Glucocorticoids

Describe the process of steroid synthesis. Include the enzymes involved (It may help to draw this out)

1. Acetyl CoA is converted to squalene by the HMG-CoA reductase 2. Squalene is converted to cholesterol which is then converted to pregnenolone 3. Pregnenolone is used to make progesterone which is then used to make aldosterone 4. Pregnenolone can also be converted to 17 alpha hydroxypregnenolone which is used to make cortisol and androstenedione 5. Androstenedione is made into estrone by the aromatase enzyme or is converted to testosterone in an equilibrium 6. 5-alpha reductase can then convert testosterone into 5alpha-dihydrotestosterone

Why are glucocorticoid receptor antagonists typically larger molecules?

they are large enough so that they can displace helix 12 to prevent binding of the coactivator and receptor activation

What are the binding requirements for a glucocorticoid receptor?

11'OH and trans juncture at C5 and C19

What enzymes metabolize cortisol?

11 beta hydroxysteroid oxidizes the 11'OH into a ketone; 5 beta reductase reduces the 4-5 double bond into a bent structure

In what four ways do deltacoids enhance and prolong glucocorticoid activity?

bind GR tighter, low mineralocorticoid activity, not 5-beta reductase substrate, produce active metabolites

What is a depo drug? What modification makes an glucocorticoid behave like a depo drug?

A drug that works over a long period of time; the presence of alkyl esters make the molecule more lipophilic allowing them to be slowly hydrolyzed over a week

What is a deltacoid?

a double bond located between C1 and C2 in a steroid

What does a fluorine at position 9 on a glucocorticoid do?

Increases GR and mineralocorticoid activity by providing more binding interactions

What two structural components allow topical glucocorticoids to stay in the tissue? Which structure is preferred?

Cyclic ketals and acetate esters increase the lipophilicity of the molecule allowing it to stay in the tissue. Acetate esters can be hydrolyzed and go systemic while cyclic ketals are inactivated by liver enzymes if they go systemic. Therefore, cyclic ketals are preferred

What is the purpose of inhibitors of adrenocortical synthesis? Name a few.

They're used as cushing's disease treatments before mifepristone. Ex: metyrapone, trilostane, aminoglutethimide, ketoconazol

True or False: Inhibitors of adrenocortical synthesis resemble steroids.

false; they do not

Why are ephedrine, epinephrine, and isoproterenol not preferred therapy in asthma?

They are nonselective and therefore have more side effects. Epinephrine- tachycardia, arrhythmia, angina; isoproterenol- lethal arrhythmias; ephedrine- CNS effects

True or False: LABAs can be used for monotherapy treatment in asthma.

False; must be paired with a glucocorticoid

What are some side effects associated with beta-2 agonists?

tachycardia, tremor, angina, HA, insomnia, Tachyplaxis (loss of receptor sensitivity), hyperactivity, dry mouth, throat irritation

What patients should take caution before using beta-2 agonists?

diabetics and patients with cardiovascular disease

What are ipratropium and tiotropium preferred over atropine?

they are charged molecules which makes them less likely to enter the periphery

How does theophylline provide relief to asthmatics?

it targets smooth muscle relaxation and has antiinflammatory effects

What are the 2 possible MOAs of theophylline?

Phosphodiesterase inhibition leading to bronchodilation and Adenosine receptor antagonism leading to anti inflammatory effects

What are some side effects of theophylline?

excitation, nervousness, positive inotropic and chronotropic effects, upset GI, tremors, convulsions, P450 substrate with many drug interactions

How can NSAIDs exacerbate asthma?

In inhibiting COX, more arachidonic acid is available to be made into LTs which can exhibit inflammatory properties

What does zileuton block?

5-LOX

What drugs target LT receptors?

montelukast and zafirlukast

What is the target of Xolair and what is it indicated for?

Omalizumab- free IgE, allergic asthma

What is the target of Nucala and Cinquair and what are they indicated for?

Mepolizumab and Reslizumab- bind IL-5, eosinophilic asthma

What is the target of Fasenra and what is it indicated for?

Benralizumab- IL-5 receptor; eosinophilic asthma

What is the target of Dupixent and what is it indicated for?

Dupilumab- IL-4 and IL-13 receptor; asthma and atopic dermatitis

What are some side effects of biologics? What drugs should they non be used with?

increased risk of viral infections, HA, nasopharyngeal effects, hypersensitivity; avoid concomitant use with immunosuppressants

Describe the MOA of glucocorticoids.

1. Steroid enters the cell and binds the steroid receptor causing it to dissociate from heat shock proteins 2. Steroid+Receptor complex enter nucleus where it dimerizes with another Steroid+Receptor complex 3. Dimer binds to hormone responsive element in the promoter allowing the Co-Activator to displace the CO-repressor 4. Gene transcription is activated 5. Annexin A1 is made, COX-2 enzyme production is decreased,

What are the major physiologic outcomes of glucocorticoids that are beneficial to asthma?

Annexin A1 decreases arachidonic acid by decreasing phospholipase A (anti inflammatory), suppresses lymphocyte infiltration, restores sensitivity to Beta agonists, suppressed transcription of pro inflammatory mediators (COX,NFkappaB, and AP1)

What are the physiological effects of cortisol?

Make glucose, redistribute fat, decrease insulin sensitivity, increase Na reabsorption, decrease circulating lymphocytes, needed for normal muscle function

What disease states can be exacerbated by glucocorticoids?

congestive heart failure and diabetes

Which aerosol is a strong ICS?

fluticasone

Which ICS is a pro drug?

ciclesonide

Why should systemic corticosteroid use not be abruptly stopped?

Pt.s on corticosteroids for over 2 weeks are at risk for adrenal suppression. Weaning is necessary to allow the body to rebuild its cortisol levels.

What do beta and alpha mean with regard to glucocorticoid structure?

Alpha- below molecule; Beta- above molecule

What is the MOA and indication of mifepristone?

GR and PR antagonist; used in Cushings disease, can block embryo implantation