Nitrates enhance coronary flow by coronary vasodilation and reduce ventricular preload by systemic venodilation. The venodilation diminishes venous return to the heart, reducing ventricular volume and pressure, and thus a reduction in ventricular preload occurs. The use of nitrates is not associated with reduction in mortality.

Nitrates are initially administered sublingually (0.4 mg nitroglycerin sublingual tablet) followed by close observation for improvement in symptoms or change in hemodynamics. If an initial dose is well tolerated and appears of benefit, further nitrates should be administered, with monitoring of vital signs. Marked hypotension (systolic blood pressure <90 mmHg), bradycardia, and suspected right ventricular infarction are contraindications to nitroglycerin [33].

If chest pain persists or recurs, intravenous nitroglycerin may help to control ischemic pain; this requires close monitoring of blood pressure. Intravenous nitroglycerin should be initiated at 5–10 μg/min and gradually increased with a goal of 10–30 % reduction of systolic blood pressure and/or relief of chest pain. Long-acting nitrate preparations should not be used. Moreover, nitrates should not be given within 24 h of use of phosphodiesterase (PDE) inhibitors (e.g., sildenafil) because the combination may result in severe systemic vasodilation and life-threatening hypotension.

Another important aspect in the use of nitrates is nitrate tolerance. Although this is most commonly observed with chronic nitrate therapy for chronic angina, it remains a characteristic of nitrate therapy in general. The mechanism by which nitrate tolerance occurs is not fully understood. One proposed mechanism is thought to be by reduction of nitric oxide availability via inhibiting conversion of nitroglycerin to 1,2-glyceryl dinitrate by directly impairing the function of mitochondrial aldehyde dehydrogenase-2 (mtALDH) enzyme [34]. Another theory postulates that nitrate tolerance is secondary to the reduced bioactivity of nitric oxide, supported by findings in animal models that exhibited tolerance to nitrates despite high levels of nitric oxide [35].

Morphine is the drug of choice to treat pain not relieved by maximally tolerated anti-ischemic therapy associated with STEMI. An initial dose of 2–4 mg as an intravenous bolus is given with increments of 2–4 mg repeated at 5–10 min intervals. Morphine may cause hypotension and respiratory depression; these side effects preclude further use of the drug.

Morphine acts by decreasing anxiety and restlessness triggered by activation of the autonomic nervous system, suppression of which results in reduction of myocardial oxygen demand. In patients with pulmonary edema, morphine has additional benefits of peripheral arterial and venous dilatation, reduced work of breathing, and slowing of heart rate due to increased vagal tone. Nausea and vomiting may be troublesome side effects of large doses of morphine and can be treated with a phenothiazine. In high doses, morphine overdose may be problematic, and classic signs of opioid intoxication may develop including depressed mental status, decreased respiratory rate, decreased bowel sounds, and pinpoint miotic constricted pupils.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with increased risk of adverse cardiovascular events in patients with STEMI and should be avoided throughout the hospitalization for STEMI [36, 37].

Heparin use is a class I indication for STEMI patients who will undergo primary PCI or fibrinolytic therapy [30]. Unfractionated heparin binds to antithrombin III and inhibits the activation of thrombin and therefore lacks the ability to inhibit thrombin that is clot bound. It has a molecular weight range of 12,000–30,000 Da. The usual dose is an intravenous initial bolus of 60 U/kg (4,000 U maximum) followed by a 12 U/kg/h (1,000 U/h maximum) infusion, given promptly, with a goal-activated partial thromboplastin time (aPTT) of 1.5–2.0 times normal. A disadvantage of unfractionated heparin is its unpredictable anticoagulation effects, due to variability in protein binding and the time delay until therapeutic levels are achieved. Unfractionated heparin use in myocardial infarction has an abundance of data and usually is part of the standard treatment arm in trials comparing newer agents or combinations of antithrombotic regimens. It currently can be used in all three-treatment strategies: to support PCI, fibrinolytics [38], or medical management. In patients receiving fibrinolytic therapy and aspirin, the addition of UFH is of proven benefit in patients treated with fibrin-specific thrombolytics, which are now preferred [39]. UFH may also be of benefit for patients receiving streptokinase who are at high risk for systemic thromboembolism. Thus, all patients with STEMI should be treated with anticoagulant therapy regardless of choice of fibrinolytic agent.

LMWHs are glycosaminoglycans with chains of residues of D-glucosamine and uronic acid in an alternate fashion. Compared to UFH, these agents have a molecular weight that ranges from 4,000 to 6,000 Da. The usual dose is an intravenous bolus of 30 mg of enoxaparin, followed by 1 mg/kg subcutaneous injection every 12 h. Unlike unfractionated heparin, LMWHs are stronger inhibitors of factor Xa than thrombin; therefore, the anticoagulation effect cannot be measured routinely. The advantages of LMWHs are a longer half-life, better bioavailability, and dose-independent clearance, resulting in more rapid predictable anticoagulation compared to unfractionated heparin. However, LMWH is associated with increased risk of major and minor bleeding in the clinical trials [40–43]. Due to this fact and given the lack of superiority to unfractionated heparin, many experts do not use LMWH in patients undergoing primary PCI and choose unfractionated heparin or bivalirudin. In current practice guidelines, LMWH with doses adjusted to age, weight, and renal function can be used as an adjunct preferentially in those patients undergoing therapy with fibrinolysis [30].

Neither unfractionated heparin nor LMWH crosses the placenta and thus does not result in fetal anticoagulation. In general, the use of LMWH is preferred over UFH due to the efficacy and ease of administration. However, UFH appears to be a more appropriate alternative to LMWH when more control of anticoagulation is needed (e.g., near the time of delivery) or patients with severe renal insufficiency [44, 45]. Current practice guidelines do not specify use of one form of heparin over the other, mostly due to lack of data from clinical trials that target this patient population.

These agents bind directly to thrombin and can be used safely in patients with previous heparin-induced thrombocytopenia. Both Hirulog and bivalirudin were compared to heparin in STEMI. In patients undergoing reperfusion by fibrinolysis, direct thrombin inhibitors significantly reduced recurrence of MI but did not reduce mortality and had significantly higher rates of major bleeding [43]. When used in patients undergoing reperfusion by PCI, bivalirudin had significantly lower major bleeding and was associated with a significant reduction of 30-day and 1-year mortality; however, it was associated with increased stent thrombosis compared to heparin and glycoprotein IIb/IIIa receptor blockers [46].

Administration of fondaparinux, a factor Xa inhibitor, was evaluated in STEMI clinical trials compared to placebo, unfractionated heparin, or enoxaparin. The use of fondaparinux is reasonable in patients with STEMI undergoing reperfusion with PCI, although concomitant unfractionated heparin is recommended to prevent occurrence of guide catheter clots and stent thrombosis [47, 48].