Asthma/COPD Medchem Flashcards Preview

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

Flashcards in Asthma/COPD Medchem Deck (31):
1

Q image thumb

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

2

Q image thumb

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)

3

Q image thumb

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

4

Q image thumb

8-chlorotheophylline

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

5

Q image thumb

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

6

Q image thumb

Pyrilamine | ethylenediamine derivative | Antihistamine component of Robitussin Night Relief

Reduced antimuscarinic effects compared with aminoalkyl ethers

Retains sedative SEs

7

Q image thumb

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

8

Q image thumb

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

9

Q image thumb

Meclizine | Piperazine H1 antagonist

Antiemetic for motion sickness

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

10

Q image thumb

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

11

Q image thumb

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)

12

Q image thumb

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

13

Q image thumb

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

14

Q image thumb

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)

15

Q image thumb

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

Structurally similar to desloratadine

16

Q image thumb

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

17

Q image thumb

Olopatadine | H1 antagonist/mast cell stabilizer

Acetic acid derivative of doxepin

Zwitterionic character

18

Q image thumb

Azelastine | H1 antagonist/mast cell stabilizer

A structured variant

Used as racemate | both enantiomers equally effective

19

Q image thumb

N(alpha)-guanylhistamine

Partial agonist at H2 receptors

Starting point of development of H2 antagonists

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

20

Q image thumb

Burimamide

First full H2 antagonist

Thiourea group

Not orally available

21

Q image thumb

Metiamide | H2 antagonist

Orally active | full antagonist

Caused agranulocytosis in animals

22

Q image thumb

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

23

Q image thumb

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)

24

Q image thumb

Nizatidine | 2nd generation H2 antagonist
| thiazole group

10x more potent than cimetidine

t1/2 = 1-2 hours

No P450 inhibition

 

25

Q image thumb

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

40x more potent than cimetidine

t1/2 = 2.5-4.5 hours

No p450 inhibition

26

Q image thumb

Omeprazole | benzimidazole group

Stable at pH above 5

Considered a prodrug

*review metabolism*

27

Q image thumb

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

28

Q image thumb

Lansoprazole

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

Dexlansoprazole (Dexilant) is R-enantiomer

29

Q image thumb

Rabeprazole

30

Q image thumb

Pantoprazole

In special dual release formulation with Rabeprazole

31

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)