Cardio IE2 ELSAID

Anticoagulants

how does a blood clot form?

injury → trigger protein activation → activate substrate → clot forms

purpose of clot

prevent bleeding from vessel

2 main processes of blood clot formation

• coagulation cascade

• platelet plug formation

hemostatic clot

thrombin, fibrin aggregated platelets combined

coagulation casacade pathways

• intrinsic (coagulation w/o blood vessel)

• extrinsic pathway

• common pathway

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

triggers of platelet activation

• blood vessel injury

• plaque disruption

what 2 mediators released to act on platelets and activate them?

• TXA₂^.

• ADP

GP IIb/IIIa receptor

how platelets aggregate

P2Y12 receptor

where ADP binds

Aspirin (Salicylate) therapeutic uses

• pain

• arthritis

• HA

• migraines

• fever

• angina

• MI

• TIA

• PCI

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

causes of arrhythmias

• electrolyte imbalances

• enhanced automaticity

  • accelerate pacemaker rate

• triggered automaticity

• re-entry

triggered automaticity

• delayed afterdepolarization (DAD)

• Early afterdepolarization (EAD)

• DAD

  • intracellular Ca overload

  • arise from resting potential

• EAD

  • slow HR, low extracellular K, drugs that prolong AP

  • arise from plateau phase

  • phase 3 repolarization prolonged → polymorphic ventricular tachycardia w/ long QT interval (Torsades de Pointes)

re-entry

impulses propagate thru more than 1 pathway between 2 points in the heart

heart block (AV block)

• 1st degree

• 2nd degree

• 3rd degree (complete)

impulse from atria unable to get into ventricle; AV node slows down

• 1st degree

  • asymptomatic, prolonged PR interval

• 2nd degree

  • constant but prolonged PR interval

  • reduced CO

• 3rd degree

  • complete heart block

  • sudden cardiac arrest

atrial flutter

atrial rate 250 - 300 bpm (sawtooth P wave)

atrial fibrillation

• atrial rate 350 - 400 bpm (no P wave), erratic, disorganized EKG

• digoxin reduces atrial rate

ventricular tachycardia

wide complex QRS, no discernable P wave

ventricular fibrillation

erratic disorganized EKG

T or F:

• antiarrythmic drugs can control and cause arrhythmias

• all arryhthmias require treatment

true

arrhythmia symptoms

• asymptomatic

• presyncope/syncope/cardiac arrest

• palpitations

• decreased CO

• breathlessness

Antiarrhythmic drugs may slow automatic rhythms by altering any determinants of spontaneous pacemaker discharge:

• increase max diastolic potential

• decrease phase 4 slope

• alter threshold

• potential

• increase AP duration

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

cholesterol

• steroid/sex hormones

• vitamin D synthesis

• cell membrane structure/fluidity

triglyceride

• 3 fatty acids + 1 glycerol backbone

• FA used as back-up energy source

chylomicrons

lipoproteins: proteins, TG, cholesterol

lipoprotein lipase (LPL)

responsible for TG breakdown in chylomicrons

takes up proteins and cholesterol remaining

what is needed for fats to be absorbed from small intestine?

bile salts

cholesterol transport pathway

dietary fats and cholesterol absorbed by bile salts → enter blood as chylomicron → hysrolyzed by LPL → fat uptaken as energy source or storage and remnants back to lover

very low density lipoprotein (VLDL)

• function

• production

• LPL action

• remnants

• function

  • distributes TG and cholesterol in peripheral tissues

• production

  • produced by lover

• LPL action

  • acted upon LPL → hydrolyze TG into glycerol and free FA

• remnants

  • cholesterol remains

more fat = ?

lower the density

low density lipoprotein (LDL)

• function

goes to peripheral tissues to supply cholesterol or go back to lover

bad cholesterol

high density lipoprotein (HDL)

• function

for reverse transport (transport of cholesterol from peripheral back to liver)

plaques

• definition

• function

• definition

  • deposition in walls of arteries

• function

  • reduce elasticity of arteries

  • forms thrombus

  • want to reduce this