Term
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Definition
| Fatty acid derivatives of arachidonic acid - dilate arterioles, constrict pulmonary. Contract the uterus, responsible for gastric secretions, swelling, and edema. |
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Term
| What is the function of COX? |
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Definition
Converts Arachidonic acid to PgG2 --> PgH2 --> end prostaglandins. O2 added to carbon 11 --> cyclization.
Arachidonic acid is the substrate for Cox! NSAIDs mimic and block. |
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Term
| What are the main features of the COX active site? |
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Definition
ARG residue is basic/positive = acidic active site. Forms an ionic bond
Tyrosine - pi pi stacking
Difference between Cox1 and Cox2 --> ILE --> Val makes a pocket |
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Term
| How does pKa and ionization affect ASA? |
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Definition
If the pH is less than the pKa in an ACID, the compound will be unionized and unchanged. pH of the stomach is 2, and pKa of ASA is 3 = unchanged. In the body, pH is higher --> ionizes as it crosses the cells of the stomach.
In a base (NE), if pH is less than pKa, it is ionized. |
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Term
| How does ASA work on COX? |
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Definition
ASA acetylates the serine residue irreversibly - COX inhibited in a platelet for than platelet's lifetime.
Salicylic acid is left over --> non-covalently blocks COX |
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Term
What is the SAR of COX?
How is it gastricly toxic? |
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Definition
Effects on COX1 and GI-effects are due to carboxylic acid.
Has a pKa of 3, is unionized in the stomach. Crosses cells, becomes ionized at trapped. Inhibits cox, decreases mucous and blood flow --> increased permeability and less buffer made
Dual insult - direct acid damage and PgE2 inhibition |
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Term
| How can the SAR of ASA be affected? |
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Definition
If the carboxylic acid is changed to remove the hydroxy - more lipophilic and more toxic
- Acetyl group is in the ortho position. Movement to -m or -p cannot bind to serine.
- Addition at the 5 position adds AIF activity |
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Term
| What is the difference between dolobid and ASA? |
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Definition
No acetyl group - is reversible
More electron-withdrawing = lipophilic |
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Term
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Definition
| An ester bond is formed at the 5- position of ASA, and there is no acetyl. Cleavage gives 2 salacylic acids. |
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Term
| What is the general SAR of nonselective NSAIDs? |
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Definition
| Non-selective COX inhibitors have an acid center, usually adjacent to a ring. A methyl on this adjacent carbon increases activity - profens. |
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Term
| What is indomethacin and sulindac mimicing? |
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Definition
Serotonin
Need the carboxyl group, indole ring not necessary
- Indomethacin - VERY potent but very toxic
- Sulindac - prodrug, not active until the circulation thus less GI side effects. Fluoride = better analgesic
- Z isomer = better AIF |
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Term
| How is sulindac metabolized? |
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Definition
Sulindac, a prodrug, gets reduced to become active. Must be the Z isomer to get reduced
Active has a -S-CH2 group on the phenyl |
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Term
| What do Tolmentin/Etodolac/Diclofenac/Ketorolac have in common? |
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Definition
They all have the acid core, and they all have a nitrogen, usually in a ring. Some have 2 rings.
All are derivatives of Indomethacin. |
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Term
| What kind of a structure is tolmetin? |
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Definition
| Similar to indomethacin, but has a pyrole (2 double bonds) instead of an indole). Strictly AIF |
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Term
| What kind of a structure is Ketorolac? |
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Definition
| Very similar to tolmetin, but has a fused ring. Only Analgesic activity. |
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Term
| What kind of a structure is Diclofenac? |
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Definition
| Like it's name, has 2 chloro's on the 2nd ring. Also inhibits LPO and arachidonic acid release. Rings are anti-planar |
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Term
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Definition
| A prostaglandin analog added to diclofenac (Arthrotec) to reduce GI upset and ulcers. Addition of a methyl at position 16 adds bioavailability. Causes diarrhea. |
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Term
| What is significant about Etodolac? |
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Definition
| Distance from indole to acid increased - less potent. May be preferential to cox 2, and far less gastric toxicity. Only the S is AIF. Acid at 1 and ethyl at 2 REQUIRED |
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Term
| What is the significance of Nabumetone's SAR? |
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Definition
| It is also a prodrug, and the prodrug is not an acid, reducing GI distress. Absorbs from the duodenum --> 6MNA metabolite. Oxidation of ketone to acid |
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Term
| What drugs are arylpropionic acids? |
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Definition
-profens! Ibuprofen:
Has chirality, S- isomer is active. However the R is inverted in vivo, thus both become active.
Extensively ionized at a pKa of 4: excretion.
Fenoprofen is weaker than Ibu, S is also active.
Ketoprofen is very lipophilic, good in muscle injuries
Flurbiprofen has an extra aromatic ring
Naproxen is racemic, more potent than Ibu. Same as 6MNA but has a methyl at 2- |
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Term
Where is the acidity in Oxicams derived from?
What is the general SAR? |
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Definition
Longer half life, just as good as indomethacin. GI side effects. NO ACID CORE, comes from bronsted-lowry acidity. Has 2 R groups - both at the amines.
Increased acidity increases pKa - due to enolate N. Hydrogen bonds move to form acid.
- Mobic - Replace pyridine on piroxicam w/ methyl thiazolyl gives COX2 activity. Can be unionized at inflammation sites --> low gastric side effects |
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Term
| What is the difference between COX1 and COX2? |
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Definition
COX2 has a valine residue instead of ILE --> less bulky, provides a cleft.
COX2 found in alzheimer's, colon cancer |
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Term
| What is the SAR of -coxibs? |
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Definition
- non-acidic
- PARA-sulfonamide group selective for pocket
Metabolized by 2C9, inhibits 2D6. If a slow 2C9 metabolizer, can get toxic. 2D6 - SSRIs
- Less GI, BUT can cause CV side effects. |
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Term
| What is the SAR of APAP? How does it work? |
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Definition
Purely analgesic and antipyretic, can inhibit COX3
Basic at a pKa of 9.5. Metabolism by conjugation
Still not sure of SAR!
Children sulfate APAP, while adults use glutathione, which allows for renal excretion. |
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Term
| What are the 2 groups of steroids? |
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Definition
- Glucocorticoids - regulate carbs, lipids, protein using ACTH and CRH - potent AIF. 4 rings with 2 methyls
- Mineralocorticoids - regulate salt balance, have no AIF |
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Term
What is steroid stereochemistry?
How do they work? |
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Definition
The delta is where the double bond is. Can be alcohols or ketones at the #3 position
Specific for the glucocorticoid receptor --> AIF, immunosuppression. 3 step oxidation to pregnenolone |
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Term
| What is the difference between hydrocortisone and cortisone? |
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Definition
| At the 11 position, cortisone has a ketone, and hydrocortisone has an alcohol. REQUIRED for GR, but not MR. C17-OH also gives GR activity. Hydrocortisone more orally bioavailable, but also more MR activity --> C21 -OH group grants MR activity. Remember feedback mechanism --> reason for tapering. |
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Term
| How does fludrocortisone compare to Cortisol? |
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Definition
| -9Falpha substitution, more potent GR activity BUT WAY more MR activity. Used for addison's disease. |
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Term
| How do prednisone and prenisolone compare to Cortisol? |
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Definition
| Addition of a C-C double bond between 1 and 2 increases GR and duration. Prednisone has a ketone at 11, while prenisolone has a -OH at 11 (like cortisol, higher GR activity). Boat conformation! |
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Term
| How does methylprednisolone compare to Cortisol? |
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Definition
| Addition of a methyl group at 6 increases GR activity while removing MR. |
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Term
| How does Triamcinolone compare to Cortisol? |
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Definition
Addition of a -9F (like fludrocortisone), and also a -16OH, which adds AIF and lowers MR affinity.
NOT orally bioavailable |
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Term
| How does dexamethasone compare to Cortisol? |
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Definition
| Used in cortisone shorts, a long acting steroid with high GR affinity, no MR affinity. Has the 1-2 double bond, the -9F, and a -16methyl which increases lipophilicity unlike the -16OH in triamcinolone |
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Term
| How does betamethasone compare to Cortisol? |
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Definition
SAME structure as dexamethasone, but the -16methyl is a BETA (solid line)
Less toxic, slightly more active. |
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Term
How is uric acid reabsorbed?
How does therapy work? |
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Definition
renal tubular absorption
weakly acidic with a pKa of 5.7. Therefore a decrease in pH leads to an increase in crystals. Therapy:
- Inhibit Xanthine Oxidase
- Reduce inflammation
- Increase uric acid excretion |
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Term
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Definition
An isomer of hypoxanthine, allopurinol competes for xanthine oxidase with a greater affinity --> inhibition and lower uric acid.
Metabolite - oxypurinol has a longer half life, inhibits XO non-competitively. |
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