Pharmacology: Ischemic Heart Disease

Front 1

Stable Angina Pectoris: Definition

Back 1

*Diagnosis is made by the patient’s HISTORY.
*Chest discomfort due to EXERTION and RELIEVED by REST.

*Due to an imbalance of “oxygen supply” and “oxygen demand”--
1) Supply:
-Inadequate blood flow.
-Inadequate oxygenation, e.g. severe anemia, hypoxia.
2) Demand:
-Wall tension.
-Heart rate.
-Contractility.

*Most common cause is atherosclerotic CAD.
*Treatment directed to improving blood flow or reducing MVO2 demand or both.

Front 2

Back 2

Atherosclerosis. Slow, gradual buildup that occludes or nearly occludes vessel--> gradual buildup.

Front 3

Atherosclerosis Timeline

Back 3

Angina: probably 70% blockage. Plaque started 10-20 years before sx.

Front 4

Back 4

Front 5

Ischemic Cascade: progression of symptoms leading to angina:

Back 5

Front 6

Back 6

Cath results: Patient with Angina Due to Diffuse LAD Disease.

Front 7

Back 7

*Angina patient with Diffuse LAD Disease.
*Before and After Four Drug-eluting Stents.

Front 8

What are the Acute Coronary Syndromes: discuss.

Back 8

1) Unstable angina: Angina at rest, or a ∆ in the angina.

2) Myocardial infarction:
-Definition: Myocardial cell necrosis due to reduction in blood supply.
-Types (based on the electrocardiogram/pathogenesis):

*STEMI:
-Due to acute, total coronary occlusion-thrombus almost always a component of obstruction

-Non-ST elevation myocardial infarction (NSTEMI):
*Due to partial or transient total coronary occlusion.
*Thrombus may be a component of obstruction.
*Due to excess in DEMAND (sepsis, etc.).
*Dynamic coronary artery spasm may contribute to obstruction.

Front 9

Pathogenesis of Acute Coronary Syndromes:

Back 9

Tissue factor causes platelet aggregation.

Front 10

Back 10

Acute Coronary Syndromes - STEMI

Front 11

Back 11

*ST elevations are localizing--EKG would reflect STE on anterior leads (therefore, LAD occlusion).

Front 12

Back 12

Acute Coronary Syndromes – NSTEMI. NOT as localizing as STEMI.

Front 13

Back 13

ST depression (EKG is non-localizing).

Front 14

Back 14

Myocardial Infarction: Right Coronary Artery
Left: STEMI
Right: NSTEMI

Front 15

Clinical Diagnosis of Acute MI summary diagram:

Back 15

Front 16

Anti-thrombotic Therapy in ACS:
2 broad categories.

Back 16

1) Antithrombins:
*Heparins
-Unfractionated (UFH)
-Enoxaparin (Lovenox)

*Direct antithrombins
-Lepirudin (Refludin)
-Bivalirudin (Angiomax)
-Argatroban

2) Antiplatelet Agents:
*Aspirin

*P2Y12 inhibitors
-Thienopyridines: Ticlopidine (Ticlid), Clopidogrel (Plavix), Prasugrel, Ticagrelor.

*GP IIbIIIa receptor inhibitors
-Abciximab (ReoPro)
-Tirofiban (Aggrastat)
-Eptifibitide (Integrilin)

Front 17

Flow chart of the Anticoagulation Cascade:

Back 17

*Note initiation with enzyme activation. Activation of Xa is key here to thrombus formation.

Front 18

Unfractionated Heparin:
examples--
mechanism of action--
PK--

Back 18

*Examples
-Only one agent (UFH).
-Naturally occurring macromolecule in mast cells.
-Porcine intestine and bovine lung sources.
-Use is very common.

*Mechanism of action
-Acts indirectly by binding to antithrombin-3 (AT-3) to inhibit serine proteases including clotting factors (thrombin, Factor IIa) and Factor Xa.
-Activates platelets

*Pharmacokinetics
-IV-acts rapidly, within minutes-most common method of administration.
-SQ-acts within 1-2 hours.
-Depolymerized by monocyte/macrophage systems.
-Monitored by tests of coagulation (aPTT or ACT).
-IV half-life is 2 hours.
-Prolonged half-life in hepatic or renal failure.

Front 19

Unfractionated Heparin:
adverse effects--
CIs--

Back 19

*Adverse effects
1) Bleeding--
-main complication.
-heparin effect can be reversed by protamine sulfate.

2) Heparin-induced thrombocytopenia (HIT)--
*HIT-1: benign.

*HIT-2:
-Potentially serious illness.
-Heparin/platelet factor 4 complex activates platelets.
-Diffuse vascular thrombosis.
-Thrombocytopenia.
-Delayed onset.

*Contraindications:
-Active bleeding
-Recent surgery-especially closed space
-Trauma
-Known HIT

Front 20

Discuss Antithrombins: discuss Low-molecular Weight Heparin:

Back 20

*Enoxeparin (Lovenox)
-Predominant anti-Xa effect.
-Potentially more effective than UFH (inhibits circulating thrombin and reduces formation of thrombin) and SQ administration effective.
-Possibly less platelet activation than UFH.
-Administered SQ and IV.
-Indicated for ACS and as adjunct for thrombolytic therapy.
-Following SQ administration, delay in action until 4-6 hours.
-Cautionary use in renal insufficiency.
-Less association with HIT.

Front 21

Diagram of the Mechanism of action of UFH vs LMWH:

Back 21

Front 22

LMWH:
advantages--
disadvantages--

Back 22

*Advantages:
-Inhibits platelet-bound factor Xa (UFH does not).
-Less binding to plasma proteins.
-More resistant to platelet factor 4:
-Longer half-life: once or twice daily SC injections.
-More predictable bioavailability: does not require monitoring.
-Less effect on platelet function; less likely to cause bleeding complications.
-Less likely to cause HIT and osteoporosis.

*Disadvantages:
-More expensive.
-Difficult to reverse: protamine does not completely reverse the anti-factor Xa activity. So if you have someone who is prone to bleeding, maybe don't use it.
-Renal excretion: higher risk in renal insufficiency.

Front 23

Discuss Direct Thrombin Inhibitors: what distinguishes them from indirect thrombin inhibitors?

Back 23

*Inactivate both free thrombin and fibrin-bound thrombin.
*Do not require antithrombin cofactor.

*High-molecular-weight DTIs (hirudin, bivalirudin) act as two sites on thrombin:
-Active site: catalytic site.
-Exosite: fibrinogen binding site.

*Low-molecular-weight DTIs (argatroban, efegatran) act only at the active site.

Front 24

DTIs: diagram of their Mechanism--

Back 24

Front 25

Antithrombins-Direct-Acting; discuss Bivalirudin (Angiomax):

Back 25

*Previously known as hirulog, a synthetic form of hirudin.

*Cleared by proteolysis, hepatic metabolism and to lesser degree renally.

*Less bleeding than heparin.

*Administered IV in-hospital as a substitute for unfractionated heparin in patients with ACS or having percutaneous coronary intervention.

Front 26

Discuss the use of Fibrinolytic Drugs:
how do they work?

discuss the 3 generations of these drugs.

Back 26

*Used ONLY in the setting of STEMI.
*Convert plasminogen to plasmin.
*Plasmin degrades fibrin, fibrinogen, and any protein with an available arginyl-lysine bond.
*Indiscriminate plasmin activity --> systemic lytic state.
*The ideal fibrinolytic agent would act specifically at the fibrin surface in a thrombus.

*Fibrin specific agents: bind to fibrin, produce only fibrin-bound plasmin from fibrin-bound plasminogen.
-First generation: streptokinase, urokinase.
-Second generation (fibrin-specific): recombinant t-PA.
-Third generation: r-PA (reteplase), TNK-ase (tenecteplase).

Front 27

Targets of Antiplatelet Agents (diagram):

Back 27

*Long pathway--> many drug targets.
*Don't have to memorize.

Front 28

Discuss Thromboxane A2 Synthesis:

Back 28

*During platelet activation, platelet phospholipase A2 is stimulated, forming arachidonic acid from membrane phospholipids.
*Arachidonic acid is metabolized to thromboxane A2 by cyclooxygenase-1 (COX-1).

Front 29

Discuss the action of Thromboxane A2:

Back 29

*Once formed, TX A2 can diffuse across the plasma membrane and activate other platelets through SIGNALING pathways.
*This leads to platelet conformational change, secretion, and aggregation.

Front 30

Discuss the mechanism of action of aspirin:

Back 30

*Aspirin acetylates COX-1, causing it to be irreversibly inactivated.
*By interfering with the synthesis of TX A2, platelet activation is inhibited.

Front 31

Oral Antiplatelet Agents--discuss aspirin:

Back 31

*Administered orally.
*Doses: 81-325 mg.
*Irreversible acetylation inactivates cyclo-oxygenase for the lifetime of the platelet and reduces platelet-synthesized thromboxane A2.
*Improves outcomes in ACS patients and has secondary prevention benefits.
*No major interactions with statins.
*Often supplemented with clopidogrel.
*Patients with aspirin resistance identified-biochemical marker associated with lack of clinical effectiveness.
*Almost universally indicated for patients with cardiovascular disease.

Front 32

Discuss Thienopyridine Derivatives:

Back 32

*Clopidogrel and Ticlopidine are structurally related thienopyridine derivatives.
*They act by inhibiting the ADP-dependent pathway of platelet activation.

Front 33

How do Thienopyridine Derivatives:

Back 33

*Thienopyridines inhibit the ADP-dependent pathway of platelet activation.
*Prodrugs that depend on active metabolites for their effects.
*After oral administration, these agents undergo modification to their active forms via cytochrome P450 metabolism.
*These metabolites block the platelet P2Y12 receptor.

Front 34

Oral Antiplatelet Agents: discuss Ticlid:

Back 34

Ticlopidine:
*A thienopyridine.
*Interferes with binding of ADP to its receptor and thus inhibits activation of GP IIb/IIIa receptors.
*Metabolized by liver to active metabolite.
*Significant hematologic side effects including neutropenia and TTP, serial monitoring required.
*Administered orally, bid (250 mg) regimen.
*Food interferes with absorption.
*Not approved in some European countries due to toxicity.
*Replaced by clopidogrel; use is limited to patients with unacceptable clopidogrel side-effects.
*WE REALLY DON'T USE THIS MUCH.

Front 35

Oral Antiplatelet Agents: discuss Clopidogrel:

Back 35

*Plavix.
*Oral, once a day, daily dose (75 mg) administration.

*Indications:
-Secondary prevention cardiovascular disease.
-Percutaneous coronary interventions, especially drug-eluting stents-- CRITICAL! Stay on the med for A YEAR!!!
-ACS-less recurrent ischemic events.

*Loading dose (600 mg) when used for ACS/PCI.
*Concerns regarding inhibition of effectiveness by certain medication.
*Use associated with mild increases in overall bleeding rates.

Front 36

Discuss Limitations of Clopidogrel:

Back 36

*Delayed onset of antiplatelet effects (several hours after ingestion).

*Substantial variability in response among patients:
-Absorption.
-Medication interactions.
-Genetic polymorphisms.

*Poor antiplatelet response to clopidogrel is linked to adverse clinical outcomes:
-coronary ischemia.
-stent thrombosis.

Front 37

Chart of Variability in Clopidogrel Response:

Back 37

*Due to genetic polymorphisms--large dose mitigates this.

Front 38

Oral Antiplatelet Agents: discuss Prasugrel:

Back 38

*Requires enzymatic metabolism for antiplatelet effect
*The active metabolite binds irreversibly to the platelet P2Y12.
*Concentration peaks in the plasma at 30 minutes.
*Loading dose 60mg, daily dose 5-10mg daily.
*No clinically relevant interactions with inducers or inhibitors of the cytochrome P450 system.
*More potent antiplatelet effect than clopidgrel.

*Higher bleeding risk:
-Contraindicated in patients with prior STROKE.
-Caution age >75, weight <60kg.

Front 39

Compare effectiveness of plavix and prasugrel:

Back 39

*More effective than plavix, more bleeding risk, too.
*Not terrible different from plavix, though.

Front 40

Oral Antiplatelet Agents: discuss Ticagrelor:

Back 40

*Cyclopentyltriazolopyrimidine, reversible inhibitor of P2Y12 ADP-receptor.
*Loading dose 180mg, daily dose 90mg twice daily.
*Metabolized by CYP3A, avoid or dose adjust drugs with similar metabolism (simva/pravachol).
*More potent antiplatelet effect than clopidogrel.

*Bleeding risk (major and minor) higher than clopidogrel.
*Low dose aspirin recommended: 100mg or less.

*Contraindicated: prior ICH, active bleeding, liver failure.

*Side effect to monitor dyspnea 14% and bradycardia/pauses 6%.

Front 41

Mean inhibition of platelet aggregation (IPA) with Ticagrelor:

Back 41

*Pretty darn effective.
*This is a new drug. We'll be seeing it again in the future.

Front 42

Significance of the PLATO Study:

Back 42

*Randomized double-blind study comparing ticagrelor (N=9333) to clopidogrel (N=9291) in ACS.

*Composite of CV death, MI, or stroke
-9.8 vs 11.7% HR0.84 (0.77, 0.92) 0.0003

*Lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.0091).

*Take away: ticagrelor works.

Front 43

Diagram of Plavix and prasugrel Metabolism:

Back 43

*First step in clopidogrel metabolism inactivates 85% of the parent compound.
*Ticagrelor: No in vivo biotransformation.
*The CYP enzymes are polymorphic and are responsible in part for the interpatient variability of clopidogrel response.
*Liver metabolism is key!

Front 44

Discuss Glycoprotein IIb/IIIa Antagonists:

Back 44

*Regardless of the stimulus for their activation, the aggregation of platelets is finally regulated through their membrane binding sites for fibrinogen in the Gp IIb/IIIa receptor complex.

Front 45

Diagram of platelet aggregation:

Back 45

*A key point in coagulation cascade.

Front 46

Discuss IV Antiplatelet Agents: GP IIbIIIa Receptor Antagonists: discuss Abciximab (ReoPro)--

Back 46

*Administered IV.
*Monoclonal antibody against GP IIbIIIa receptor, prototype of class-most extensively evaluated and used as reference for comparison by other agents.

*Most consistent effect is to reduce the frequency of elevations of CK-MB associated with PCI.
*In balloon angioplasty alone, a lower incidence of abrupt closure and possible impact on events such as death and MI especially in AMI PCI.
*Less effective than other agents as an upstream treatment for ACS-- contraindicated in the absence of PCI.

*Substantially increases risk for minor and major bleeding
*More expensive and slower reversibility compared to other small molecule agents.
*May “facilitate” primary PCI.

Front 47

IV Antiplatelet Agents: GP IIbIIIa Receptor Antagonists: discuss Tirofiban (Aggrastat)--

Back 47

*Reversible, direct acting synthetic blocker.

*A “small molecule” agent.

*Extensive investigation supporting upstream use for ACS with reduction in recurrent MI, particularly among patients undergoing PCI.

*Less expensive and more reversible than abciximab.
*A VERY PROMISING AGENT.

Front 48

IV Antiplatelet Agents: GP IIbIIIa Receptor Antagonists: discuss Eptifibitide (Integrilin)--

Back 48

*Reversible, direct acting “small molecule.”

*In combination with UFH, reduced MI during PCI when compared to UFH alone.

*Effective for use in ACS patients.

*Major impact as a replacement for abciximab for PCI-now the standard.

*Doesn't sound terribly important, but he says it is going to replace abciximab.

Front 49

Clinical Practice: which drugs do we actually use and when?

Back 49

A) ACS:
1) Asprin

2) At least 1 antithrombin (unfractionated heparin or enoxaparin); Bivalirudin can be used as alternative

3) Clopidogrel or prasugrel/ticagrelor unless high suspicion for need for CABG.
-Dual antiplatelet therapy (DAT) for 12 months for ACS or coronary stent
-Optimal duration of DAT unknown

4) GP2b3a inh for high risk patients undergoing PCI. Last result. "I've never had to give this as long as Plavix has been out."

B) Secondary Prevention of CAD: ASA or clopidogrel.

Front 50

Organic Nitrates:
examples--
mechanism--
CIs--

Back 50

*Examples:
-Nitroglycerin (sublingual, spray, cutaneous, IV).
-Isosorbide mono-or dinitrate (oral, patch).

*Mechanism of action:
-Dual action.
-Supply: selective vasodilation of epicardial coronary arteries to increase supply.
-Demand: reduction in systemic blood pressure (especially preload) and left ventricular volume to decrease myocardial oxygen consumption.

*Contraindications:
HYPOtension.
Volume depletion.
Right ventricular infarction (dropped preload here would be bad).
Use of phosphodiesterase inhibitors (Viagra, etc).

Front 51

Nitrates: Pharmacokinetics

Back 51

*Fast and slow versions.

Front 52

Organic Nitrates:
discuss tolerance--
side effects--

Back 52

*Tolerance:
-Definition: Lack of response following prolonged administration.
-Originally described in certain munitions factory workers who experienced vasoconstrictive disorders on weekends off work.
-Can avoid by a “nitrate free interval” of 12-14 hours.
-Patch on for 12 hours off for 12 hours.

*Side effects:
-Headache (most common, especially with sublingual).
-Hypotension.
-“syncope.”
-Potentiated by phosphodiesterase inhibitors e.g. sildenafil (Viagra); nitrates should be avoided for 24 hours.

Front 53

Beta-adrenergic Blockade
examples--
Mechanism--
prevention effects?

Back 53

*Examples:
-Propranolol-non-selective (blocks Beta-1 and Beta-2).
-Metoprolol-selective (Beta-1 antagonist).
-Atenolol-selective (Beta-1 antagonist).
-Selectivity is dose related.

*Mechanism of action:
-Reduce heart rate via beta-adrenergic receptor antagonism
-Reduce blood pressure and contractility (minimal effect)
-Supply: No effect.
-Demand: Significant reduction in demand by attenuation of stress (e.g. exercise) induced increase in heart rate. Also, they reduce contractility.

*Secondary prevention effects are important-post myocardial infarction.
*Reduction in coronary events has been demonstrated; unique for these agents.

Front 54

Beta-adrenergic Blockade:
PK--
CIs--
Withdrawal considerations--

Back 54

*Pharmacokinetics:
-IV-minutes.
-PO--> 12 hour duration with long-acting agents.

*Contraindications:
-Asthma-non-selective agents.
-Bradycardia.
-Heart block.
-Listed contraindications for diabetes, peripheral arterial disease and chronic obstructive lung disease are not absolute and such patients should be considered as candidates on an individual basis.
-Vasospastic angina, cocaine induced infarction.
-Usually extremely well tolerated.

*Withdrawal:
-Cessation should be tapered to avoid rebound phenomenon.

Front 55

Calcium Channel Blockers: give examples. 4

Back 55

Nifedipine (PO, SL)
Verapamil (IV, PO)
Diltiazem (IV, PO)
Amlodipine (PO)

Front 56

List effects of Ca channel blockers:

Back 56

Front 57

Calcium Channel Blockade:
mechanism--
prevention effects?

Back 57

*Mechanism of action/cardiovascular effects:
-The different agents have different relative actions
-Reduce heart rate (verapamil, diltiazem)
-Reduce blood pressure –systemic arteriolar vasodilation
-Supply: epicardial and arteriolar vasodilation (nifedipine, amlodipine).
-Demand: oxygen consumption
-Mild reduction in heart rate (verapamil, diltiazem)
-Reduce contractility (verapamil)
-Reduction in blood pressure

*No secondary prevention benefits!!!!
*"This is a second line drug."

Front 58

Calcium Channel Blockers:
PK--
metabolism--
CIs--

Back 58

*Pharmacokinetics:
-IV-minutes (diltiazem, verapamil for arrhythmia).
-PO: Short and long-acting preparations; >12 hour duration with long-acting preparations.

*Metabolism/elimination:
-Hepatic metabolism.
-Urine and fecal elimination depending on agent.

*Contraindications:
-Bradycardia-- verapamil, diltiazem.
-Heart block-- verapamil, diltiazem.
-CHF-- verapamil, diltiazem.
-Hypotension-- especially nifedipine and amlodipine.
-Concomitant use of digoxin-- verapamil.
-Liver failure.
-Short-acting nifedipine associated with increased late mortality. Long acting version is okay.

Front 59

Discuss Ranolazine (Ranexa):
mechanism--

Back 59

*Approved January 2006 for chronic stable angina.
*Orally-active piperazine derivative.
*Reduces angina frequency and NTG use compared to placebo.
*Incremental efficacy is documented.

*Mechanism of action: unknown.
-not dependent on reduction of heart rate or BP.
-does inhibit fatty acid oxidation and preferred glucose oxidation which requires less oxygen for a given level of myocardial work.

Front 60

Ranolazine (Ranexa):
metabolism--
CIs--
side effects--
dosing--

Back 60

*Metabolized in the liver and metabolized by CYP3A, potentially inhibited by diltiazem and verapamil (no concurrent use!).

*Contraindicated with hepatic impairment.
*Excreted in the urine.
*In general well tolerated.

*Principal side effects dizziness, constipation, asthenia, headache.
*Can prolong QT but no torsades de pointes.

*Dose: 500 mg po bid, maximum 2000 mg/day.
*Recommendations: Use only in those who do not respond to triple therapy.

Front 61

“Statins”-- how do they work?

Back 61

Block the rate limiting step in cholesterol synthesis.

Front 62

Statins: discuss their Pleiotropic Effects:

Back 62

many benefits. improve survival.

Front 63

Statins: do they work?

Back 63

improves survival.

Front 64

Statins: Targets--

Back 64

due to change soon; we'll see.

Front 65

Renin-Angiotensin System: diagram--

Back 65

Front 66

ACE inhibitors: Mechanisms of action--

Back 66

*ACE inhibitors block the conversion of angiotensin I to angiotensin II.

*Inhibit the production of angiotensin II: potent vasoconstrictor and growth promoter.

*Increase concentrations of the vasodilator bradykinin by inhibiting its degradation.
-Bradykinin has been shown to have beneficial effects associated with the release of nitric oxide and prostacyclin, which may contribute to the positive haemodynamic effects of the ACE inhibitors.

*Lower BP; increase cardiac output, lower renovascular resistance, and lead to increased natriuresis (urine sodium excretion). Lower afterload.

Front 67

ACE Inhibitors: Cautions/Contraindications

Back 67

*Hypotension, cough, angioedema; Probably related to Bradykinin.

*Renal impairment:
-Effect on renal blood flow, vasodilates efferent arterioles and reduces GFR (caution RAS, NSAIDS).

*Hyperkalemia.

*Decrease in aldosterone levels.

*ACE inhibitors are Pregnancy category D and are known to cause birth defects.

Front 68

Clinical Practice--what regimens do we use to treat ischemia?

Back 68

*Minimal therapy: ASA , statin, beta-blocker.
*Two or more agents commonly used in combination.
*Nitrate and beta-blocker most common.
*Amlodipine, diltiazem most common, nifedipine more often for hypertension, verapamil uncommon.

*Triple therapy may be ineffective- consider ranolazine.

*Most patients with disabling angina undergo revascularization.

*Adjunctive therapy:
-ACE-inhibition.
-Weight reduction.
-Exercise.
-Smoking cessation.

Front 69

What tests do we do when we suspect a pt has angina?

Back 69

Stress tests and perfusion tests.