Asthma/COPD Medchem Flashcards Preview

Pharmacy School 2016-17 > Asthma/COPD Medchem > Flashcards

Flashcards in Asthma/COPD Medchem Deck (31):

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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


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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)


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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


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Used to form salt form drug with diphenhydramine (Dimenhydrinate, AKA Dramamine) | used to prevent motion sickness


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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


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Pyrilamine | ethylenediamine derivative | Antihistamine component of Robitussin Night Relief

Reduced antimuscarinic effects compared with aminoalkyl ethers

Retains sedative SEs


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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


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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


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Meclizine | Piperazine H1 antagonist

Antiemetic for motion sickness

Low affinity for M1 receptors compared with other 1st generation antagonists


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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


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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)


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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


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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


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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)


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Ketotifen | ketone group | H1 antagonist for topical eye use/mast cell stabilizer

Structurally similar to desloratadine


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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


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Olopatadine | H1 antagonist/mast cell stabilizer

Acetic acid derivative of doxepin

Zwitterionic character


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Azelastine | H1 antagonist/mast cell stabilizer

A structured variant

Used as racemate | both enantiomers equally effective


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Partial agonist at H2 receptors

Starting point of development of H2 antagonists

General structure (imidazole - spacer - polar,non-basic group)


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First full H2 antagonist

Thiourea group

Not orally available


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Metiamide | H2 antagonist

Orally active | full antagonist

Caused agranulocytosis in animals


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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


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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)


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Nizatidine | 2nd generation H2 antagonist
| thiazole group

10x more potent than cimetidine

t1/2 = 1-2 hours

No P450 inhibition



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Famotidine | thiazole, guanidine groups | 2nd generation H2 antagonists

40x more potent than cimetidine

t1/2 = 2.5-4.5 hours

No p450 inhibition


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Omeprazole | benzimidazole group

Stable at pH above 5

Considered a prodrug

*review metabolism*


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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


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Metabolism by 3A4 (to sulfone) and 2C19 ("para" hydroxylation) | this metabolism is generally shared by all PPIs

Dexlansoprazole (Dexilant) is R-enantiomer


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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)