Sildenafil, commercially known as Viagra, is the most effective first-line treatment for erectile disfunction (ED) in the UK (Chamsi-Pasha, 2001; National Institute for Health and Care Excellence (NICE), 2014a). ED is estimated to affect more than 100 million men worldwide (Chamsi-Pasha, 2001), with one in four patients seeking help for the onset of ED being younger than 40 years (Capogrosso et al, 2013). However, its prevalence varies greatly. It is estimated to affect more than 30% of the population subgroup of men aged between 30 and 70 years worldwide (Feldman, 1994). A German study identified 19.2% of men aged between 30 and 80 years with this condition (Braun et al, 2000). This data should be treated with caution however, as it could potentially be an underestimation. For example, there are men who, for various reasons (e.g. embarrassment), do not report ED issues.
Currently, there is no UK-wide study on the prevalence of ED. Therefore, guidelines, such as NICE (2014a), are based on these reports. Although ED cannot be cured, it can be treated successfully with an oral selective phosphodiesterase-5 (PDE5) inhibitor such as sildenafil (Goldman et al, 1998; NICE, 2014a). This is usually the first-line treatment option irrespective of the cause for this condition (NICE, 2014a; 2014b). Risk factors for ED such as age, hypertension, smoking, diabetes mellitus, and hypercholesterolaemia can overlap with those for stable angina, acute coronary syndrome (ACS), and heart failure. Therefore, men with ED are usually in the same group of patients that have at least one of these conditions (Jackson, 2000; NICE, 2014b).
Cardiac chest pain
Glyceryl trinitrate (GTN) is a nitric oxide (NO) donor, which can be used to provide immediate relief for cardiac chest pain, and lower blood pressure. Cardiac chest pain is usually as a result of stable or unstable angina, myocardial infarctions, or acute pulmonary oedema (Joint Royal Colleges Ambulance Liaison Committee (JRCALC), 2016). Angina—the most common reason for administration of GTN—is often experienced as a sudden pain or discomfort in the chest area or radiating pain in the arms, neck or jaw area (Zitkus, 2010).
This pain or discomfort can manifest as tightness in the chest, a crushing sensation in the chest, or a heavy or dull ache due to an imbalance between oxygen demand and supply to the heart muscles (Zitkus, 2010). This is caused by coronary heart disease—the narrowing and obstruction of coronary arteries by atherosclerosis—resulting in reduced blood flow to the heart and, consequently, ischaemia and even infarction (Jackson, 2000).
In the UK, 320 000 new angina patients visit their GPs every year, and an estimated 174 000 are males (Ghandi et al, 1995; Rayner et al, 2001). In 2015/16, 79 686 inpatients in UK NHS hospitals were admitted for angina and 60% of these were males (British Heart Foundation (BHF), 2017).
GTN treatment aims to relieve the painful symptoms of cardiac ischaemia and prevent future episodes, as well as possible myocardial infarctions (NICE, 2011). In emergency situations, the vasodilatory effects of GTN are essential to relieve coronary spasm through dilation of the coronary arteries, and of systemic veins, resulting in reduced pre-load and overall reduction in blood pressure (Oliver et al, 2009; JRCALC, 2016).
The drugs at work
An important mediator of cardiovascular function is NO, because it induces relaxation of the smooth muscle cells, resulting in vasodilation. Over-stimulation of NO receptors through the administration of NO can cause a significant drop in systemic blood pressure, resulting in hypotension (Webb et al, 2000). Administration of GTN results in NO production within tissues, and immediate vasodilation (Parker and Parker, 1998; Webb et al, 2000).
Normally, penile erection is regulated by the neurotransmitter NO, which produces cyclic guanosine monophosphate (cGMP) (Jeremy et al, 1997; Moreland et al, 1998). High cGMP levels relax the smooth muscle in the corpus cavernosum of the penis, and results in its engorgement with blood and an erection (Figure 1; Figure 2) (Jeremy et al, 1997; Moreland et al, 1998). PDE-5 is found in high concentrations in the corpus cavernosum, where it is responsible for the degradation of cGMP. Sildenafil is one of three such oral PDE-5 inhibitors. Sildenafil inhibits PDE-5 action, resulting in accumulation of cGMP and an erection (Webb et al, 2000). After administration of sildenafil alone, blood pressure is reduced minimally (Webb et al, 2000; Greenland, 2006), and not as strongly as with GTN (Parker and Parker, 1998; Greenland, 2006).
Both sildenafil and GTN act on the NO-cGMP pathway but they do this at different points. Therefore, co-administration has a high chance of causing a dramatic drop in blood pressure (Figure 1; Figure 2). In a double-blind, placebo-controlled, crossover study, Webb et al (1999) found that sildenafil more than quadruples the hypotensive effects of GTN, resulting in potentially fatal consequences.
Sildenafil prevents the degradation of cGMP, and so the activity of GTN on the vasculature is amplified. Sildenafil alone has limited effects on the cardiovascular system as it has low affinity for the PDE forms important for cardiovascular regulation. Furthermore, because of this serious hypotensive effect, the manufacturers have strictly contraindicated the use of sildenafil in patients who are currently using organic nitrates in any form, including those inhaled for recreational use (e.g amyl nitrite, butyl nitrate, also known as ‘poppers’ and nitric oxide known as ‘laughing gas’) (Taylor et al, 2004; Greenland, 2006).
Interval time
Current guidelines state that a 24-hour time interval between the administration of sildenafil and GTN is essential to avoid complications (JRCALC, 2016). However, a recent double-blind, placebo-controlled, randomised, crossover study by Oliver et al (2009) showed that the plasma half-life of sildenafil is 3–5 hours. It demonstrated that the dangerous side-effects of co-administration of both drugs are only present in healthy males for up to 1 hour, and in men with angina for 6–8 hours, after which the effects are only additive without hypotension.
Additionally, in another trial, Crowley et al (2004) evidenced that in healthy patients, the haemodynamic interaction between sildenafil and GTN only lasted up to 4 hours, with a significantly greater decrease in blood pressure seen at 1 hour compared to those patients who were administered a placebo instead of GTN.
Asking the awkward questions
Contraindications for paramedics when administering GTN to patients include hypotension, unconsciousness, and sildenafil usage within the past 24 hours (JRCALC, 2016). The latter obfuscates the work of paramedics who must respond to emergencies and, in certain cases, it is difficult to obtain a detailed patient history. There may be some physical barriers, but there are likely some non-physical barriers, especially with this topic. Patients may feel too embarrassed to volunteer that they have taken sildenafil unless directly asked (Jackson et al, 2005). Several studies including Boyle (2007), Blaber and Harris (2011) and Chao and Hwang (2013) have shown that patients often do not want to admit to having used sildenafil, even if they are experiencing emergency complications. This is even more so the case if the patients' partners are present.
Paramedics therefore must deal with the question very sensitively, ensuring they provide the necessary environment to facilitate disclosing its use. This may be managed by asking the patient privately without the presence of family members, their partner or bystanders (Boyle, 2007), and by thoroughly explaining the relevance of the question and the adverse effect on the patient's health should they be co-administered.
The author of this article argues that while some clinicians may feel awkward asking a patient if they have had sildenafil within the last 24 hours, the life-threatening hypotension caused by GTN and sildenafil interacting can easily be avoided.
Greenland (2006) reports that the patient's health should take priority over any embarrassment or awkwardness that may occur. A paramedic not asking this question would go against their regulatory bodies' standards of proficiency and standards of conduct, performance and ethics (Health and Care Professions Council (HCPC), 2008; 2014). There is no justification for not checking with a patient the relevance of this contraindication. A paramedic should use his or her interpersonal and communication skills, and adapt them to meet the circumstances—thus ensuring the best care is given to the patient at all times.
Conclusion
Paramedics who respond to emergency situations need to be aware of the potentially fatal hypotensive effect of administering GTN to patients who have had sildenafil within the last 24 hours. This severe consequence of co-administration is caused by both drugs acting at different levels of the NO-cGMP pathway leading to dramatic vasodilation and hypotension, which can have a fatal outcome. Additionally, the current article has highlighted the possible occurrence of this adverse reaction, as a result of recreational use of other forms of nitrate.
The author acknowledges that available evidence suggests that the dangerous side-effects of co-administration of both GTN and sildenafil are only present for up to 8 hours. Therefore, the author recommends that further research is conducted into this topic to see whether the current guidance around the 24-hour time frame of co-administration is too strict, and can be relaxed in line with the available evidence.
It is of paramount importance that paramedics and all other health professionals who administer GTN are aware of the interaction with sildenafil. They must ensure they ask their male patients whether or not they have had sildenafil or similar drugs within the past 24 hours before administering GTN. While it is recognised that there may be some social, cultural and ethical barriers in place when asking this question, these cannot prevent the paramedic from doing so. Paramedics should ensure that the appropriate environment is available to facilitate a reliable answer being given. Doing so will allow for safe practice, minimising any adverse consequences, and ensuring the best care for the patient.