PDA 2 Exam 3 Molecules

Digoxin

•a cardiac glycoside that consists of three sugar residues attached to a steroid group.

•binds near the extracellular side of the Na+/K+ ATPase and blocks the potassium binding site non-competitively

-> indirect increase in intracellular Ca2+ levels

Milrinone

PDE-3 inhibitor in different cell types

inodilator (positive inotrope and vasodilator) used for the treatment of acute and chronic heart failure

•short half-life (2 to 2.5 hours), so, it is generally administered as a continuous IV infusion.

•mostly excreted unchanged in the kidney (~85%) with some liver metabolization (O-glucuronidation)

Dobutamine

selectively stimulates β1-adrenergic receptors -> increase in intracellular levels of cAMP.

This results in enhanced calcium influx into cardiac myocytes during systole -> increased myocardial contractility

Typically, it causes no significant increase in heart rate

Available as a racemic mixture

main metabolite, 3-O-methyldobutamine, is mostly inactive

Levosimendan

a calcium sensitizer that has a dual mechanism of action:

1. During systole (contraction)= It makes the heart muscle more sensitive to calcium, so it contracts stronger without using extra energy

---sensitizes troponin C to calcium in a manner dependent on the calcium concentration, thereby increasing the effects of calcium on cardiac myofilaments and improving contraction at low energy cost

2. During diastole (relaxation)= when calcium levels drop, the effect goes away, so the heart can relax normally (or even better)

---sensitization is diminished due to a plunge in calcium concentration level which does not cause a deterioration of diastolic relaxation but, on the contrary, does cause an improvement

Nitroglycerin (NTG, Glyceryl trinitrate, GTN)

Organic nitrate (a volatile oil)

Onset is 1-4 minutes, DOA is 30 minutes

Taken sublingually to prevent first-pass metabolism

Isosorbide dinitrate (ISDN, Dilatrate®, Isordil®)

Organic nitrate

Sugar scaffold increases bioavailability ~29%

80% of it is converted o 2 active metabolites= greatly extended activity of the drug

Isosorbide-5- Mononitrate

Metabolite of ISDN with 100% bioavaibility

t1/2= 5h

Isosorbide-2- Mononitrate

Metabolite of ISDN

t1/2= 2h

Hydralazine

Used in combination with ISDN (Combo called BiDil®)

BiDil® decreases mortality and reduces rate of first hospitalization in heart failure patients self-identified as black

MOA: (not fully known) Directly relaxes arteriolar smooth muscle -> reduced afterload and vasodilation

Sodium nitroprusside

Inorganic nitrate

Spontaneously releases NO -> sGC activation causes vasodilation (NO ENZYME= no tolerance)

•Dilates arteries and veins to the same degree

•Parenteral administration

•Used in HTN emergency or heart failure

•DOA: 1-10 min

•Can decrease BP in 30 seconds

•Used just enough to titrate the BP

Keep away from light

Hydroxocobalamin

Antidote for cyanide toxicity

Chelate cyano group at central OH= Cyanocobalamin

Fenoldopam

Selective Peripheral D1 Receptor Agonist

Indicated for short-term treatment of severe hypertension -> used parenterally

Equivalent to nitroprusside in lowering blood pressure

Poorly soluble in lipids -> does not penetrate BBB and has no CNS effects

Phentolamine

Alpha 1 adrenergic antagonist for ED

Non-oral (intracavernous)

Alprostadil (IDK IF ON EXAM)

PGE1 derivative used for ED

Stimulates adenylyl cyclase to increase cAMP= smooth muscle relaxation

Non-oral (intracavernous)

Papaverine (IDK IF ON EXAM)

PDE2, 3, and 4 inhibitor used for ED

Alkaloid found in opium

Non-oral (intracavernous)

Citrulline

Product (in additon to NO) of arginine and eNOS

Used for Ed because it gets metabolized by kidneys back into arginine= increased Arg blood levels= increased bioavailability of arginine/smooth muscle relaxation

Arginine F= 10-20%

Citrulline F= 60-70%

Sildenafil (Viagra)

Oral Nucleotide-like PDE5 Inhibitor for ED

Resembles cGMP (methyl)

Also used for Pulmonary arterial hypertension(PAH)

Vardenafil

Oral Nucleotide-like PDE5 Inhibitor for ED

Resembles cGMP (ethyl + extra N)

Highest potency

Tadalafil

Oral non-nucleotide-like PDE5 inhibitor for ED

Also used for BPH and PAH

Called "the weekend" due to 36h DOA (if you take on Friday)

Longest onset time and DOA

Avanafil

Oral non-nucleotide-like PDE5 inhibitor for ED

Shortest onset + DOA

Riociguat

Soluble Guanylate Cyclase (sGC) Stimulator

Indications: PAH, Chronic thromboembolic pulmonary HTN (CTEPH)

Oraly active

Short DOA (methyl causes shorter T1/2)

TID dosing

Vericiguat

Soluble Guanylate Cyclase (sGC) Stimulator

Indications: Heart failure

Orally active

Longer DOA (F increases potency)

once a day dosing

Nisolidipine

Asymmetric 1,4-DHP

Ortho group on C4 phenyl= optimal

Nicardipine

Asymmetric 1,4-DHPs

Meta group on C4 phenyl= optimal

pKa ~7.2= allows it to be formulated into IV

Faster onset= used in hypertensive crises

Felodipine

Asymmetric 1,4-DHPs

Meta and Ortho groups on C4 phenyl= optimal

t1/2: 25 hours

Nimodipine

Asymmetric 1,4-DHPs

Meta group on C4 phenyl= optimal

Increased lipophilicity = Better BBB penetration

Used for Cerebral vasospasms

Isradipine

Asymmetric 1,4-DHP

Meta and Ortho groups on C4 phenyl= optimal

Amlodipine

Asymmetric 1,4-DHP

Ortho group on C4 phenyl= optimal

Better bioavailability than other DHPs; circumvents metabolism the most

Levamlodipine

Asymmetric 1,4-DHP

Enhanced potency by altering groups at R5 (bottom right ether)

t1/2 = 30 – 50 hours

Clevidipine Butyrate

Asymmetric 1,4-DHP

Soft drug!! (Similar to frlopdipine)

IV only

Ultra–short acting (rapid onset & offset); t1/2: 1-15 minutes

Verapamil

phenylalkylamine (non-DHP CCB)

in addition to hypertension, angina, and arrhythmias Verapamil is also used for the treatment of...

1. supraventricular tachycardia (rapid and regular)

2. atrial fibrillation (irregular).

•It is also used off-label for migraine and cluster headache prevention.

t1/2 = 3 to 7 hours

Metabolized by CYP3A4 9demethylated at N in the middle) to norverampamil

--t1/2 = 5 to 13 hours (20% potency)

S isomer is 10-20x more potent but more subject to 1st pass metabolism

Diltiazem

benzothiazepine (non-DHP CCB)

•preferred for patients who need treatment for hypertension and cardiac issues -> more balanced yet less robust effect

can be allosterically coupled with 1,4-DHPs

Metabolized by esterases, CYP3A4 (N-Demethylation), and CYP2D6 (O-Demethylation)

Acetazolamide

Carbonic Anhydrase Inhibitor diuretic (PCT)

Oral (ER capsule/Tablet/powder for injection)

Tx Nephrogenic Diabetes insipidus Tx

Oral form used off label for Primary hypokalemic and hyperkalemic periodic paralysis attacks

Methazolamide

Carbonic Anhydrase Inhibitor diuretic (PCT)

Oral tablet

Weaker than acetazolamide

Dichlorphenamide

Carbonic Anhydrase Inhibitor diuretic (PCT)

Oral tablet

Used in Tx of Primary hypokalemic and hyperkalemic periodic paralysis attacks (opening Ca2+-activated K+ channels in myocytes allowing influx of potassium)

Dorzolamide

Carbonic Anhydrase Inhibitor diuretic

Ophthalmic solution

Tx of open-angle glaucoma

Brinzolamide

Carbonic Anhydrase Inhibitor diuretic

Ophthalmic solution

Tx of open-angle glaucoma

Furosemide

Loop diuretic (TAL)

Oral, IV, Or Sc infusion

Bumetanide

Loop diuretic (TAL)

Most potent: 40x more potent than furosemide

Torsemide

Loop diuretic (TAL)

Acidic proton pka= 7.1

Lonest T1/2

Ethacrynic Acid

Loop diuretic (TAL)

Lowest potency

Do not see much

Chlorothiazide

Thiazide diuretic (DCT)

Only thiazide that can be formulated as a solution for injection (nitrogen next to the S gets protonated at pka 6.7)

Hydrochlorothiazide

Thiazide diuretic (DCT)

Decreased acidity from Chlorothiazide (pka 7.9)

Oral only

many combination products

Bendroflumethiazide

Thiazide diuretic (DCT)

Fluoro group is more lipid soluble= longer DOA + Increased diuretic potency

Only available in combination with nadolol as "Corzide")

Metazolone

Thiazide-like diuretic (DCT)

Oral only

Can be used for edema in HF

Indapamide

Thiazide-like diuretic (DCT)

Oral only

Chlorthalidone (masked carbonyl)

Thiazide-like diuretic (DCT)

in an equilibrium due to the masked carbonyl

Chlorthalidone (unmaksed carbonyl)

in an equilibrium due to masked carbonyl

in an equilibrium due to masked carbonyl

Spironolactone

Potassium-Sparing Diuretic/MRA (DCT + CD)

2 active metabolites

Half-life after one dose is 1.3-2h but after multiple doses its 2-3 days

Used in HF because it blocks deleterious CV effects

Aldosterone

The natural Potassium-Sparing Diuretic/MRA (DCT + CD)

Exists in the hemiacetal form

7a-Thiomethylspirolactone

Potassium-Sparing Diuretic/MRA (DCT + CD)

Major metabolite of spironolactone

Active

1. Thioester hydrolyzed

2. Thiol methylated

Canrenone

Potassium-Sparing Diuretic/MRA (DCT + CD)

Active (not major) metabolite of spironolactone

Lactone opens and closes (closed= active)

Canrenoate

Potassium-Sparing Diuretic/MRA (DCT + CD)

Active (not major) metabolite of spironolactone

Lactone opens and closes (open= inactive)

Potassium Canrenoate

Prodrug that gets turned into canrenoate:

active (not major) metabolite of spironolactone

not in the U.S.

Eplerenone

Potassium-Sparing Diuretic/MRA (DCT + CD)

Selective Mineralocorticoid Receptor Antagonist

Epoxide and ester decrease its affinity, so its less potent but more selective

beneficial effects on long-term survival and cardiovascular outcomes

Finerenone

Potassium-Sparing Diuretic/MRA (DCT + CD)

Nonsteroidal selective Mineralocorticoid Receptor Antagonist

Indications:

• to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D)

• to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adult patients with heart failure with left ventricular ejection fraction (LVEF) ≥ 40%

Triamterene

Potassium-Sparing Diuretic/MRA (DCT + CD)

Non-aldosterone Mineralocorticoid Receptor Antagonist

Gets para hydroxylated by CYP1A2 then conjugated to a sulfate (Sulfate conjugate is active)

Amiloride

Triamterene

Potassium-Sparing Diuretic/MRA (DCT + CD)

Non-aldosterone Mineralocorticoid Receptor Antagonist

100x more potent than triamterene

Clopidogrel

P2Y12 antagonist

Prodrug (main= CYP2C19)

Irreversible (forms covalent disulfide bond with the receptor)

Prasugrel

P2Y12 antagonist

Prodrug (hCE2/hCE1)

Irreversible (forms covalent disulfide bond with the receptor)

Active metabolite of clopidogrel that forms a disulfide bond with P2Y12

Cangrelor

Nucleotide P2Y12 antagonist (reversible)

SOFT DRUG

--metabolized by ectonucleases

--phosphates into OH

--T1/2= 3-6min

Highly selective for P2Y12

Rapid onset/short DOA= good for acute settings

IV adjucnt to PCI

Chloro groups give it resistance to metabolism

Ticagrelor

Nucleoside P2Y12 antagonist (reversible)

Oral drug

Metabolized by CYP3A4

OH does not get glucuronidated

Selatogrel

Subcutaneous P2Y12 antagonist under investigation (in phase 3 rn)

For use pre-hospital Tx of Mi: for people to self admin if they've had a previous MI

Has portion (aminopyridine) of ticgrelor

Phosphonic acid has more potency and less metabolism, allowing its quick onset (T1/2= 4-7h)

Himbacine

NO PAR-1 Activity

Used as template for antithrombin

The active enantiomer of a lead compound found in high throughput screen for the design of vorapaxar

Vorapaxar

competitive + selective PAR-1 antagonist

reversible

dissociation 1/2 off the receptor is 12h (good for tethered ligand)

decreases CV events in people with MI and PAD

Metabolized by CYP3A4 + 2j2

M20

Active metabolite of Vorapaxar metabolized by CYP3A4 + 2j2 (omega hydroxylation)

23% of the circulating drug

Dipyridamole

Phosphodiester ease inhibitor (increases cAMP= vasodilation)

Cilostazol

Used in the Tx of intermittent claudication of PAD (painful walking due to ischemia)

oral PDE3 inhibitor (increases cAMP= vasodilation)

CONTRAINDICATED in HF due to increased mortality

Active metabolite accounts for 15% of activity= reduce dose 50% when co-administered with CYP3A4 and CYP2C19 inhibitors

Eptifibatide

Intravenous GPIIb/IIIa Receptor Antagonist

Reversible

Mimics RGD sequence of fibrinogen

Amine and Carboxylic acid have appropriate distance from each other to resemble RGD best

Cyclic Peptide

Mimics RGD sequence of fibrinogen

Ionized homoarginine mimics arginine of RGD and increases potency (positions charges correctly)

Indole ring + Cys also increases potency

Proline restricts the flexibility for spacing

Binding:

Binds to Mg on the beta 3 subunit MIDAS (metal-ion adhesion site)

Causes thrombocytopenia!!

Tirofiban

Intravenous GPIIb/IIIa Receptor Antagonist

Mimics RGD sequence of fibrinogen

Reversible

Amine and Carboxylic acid have appropriate distance from each other to resemble RGD best

More potent that eptifibatide due to sulfonamide

Binding:

Binds to Mg on the beta 3 subunit MIDAS (metal-ion adhesion site)

Causes thrombocytopenia!!

Zalunfiban (RUC-4)

a non-RGD-mimetic GPIIb/IIIa antagonist

For SC injection for prehospital admin in patients with an ST level elevation in MI

In an autoinjector for EMS to use

Rapid onset of 15mn and DOA 2h

In phase 3 trials

Metabolism: glycine cleaved and excreted in urine

Binding:

No arginine mimetic because no Arginine; Instead has primary amine

Primary amine binds to the glutamate residue instead of Mg= no conformational change

Displaces Mg in the MIDAS binding site

No thrombocytopenia!!

Heparin (Unfractionated Heparin, UFH) MOA

Composed of a mixture of fragments from 3,000 to 30,000 daltons

Partial structure pictured because fragment sizes vary:

--To have IIa activity it requires at least 18 saccharide units (larger)

--Xa just requires the typical Penta saccharide unit

Ratio of anti-factor 10a:2a is 1:1

The negative charges on heparin form ionic links to ATIII (antithrombin III) at positively charged lysine residues

T1/2= 1-6h depending on patient

Binds platelet factor 4; it undergoes and conformational change and exposes epitopes that IgG antibodies can bind to= associated with HIT

Not orally active because it’s too big\polar and glycosidic linkages would be hydrolyzed in the stomach

It’s IV and SQ- too painful and too high risk for I

Protamine sulfate

Heparin antidote

Mostly Arg residues that ionically bind to UFH's polyanionic structure

Administered IV and will neutralize heparin in ~5min

May work on 60% of LMWH= need two doses for Delteparin/Enoxaparin

Fondaparinux

Indirect factor Xa inhibitor

Contains only the Essential Penta saccharide sequence that binds to antithrombin 3

Has indirect Xa activity= indirect because it binds antithrombin 3 (Avoids non specific binding)

More potent (94% binds antithrombin 3)

Not protein bound

T1/2= 17h once a day dosing

No HIT + No monitoring

Too small for protamine to work as an antidote

Rivaroxaban

DOAC

Binds directly to Xa

Used in preventing a thrombus from forming or growing (so many PE and CV indications/to decrease stroke risk)

Small molecule oral drug with predictable pharmacokinetics

No monitoring required

Binds the S4 ad S1 pockets in the active site of factor Xa (V-shape)

--Rivaroxabans Cl group has an electrostatic interaction with edges of Tyr residue

Apixaban

DOAC

Binds directly to Xa

Used in preventing a thrombus from forming or growing (so many PE and CV indications/to decrease stroke risk)

Small molecule oral drug with predictable pharmacokinetics

No monitoring required

Edoxaban

DOAC

Binds directly to Xa

Used in preventing a thrombus from forming or growing (so many PE and CV indications/to decrease stroke risk)

Small molecule oral drug with predictable pharmacokinetics

Edoxaban also binds an "cation hall" due to the methyl on the nitrogen, causing it to have a positive charge

No monitoring required

Milvexian

Oral Factor XIa inhibitor in phase 3 right now

Binds S1 (due to phenyl- triazole) and S2' of factor 11a

Patients who are deficient in factor Xia have a lower risk for VTE AND Ischemic stroke + rarely have spontaneous bleeding

Factor 11a is an important driver for thrombus growth but not really important for homeostasis= ideal for pathological thrombosis

Overall benefit is less bleeding risk

Asundexian

Oral Factor XIa inhibitor in phase 3 right now

Binds S1 (due to phenyl- triazole) and S2' of factor 11a

Patients who are deficient in factor Xia have a lower risk for VTE AND Ischemic stroke + rarely have spontaneous bleeding

Factor 11a is an important driver for thrombus growth but not really important for homeostasis= ideal for pathological thrombosis

Overall benefit is less bleeding risk

Warfarin

Vitamin K antagonist--> inhibits factors II, VII, IX, and X (also proteins C and S)

Coumarin derivative

Antagonizes by inhibiting VKOR

1,3-dicrbonyls make it acidic= comes as sodium salt

Sold as racemic mixture but S isomer accounts for all important activity (R=weakly active)

Argatroban

Univalent DTI

Reversible

Peptidomimetic small molecule

Still administered IV because low lipophilicity

USED TO TREAT HIT

May increase INR so caution when bridging with warfarin

Dabigatran

Type of DOAC + DTI (double)

PRODRUG

Binds S1, S2, and S4 sites of thrombin

Once ester and carbamide are cleaved= active

Glucuronide metabolite is still pharmacologically active (not a part of binding site; CA makes it more lipophilic)

Activation is esterase-mediated (hCE1/hCE2), NOT CYP450= less drug interactions compared to CYP-metabolized drugs