8.3 AI Learning objectives answered

General structural feature of β2 agonists

Phenylethanolamine core with β-hydroxylamine and substituted aromatic ring

Predominant receptor in the heart

B1

Predominant receptor in smooth muscle

b2

How does epinephrine bind to b2 receptors?

Hydrogen bonding of catechol OH groups to 2 Ser residues

How is norepinephrine metabolized?

COMT transfers a methyl

MAO replaces CH2NH2 with aldehyde

Monoamine Oxidase (MAO) is dependent on what enzymes and yields what?

Dependent on flavin enzymes (ie FAD) and the reaction yields aldehyde +amine

Effect of bulky N-substituents on β2 agonists

Increase β receptor selectivity and reduce α activity

Blocks or decreases MAO activity

What do aromatic ring substitutions do?

Can make resistant to COMT but still be capable of interacting with receptor

Ring substitutions that resist COMT metabolism

Salicyl alcohol and resorcinol patterns

COMT-resistant example with β2 selectivity

Albuterol with salicyl alcohol and tert‑butyl amine (bulky N group)

Albuterol S isomer may be associated with ______

bronchial hyperresponsiveness

Structural feature increasing duration for salmeterol

Long lipophilic chain on amine holds drug near receptor

Salmeterol is resistant to metabolism by what?

COMT and MAO

Salmeterol duration of action

12 hours

Salmeterol is combined with corticosteroid in what product?

Advair, T

Fluticasone propionate/Salmeterol

Formoterol feature affecting onset

More hydrophilic than salmeterol, faster receptor access and rapid onset

Formoterol contains how many possible stereoisomers?

4

What formoterol racemic is active and which is inactive?

Active: RR (Arformoterol)

Inactive: SS

Formoterol is use in combo with corticosteroid in what product?

Symbicort (Budesonide/Formoterol)

What are examples of Ultra long acting beta2 agonists (3)

Vilanterol, Olodaterol, Indacaterol

Vilanterol is only available in what combo products

Corticosteroid (Breo), antimuscarinic (Anoro), antimuscarinic +corticosteroid (Trelegy)

How many times a day are ultra long acting b2 agonists taken for COPD?

once

Olodaterol half life

18 hours

Olodaterol has _____B2 selectivity compared to salmeterol and formoterol

higher

The N substituent on Indacaterol is _____

hydrophobic

How catechol analogs are metabolized

COMT methylation and MAO oxidative deamination

Structural change reducing MAO metabolism

β‑substitution and bulky amines

Carbon and ring number of corticosteroids

21‑carbon steroid with four fused rings

Cortisone acts as a ______

prodrug

Active endogenous glucocorticoid

Cortisol

Enzyme converting cortisone to active form Cortisol

11β‑hydroxysteroid dehydrogenase

Ketone on position 11 becomes OH

Cortisol interacts with  _______receptor, resulting in salt retention

mineralocorticoid

What hydroxyls enhance salt retention

17a and 21

11ß-OH only enhances ______ activity

glucocorticoid

How is aldosterone structurally different from cotisol

Addition of aldehyde on C18 and no hydroxy on 17a

Effect of 9α‑F or 9α‑Cl on corticosteroids

Increase glucocorticoid and mineralocorticoid activity and slow 11β‑OH oxidation

Glucocorticoid receptor mechanism

Steroid diffuses passively into cell and binds receptor. Receptor dimerizes, enters nucleus and binds to DNA to inhibit cytokine production

Corticosteroid metabolism

Reduction of A ring and cleavage of side chain

Effect of Δ1 double bond

Increases glucocorticoid activity and decreases mineralocorticoid activity

Effect of 6α‑methyl

Increases glucocorticoid activity and decreases mineralocorticoid activity

Effects of 6a- F

Increases glucocorticoid activity

Effects of 9a- F or Cl

Increase both anti-inflammatory (GC) and mineralocorticoid activity

Slows oxidation of 11ß-OH by 11ß-HSD

Effect of 16α,17α‑acetonide

16a-OH

16a- and 16B methyl

Decreases mineralocorticoid activity

Esters w/ ionizables groups has what effects?

increased water solubility and can be used in injectible products

Lipophillic esters have effects/

local activity w/ less systemic absorption

Esters are readily hydrolyzed by what?

plasma esterases

Hydroxyl at what position is a requirement for corticosteroid receptor binding and makes it a prodrug?

Free C21 hydroxyl

What position esters are active w/o hydrolysis?

C17

Example of corticosteroid prodrug

Prednisone or beclomethasone dipropionate

How is prednisone converted to prednisolone?

11 ketone converted to alcohol by 11ß-HSD to give prednisolone

Prednisolone (T) 4-fold higher potency than hydrocortisone due to what reason?

Double bond between C1 and C2

Slows metabolism and increases duration

Example of active corticosteroid

Prednisolone or flunisolide

Beclomethasone diproproprionate is a prodrug with what features?

9a-Chloro increases both glucocorticoid and mineralocorticoid activity, 16ß-methyl decreases mineralocorticoid activity

Fluticasone has what structural features?

9a-F increases both glucocorticoid and mineralocorticoid activity, 6a-F enhances only glucocorticoid activity

What has a higher glucocorticoid receptor affinity: fluticasone proprionate or beclomethasone

fluticasone proprionate

Mometasone structural featues

9a-Cl increases both glucocorticoid and mineralocorticoid activity, 16a-methyl decreases mineralocorticoid activity

How are cyclic ketals formed?

formed with 16a plus 17a alcohols

How do ketals/acetals affect mineralocorticoid activity?

decreases

Flunisolide is used to treat ______

allergies

Flunisolide has what structural features?

6a-F increases glucocorticoid activity

not a prodrug

Why does flunisolide have minimal systemic adverse effects?

40% of inhaled dose is systemically bioavailable, but it is rapidly metabolized to the minimally active 6ß-hydroxy metabolite

Budesonide is an acetal devired from _____

butanal

what causes Budesonide 2 fold decrease in potency?

Chiral center at acetal carbon

Budesonide is metabolized to what?

minimally active metabolites

Ciclesonide is both _______

ester and acetal

Prodrug that requires activation

Ciclesonide acetal is formed from what?

cyclohexylcarbonaldehyde

________is an endogenous neurotransmitter

Acetylcholine

What 2 receptor classes stimulate acetylcholine?

nicotinic and muscarinic receptors

M1, M3, and M5 GPCR utilize what?

Gq/G11

Hydrolysis of phosphatidylinositol 4,5-diphosphate in Gq/G11 leads to what?

diacyl glycerol + inositol triphosphate

Activation of M3 receptors causes what?

bronchoconstriction

M2 and M4 couple through _____ and inhibit ______

Gi /Go

adenyl cyclase

Core structure of antimuscarinics

Aminoalcohol esters related to tropine

Structurally related to tertiary amines atropine and scopolamine

quaternary amine

Structural feature limiting CNS penetration

Permanent quaternary amine

What is a short acting antimuscurinic?

Ipratropium bromide

How is Ipratropium bromide administered?

inhalation; bronchodilator effects

is Ipratropium bromide selective or nonselective?

non-selective

Side effects common to antimuscarinics

dry mouth, blurred vision

Examples of LAMA

Tiotropium bromide (T), Aclidinium bromide, Umeclidinium bromide

What is the only antimuscurinic that binds preferentially to M3 over M2 muscarinic receptors?

Glycopyrrolate (glycopyrronium bromide)

How is Glycopyrrolate (glycopyrronium bromide) excreted?

Rapidly excreted by kidney, largely in unchanged form (hydrolysis in plasma slow)

How is Revenefacin 1,2 very structurally different than other antimuscarinics? 

Has carbamate, not esters, and also shows kinetic selectivity for M3 over M2 receptors

How does Rivenfacine minimize side effects?

Terminal amide stable in lungs, but hydrolyzed to carboxylic acid in circulation

Roflumilast and Ensifentrine are examples of what?

Phosphodiesterase Inhibitors

Reaction inhibited by PDE inhibitors

Hydrolysis of cAMP (leads to anti-inflammation)

Effect of PDE3 inhibition

Bronchodilation

Effect of PDE4 inhibition

Anti‑inflammatory by increasing cAMP in inflammatory cells

Example of selective PDE4 inhibitor

Roflumilast

Roflumilast duration and administration technique

10 hour half life

administered orally

What metabolite is also a PDE4 inhibitor?

N-Oxide metabolite

What limits use of Roflumilast?

systemic side effects

Example of selective PDE3 inhibitor

Ensifentrine

3000 times more potent PDE3 inihibition vs PDE4

How is Ensifentrine administered?

inhalation

Two mechanisms decreasing leukotriene effects

Inhibit biosynthesis or block cysteinyl leukotriene receptors

Enzyme inhibited by zileuton

5‑lipoxygenase. Can’t convert arachnidonic acid to leukotrine

What group is essential for zileuton activity?

N-Hydroxyl group

O- glucuronide metabolite is inactive

zileuton is administered _____

orally

cysLT receptor endogenous agonist

Glutathione- adducts LD4 and its metabolites to cysLT 1 receptors

Antagonists used clinically to block inflammatory activity of leukotrienes is selective for what?

cysLT 1 receptors

Functional group in leukotriene antagonists mimicks what?

Acidic functionality mimics C1 acid of leukotrienes in agonists