secrete histamine in the following locations:
a. skin, mucous membranes, lung, blood vessels
b. circulating blood
c. gastric mucosa
d. brain
histamine secretion:
a. mast cells - skin, mucous membranes, lung, blood vessels
b. basophils - circulating blood
c. enterochromaffin-like cells - gastric mucosa (regulation of gastric acid secretion)
d. histaminergic neurons - brain
what 2 metabolites of histamine can be detected in urine?
- via oxidative deamination —> lmAA
- via methylation + oxidation —> methyl lmAA
(1-methyl-4-imidazoleacetic acid)
(for example, if someone was having a massive allergy attack)
in mast cells and basophils, histamine is bound in ____
in ECL cells (enterochromaffin-like cells, stomach) and histaminergic neurons, histamine is stored in _____
mast cells/ basophils - histamine in cytoplasmic granules
ECL/neurons - histamine in vesicles
4 mechanisms (causes) of histamine release
- immune response: antigens bind IgE on surface of pre-sensitized mast cells and basophils, causing degranulation
- mast cell injury (rapid, local release)
- endocrine/ neuronal (ECL cells of stomach mucosa, histaminergic neurons)
- chemical displacement: stimulate direct release of histamine from mast cells (without pre-sensitization) - displaces histamine from cytoplasmic granules
*major concern because a rapid, severe reaction can occur (anaphylactic shock)
describe what happens in initial and subsequent exposure during IgE-mediated histamine release
Type I hypersensitivity response
Initial exposure = sensitization, IgE bind mast cells and basophils
subsequent exposure - antigen cross-links with IgE on mast cell/basophil surface, causing histamine release
(+ other primary/secondary inflammatory mediators from these cells)
what is the distribution of the 4 histamine receptor subtypes, and what are their respective post-receptor signaling and effects?
H1: smooth muscle, endothelium, peripheral afferent neurons, postsynaptic histaminergic neurons —> G(alpha)q —> increase IP3, DAG —> itch, pain, vasodilation, edema, etc
H2: parietal cells, cardiomyocytes, smooth muscle, mast cells, basophils, postsynpatic histaminergic neurons —> G(alpha)s —> increase cAMP —> gastric acid secretion, vasodilation, tachycardia, negative feedback
H3: presynaptic histaminergic neurons, myenteric plexus —> G(alpha)i —> decrease cAMP —> decrease NT release
H4: WBC —> G(alpha)i —> decrease cAMP —> differentiation of WBC precursors, chemotaxis, cytokine secretion, adhesion factor upregulation
what effect does histamine have on the CNS and peripheral sensory nerve terminals, respectively?
histamine effects:
CNS: NT (H1/2/3), circadian/feeding rhythms, appetite/satiety (H1/3), wakefulness (H1/3), modulator of NT release (H3)
peripheral sensory nerve terminals: depolarization of afferent nerve endings causing itch/pain (H1), urticarial response (to stinging insects/plants), sneezing trigger
3 effects of histamine on cardiovascular system (and which receptors mediate)
- vasodilation:
- H1: NO production
- H2: smooth muscle cAMP production
- increased capillary permeability: H1 (contraction of vascular endothelial cells, allowing fluid/cell escape), decrease in blood pressure
- heart:
- reflex tachycardia: indirect response to histamine-mediated decrease in systemic bp
- H2 -mediated direct increase in force/rate of cardiac contraction
which histamine receptor mediates histamine effect on respiratory system?
H1 signaling —> bronchoconstriction
patients with asthma are hypersensitive to histamine/ other inflammatory mediators (leukotrienes)
which histamine receptors mediate histamine effects on digestive system?
H1 signaling —> contraction of intestinal smooth muscle (may cause diarrhea)
H2 signaling —> gastric acid secretion from parietal cells and mucus secretion in intestines
spoiled scombroid fish or meat, sardines, fermented foods, beans, nuts, and cocoa based products are high in this inflammatory mediator
histamine
H1 histamine receptor induces _____ signaling
what biological effects does this have?
H1: Ga(q) signaling —> increase IP3 and DAG
effects: itch (pruritus), pain, mucosal secretion, bronchoconstriction, edema, contraction of gut, vasodilation
an increase in gastric acid secretion, vasodilation, heart rate, and negative feedback of histamine release is mediated through which receptor and signaling pathway?
H2: Ga(s) signaling —> increased cAMP
found on parietal cells, cardiomyocytes, mast cells and basophils, poststynaptic histaminergic neurons
which histamine receptor is found on PRE-synaptic histaminergic neurons, and what signaling pathway does it activate?
H3: pre-synaptic histaminergic neurons, myenteric plexus
induces Ga(i) signaling —> decrease cAMP (—> and NT release)
which two histamine receptors cause a decrease in cAMP?
H3: presynaptic histaminergic neurons
H4: WBC
both induce Ga(i) —> decrease cAMP
what is the role of signaling through H4 histamine receptor (biological consequences)?
H4: found on WBC, signal through Ga(i) —> decrease cAMP
effects: differentiation of myeloblasts and promyelocytes, chemotaxis, cytokine secretion, upregulation of adhesion factors
allergic rhinitis and conjunctivitis, allergic bronchospasm (bronchoconstriction), urticaria (hives), and anaphylaxis are due to the actions of ______
histamine
all these pathologies are due to vasodilation, increased capillary permeability, and edema in different parts of the body
(anaphylaxis is due to systemic distribution of allergen - these effects seen everywhere)
3 pharmaceutical strategies to block histamine action
- antihistamines: specific for H1 and H2 only (not enough alone due to other inflammatory mediators released in granules)
- inhibitors of mast cell degranulation: block Cl- channels, inhibiting Ca2+ mobilization and degranulation (must be inhaled - inhalers or nasal spray, can prevent asthma attacks) —> Cromolyn and Nedocromil
- Epinephrine (and other drugs that counteract histamine action): agonist of alpha/beta adrenergic receptors, powerful mediator of bronchodilation and vasoconstriction (treatment for anaphylaxis)
1st generation vs 2nd generation H1 antihistamines
1st generation: neutral/hydrophobic at physiological pH (readily cross BBB), highly sedative, anti-emetic (nausea) and anti-itch, short acting
2nd generation: ionized at physiological pH, not sedative or anti-emetic, highly selective, longer acting
what type of H1 antihistamine (generation) can be used to treat motion sickness, but are highly sedative?
describe other features, as well
1st generation H1 antihistamines:
- neutral/hydrophobic at physiological pH
- sedative (because of H1 receptors affecting circadian rhythm in brain, and these can pass BBB) —> can treat insomnia
- anti-emetic (nausea) and anti-itch
- non-specific effects (anti-cholinergic, anti-alpha-adrenergic, anti-serotonin)
- short acting (6-12 hours)
what generation of H1 antihistamines are longer-acting (between 12-24 hours)?
2nd generation H1 antihistamines:
- ionized at physiological pH (don’t cross BBB)
- highly selective
- longer-acting (12-24 hours)
why are 1st generation H1 antihistamines highly sedative, but not 2nd generation?
1st generation are hydrophobic, can cross BBB to reach H1 receptors in brain that control circadian rhythm
therefore, they can be used to treat insomnia
[2nd generation are ionized, cant’ cross BBB]
Diphenhydramine, more commonly known as Benadryl, is a ____ generation ____ antihistamine
Diphenhydramine (Benadryl): 1st generation H1 antihistamine
uses: allergy symptoms, hives, itching, motion sickness, insomnia, certain symptoms of Parkinson’s
side effects (think about general effects/ properties of 1st generation antihistamines and these make sense): drowsiness, dry mouth (anticholinergic), dizziness, others
Benadryl is a ______ type of antihistamine that also goes by the name of ______
Diphenhydramine (Benadryl): 1st generation H1 antihistamine
uses: allergy/cold symptoms, hives, itching, motion sickness, insomnia, symptoms of Parkinson’s
Tripelennamine, more commonly known as PBZ, is a _____ generation ____ antihistamine
Tripelennamine (PBZ): 1st generation H1 antihistamine
uses: allergy/cold symptoms
side effect (typical of 1st gen H1): drowsiness, fatigue, dizziness, dry mouth, difficulty urinating
PBZ, also known as _______, is what kind of antihistamine?
Tripelennamine (PBZ): 1st generation H1 antihistamine
*pbZ gives you the Zzzs, since sleepiness is a side effect. Sleepiness is a typical side effect of 1st gen H1 antihistamines because they can cross BBB (hydrophobic) and bind H1 receptors in brain that mess with circadian rhythm
Chlorpheniramine, branded as Chlor-Trimenton, is a ____ generation _____ antihistamine
Chlorpheniramine (Chlor-Trimenton): 1st generation H1 antihistamine
uses: allergy/cold/flu symptoms
side effects: typical of 1st gen H1 antihistamines (dizziness, drowsiness, dry mouth, blurred vision, others)
Chlor-Trimenton is known by what other name, and what kind of antihistamine is it?
Chlorpheniramine (Chlor-Trimenton): 1st generation H1 antihistamine
uses: allergy/cold/flu symptoms
Promethazine, branded as Phenergan, is a ____ generation ____ antihistamine
Promethazine (Phenergan): 1st generation H1 antihistamine
uses: allergy symptoms, motion sickness, nausea after surgery, sedative
side effects: typical of 1st gen H1 (drowsy, dizzy, double vision, dry mouth)
Phenergan is also known as _____ and is what kind of antihistamine?
Promethazine (Phenergan): 1st generation H1 antihistamine
uses: allergy symptoms, motion sickness, nausea after surgery, sedative
Hydroxyzine (Atarax, Vistaril) and Cyclizine/Meclizine (Marezine, Antivert) are both piperazines (organic chemistry) that function as antihistamines. What kind of antihistamines are they and what are their uses?
Hydroxyzine (Atarax, Vistaril): 1st generation H1 antihistamine
uses: skin allergies - urticaria (hives) or contact dermatitis; sedative for anxiety, anti-nausea
Cyclizine/ Meclizine (Marezine, Antivert): 1st generation H1 antihistamine
uses: nausea, dizziness from motion sickness, vertigo (from diseases affecting inner ear)
both have typical 1st gen H1 antihistamine symptoms
what are the special uses of Hydroxyzine, and what kind of antihistamine is it?
bonus: what brand names does it go by?
Hydroxyzine: 1st generation H1 antihistamine
treats allergic skin reactions - urticaria (hives), contact dermitis
also works as sedative for anxiety, and controls nausea
brand names: Atarax, Vistaril
what are the special uses of Cyclizine/ Meclizine (do the same thing), and what kind of antihistamine is it?
bonus: what brand names do these go by?
Cyclizine/ Meclizine: 1st generation H1 antihistamines
treat nausea from motion sickness, vertigo from diseases affecting inner ear
brand names:
Cyclizine = Marezine
Meclizine = Antivert