Term
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Definition
| what is the stereochemistry of nearly all important corticosteroids? |
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Term
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Definition
in steroids with all-trans ring fusions, the rings are conformationally locked in chair formations.
there are 2 surfaces to the rigid all trans system: the top side ( ) and the bottom side ( ) |
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Term
all cellular responses to glucocorticoids are attributed to their binding to the intracellular glucocorticoid receptor, translocation to the nucleus followed by dimerization and modulation of gene expression
desired cellular responses are:
anti-inflammatory
immunosuppressive: lowers lymphocyte numbers, alteration of their responses
repression of:
NF-kB
IL-1
IL-6
TNFa
synthesis of annexin-1: inhibitor of PLA2 (causes release of arachidonic acid) leading to downregulation of prostaglandins
down-regulates COX2 expression |
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Definition
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Term
increases gluconeogenesis
increases glycogenesis
increases protein catabolism
decreases antibody response
anti-inflammatory response
ex) cortisol |
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Definition
| functions of glucocorticoids |
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Term
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Definition
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Term
increase Na and water retention
promote K loss
ex) aldosterone |
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Definition
| function of mineralocorticoids |
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Term
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Definition
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Term
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Definition
| short acting glucocorticoids |
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Term
11B-HSD1: liver enzyme that reversibly interconverts hydrocortisone to cortisone (inactive metabolite; serves as a storage depot)
11B-HSD2: kidney enzyme that irreversibly converts hydrocortisone to cortisone; prevents hydrocortisone from binding to mineralocorticoid receptors preventing some kidney issues |
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Definition
| metabolism of hydrocortisone |
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Term
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Definition
| activity of hydrocortisone |
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Term
[image]
urocortisol is the major metabolite (along with its conjugates) and has the 5-beta configuration - give a cis-A/B ring fusion that is inactive |
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Definition
| illustration of hydrocortisone metabolism |
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Term
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Definition
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Term
11X as potent as hydrocortisone in RA
MR activity increased 300-800 times!
intense Na retaining activity |
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Definition
| activity of fludrocortisone |
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Term
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Definition
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Term
more potent antirheumatic and antiallergenic agents than cortisol derivatives
prednisone and prednisolone are 3-4x more potent anti-inflammatories than hydrocortisone but their mineralocorticoid activity was not proportionally increased |
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Definition
| activity of prednisone and prednisolone |
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Term
prednisone
prednisolone
methylprednisolone
triamcinolone |
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Definition
| intermediate acting glucocorticoids |
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Term
prednisone and prednisolone are interconvertable by 11B-HSD in the liver
equipotent and can be used interchangably
prednisone is metabolized to a number of hydrophilic and less active metabolites
MAJOR METABOLITES: 6B- and 16a-hydroxy are excreted as glucuronide conjugates in urine |
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Definition
| metabolism of prednisone and prednisolone |
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Term
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Definition
| evolution of the delta-1 corticoids |
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Term
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Definition
| illustration of prednisone metabolism |
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Term
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Definition
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Term
extensive: 10% recovered unchanged in the urine
[image]
reduction of C20 ketone
oxidation of 17B-ketol group to the C21 acid and the C20 etio acid
6B-hydroxylation by CYP3A4
CYP3A4 inhibitors such as antifungals, ketoconazole, itraconazole can potentiate the effects of MP |
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Definition
| metabolism of methylprednisolone |
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Term
| ~20% more potent than prednisolone |
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Definition
| activity of methylprednisolone |
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Term
triamcinolone
may actually cause Na excretion
other side effects: anorexia, muscle weakness, leg cramps, nausea, dizziness, and a general toxic feeling |
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Definition
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Term
[image]
6B-hydroxylation through CYP3A4 |
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Definition
| metabolism of triamcinolone |
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Term
| ~20% more potent than prednisone |
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Definition
| activity of triamcinolone |
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Term
16-methyl corticoids:
dexamethasone and betamethasone |
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Definition
| long acting glucocorticoid |
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Term
dexamethasone: a 16-methyl corticoid
like 16a-OH, the methyl greatly reduces salt retaining properties (MR) |
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Definition
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Term
| similar to prednisone, 6B-hydroxy major metabolite in urine |
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Definition
| metabolism of dexamethasone |
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Term
30X potency of hydrocortisone
5X potency of prednisone
Dex-21-phosphate for IV |
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Definition
| activity of dexamethasone |
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Term
| betamethasone: a 16-methyl corticoid |
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Definition
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Term
| similar to methylprednisone and prednisone |
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Definition
| metabolism of betamethasone |
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Term
slightly more active than dexamethasone
overall very similar |
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Definition
| activity of betamethasone |
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Term
all trans B/C and C/D is necessary for activity
[image]
suggested that beta surface of C/D and 17B-ketol are most important for association with GR
generally, bulky beta-substituents abolish GR activity whereas alpha-side does not
[image]
17a-CH3, 16a-CH3, 16B-CH3, 16a-CH3O, 16a-OH reverse or even abolish Na retaining activity (MR activity)
[image]
[image]
inserting a-CH3 at position 2, 6, 16 in 11B-OH compounds improves GR activity
2a-CH3 prevents metabolic reduction of the double bond
[image]
alkyl substitution at 4, 7a, 9a, 11a, and 21 decrease activity
most of the time need 11B-OH for activity
9a-F group increases GR/MR activity and nearly prevents metabolic oxidation of 11B-OH (increases acidity of OH - better H-bond donor to GR) |
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Definition
| summary of glucocorticoid SAR |
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Term
1) anti-inflammtory:
decrease in vasodilator prostaglandins (PGE2, PGI2) affords less vasodilation and therefore less edema
prostaglandins enhance leukocyte infiltration by promoting blood flow
2) analgesic:
decreased in prostaglandins generation affords less sensitization of nociceptive nerve endings to bradykinin and 5-HT
also, prostaglandins are part of the neuroimmune activation response of glial cells
3) antipyretic:
decrease in mediator prostaglandin (generated in response to IL-1) that is responsible for elevating the hypothalamic set-point for temperature control in fever |
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Definition
| NSAIDs have 3 major actions resulting from inhibition of COX (and thus decreasing prostaglandin formation): |
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Term
arachidonate is stored in cell membranes esterified at glycerol C2 of phosphatidyl-inositol and other phospholipids
[image]
cleavage is mediated by phospholipase A2
corticosteroids are anti-inflammatory agents because they inhibit (indirectly) PLA2, reducing the rate of arachidonic acid production |
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Definition
| storage and mobilization of arachidonic acid and corticosteroid's role in this process |
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Term
[image]
COX activity:
COX has an iron center; usually Fe-4 and is activated to Fe-5
the iron center of COX forms a radical from tyrosine
radical tyrosine produces an allylic shift and a cycle is formed
proton is returned to tyrosine
end result is PGG2
peroxidase activity:
hydroperoxide converted to an alcohol
different prostaglandins will be formed depending on the tissue |
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Definition
| mechanism of prostaglandin formation |
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Term
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Definition
the prostaglandins derived from this COX are found mainly at sites of inflammation and are thought to trigger and/or exacerbate the inflammation process
expression is induced by: IL-1, IL-2, TNFa, and growth factors
expression is repressed by: IL-4 and IL-10, IL-13, glucocorticoids |
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Term
COX1 is 67% identical to COX2 with respect to primary amino acid sequences
COX1 has isoleucine in the active site
COX2 has valine in this position
[image]
the difference of a single methyl group (between valine and isoleucine) gives raise to COX1 having a 25% smaller pocket than COX2
the side-pocket feature of COX2 has be exploited to afford selective inhibitors |
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Definition
| differences between COX1 and COX2 binding sites |
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Term
salicylates inhibits both COX1 and COX2, but are more selective for COX1
most are reversible inhibitors (except for aspirin - acetyl salicylic acid)
also inhibit platelet activation |
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Definition
MOA of salicylates
[image] |
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Term
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Definition
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Term
aspirin covalently and irreversibly modifies both COX1 and COX2 by acetylating serine-530 in the active site
[image]
acetylation of COX1 blocks entrance of arachidonic acid to active site
acetylation of COX2 retains some COX and peroxidase activity
acetylated COX2 gives raise to aspirin-triggered lipoxin: anti-inflammatory agent, protect endothelial cells, resolves inflammation
[image] |
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Definition
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Term
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Definition
| general SAR of arylalkanoic acids (largest group of NSAIDs) |
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Term
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Definition
| indole, indene acetic acids |
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Term
[image]
converted to inactive metabolites
50% is 5-O-demethylated by CYP2C9
10% glucuronidated in liver
non-hepatic enzyme systems N-deacylate indomethacin |
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Definition
metabolism of indomethacin
[image] |
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Term
[image]
prodrug: sulindac is absorbed as sulfoxide which is not a COX inhibitor (solubility)
thus no inhibition of prostaglandins in GI tract - fewer side effects
reduces sulfide in blood
active metabolite has 2X t1/2 of parent
overall side effects are less than indomethacin but still see some irritation of the GI tract
longer term uses |
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Definition
metabolism of sulindac
[image] |
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Term
[image]
extensive 1st pass metabolism
excreted in urine
less active than indomethacin
metabolized by oxidation of methyl to alcohol and then acid (conjugation)
[image]
very potent
metabolized by CYP2C9 p-hydroxy derivative and then to conjugates excreted in urine |
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Definition
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Term
diclofenac
[image]
structural characteristics of both arylalkanoic acid and anthanilic acid (benzyl-N) classes
2x the potency of indomethacin and 450x the potency of aspirin for anti-inflammatory
6x the potency of indomethacin and 40x the potency of aspirin as an analgesic
2x the potency of indomethacin and >350x the potency of aspirin as an antipyretic |
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Definition
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Term
1) inhibition of COX enzymes - decreased prostaglandins and thromboxanes
2) inhibition of the lipoxygenase pathway - decreased leukotrienes (LTB4)
3) inhibition of arachidonic acid release and stimulation of its reuptake |
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Definition
| unique 3-fold MOA of diclofenac |
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Term
[image]
major metabolite via CYP3A4 is 4'-hydroxy: para orientation in an aromatic ring is BAD = liver toxicity!
other metabolites through CYP2C9
remaining drug is excreted as sulfate conjugates
[image]
glutathione can neutralize the reactive metabolite |
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Definition
metabolism of diclofenac
[image] |
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Term
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Definition
| propionic acid derivatives |
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Term
marketed as a racemate but S-(+) is active isomer
more potent than aspirin but less than indomethacin
a-methyl group increases activity and decreases toxicity |
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Definition
| activity of ibuprofen (propionic acid derivative) |
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Term
12X potency of aspirin, 3-4x potency of ibuprofen inhibiting PGH2 production
300X less potent than indomethacin
[image]
SAR - 6 substitution gives optimal anti-inflammatory activity (CH3O was most potent) |
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Definition
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Term
60% eliminated unchanged
10% as unchanged conjugates
remainder de-methylated by CYP3A4 and CYP1A2 then to glucuronide |
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Definition
metabolism of naproxen
[image] |
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Term
[image]
when administered as a racemate or individual enantiomers, the major metabolite isolated is always S-(+)
[image]
R-(-) enantiomer is epimerized to the S-(+) in vivo via a acetyl-CoA intermediate - thus the 2 enantiomers are bioequivalent |
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Definition
metabolism of ibuprofen
[image] |
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Term
oxaprozin
anti-inflammatory with rapid onset of action and prolonged duration of action (equipotent with aspirin) |
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Definition
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Term
little first pass metabolism
5% excreted unchanged
microsomal oxidation (CYP2C9)
glucuronidation
ester conjugation
small amounts of phenol metabolites |
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Definition
metabolism of oxaprozin
[image] |
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Term
flurbiprofen
most potent derivative of a series of phenyl alkanoic acids
first marketed as the 1st topical NSAIDs for ophthalmic use
536x potency of aspirin in inflammation
0.5x potency of methylprednisolone
403x potency of aspirin as an analgesic
26x potency of ibuprofen as an analgesic |
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Definition
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Term
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Definition
metabolism of flurbiprofen
[image] |
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Term
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Definition
| SAR of N-arylanthranilic acids: fenamates |
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Term
[image]
meclofenamate:
[image] |
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Definition
| example of an N-arylanththranilic acid |
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Term
[image]
metabolism by CYP2C9
50-55% renal (gluc) |
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Definition
| metabolism of mefenamic acid |
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Term
piroxicam:
[image]
meloxicam:
[image] |
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Definition
| examples of enolic acids: the "oxicams" |
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Term
non-carboxylic acid anti-inflammatory
[image] |
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Definition
| SAR of enolic acids: the "oxicams" |
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Term
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Definition
metabolism of piroxicam
[image] |
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Term
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Definition
| activity and metabolism of meloxicam |
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Term
considered a COX2 selective inhibitor
[image] |
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Definition
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Term
CYP2C9 hydroxylation of 4-methyl group
[image]
metabolites do not inhibit COX1 or COX2
celecoxib also inhibits CYP2D6
may increase risk of serious cardiovascular thrombotic events
suppression of PGI2 may result in elevated BP and atherogenesis with heightened thrombotic response to plaque ruptures
suppresses prostaglandins (vasodilator) but do not inhibit platelet action = CV events |
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Definition
metabolism of celecoxib
[image] |
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Term
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Definition
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Term
nabumetone
new class of non-acidic NSAID prodrugs
since non-acidic it does not produce a significant "primary insult"
it is also not an inhibitor of COX in the GI mucosa so produced a minimal "secondary insult"
13x anti-inflammatory potency of aspirin |
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Definition
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Term
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Definition
metabolism of nabumetone
[image] |
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Term
causes decreased PGE2 levels in CNS (where COX3 is found)
no ulcerogenic activity like aspirin or other NSAIDs
acetaminophen is only effective when COX2 is at low levels
inhibits the activation of COX2 by inhibiting oxidation of the central iron from Fe4 to Fe5 |
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Definition
MOA of acetaminophen
[image] |
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Term
[image]
[image]
rapid first pass metabolism primarily by conjugation
CYP2E1 leads to small amount but significant N-OH and then to the quinone
normally, immediate detox by glutathione takes place
overdoses leads to S-mediated addition of hepatic proteins
N-acetylcysteine used as a rescue (mucomyst) |
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Definition
| metabolism of acetaminophen |
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Term
methotrexate
rate limiting enzyme of TMP synthesis is thymidylate synthase
methotrexate inhibits DHFR causing levels of 7,8-dihydrofolate to build up
high levels of 7,8-dihydrofolate causes feedback inhibition of thymidylate synthase and pyrimidine synthesis cannot occur
[image] |
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Definition
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Term
[image]
methotrexate is actively transported into the urine
probenacid, NSAIDs, penicillin G produce life-threatening drug interactions with methotrexate
dose-dependent inhibition of OATs |
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Definition
| metabolism of methotrexate |
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Term
DMARD: anti-inflammatory, immunosuppressant
well-absorbed - PRODRUG
[image]
exact MOA unknown but involves B-cell proliferation
[image] |
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Definition
MOA of leflunomide
[image] |
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Term
5-10% excreted unchanged
glucuronide conjugation
omega-oxidation of propyl: oxidation of resulting alcohol to acid
omega-1-oxidation of propyl
N-dealkylation |
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Definition
metabolism of probenecid
[image]
enhances excretion of urate through inhibition of URAT1 |
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Term
substrate of XO with 15-20x the affinity of xanthine and reversibly inhibits the enzyme
rapidly metabolized via oxidation - forms numerous ribonucleoside derivatives
oxypurinol is major metabolite - also inhibits XO
[image]
drug interaction with 6-mercaptopurine |
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Definition
MOA of allopurinol
[image] |
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