Med Chem - Asthma & COPD Flashcards
Overview
Requires drugs that treat bronchoconstriction and inflammation symptoms
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)
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
Natural Andrenocorticoids Classes
- Glucocorticoid - cortisol (maximize these effects)
- Mineralocorticoid - aldosterone (minimize these effects)
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
Cortisol v.s. Aldosterone Groups
C18 - CH3 + 17 - OH = cortisol
C18 - CHO + 17 - H = aldosterone
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
Steroid Modifications Goals
- Separate glucocorticoid and adrenocorticoid activity
- Increases potency
- Increases duration of action
- Optimize administration routes (inhalation)
REQUIRED Features for MC
- Pregnane
- C4-5 ene
- C3 - ketone
- C17 B - ketol
MC Side Effects
- From exaggerated metabolic function from MC
- Excessive Na+ retention
- Excessive K+ retention
- Negative nitrogen balance
- Increase gastric activity
- Edema
- Psychosis
Steroid Modifications
- Delta1 - corticosteroid
- 9-Halogen substitutions
- Methyl/hydroxyl substitutions
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)
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
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
Inhaled Corticosteroids
- Anti-inflammatory in lungs
- Systemic effects are the adverse effects
ICS Desired Properties
- High lipophilicity
- Low bioavailability with high clearance
- High protein binding
- Rapid systemic clearance with inactive metabolites
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
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)
Budesonide Feature
Acetal between 16alpha and 17 alpha
Fluticasone Propionate Features
- C20 thiofluoromethyl and 17alpha propionate ester
- 6alpha fluoride - ONLY GC action
- BID
Fluticasone Furoate
- 2 furoic acid ester that occupies receptor more completely
- Therefore increases affinity
- ONLY once daily dosing
