Chapter 18: Histamine and Histamine Antagonists

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Endogenous organic molecules with potent pharmacologic effects, that are not part of traditional immune or autonomic groups, including histamine, serotonin, bradykinin, prostaglandins, and nitric oxide.



What amino acid is histamine derived from?

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What are the functions of histamine?

  1. modulates local immune responses
  2. regulates physiologic functions, including:
    1. gastric secretion
    2. neurotransmission
    3. microcirculation
  3. involved in inflammatory and anaphylactic reactions

In which tissues is histamine found in highest concentrations? (3)

  1. lung
  2. skin
  3. intestinal mucosa

In which cells is histamine found in highest concentrations? (3)

  1. mast cells
  2. leukocytes (basophils and eosinophils)
  3. enterochromaffin cells

What is the process of exocytosis of histamine by mast cells called?

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Neoplasms that secrete autacoids, including histamine, creating a syndrome of flushing, diarrhea, heart failure, vomiting and bronchoconstriction.



What are the chief stimuli for the release of histamine? (3)

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  1. tissue injury (particularly of the skin or mucosa)
  2. allergic reactions (mediated by IgE antibodies)
  3. drugs (including opioids and antimalarial drugs)

What are the two routes by which histamine is rapidly inactivated?

Histamine is rapidly inactivated by two routes:

  1. methylation by histamine-N-methyltransferase
  2. oxidative deamination by diamine oxidase

All metabolites are inactive and excreted by the kidney.


How many types of histamine receptors are there and what is their mechanism?

Histamine exerts its effects by binding to four different G protein–coupled histamine receptors, designated H1 through H4.


What are the adverse effects of histamine? (6)

The toxic effects of histamine are predictable based on its pharmacologic actions:

  1. cutaneous flushing
  2. hypotension
  3. headache
  4. visual disturbances,
  5. dyspnea
  6. gastrointestinal disturbances

Which histamine receptor is described by the following features?

  • found in the CNS and PNS
  • Gq/IP3/DAG mechanism
  • regulates sleep–wake cycle; causes bronchoconstriction

H1 receptor


Which histamine receptor is described by the following features?

  • found on parietal cells and vascular smooth muscle cells
  • Gs/CAMP mechanism
  • stimulates gastric acid secretion; involved in vasodilation

H2 receptor


Which histamine receptor is described by the following features?

  • found in the CNS and PNS
  • Gi/CAMP mechanism
  • decreases neurotransmitter release

H3 receptor


Which histamine receptor is described by the following features?

  • found on basophils, thymus, small intestine, spleen, and colon
  • Gi/CAMP mechanism
  • plays a role in mast cell chemotaxis

H4 receptor


A group of compounds with the characteristic ability to block the actions of histamine.



Which of the following are LEAST likely to produce CNS effects?

  1. diphenhydramine (Benedryl)
  2. chlorpheniramine (Chlor-Trimeton)
  3. brompheniramine (Dimetapp)
  4. fexofenadine (Allegra)
  5. cetirizine (Zyrtec)
  6. loratadine (Claritin)

(D), (E), and (F)

Second-generation H1 antihistamines are largely devoid of effects on the CNS. This group of agents includes:

  1. fexofenadine
  2. levocabastine
  3. loratadine
  4. acrivastine
  5. cetirizine
  6. azelastine

What type of smooth muscle contraction is inhibited by H1 antihistamines?

These agents inhibit the contraction of gastrointestinal and bronchial smooth muscle.


What classic vascular response is inhibited by H1 antihistamines?

These agents decrease capillary permeability and the flare and itch components of the “triple response.”


What type of inhibition do H1 antihistamines produce?

  1. reversible
  2. irreversible
  3. competitive
  4. non-competitive
  5. uncompetitive

(A) and (C)

Antihistamines exhert reversible, or competitive inhibition, because it can be overcome by increasing the concentration of histamine.


Why is epinephrine more effective than diphenhydramine for relieving bronchospasm associated with asthma, anaphylaxis, and other allergic reactions?

The action of H1 antihistamines is specific; they “reverse” the effects of histamine by inhibiting its action, but do not have directly opposing actions of their own.

Epinephrine nonspecifically antagonizes histamine by exerting its own effects, such as vasoconstriction, bronchodilation, and decreased gastrointestinal motility.


The older H1 antihistamines (e.g. diphenhydramine) are sedative agents with significant autonomic receptor blockade. Why don't second-generation H1 blockers (e.g. cetirizine, fexofenadine, and loratidine) have similar effects?

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They have less lipid solubility than first-generation agents and do not cross the blood–brain barrier.


What clinically useful CNS effect of first-generation H1 antihistamines indicates them for treatment of motion sickness?

inhibition of nausea and vomiting


Which of the following have the GREATEST anesthetic activity?

  1. diphenhydramine
  2. cetirizine
  3. promethazine
  4. pyrilamine
  5. fexofenadine
  6. tripelennamine
  7. loratidine

(A), (C), (D), and (F)

Antihistamines have occasionally been used when conventional local anesthetics are contraindicated. This property is most notable in diphenhydramine (A), promethazine (C), pyrilamine (D), and tripelennamine (F).


Which second generation antihistamine is transformed to an active metabolite with an average elimination half-time of greater than 24 hours?

  1. fexofenadine
  2. levocabastine
  3. loratadine
  4. acrivastine
  5. cetirizine
  6. azelastine

C. loratadine

In contrast to first-generation H1 antihistamines most second-generation H1 antihistamines have a considerably longer duration of action.


What are the primary clinical applications of H1 antihistamines? (7)

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  1. nasal allergies, seasonal (e.g. hay fever) or perennial (nonseasonal)
  2. allergic dermatoses (e.g. urticaria, angioedema)
  3. acute manifestations of bronchial asthma (minimally effective)
  4. symptomatic relief of the common cold (especially chlorpheniramine)
  5. nausea and vomiting of motion sickness (first-generation only)
  6. used as hypnotics to induce sleep (especially diphenhydramine)
  7. reduction of tremors and muscle rigidity in Parkinson disease

What are the adverse effects of H1 antihistamines? (6)

  1. CNS depression (drowsiness, lethargy) - common
  2. anticholinergic effects (insomnia, tremors, dry mouth, blurred vision)
  3. gastrointestinal disturbance (nausea, vomiting) - rare
  4. allergic reactions (more frequent after topical application)
  5. blood dyscrasias (hemolytic anemia, agranulocytosis, pancytopenia)
  6. variably excreted in breast milk (should be avoided in nursing women)

What are the dental uses of H1 antihistamines? (4)

  1. may be used in minimal–moderate sedation
  2. reduce postoperative nausea and vomiting
  3. can provide some local anesthetic activity
  4. treatment of allergic lesions of oral mucosa

Which of the following are H2 receptor agonists?

  1. diphenhydramine
  2. cetirizine
  3. cimetidine
  4. famotidine
  5. fexofenadine
  6. nizatidine
  7. ranitidine
  8. tripelennamine
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(C), (D), (F) and (G)

H2 antihistamines are basically structural analogues of histamine. The four drugs in this group are cimetidine (C), ranitidine (G), famotidine (D), and nizatidine (F).


What is the main main therapeutic effect of H2 blockers?

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reduction of gastric acid secretion


What are the clinical indications for H2 antihistamines? (4)

  1. duodenal ulcer disease (active or in maintenance)
  2. active gastric ulcer disease
  3. gastroesophageal reflux disease (GERD)
  4. hypersecretory conditions (e.g. Zollinger-Ellison disease)

What are the adverse effects of H2 antihistamines?

Most adverse effects are associated with cimetidine:

  1. CNS symptoms (dizziness, lethargy, confusion, seizures)
  2. endocrine disturbance (gynecomastia, galactorrhea)
  3. drug interactions (warfarin, β-blockers, Ca2+ blockers, lidocaine)

Ranitidine, famotidine, and nizatidine have fewer adverse effects than cimetidine.