Continuing Education Activity

Isosorbide is a medication used in the treatment and prevention of angina pectoris in patients with coronary heart disease. It is in the nitrate class of drugs. This activity describes the indications, action, and contraindications for isosorbide as a valuable agent in the treatment of angina pectoris due to coronary artery disease, heart failure with reduced ejection fraction, and achalasia. This activity will highlight the mechanism of action, adverse event profile, off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions pertinent for members of the health care team in the management of patients with angina pectoris due to coronary artery disease and related conditions.

Objectives:

• Identify the mechanism of action and administration of isosorbide.
• Describe the adverse effects and contraindications of isosorbide.
• Review the appropriate monitoring and toxicity of isosorbide.
• Summarize the importance of collaboration and communication amongst the interprofessional team to enhance the delivery of care and to improve outcomes for patients with angina pectoris who are receiving isosorbide.

Indications

Porje initiated the research on isosorbide in Stockholm, and the drug was marketed in Sweden in 1946. Isosorbide dinitrate was synthesized in the United States in the 1950s by Harris and colleagues. After the introduction of isosorbide, its popularity temporarily decreased as Needleman and his colleagues questioned the efficacy of isosorbide as it underwent extensive biotransformation in the liver.[1] This opinion changed after a few years, and now it gained worldwide acceptance. Isosorbide belongs to the nitrate group of medications that acts by releasing nitric oxide (N0), thereby causing vasodilation. Isosorbide is available in two forms as isosorbide mononitrate and isosorbide dinitrate.

 FDA approved indications for isosorbide dinitrate  

• Prevention or treatment of angina pectoris resulting from coronary artery disease - however, it is not recommended for use once the anginal episode has started because the onset of action is not sufficiently rapid enough to abort an acute anginal event. In the latter case, glyceryl trinitrate is preferable.
• Treatment of congestive heart failure. A fixed-dose combination of isosorbide dinitrate and hydralazine is approved to treat congestive heart failure in African Americans.[2]

Non-FDA approved indications for isosorbide dinitrate

• Achalasia[3][4]
• Diffuse esophageal spasms[5]

FDA approved indications for isosorbide mononitrate

• Treatment of chronic angina pectoris due to coronary artery disease
• Along with non-selective beta-blockers (NSBB), it can be used as secondary prophylaxis in the prevention of recurrent variceal hemorrhage.[6]

Mechanism of Action

Isosorbide is a nitrate that exerts its pharmacologic effect by releasing nitric oxide (NO), an endothelium-derived relaxing factor (EDRF).NO is endogenously produced in the endothelium to dilate the blood vessels. Isosorbide undergoes bioactivation in the endoplasmic reticulum through the cytochrome P450 enzymes to release NO[7], which activates the enzyme soluble guanylyl cyclase in the vascular smooth muscles, thereby increasing the levels of intracellular cGMP and the associated protein kinases such as cGMP- dependent protein kinases(cGK-I). The cGMP activates the myosin light chain phosphatase (MLCP), causing dephosphorylation of myosin light chain. cGMP-cGK-I inhibits the inositol-1,4,5-trisphosphate (IP3)-dependent calcium release, decreasing the intracellular calcium.[8][9] The decreased intracellular calcium inhibits the myosin light chain kinase(MLCK).[10] The MLCK, along with the unphosphorylated myosin light chain, causes the myosin head to detach from the actin component of the smooth muscle, resulting in smooth muscle relaxation and causing vasodilation. Isosorbide dilates the venous capacitance vessels, arterioles, and coronary arteries. But Its maximal effect is seen in venous capacitance vessels.[7]

Hemodynamics

Isosorbide helps to alleviate the symptoms of angina by increasing the myocardial blood flow and decreasing the myocardial oxygen demand. At therapeutic levels, it predominately dilates the venous capacitance vessels but also the coronary arteries and the arterioles. The predominant venodilation results in decreased venous return to the heart, thereby reducing the left ventricular end-diastolic volume, left ventricular end-diastolic pressure(preload), and the ventricular wall tension thereby indirectly facilitating subendocardial blood flow.[11] At higher doses, It directly increases the myocardial blood flow by dilating the large and medium-sized coronary arteries.[11] It decreases systemic vascular resistance (afterload) by dilating the peripheral arterioles. Because of this decrease in the workload of the heart, myocardial oxygen demand becomes reduced. Long term isosorbide therapy with appropriate drug-free intervals can improve the exercising capacity and exercise hemodynamics in patients with chronic congestive heart failure.[12]

Administration

The two forms of isosorbide (isosorbide mononitrate and isosorbide dinitrate) vary extensively in their pharmacokinetic properties. The liver contains organic nitrate reductase, which removes the nitrate group in a stepwise manner and ultimately inactivates the drug. After oral administration, isosorbide dinitrate undergoes an extensive first-pass effect in the liver, reducing the oral bioavailability to 20 percent.[13] Hence the sublingual route, which avoids the first-pass effect, is preferred to achieve the therapeutic levels rapidly. In contrast, isosorbide mononitrate, an active metabolite of isosorbide dinitrate, does not undergo the first-pass effect, and its bioavailability is 100 percent after oral administration.[14][15][16] The elimination half-life of isosorbide dinitrate is 1 hour while the elimination half-life of isosorbide mononitrate is 5 to 6 hours.[15]when a longer duration of action is needed, a slow-release oral preparation can be given that contains an amount of drug to withstand the hepatic metabolism and maintain the required therapeutic level. Isosorbide is excreted primarily through the kidney as glucuronide derivatives of the de-nitrated metabolite.[17] Isosorbide does not need dose adjustment in patients with renal and hepatic dysfunction.

The commonly available forms of isosorbide are[18][19]:

Short-acting

• Isosorbide dinitrate, sublingual - 2.5 to 10 mg (duration of action - 10 to 60 minutes)

Long-acting

• Isosorbide dinitrate, oral - 10 to 40 mg 3 times a day (duration of action - 4 to 6 hours)
• Isosorbide dinitrate, spray - 1.25 mg per dose
• Isosorbide dinitrate, oral sustained-release capsules/tablets - 40 mg,14 hours apart (duration of action -12 to 14 hours)
• Isosorbide mononitrate, oral - 20 mg twice daily, 7 hours apart (duration of action - 6 to 10 hours)
• Isosorbide mononitrate, oral sustained-release tablets - 30 to 120 mg daily
• A fixed-dose combination of isosorbide dinitrate (20 mg) and hydralazine hydrochloride (37.5 mg) has approval for use in the treatment of heart failure in African-Americans.[20] 

Adverse Effects

The adverse effects of isosorbide are due to the vasodilation of the venous capacitance vessels and the arterioles. The venodilation resulting in peripheral pooling of blood along with arteriolar dilation lowering the systemic vascular resistance (afterload) results in lowering the blood pressure. Other adverse effects can be due to the reflex activity of the sympathetic nervous system due to the vasodilation.

The adverse effects of isosorbide are[11][21]

• Headache (greater than 10 percent)[22]
• Reflex tachycardia (0.1 to 10 percent)
• Orthostatic hypotension (0.1 to 10 percent)
• Hypotension (0.1 to 10 percent)
• Cutaneous flushing (0.1 to 10 percent)
• Nausea, vomiting (0.1 to 10 percent)
• Dizziness (0.1 to 10 percent)
• Lightheadedness (0.1 to 10 percent)
• syncope (0.1 to 10 percent)
• Monday disease -  Monday disease is due to the development of tolerance over the course of therapy, and it presents with tachycardia, dizziness, and headache during re-exposure after a drug-free interval.
• Methemoglobinemia(rare)[23] - Nitrate ions released during the metabolism of isosorbide oxidize the hemoglobin into methemoglobin. However, routinely used dosage of isosorbide usually cause clinically insignificant elevation of methemoglobin, but it may be important in patients with coronary ischemia and anemia.

Contraindications

Several contraindications exist for the use of isosorbide.[18] They are as follows:

• Allergic to nitrates
• Concomitant use of isosorbide with PDE inhibitors such as sildenafil and tadalafil
• Concomitant use of isosorbide with riociguat, a soluble guanylate cyclase stimulator used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension[24]
• Right ventricular infarction
• Hypertrophic cardiomyopathy

PDE inhibitors such as tadalafil and sildenafil work by inhibiting the phosphodiesterase (PDE) enzyme, which is involved in breaking down the cGMP. Concomitant use of isosorbide with PDE inhibitors will cause increased cGMP, resulting in life-threatening hypotension.[21]

Isosorbide releases NO, which stimulates the soluble guanylate cyclase. Therefore, the concomitant use of isosorbide with riociguat (a soluble guanylate cyclase stimulator) will cause an increased level of cGMP resulting in life-threatening hypotension.[24] 

Patients with right ventricular infarction are preload sensitive. Isosorbide decreases the preload and worsens the right ventricular output causing severe hypotension.

In patients with hypertrophic cardiomyopathy, isosorbide decreases the preload and hence the left ventricular volume, which worsens the left ventricular outflow tract obstruction.[11]

Isosorbide use requires caution in the following conditions:

• Elderly patients with autonomic dysfunction due to high risk of orthostatic hypotension
• Patients on diuretics will be volume depleted and can develop severe hypotension
• Patients who are taking other vasodilators due to the risk of severe hypotension

Monitoring

Generally, isosorbide does not need any monitoring. However, monitoring is recommended in:

• Patients who have low blood pressure and low heart rate
• Patients who are on chronic diuretic therapy
• Elderly patients with underlying autonomic dysfunction
• Patients with right ventricular infarction who are preload sensitive
• Patients who are volume-depleted like chronic diarrhea and vomiting 
• Patients who are taking other types of vasodilators

In the above patients, close monitoring of blood pressure and heart rate is recommended to avoid severe hypotension and bradycardia. Though methemoglobinemia is a rare complication, Patients who are more susceptible to develop methemoglobinemia require close monitoring for signs and symptoms. The diagnosis of methemoglobinemia requires arterial or venous blood gas with co-oximetry.[25]

Development of tolerance is a significant concern during long term isosorbide therapy.[26] Tolerance may develop as quickly within 12 to 24 hours, and the clinical effects of isosorbide can become subsequently reduced; this necessitates the need for a drug-free interval of at least 10 to 12 hours a day. The recommended  drug-free intervals for preventing the development of tolerance for oral sustained release isosorbide dinitrate are as follows[27]:

• 12-hour drug-free interval with 40 mg dose
• 18-hour drug-free interval with 80 mg dose
• 24-hour drug-free interval with 120 mg dose

The patients should understand regarding the possibility of developing anginal episodes during the drug-free interval. Chronic isosorbide use without drug-free interval may cause poor symptom control and endothelial dysfunction due to the release of excessive free radicals.[26]

Toxicity

Isosorbide is relatively safe within the therapeutic range. The oral lethal dose LD50 of isosorbide is 2010 mg/kg in rats and 1771 mg/kg in mice. Lethal dose LD50 of isosorbide has not been a topic of sufficient research in the human population. The symptoms of isosorbide overdose may arise from its vasodilating property causing profound systemic hypotension, heart block with bradycardia, syncope, nausea, vomiting, increased intracranial tension (probably along with persistent throbbing headache, fever, confusion), diaphoresis, dizziness, and palpitations. There is limited clinical information available for the management of isosorbide overdose. The venous hypotension and the arterial hypovolemia of isosorbide overdose can be managed clinically by:

• Administring normal saline. However, this may be hazardous in patients with renal failure and congestive heart failure.
• Passive elevation of the patient's legs to reduce the venous pooling of blood
• Invasive monitoring of central fluid volume is advised in patients with renal failure and congestive heart failure.
• The usage of epinephrine and other vasoconstrictors are generally not recommended.
• The methemoglobinemia associated with isosorbide toxicity is manageable by supportive care and cessation of isosorbide. Methylene blue can work as an antidote.[11] 

There is currently no evidence of teratogenicity or carcinogenicity potential of isosorbide.[11]

Enhancing Healthcare Team Outcomes

Due to the high prevalence of cardiovascular disease among the general population, effective management of anginal pain and heart failure with significant interprofessional communication plays a crucial role in reducing the mortality and the readmission rates with long term benefits of improved exercise tolerance and quality of life. Isosorbide is used in the management of anginal pain due to coronary artery disease, and it has approval for use in heart failure. The challenges of isosorbide therapy are drug interactions, adverse effects, and the development of tolerance during chronic isosorbide therapy. Multiple health care professionals such as cardiologists, general practitioners, nurses, pharmacists, home care workers, and dieticians can work together to overcome these challenges of isosorbide therapy. Some of the patient education strategies include educating regarding the following:

• The possibility of developing orthostatic hypotension in elderly patients
• The possibility of developing severe hypotension when combined with Phosphodiesterase(PDE) inhibitors in male patients 
• The development of tolerance during chronic isosorbide therapy and drug-free intervals 
• The possibility of developing anginal pain during drug-free intervals

Home care workers can help elderly patients who are prone to develop orthostatic hypotension with Home safety measures. Nurses and general practitioners should ensure that isosorbide therapy is not an option for patients with erectile dysfunction who are taking phosphodiesterase (PDE) inhibitors. Nurses and pharmacists can verify the compliance of the medication, appropriate drug-free intervals, common adverse effects, drug interactions, and report appropriately to the prescribing general practitioner when needed. Together, isosorbide therapy in angina and heart failure requires an interprofessional team approach to achieve optimum results.