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35 terms

HISTAMINE ANTAGONISTS & Immunosuppresive Mast Cell Inhibitors

Learning Objectives: • Compare first and second generation H1 receptor antagonists with respect to selectivity for H1 receptors relative to other G-protein coupled receptors. • Compare first and second generation H1 receptor antagonists with respect to selectivity for peripheral vs. central effects. • Distinguish H1 from H2 receptor antagonists with respect to therapeutic use. • Compare aspirin, ibuprofen, and acetaminophen with respect to therapeutic and toxic effects. • Explain the relati…

(name the prototype)

H1 receptor antagonists
First generation
Second generation

Nonopioid analgesics
COX2 inhibitors
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Disease-modifying antirheumatic drugs (DMARDs)
Biological response modifiers: TNFa inhibitors

-other deck
Acetaminophen, Aspirin, Ibuprofen
Aspirin, Ibuprofen

Hydrocortisone (cortisol)
Cortisone, Prednisone, Dexamethasone
1.Stored in
a. Mast Cells
b. Basophils
c. Enterochromaffin-like cells

Q1: What are 3 endogenous stimulators of degranulation?

Q2: Name 2 exogenous stimulators of degranulation?

Q3: Where and what are the two ECLcells of the GI mucosa stimulated by?

Q4:Of the two "stores" of histamine, which are considered fast versus slow?
-mast cells and basophils; slow turnover; degranulation via endogenous (bradykinin, C3a and C5a).

-exogenous stimulators are substances (antigen with IgE, and Basic drugs such as morphine).

-Fast turnover in enterochromaffin-like cells of the gastric mucosa.

-where release is regulated by (neural and hormonal input) from histaminergic neurons of the CNS, and in the epidermis.
Physiological and Pathological Roles for Histamine
A. Allergy and anaphylaxis: particularly itch, urticaria, and angioedema; minor role in bronchospasm

B. Gastric acid secretion: released from enterochromaffin cells in response to vagal and gastrin stimulation to cause H+ output from parietal cells

C. CNS role: involved with arousal, neuroendocrine release (ACTH, vasopressin), thermoregulation, eating and satiety

D. Hypotension: due to drug-induced release from mast cells (e.g. morphine)
H1-(Central)-[Gq] Receptors

Gs and Gi effect:

Gq effect:
eq H2-Activated by histamine causes an increase in cAMP.

Gquer->IP3 and DAG
1st-generation.H1 (CNS)

Antiemetic, antihistamine, sedative. Blocks vomiting center. Blocks allergic reactions. Causes drowsiness. Used for motion sickness and sleeping.
H1 agonist
H2-[Gs/cAMP] Receptor
a. 4-methylhistamine
b. Impromidine

H2 receptor agonist. (now H4)

cAMP increased
H2 receptors AGONIST

It has been used diagnostically as a gastric secretion indicator.
rantidine (also Cimitidine)
Histamine H2 antagonist; GERD & hearburt
H1 Receptor mediated Responses.

(For allergies and sleep)
1. Dilation of arterioles and venules, mediated by release of NO from vascular endothelium

2. Increased capillary permeability

3. Constriction of large arteries and veins

4. Constriction of bronchial smooth muscle

5. Stimulation of sensory nerve endings (itch, flare)

6. **CNS arousal
H2 Receptor mediated Responses

(Heart) similar to Beta1Adrenergic
1. Stimulation of gastric acid secretion

2. Vasodilation (slower onset and longer duration relative to H1 effect), mediated by H2 receptors on smooth muscle

3. Effects on cardiac contractility and rate similar to beta-1 adrenergic stimulation
H1 Receptor *Antagonists Generally
Highly selective for H1 as ***compared to H2 receptors.
(but not otherwise.)

Doses that inhibit the H1 mediated effects of histamine released from mast cells have no effect on histamine-induced acid secretion by parietal cells in the stomach

Competitive Inhibition.

First generation differ greatly from second generation H1's.

The second generation drugs have minimal anticholinergic activity and insignificant sedative effects due to limited access to the CNS. Some are prodrugs, some are cleared predominantly by the kidney, and some are formulated for topical administration (intranasal or ophthalmic use).
H1-1st.generation Antagonists. Discussed in comparison to H1 2ndgen


-relatively nonselective with respect to actions including:
-local anesthetic action, -muscarinic receptor blockade
-weak alpha-adrenergic blockade
-*CNS prominent sedative effects.

led to the discovery of treatments of psychosis.
H1-2nd.generation Antagonists.
Discussed in comparison to H1 1st gen block.

(NON-CNS, less effects)
-minimal anticholinergic activity
-Insignificant sedative effects due to limited access to the CNS.
-Not limited to oral route as the "other generation."
-cleared predominantly by the kidney
-Some topical administrations

(intranasal or ophthalmic use).
First Generation H1 blocker
First Generation H1 blocker
Second Generation H1 blocker
and others.
2nd-gen Antihistamine (H1 blocker).


Uses: Allergies.
Tox: Less sedation than 1st generation due to reduced CNS entry
(Desloratidine is similar)
2nd-gen Antihistamine (H1 blocker).


Uses: Allergies.
Tox: Less sedation than 1st generation due to reduced CNS entry
Structural Characteristics of the

(?)-All have a bicyclic benzene ring that induces lipophilicity through the BBB.

(?) Have carboxylate residue, are charged at physiological pH, and have much less distribution into the CNS.

(?) All have an an imidazole moiety like histamine.
1st-gen Antihistamine (H1 blocker). "Chlor-trimaton"
Uses: Allergies, motion sickness, sleep aid
Tox: Sedation, anti-muscarinic action
first generation H1 receptor blocker. Allergic rhinitis and urticaria, motion sickness, marked sedation. Also used as antiemetic.
First generation antiH1
a. Allergic responses such as allergic rhinitis, conjunctivitis, and urticaria
b. Anti-emetic, motion sickness, sedative-hypnotics with OTC availability
Second generation anti *H2*
Allergic responses such as allergic rhinitis, conjunctivitis, and urticaria;

treatment of mastocytosis!! antiH1's (both of them, do NO such thing)

reduce nasal itching, watery eyes, rhinorrhea, and sneezing associated with allergic rhinitis, but not the nasal congestion; nasal corticosteroids in contrast reduce the latter symptom.
H1 and H2 Receptor Antagonists in combination
Rarely, inflammatory effects of histamine released from mast cells and basophils are mediated by H2 receptors, as well as H1 receptors. Under those conditions, H2 receptor antagonists are used in combination with H1 receptor antagonists. H2 receptor antagonists, for which ranitidine is prototypic, are highly selective for H2 as compared to H1 receptors. Their primary clinical indications are prevention and treatment of gastrointestinal ulcers, gastric acid hyper-secretory conditions, and gastro-esophageal reflux disease. (These drugs will be discussed further in the Gastroenterology Module.)
Side Effects-First Generation
Sedation, antimuscarinic effects (acute toxicity resembling atropine poisoning with CNS excitation); allergic dermatitis a common paradoxical effect of topical antihistamines
Side Effects-Second Generation
Lack of sedative or antimuscarinic effects.

Several agents were found, after marketing, to cause a potentially fatal arrhythmia (a ventricular tachycardia referred to as torsades de pointes), because of block of certain potassium channels in the heart. The risk, which was rare, increased when these agents were taken with drugs that inhibited their biotransformation by CYP 3A4 (such as erythromycin). One of these, terfenadine (SELDANE) was withdrawn from the market and replaced by its metabolite, fexofenadine, which is not cardiotoxic.
When taken with


Which drugs where/are Cardiotoxic (Torsades and Ventricular tachy and arrythmia)
-Seldane (replaced by its metabolite Fexofenadine)

*Act to inhibit enzymatic degredation/biotransformation (viaCYP 3A4) of what drug!?
Inhibitors of Histamine Release
is a humanized monoclonal antibody with affinity for the Fc region of IgE. Binding blocks the ability of IgE to bind to the FcεRI receptor on mast cells, basophils and other cell types. This IgG therapeutic, administered s.c., is very slowly absorbed and has a long elimination half-life (26 days). Due to risk of anaphylaxis, the drug must now be administered by a health-care provider and not by the patient. An expensive agent, its use is limited to those patients for whom other therapeutic agents have been found inadequate.
What intracellular signal changes with blockade of the H2 receptors?
DECREASED cAMP in ANTI-Histamines.
1) H2 receptor antagonist: antagonizes receptor on parietal cell-->decrease acid production
2) SE: gynemastia, anti-androgen: Cimitidine makes you into a girl
An H1 blocker that interacts poorly with antibiotics that inhibit CYP450. Causes cardiac problems with increased toxicity. Was replaced by 2nd generation H1 blockers because of dangerous cardiac effects.