Derm Exam 2: Kaur

______

• Structure

  • Imidazole ring

  • Aliphatic primary amine → Basic amine → needs protonation

  • Single bonds between the ring and side chain allow free rotation

• The monocation is sufficient for agonist activity

Histamine

Histamine

• Structure

  • ______

  • ______ amine → ______ amine → needs ______

  • ______ bonds between the ring and side chain allow free rotation

• The ______ is sufficient for ______ activity

Imidazole ring, aliphatic primary, basic, protonation, single, monocation, agonist

______ → 2C + 2N

• Sedation

• These drugs also effect at the other receptors such as cholinergic, adrenergic, dopaminergic, and serotonergic

Ethylenediamines

Ethylenediamines → ______

• ______

• These drugs also effect at the other receptors such as cholinergic, adrenergic, dopaminergic, and serotonergic

2C and 2N, Sedation

______ → C–O–C

• ______ (______): Short t_1/2 and sedation → can be used as OTC sleep aid

• ______ (______): motion sickness and decreased sedative SEs (caffeine = 9-chlorotheophyllinate salt)

Ethanolamine Ethers, Diphenhydramine, Benadryl, Dimenhydrinate, Gravol

Ethanolamine Ethers → ______

• Diphenhydramine (Benadryl): ______ and ______ → can be used as ______

• Dimenhydrinate (Gravol): ______ and decreased ______ (caffeine = 9-chlorotheophyllinate salt)

C-O-C, short half-life, sedation, OTC sleep aid, motion sickness, sedative SEs

______ → C

• Longer duration (24 half-lives)

• Decreased sedation compared to Ethylenediamines and Ethanolamine Ethers

• Geometric Isomers (E/Z) → E (trans) is 1000-fold MORE potent

Alkylamines

Alkylamines → ______

• ______ (__ half-lives)

• ______ compared to Ethylenediamines and Ethanolamine Ethers

• ______ (E/Z) → ______ (______) is 1000-fold MORE potent

C, longer duration, 24, decreased sedation, geometric isomers, E, trans

______ → 2C + 2N + Ring (Heterocycle → not all carbons)

• Acid metabolite of hydroxyzine is cetirizine formed from oxidation of the terminal primary alcohol to the corresponding carboxylic acid

• Cetirizine is a zwitterionic and usually classified with the 2nd Gen non-sedating AHs

• ______ = prodrug + OH metabolized to COOH (______)

Piperazines, Hydroxyzine, Cetirizine

Piperazines → ______ (______ → not all carbons)

• Acid metabolite of ______ is ______ formed from ______ of the terminal ______ to the corresponding carboxylic acid

• ______ is a zwitterionic and usually classified with the 2nd Gen non-sedating AHs

• Hydroxyzine = ______ + ______ metabolized to ______ (cetirizine)

2C and 2N and Ring, heterocycle, hydroxyzine, cetirizine, oxidation, primary alcohol, Cetirizine, prodrug, OH, COOH

Tricyclics → ______ 

3 rings and basic amine

______ → 3 rings and basic amine

Tricyclics

2nd Gen AHs

• Vary widely in structure

• ______ (______) → Zwitterionic

  • ______ = Basic and ______ = Acidic

• ______ (______) → Zwitterionic

• ______ (______) → NOT Zwitterionic BUT ______

• ______ (Aerius) → ______ H1 antagonist than Loratadine + ______

• Loratadine = ______ and Desloratadine = ______

• Improved H1 ______

• Little or no ______ qualities

• ______

Fexofenadine, Allegra, N, COOH, Cetirizine, Zyrtic, Loratadine, Claritin, efflux, Desloratadine, more potent, rapid onset, prodrug, metabolite, selectivity, sedative, long half-life

Topical AHs

• ______, ______, ______, ______, ______, and ______ (OLEAEB)

• ______ H1-receptor antagonist

• Prevents release of histamine from ______ (inhibitor of histamine release)

• Nasal spray and/or eye drops for allergic conjunctivitis

Olopatidine, Levocabastine, Emedastine, Azelastine, Epinastine, Bepotastine, potent selective, mast cells

Decongestants Alpha-Adrenergic Receptor Agonists

• ______lamines

• ______lamines

• ______-Agonists

  • ______

  • ______

Catecho, Phenylethano, Synthetic Selective Alpha-1, Phenylethanolamines, Imidazoline Agonists

Catecholamines

• ______ (R= H) and ______ (R= CH3)

• ______ bioavailability → ______ metabolism by ______ (Catechol O-Methyl Transferase) and ______ (______)

• ______

NE, EPI, poor oral, rapid, COMT, MAO, 1-2 mins, Non-Selective

______

• NE (R=H) and Epinephrine (R=CH3)

• Poor oral bioavailability → rapid metabolism by COMT (Catechol O-Methyl Transferase) and MAO (1-2 mins)

• Non-Selective

Catecholamines

______

• Ephedrine/Pseudoephedrine → ______

• CH3 = ______

Phenylethanolamines, natural/plant, slows metabolism

Phenylethanolamines

• ______ → Natural/Plant

• ______ = slows metabolism

Ephedrine/Pseudoephedrine, CH3

Synthetics Selective Alpha1-Agonists

• Phenylethanolamines

  • Phenol = ______

• Imidazoline Agonists

  • ______ (contains ______ amine)

  • ______ amine maintained

  • ______ (______)

acidic, Oxymetazoline, basic, phenylethyl, highly ionized, zwitterionic

Alpha-Adrenergic Receptor Agonists

• Phenylethanolamines – Agonists

  • ______ product (Chinese herbal medicine: Ma Huang)

  • ______ activity → ______ at position-______

• SAR of Phenylethanolamines: ______

natural, good oral, methyl, 2 slows MAO metabolism, Selective Alpha-1 Agonists

Alpha-Adrenergic Receptor Agonists

• Phenylethanolamines – Agonists (ENTER AFTER EACH BULLET POINT)

  • Pharmacophore: Phenylethanolamine Agonists

    • Substituted ______

    • ______ separated from benzene by ______

    • (__)-______ at ______ carbon

    • __ configuration gives ______ activity

    • ______ (no methyl) → ______

    • ______ and ______ → ______ Duration of Action (NOT substrate for COMT or MAO)

    • ______ substituted benzene ring

    • ______-containing compounds have ______ oral activity

    • If phenyl substitution is only a 3’-OH → activity reduced at ______ sites + almost eliminated at ______ sites → affording selective alpha agonists

    • ______ sites have a wider range of substituent tolerance for agonist activity

benzene

aliphatic amine, 2 Cs

R, hydroxyl, C1

R, max direct

Phenylephrine, substrate for MAO

Metaraminol, Methoxamine, longer

3,4-dihydroxy

catechol, poor

alpha, beta

alpha

KNOW IMAGE

An agitated man comes into your pharmacy with a homemade capsule he confiscated from his teenage son’s room. The son confessed that he bought the drugs at school, and that they were supposed to contain methamphetamine.

After having the capsule analyzed by a local school of pharmacy chemistry faculty member you find that it contains the structure shown below. How do you counsel this distraught dad?

A. Tell him not to worry, the drug has no central stimulating activity.

B. Tell him the bad news.

C. Tell him there is good news and bad news….the drug does stimulate the CNS, but is not a controlled substance.

C

An agitated man comes into your pharmacy with a homemade capsule he confiscated from his teenage son’s room. The son confessed that he bought the drugs at school, and that they were supposed to contain methamphetamine.

After having the capsule analyzed by a local school of pharmacy chemistry faculty member you find that it contains the structure shown below. How do you counsel this distraught dad?

• This is ______ or ______.

• While this agent most certainly is NOT stimulating as methamphetamine, it has some functional groups which promote ______ but others attempting to slow down.

• It is marketed as a ______ but can cause some central ______-receptor agonist effects.

ephedrine, pseudoephedrine HCl, BBB penetration, decongestant, alpha

What functional group(s) on adrenergic agonist molecules keeps them out of the CNS?

A. Phenolic hydroxy groups

B. The alcoholic OH group at position-1

C. CH3 group at position-2

A

What functional group(s) on adrenergic agonist molecules keeps them out of the CNS?

• ______ groups are weakly acidic and therefore ______. Even one ______ provides enough hydrophilic character to keep drug mostly out of ______.

• The ______ group at position-__ will perhaps ______ entry.

Phenolic OH, ionizable, phenolic OH, CNS, alcoholic OH, 1, slow down CNS

Which of the functional groups found on our structure facilitate BBB penetration and central stimulation?

A. The alcoholic OH group at position-1

B. CH3 group at position-2

C. The N-CH3 group

D. CH3 group at position-2 and N-CH3 group

D (Both increase lipophilicity)

The boy who sold the capsule claimed that the drug could be taken orally or the capsule contents could be dissolved in water and injected IV. Do you anticipate that the molecule will be active by the oral route?

• A: ______, ______ groups will help absorption, and drug is ______ for ______ (NOT metabolized by ______ and metabolism by ______ is slowed down due to ______ at position-__)

Yes, lipophilic, stable, oral route, COMT, MAO, methyl, 2

Is this molecule expected to have good water solubility? Can it be injected?

Yes, charged HCl salt and polar OH group