H1 Antagonists

Histamine

• histamine = a ______ ______ (biologically synthesized)

• exists mostly in a ______ (positively/negatively) charged cationic form (NH3+) at pH of _____ —> ______ form that binds histamine receptors

• L-Histidine —> via histidine decarboxylase + cofactor: ______ ______ ( ______ ____ derivative) —> Histamine

• involved in the initial stages of ______ ______

• biogenic amine

• positively, 7.4, active

• pyridoxal phosphate, vitamin b6

• allergic response

IgE Mediated Hypersensitivity Reaction

1. Exposure = ______ ______

2. IgE bings to ______ receptors of mast cells or basophils

3. ______ antigen exposure + IgE ______ = ______

4. degranulation = histamine ______ and inflammatory ______

• IgE synthesis

• Fce

• secondary, crosslinking, degranulation

• release, response

what type of receptors are histamine receptors?

GPCRs

H1 Antagonist — MOA

• the protonated amine of histamine binds to ______ ______ (Asp107) in transmembrane domain 3 (______) of the H1 receptor

• H1 antagonists were thought to work as ______, ______ inhibitors

• H1 antagonists are now known as ______ ______

  • exists in equilibrium between its ______ and ______ states

  • histamine (natural agonist) binds and stabilizes its ______ conformation

  • antihistamines (H1 antagonists) bind and stabilize its ______ conformation

• aspartate 107, TM3

• competitive, reversible

• inverse agonists

• active, inactive

• active

• inactive

First Generation vs. Second Generation

• 1st generation agents = ______ lipid solubility + ______ cross BBB = ______ sedative effects

• 2nd generation agents = ______ lipid solubility + ______ cross BBB = ______ sedative effects

• breast feeding — preferred agents —> 2nd generation due to ______ anti-cholinergic effects

• more, easily, more

• less, less, less

• less

what do all antihistamine antagonists contain?

an agonist structure

which word is longer? agonist or antagonist?

antagonist —> structurally larger

if the structure was similar to histamine, how would they act? antagonist or agonist?

agonist

why are chlorofenramine and bromenramine such potent antihistamines?

halogen in para position

H1 Antagonists - SAR

• Aryl (Ar) groups —> two aromatic (aryl) rings are present

• X —> connects the aromatic rings to the carbon chain

• Carbon Chain

• Basic Amine

• more lipophilic than histamine

• can be C, O, or N

• potency ranking: n = 3 > 2 > 1. needs to be protonated to interact w/ Asp107. substituents R and R’ = CH3 —> small group. larger substituents dec. potency.

1st Generation — Alkylamines (X = C)

• halogenation at para position (Cl, Br, etc.) —> ______ (increase/decrease) potency

• 2-pyridyl substitution —> ______ (increase/decrease) potency, but also ______ anticholinergic effects and ______ sedation

• brompheniramin relative to chlorpheniramin:

  • slightly ______ potetnt

  • relatively ______ half-life (~24 hours)

• increase

• increase

• increase

• increase

• more

• longer

1st Generation — Piperazine (X = N)

• piperazine ring —> ______ (increase/decrease) lipophilicity —> ______ CNS penetration —> ______ duration of action & central ______ activity

  • ______ sedation & ______ anticholinergic effects

• cyclizine —> ______ (most/least) potent antihistamine —> no halogen at para position

• hydroxyzine —> has an ______ tail —> risk of ______

• increase, better, prolonged, antinausea

• least

• ethoxyethanol, cardiotoxicity

1st Generation — Piperidines (X = C)

• Cyproheptadine HCl

  • ____ more potent than diphenhydramine

  • ______ and ______ activity —> super dry mouth

  • pronounced ______

• Ketotifen

  • ______ product

  • potent antihistamine activity

  • ______ histamine release by stabilizing mast cells

• 150x

• anti-serotonergic, anti-cholinergic

• sedation

• ophthalmic

• inhibit

1st Generation — Ethanolamines (X = O)

• Diphenhydramine

  • ______ N-demethylation —> short-acting (4-6 hours)

  • effects (3)

• Diphenhydrinate

  • ______ + CNS stimulant: ______

  • still sedative but used for ______ ______

• Doxylamine Succinate

  • very ______ sedative

  • OTC sleep aid

• Clemastine

  • structure: ______ ______

  • ______ potency

  • ______ duration (~12 hours)

• fast

• sedative, anticholinergic, anti-emetic

• diphenhydramine, theophylline

• motion sickness

• potent

• 3-carbon linker

• more

• longer

1st Generation — Phenothiazines (X part of phenothiazine ring)

• Promethazine

  • potent ______ effects + ______ duration of action

  • potent ______ effects and QT prolongation

  • moderate ______ effects —> aromatic rings are not coplanar —> weaker binding to histamine receptors

  • treat nausea and vomiting associated with motion sickness

• sedative, long

• anti-cholinergic

• anti-histamine

1st Generation — Miscellaneous

• potent _____ ______

• ______ cream for pruritis

• ______ and _____ 

• H1 antagonist

• Zonalon

• anti-cholinergic, sedation

2nd Generation — Cetirizine

• Cetirizine

  • oxidized metabolite of ______

  • conversion adds a ______ group —> ______ H1 receptor selectivity & prevents ______ ______

  • ______ mixture

  • exists as a ______ —> ______ CNS penetration —> less sedating

• Levocetirizine 

  • pure ____-enantiomer of cetirizine

  • ____ more potent than the S-enantiomer

  • more potent than fexofenadine and loratidine for wheal-and-flare

• hydroxyzine

• COOH, increases, cardiac toxicity

• racemic

• zwitterion, less

2nd Generation — Fexofenadine

• active metabolite of ______

• COOH —> ______ H1 receptor selectivity = anti-cholinergic effects

• exists as a ______ —> limits BBB penetration —> ______ sedation

• ______ Pgp substrate = high potential for drug-drug interactions

• terfenadine

• higher

• zwitterion, less

• strong

2nd Generation — Loratadine

• structure: ______ antihistamine

• ______ ______ —> responsible for non-sedative property

• ______ N = neutral —> rapid absorption and fast acting

• converted to ______ by CYP3A4 and CYP2D6

  • ____ more potent than loratadine

  • ______ onset of action

  • does not cross ______ —> minimal sedation —> due to nitrogen going to be ______ charged

  • lacks ______ group

• tricyclic

• ethoxycarbonyl

• carbamate

• desloratadine

• 15x

• faster

• BBB, positively

• carbamate

2nd Generation — Olapatadine

• Doxepin + ______ = olapatadine

• H1 antagonist + inhibits histamine release + other inflammatory mediators (PGD2/tryptase) from mast cells

• COOH = ______ sedating

• rapid onset

• strong binding affinity = slow receptor dissociation = LONG ______

• CH2COH

• less

• duration

H1 Antagonists — Photosensitivity

• MOA — photosensitizing agents/drugs absorb photons from solar radiation, leading to their activation and chemical reactions 

• many antihistamines are metabolized into ______ ______ when exposed to UV/solar radiation

• two types of reactions: ______ & ______

• H1 antagonists with the greatest risk —> ______

• free radicals

• photosensitivity & phototoxicity

• promethazine

H2 Antagonist

• H1 antagonist do _______ block histamine mediated secretion

• H2 antagonist = ______ lipophilic than H1 antagonist

• ____ antagonist were developed to specifically reduce gastric acid

Cimetidine (Tagamet)

• 1st generation agent — contains “______” ring

• MOA —> ______ antagonist at H2 receptors

• POTENT ______ INHIBITOR —> involved in multiple drug-drug interactions

• antacids MUST be given ______ OR _______ cimetidine

• cimetidine a ______ hydrophilic drug = requires ______ environment for solubilty/absorption

• imidazole

• competitive

• CYP3A4

• before, after

• BASIC, ACIDIC

5 key enzymes involved in drug-drug interactions:

• CYP3A4

• CYP1A2

• CYP2C9

• CYP2C19

• CYP2D6

Ranitidine (Zantac)

• 2nd Generation —> ______ potent than cimetidine

• MOA —> _______ antagonist at H2 receptors

• ______ CYP enzyme inhibitor

• antacids MUST be given ______ OR ______ ranitidine

• ranitidine a ______ hydrophilic drug = requires ______ environment for solubility/absorption

• presence of carcinogenic N-nitrosodimethylamine (______) contaminant

• more

• competitive

• weak

• before, after

• basic, acidic

• NDMA

Famotidine (Pepcid)

• 2nd gen agents — ______ potent than cimetidine + ranitidine

• MOA —> ______ antagonist at H2 receptors

• does ______ inhibit CYP enzymes

• antacids and food do ______ affect oral bioavailability

• more

• competitive

• not

• not