Prescriptions that Promote and Pharmaceuticals that Prevent Ischemic Preconditioning

Take Away Message:

Commonly used prescription medicines like the diabetic drug family of sulfonylureas like glyburide and glibenclamide, the asthma drug aminophylline, and the opioid reversal agent naloxone can worsen the outcome of a heart attack or stroke by interfering with ischemic preconditioning.

Review of Ischemic Preconditioning (IPC)

What is Ischemic Preconditioning? is an introduction to the subject of IPC. IPC is a method to increase the resistance of the different body organs against ischemia. Ischemia occurs when blood and oxygen supply is not enough for an organ to operate. It is the mechanism of injury in heart attacks and strokes.

Many studies have shown that preconditioning any organ can result in fewer complications and increased survival.

Cellular Mechanisms of Ischemic Preconditioning

To understand the effects of different medications on IPC, it helps to know the many cellular components that have to work together to make it possible. They are the bradykinin, adenosine receptors, mitochondrial potassium ATP channels, heat shock proteins, antioxidant enzymes, and opiate receptors.

Prescriptions that Promote Ischemic Preconditioning

Adenosine is an intravenous drug that is commonly used in the emergency room to convert a very rapid heart rate during supraventricular tachycardia back to a normal rhythm. It works on the adenosine receptors.

Angiotensin-converting enzyme inhibitors or ACEI like lisinopril, captopril, and are popular drugs for diabetes and hypertension. The mechanism is possibly by inhibition of bradykinin degradation leading to enhanced B2-bradykinin receptor activation. ACEI are well recommended for patients with heart failure. Its IPC promoting properties may also be another reason why it works very well in heart failure patients.

Morphine and other opiates like methadone act on the opiate receptors and facilitate IPC. For a long time, morphine has been indicated in patients having a heart attack and in severe pain. It alters the blood flow of the body, reducing the work of the heart, but it is only known now recently that it can also facilitate IPC.

Methadone intravenously 5 has been used for ischemic preconditioning, but it carries the risk of the deadly arrhythmia called prolonged Q-T syndrome. In this light, this website does not promote starting or increasing the dose of opiates to pursue IPC.

Drugs that Destroy Ischemic Preconditioning

The following medications have been shown to lead to worse outcomes in myocardial infarctions.

Sulfonylureas like Glyburide, Glibenclamide, and glipizide, are commonly used for diabetes. It has been known that diabetic patients on oral hypoglycemic agents have adverse outcomes after a heart attack compared to diabetics treated with diet alone (9) or with insulin (10). Sulfonylureas oppose the mitochondrial potassium ATP channels leading to worse heart attack outcomes in diabetic patients.

Aminophylline is a commonly used drug before for asthma. It blocks adenosine receptors.

Bamiphylline another drug for asthma that is sold in Italy. It also blocks adenosine receptors.

Naloxone is a drug given to counteract the effect of narcotics. Commonly used in opiate abusers who are found blue and not breathing because of the depressive actions of opiates on breathing. The body also makes its own opiates called endorphins that also promote IPC. Naloxone can block both exogenous and endogenously produced endorphins. 

Phentolamine is used for hypertension and hypertensive emergencies. It also blocks the adenosine receptors.

Parting Thoughts

If you see your medication as one of the drugs that can prevent ischemic preconditioning, don’t stop it yourself. Have a talk with your doctor if there are alternatives. The lengthy references below are listed as the basis of this article.

Further Readings:

1. What is Ischemic Preconditioning? 
2. High-Intensity Interval Training can Activate Ischemic Preconditioning
3. What is Insulin Resistance?
4. Hyperinsulinemia
5. What is the Goal of Diabetes Treatment?
6. I’m Only Pre-Diabetic, So I’m Still OK, Right?
7. Osteoarthritis and Metabolic Syndrome
8. Gout and Metabolic Syndrome
9. Psoriasis and Metabolic Syndrome
10. Skin Signs of Secret Sickness

References:

1. Fabrizio Tomai, Filippo Crea, Luigi Chiariello, and Pier A. Gioffrè. Ischemic Preconditioning in Humans Models, Mediators, and Clinical Relevance
   Originally published3 Aug 1999https://doi.org/10.1161/01.CIR.100.5.559Circulation. 1999;100:559–563
2. M. J. Claeys, C. J. Vrints, J. M. Bosmans, V. M. Conraads, J. P. Snoeck, Aminophylline inhibits adaptation to ischaemia during angioplasty Role of adenosine in ischaemic preconditioning, European Heart Journal, Volume 17, Issue 4, April 1996, Pages 539–544, https://doi.org/10.1093/oxfordjournals.eurheartj.a014906
3. F. Tomai, F. Crea, A. Gaspardone, F. Versaci, R. De Paulis, P. Polisca, L. Chiariello, P. A. Gioffrà, Effects of A1 adenosine receptor blockade by bamiphylline on ischaemic preconditioning during coronary angioplasty, European Heart Journal, Volume 17, Issue 6, June 1996, Pages 846–853, https://doi.org/10.1093/oxfordjournals.eurheartj.a014965
4. Tomai F, Crea F, Gaspardone A, Versaci F, De Paulis R, Penta de Peppo A, Chiariello L, Gioffrè PA. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation.1994; 90:700–705.
5. Tomai F, Crea F, Gaspardone A, Versaci F, Ghini AS, De Paulis R, Chiariello L, Gioffrè PA. Phentolamine prevents adaptation to ischemia during coronary angioplasty. Role of α-adrenergic receptors in ischemic preconditioning. Circulation.1997; 96:2171–2177.
6. Xenopoulos NP, Leesar M, Bolli R. Morphine mimics ischemic preconditioning in human myocardium during PTCA. J Am Coll Cardiol. 1998;31(suppl A):65A. Abstract.
7. Joseph C. ClevelandJr, Daniel R. Meldrum, Brian S. Cain, Anirban Banerjee, and Alden H. Harken. Oral Sulfonylurea Hypoglycemic Agents Prevent Ischemic Preconditioning in Human Myocardium. Two Paradoxes Revisited
   Originally published1 Jul 1997https://doi.org/10.1161/01.CIR.96.1.29Circulation. 1997;96:29–32
8. Morris SD, Yellon DM. Angiotensin-converting enzyme inhibitors potentiate preconditioning through bradykinin B2 receptor activation in human heart. J Am Coll Cardiol.1997; 29:1599–1606
9. Klimt CR, Knatterud GL, Meinert CL, Prout TE (UDGP). A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes.1970; 19:747-830.
10. Rytter L, Troelsen S, Beck-Nielsen H. Prevalence and mortality of acute myocardial infarction in patients with diabetes. Diabetes Care.1985; 8:230-234.

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