Med Chem - Asthma & COPD Flashcards Preview

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Flashcards in Med Chem - Asthma & COPD Deck (21)
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1
Q

Overview

A

Requires drugs that treat bronchoconstriction and inflammation symptoms

2
Q

Asthma/COPD Drug Pathway Options

A
  • Affecting adrenergic or cholinergic bronchial smooth muscle tone (adrenergic agonist or antimuscarinic)
  • Inhibit inflammatory process (Corticosteroids, mast cell stabilizers, LT modifiers)
3
Q

Steroid Hormone Action

A
  • Steroid enters cells, binds with receptor
  • Creates a complex that enters the nucleus and affects gene expression
  • Induces protein for altered cell function or autocrine/paracrine effects
  • Same general process, varies in specificity of receptors, genetic process initiated, and specific cellular response
4
Q

Natural Andrenocorticoids Classes

A
  • Glucocorticoid - cortisol (maximize these effects)

- Mineralocorticoid - aldosterone (minimize these effects)

5
Q

Common Features - All Adrenocorticoids

A
  • Pregnane backbone (21 carbons)
  • Delta4 - 3-one A ring
  • 17B - ketol (COCH2OH) - ketone that has OH group near the C=O group
  • 4-5 double bond also essential for activity
  • 11B hydroxyl group
6
Q

Cortisol v.s. Aldosterone Groups

A

C18 - CH3 + 17 - OH = cortisol

C18 - CHO + 17 - H = aldosterone

7
Q

Gluco-Enhancing Features

A
  • 11B & 17 alpha hydroxyls - present in ALL synthetic glucocorticoids
  • 11B OH becomes a ketone in oxidative metabolism that becomes inactive
  • Unique “bonding pocket” that binds with many AA via hydrogen bonding
  • Reduction can also occur at C3, C4, and C20 which needs to be slowed to increase activity
8
Q

Steroid Modifications Goals

A
  • Separate glucocorticoid and adrenocorticoid activity
  • Increases potency
  • Increases duration of action
  • Optimize administration routes (inhalation)
9
Q

REQUIRED Features for MC

A
  • Pregnane
  • C4-5 ene
  • C3 - ketone
  • C17 B - ketol
10
Q

MC Side Effects

A
  • From exaggerated metabolic function from MC
  • Excessive Na+ retention
  • Excessive K+ retention
  • Negative nitrogen balance
  • Increase gastric activity
  • Edema
  • Psychosis
11
Q

Steroid Modifications

A
  • Delta1 - corticosteroid
  • 9-Halogen substitutions
  • Methyl/hydroxyl substitutions
12
Q

Delta1-corticosteroids

A

-Flattens A ring, increases gluco receptor affinity
-Decreases affinity for MC
-ALSO slow reduction of A-ring which increases duration
-MORE potent anti-inflammatory with decreased SE
EX: Prednisone and Prednisolone (interchangable)

13
Q

9-Halogen Substitutions

A

-Bromide - 1/3 cortisone activity
-Fluoride - 11x cortisone activity
-Increases MC and GC activity
-Inverse activity effect to size of halogen
-Creates inductive effect, increase H-bond of 11-OH for glucoreceptors
EX: Triamcinolone, increases selectivity by 16-alpha hydroxyl which decreases MC activity

14
Q

Methyl/Hydroxyl Substitutions

A
  • OH at C17, CH3 at C16
  • Latter counteracts MC effect of halogen at C9 (mineralo-abolishing group)
  • Added to increase GC activity in glucocorticoids with little salt retention
  • Selective for GC activity
  • Inhibits 17-alpha hydroxyl oxidation
  • Increases anti-inflammatory affect and increases lipophilicity/receptor affinity
  • EX: Betamethasone and Dexamethasone
15
Q

Inhaled Corticosteroids

A
  • Anti-inflammatory in lungs

- Systemic effects are the adverse effects

16
Q

ICS Desired Properties

A
  • High lipophilicity
  • Low bioavailability with high clearance
  • High protein binding
  • Rapid systemic clearance with inactive metabolites
17
Q

ICS SARS

A

-C17 and C16 hydroxyls that form diesters and ketols to increase lipophilicity
-Diesters = prodrugs, increased duration
-Ketols are NOT prodrugs unless they have a C21 ester
EX: Beclomethasone dipropionated - lipophilic prodrug, 20% bioavailable, 16B-methyl AND 9alpha-chloride groups

18
Q

ICS Pharmacore

A
  • 11B, 17alpha, and C21 hydroxyl
  • 1-2 and 3-4 diene
  • 9alpha halogen
  • C21 - ester? prodrug with increased absorption and duration
  • C20 - fluoromethyl = anti-inflammatory action when inhaled (-SCH2F)
19
Q

Budesonide Feature

A

Acetal between 16alpha and 17 alpha

20
Q

Fluticasone Propionate Features

A
  • C20 thiofluoromethyl and 17alpha propionate ester
  • 6alpha fluoride - ONLY GC action
  • BID
21
Q

Fluticasone Furoate

A
  • 2 furoic acid ester that occupies receptor more completely
  • Therefore increases affinity
  • ONLY once daily dosing