6115Lec - [J] CVD PART 2

Known as a cardiac glycoside

Digoxin

may be very toxic presenting several ADRs like ventricular tachycardia, AV block, and ventricular fibrillation.

Digoxin

Digoxin Toxicity is increased with?

thiazide diuretics, glucocorticoids, hypercalcemia (high calcium levels).

After discontinuance of digoxin ____must be provided to cardiac glycoside-induced toxicity

KCl

blocks Na+-K+-ATPase leading to increase intracellular Ca+2 that leads to increase heart contraction

Digoxin

the binding activity of digoxin is attributed to?

Ring A-B and C-D must be cis- fused

It is essential for the binding of digoxin

𝛼,β-unsaturated C17 lactone

essential for cardiotonic activity in digoxin

c14-OH

Enumerate Bipyridines

Inamrinone, Milrinone

It is a bipyridines that contains 2 pyridine rings

Milrinone

inhibits PDE to increase cAMP = increase contraction

Bipyridine

acts on the pacemaker current leading to lower HR and heart O2 demand

Ivabridine

used for heart failure not managed by beta-blocker monotherapy

Ivabridine

Class I are?

Na blockers

Class II are?

Beta Blockers

Class III are?

K+ blockers

Class IV are?

Ca+ blockers

Site of action of Class IA

atrial and ventricular tissue

Site of action of Class III

atrial and ventricular tissue

Site of action of Class IC

ventricular tissue

Site of action of Class IB

ventricular tissue

Site of action of Class II

sinoatrial (SA) /atrioventricular (AV) node

Site of action of Class IV

sinoatrial (SA) /atrioventricular (AV) node

Class IA Drugs

Disopyramide, Procainamide, Quinidine, Moricizine

Class IB Drugs

Lidocaine, Mexiletine, Phenytoin (non-FDA approved)

Class IC Drugs

Flecainide, Propafenone

Class II Drugs

Propranolol, Sotalol, Esmolol (cardioselective)

Class III Drugs

Amiodarone, Dronedarone, Dofetilide, Ibutilide, Sotalol (II and III)

Class IV Drugs

Diltiazem, Verapamil

increases refractory period leading to decrease conduction velocity and spontaneous diastolic depolarization of pacemaker cells.

Class IA Drugs

weakly blocks Na+ channel leading to shortened repolarization, decreasing duration of action potential.

Class IB Drugs

blocks Na+ channel to slow down conduction of electrical impulse.

Class IC Drugs

block sympathetic cardiac stimulation resulting to decreases Ca+2 influx and decreasing force and rate of cardiac contraction

Class II Drugs

blocks K+ channel leading to prolonged action potential.

Class III Drugs

blocks slow inward current carried by Ca+2, decreasing AV conduction and spontaneous depolarization, blocking conduction of premature impulses

Class IV Drugs

natural Class IC

PROPAFENONE

structural similar to Propranolol, thus exhibits beta-blocker activity as well

PROPAFENONE

Class III DOC for Tachyarrhythmias, contains iodine, may pose iodine- related problems

AMIODARONE

amiodarone analog w/o iodine

DRONEDARONE

Enumerate Bile acid Sequestrants

cholestyramine, colestipol, colesevelam

binds and excretes bile acid, stimulating the body to use cholesterol to produce bile leading to lower serum cholesterol and LDL.

Bile acid Sequestrants

essentail for binding bile acid

Cationic Amines

For hypercholesterolemia

Bile acid Sequestrants

selectively blocks cholesterol-active transporting protein leading to reduced intestinal cholesterol absorption from dietary sources.

Ezetimibe

It is used for hypercholesterolemia (best in combination with simvastatin)

Ezetimibe

This is esential for activity in Ezetimibe

1,4-diaryl-β-lactam

This results in the Longer DOA in Ezetimibe

p-fluoro substitutions prevents aromatic hydroxylation

________________ localizes the drug in the small intestine

Phenolic and alcoholic hydroxyls

inhibits DAGAT2, preventing acylation of diacylglycerides to TAGs.

Niacin / Nicotinic Acid

prevent receptor-mediated uptake of HDL

Niacin / Nicotinic Acid

the prevention of receptor-mediated uptake of HDL results in

increasing HDL levels

Any modification of niacin structure results to

Inactivity

These are essential for the acivity of Niacins

anionic state and -COOH

Amide forms in Niacins are?

Inactive

It is used for hypertriglyceridemia

Niacin / Nicotinic Acid

Enumerate Fibrates / Fibric Acids

Gemfibrozil, Fenofibrate

Fibrates / Fibric Acids are derivatives of

phenoxyisobutyrate

activates PPAR𝛂 → increases lipoprotein lipase expression

Fibrates / Fibric Acids

reduces TAGs and VLDL levels, increases HDL levels.

Fibrates / Fibric Acids

They are essential for activity in Fibrates

phenoxy and isobutyric acid moiety

Competitively inhibits HMGR leading to inhibition of de novo cholesterol biosynthesis resulting to lower LDL.

HMG-CoA Reductase Inhibitors

Statins must be

anionic state and -COOH

In HMG-CoA Reductase Inhibitors this is essntial for activity

dihydoxyhepatan(en)oic acid

In HMG-CoA Reductase Inhibitors C3 -OH must be in __configuration

R

In HMG-CoA Reductase Inhibitors C5-OH can be?

R or S

Statins with polar functional group increase affinity and potency for

Rosuvastatin and Atorvastatin

Statins with polar functional group deccrease affinity and potency for

Pravastatin

Natural HMGR inhibitors contain?

Decalin with lactone

Synthetic HMGR inhibitors contain?

,5-DIHYDROXY-COOH and p-FLUOROPHENYL

Enumerate Natural HMGR inhibitors

Lovastatin, simvastatin

isolated from Aspergillus terreus

Lovastatin

6 membered ring

Rosuvastatin

5 membered ring

Atorvastatin

Enumerate Orphan Drugs

Lomitapide and Mipomersen

used for genetic mutation in HoFH (lack of LDL receptors)

Lomitapide and Mipomersen

inhibitor TAG incorporation in VLDL and LDL

Lomitapide and Mipomersen

people with liver disease and with CYP 3A4 inhibitors, serious risk of hepatotoxicity.

Lomitapide and Mipomersen

cause vasoconstriction to prevent blood loss and pathogen spread

Thromboxanes

Inhibition of ADP binding on P2Y12 receptor

Clopidogrel, Ticlopidine, Prasugrel

Inhibition of thromboxane A2 (TXA2)

Aspirin

Binds to Glycoprotein IIb/IIIa (GP IIb/GP IIIa)

Abcixima, Eptifibatide, Tirofiban

has anti-inflammatory activity and affects prostaglandin synthesis

Aspirin

irreversibly inhibits COX-1 near active site → inhibits TXA2 synthesis → reduced lately activation

Aspirin

inhibits PDE leading to increased cAMP = reduces platelet activity

PDE inhibitors

Dipyridamole, Cilostazol

PDE inhibitors

Increased camp will result to?

Reduced platelet activity

binds to P2Y purinergic receptors leading to decreased ADP binding

(thienopyridines

decreased ADP binding will result in

Decreased platelet aggregatiojn

P2Y / ADP Inhibitors

Clopidogrel, Ticlopidine, Prasugrelm, Ticagrelor

Inhibition of Factor IIa (thrombin)

Heparin, Enoxaparin, Fondapirinux

Inhibition of Factor Xa

Apixaban, Rivaroxaban, Edoxaban

Inhibition of Vit. K-dependent Factors

Warfarin

sulfate glycosaminoglycan.

Heparin

requires monitoring of use.

Unfractionated heparin (UFH)

more predictable w/ less monitoring.

Low Molecular Weight heparin (LMWH) and Fondaparinux

ADR of Heparin

Bleeding

Bleeding due to heparin may be relieved by

Protamine

from Hirudo medicinalis, medical leech

Direct Thrombin Inhibitors

Enumerate Direct Thrombin Inhibitors from leech

Hirudin, Lepirudin, Desirudin, Bivalirudin

Enumerate Direct Thrombin Inhibitors from lsmall mlecule inhibitors

Argatroban, Dabigatran