DERM IE2 Material: Antihistamine MEDCHEM

Histamine structure

• imidazole ring (basic, pKa 5.8)

• aliphatic primary ring (basic, pKa 9.4)

• single bonds in side side chain allow free rotation

at physiological pH (7.4), histamine exists as a —-? what is the significance for its activity?

• monocation

  • sufficient for agonist activity

  • protonation of heterocyclic (imidazole) ring NOT required

how do 1st gen AH relate to histamine’s strucure?

• mimics moncation form of histamine

• has protonable amine at similar distance form aromatic system, allowing them to bind to and block H1 receptor

general pharmacophore for 1st gen AH

• 2 aromatic groups (Ar)

• linker (X) → O, N, or C

• protonable tertiary amine

2 main characteristics/side effects of 1st gen AH

• sedation (crosses BBB)

• affects other receptors (cholinergic, adrenergic, dopaminergic, serotonergic)

subclasses of 1st gen AH

• ethylenediamines

• ethanolamine ethers

• alkylamines

• tricyclics

• piperazines

ethylenediamine: characteristic linker structure

2 carbons between 2 nitrogens (N-C-C-N)

ethanolamine ethers: characteristic linker structure

C-O-C

ethanolamine ether: drugs

• Diphenhydramine (Benadryl)

  • short t ½

  • significant sedation → OTC sleep aid

• Dimenhydrinate (Gravol)

  • 8-chlorotheophyllinate salt of Diphenhydramine

  • for motion sickness

Alkylamines: characteristic linker structure

C

alkylamine distinguishing properties compared to ethylenediamines and ethanolamines

• longer duration of action (t ½ up to 24 hrs)

• decreased sedation

major metabolic pathway for alkylamines

N-dealkylation

alkylamines can contain

maleate salt

Alkylamine: Triprolidine HCl (Actidil)

E isomer more potent (by 1000 fold)

Piperazines: structural feature

piperazine (hexagon) ring

how is Cetirizine (Zyrtec) related to Hydroxyzine?

Cetirizine = acid metabolite of Hydroxyzine

OH of hydroxyzine → oxidized → COOH

cetirizine classification, despite its origin from a 1st gen drug

2nd gen, non-sedating AH

Tricyclics: structural feature

tricyclic ring system

main metabolic pathways for tricyclic

• N dealkylation

• aromatic hydroxylation

2nd gen AH advantages

• improved H1 selectivity

• little to no sedative effects

• less anticholinergic activity

• long half life

which 2nd gen AH contains COOH

fexofenadine (Allegra)

wwhich 2nd gen AH has active metabolite of Loratadine (Claritin)? key properties?

• Desloratadine (Aerius)

• more potent than Loratadine and rapid onset of action

what special chemical characteritic describes Cetirizine (Zyrtec)

zwitterionic (positive and negative charges)

Mechanisms of action of topical AH

• potent, selective H1 receptor antagonist

• prevent release of histamine from mast cells

what are topical AH used for?

• nasal sprays

• eye drops

examples of topical AH

decongestants are

alpha-adrenergic receptor agonists

decongestant: catecholamines

• NE (R=H) and Epi (R=CH3)

• nonselective

who do catecholamines have poor oral bioavailability and short DOA

• poor oral bioavailability → given IV

• rapidly metabolized by COMT and MAO

  • DOA = 1 - 2 mins

decongestant: phenylethanolamine agonists

• components

• drugs

• components

  • substituted benzene rig

  • aliphatic primary or secondary amine separated from benzne by 2 carbons

  • R-hydroxyl at C1 carbon

• drugs

  • ephedrine/pseudoephedrine (added CH3 on position 2)

what specific substitution on phenylephrine makes it a selective alpha-agonist

3-OH substitution on benzene ring → keeps out of CNS

why do Metaraminol and Methoxamine have onger DOA than phenylephrine?

they are NOT subtrates for COMT or MAO

what is key characteristic of Amphetamine and Methamphetamine? clinical implication?

• highly lipophilic (log P ≥ 2)

• crosses BBB → increased risk of drug abuse

MDMA? key properties?

• 3,4-methylenedioxymethamphetamine

• highly lipophilic

• high risk of drug abuse

decongestant: imidazole alpha 1 agonist example

Oxymetazoline

characteristic that describes imidazoline alpha1 agonists? affect on administration?

• highly ionized (zwitterionic)

• topically used only due to high ionization limiting systemic absorption