Antihistamines - Fondell 4/12/16 Flashcards Preview

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Flashcards in Antihistamines - Fondell 4/12/16 Deck (33):


  • essential mediator of allergic and infl processes
  • significant regulator of gastric acid secretion
  • important neurotrans in CNS


synthesis from histidine

  • His synthesized in 4 major cell types
    • mast cells (skin, mucus membranes, lungs, bl vessels)
    • basophils (circ blood)
    • enterochromaffin-like cells (ECL cells - stomach)
    • histaminergic neurons (brain)

decarboxylation of His → histamine


degradation of histamine

  • half life of 30-60s, after which degradation by either...
    • ring methylation + oxidation [predominant bc key enzyme is widely expressed]
    • ox deamination + conj with ribose


storage of histamine

histamine is sequestered and bound in cytoplasmic granules of mast cells and basophils

  • contains GAGs (incl -heparin → forms complexes with +histamine), proteases, cytokines

histamine is produced and stored in vesicles of ECL cells of gastric mucosa in stomach and histaminergic neurons of CNS


mechanisms of histamine release

1. immunological release

  • antigens/allergens bind to IgE on surface of pre-sensitized mast cells and basophils → aggregation of high-affinity IgE receptors (FCeRI) → degranulation

2. mast cell injury/damage

  • rapid degranulation → local release of histamine

3. endocrine or neuronal stimulation

  • endocrine stimulation of ECL cells or neuronal stimulation of histaminergic neurons → rapid histamine exocytosis

4. chemical displacement

  • drugs/other compounds trigger direct release of histamine from mast cells (no prior sensitization required) → "displacement"
  • ex. organic bases or basic peptides (morphine, tubocuranine, some antibiotics, wasp venom, etc.)


IgE mediated histamine release

basic allergic response: sensitization & subsequent exposure/response

type I hypersensitivity

1. sensitization: allergen makes it into blood, B cells recognize (are assisted by Th2 cells) → produce IgE

  • IgE binds to FCepsilon receptors on mast cells and basophils = mast cells are now sensitized!

2. subsequent exposure: multivalent antigens can now bind to antibodies on mast cells → crosslinking of IgE → FCepsilon receptors aggregated, activated

  • LYN/SYK (beta and gamma subunits of receptor) → phosphorylation of LAT → IP3 and DAG activated → mobilize Ca, activation of PKC
  • increase in intracellular Ca → trigger for degranulation → histamine and other infl mediators released → inflammation!

also occuring:

  • MAPK pathway → prostaglandins/leukotrienes
  • MAPK and CA → transcription and release of cytokines


histamine receptors → signaling (distribution)

  • fx



H1 → Galpha q → increased IP3, DAG

(sm muscle, endothelium, periph neurons, brain)

  • pruritis, pain, mucosal secretion, NO-mediated vasodil, edema, bronchoconst, contraction of gut


histamine receptors → signaling (distribution)

  • fx



H2 → Galpha s → increased cAMP

(gastric mucosa, cardiac muscle, vasc smooth muscle, mast cells, basophils, brain)

  • gastric acid secretion, vasodilation (cAMP), heart rate


histamine receptors → signaling (distribution)

  • fx



H3 → Galpha i → decreased cAMP

(presynaptic histaminergic neurons in brain, myenteric plexus, other neurons)

  • decreased neurotransmitter release


histamine receptors → signaling (distribution)

  • fx



H4 → Galpha i → decreased cAMP

(cells of hematopoeitic origin: eosinophils, neutrophils, DCs, basophils, monocytes, T cells)

  • differentiation of promyelocytes and myeloblasts, chemotaxis, secretion of cytokines, upreg of adhesion factors


G protein coupled receptor classes

7 alpha helix transmembrane domain

signal through heterotrimeric complex of proteins (alpha, beta, gamma subunits)

4 subtypes of GPCR (alpha s, i, q, 12/13)

  • i: H3/H4 → decrease cAMP
  • q: H1 → increase IP3, DAG
  • s: H2 → increase cAMP


effects of histamine on tissues/organ systems


nervous system

1. peripheral sensory nerve terminals

  • induce depol of afferent nerve endings → itch, pain sensation (H1)
  • component of urticaria response to stinging instects/plants

2. CNS

  • neurotrans for histaminergic neurons (H1, H2, H3)
  • modulation of nt release (H3)
  • homeostatic and higher brain fx - sleep/wake cycle, circadian, feeding rhythms
  • appetite suppression and satiety (H1, H3)
  • increased wakefulness (H1, H3)


effects of histamine on tissues/organ systems


cardiovascular system

1. vasodilation

  • dilation of terminal arterioles, postcap venules, precap sphincters (H1 - endothelial NO + H2 - cAMP production → max sm muscle dilation)

2. increased cap permeability

  • contraction of vascular endothelial cells (H1) → escape of fluid, pl proteins, immune cells from postcap venules
    • → edema
    • → decrease in local bp
  • in some vasc beds, constriction of veins → upstream pressure → edema (H1)

3. heart

  • indirect: reflex tachycardia (vasodil + systemic hypotension)
    • most pronounced effect of antihists at heart
  • direct: stimulation of atrial/ventricular contraction (H2) → increased pacemaker and HR


histamine-mediated vasodilation and cap permeability

causes wheal and flare 

  • gives immune cells access to site of insult
  • gives plasma proteins (clotting factors) access to site of insult
  • has chemotactic props (along with other cytokines) → leukocyte recruitment
  • action on local afferent neurons → sensation of foreign object


effects of histamine on tissues/organ systems


respiratory system

1. bronchoconstriction

  • constriction of bronchial smooth muscle (H1)
    • pts with asthma are usually hypersensitive to histamine!
    • hist can also have bronchodilation effect via H2, but pretty trivial in humans


effects of histamine on tissues/organ systems


digestive system

1. gastrin-induced acid secretion

  • facilitates acid secretion from parietal cells in stomach (H2)

2. contraction of intestinal sm muscle → diarrhea (H1)

3. stimulation of mucus secretion in sm and large intestines (H2)


pathophysio of histamine: allergic rxns



immediate hypersensitivity rxns

  • skin contact
  • ingestion
  • injection
  • inhalation


pathophysio of histamine:


symptoms - reasoning

allergic rhinitis and conjunctivitis

  • vasodilation, increased cap permeability, edema in nasal mucosa and surrounding tissues
  • increased secretions from nasal/eye mucus membranes
  • nasal congestion

allergic bronchospasm

urticaria (hives)

  • pruritic, erythematous, edematous plaques on skin
  • vasodil, increased cap permeability, edema → wheal and flare


  • allergen distributed systematically → systemic mast cell/basophil degranulation → explosive release of histamine and other infl mediators
  • severe bronchoconst, laryngeal swelling, angioedema
  • systemic vasodil and cap permeability → profound drop in bp
  • rapid, weak puls


strategies to block histamine action

1. antihistamines

  • aimed at H1, H2 receptors
  • generally function as inverse agonists

2. inhibition of mast cell degranulation

  • prophylactic use of cromolyn and nedocromil → block Ca entry to cell → prevent degranulation
    • can be used to prevent asthma attacks (kids)
  • lousy solubility, so wont be absorbed across GI tract well → need to be inhaled
    • inhaler: prevent bronchospasm
    • spray: prevent rhinoconjunctivitis

3. drugs that counteract histamine action

  • epinephrine → agonist of alpha and beta adrenergic receptors
    • powerful mediator of bronchodilation, vasoconstriction → increase bp



two state model of histamine receptor

inactive state ⇔ active state

[exist in equilibrium in absence of histamine; almost 50/50 → histamine receptors are thought to be const active]

  • histamine binds preferentially to active state receptors and stabilizes them → shift towards active conformation 


***antihistamines do not act as true antagonists → don't block binding of histamine to receptor***

  • instead, act by preferentially binding to inactive conformation and stabilizing it to effect a shift in that direction 
  • not true antagonists...actually inverse agonists


H1 antihistamines


1st generation

neutral at physiological pH, hydrophobic (lipid-soluble) → readily enter CNS (cross blood/brain barrier)

generally short-acting (4-12h)


  • highly sedative
  • strong anti-emetic activity
    • component of OTC drugs for insomnia, motion sickness, anti-itch
  • nonspecific effects: anticholinergic, anti-alpha-adrenergic, anti-5HT (serotonin)


H1 antihistamines


2nd generation

ionized at physiological pH, hydrophilic → readily enter CNS (cross blood/brain barrier)

generally longer-acting (12-24h)


  • not sedative
  • no anti-emetic activity
  • v specific: no cross-talk with other receptors


1st generation H1 antihistamines


1. ethanolamines

  • diphenhydramine (Benadryl)

2. ethylenediamines

  • tripelennamine

3. alkylamines

  • chlorpheniramine

4. phenothiazines

  • promethazine

5. piperazines

  • hydroxyzine
  • cyclizine, meclizine

6. piperidines

  • cyproheptadine

overall features

  • mainly used to treat allergy symptoms (123) and/or nausea (456)
  • dizziness, drowsiness side effects → sedative!
  • anticholinergic/antimuscarinic effects indicative of nonspecific receptor crosstalk
    • dry mouth, blurry vision, GI upset, constipation/difficulty urinating
  • most are metabolized in liver cytochrome P450 system → OD is a real concern, not uncommon


2nd gen H1 antagonists


2gen piperazines

  • cetirizine (Zyrtec)

2gen piperidines

  • loratadine (Claritin)
    • metabolized by liver into active metabolite, so foods/drugs that occupy or inhibit cytP450s can affect its effect
  • fexofenadine (Allegra)

general features

  • ionized/hydrophilic → do not cross blood/brain barrier easily → few CNS effects!
    • not sedative → drugs of choice for daytime antihistamine relief!
  • high specificity (few anti-cholinergic/muscarinic effects)
  • all are formulated with pseudo-ephedrine (agonist of alpha adrenergic receptors) → side effects of insomnia, restlessness, increased HR


3rd gen H1 antihistamines


  • active R enantiomer of cetirizine
  • high potency, can be used at small dosage


  • active/major metabolite of loratadine
    • inhibitors of CYP dont affect this drug's action (already active)
    • high potency


which H1 antihistamine(s) would you use to treat...

  • allergic rxns?
  • motion sickness, vertigo, insomnia?
  • antiemetics

allergic rxns → 1st, 2nd, 3rd generation H1 antihistamines

  • hit hives, rhinitis, allergic conjuctivitis, etopic dermatitis, pruritis
    • mostly ineffective to treat asthma or common cold
  • can be used prophylactically to treat allergic rxn
  • might have adjuvant role in treating systemic anaphylaxis, angioedema; epi is critical in these conditions


which H1 antihistamine(s) would you use to treat...

  • allergic rxns?
  • motion sickness, vertigo, insomnia?
  • antiemetics

motion sickness, vertigo, insomnia → 1st generation H1 antihistamines

  • sedative, sleep aid
  • vestibular disturbances
  • Meniere's disease


which H1 antihistamine(s) would you use to effect...

  • allergic rxns?
  • motion sickness, vertigo, insomnia?
  • antiemetics

if you want an antiemetic → 1st generation H1 antihistamines

  • taken in cases of chemo


adverse effects of H1 antihistamines


CNS toxicity

CNS toxicity (1st gen drugs)

  • normal doses → drowsiness, sedation, fatigue, lassitude
  • other effects can include: dizziness, tinnitus, impairment of cog fx/memory/psychomotor skills, agitation
  • overdose → CNS hyperstimulation → restlessness, tremors, nervousness, anxiety, hallucinations, convulsions (esp infants)

contraindicated for pregnant women, newborns, young infants,  


adverse effects of H1 antihistamines


non-CNS effects

anticholinergic/antimuscarinic effects (1st gen drugs)

  • dilated pupils, blurry vision, double vision (diplopia), dry eye, dry mouth, dry resp passages

digestive tract

  • nausea, loss of appetite, increased appetite, weight gain, constipation, diarrhea

OD of 2nd gen drugs [astemizole, terfenadine] → cardiac arrythmias


adverse effects of H1 antihistamines


drug interactions

1st gen drugs + alcohol/CNS depressants → additive effect that can lead to significantly impaired motor skills

1st gen drugs + drugs that impair hepatic CYP metabolism → increased levels/action of gen1 drugs

  • ex. ketoconazole, itracanazole, macrolide antibiotics


H2 antihistamines


mechanism of action (i.e. role of histamine and H2 receptor)

primary site of action: fundus of stomach

H2 functions in regulating gastric acid secretion by parietal cells


1. sight/smell of food, distension, etc trigger signals that lead to secretion:

  • antral G cells: gastrin
  • vagal postgang neurons: Ach

2. in resp to signals, enterochromaffin cells (ECL cells) → release histamine

3. parietal cells respond to...

  • Ach, gastrin → increase in intracellular Ca
  • histamine → cAMP signaling

4. gastric acid secretion from parietal cells, lowering of luminal pH


H2 antihistamines




  • inhibits multiple CYP drug metab pathways → potential for drug-drug interactions


  • shows some inhibition of CYP pathways (< cimetidine)


  • most potent H2 antihistamine
  • no CYP interference


  • no CYP interference


general features

  • hydrophilic; do not enter CNS
  • high specificity (don't affect H1 or H3 receptors)
  • used to treat GERD, Zollinger-Ellison (hyper-gastrin-secretion); heal ulcers
  • can be used prophylactically to treat stress-induced GERD
  • being steadily replaced by omeprazole and other proton pump inhibitors (H/K ATPase pump inhibitors) for clinical apps


adverse effects of H2 antihistamines

generally well tolerated - small fraction of users have adverse effects

  • drug interactions (esp cimetidine): interference with hepatic CYP pathways → increased half life of other drugs metabolized in these pathways
    • (1st gen antihistamines!!!)
  • neurological effects: can occur in pts with impaired renal or hepatic fx
    • confusion, slurred speech, delusions, hallucinations, agitation
    • primarily elderly patients receiving IV treatment
  • anti-androgen action, inhibition of estradiol metabolism (cimetidine)
    • gynecomastia, impotence [males]
    • galactorrhea [females]

other: headaches, diarrhea, fatigue, dizziness, muscle pain, constipation


major drugs:

1st gen H1 antihistamines (8)

2nd gen H1 antihistamines (3)

3rd gen H1 antihistamines (2)


degranulation inhibitors (2)


H2 antihistamines (4)