Exam 5: Adrenocorticoids Flashcards
(96 cards)
1
Q
What is a steroid?
A
An organic molecule containing in its chemical nucleus the tetrahydrocyclopentanophenanthrene ring system
2
Q
How do you number a steroid molecule?
A
3
Q
What is the difference between a and b designation?
A
a is below the plane of the carbocycle
b is above the plane
4
Q
What is the designation between a and e?
A
Axial and equatorial groups
5
Q
What is a cholestane?
A
A steroid with 27 carbons that include a 8 carbon side chain
6
Q
What type of process converts cholesterol to pregnenolone?
A
Oxidative cleavage and NADPH in the adrenal glands
7
Q
What is pregnenolone?
A
Biosynthetic precursor of adrenocorticoids
8
Q
What initiates the biotransformation of cholesterol?
A
CYP 450 enzyme complex
9
Q
What enzymes of are in CYP450 enzyme complex?
A
Cyp11A1, adrenodoxin, and adrenodoxin reductase
10
Q
What occurs due to defects in CYP11A1?
A
Lack of glucocorticoids, feminization and hypertension
11
Q
What is another name for pregnenolone biosynthesis?
A
Desmolase activity (breaking of C-C bonds)
12
Q
Describe the 3 oxidative processes of pregnenolone biosynthesis?
A
All reactions require NADPH and O2
1. Addition of a hydroxl forming a diol
2. Addition of hydroxyl forming a triol
3. Cleavage of isocaproic side chain synthesizing pregnenolone
13
Q
What are examples of pregnenole isomers at C21?
A
- Pregnane
- Pregesterone
- Hydrocortisone
- Corticosterone
- Aldosterone
14
Q
What are pregnenole isomers that yield C19 steroids?
A
- Androstane
- Testosterone
- Dihydrotestosterone
15
Q
What are pregnenole isomers that yield C18 steroids through oxidative aromatization?
A
Estrane
Estradiol
16
Q
What is the on/off switch between hydrocortisone and cortisone?
A
11b-hydroxysteroid dehydrogenase
17
Q
What are isoforms of 11bHSD?
A
1 and 2
18
Q
What is the difference between 11bHSD isoforms?
A
1: liver isozyme
2: kidney isozyme
19
Q
What is the difference between hydrocortisone and cortisone?
A
H: active
C: inactive
20
Q
What reaction does 11b-HSD initiate?
A
C-11 keto-enol isomerization
21
Q
What reaction does 3a-HSD and 5b-reductase initiate?
A
Ring A reduction
22
Q
What enzyme initiates C-17 oxidation?
A
C-17 oxidase
23
Q
What are the enzymatic steps of adrenocorticoid biosynthesis to hydrocortisone?
A
a. Side chain cleavage from cholesterol to pregnenolone
b. pregnenolone to 17a-hydroxypregnelone by 17 a-hydroxylase (CYP17)
c. 17a-hydroxypregnelone to 17a-hydroxyprogesterone by 5-ene-3b-hydroxysteroid dehydrogenase
d. 3-oxosteroid-4,5-isomerase
e. 17a-hydroxyprogesterone to 11-deoxycortisol by 21-hydroxylase (CYP21)
f. 11-deoxycortisol to hydrocortisone by 11b-hydroxylase (CYP11B2)
24
Q
What are the enzymatic steps of adrenocorticoid biosynthesis to aldosterone?
A
a. Side chain cleavage from cholesterol to pregnenolone
c. pregnelone to progesterone by 5-ene-3b-hydroxysteroid dehydrogenase
d. 3-oxosteroid-4,5-isomerase
e. progesterone to 21-hydroxyprogesterone by 21-hydroxylase (CYP21)
f. 21-hydroxyprogesterone to corticosterone by 11b-hydroxylase (CYP11B2)
g. corticosterone to aldosterone by 18-hydroxylase
25
What do all biologically active adrenocorticoids contain?
Ketone at the 3-posistion and a double bond at the 4,5 position (ene-one)
26
How are 5b metabolites formed?
4,5 double bond is reduced by 5b-reductase
27
What enzymes reduce 3-ketone of an adrenocorticoids?
1. 3a-hydroxysteroid dehydrogenase provides the 3a-hydroxyl configuration
2. 3β-hydroxysteroid dehydrogenase provides the 3β-hydroxyl configuration
28
What is the biomarker for determining the level of HPA suppression and adrenal insufficiency?
Formation of 6b-hydroxyhydrocortisone
29
What other steroid metabolisms can occur other than 3,4,5 ene-one?
1. 20 ketone reduction
2. Oxidation of 17-ketol to carboxylic acid
3. 6b-hydroxylation
30
Is prednisone active or inactive?
Inactive
31
Describe prednisone metabolism into active and inactive metabolites?
1. Prednisone to prednisolone (active) by 11b-hydroxysteroid dehydrogenase
2. Prednisolone to 6b or 16a-hydroxyprednisolone (active) by CYP450
3. Prednisolone to 20a/b-hydroxyprednisolone (inactive) by 20a/b-hydroxyprednisolone dehydrogenase
32
Describe the SAR of steroid receptor binding?
1. H-bond with 3-ketone and Arg or Gln
2. H-bond with 11 and 19 OH and Asn
3. H-bond with 18C=O and Thr
4. H-bond with 17 OH and Gln
33
What is the SAR of steroid structures?
1. The 3-keto and the 4,5-double bond are essential for both MC and GC activity
2. 11-hydroxyl on the C ring is required for GC activity, not for MC activity
3. A C21-hydroxyl is required for MC activity, not for GC activity (some exceptions)
4. For optimum potency, GC have a 17-hydroxyl group on the D ring (ester or acetonide)
5. A 1,2-double bond enhances the ratio of GC to MC potency
6. An all trans backbone configuration in the polycyclic ring system is essential for activity
7. Conformation of the A ring can dramatically effect activity
34
What is the therapeutic use for cortisone?
Corticosteroid of choice for replacement therapy in patients with adrenocortical insufficiency
35
How is cortisone administered?
Orally or IM as the 21-acetate
36
Describe the metabolism of cortisone?
1. Hydro and cortisone are rapidly deacetylated by first-pass metabolism
2. Oral cortisone is inactivated by oxidative metabolism before hydrocortisone conversion
37
What is the difference between cortisone acetate and hydrocortisone acetate?
C: slow absorption after IM (24-48hr)
H: complete absorption with 1-2hr half life (95% bioavailability)
38
What is this drug?
Cortisone
39
What is this drug?
Cortisone acetate
40
What ester derivatives of cortisone are used topically?
1. Butyrate
2. Butyrate
3. Valerate
41
What is this drug?
Hydrocortisone butyrate and buteprate
42
What ester derivative is insoluble and has a slower absorption in GI?
Hydrocortisone cypionate and valerate
43
What ester derivatives are salt forms giving them extreme water solubility (IV and IM in emergencies)?
Hydrocortisone sodium phosphate and sodium succinate
44
What is 9a-fluoro analogue more potent that cortisone acetate?
1. Halogen increases binding affinity and protects 11B-OH
2. Effective in patients with rheumatoid arthritis at one-tenth the dose of cortisone acetate
45
Would fludrocortisone have more GC or MC activity?
MC due to fluoro group
46
What happens if you add a hydroxyl group to the 16C of fludrocortisone?
Shifts activity to GC
47
What are the 1-dehydro derivatives?
Prednisone and prednisolone
48
Why is Prednisone and prednisolone more potent (3-4x) than cortisone and hydrocortisone?
1. Changes in A-ring
2. Increased affinity for GC receptors
3. Modestly alters that pharmacokinetics by changing metabolic profiles
49
What is the oral bioavailability of Prednisone and prednisolone?
80%
50
What enzyme interchanges Prednisone and prednisolone?
11b-HSD1
51
What are the properties of Prednisolone acetate?
Suspension and ointment for external use
52
What are the properties of prednisolone butylate?
Suitable for injection only, Long DOA due to minimal solubility and slow rate of hydrolysis
53
What are the properties of prednisolone tert-butyl acetate?
Used as suspension and injection for similar uses as 21-ester derivatives of hydrocortisone
54
What are the properties of prednisolone sodium phosphate?
Extremely water soluble and is dose IV or IM (half life is 5 minutes)
Ophthalmic solution
55
What is methylprednisolone?
1. First 6a-ethyl derivative to be introduced
2. Extensively metabolized (10% excreted unchanged)
3. Sodium retention and potassium loss are slightly less than with prednisolone
56
What is triamcinolone?
1. Uses a 1,2 double bond and 9a-fluro substituent
2. Insertion of a 16a-hydroxy diminishes the increased MC activity
57
How does triamcinolone differ from prednisolone?
1. Equipotent, but less MC activity
2. Decreased oral bioavailability due to increased hydrophilicity
3, May cause sodium extortion rather than retention
58
What are the triamcinolone derivatives?
Dictate and hexacetonide
59
Compare the DOA of triamcinolone acetate and hexacetonide?
A: 1-8 weeks
H: 3-4 weeks
60
How are triamcinolone derivatives dosed?
D: 17,21 diacetate
H: 16,17 hexacetonide
Both administered IM or intra-articularly
61
What is dexamehthasone?
First 16α-methyl corticoid derivative, which was designed in an effort to improve bioavailability and improve metabolic stability at the 20-position (ketone)
62
How is 16a-methyl in dexamethasone beneficial?
16-methyl decreases the reactivity of the 20-ketone, increases the stability of the molecule in human plasma, and increases anti-inflammatory properties through increased lipophilicity
63
What are the properties of 21-disodium phosphate derivative of dexamethasone?
1. Peak plasma concentration: 10-20 minutes
2. Not an agent of choice but can be used in patients who do not respond to prednisolone
64
What is the difference between dexamethasone and hydrocortisone?
1. 5x the anti-inflammatory activity of prednisolone and 7x the antirheumatic activity
2. 20-30x more potent
65
Describe the properties of bethamethasone?
1. 16β-methyl derivative of dexamethasone, which is predominantly used as a topical agent in the treatment of rheumatic and dermatological disorders
2. The topical formulation is usually the valerate ester
3. slightly more active than dexamethasone, while being slightly less toxic
4. only indicated for short term therapy due to unwanted side-effects
5. A 0.5 mg tablet of betamethasone is as effective as a 5 mg tablet of prednisolone
66
What is the benefit of choline substitutions at the 21-position?
1. Much more lipophilic than the typical hydroxyl
2. Greatly enhances topical anti-inflammatory activity
3. Agents are generally considered among the high and veery high potency topical agents
67
What are examples of low potency glucocorticoids (topical)?
1. Alclometasone dipropionate
2. Desonide
3. Dexamethasone, dexamethasone sodium phosphate
4. Fluocinolone acetonide
5. Hydrocortisone, hydrocortisone acetate
6. Prednicarbate
68
What are low potent glucocorticoids (topical) used for??
Modest anti-inflammatory effects and safe for chronic use
69
What are examples of medium potent glucocorticoids?
1. Betamethasone benzoate, betamethasone dipropionate, betamethasone valerate
2. Clorcortolone pivalate
3. Desoximetasone
4. Fluocinolone acetonide
5. Flurandrenolide
6. Fluticasone propionate
7. Hydrocortisone butyrate, hydrocortisone valerate
8. Mometasone furoate
9. Triamcinolone acetonide
70
What are medium potent glucocorticoids used for?
Modest dermatoses of limited duration
71
What are examples of high potency glucocorticoids?
1. Amcinonide
2. Augmented betamethasone dipropionate, betamethasone dipropionate, betamethasone valerate
3. Desoximetasone
4. Diflorasone diacetate
5. Fluocinolone acetonide
6. Fluocinonide
7. Halcinonide
8. Triamcinolone acetonide
72
What are high potent glucocorticoids used for?
More severe inflammatory dermatoses, but only for a short duration of treatment
73
What are examples of very high potency glucocorticoids?
1. Augmented betamethasone dipropionate
2. Clobetasol propionate
3. Diflorasone diacetate
4. Halobetasol propionate
74
What are very high potency glucocorticoids used for?
1. Alternative to systemic corticosteroid therapy
2. Used when only local areas are involved
3. Used only over small surface areas for short durations of therapy
75
What is a major concern for systemic exposure and toxicity of intranasal steroids?
Lungs and nasal cavity tissues provide a large surface area for absorption
76
What are ideal inhaled/intranasal glucocorticoid PK properties?
1. Fast systemic clearance after GI absorption (high degree of intestinal and first-pass metabolism)
2. Short half-life
3. Lack of active metabolites
4. High affinity for the glucocorticoid receptor
77
How much of a inhaled/intranasal glucocorticoid is effective in the airway?
10-40%
78
How much of a inhaled/intranasal glucocorticoid impact the back of the mouth and throat?
60-90%
79
What is the critical importance for dissolution, penetrability, and absorption of intranasal corticoids?
Balance between lipophilicity and hydrophilicity
80
What is triamcinolone acetonide used for?
treatment of lung diseases
81
What are the properties of triamcinolone acetonide?
1. Can become systemically available if swallowed and absorbed unchanged from the GI, which can lead to undesirable systemic effects
2. The absorbed portion is metabolized to the 6β-hydroxy, 21-carboxy, and the 21-carboxy-6β-hydroxy acetonide metabolites
82
How does acetonide make a difference with triamcinolone?
Gives the molecule resistance to hydrolytic cleavage
83
How is triamcinolone acetonide delivered?
1. It is delivered as a microcrystalline suspension in an aerosol propellant for pulmonary delivery.
2. Triamcinolone acetonide is approximately 8x more potent than prednisolone
84
What is Beclomethasone Dipropionate used to treat?
treatment of asthma and rhinitis
84
What are the properties of Beclomethasone Dipropionate?
1. BDP is a prodrug that is rapidly metabolized by esterases
2. 17α-monopropionate has about 14x greater affinity than dexamethasone
3. Oral BDP is also rapidly metabolized in the liver and GI to primary the 17α-monopropionate
85
What are the properties of flunisolide?
1. A rapidly absorbed inhalation/intranasal glucocorticoid that is rapidly and efficiently metabolized by the liver to inactive metabolites
2. Does not produce any unwanted systemic effects on prolonged therapy
86
How is flunisolide metabolized?
1. Metabolized primarily by CYP 3A4 to the 6β-hydroxy metabolite
2. Further metabolism involves elimination of the 6α-fluoro
3. Flunisolide and its 6β-hydroxy metabolite are subject to glucuronidation and sulfation
87
What are the properties of budesonide?
1. Highly potent, nonhalogenated glucocorticoid intended for the local treatment of lung disease and rhinitis
2. Very high ratio between local and systemic effects.
88
Describe the metabolism of budesonide?
1. Rate of topical uptake into epithelial tissues is 100x faster than hydrocortisone or dexamethasone
2. Metabolized by CYP 3A4 to the 6β-hydroxy metabolite, which only has 1/100 the activity of the parent molecule
3. Rapid metabolism is an important inactivation step that limits systemic toxicity
89
How does budesonide have a great retention in the airways despite low lipophilicity?
1. Formation of intracellular fatty acid esters at the 2-hydroxyl
2. Fatty acid esters are inactive and reversible, but behave like intracellular depots slowly releasing the drug
90
Describe the properties of mometasone furoate?
1. Furoate demonstrated the greatest increase in potency
2. Also incorporates a 21-chloro, which also adds to the increased potency
91
Describe the potency of mometasone furoate?
1. Oral bioavailability is less than 1%
2. Following intranasal delivery, the plasma levels were below a quantifiable level
3. 80% metabolized to the 6β-hydroxy and 21-hydroxy metabolites, which are further conjugated (42%) before elimination
4. 5-10x more potent than betamethasone benzoate
92
Describe the structure of fluticasone propionate?
1. Designed to be metabolically susceptible to hydrolysis in the liver to ensure low systemic bioavailability
2. Thioester and electronegative fluorine increase the rate of systemic metabolism
3. Based on the androstane 17β-carbothiolate nucleus
93
Describe the potency of fluticasone propionate?
1. Potency is approximately equal to mometasone furoate
2. When administered by inhalation or intranasally, it is nondetectable in plasma
3. Rate of topical uptake is more than 100x faster than for hydrocortisone
94
How is fluticasone propionate metabolized?
Major metabolite is the 17β-carboxylate (notice the numbering).
Only has 1/2000 the affinity for the glucocorticoid receptor
95
What is the affinity for fluticasone furoate?
1. Has the greatest affinity for the glucocorticoid receptor
2. 1.7x affinity than fluticasone propionate and only slightly better than mometasone furoate
3. the plasma levels are below quantifiable levels after inhalable or intranasal administration
