CARDIO FINAL ELSAID: ARRYTHMIAS, DYSLIPIDEMIA, ANTICOAG/PLATELETS

Anticoagulants

common pathway

factor X → factor Xa → prothrombin (factor II) → thrombin (factor IIa) → fibrinogen (factor I) → fibrin (factor Ia) → clot

Platelet Plug Formation

• GP Ia receptor bind to collagen

• GP Ib recepto bind to vWF

• GP IIb/IIIa bind to fibrinogen

• PGI₂ released

• aggregating substances released from platelet

  • ADP

  • TXA₂

  • 5HT

heparin

• acts in

• activates what

• acts in blood

• activates antithrombin → inactivates factr TF, Xa, thrombin, XIa, IXa

warfarin

• acts in

• does what

• acts in liver

• inhibits synthesis of Vitamin K-dependent factors

Parenteral agents (SQ/IV) - 4

• Unfractioned heparin (UFH)

• low molecular weight heparin (LMWH)

• factor Xa inhibitors

• direct thrombin inhibitors (DTIs)

Oral agents (3)

• vitamin K antagonists

• direct thrombin inhibitors (DTI)

• factor Xa inhibitors

indirect inhibitors

• target

• types

• enhance ability of natural anticoagulant called antithrombin (AT); does not block factors directly

• UFH, LMWH, factor Xa inhibitor (Fondaparinux)

UFH

• structure

• target/MOA

• administration

• monitoring

• renal adjustment

• reversal agent

• HIT risk

• indications

• large polysaccharide

• binds to AT → ehnace inhibiton of Xas and IIa

• IV or SQ

• required monitoring

• no renal adjustment/short half life

• Protamine (complete)

  • positive base

• highest HIT risk

• prophylais/treatment of DVT/PE, ACS, Af cardioversion

LMWH (Enoxaparin)

• other drugs

• structure

• target/MOA

• administration

• monitoring

• renal adjustment

• reversal agent

• HIT risk

• indications

• Dalteparin (Fragmin), Tinzaparin (Innohep)

• shorter polysaccharide chains

• binds to AT, enhance inhibiton of Xa > IIa

• SQ

• not routine

• renal adjustment needed (CrCl < 30)

• Protamine (partial)

  • postive base

• low HIT risk

• prophylaxis and treatment of DVT/PE, ACS, preferred in onclgy and pregnancy

UFH vs LMWH

• which binds to both thrombin and heparin? why?

• which has higher risk of bleeding and HIT

• UFH binds to both thrombin and heparin due to larger length (5-sacchiride sequence - allosteric activation, >18-sacchirde for thrombin activation)

• UFH has higher risk of bleeding and HIT

Fondaparinux (Arixtra)

• structure

• target/MOA

• administration

• monitoring

• renal adjustment

• reversal agent

• HIT risk

• Indications 

• synthetic pentasaccharide

• binds to AT, enhance inhibiton of Xa

• SQ

• not routine

• CI in CrCl < 30

• no reversal agent

• very low HIT risk

• Indications 

  • DVT prophylaxis 

  • Treatment of DVT/PE

  • ACS

  • Can use in HIT pts

Heparin-Induced Thrombocytopenia (HIT)

• what is it?

• result

• management

• onset

• immune reaction where antibodies form against heparin-platelet complex

• platelet activation (leading to clotting) and platelet consumption (leading to low platelets

• stop all heparin products → start non-heparin anticoagulant DTI

• 5 - 10 dats after starting heparin

parenteral DTIs

• drugs

• MOA

• place in therapy

• dose adjustment

• administration

• Argatroban (hepatic) and Bivalirudin (renal) — IV

• directly bind to and inhibit thrombin

• go-to anticoagulant for pts w/ HIT

• IV bolus + IV continuous infusion

Warfarin (Coumadin) — Vitamin K Antagonist (VKA)

• MOA

• onset

• monitoring

• ADE

• CI

• interactions

• work in liver toblock VKOR enzyme

  • prevent recycling of VIt K (essential for clotting factors)

• slow onset (3 - 7 days)

  • prevents only formation of new factors

• INR monitoring

  • goal: 2 - 3

  • high INR = high bleeding risk

• ADEs

  • bleeding, purple toe syndrome, skin necrosis

• CI

  • teratogenic (pregnancy Category X)

• interactions

  • MANY DDIs (amiodarone, bactrim)

  • food interactions (rich in vitamin K)

Dabigatran (Pradaxa)

• other drugs

• type

• MOA

• indications

• key pearl

• reversal agent

• rivaroxaban, apixaban, edoxaban

• DOAC (DTI)

• directly inhbit thrombin (factor IIa)

• indications

  • nonvalvular AF and DVT/PE treatment

• take w/ food to reduce dyspepsia, avoid in renal impairment; dialyzable

• Idarucizumab (Praxbind)

DOAC — Oral direct factor Xa inhibitors

• drugs

• MOA

• reversal agent

• rivaroxaban (Xarelto)

• apixaban (Eliquis)

• Edoxaban (Sayvaysa)

• directly inhibit factor Xa

• Andexanet Alfa (Andexxa) — removed from market

DOAC advantages vs Warfarin

• rapid onset

• fixed dosing

• no routine montioring

• fewer drug/food interactions

DOAC disadvantages

• renal dose adjustments critical (CI in CrCl < 30ml/min)

• expensive

warfarin reversal agents

• vitamin K (slow)

• Kcentra (fast)

Antiplatelets/Fibrinolytics

platelet activation

platelets activated → aggregation and formation of platelet plug

Aspirin (Salicylate)

• MOA

• ADE

• toxicity

• MOA

  • irreversibly inhibit COX-1, TXA₂ synthesis

• ADE

  • GI hemorrhage, hypersensitivity reactions

• toxicity

  • n/v, tinnitus

  • metabolic acidosis (hyperventilation)

  • HA, dizziness, mental confusion convulsions, coma

ADP Receptor (P2Y12) Antagonists (Antiplatelets) drugs

• Clopidogrel (Plavix)

• Prasugrel (Effient)

• Ticagrelor (Brillinta)

• Cangrelor (Kengreal)

Clopidogrel (Plavix)

• place in therapy

• prodrug

• DDI

• BBW

• place in therapy

  • ACs, ischemic stroke, primary PCI

• prodrug

  • 2 step conversion to its active metabolite (Act-Met)

• DDI

  • affected by 2C19 inhibition

• BBW

  • Poor 2C19 metabolizers → decreased efficacy due to lack of conversion to active metabolite → decreased platelet inhibition

Prasugrel (Effient)

• potency

• bleeding

• CYP

• indications

• warnings

• potency

  • higher and better than Clopidogrel

• bleeding

  • high rates

• CYP

  • does not need 2C19

• indications

  • primary PCI for MI pts, STEMI, diabetic pts

• warnings

  • CI in pts w/ history of stroke or TIA

  • pts 75+ or weight less than 60 kg → high risk of bleeding

Ticagrelor (Brillinta)

• potency

• bleeding

• indications

• CI

• avoid

• ADE

• potency

  • higher than Clopidogrel

• bleeding

  • no increased bleeding

• indications

  • ACS

  • ischemic stroke

• CI

  • intracranial hemorrhage history

  • do not use w/ aspirin doses > 100 mg (reduces effectiveness)

• avoid

  • CYP3A4 inhibitors and inducers

• ADE

  • bleeding

  • dyspnea (goes away w/ continued treatment

Cangrelor (Kengreal)

• administration

• use

• bleeding

• clinical pearl

• ADE

• administration

  • IV

• use

  • only for PCI or bridge therapy to CABG

• bleeding

  • higher incidence than clopidogrel

• clinical pearl

  • need to use another PO P2Y12 inhibitor after PCI

• ADE

  • bleeding

GP IIa/IIIa Inhibitors

• MOA

• use

• CI

• complications

• drugs

• indication and monitoring

• MOA

  • blcok final common pathwat of platelet aggregation

• use

  • in additon to anticoagulant and P2Y12 inhbitor during PCI

• CI

  • do not use in combo w/ Bivalirudin (DTI) → bleeding

• complications

  • drug-induced thrombocytopenia (DIT) → lead to HIT → platelet activation

• Drugs

  • Abciximab (Reopro)

  • Eptifibatide (Integrillin)

  • Tirofiban (Aggrastat)

• indication

  • STEM PCI or NSTEMI PCI

• monitoring

  • bleeding, Scr, platelet count

Abciximab (Reopro)

• duration if PCI

• dose adjustment

• duration if PCI

  • 12 hrs

• dose adjustment

  • no

Eptifibatide (Integrillin)

• duration if PCI

• dose adjustment

• duration if PCI

  • 18 - 24 hrs

• dose adjustment

  • CrCl < 50 → reduce infusion 50%

Tirofiban (Aggrastat)

• duration if PCI

• dose adjustment

• duration if PCI

  • 12 - 24 hrs

• dose adjustment

  • CrCl < 30 → reduce infusion 50%

fibronolytic MOA

• recombinant t-PA (tissue plasminogen activator) bind to fibrin in thrombus (clot)

• plasminogen → plasmin → initiates fibrinolysis

Alteplase (Activase)

• class

• indication

• stroke dosing

• CI

• class

  • t-PA

• indication

  • stroke, PE, acute MI

• stroke dosing

  • 0.9 mg/kg (max: 90 mg)

• CI

  • internal bleeding

  • SBP > 185 mmHg or DPB > 110 mmHg

  • bleeding diathesis

  • INR > 1.7

  • heparin within 48 hrs w/ abnormal aPTT

  • LMWH within 24 hrs

  • platelets < 100K

  • CT showing acute hemorrhage

Tenecteplase (TNKase)

• class

• place in therapy

• advantages

• dose

• class

  • t-PA

• place in therapy

  • alternative to alteplase

• advantages

  • increased in use, ease of dosing

• dose

  • 0.25 mg/kg IV bolus, max: 25 mg

Arrythymias

conduction pathway

SA node → atrium → atrium contraction → AV node → atria repolarize/relax → ventricles → ventricles contraction → ventricles repolarize/relax

refractory period

time when atria/ventricles are depolarized and cannot produce a new electrical current until they are repolarized

p wave

atrial depolarization

QRS duration

• what happens if signal is delayed or blocked?

ventricular muscle depolarization

• wider QRS

T wave

ventricular repolarization

PR interval

• proxy for which node?

• what happens if that node is blocked?

measure of conduction time from atrium to ventricle

• AV node

• longer PR interval

QT interval

• long QT interval mean?

furation of ventricular action potential (depolarization → repolarization)

• takes long time to contract again → risk of arrhythmia

conduction properties

• anisotropic = direction dependent

• slows in AV node → due to calcium current

fast response tissues

• atria

• ventricles

• His-Purkinje cells

slow response tissues

• SA node

• AV node

sinus tachycardia

• increase in HR

  • more SA firing rate

sinus bradycardia

• slows down HR

  • delay in action potential

  • SA not able to depolarize due to opening of K channels

atropine sulfate

• MOA

• action

• MOA

  • anticholinergic (M2 receptor antagonist)

• action

  • manage bradycardia

  • block vagus nerve → K+ channels do not open → depolarization can occur

T or F:

• antiarrythmic drugs can control and cause arrhythmias

• all arryhthmias require treatment

true

Class I

Na+ channel blockade → slows depolarization in fast AP cells

Class II

beta blockers → slows depolarization in slow AP cells

Class III

K+ channel blockade → prolong AP duration

Class IV

Ca2+ channel blockade → slows depolarization in slow AP cells

Class IA

• drugs

• disassociation

• other info

• Quinidine, Procainamide

• blocks K+ channels too

• increases QRS and QT

Class 1B

• drugs

• disassociation

• other info

• Lidocaine, Mexiletine

• fast disassociation

• for ischemic myocardium

• decreased QT (safe in long QT)

Class 1C

• drugs

• disassociation

• other info

• Flecainide, Propafenone

• slow disassociation

• increases QRS

Class II (beta blockers)

• affects which tissues

• MOA

• use

• examples

• CI

• affects which tissues

  • slow response tissues (nodes)

• MOA

  • block sympathetic activation (normally increases sinus rate and AV node conduction velocity)

  • increases PR interval

  • control HR and conduction velocity

• use

  • re-entry tachycardia

  • rate control in tachyarrhythmias (A-fib)

• examples

  • Esmolol, Sotalol

• CI

  • AV block

esmolol

• affects only AV and SA node

• selective

sotalolol

• also a class 3 (K+ blocker)

• nonselective

• control HR and conduction velocity

• increase ERP

• slows sinus rate

class III (K+ channel blockers)

• MOA

• effect on EKG

• drugs

• MOA

  • inhibit K+ channels → prolong AP duration and ERP

• effect on EKG

  • QT prolongation → Torsades

• drugs

  • sotalol

  • ibutilide

  • dofetilide

  • amiodarone

  • dronedarone

Ibutilide

• IV

• activates slow inward Na+ currents during early phase 3

• delays repolarization

• increase ERP

• can cause ventricular arrhythmias

dofetilide

• approved for atrial flutter/fib

• selective

• can cause ventricular arrhythmias

amiodarone

• oral/IV

• decreases phase 4 slope and conduction velocity

• long half lide

• ADEs

  • pulmonary fibrosis, hypo/hyperthyroidism, hepatotoxicity, corneal micro-deposits, skin discoloration

dronedarone

• similar to amiodarone but non-iodinated

• shorter half life

• less toxic

• less efficacious

• CI

  • severe, decompensated symptomatic heart failure

Class 4 (Ca2+ channel blockers)

• drugs

• MOA

• effects

• other

• drugs

  • non-DHP CCBs (Verapamil, Diltiazem)

• MOA

  • blocks Ca2+ channels → slows depolarization in slow AP cells

• effects

  • sinus rate control in A-fib

  • reduces conduction velocity thru AV node (increases PR interval)

  • useful in re-entry SVT

• other

  • magnesium (natural Ca channel blocker)

Adenosine

• IV

• fast onset and offset

• reduces conduction velocity thru AV node

• acts on SA node to decrease HR

• to manage SVT

digoxin

• cardiac glycoside

• Na+/K+ ATPase inhibition → positive inotropic effect

• increases vagal tone → negative chronotropic effect

  • decreases HR a rest

  • no effect during physical activity

• controls HR in A-fib

Dyslipidemia

more fat = ?

lower the density

lipid targets in managing hypercholesterolemia

• lower LDL or TG

• increase HDL → ability to shrink plaques

drug action sites

• liver

• intestine

• liver

  • statins, bempedoic acid, PCSK9 inhibitors

• intestine

  • ezetimibe and bile acid sequestrants (BAS)

LDL-C lowering agents

• HMG-CoA reductase inhibitors (statins)

• ACL inhibitor (bempedoic acid)

• PCSK9 inhibiting agents

• BAS

• cholesterol absorption inhibitor (ezemtimibe)

TG lowering agents

• fibrates or fibric acid

• omega 3 fatty acids

• niacin or nicotinic acid

statins

• MOA

• result

• pleiotropic effects

• CI

• ADE

• MOA

  • decrease cholesterol production

  • increase LDL-receptor expression

  • inhibit HMG-CoA reductase

• result

  • lower LDL-C, non-HDL-C, apoB

  • increase HDL

• pleiotropic effects

  • improved endothelial function

  • inhibition of platelet aggregation/thrombin generation

  • stabilize atherosclerotic plaques

• CI

  • pregnancy

• ADE

  • SAMS (muscle symptoms)

  • new onset diabetes

primary vs secondary prevention

• primary

  • pts w/o disease

• secondary

  • clinical ASCVD → high intensity statin

high intensity statins

• atorvastatin

  • high log P

  • t ½ = 14 hrs

• rosuvastatin

  • low log P

  • t ½ = 19 hrs

• taken any time

pravastatin

non-cyp, low log P

ezetimibe

• MOA

• Result

• clinical use

• ADE/practical notes

• MOA

  • inhibit absorption of cholesterol at border of small intestine

  • target NPC1L1 sterol transporter

• Result

  • decreased cholesterol to lover

  • increased clearance of plasma cholesterol

• clinical use

  • adjunct to statins or fibrates

  • add on in pts w/ high ASCVD risk

  • monotherapy in pts w/ statin intolerance

• ADE/practical notes

  • GI effects

  • no hepatic/renal dose adjustments

PCSK9 inhibitors

• characterisitics

• MOA

• features

• examples

• characterisitics

  • chaperone protein, in liver

• MOA

  • bind to LDL receptor → LDL degraded

• features

  • humanized ABs

  • SQ every 2 - 4 weeks

  • no renal elimination

• examples

  • alirocumab (Praluent)

  • Evolocumab (Repatha)

Inclisiran

• MOA

• injectable

• 2 RNA molecules

• GalNAc moiety aids in targeted hepatic delivery

• passenger strand disassociated from guide

• guide strand assembles and binds to RISC

• RISC-guide strand binds to PCSK9 mRNA → block translation → degradation of PCK9 mRNA

Bempedoic Acid

• MOA

• prodrug

• indication

• MOA

  • ACL inhibitor

    • inihibit cholesterol synthesis in liver upstream of HMG-CoA reductase

    • upregulate LDL receptors → decrease plasma LDL-c

• prodrug

  • activated in liver

• indication

  • adjunct to diet and max tolerated statin for treatment of HeFH or ASCVD

• no muscle pain

BAS or Resins

• MOA

• result

• ADE

• clinical use

• CI

• formulations/drugs

• DDI

• MOA

  • increase BA excretion

  • increase hepatic conversion of cholesterol to BA

  • increase hepatic uptake of serum cholesterol

• result

  • LDL-C lowering (adjunct to statins)

• ADE

  • limited GI effects

• clinical use

  • stain-intolerant pts

• CI

  • bowel obstruction

  • TG >/= 300 mg/dL

• formulations

  • Colesevelam (Welchol)

  • Colestipol (Colestid)

  • Cholestyramine (Questran)

• DDI

  • cyclosporine, glimepiride, glipizide, glyburide, levothyroxine, olmesartan, medoxomil, oral contraceptives

    • management: adminster 1 hr before or 4 hrs after BAS

    • decreases effect

fenofibrate

• MOA

• ligand agonist (PPAR-nuclear factor)

• helps in lipoprotein metabolism

• increase LPL expression

fibric acids

• ADE

• CI

• example

• ADE

  • GI intolerance

  • increased gallstones risk

  • transient LFT elevations

  • myopathy/myositis (if statin + gemfibrozil)

  • reversible increased Scr

• CI

  • renal dysfunction (< 30)

  • active liver disease or elevated LFTs

  • gallbladder disease

• example

  • gemfibrozil (Lopid)

nicotinic acid

• lipid effects

• MOA

• ADE

• DDI

• CI

• lipid effects

  • lowers TC, LDL-C, TG, apoB, Lp(a)

  • increase HDL-C

• MOA

  • FFA release inhibitor from adipose tissue

  • increase LPL activity

  • reduced rate of VLDL and LDL synthesis

• ADE

  • flushing, skin abnormalities, glucose intolerance, hyperuricemia, increased LFT, hepatic dysfunction, changees in CBC< blurred vision, GI intolerance

• DDI

  • myalgias if used w/ statin

• CI

  • hepatic disease or elevates transaminases

  • active peptic ulcer

  • arterial hemorrhage

omega 3 fatty acid

• MOA

• clinical use

• components

• ADE

• products

• MOA

  • inhibit TG sythesizing enzymes

  • increase LPL

  • reduce heaptic synthesis and VLDL secretion

• clinical use

  • to treat TG >/= 500 mg/dL

• components

  • EPA

  • DHA

• ADE

  • GI upset

  • eructation

  • arthralgia

• products

  • omega 3 fatty acid ethyl esters

  • iscoaspent ethyl

  • O3FA COOH