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21 Cards in this Set
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- Back
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3,5-dihydroxy acid
HMG-CoA Reductase Inhibitors (HMGRIs) |
3,5-Dihydroxy acid essential for HMG-CoA reductase inhibitory activity
Lactones= Prodrugs (ex: simvastatin, lovastatin) 3, 5 dihydroxy group is actually doing the inhibition |
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Ring A
HMG-CoA Reductase Inhibitors (HMGRIs): |
Two cyclohexene rings are essential
Methyl substitution at R2 increases activity Ring A keeps the compound active, the rest of the structure keeps it anchored to the active site Lovastatin Simvastatin Pravastatin |
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Ring B
HMG-CoA Reductase Inhibitors (HMGRIs): |
If R group = Aryl groups/hydrocarbon chains/amides/SO2NH2
↑ Lipophilicity = ↑ Inhibitory activity Atorvastatin Fluvastatin Rosuvastatin |
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Lovastatin/Simvastatin
(Ring A) |
Lipophilic, Lactone derivatives
Prodrugs Bioactivated in liver (B/c of the absence of an acid functional group on the parent molecule, this compound is taken up by the hepatocytes by passive diffusion, they do NOT depend on active transporters) Neutral drugs Shorter duration of action Metabolized by CYP3A4 Extensive first-pass metabolism Bioavailability ~ 5% PgP substrate Excreted mainly in feces (80-85%) Lovastatin excreted renally ( ~10%) Simvastatin excreted renally (~13 %) Lovastatin – naturally derived from oyster mushrooms Administer a statin in the evening b/c cholesterol is synthesized based on circadian rhythm peaks in cholesterol at early morning |
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Pravastatin
(Ring A) |
Acidic and hydrophilic statin
Extensive first-pass metabolism Substrate of PgP Transported to hepatocytes by OATP1B1 (canNOT undergo passive diffusion into hepatocytes) Pharmacokinetics affected by OATP1B1 levels (OAT1B1 has polymorphism (not expressed equally in different populations) Level may depend on ethnicity There are also drugs that can inhibit this transporter) If inhibited, can potentiate the muscle weakness and rhabdomyalgia SE) Metabolized into a metabolite with 15-20% HMG-CoA inhibitory activity Elimination –feces (70%), urine (20%) unchanged (8% in urine) **Not a Prodrug** |
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Atorvastatin (lipitor)
(Ring B) |
Acidic, lipophilic statin
(into hepatocytes by passive diffusion since lipophilic) Longer duration of action Extensive first-pass metabolism Metabolized by CYP3A4 Metabolized into an active metabolite with increased half-life Substrate of PgP Substrate of OATP1B1 (Transport (uptake into liver): both active & passive transport) Significant interactions with drugs affecting CYP3A4, PgP and OATP1B1 Minimally excreted by kidneys (<2%) polymorphism of OATP1B1 is not very pronounced in atorvastatin b/c of its dependence on passive transport |
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Atorvastatin Metabolism
-What is it metabolized by? - What is the activity of the metabolite? |
Atorvastatin is metabolized by CYP3A4 to a hydroxy derivate
The metabolite is equipotent, it is equally as active as the parent drug in terms of HMG CoA reductase inhibition. The therapeutic activity of atorvastatin is a combination of the parent drug & the metabolite |
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Fluvastatin
(Ring B) |
Acidic, lipophilic statin
(passively transported) Racemic mixture Extensive first-pass metabolism Metabolized mainly by CYP2C9 (CYP3A4 and CYP2C8 contribute to a lesser extent) Strong affinity for CYP2C9 (Inhibitor) Metabolized into an inactive metabolites ,no significant active metabolites detected in serum Not a substrate of PgP Substrate of OATP1B1 (active transport for transport into hepatocytes) Fluvastatin is metabolized by CYP2C9 and can also act as an inhibitor of this enzyme. Minimally excreted by kidneys (~5%) 2 types of polymorphisms: OATP1B1 CYP2C9 |
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Rosuvastatin (Crestor)
(Ring B) |
Amphoteric (acid or base), Hydrophilic statin
Longer half-life First-pass extraction Metabolism by Cyp2C9 (~10%) Substrate of OATP1B1 (due to the COOH) (polymorphisms to OATP1B1 will dec the therapeutic efficacy of this drug) Extrahepatic distribution depends on expression of OATP1B1 (uptake & excretion) Excreted unchanged (~ 90%) in feces Rosuvastatin depends on OATP1B1 for both UPTAKE & EXCRETION (polymorphism will have a dramatic effect) |
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Pitivastatin
(Ring B) |
Newest statin approved by FDA in August 2009
Longer half-life High bioavailability (~50- 70%) 99% protein bound Majorly metabolized by UDP-glucuronosyltransferase (UGT1A3 and UGT2B7) -Lopinavir, a protease inhibitor, is known to be a very potent inhibitor of this enzyme Substrate of OATP1B1 (polymorphisms to OATP1B1 will dec the therapeutic efficacy of this drug) ****NOT metabolized by a CYP based enzyme***** *****Less CYP based DDI**** Excreted in feces (~80%) and urine (~15%) |
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Bile Acid Sequestrants
MOA |
Polymers with positively charged amines
Bind negatively charged bile acids in the intestine and increases their fecal excretion Increase in bile acid elimination Increase in the hepatic conversion of cholesterol to bile acids thus, decreases cholesterol in liver Increase in LDL receptors on the liver Increase in LDL clearance from plasma Decrease in fatty acid absorption Compensatory Effects: Increase in HMG-CoA activity and biosynthesis of cholesterol Also increase in triglyceride synthesis and a transient rise in VLDL levels Insufficient to counteract the increase in cholesterol catabolism and clearance. |
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Cholestyramine
(Bile acid sequestrant) |
Copolymer consisting primarily of polystyrene, with a small amount of divinylbenzene as the cross-linking agent.
Contains approximately 4 mEq of fixed ***quaternary ammonium groups ***per gram of dry resin These positively charged groups function as binding sites for anions ****Not orally absorbed (stays in GI tract and eliminated)***** Could bind with other anionic drugs |
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Colestipol
(Bile acid sequestrant) |
The key functional groups on Colestipol are the basic secondary and tertiary amines
The functional anion-exchange capacity of the resin depends on intestinal pH Less adsorption capacity as compared to cholestyramine |
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What are the differences between Cholestyramine and Colestipol?
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colestipol is LESS potent than cholestyramine (b/c has a secondary and tertiary amine as its positive moieties instead of quaternary ammonium groups)
-for colestipol, the ionization depends on the pH -the quaternary charge in cholestyramine is more stable and can bind to more bile acids than colestipol -colestipol is less potent compared to cholestyramine due to its secondary and tertiary amine groups Colestipol adsorbs less bile acids b/c it has less adsorption capacity |
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Colesevelem
(Bile acid sequestrant) ***TEST QUEST*** What are 3 reasons Colesevelem is better than Cholestyramine? |
1. Pill form so better dosage from for compliance
2. more selective for Bile Acids, so less drug interactions with negatively charged drugs 3. More porous (due to -OH groups) = more H2O absorption capacity= Increased H2O absorption= soft gel formation (vs. hard polymer) = less constipation |
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PPARa Activators
(Gemfibrozil/Fenofibrate) MOA |
PPAR – nuclear receptor. Function as a transcription factor – regulate expression of genes: protein expression-fatty acid metabolism
Agonists of PPAR : DECREASE cholesterol levels inhibits the synthesis of cholesterol as well as enhance its elimination as bile salts DECREASE TG synthesis for VLDL INCREASE fatty acid oxidation INCREASE Breakdown of TG INCREASE HDL |
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Peroxisome proliferator-activated receptor (PPAR) Activators
SAR |
These drugs have 3 components:
1. aromatic ring 2. spacer (may or may not be present) 3. t-butyl acid functionality (required for activity) Sometimes called as ‘Fibrates’ Active form is an acid e.g. Gemfibrozil Substitution at the para position of the aromatic ring with a chloro group or a chlorine containing ring produces compounds with significantly longer half-lives |
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Gemfibrozil
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Acidic, lipophilic compound
Highly bound to plasma proteins (~99%) Inhibitor of CYP2C8, CYP 2C9, CYP2C19 Metabolized into Glucuronide conjugate which is an even potent inhibitor of 2C8 (gemfibrozil AND its metabolite are potent inhibitors of 2C8) Inhibitor of OATP1B1 Significant interactions with statins b/c -it inhibits transport to the hepatocytes (OATP1B1) -it decreases metabolism - can only use with Lova and Simvastatin |
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Fenofibrate
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Prodrug
Bioactivated by esterases to the free carboxylic acid form Half life (20h)is ~ 7 times more than gemfibrozil Metabolized into glucoronide conjugates Mild inhibitor of CYP2C9 and PgP Primarily eliminated by kidneys (60%) |
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What are the reasons Fenofibrate is better than Gemfibrozil?
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-para position is substituted by an aromatic group w/chlorine
-this increases the half life by 7X compared to gemfibrozil -this drug isn’t known to cause inhibition of OATP1B1 -it’s a mild inhibitor of 2C9 and PGP |
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Ezetimibe (Zetia)
(Affects cholesterol absorption by inhibits the transporter that plays a role in cholesterol absorption) |
Beta lactam structure is required for activity--it allows it to bind to the transporter
Blocks transport in the intestinal epithelial cells-decreased absorption of cholesterol Niemann-Pick C1 like 1 (NPC1L1) protein LDL receptors on liver Metabolized in the intestinal wall and liver to ACTIVE GLUCORONIDE METABOLITE** OATP1B1 substrate (no relevant polymorphism b/c OATP1B1 is mainly in liver and this Site of action is in Intestine) Enterohepatic recycling Primarily excreted in feces |
