Pharmacotherapeutics I - 2nd Pharm D

1. MYOCARDIAL INFARCTION

2. • Acute coronary syndromes (ACSs) is a term that includes all clinical
syndromes compatible with acute myocardial ischemia resulting from an
imbalance between myocardial oxygen demand and supply.
• In contrast to stable angina, an ACS results primarily from diminished
myocardial blood flow secondary to an occlusive or partially occlusive
coronary artery thrombus.
• ACSs are classified according to electrocardiographic changes into
 ST-segment-elevation ACS (ST-elevation MI [STEMI]
 Non-ST-segment-elevation ACS (non-ST-elevation MI [NSTEMI]
 unstable angina [UA]
• NSTEMI differs from UA in that ischemia is severe enough to produce
myocardial necrosis, resulting in the release of a detectable amount of
biochemical markers, mainly troponins T or I and creatine kinase (CK)
myocardial band (MB) from the necrotic myocytes, in the bloodstream.

4. ETIOLOGY
• A number of factors are directly responsible for the development and
progression of endothelial dysfunction and atherosclerosis, including
hypertension, age, male gender, tobacco use, diabetes, obesity, elevated
plasma homocysteine concentrations, and dyslipidemias.
PATHOPHYSIOLOGY
Rupture of atherosclerotic plaque
Following plaque rupture, a partially occlusive or completely occlusive thrombus,
a clot, forms on top of the ruptured plaque. The thrombogenic contents of the
plaque are exposed to blood elements.
Exposure of collagen and tissue factor induce platelet adhesion and activation,
which promote the release of adenosine diphosphate (ADP) and
thromboxan A2 (TXA2)
vasoconstriction and potentiate platelet activation

5. During platelet activation, a change in the conformation in the glycoprotein
(GP) IIb/IIIa surface receptors of platelets occurs that cross-links platelets
to each other through fibrinogen bridges. Other substances known to
promote platelet aggregation include serotonin, thrombin, and
epinephrine. Inclusion of platelets gives the clot a white appearance
A thrombus containing more platelets than fibrin, or a “white” clot,
generally produces an incomplete occlusion of the coronary lumen and is
more common in non-ST-segment-elevation ACS

6. Simultaneously, the extrinsic coagulation cascade pathway is activated as a
result of exposure of blood components to the thrombogenic lipid core
and endothelium, which are rich in tissue factor. This leads to the
production of thrombin (factor IIa), which converts fibrinogen to fibrin
through enzymatic activity. Fibrin stabilizes the clot and traps red blood
cells, which give the clot a red appearance.
In patients presenting with an ST-segment-elevation ACS, the vessel generally
is completely occluded by a “red” clot that contains larger amounts of
fibrin and red blood cells

7. COMPLICATIONS
• The most serious complication is cardiogenic shock
• Other complications that may result from MI are
 heart failure
 valvular dysfunction
 ventricular and atrial tachyarrhythmias
 bradycardia
 heart block
 pericarditis
 stroke secondary to left ventricular (LV) thrombus embolization
 venous thromboembolism
 LV freewall rupture.

10. BIOCHEMICAL MARKERS
• Troponins (troponin I or troponin T) are cardiac muscle proteins which are
released following myocardial cell damage and are highly sensitive and
specific for myocardial infarction.
• They are useful in diagnosing patients with ACS and for predicting
response to drug therapy; they are now key to the management of these
patients and have replaced cardiac enzymes such as creatinine kinase
(CK), aspartate transaminase (AST) and lactate dehydrogenase (LDH).
• Typically, blood is obtained from the patient at least three times, once in
the emergency department and two additional times over the next 12 to
24 hours, in order to measure troponin and CK MB.
• While troponins and CK MB appear in the blood within 6 hours of
infarction, troponins stay elevated in the blood for up to 10 days, whereas
CK MB returns to normal values within 48 hours.

11. TREATMENT OF ST ELEVATION MYOCARDIAL INFARCTION (STEMI)
Treatment of STEMI may be divided into three categories:
• provide immediate care to alleviate pain, prevent deterioration and improve
cardiac function;
• manage complications, notably heart failure and arrhythmias;
• prevent further infarction or death (secondary prophylaxis).
IMMEDIATE CARE TO ALLEVIATE PAIN, PREVENT DETERIORATION
AND IMPROVE CARDIAC FUNCTION
• PAIN RELIEF : Patients with suspected STEMI should receive sublingual GTN
under the tongue, oxygen administered and intravenous access established
immediately.
• If sublingual GTN fails to relieve the chest pain, intravenous morphine may be
administered together with an antiemetic such as prochlorperazine or
metoclopamide.

12. • ANTIPLATELET THERAPY: An aspirin tablet chewed as soon as possible
after the infarct and followed by a daily dose for at least 1 month has been
shown to reduce mortality and morbidity.
• Clopidogrel, given in addition to aspirin, can further improve coronary
artery blood flow.
RESTORING CORONARY FLOW AND MYOCARDIAL TISSUE PERFUSION
• Treatment within 1 h has been found to be particularly advantageous,
although difficult to achieve.
• Several studies indicate that giving fibrinolytics an average of 30–60 min
earlier can save 15 lives per 1000 treated.

13. • FIBRINOLYTICS : Fibrinolytic agents fall into two categories:
 fibrin specific (alteplase, tenecteplase and reteplase)
 fibrin non-specific (streptokinase).
• Fast injection of fibrin-specific agents is better than slower infusion of
streptokinase, especially in younger patients with anterior infarcts.
• Tenecteplase and reteplase have the advantage that they can be
administered by bolus injection, which facilitates pre-hospital
administration and reduces errors.
• All fibrinolytics cause haemorrhage, which may present as a stroke or a
gastro-intestinal bleed, and there is an increased risk with regimens that
use intravenous heparin.
• Streptokinase induces cross-reacting antibodies which reduce its potency
and may cause an anaphylactoid response.

16. • PERCUTANEOUS CORONARY INTERVENTION : The introduction of primary
PCI (angioplasty and/or stent insertion without prior or concomitant
fibrinolytic therapy) has demonstrated superiority to fibrinolysis.
• PCI involves the passing of a catheter via the femoral or radial artery and
aorta into the coronary vasculature under radio-contrast guidance.
Inflation of a balloon at the end of the catheter in the area of the
atheromatous plaques opens the lumen of the artery.
• ANTIPLATELET AND ANTICOAGULANT THERAPY. After stent insertion
there is a short-term risk of thrombus formation until the endothelial
lining of the blood vessel has been re-established.
• The combination of clopidogrel (600 mg initiated pre-procedure and 75
mg daily thereafter) and aspirin has been shown to reduce the risk of
myocardial infarction and need for reperfusion therapy and decrease the
length of hospital stay.

17. • Patients undergoing primary PCI should receive aspirin and clopidogrel as early as
possible. The patients should receive 300 mg of aspirin and 600 mg of
clopidogrel.
• Heparin is routinely administered during the PCI procedure and is titrated to
maintain an activated clotting time (ACT) of 250–350 s.
• Glycoprotein IIb/IIIa receptor antagonists, particularly abciximab, have been
shown to reduce mortality if used during the procedure. These are used in
combination with heparin, and a lower ACT (200–250 s) is targeted to reduce
bleeding complications.
• Bivalirudin, a direct thrombin inhibitor, has demonstrated less bleeding
compared to abciximab and may be useful in those at risk of increased bleeding.
• Intracoronary administration of vasodilators such as adenosine, verapamil,
nicorandil, papaverine, and nitroprusside during and after primary PCI has been
shown to improve flow in the infarct-related coronary artery and myocardial
perfusion, and/or to reduce infarct size.

18. MANAGEMENT OF COMPLICATIONS
Heart failure.
• It should be managed with oxygen, intravenous furosemide and nitrates.
• More severe failure or cardiogenic shock (tissue hypoperfusion resulting
from cardiac failure with symptoms of hypotension, peripheral
vasoconstriction and diminished pulses, decreased urine output and
decreased mental status) should be treated with inotropes and/or inter-
aortic balloon pumps to maintain the systolic blood pressure above
90 mmHg.
Arrhythmias
• The early administration of an intravenous β-blocker was shown to limit
infarct size and reduce mortality from early cardiac events.

19. • If β-blocker is contraindicated because of respiratory or vascular
disorders, verapamil may be used.
• Diltiazem is less effective but may be used as an alternative.
• Magnesium infusions are used to correct low serum magnesium levels if
cardiac arrhythmias are present.
• Sinus bradycardia and heart block may also occur after a myocardial
infarction and patients may require temporary or permanent pacemaker
insertion.
Blood glucose
• Patients with a myocardial infarction are often found to have high serum
and urinary glucose levels, usually described as a stress response.
• In these patients, an intensive insulin regimen, both during admission
and for 3 months after, was found to save lives.

20. PREVENTION OF FURTHER INFARCTION or DEATH
(SECONDARY PROPHYLAXIS)
Lipid-lowering agents.
• Patients with established CHD should be treated to ensure LDL-C is less
than 2 mmol/L and total cholesterol less than 4 mmol/L.
• In patients with AMI or high-risk NSTEMI, there was a reduction in the
complications when patients were treated with high intensity statin
(Atorvastatin 80 mg) compared to standard statin therapy.
Beta-Blockers.
• Long-term use of a β-blocker has been shown in several studies to
decrease mortality in patients in whom there is no contraindication.

21. Angiotensin-converting enzyme inhibitors
• Patients were given an ACE inhibitor for 4–6 weeks and treatment continued
in patients with signs or symptoms of heart failure or left ventricular
dysfunction.
• Angiotensin receptor blockers are probably suitable in patients who cannot
tolerate an ACE inhibitor.
Eplerenone
• In patients with heart failure, post-AMI, an improvement in survival and
decreased cardiovascular mortality and hospitalisation was seen in those
taking the aldosterone antagonist, Eplerenone.
• Serious hyperkalemia occurred more frequently in the eplerenone and
monitoring of serum potassium is warranted when used in practice.

22. Antidepressants
• There is concern about the potential for older antidepressants, such as
tricyclic antidepressants, to increase the QT interval and cause
arrhythmias.
• Newer antidepressants are less prone to cause these arrhythmias and
selective serotonin receptor inhibitors (SSRIs) are preferred.
Nitrates
• Nitrates improve collateral blood flow and aid reperfusion, thus limiting
infarct size and preserving functional tissue.
• Sublingual nitrates may be given for immediate pain relief, and the use of
intravenous or buccal nitrates can be considered in patients whose
infarction pain does not resolve rapidly or who develop ventricular failure.

23. Anticoagulants and antiplatelets
• Anticoagulation with warfarin is not generally recommended following a
myocardial Infarction.
• Aspirin does not have the same need for expensive and time-consuming
follow-up and monitoring as warfarin, and is associated with fewer drug
interactions.
• Clopidogrel has been shown to be beneficial, in addition to aspirin, in
patients who have had a myocardial infarction.
• For the patients who receive a stent , the combination of aspirin and
clopidogrel for a year or longer is now prescribed.

24. TREATMENT OF NON-ST ELEVATION ACUTE CORONARY SYNDROMES
Antiplatelet and anticoagulant drugs
• In the early 1990s, unfractionated heparin, when combined with aspirin
showed a reduction in death and subsequent myocardial infarction compared
with aspirin alone.
• The use of the low molecular weight heparin (LMWH), enoxaparin,
subsequently demonstrated superiority over unfractionated heparin, with
both usually continued for 48 h, or until chest pain resolved or discharge.
• Clopidogrel is given as a loading dose of 300 mg followed by 75 mg daily in
combination with aspirin and heparin, reduced the combined end point of
death, myocardial infarction and revascularisation in all patients with NSTEMI.
• Clopidogrel needs to be continued for 12 months but should be stopped 5–7
days before any major surgery to reduce the risk of bleeding.

25. • Glycoprotein IIb/IIIa inhibitors bind to the IIb/IIIa receptors on platelets
and prevent cross-linking of platelets by fibrinogen.
• There are three classes of these agents:
 Murinehuman chimeric antibodies,, abciximab;
 Synthetic peptides, eptifibatide; and
 Non-peptide synthetics, tirofiban.
• In high-risk patients undergoing PCI and receiving background heparin,
triple antiplatelet therapy (aspirin, clopidogrel and a glycoprotein IIb/IIIa
inhibitors) has been shown to be superior to standard dose dual-
antiplatelet therapy (aspirin and clopidogrel) particularly in troponin
positive individuals.

26. • Currently, all patients with a likely or definite diagnosis of NSTEMI should
receive a loading dose of aspirin 300 mg
• Patients undergoing PCI intervention should have a higher loading dose of
600 mg of clopidogrel or 60 mg of prasugrel, unless contraindicated, to
reduce events during and after PCI.
• Clopidogrel is often given as 300 mg on admission and a further 300 mg
when the decision to intervene is made.
• All patients should receive heparin, bivalirudin or fondaparinux.
• Unfractionated heparin is preferred for patients with compromised renal
function.
• Fondaparinux, a synthetic pentasaccharide factor Xa inhibitor which has
predictable and sustained anticoagulation with fixed dose, once-a-day
subcutaneous administration, causes less bleeding than enoxaparin, an
LMWH.

28. Anti-ischaemic drugs
• The use of both β-blockers and nitrates in the management of patients
with NSTEMI is based on studies of their use in stable angina and AMI.
Statins
• They are usually started on admission if the diagnosis of CAD is definite,
independent of the patient‘s cholesterol level.
• Treatment should aim to achieve total cholesterol of <4 mmol/L and an
LDL-C of <2 mmol/L.