Adrenocorticoids (Inflammation) PDF Lecture Notes

1/19/2023 Adrenocorticoids (Inflammation) E. Blake Watkins, PhD Union University College of Pharmacy 1 1 1/19/2023 Objectives  Understand the role that glucocorticoids play in management and treatment of inflammation and inflammatory diseases, both locally and systemically  Describe the mechanism...

1/19/2023 Adrenocorticoids (Inflammation) E. Blake Watkins, PhD Union University College of Pharmacy 1 1 1/19/2023 Objectives  Understand the role that glucocorticoids play in management and treatment of inflammation and inflammatory diseases, both locally and systemically  Describe the mechanism of action of the glucocorticoids in treating inflammation  Be able to draw the steroid structural framework and number atoms  Know key compounds involved in glucocorticoid and mineralocorticoid biosynthesis      as well as the endogenous glucocorticoid (cortisol) and mineralocorticoid (aldosterone) Distinguish between structural features of glucocorticoids and mineralocorticoids Understand the SAR of glucocorticoids in terms of receptor binding (GR) Understand the implications of structure modifications in terms of SAR and route of administration (oral, injection, inhalation, topical) Predict potency, selectivity, and DOA in terms of SAR. Predict metabolites of each agent in each drug class discussed. 2 2 1/19/2023 Inflammation  Inflammation is a complex response of cells to harmful stimuli:  Pathogens  Damaged cells  Cytokines  Heat  Etc. 3 3 1/19/2023 Inflammation  Inflammation is characterized by swelling, redness, and pain of the surrounding tissue.  Treatment involves targeting the pro-inflammatory agents that result in these symptoms.  Targeting inflammation does not necessarily treat the underlying cause.  Three primary anti-inflammatory classes:  Glucocorticoids  NSAIDS (non-steroidal anti-inflammatory drugs)  Biologics/DMARDS (disease-modifying anti-rheumatic drugs) 4 4 1/19/2023 Inflammatory Disease Indications  Allergic reactions  Asthma  Lupus erythematosus  Inflammatory bowel disease  Leukemia  Sepsis  Arthritis  Etc., Etc. 5 5 1/19/2023 Steroids (Adrenocorticoids)  Adrenocorticoids (corticosteroids, produced in the adrenal cortex)  Glucocorticoids (affect glucose homeostasis but also possess anti-inflammatory activity) cortisol  Mineralocorticoids (affect sodium and water retention) aldosterone  We will focus only on the glucocorticoids and their roles in the treatment of asthma and COPD and other inflammatory responses.  We will also discuss structural modifications that impact methods of delivery. 6 6 1/19/2023 Steroids  Ring junctions have trans regio    chemistry Steroid nucleus is a 6,6,6,5 tetracyclic ring system 6-membered rings are in chair conformations Methyl groups at C-10 and C13 along with an ethyl group at C-17 make these agents 21-carbon steroids called pregnanes. Glucocorticoids are substituted pregnanes. 7 7 1/19/2023 Steroids in 2D and 3D beta face (b) “above” alpha face (a) “below”  In steroids, alpha (a) substituents extend below the plane of the steroid nucleus (shown with dashed bonds) and beta (b) substituents extend above the plane of the steroid nucleus (shown with solid bonds). 8 8 1/19/2023 Steroid Biosynthesis 9 9 1/19/2023 Steroid Biosynthesis mineralocorticoids glucocorticoids 10 10 1/19/2023 Anti-inflammatory Glucocorticoids 11 11 1/19/2023  Phospholipids of lipid bilayer in the cell membrane. 12 12 1/19/2023 Anti-inflammatory Glucocorticoids ❑ Prevent release of arachidonic acid ❑ Glucocorticoids bind to their cytoplasmic receptors. ❑ The complex dimerizes, diffuses into the nucleus, and binds to DNA, affecting protein synthesis. ❑ They stimulate the synthesis of lipocortin, a protein which inhibits phospholipase A2 to prevent the release of arachidonic acid. ❑ Inhibit interleukin-1 synthesis ❑ Results in a decrease in T- and B-lymphocytes which produce cytokines and antibodies which are part of the inflammatory and immune responses. ❑ Inhibit synthesis and release of histamine 13 13 1/19/2023  Glucocorticoids bind to hormone nuclear receptors (Type I) 14 14 1/19/2023 Prostaglandin Synthesis 15 15 1/19/2023 Glucocorticoid Binding 16 16 1/19/2023 SAR  Natural glucocorticoids possess some mineralocorticoid activity and therefore have some salt-retaining properties.  The goal is therefore to design agents with minimal mineralocorticoid activity and maximal antiinflammatory activity. 17 17 1/19/2023 SAR Anti-inflammatory activity increased Mineralocorticoid activity decreased 1-dehydro (double bond) 6a-CH3 6a-F 16a- & 16b-CH3 9a-F* or 9a-Cl* 16a, 17a-acetonide 16a-OH 18 18 1/19/2023 19 19 1/19/2023 Pharmacokinetics  Glucocorticoids are lipophilic in spite of having 3+ hydroxyl groups.  The hydroxyl groups can be esterified to either increase or decrease this lipophilicity.  Increasing lipophilicity increases logP thus reducing systemic absorption and lowering side effects.  Increasing lipophilicity also leads to an increase in duration of action and a slower onset (steric hindrance slows activation)  How do we alter lipophilicity in steroids? 20 20 1/19/2023 Structure Modification  Hydroxyl groups are easily modified through esterification.  The ester groups may be lipophilic or hydrophilic.  The C-21 hydroxyl is the most easily accessible and easiest to esterify.  The C-17 hydroxyl is also easy to esterify.  The C-11 hydroxyl is hindered by the C-10 and C-13 methyls and will not form esters easily.  C-21 esters are prodrugs and must be activated (hydrolyzed) to free the C-21 hydroxyl to H-bond with Asn-564. This slows onset and prolongs duration of action.  Esterification of the C-17 hydroxyl slows C-17 oxidation and thus prolongs activity. 21 21 1/19/2023 Structure Modification R-group Name -CH3 Acetate -CH2-C(CH3)3 t-Butylacetate -(CH2)2CH3 Butyrate -C(CH3)3 Pivalate -(CH2)3CH3 valerate 22 22 1/19/2023 Structure Modification Key point: The hydroxy groups at C16, C17, and/or C21 can be modified as esters, etc. in order to obtain the desired logP for the intended route of administration. 23 23 1/19/2023 Structure Modification 24 24 1/19/2023 Structure Modification Key point: this is how we make steroids water soluble…ionized! ❑Hydrophilic esters are used to increase solubility, making them water-soluble prodrugs that can be administered IM or IV. ❑These agents are rapidly hydrolyzed due to their solubility by plasma esterases so they have a rapid onset of action. Phosphate has a plasma half-life of 5 minutes. 25 25 1/19/2023 Glucocorticoid Therapy (Systemic)  SAR  trans ring fusions  C-11 and C-17 hydroxyls  C-21 is unprotected Key point: Using the information just discussed, you should be able to compare drugs based on their antiinflammatory activities, their side effect profiles, and their duration of action.  Esterification can be used to alter delivery (topical, IM, IV, etc.)  Endogenous agent to which all drugs are compared 26 26 1/19/2023 Glucocorticoid Therapy (Systemic)  Derivative of hydrocortisone with an additional double bond (3-4X more potent).  SAR  trans ring fusions  Second double bond  C-11 and C-17 hydroxyls??  C-21 hydroxyl is unprotected  Prednisone is a prodrug of prednisolone…why? How does it become active?  Patients with hepatic dysfunction may not be able to activate prednisone. 27 27 1/19/2023 Glucocorticoid Therapy (Systemic)  SAR  The 6a-methyl group increases glucocorticoid action and eliminates mineralocorticoid action.  C-11 and C-17 hydroxyls  Additional double bond in A-ring  C-21 hydroxyl is unprotected  Solu-Medrol is the C-21 sodium succinate ester of medrol…water soluble!! 28 28 1/19/2023 Glucocorticoid Therapy (Systemic) Betamethasone is the 16bmethyl analog  SAR  The 9a-fluorine increases mineralocorticoid and glucocorticoid action.  16a-methyl decreases mineralocorticoid activity.  Increased lipophilicity improves glucocorticoid action  C-11 and C-17 hydroxyls  Additional double bond in A-ring  C-21 hydroxyl is unprotected 29 29 1/19/2023 Glucocorticoid Therapy (Inhalation)  Lipophilic prodrug…inhaled  16b-methyl decreases mineralocorticoid action  9a-chloro increases both, result is little salt-retaining effects.  C-21 ester is hydrolyzed during absorption (activation)  C-17 ester is hydrolyzed in the liver following absorption  Other key groups from SAR? 30 30 1/19/2023 Glucocorticoid Therapy (Inhalation)  Acetal formed from butanal  16,17-acetal decreases mineralocorticoid action  C-21 hydroxyl is unprotected so activation is not required  Other SAR?  Major metabolite is 6b-OH (active). 31 31 1/19/2023 Glucocorticoid Therapy (Inhalation)  Acetonide of C-16 and C-17 hydroxy groups  Acetonide decreases mineralocorticoid action  6-fluoro increases glucocorticoid action  6-fluoro is metabolized to the 6- hydroxy (active metabolite)  Rapidly metabolized and eliminated (glucuronidation) 32 32 1/19/2023 Glucocorticoid Therapy (Inhalation)  Unique C-20 thiofluoromethyl group and 17-propionate ester give it 36X greater affinity than beclomethasone  9-fluoro increase min. and gluco. action  6-fluoro increases gluco. action  Metabolized only to 17bcarboxylic acid 33 33 1/19/2023  Crystal structure of fluticasone furoate in the glucocorticoid receptor showing F-Hbond and C-17 group binding pocket 34 34 1/19/2023 Overall Considerations: Key Points  Topical  High logP  Increased risk for systemic side effects for highly potent steroids with high logP values  Generally, lower potency steroids are used topically if treatment is long-term  High potency steroids are safely used for short-term treatment 35 35 1/19/2023 Overall Considerations: Key Points  Intranasal/Inhalation Delivery  High logP (too high and absorption issues arise)*  Ideally, metabolically unstable if systemically absorbed  Systemic absorption otherwise can lead to significant side effects especially during long-term therapy *high logP can be advantageous since it limits oral absorption also. In the lungs and nasal passages the slow absorption can prolong the drug in these tissues but increases the risk of the drug being carried away prior to absorption. 36 36 1/19/2023 Overall Considerations: Key Points  Systemic Delivery  Limited number of glucocorticoids available for systemic use due to side effects (prednisone, prednisolone, methylprednisolone, and dexamethasone)  Primarily metabolized in the liver and eliminated as glucuronides  Suppress HPA axis, glaucoma, cataracts, with long-term therapy 37 37