HEENT 03: Chemistry of Antihistamines and Mast Cell Stabilizers Flashcards
What are the effects of mast cell degranulation as an allergic response (histamine release)?
- neurotransmission
- smooth muscle contraction
- vasodilation and vascular permeability
- inflammation
- ECM deposition
- protection from venoms
- distant effects
Mast Cell Stabilizers
What is khellin?
modulates release of histamines and other inflammatory mediators – help reduce symptoms associated with allergic reactions and inflammation
- chromosome derivative
Mast Cell Stabilizers (3)
- sodium cromoglycate
- nedocromil sodium – 10x more potent than sodium cromoglycate
- lodoxamide tris – 2500x more potent than sodium cromoglycate
Mast Cell Stabilizers
What do mast cell stabilizers do?
facilitate immobilization of mast cell granules by several possible mechanisms
- no antihistaminic activity
- no anti-inflammatory activity
Describe histamine enzymatic production.
- histamine synthesized in Golgi apparatus of mast cells and basal cells via enzymatic decarboxylation of L-histidine (pyridoxal phosphate serves as a cofactor) by HDC
- schiff base formation: serves as key intermediate to set up decarboxylation
- pyridoxal phosphate: serves as electron sink during decarboxylation reaction
What are histamine receptors?
- GPCRs
- constitutive, histamine-independent activities
What do H1 receptors target?
smooth muscle of lungs/gut/uterus, endothelium, CNS, nerve endings
- targeted for allergic anti-inflammatory disorders
What do H2 receptors target?
parietal cells of stomach
- targeted for gastric hypersecretory disorders with H2 antihistamines
What do H3 receptors target?
presynaptic in CNS
- decreases release of neurotransmitters
What do H4 receptors target?
eosinophils, mast cells
- chemotactic responses
What are 1st generation H1 antihistamines?
- inverse agonists
- treatment of allergic responses
- also impact other receptors – cholinergic, adrenergic, dopaminergic, serotonergic
What are the side effects of 1st generation H1 antihistamines?
- peripheral: cholinergic blockade – blurred vision, dry mouth, urinary retention, constipation
- central: sedation, drowsiness, decreased cognitive ability
What is the structure of 1st generation H1 antihistamines?
two aromatic groups linked through short chain (spacer) to 3’ aliphatic amine
1st Generation H1 Antihistamines
Ethanolamine Ether
diphenhydramine
- OTC sleep aid
- 8-chlorotheophyllinate salt is dimenhydrinate (dramamine) used for motion sickness
1st Generation H1 Antihistamines
Alkylamine
chlorpheniramine
- S-enantiomer (dexchlorpheniramine) has greater affinity for H1 receptor
- S-enantiomer has greater selectivity for H1 receptor over cholinergic and adrenergic receptors
- less sedative side effects compared to ethanolamine ethers
1st Generation H1 Antihistamines
Piperazine
hydroxyzine
- antihistamine and antiemetic (central mAChR and H1R effects)
- oxidation of terminal alcohol generates cetirizine (2nd generation antihistamine)
1st Generation H1 Antihistamines
Tricyclic
doxepin
- significant affinity for other receptors and CNS-depressant (NSRI) activities
- exists as mixture of Z-isomers (3x more potent, 15%) and E-isomers (85%)
What are 2nd generation H1 antihistamines?
- selective
- peripheral
- causes some drowsiness in limited cases
- little to no affinity for cholinergic, adrenergic, and serotonergic receptors
- mostly amphoteric – less likely to cross BBB (non-sedating)
2nd Generation H1 Antihistamines
Loratadine and Desloratadine
- loratadine: the only non-zwitterionic, non-sedating H1 antihistamine
- desloratadine: more potent metabolite of loratadine that exhibits 100x slower H1 receptor off-rate than 1st generation antihistamines
2nd Generation H1 Antihistamines
Terfenadine and Fexodenadine
- terfenadine: (seldane) no longer used – dangerous cardiac arrhythmias (long QT syndrome) in patients taking other medications that are CYP3A4 substrates (ketoconozaole, macrolide antibiotics)
- fexofenadine: major metabolite of terfenadine responsible for H1 antagonist activity – no cardiac affects, no affinity toward cholinergic and adrenergic receptors, zwitterion is too polar to cross BBB therefore non-sedating
2nd Generation H1 Antihistamines
Cetirizine
- highly selective H1 antihistamine
- no cardiotoxicity
- can cause drowsiness
- R-enantiomer (levocetirizine) has 30x higher H1 receptor affinity (20x slower dissociation) than S-enantiomer
2nd Generation H1 Antihistamines
Levocabastine
- potent selective H1 receptor antagonist
- exists as zwitterion (amphoteric), therefore unlikely to cause drowsiness
What do zwitterions form interactions with?
acidic and basic portion of zwitterions in 2nd generation H1 antihistamines form ionic interactions with H1 receptor
