Myocardial ischemia treatment

The major goals for the treatment of ischemic heart disease are to prevent acute coronary syndromes and death, alleviate acute symptoms of myocardial ischemia, prevent recurrent symptoms of myocardial ischemia, and avoid or minimize adverse treatment effects. 

Robertson, R.M. and Robertson, D., Drugs used for the treatment of myocardial ischemia, in Goodman and Gilman s The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J.G. and Limbird, L.E., Eds., McGraw-Hill, New York, 1996, chap. 32. 

While the role of PHD inhibitors in the treatment of anemia is now validated, therapeutic validation is less certain in other HIF-associated pathologies such as wound healing, ulcerative colitis, therapeutic angiogenesis, and treatment of acute ischemic events such as myocardial ischemia and stroke. All of these indications are supported by a compelling array of in vitro and in vivo preclinical studies but their utility in the clinical setting remains to be evaluated and represents exciting possibilities for the future of small-molecule inhibitors of PHD enzymes. 

Molsidomine (8.159, Fig. 8.18), a very special example of a carbamate prodrug that acts by vascular smooth muscle relaxation, is an anti-angina agent effective mainly in the treatment of myocardial ischemia [207], Molsidomine undergoes enzymatic hydrolysis in the liver to form the imine 8.160 (Fig. 8.18) [208]. This metabolite is inactive and unstable, breaking down spontaneously to the A-nitroso secondary metabolite known as Sinl A (8.161, Fig. 8.18). The latter was found to be active, but there are reasons to believe that it acts by releasing nitrogen monoxide in the form of nitroxyl (HNO), which dissociates to the nitroxide ion NO, i. e., the reduced form of NO. 

Myocardial ischemia and infarction cause abnorma myocardial metabolism, decreased left ventricular (LV) systolic function, diastolic dysfunction, congestive heart failure, and decreased survival. Consequently, revascularization techniques, either surgical or catheter based, have become integral to treatment of severe ischemic heart disease. 

Duan HF, Wu CT, Wu DL, Lu Y, Liu HJ, Ha XQ, Zhang QW, Wang H, Jia XX, Wang LS. Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Mol Ther 2003 8 467-474. 

Arterial thrombi (white thrombi) are formed initially from both platelets and fibrin in medium-sized arteries on the basis of atherosclerosis. These thrombi can lead to symptoms of, among others, myocardial ischemia and myocardial infarction. The treatment is primarily aimed at prevention of thrombus formation with platelet aggregation inhibitors. For the treatment of myocardial infarction thrombolytic agents are used and for secondary prevention both oral anticoagulants and anti-platelet drugs are employed. 

Since diazoxide is not often used for long-term treatment, toxicities associated with chronic use are rare. The chief concern is the side effects associated with the increased workload on the heart, which may precipitate myocardial ischemia and Na+ and water retention. These undesirable effects can be controlled by concurrent therapy with a (3-blocker and a diuretic. 

Phentolamine is a potent competitive antagonist at both K and k2 receptors (Table 10-1). Phentolamine reduces peripheral resistance through blockade of K receptors and possibly k2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic k2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and Hi and H2 histamine receptors. Phentolamine s principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States. 

The treatment of established angina and other manifestations of myocardial ischemia includes the corrective measures previously described as well as treatment to prevent or relieve symptoms. Treatment of symptoms is based on reduction of myocardial oxygen... 

The relief produced by intravenous morphine in dyspnea from pulmonary edema associated with left ventricular heart failure is remarkable. Proposed mechanisms include reduced anxiety (perception of shortness of breath), and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). However, if respiratory depression is a problem, furosemide may be preferred for the treatment of pulmonary edema. On the other hand, morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema. 

Two women developed myocardial ischemia during treatment with gemeprost for termination of pregnancy (3). 

Dose-related adverse effects of vasopressin include skin pallor, hypertension, cardiac dysrhythmias, and myocardial ischemia or infarction treatment has to be stopped in 20-30% of patients because of these effects (3). 

Michel T. Treatment of myocardial ischemia. In Brunton L, et al, eds. The Pharmacologic Basis of Therapeutics. 10th ed. New York McGraw-Hill 2006. 

Abbreviations ACS. acute coronary syndrome AECG. ambulatory electrocardiogram FLORIDA, fluvastatin on risk diminishment after acute myocardial infarction Ml. myocardial infarction MIRACL, myocardial ischemia reduction with aggressive cholesterol lowering nfMI. nonfatal myocardial infarction PACT, pravastatin in acute coronary treatment PROVE-IT TIMI 22. pravastatin or atoivastatin evaluation and infection therapy—thrombolysis in myocardial infarction 22 UAP, unstable anginapectoris. 

Hedman M, Hartikainen J, Syvanne M, et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia. Circulation 2003 107 2677-2683. 

Proarrhythmic effects of antiarrhythmic drugs In the Cardiac Arrhythmia Suppression Trial (CAST) treatment with encainide and flecainide, two class IC antiarrhythmic agents, successfully prevented ventricular ectopic beats in patients who had myocardial infarction. However, continued therapy with either drug was associated with a two- to three-fold increase in death due to cardiac arrhythmias. Similar results were reported for moricizine. Increased death was probably due to drug-induced fatal arrhythmias triggered by recurrent myocardial ischemia. 

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