Shared Flashcard Set

Details

Med chem NSAIDs/Steroids
Lecture 7
35
Pharmacology
Professional
09/02/2012

Additional Pharmacology Flashcards

 


 

Cards

Term
What are prostaglandins?
Definition
Fatty acid derivatives of arachidonic acid - dilate arterioles, constrict pulmonary. Contract the uterus, responsible for gastric secretions, swelling, and edema.
Term
What is the function of COX?
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.
Term
What are the main features of the COX active site?
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
Term
How does pKa and ionization affect ASA?
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.
Term
How does ASA work on COX?
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
Term
What is the SAR of COX?
How is it gastricly toxic?
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
Term
How can the SAR of ASA be affected?
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
Term
What is the difference between dolobid and ASA?
Definition
No acetyl group - is reversible
More electron-withdrawing = lipophilic
Term
What is Salsalate?
Definition
An ester bond is formed at the 5- position of ASA, and there is no acetyl. Cleavage gives 2 salacylic acids.
Term
What is the general SAR of nonselective NSAIDs?
Definition
Non-selective COX inhibitors have an acid center, usually adjacent to a ring. A methyl on this adjacent carbon increases activity - profens.
Term
What is indomethacin and sulindac mimicing?
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
Term
How is sulindac metabolized?
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
Term
What do Tolmentin/Etodolac/Diclofenac/Ketorolac have in common?
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.
Term
What kind of a structure is tolmetin?
Definition
Similar to indomethacin, but has a pyrole (2 double bonds) instead of an indole). Strictly AIF
Term
What kind of a structure is Ketorolac?
Definition
Very similar to tolmetin, but has a fused ring. Only Analgesic activity.
Term
What kind of a structure is Diclofenac?
Definition
Like it's name, has 2 chloro's on the 2nd ring. Also inhibits LPO and arachidonic acid release. Rings are anti-planar
Term
What is misoprostol?
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.
Term
What is significant about Etodolac?
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
Term
What is the significance of Nabumetone's SAR?
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
Term
What drugs are arylpropionic acids?
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-
Term
Where is the acidity in Oxicams derived from?
What is the general SAR?
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
Term
What is the difference between COX1 and COX2?
Definition
COX2 has a valine residue instead of ILE --> less bulky, provides a cleft.
COX2 found in alzheimer's, colon cancer
Term
What is the SAR of -coxibs?
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.
Term
What is the SAR of APAP? How does it work?
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.
Term
What are the 2 groups of steroids?
Definition
- Glucocorticoids - regulate carbs, lipids, protein using ACTH and CRH - potent AIF. 4 rings with 2 methyls
- Mineralocorticoids - regulate salt balance, have no AIF
Term
What is steroid stereochemistry?
How do they work?
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
Term
What is the difference between hydrocortisone and cortisone?
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.
Term
How does fludrocortisone compare to Cortisol?
Definition
-9Falpha substitution, more potent GR activity BUT WAY more MR activity. Used for addison's disease.
Term
How do prednisone and prenisolone compare to Cortisol?
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!
Term
How does methylprednisolone compare to Cortisol?
Definition
Addition of a methyl group at 6 increases GR activity while removing MR.
Term
How does Triamcinolone compare to Cortisol?
Definition
Addition of a -9F (like fludrocortisone), and also a -16OH, which adds AIF and lowers MR affinity.
NOT orally bioavailable
Term
How does dexamethasone compare to Cortisol?
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
Term
How does betamethasone compare to Cortisol?
Definition
SAME structure as dexamethasone, but the -16methyl is a BETA (solid line)
Less toxic, slightly more active.
Term
How is uric acid reabsorbed?
How does therapy work?
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
Term
What is allopurinol?
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.
Supporting users have an ad free experience!