T3 - IE3 - Cardiology - Kaur - Venous Thromboembolism & Dyslipidemia Medicinal Chemistry

Warfarin has a ____________, ________ structure

- lactone

- coumarin

Warfarin has an ________ 4-hydroxyl group

- acidic

Warfarin has an acidic ___-_________ group

- 4-hydroxyl group

Most hydroxyl groups are neutral unless attached to a phenyl group

The (__)-warfarin is more potent than the (__)

- S

- R

Most hydroxyl groups are _________ unless attached to a benzene ring, which makes it ________

- neutral

- acidic

Warfarin has an acidic 4-hydroxyl group due to conjugation

Warfarin is _________ and _________ absorbed

- rapidly

- completely

~100% after administration

Warfarin peak plasma concentration in ____ _______

- three hours

(S)-warfarin is metabolized by ___________ to inactive metabolites __- and ___-_______________

- CYP2C9

- 6

- 7-hydroxywarfarin

Reductive metabolism of Warfarin side chain carbonyl gives...

diastereometric Z-hydroxyWarfarin

Drug-Drug Interactions of Warfarin

Associated with enhanced or inhibited metabolism of warfarin (induction or inhibition of CYP2C9)

HMW

high molecular weight

LMW

low molecular weight

______________ has almost no unchanged drug excreted in urine

- Warfarin

Everything is relatively metabolized / changed when excreted.

Warfarin has almost ___ _______ drug excreted in urine

- no unchanged

Heparin has a _______ ________ structure

- HMW polysaccharide (5-30 kDa)

Heparin is administered...

IV or subcutaneous but not orally due to PK

Heparin Physicochemical properties

sulfated, negatively charged, acidic molecule mostly used as sodium salt

Same physiochemical properties as Enoxaparin, Dalteparin, Fondaparinux

Heparin-based Anticoagulants

Heparin

Enoxaparin

Dalteparin

Fondaprinux

_________ and ________ are more selective compared to heparin

- Enoxaparin

- Dalteparin

Enoxaparin and Dalteparin are _______ _______ compared to heparin

- more selective

Both are LMW polysaccharides (4-6kDA) compared to (5-30 kDA) Heparin

Fonaparinux (heparin-based anticoagulant) has a _________ _________ structure

- synthetic pentasaccharide

Whereas, Heparin has a HMW polysaccharide structure (5-30 kDa); Enoxaparin and Dalteparin have LMW (4-6 kDa) polysaccharide structures.

Enoxaparin and Dalteparin have _________ _________ PK/PD profile in comparison to heparin

- more favorable

Fondaparinux is a prototype of a novel class of anticoagulants with significant advantages compared to their structurally related heparin. It is the first _________ ________ _____ _______

- selective factor Xa inhibitor

Fondaprinux is a ________, ________ sulfonated pentasaccharide. The immediate advantage of fondaprinux is that as a synthetic drug, its composition will _________ _________, which results in improved pharmacokinetics and more selective anticoagulant action

- synthetic

- highly

- not change

Fondaprinux is a synthentic, highly sulfonated pentasaccharide. The immediate advantage of fondaprinux is that as a synthetic drug, its composition will not change, which results in __________ __________ and _________ _________ anticoagulant action

- improved pharmacokinetics

- more selective

Fondaparinux is administered via ___________ _______ with a _______ _____ dose and shows complete absorption

- subcutaneous

- single daily

Fondaparinux has _________ _________ effect

- predictable anticoagulant

Does not require routine coagulation monitoring

Fondaparinux is ______ _______ and is excreted in the urine _______ in patients with normal renal function

- NOT metabolized

- unchanged

Elimination half-life of 17 hours

Fondaparinux Half-life

17 hours

Hirudin structure

small protein (65 amino acids)

Lepirudin structure

recombinant protein (65 amino acids)

Same as desirudin

Desirudin structure

recombinant protein (65 amino acids)

Same as lepirudin

Bivalirudin Structure

Peptide (20 amino acids)

Argatroban has a _________-_______ structure

- peptide-mimetic

Looks a lot like a peptide but not a peptide

Dabigatran etexilate structure

non-peptide mimetic prodrug

Direct Thrombin Inhibitor Drugs

Hirudin

Lepirudin

Desirudin

Bivalirudin

Argatroban

Dabigatran etexilate

Hirudin MOA

irreversible inhibition of thrombin (both free thrombin and thrombin bound to fibrin)

Binds active and exosite of thrombin

Lepirudin and Desirudin have same mechanism of action

Bivalirudin MOA

reversible inhibitor, therefore less risk of bleeding

Argatroban and Dabigatran are also reversible inhibitors

Bivalirudin binds to both _______ _____ of thrombin and _____ of thrombin

- active site

- exosite

______ amino acids of Bivalirudin structure that binds to active site. Whereas ____ amino acids bind to the exosite

- 4

- 12

Active Site:

D-Phe

Pro

Arg

Pro

Exosite:

Asn

Gly

Asp

Phe

Glu

Glu

Ile

Pro

Glu

Glu

Tyr

Leu

Hirudin PK

IV

Lepirudin PK

IV

Half-life: 1.3 hours

Desirudin PK

SC

Half-life: 2-3 hour

Bivalirudin PK

IV

Rapid onset and short duration of action

Argatroban PK

IV or SC

Dabigatran is ________ ______, with RAPID onset and SHORT duration of action

- orally active (however, low bioavailability)

Argatroban has ___________ metabolism

- oxidative

Argatroban's ____________ metabolite retains 20-30% of activity

- aromatic

Whereas the hydroxylated metabolite is inactive

Argatroban's _________ metabolite is inactive

- hydroxylated

Argatroban aromatic metabolite retains...

20-30% activity

Argatroban's hydroxylated metabolite is ____________

- inactive

Due to dabigatran's rapid onset and rapid offset, the drug does _________ __________ coagulation monitoring, which represents a major advantage over other anticoagulant therapy

- not require

However, the drug is reported to produce increase in risk of major GI bleeding, and the patients should be aware

Dabigatran etexilate is metabolized to the prodrug by ____________

- esterases

Prodrug is fairly neutral because charged group have esters, after esters hydrolyze group

Dabigatran (non-prodrug) has _______________ charge

- zwitterionic

However, due to its charged groups - it has difficulty for absorption. It's prodrug form allows it to be orally active

Thrombolytic Drugs

Streptokinase (1st generation)

Alteplase (2nd generation)

Tenecteplase (3rd generation)

Streptokinase has a _____ _____ ______ ________ structure

- 414 amino acid protein

Alteplase has a _______ ______ structure

- serine protease (527 amino acid protein)

Tenecteplase has a _______ _______ structure

- serine protease (527 amino acid protein)

However, it has a three point mutations compared to 2nd generation alteplase. That allows for higher fibrin specificity, improved activity

Alteplase is ______-_______ _____ _____

- fibrin specific selective agent

Whereas, the 1st generation streptokinase is fibrin NON-specific

Streptokinase MOA

fibrin-non specific agent

Alteplase has LOW affinity for ______ ________ and very HIGH affinity for plasminogen _________ to fibrin

- free plasminogen

- bound

However, tenecteplase has HIGHER fibrin specificity, improved activity

Tenecteplase has similar structure to alteplase but contains _____ _______ _______, which gives it _______ fibrin specificity and _______ activity

- three point mutations

- higher

- improved

Alteplase PK

very short half-life (~5 minutes)

Tenecteplase PK

prolonged half-life (~17 minutes); allows for a single bolus application

Bile Acid Sequestrants structure contains ________ ________ ________ and ___________ ________ groups and ________/_________ ________

- positively charged resins

- quaternary ammonium

- secondary/tertiary amines

Normal pKa values for the amines range from 9.0 to 10.5, thus ALL of these groups should be primarily ionized at intestinal pH

Bile Acid Sequestrants amines have normal pKa values of _____ to _____. Thus, all of the these groups should be primarily _______ at intestinal pH

- 9.0

- 10.5

- ionized

Bases are ionized from the beginning but lose their charge once pH > pKa

Bile Acid Sequestrants positively charged resins form ________ ______ with bile acids

- electrostatic interactions

Bile acids are negative, thus, are attracted to the positive bile acid sequestrants

Bile Acid Sequestrants PK/Metabolism

Taken orally, but NOT absorbed (thus, minimal side effects)

Bile Acid Sequestrants Onset of Action

24-48 hours; can take up to 1 month to achieve peak response

Bile Acid Sequestrants are excreted in _____ as insoluble complex with bile acids

- feces

Bile Acid Sequestrants Drug Interaction

Potentially bind and sequester ANY acidic drug such as warfarin

HMGRIs (Statins)

HMG-CoA Reductase Inhibitors

Statins pharmacophore consists of...

3,5-dihydroxyheptanoic acid and decalin or OTHER aromatic ring

3R, 5R stereochemistry at 3- and 5- positions are very important

In their active forms, all HMGRIs contain a...

carboxylic acid

In their _______ forms, all HMGRIs contain a carboxylic acid

- active

Lovastatin is _________, whereas simvastatin is _________

- natural (R = H)

- synthetic (R = CH3)

Lovastatin and simvastatin are __________

- prodrugs

Their active forms contain a carboxylic acid

The inactive lactone prodrugs of HMGRIs must undergo in vivo __________ to produce effects

- hydrolysis

Good first-pass metabolism so, it has low oral bioavailability: 5-20% except pitavastatin (51%)

HMGRIs have good ____-_____ _______

- first-pass metabolism

Thus, low oral bioavailability (5-20%) with the exception of pivastatin (51%)

HMGRIs peak reduction of plasma cholesterol:

4-6 weeks of therapy (except atorvastatin - only 2 weeks)

HMGRI elimination half-life

1-4 hours

Except atorvastatin and rosuvastatin (19 hours)

HMGRIs (statins) should be administered at _________

- bedtime

Except atorvastatin and rosuvastatin

_________ and _________ are the only HMGRIs that do not need to be administered at bedtime due to their _______ ______ ___-______

- Atorvastatin

- Rosuvastatin

- long elimination half-life (19 hours)

Cholesterol Absorption Inhibitor Drugs

Ezetimibe

After oral administration, ezetimibe is ______ and _____ metabolized in the intestinal wall and the liver to its _________ _______

- rapidly

- extensively

- active metabolite (phenol glucuronide)

Ezetimibe has a ______ ______ structure

- small molecule

A small amount (<5%) of ezetimibe undergoes __________ to convert the benzylic hydroxyl group to a ketone

- oxidation

Ezetimibe is adminsitered _______; however, its absolute bioavailability cannot be determined because of its ________ _______ and lack of an ________ formulation

- orally

- aqueous insolubility

- (lack of) injectable formulation

Both ezetimibe and its glucuronide conjugate have a half-life of approximately...

22 hours

Fibrates Pharmacophore

phenoxy, spacer group, isobutyric acid

Compounds containing esters are prodrugs

_______-_________ of fibrates produces compounds with significantly longer half-life

- Para-substitution

Fibrates inactive ester prodrugs must undergo ____ _______ ______ to produce effects

- in vivo hydrolysis

Oxidation of the aromatic methyl groups produces inactive hydroxymethyl analogs

As a drug class, fibrates and their oxidized analogs are primarily excreted as...

glucuronide conjugates in the urine

Fibrates PK

excellent bioavailability (60-90%) food can ENHANCE oral absorption (should be taken with or just BEFORE meals)

Nicotinic acid is freely soluble in ________ _______

- alkaline solutions

Nicotinic acid is a _______, ________, _______, ______ powder

- stable

- nonhygroscopic

- white

- crystalline

Nicotinic Acid pKa

4.76

Therefore, it is primarily ionized at physiologic pH.

The pyridine nitrogen is a very weak base (pKa = 2.0) and primarily exists in un-ionized form.

Niacin's pyridine nitrogen is a _______ _________ base

- very weak (pKa = 2.0_

Therefore exists in the un-ionized form

Small doses of niacin used for dietary supplementation are primarily excreted as metabolites, whereas large doses used for hyperlipoproteinemia, are primarily excreted...

unchanged by the kidney

Niacin is readily ________, with peak plasma concentration occurs within ____ ______

- absorbed

- 45 minutes