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

Overview

Requires drugs that treat bronchoconstriction and inflammation symptoms

2

Asthma/COPD Drug Pathway Options

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

3

Steroid Hormone Action

-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

Natural Andrenocorticoids Classes

-Glucocorticoid - cortisol (maximize these effects)
-Mineralocorticoid - aldosterone (minimize these effects)

5

Common Features - All Adrenocorticoids

-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

Cortisol v.s. Aldosterone Groups

C18 - CH3 + 17 - OH = cortisol
C18 - CHO + 17 - H = aldosterone

7

Gluco-Enhancing Features

-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

Steroid Modifications Goals

-Separate glucocorticoid and adrenocorticoid activity
-Increases potency
-Increases duration of action
-Optimize administration routes (inhalation)

9

REQUIRED Features for MC

-Pregnane
-C4-5 ene
-C3 - ketone
-C17 B - ketol

10

MC Side Effects

-From exaggerated metabolic function from MC
-Excessive Na+ retention
-Excessive K+ retention
-Negative nitrogen balance
-Increase gastric activity
-Edema
-Psychosis

11

Steroid Modifications

-Delta1 - corticosteroid
-9-Halogen substitutions
-Methyl/hydroxyl substitutions

12

Delta1-corticosteroids

-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

9-Halogen Substitutions

-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

Methyl/Hydroxyl Substitutions

-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

Inhaled Corticosteroids

-Anti-inflammatory in lungs
-Systemic effects are the adverse effects

16

ICS Desired Properties

-High lipophilicity
-Low bioavailability with high clearance
-High protein binding
-Rapid systemic clearance with inactive metabolites

17

ICS SARS

-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

ICS Pharmacore

-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

Budesonide Feature

Acetal between 16alpha and 17 alpha

20

Fluticasone Propionate Features

-C20 thiofluoromethyl and 17alpha propionate ester
-6alpha fluoride - ONLY GC action
-BID

21

Fluticasone Furoate

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