Asthma/COPD Medchem Flashcards
Histamine
97% in monoprotonated form at pH 7.4 | Biosynthesized from histidine through decarboxylation
Efficiently inactivated by MAO and diamine oxidase or by histamine-N-methyltransferase
H1 antagonist SAR
X= CH-O, N, CH, or CH-N
n = 2 or 3
N should be trisubstituted amine (generally a tertiary amine); usually a dimethyl (R1=R2=CH3 or an alicyclic ring); nitrogen is predominately protonated at physiological pH; involved in an important ionic interaction with the H1 receptor
AR1 and AR2 can be separate aromatic rings or joined (tricyclic)
Diphenhydramine | H1 antagonist, Aminoalkyl Ether
Side effects include sedation (due to central H1 receptors) and antimuscarinic effects | Sominex is a brand name drug that exploits sedation
8-chlorotheophylline
Used to form salt form drug with diphenhydramine (Dimenhydrinate, AKA Dramamine) | used to prevent motion sickness
Clemastine | Aminoalkyl ether
4 possible isomers (R,R - 7x more potent than R,S; R,S - 20-40x more potent than S,R and S,S) | configuration at chiral center closer to phenyl rings is more important for potency than second chiral center
Some antimuscarinic and sedative SEs
Pyrilamine | ethylenediamine derivative | Antihistamine component of Robitussin Night Relief
Reduced antimuscarinic effects compared with aminoalkyl ethers
Retains sedative SEs
Propylamine derivatives
R=H Pheniramine (in Visine A)
R=Cl Chlorpheniramine (10x more potent than pheniramine; S-dextro isomer is active = Dexchlorpheniramine)
R=BR Brompheniramine (similar potency to chlorpheniramine; used as racemate and dexbrompheniramine)
The pheniramines are least sedating of 1st gen H1 antagonists
Promethazine | tricyclic group, phenothiazine
Used typically as antiemetic
Significant antimuscarinic effects
Should not be in patients younger than 2 yeas of age due to fatal respiratory depression
Meclizine | Piperazine H1 antagonist
Antiemetic for motion sickness
Low affinity for M1 receptors compared with other 1st generation antagonists
Hydroxyzine | piperazine H1 antagonist
Polar end group - helps to limit M1 antagonism
Used systemically for hives | can be used as antianxiety agent (minor tranquilizer due to strong central effects)
Available as both HCl and Pamoate salts (pamoate less soluble in water)
Metabolized to Cetirizine by P450s
Cetirizine | key active metabolite of hydroxyzine | piperazine H1 antagonist
Zwitterionic character (reduces CNS access) | greatly reduced sedative effects
P-glycoprotein substrate, further limiting CNS access
Minimal metabolism (characteristic of molecules that exhibit zwitterionic character) | t1/2 = 8 hours
R-levocetirizine is active enantiomer (Xyzal)
Fexofenadine | 2nd generation, piperidine
Zwitterionic characteristic helps limit CNS access and minimalize metabolism | t1/2 = 14 hours
PGP substrate
Absorption mediated by organic anion transporter (OATP) | transport inhibited by some fruit juices (grapefruit, orange, apple) | **recommend taking with water
Loratadine | 2nd gen antagonist | piperidine
Bottome nitrogen not basic | carbamate group
Metabolized by O-dealkylation to Carbamic acid (unstable) which then loses a CO2 to give Desloratadine (active) | can also undergo 3A4/2D6 metabolism to give Desloratadine
t1/2 = 10 hours
Desloratadine | 2nd generation antagonist | piperidine
Activ metabolite of Loratadine | greater affinity for H1 receptor than Loratadine
PGP substrate
t1/2 = 27 hours | metabolzied to 3-hydroxydesloratadine (active)
Ketotifen | ketone group | H1 antagonist for topical eye use/mast cell stabilizer
Structurally similar to desloratadine
Alcaftadine | topical H1 antagonist for use in eyes/mast cell stabilizer
Aldehyde group = better for absorption than carboxylate
Rapid oxidation of aldehyde to an active carboxylate (zwitterionic) | product of oxidation gives bulk of antagonist action
Olopatadine | H1 antagonist/mast cell stabilizer
Acetic acid derivative of doxepin
Zwitterionic character
Azelastine | H1 antagonist/mast cell stabilizer
A structured variant
Used as racemate | both enantiomers equally effective
N(alpha)-guanylhistamine
Partial agonist at H2 receptors
Starting point of development of H2 antagonists
General structure (imidazole - spacer - polar,non-basic group)
Burimamide
First full H2 antagonist
Thiourea group
Not orally available
Metiamide | H2 antagonist
Orally active | full antagonist
Caused agranulocytosis in animals
Cimetidine | Cyanoguanidine
1st successful H2 antagonist (1976)
Fairly short t1/2 = 2 hours
Moderate inhibition of several P450s (1A2, 2D6, 3A4) and also aldehyde oxidase | eliminate imidazole = decreased P450 inhibition
Ranitidine | 2nd generation H2 antagonist | furan group
6x more potent than cimetidine
t1/2 = 2-3 hours
Weak P450 inhibitor (removed imidazole = decreased P450 inhibition)
Nizatidine | 2nd generation H2 antagonist
| thiazole group
10x more potent than cimetidine
t1/2 = 1-2 hours
No P450 inhibition
Famotidine | thiazole, guanidine groups | 2nd generation H2 antagonists
40x more potent than cimetidine
t1/2 = 2.5-4.5 hours
No p450 inhibition
Omeprazole | benzimidazole group
Stable at pH above 5
Considered a prodrug
*review metabolism*
Esomeprazole | S-enantiomer of omeprazole | assymmetric centeris sulfur atom (with lone pair)
Sulfoxides are stable, allowing for synthesis or separtion of discrete enantiomers
Both enantiomers active PPIs | S-enantiomer metabolized more slowly
Metabolism by 3A4 (to sulfone) and 2C19 (to b-hydroxy omeprazole, watch out for genetic polymorphisms – less important for Omeprazole which is metabolizes predominately by 3A4)
Bioavailability of omeprazole is 30-40%, 65% for esomeprazole
Lansoprazole
Metabolism by 3A4 (to sulfone) and 2C19 (“para” hydroxylation) | this metabolism is generally shared by all PPIs
Dexlansoprazole (Dexilant) is R-enantiomer
Rabeprazole
Pantoprazole
In special dual release formulation with Rabeprazole
Type of histaminergic receptors
Four types | All G-protein coupled receptors
H1 (bronchoconstriction, dilation of small blood vessels, and itching in the epidermis; central H1 involved in sleep)
H2 (regulation of gastric acid secretions)
H3 (located mainly in CNS, some in peripehral tissues including gastric mucosa)
H4 (immune cell function modulators)
