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The Mechanism for Hypotension with Nitroglycerine Use in Patients Taking Type 5 Phosphodiesterase Inhibitors (PDE5; Avanafil, Sildenafil, Tadalafil, Vardenafil)

Summary:

  • Patients with erectile dysfunction (ED) commonly have underlying coronary artery disease that may require use of nitroglycerin products (i.e. nitrates) to treat chest pain or angina.
  • Nitrates and type 5 phosphodiesterase inhibitors (i.e., avanafil (Stendra), sildenafil (Viagra); tadalafil (Cialis); vardenafil (Levitra) can both cause vasodilation of blood vessels.
  • PDE5 inhibitors interact with nitrates by decreasing the metabolism of nitric oxide induced activation of cGMP, thereby allowing more cGMP mediated smooth muscle relaxation or vasodilation.
  • When nitrates are given to patients who have taken a PDE5 inhibitor in the past 24 hrs for sildenafil and vardenafil and up to 36 hours for tadalafil, a significant drop in the blood pressure can occur.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers: 
Jon D. Herrington, PharmD, BCPS, BCOP and Donald S. Nuzum, PharmD, BCACP, CDE
Last Reviewed:
October 2015

Explanation

  • Nitroglycerin, regardless of the dosage form, is converted to nitric oxide (NO) once in the body.  It is commonly used in the treatment of angina (chest pain) in patients with underlying ischemic heart disease (IHD).  Since IHD can result in decreased coronary blood perfusion to the heart, the use of nitroglycerin can help vasodilate these vessels to increase coronary perfusion, thereby reducing the severity of angina.

    Nitric oxide causes vasodilation through a combination of cellular processes.  The first is by activation of guanylate cyclase, which promotes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).1,2 The increasing cGMP binds to regulatory binding sites for protein kinase G thereby activating the catalytic units that enable protein kinase G to reduce cytosolic Ca2+ levels needed for smooth muscle contraction within blood vessels.1,2  In addition, NO is also known to cause direct activation of Ca2+-dependent K+ channels resulting in a hyperpolarization and relaxation of vascular smooth muscle cells that allow for increased blood flow.3

                     Nitroglycerine and Type 5 Phosphodiesterase Inhibitor Drug Interaction and Hypotension 

    The problem with the co-administration of a type-5 phosphodiesterase (PDE5) inhibitor [i.e., sildenafil (Viagra); tadalafil (Cialis); vardenafil (Levitra)] with a nitrate has to do with their effects on cGMP.  Phosphodiesterase inhibitors are most commonly prescribed for the treatment of erectile dysfunction (ED) and work by selectively blocking PDE5, the enzyme necessary for the degradation of cGMP.4  The accumulation of cGMP in the corpus cavernosum of the penis results in the increased vasodilation necessary for an erection.4  Therefore when both nitrates and PDE5 inhibitors are administered closely together (within the past 24 hours for sildenafil and vardenafil and within the past 36 hours for tadalafil due to its longer half-life), the PDE5 inhibitor prevents the breakdown of NO mediated increases in cGMP.  This results in a greater effect of cGMP to cause a greater degree of vasodilation.  This degree of vasodilation can result in clinically significant reductions in blood pressure or hypotension.5  The most prominent example of this interaction is when patients taking PDE5 inhibitors for their ED are given nitrates in the emergency department for acute coronary syndrome with resultant drops in blood pressure.  This problem became significant enough that the American Heart Association published a position statement reminding providers to consider this interaction when using nitrates for this cardiac condition.6

    References:

    1. Lincoln TM, Cornwell TL.  Towards an understanding of the mechanism of action of cyclic AMP and cyclic GMP in smooth muscle relaxation.  Blood  Vessels 1991;28(1-3):129-37.
    2. Lincoln TM, Cornwell TL.  Intracellular cyclic GMP receptor proteins.  FASEB J 1993;7(2):328-38.
    3. Bolotina VM, Najibi S, Palacino JJ et al. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle.  Nature 1994;368(6474):850-853.
    4. Boolell M, Allen MJ, Ballard SA et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.  Int J Impot Res  1996;8(2):47-52.
    5. Webb DJ, Muirhead GJ, Wulff M et al. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina.  J Am Coll Cardiol 2000;36(1):25-31.
    6. Cheitlin MD, Hutter AM Jr, Brindis RG et al.  Use of sildenafil (Viagra) in patients with cardiovascular disease. Technology and Practice Executive Committee.  Circulation 1999;99(1):168-77.

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MESH Terms & Keywords

  • Nitroglycerin, NTG, PDE Inhibitors, Type 5 PDE Inhibitors, Sildenafil, Viagra, Vardenafil, Levitra, Tadalafil, Cialis, Avanafil, Stendra