Lecture 6: Histamine Flashcards
H1 Blockers
Diphenhydramine Dimenhydrinate Chlorpheniramine Promethazine Fexofenadine Loratadine Desloratadine Cetirizine
H2 Blockers
Cimetidine
Ranitidine
Famotidine
Other
Cromolyn sodium
Omalizumab
Major pharmacologic effect of H1 antagonists
- By blocking histamine receptors on vascular tissue, reduce the symptoms associated with allergic responses/inflammation
a. ) inhibition of vascular permeability
b. ) suppress itching
c. .) No effect on BP or bronchoconstriction - CNS
a. ) 1st generation and sedation
b. ) 1st generation and stimulation in children
c. ) 1st generation and motion sickness (CNS anti-cholinergic effect) - Peripheral and central anticholinergic effect seen with many 1st generation drugs
a. ) Atropine-like effects
b. ) Dry mucus membranes
c. ) Urinary retention
d. ) think about anticholinergic syndrome - Local anesthetic effect
a. ) Block nerve conduction
b. ) Seen with some 1st generation at high dose like PROMETHAZINE
Diphenhydramine
1st generation with most sedative effect
Uses: Allergies, Motion sickness, Sleeping, Early stage Parkinson’s disease
Dimenhydrinate
1st generation
Uses: Allergies, Motion sickness, Vestibular disturbances
Chlorpheniramine
1st generation
Promethazine
1st generation
Uses: Allergies, Motion sickness, Chemotherapy induced nausea and vomiting
Fexofenadine
2nd generation
NOT metabolized by P450
Loratadine
2nd generation
Metabolized by CYP450 to desloratadine
Cetirizine
2nd generation with most sedative effect
Active metabolite of hydroxyzine
Cimetidine
H2 receptor antagonist
Has the most potential for adverse effect due to inhibiting P450 metabolism
Famotidine
H2 receptor antagonist
Ranitidine
H2 receptor antagonist
Also inhibits P450 metabolism but to less of an extent than Cimetidine
Cromolyn sodium
Mechanism: Stabilizes mast cell membrane to prevent release of histamine.
Uses:
Chronic control of asthma and prophylaxis of bronchospasm (allergen or exercise induced). NOT A RESCUE MEDICINE
Nasal formulation for allergies
Opthalmic formulation for conjunctivitis
Oral formulation for systemic mastocytosis (significant increases in mast cell numbers in the skin and internal organs)
Off label uses for food allergy and irritable bowel syndrome
SE: Safe drug/few side effects
Omalizumab
Mechanism: IgG monoclonal antibody for which the antigen is the Fc region of the IgE antibody. Forms omalizumab-IgE complexes ergo no affinity for FcRI
Uses: Decreases amount of antigen specific IgE that normally binds to and sensitizes mast cells,
SE: Injection site reaction, anaphylaxis after the first dose and in some cases >1 year after initiation of regular treatment.
Synthesis of histamine
L-histidine converted to histamine by histidine decarboxylase (an inducible enzyme with PLP) which is inhibited by methylhistidine.
Storage of histamine
(Mostly found in lung, skin, GI). Synthesized and stored in secretory granules in inactive form bound to proteoglycans. Heparin-sulfate+ATP: mast cells: tissues Chondroitin sulfate: basophils: blood Slow turn over
Non-mast cells (gastric mucosa, epidermis, neurons): continuously synthesized and released Rapid turnover (activity dependent on histidine decarboxylase activity)
Effects of histamine release
Within seconds: Burning, itching sensation Intense warmth Skin reddens BP decreases HR increases
Within minutes:
BP recovers
Hives appear
Release of histamine
- Antigen-antibody reaction:
Prior exposure (induction of IgE mediated allergic sensitivyt to drugs and other allergens, response of IgE-sensitized cells to subsequent exposure to allergens)
Calcium-dependent
Releases other mediators as well - Drugs, peptides, venoms that promote release
Drugs: succinylcholine, morphine, curare, antibiotics like VANCOMYCIN INDUCED RED MAN SYNDROME
Peptides: Bradykinin, complement, substance P=released during tissue injury
Venoms: wasp venom
*Mechanism of release is through an increase in intracellular calcium
Red man/red neck/red person syndrome
Caused by vancomycin (used for serious gram positive bacteria, a last resort antibiotic,)
Following rapid IV infusion
Rash in face, neck, upper torso
Hypotension
Due to mas cell degranulation (not allergic rxn to vancomycin)
Some evidence that altered histamine metabolism contributes to the pathogenesis
Other stimuli that release histamine
Cold urticaria
Cholinergic urticaria (increased sympathetic nervous activity w exercise and stress stimulates cholinergic fibers innervating sweat glands to release acetylcholine, leading to mast cell degranulation)
Solar urticaria
Nonspecific cell damage
Identify the major classes of histamine receptors - H1, H2 (with mention of H3 and H4) and explain their tissue distribution and function.
All GPCRs.
Only H1 and H2 are therapeutically targeted.
These two use diff secondary messengers, H1 uses increase in Ca2+ whereas H2 uses increase in cAMP
Define the principal adverse effects of the H1 and H2 receptor antagonists.
Sedation from 1st generation inhibition of central H1 mediating arousal AND central cholinergic receptors.
2nd generation with most sedation is CETIRIZINE. Remember PARADOXICAL EXCITATION IN CHILDREN
GI side effects (minor): loss of appetite, nausea, vomiting.
However in rare case, increased appetite and weight gain due to an H1 central effect to decrease appetite
Other anticholinergic side effects:
Peripheral muscarinic receptors
Seen only with some 1st generation drugs
Dry mouth, dryness of respiratory passages, urinary retention
Major CV toxicity in early second generation due to CYP450 metabolized.
Loratadine never resulted in adverse effects on CV.
