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Dr. Ku
Drugs Used in the Treatment of Ischemic Heart Disease
Page 1 of 9
Italicized points are extra info from the slides.
Picture from Board:
Heart Disease
Stroke
PAD (Peripheral Artery Disease)
Kidney Disease
I.
CO = S.V. X H.R.
Flow
Pressure
Resistance (TPR)
Systolic 120
Diastolic 80
Introduction [SS1]:
a. Normal blood pressure is 120/80
b. Stage one hypertension is a diastolic over 90
c. When the heart contracts you are in systole, relaxation is in diastole which is really a measurement of peripheral
resistance.
d. When you manage hypertension you are decreasing the resistance, therefore decreasing the diastolic pressure.
e. We don’t talk about systolic here.
i. As we get older (60-70) the blood vessels can get stiffer (not as compliant) and the systolic can grow to
140-160. This is systolic hypertension. The management of this would be different. It would include a
remodeling.
f. So what we are talking about in this lecture is related to resistance
i. Hypercholesterolemia (atherosclerosis) – flow issue
1. Restricts blood flow to the heart which causes ischemic heart disease
2. Or could cause problems in blood flow to the brain leading to a stroke
3. Or it could cause problems peripherally (Peripheral artery disease) meaning lack of blood flow to
legs, so on
g. What we want to do today is study the approach we take to treat these symptoms, not learn lists of drugs.
h. Ischemic heart disease, is not really a disease, it is symptoms. To treat these symptoms we must learn the
cause.
II. Angina (Chest Pain) [S2]
a. A symptomatic manifestation of Myocardial Ischemia, which is caused by an imbalance between myocardial
oxygen Supply and Demand.
i. Not only a flow problem but also because of the demand
ii. Try to look at both sides to alleviate the chest pain
b. Coronary atherosclerosis is generally the major underlying cause of the classic angina (angina pectoris, “angina
of effort”)
III. Pathophysiology of Angina [S3]
a. Classic Angina (Stable Angina)
i. These take a very long time, gradually get atherosclerotic lesions, gradually constrict the lumen so that you
only get 60% of blood flow
ii. Angina pectoris – gradual decrease to 50-60% lumen size – treatable because still able to maintain
demand
iii. “Angina of Effort” – when you do something that increases the demand and stressed the heart you get pain
1. Otherwise they are stable. Only get chest pain when you increase demand and because of the
decreased lumen size the blood flow cannot keep up with demand.
iv. Major underlying cause: Coronary Atherosclerosis
v. Clinical Test:
1. Coronary Angiogram – look for blockage
2. Graded Exercise (Stress) Test
vi. Clinical Managements:
1. Surgical Interventions: CABG (coronary artery bypass graph), Angioplasty, Stents
2. Pharmacologic: Drugs to decrease Demands – not much you can do to increase supply because of
the obstruction
b. [S4]Variant Angina
i. Prinzmetal Angina
1. Major underlying cause: Coronary Vasospasm: coronary artery in the heart is all the sudden spastic
and constricts
a. caused by stress and the release of catecholamines (sym. factors: norepinephrine,
angiotensin, serotonin). Once they calm down they are fine.
ii. Clinical Test: Ergonovine Provocative Test
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Dr. Ku
Drugs Used in the Treatment of Ischemic Heart Disease
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1. Not too many good tests; this drug can elicit a heart attack so it is very dangerous and we don’t often
want to use it.
iii. Clinical Managements:
1. Pharmacologic: Coronary Vasodilators to prevent vasospasm
c. [S5] Unstable Angina (Acute Coronary Syndrome)
i. Major underlying cause: Coronary Thrombosis (resulting from plaque erosion and rupture)
1. When a patient has one heart attack they are more likely to have another due to the plaque erosion
or rupture
ii. Clinical Test: None specific at the present.
iii. Clinical Managements:
1. Pharmacologic:
a. Anti-platelet and Anti-thrombin agents (to prevent another heart attack)
i. to prevent platelet aggregation and thrombosis – baby aspirin regemin
b. Thrombolytic agents (on emergency basis) to induce thrombolysis
IV. Atheroscleotic Coronary Artery [S6]
a. These lesions obstruct about 60% of the lumen
b. Eccentric lesion are very vasospastic means that the smooth muscle is very sensitive and will constrict and
when they do they decrease the lumen size even more
c. After the first heart attack the plaque begin to rupture to expose the basement membrane. This allows the
platelets to aggregation and form a thrombus. These are acute coronary symptoms, this is the unstable type.
V. Determinants of Myocardial Oxygen Supply [S7]
a. Regulation of Coronary Blood Flow and Distribution
i. Very autoregulation (mostly metabolic control), there is not much we can do to increase the supply of blood
to the heart. The heart it a very dynamic organ, if anything happens, such as a drop in blood pressure,
they autoregulate.
ii. Pressure drops 50% - Most areas, such as the skin, shut down. The brain and heart, however, maintain
blood supply because of autoregulation to these crucial areas.
b. Ok so there is not much we can do to increase blood flow to the heart, what about oxygen capacity?
i. Synthetic hemoglobin and Fluorocarbons can carry more oxygen
ii. Most of the drugs not that useful
c. We can try and increase oxygen extraction; but there is not much we can do here either because the heart is
already very efficient in this process
d. Collateral Blood Flow
i. Blood vessels from other areas to supply surrounding tissue, atheletes have a lot of collateral flow. This
would be long term not short term, so scientists are looking into this as a promising area
e. Coronary Angiogenesis
VI. Determinants of Myocardial Oxygen Demand [S8]
a. The determinants are wall tension, heart rate, and contractility
i. Heart rate and contractility are easy to understand, increase one of these and you increase the demand
b. Systolic Wall Tension (LaPlace Law)
i. T = IVP x radius / 2 x thickness (IVP means intraventricular pressure or systolic blood pressure)
1. The more wall tension you have the more demand you will have.
2. Increases ventricular diameter or systolic blood pressure increases systolic wall tension therefore
increasing demand.
3. Wall thickness because it is the denominator decreases systolic wall tension therefore decreasing
demand. The heart muscle can get thicker and stronger just like a rubber band, a stronger rubber
band does not have as much tension.
a. We know however that this is only initially good. We the hypertrophy gets too big you begin
to have problems.
4. Hypertensive patients would have a higher incidence of heart attacks. They have higher blood
pressure which means higher demand.
Demand
Systolic Wall tension ↑
↑
Ventricular Diameter ↑
↑
Ventricular Thickness ↑
↓
Systolic Blood Pressure ↑
↑
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Friday, April 24, 2009
Dr. Ku
Scribe: Hunter Neill/Laura Adams
Proof:
Drugs Used in the Treatment of Ischemic Heart Disease
Page 3 of 9
Heart Rate ↑
↑
Contractility ↑
↑
VII. LaPlace Law [S9]
a. Hypertension and congestive heart failure increase your numerator, meaning they increase wall tension and
they increase demand, meaning these patients are more likely to have a heart attack.
b. All of these factors are related, there are numerous factors!
c. Tension = LV wall tension or load on the heart
d. IVP = Intraventricular Pressure or Systolic Blood Pressure (hypertension increases this number)
e. Congestive heart failure increase the radius
f. Note: As the IVP or radius of the heart increases, it will increase the LV wall tension or load on the heart. This in
turn leads to an increase in myocardial oxygen demand.
VIII. Determinants of Myocardial Oxygen Demand [S10]
Systolic Wall tension
Nitroglycerin
Prpranolol
Ventricular Diameter
↓
↑
Ventricular Thickness
Systolic Blood Pressure
-
-
↓
↓
Heart Rate
↑Reflex
↓
Contractility
↑Reflex
↓
a. Nitroglycerine
i. Vasodilator, predominately in the veins. This decrease in blood pressure and venous return, which means
less stress on the heart because a decrease in preload. This decreases the oxygen demand on the heart.
ii. Does not change the heart rate or contractility directly but used the reflex.
1. It decreases blood pressure so the baroreceptors send signals to the brain and the sympathetic
systems breaks in. This is known as reflex tachycardia, an increased heart rate and increase
contractility
2. IT is good to keep the blood pressure balance, but this reflex increase heart rate, which increases
demand and that isn’t good.
b. Propanolol
i. Beta blocker, specifically beta-1 on the heart. This will decrease heart rate, contractility, and blood
pressure which all decrease demand.
ii. When you decrease contractility you increase end systolic volume, meaning there is more residual blood in
the ventricle. So the diameter increases, which in turn increases demand which is not good.
iii. This is why we use combination therapy – no single drug that works perfectly
IX. Anti-anginal Agents [S11]
a. Secondary and “Newer”
i. Perhexilene - mostly in Europe, not a -blocker, no bronchospasm problem, behaves like slow calcium
channel antagonist.
ii. Ranolazine - approved in 2006 in USA, unique features include no change in HR and BP, preserve tissue
ATP, and decrease Ca overload.
iii. Papaverine - direct vascular smooth muscle relaxant, inhibits phosphodiesterase and blocks slow calcium
channels.
iv. Dipyridamole - arteriolar dilator, could lead to “coronary steal” problem, but now it is used mostly for its
antiplatelet aggregation effect.
v. Nicorandil - activates KATP channels and releases NO.
vi. Fasudil - orally effective inhibitor of Rho kinase, potent vasodilator.
b. FOCUS ON THE CLASSIC DRUGS (above included for completeness)
c. Primary (Classic) Antianginal agents: been around for several years (ACE inhibitors and statins)
i. Nitrates and Nitrites
ii. -blockers
iii. Calcium channel blockers
X. Antianginal Agents [S12]
a. Nitrates and Nitrites
i. Amyl nitrite: inhalation (very fast absorption)
ii. Glyceryl trinitrate (Nitroglycerin)
Cardio: 10:00 - 11:00
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Friday, April 24, 2009
Proof:
Dr. Ku
Drugs Used in the Treatment of Ischemic Heart Disease
Page 4 of 9
1. Sublingual(under tongue), onset 2-5 mins, duration 20-30 mins
2. First-pass effect (hepatic nitrate reductase)
iii. Isosorbide Dinitrate (Isorbid ) Isosorbide Mononitrate (ISMO)
1. P.O., duration 2 to 12 hrs
iv. Nitroglycerin ointment: these are mostly psychosomatic, meaning the patient feels better because the patch
is on top of exactly where the pain is
v. Transdermal NTG patch (up to 24 hrs) vs. Transmucosal NTG (up to 5 hrs)
1. Patch is psychosomatic for patient, and lasts longer
b. ADME (what pharmacologist focus on)
i. Absorption
ii. Distribution
iii. Metabolism – want a drug with a half life of 12-24 hours so the patient only has to take once or twice a day.
If not you may have a lot of patient compliance problems. Other drugs of course are take as needed, which
is ok.
iv. Excretion
XI. Diagram [S13]
a. Endothelial cells have this L-arginine to nitric oxide pathway.
b. It is a synthetic pathway to convert arginine, a simple amino acid, to NO which can activate soluble guanylate
cyclase (sGC) which increase cGMP and cause the relaxation of smooth muscle cells.
c. So normally the endothelial cells have the blood vessel open, we thought that constriction was active and
relaxation was passive…
i. Now we realize that vessels are opened because endothelial cells are constantly making NO
1. If you have diabetes, are a smoker, or have hypercholesterolemia then you injury these cells, and
decrease their function meaning you decrease their ability to make NO and therefore you develop
high blood pressure
2. Smoking and free radicals are bad for you because they interfere with NO actions
d. Nitroglycerin, nicorandil and nitrates are nitric oxide donors.
i. Bypass the endothelial cell and directly give NO to cause relaxation in smooth muscle cells to decrease the
blood pressure.
e. Answer to student question about the importance of NO: if you block the production of NO the blood pressure
jumps up.
f. ANP/BNP, Ranolazine, Fasudil
i. they cause an increase in cGMP to cause relaxation
g. DON’T HAVE TO WORRY ABOUT THOSE JUST WANT TO PUT THOSE INTO PERSPECTIVE
XII. Nitrates and Nitrites [S14]
a. Mechanism of Action (independent of endothelial function)
i. An enzyme (Glutothione S-Tranferase) will convert nitroglycerine to nitrites and then to nitrosothiol and
nitric oxide
ii. This enzyme is in the cell membrane and is needed to transform nitroglycerin into active components which
cause relaxation
b. If you keep taking nitroglycerin you can develop a tolerance
i. You can deplete this enzyme and you can no longer convert nitroglycerin and it will no longer help you
ii. Nitroglycerin should only be taken as needed
c. Important thing to remember is that this is an independent of endothelial function
XIII. Myocardial Preconditioning [S15]
a. People who always complain usually do not have a massive heart attack, but then the people who are usually
absolutely fine can all the sudden have a deadly massive heart attack
b. What has happened which these individuals is preconditioning. This could be single or multiple brief periods of
ischemia result in a marked reduction in myocardial injury (infarction) when the hearts are exposed to a more
prolonged period of ischemia. So the people that have mini heart attacks are preconditioned and can survive
bigger heart attacks, where someone who is not preconditioned may die from the same heart attack.
c. Has 2 phases: Acute and Delayed Preconditioning
i. Acute phase lasts 1-2 Hours
ii. Delayed phase lasts 24-72 Hours
d. Nitroglycerin (GTN) produces delayed PC in animal and clinical studies.
e. TAKE HOME: Nitroglycerin can decrease your heart’s demand but in the long term it also can protects the heart
XIV.
Side Effects [S16]
a. Nitrates and Nitrites
i. Side Effects:
Cardio: 10:00 - 11:00
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Proof:
Dr. Ku
Drugs Used in the Treatment of Ischemic Heart Disease
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1. Headache, flushing sensation
a. NG is very cheap but very volatile so after time sitting in a medicine cabinet they are no
longer active. So these side effects can actually help us to know if the drug is still good or
not. If you don’t feel flush it is NOT working!
2. Postural hypotension (due to venous “pooling”), dizziness
3. Tolerance
4. Methemoglobinemia (dec. O2 affinity, pseudocyanosis)
a. Sodium nitrate (bacon preserve) – eat too much than you can cause methemoglobinemia
b. [S17] Beta blockers
i. Propranolol (Inderal) and other  -Blockers
ii. Primarily to decrease Myocardial O2 Demands
1. ↓Contractility, HR and BP
and possibly by redistributing coronary blood flow to ischemic endocardial region. The most
vulnerable area of the heart is the endocardium and beta blockers can send blood there
c. Complicating side effects are generally associated with their -blocking action.
d. Caution during   - blocker Withdrawal (you might have to stop the meds before a surgery)
i. Up regulation of -receptors or hypersensitivities to the catecholamines, which cause the patient to develop
arrhythmias. This is why you have to gradually stop medications and cannot stop over night
XV. Determinants of Myocardial Oxygen Demand [S18]
Systolic Wall tension
Nitroglycerin
Propanolol
Ventricular Diameter
↓
↑
Ventricular Thickness
Systolic Blood Pressure
Heart Rate
-
-
↓
↓
↑Reflex
↓
↑Reflex
↓
a. These drugs have some bad side effects, like decrease contractility, increase end diastolic volume. Therefore
we use combination therapy.
i. Propanlol is taken regularly; nitroglycerin is taken when a stressful situation is presenting itself.
Nitroglycerin takes away those bad side effects we just listed. With propanlol you will not have reflex
tachycardia. In the presence of both you do not have these side effects.
XVI.
Antianginal Agents [S19]
a. Calcium Channel Blockers (Verapamil, Calan )
i. These are drugs of the 80s to replace the B blockers. The drug of the 90s is ACE inhibitor. The drugs of the
new century are the statins.
ii. Primarily decreases myocardial O2 demands and increases oxygen supply (via its coronary vasodilatory
action)
1. B blocker only able to decrease demand but not able to increase supply, because it is not a dilator.
Ca channel blockers can decrease demand and increase supply, dual action.
iii. Complicating side effects you can read on your own. Hypotension and constipation are always side effects
for the elderly. Constipation is not a problem with young people, but it gets worse with age.
1. Side effects include negative inotropic effect, depression of existing sick sinus syndrome and AV
nodal disease. Hypotension, headache, dizziness, flushing and etc.
XVII. Class I II III [S20]
a. Class I, phenylalkylamines, and Class II, benzothiazepines are known as cardiac Ca channel blockers, meaning
they work on the heart. The trade names are verapamil and diltiazem.
b. The work on the heart to decrease contractility and decrease heart rate, meaning decrease blood pressure.
c. Class III drugs, dihydropyridines (Nifedipine), are known as vascular vasodialators.
d. 2nd generation dihydropyridines: have better vascular selectivity, are less lipid soluble, better pharmokinetics,
better half-life.
i. Nicardipine (Cardene®), Amlodipine (Norvasc®), Felodipine (Plendil®)
XVIII. Determinant of Myocardial Oxygen Demand [S21]
a. Verapamil can replace using beta blockers and nitroglycerin. It looks like a beta blocker, except it can also
increase coronary blood flow meaning it is a very potent coronary vasodilator.
i. Not only are you decreasing demand but increasing supply, a lot more effective than using the
combinations because with combos you always have to worry about your patient taking it correctly.
Contractility
Cardio: 10:00 - 11:00
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Proof:
Dr. Ku
Drugs Used in the Treatment of Ischemic Heart Disease
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b. Nifedipine is not good because it acts like vasodilators, like nitroglycerin. Decreases blood pressure and
decreases venous return but it also causes the reflex tachycardia.
i. However we have somewhat remedied this problem. It you have rapid onset it behaves nitroglycerin, but
now the drug companies make a extended release version.
Systolic Wall tension
Ventricular Diameter
Ventricular Thickness
Systolic Blood Pressure
Heart Rate
Nifedipine
Verapamil
↓
-
↑
-
↓
↓
↑Reflex
↓
↑Reflex
↓
Current Clinical Uses of Calcium Channel Blockers [S22]:
a. Acute Myocardial Ischemia, Hypertension, Hypertensive, Emergencies, and Supraventricular Arrhythmias.
b. Potential Uses:
i. Migraine, Reynaud’s disease (peripheral vasospasm), subarachnoid hemorrhage, cerebral ischemia, and
certain heart failure.
c. Contraindications for Calcium Channel Blockers:
i. Hypotension, sinus bradycardia (sick sinus syndrome),
ii. AV conduction defects, severe cardiac failure, etc.
XX. Contraindications of Calcium Channel Blockers [S23]: skipped and come back to in another lecture
a. Hypotension
b. Sinus bradycardia (sick sinus syndrome)
c. AV Conduction defects
d. Severe cardiac failure
XXI.
Pathophysiology of Angina [S24]
a. Unstable Angina (Acute Coronary Syndrome)
i. Major underlying cause: Coronary Thrombosis (resulting from plaque erosion and rupture)
ii. Clinical Test: None specific at the present
iii. Clinical Managements:
1. Pharmacologic:
a. Antiplatelet and Anti-thrombin agents
i. To prevent platelet aggregation and thrombosis
b. Thrombolytic agents (on emergency basis) – you have a thrombus and we try to dissolve
them by inducing thrombolysis. This buys the patient more time.
XXII. Critical Events Leading to the Formation of a Thrombus (Acute Coronary Syndrome) [S25]
a. Exposure of blood elements to thrombogenic materials such as collagen, basement membranes, tissue factors,
etc
b. Activation of platelets leading to adhesion and aggregation
c. Triggering of the coagulation cascade leading to the formation of fibrin clot / thrombus
i. Note that platelets and the coagulation system are closely interlinked but they are not the same thing.
Activated platelets accelerate the coagulation pathway because platelets cause the release thrombin, and
those coagulation proteins contribute to platelet aggregation.
XXIII. Diagram [S26]
a. You have endothelial cells, then basement membrane, then smooth muscles. Plaque ruptures, due to it being
calcified and therefore easily broken.
b. All of us already have atherosclerosis, but bodies can adapt through autoregulation. Once you start having
calcium deposits them you start having problems.
c. After the rupture you expose the thrombogenic surface, expose the collagens, basement membranes. Platelets
will then adhere to the collagen. Platelets are white, so you first see a so called white thrombus, then the
platelets activate release of coagulation factors, to attract fibrinogenin to fibrin to produce a more stable clot.
d. The platelets actually don’t stick very well, the other factors cause the clot to become more stable. If it is
unstable then blood flow can flush it out and the angina will end. But with the fibrin comes in it becomes more
stable and then red blood cells are no part of the clot. This is now a red thrombus and you have potentially
stopped the blood flow.
e. So now that we know the sequence how do we treat it?
Contractility
XIX.
Cardio: 10:00 - 11:00
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Friday, April 24, 2009
Proof:
Dr. Ku
Drugs Used in the Treatment of Ischemic Heart Disease
Page 7 of 9
i. Anti-platelet therapy first, stop the aggregation. Then use anti-thrombin or anti-coagulation to prevent the
coagulation cascade, and then finally use a thrombolytic to dissolve the clot.
XXIV. Critical Events Leading to Platelet Aggregation and Hemostasis [S27]
a. Platelet adhesion to the site of injury
i. (GPIa/IIa to collagen and GPIb to von Willebrand Factor)
b. Activation of platelet surface receptors and release of platelet products (ADP, serotonin, TXA 2, etc)
c. Aggregation
d. He said he wants us to understand the BIG PICTURE.
XXV. Diagram [S28]
a. Recap: you expose the basement membrane; you attract platelets to the collagen, via special receptors (you
don’t have to memorize those.) The platelets are then activated and they release thromboxane (TXA2),
serotonin, ADP. And these substances activate more platelets via P2Y1 and P2Y12. So this is adhesion and
aggregation via fibrinogen.
b. Normally endothelial cells release NO and prostacyclin which are protective mechanisms which prevent platelet
aggregations, through cAMP to decrease Ca. So with normal endothelial cells you prevent platelet activation
and aggregation. If you smoke, or have free radical injury then you damage NO production.
i. Oxidized LDL is a very potent free radical.
XXVI. Diagram [S29]
a. Aspirin blocks the synthesis of TXA2, thromboxane, which is a very potent activator of platelet aggregation.
b. You also have thienopyridines (Plavix), which block the ADP receptors. Prevent ADP activation of platelets.
c. Dipyridamole activated cAMP which prevents platelet activation.
d. Also have inhibitors of GP IIb/IIIa.
e. He said you don’t have to memorize all of this but understand how we should approach each one.
XXVII. Aspirin (acetylsalicylic acid, ASA, NSAIDs) [S30]
a. Mechanism of action: Irreversibly acetylates cyclooxygenase (COX 1) and inhibits the conversion of arachidonic
acid to thromboxane (TXA2) in platelets.
b. So why do we take baby aspirin?
i. Platelets lack nuclei and can not synthesize new COX1 and hence permanently unable to produce TXA 2 in
exposed platelets.
ii. Endothelial cells also utilize COX1 to produce prostacyclin, but it has nuclei and able to generate new
COX1.
iii. Thus, at low doses, aspirin will only inhibit TXA2 generation from platelets, but leave the prostacyclin
generation from endothelial cells intact.
iv. So at 650 mg or more you knock out endothelial cell action.
v. Problem with Celebrex is that they are so potent that they knock out the platelets and the endothelial cell
production of prostacyclin.
XXVIII. Aspirin [S31]
a. Limitations:
i. Only inhibits platelet TXA2 synthesis and has no effect on other factors that could initiate platelets activation
and aggregation. Multiple approach is better, so you often need 2 or 3 drugs.
b. Adverse Effects:
i. Dyspepsia, nausea, GI bleeding, hemorrhagic strokes, allergic reaction and asthma exacerbation, and
exacerbate gout.
1. You can help the bleeding by coating the pills and using a small dose.
XXIX. Thienopryridines: Clopidogrel Ticlopidine (Plavix) [S32]
a. Inhibit ADP-mediated platelet activation via blocking of the P2Y12 purinoceptor
b. Orally absorb with good bioavailability
c. Given as prodrug, requires liver conversion to active drug (delayed onset)
d. Primary indications: ACS, percutaneous coronary interventions, unstable angina*, recent MI with or without
ST-elevation*
i. If they are doing a catheter procedure (angioplasty) they worry about platelet aggregation, so you give
anti-platelet therapy.
e. Side effects: bleeding, dyspepsia and diarrhea, neutropenia and thrombocytopenic purpura (with ticlopidine)
XXX. Inhibitors of Glycoprotein (GP) IIb/IIa [S33]
a. Abciximab (a chimeric murine-human Fab fragment monoclonal antibody)
b. Tirofiban and Eptifibatide (small molecule inhibitors)
i. Activated GPIIb/IIIa receptor on platelets binds fibrinogen and von Willebrand factor leading to platelet
aggregation. These drugs stop this process.
c. Major benefits: Inhibition of microembolization
Cardio: 10:00 - 11:00
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Friday, April 24, 2009
Proof:
Dr. Ku
Drugs Used in the Treatment of Ischemic Heart Disease
Page 8 of 9
d. You don’t want to get rid of the thrombus from your heart and then have it cause a stroke, these drugs are good
a getting rid of the clot, dissolving it.
XXXI. Dipyridamole (Persantine) [S34]
a. Vasodilator
b. Primary mechanism of action is to increase cAMP via an inhibition of phosphodiesterase and/or enhance
adenosine activation of adenylate cyclase. Decrease activation of platelets.
c. Little or no benefit as an antithrombotic drug, but used in combinations
d. Used in combination with warfarin to inhibit formation of thromboemboli from prosthetic heart valves.
XXXII. Diagram [S35]
a. Thrombin is part of the cascade.
b. It has an intrinsic and extrinsic pathway.
c. It converts prothrombin into thrombin which then activated fibrinogen into fibrin which creates a very stable clot.
d. Thrombin can also activate platelets.
XXXIII. Anticoagulant Drugs (anti-thrombin drugs) [S36]
a. Indirect Thrombin Inhibitors
i. Heparin (mixed, unfractionated, LMW)
b. Mechanism of action: The unique pentasaccharide sequence binds to antithrombin and expose its active site for
more rapid inactivation of thrombin.
c. LMW heparins: enoxaparin, dalteparin and tinzaparin inhibit factor X, but less effect on thrombin than the HMW
heparins
XXXIV. Monitoring of Heparin Effect [S37]
a. Activated partial thromboplastin time (aPTT)
i. Especially with patients given UFH, but not so for LMW heparins
b. Prothrombin Time (PT)
i. International Normalized Ratio (INR)
c. Toxicities:
i. Bleeding, allergy, alopecia, osteoporosis, etc.
ii. Heparin-induced thrombocytopenia (HIT)
d. Contraindications:
i. Patients with HIT, hypersensitivity, active bleeding, hemophilia, intracranial hemorrhage, advanced liver or
renal diseases, etc.
e. Treatment of Heparin overdose: Protamine sulfate
XXXV. Anticoagulant Drugs [S38]
a. Direct Thrombin Inhibitors
i. Directly binding to the active site of thrombin
b. Hirudin and bivalirudin - bind at both active and substrate recognition site of thrombin and make them inactive
c. Argatroban and melagatran - small molecules bind only at the active site of thrombin
d. Indicated mostly for patients with HIT and venous thromboembolism.
e. Still require close monitoring for toxicity and bleeding.
f. [S39] Warfarin and Coumarin (blood thinners)
i. Orally effective. Heparin and others are not effective orally.
g. Mechanism of action:
i. Antagonize the vitamin K-dependent -carboxylation of glutamate residues in prothrombin, factors VII, IX,
and X as well as endogenous anti-coagulant proteins C and S.
ii. Rat poison uses the same mechanism, causes internal bleeding.
h. Toxicities:
i. Excessive bleeding, numerous drug interactions
ii. Crosses placenta and can cause serious birth defect, never given during pregnancy
i. Treatment of warfarin overdose: Vitamin K (phytonadione)
XXXVI. Diagram [S39]
a. So if you already have a clot, what do you do?
b. Plasminogen activated to plasmin by t-PA or streptokinase. Plasmin will dissolve the meshwork and wash the
clot out.
XXXVII. Fibrinolytic (Thrombolytic) Drugs [S41]
a. Streptokinase (cheapest option but not selective)
i. Natural streptokinase (from streptococci) - antigenic, lack selectivity for fibrin
ii. Anistreplase (Eminase) - complex of SK and plasminogen
b. Tissue Plasminogen Activators (these are faster acting and have high binding affinity, longer half-life, better
selectivities, however the high selectivity actually causes more bleeding)
Cardio: 10:00 - 11:00
Scribe: Hunter Neill/Laura Adams
Friday, April 24, 2009
Proof:
Dr. Ku
Drugs Used in the Treatment of Ischemic Heart Disease
Page 9 of 9
i. Alteplase (Activase; rtPA), short T1/2 (5 min)
ii. Retaplase (Retavase) genetically engineered, higher potency and faster acting
iii. Tenecteplase (TNK-tPA) - longer T1/2 and greater binding affinity for fibrin
c. Urokinase (Abbokinase; UK) (found in urine)
i. Non-antigenic, lack selectivity for fibrin, high cost
XXXVIII. Mechanism of Fibrinolytic Action [S42]
a. Mechanism of fibrinolytic action
i. Both SK and tPA bind to plasminogen to release the serine protease, plasmin, which in turn breaks apart
the thrombus (fibrin molecules).
ii. Excess plasmin protease can also cleave circulating fibrinogen (fibrinogenlysis) and produces undesirable
bleeding.
b. Major difference between SK and tPA
i. tPA is relatively selective for the clot-associated fibrin bound plasminogen, rather than the circulating
plasminogen, and hence less likely to release a large amount of circulating plasmin and causing systemic
fibrinogenolysis.
XXXIX. [S43]
a. Adverse effects of Thrombolytic Drugs
i. Bleeding complications
ii. GI and cerebral hemorrhages
iii. Re-thrombosis
b. Contraindications for Thrombolytic Drugs:
c. Absolute Contraindications: Suspected aortic dissection, active internal bleeding or uncontrollable external
bleeding (excluding menses), recent head trauma (< 2 weeks), intracranial neoplasms, history of proven
hemorrhagic stroke or cerebral infarction with 12 months, untreated diabetic hemorrhagic / proliferative
retinopathy, uncontrolled BP (>180/110 mmHg), etc.
d. Relative Contraindications: Pregnancy, traumatic prolonged CPR, anticoagulation or INR >1.8, bleeding
disorders, recent surgery (within 3 weeks), probable intracardiac thrombus (e.g. atrial fibrillation with mitral
stenosis), active peptic ulcer, etc.
[end: 56 min]