Medicinal Chemistry: Venous Thromboembolism & Dyslipidemia

Flashcards covering the medicinal chemistry, SAR, metabolism, and pharmacokinetics of drugs used for Venous Thromboembolism (VT) and Dyslipidemia.

Which is more potent (S)-warfarin or (R)-warfarin?

(S)-warfarin

What is the structure of warfarin include?

Lactone & coumarin

Is warfarin acidic or basic?

Acidic

Is warfarin completely absorbed?

Yes

What is (S) warfarin metabolized by?

CYP2C9

What inactive metabolites are created when (S)-warfarin is metabolized?

6- & 7-hydroxywarfarin

Which warfarin is metabolized by CYP2C9?

(S)-warfarin

What does reductive metabolism of side chain carbonyl give?

3’-hydroxywarfarin

What type of people are at greater risk for warfarin toxicity?

Compromid liver function

How is heparin mostly used as?

Sodium salt

How is heparin administered?

IV or SQ

Which drug is a synthetic pentasaccharide?

Fondaparinux

What drug is the first selective factor Xa inhibitor?

Fondaparinux

How is Fondaparinux administered?

SQ

What is the elimination half-life of Fondaparinux?

17 hours

Which DTIs are irreversible inhibition of thrombin?

Hirudin, Lepirudin, & Desirudin

Which DTIs are reversible inhibition of thrombin

Bivalirudin, Argatroban, Dabigatran

Which DTI is a prodrug?

Dabigatran

Which DTI is orally active?

Dabigatran

What type of bioavailability does dabigatran have?

Low

What type of onset does dabigatran have?

Rapid

What type of DOA does dabigatran have?

Short

Which DTI does not require coagulation monitoring?

Dabigatran

Which DTI is reported to produce major GI bleeding?

Dabigatran

Which thrombolytic drug is fibrin non-specific agent?

Streptokinase

Which drug is fibrin specific?

Alteplase

Which thrombolytic drug has the shortest half-life?

Alteplase

What is the half-life for alteplase?

Short

What is the half-life for Tenecteplase?

Long

Which thrombolytic drug has the longer half-life?

Tenecteplase

Which drug has higher fibrin specificity & improved activity?

Tenecteplase

Is bile acid sequestrants positive or negatively charged?

Positively

What groups does bile acid sequestrants contain?

Quaternary ammonium groups, secondary/tertiary amines

What type of interactions does bile acid sequestrants have with bile acids?

Electrostatic interactions

How is bile acid sequestrants administered?

Orally

What is the onset of action for bile acid sequestrants?

24-48 hours

How is bile acid sequestrants excreted?

In feces

What can bile acid sequestrants bind to?

Acidic drugs

What type of inhibitors or HMG-CoA reductase inhibitors?

Potent, competitive

What are type 1 statins derived from?

fungal metabolites

What type of structure do type 1 statins contain?

Rigid decalin ring structure

What are type 2 statins derived from?

fully synthetic

What type of groups does type 2 statins contain?

larger, bulky groups

What is part of the pharmacophore for statins?

3,5-dihydroxyheptanoic acid & decalin

What is the stereochemistry for 3 & 5?

R

What do all statins contain?

Carboxylic acid

What must inactive lactone prodrugs must undergo?

Vivo hydrolysis

What is the peak plasma conc for statins?

1-4 hours

How long does it take until statins show signs of reducing plasma cholesterol?

4-6 weeks

When should most statins be adminsitered?

Evening

How fast is ezetimibe metabolized?

Rapidly

Where is ezetimibe metabolized?

Intestinal wall & liver

What does a small amount of ezetimibe undergo?

Oxidation

How is ezetimibe administered?

Orally

What is the half-life for ezetimibe & glucuronide conjugate?

22 hours

What is the pharmacophore for fibrates?

Phenoxy, space group, isobutyric acid

what happens if fibrates contain an ester?

Prodrug

what happens if a fibrate has para substitution?

Longer half-life

How is ester prodrugs metabolized by?

Hydrolysis

What does oxidation of aromatic methyl groups in fibrates produce?

Inactive hydroxymethyl analogs

How is fibrates excreted?

glucuronide conjugates

Where is fibrates excreted?

in urine

What can enhance oral absorption for fibrates?

Food

What is the pKa of the carboxylic acid of nicotinic acid?

4.76

What is the pyridine nitrogen in nicotinic acids are?

Weak base

Is the pyridine nitrogen in nicotinic acid ionized or un-ionized?

Un-ionized

Is nicotinic acid freely soluble in alkaline solutions?

Yes

What is nicotinic acid soluble in?

Alkaline solutions

What are smaller doses of nicotinic acids used for?

Dietary supplementation

What are larger doses of nicotinic acids used for?

Hyperlipoproteinemia

Is nicotinic acid readily absorbed?

Yes

When does peak plasma concentrations occur for nicotinic acids?

45 minutes

What is the half life for nicotinic acids?

1 hour