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. 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
Non-FDA approved indications for isosorbide dinitrate
FDA approved indications for isosorbide mononitrate
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, 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. The decreased intracellular calcium inhibits the myosin light chain kinase(MLCK). 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.
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. At higher doses, It directly increases the myocardial blood flow by dilating the large and medium-sized coronary arteries. 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.
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. 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. The elimination half-life of isosorbide dinitrate is 1 hour while the elimination half-life of isosorbide mononitrate is 5 to 6 hours.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. Isosorbide does not need dose adjustment in patients with renal and hepatic dysfunction.
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.
Several contraindications exist for the use of isosorbide. They are as follows:
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.
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.
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.
Isosorbide use requires caution in the following conditions:
Generally, isosorbide does not need any monitoring. However, monitoring is recommended in:
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.
Development of tolerance is a significant concern during long term isosorbide therapy. 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:
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.
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:
There is currently no evidence of teratogenicity or carcinogenicity potential of isosorbide.
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:
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.
|||Berlin R, Historical aspects of nitrate therapy. Drugs. 1987; [PubMed PMID: 3113909]|
|||Taylor AL,Ziesche S,Yancy C,Carson P,D'Agostino R Jr,Ferdinand K,Taylor M,Adams K,Sabolinski M,Worcel M,Cohn JN, Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. The New England journal of medicine. 2004 Nov 11; [PubMed PMID: 15533851]|
|||Bortolotti M,Coccia G,Brunelli F,Sarti P,Mazza M,Bagnato F,Barbara L, Isosorbide dinitrate or nifedipine: which is preferable in the medical therapy of achalasia? The Italian journal of gastroenterology. 1994 Oct-Nov; [PubMed PMID: 7703511]|
|||Gelfond M,Rozen P,Gilat T, Isosorbide dinitrate and nifedipine treatment of achalasia: a clinical, manometric and radionuclide evaluation. Gastroenterology. 1982 Nov; [PubMed PMID: 6288509]|
|||Roman S,Kahrilas PJ, Management of spastic disorders of the esophagus. Gastroenterology clinics of North America. 2013 Mar; [PubMed PMID: 23452629]|
|||Miñano C,Garcia-Tsao G, Clinical pharmacology of portal hypertension. Gastroenterology clinics of North America. 2010 Sep; [PubMed PMID: 20951924]|
|||Daiber A,Münzel T, Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress. Antioxidants [PubMed PMID: 26261901]|
|||Etter EF,Eto M,Wardle RL,Brautigan DL,Murphy RA, Activation of myosin light chain phosphatase in intact arterial smooth muscle during nitric oxide-induced relaxation. The Journal of biological chemistry. 2001 Sep 14; [PubMed PMID: 11461918]|
|||Lincoln TM,Komalavilas P,Cornwell TL, Pleiotropic regulation of vascular smooth muscle tone by cyclic GMP-dependent protein kinase. Hypertension (Dallas, Tex. : 1979). 1994 Jun; [PubMed PMID: 8206604]|
|||Divakaran S,Loscalzo J, The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics. Journal of the American College of Cardiology. 2017 Nov 7; [PubMed PMID: 29096811]|
|||Tarkin JM,Kaski JC, Vasodilator Therapy: Nitrates and Nicorandil. Cardiovascular drugs and therapy. 2016 Aug; [PubMed PMID: 27311574]|
|||Leier CV,Huss P,Magorien RD,Unverferth DV, Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation. 1983 Apr; [PubMed PMID: 6337742]|
|||Fung HL, Pharmacokinetics and pharmacodynamics of isosorbide dinitrate. American heart journal. 1985 Jul; [PubMed PMID: 4013997]|
|||Laufen H,Aumann M,Leitold M, Oral absorption and disposition of isosorbide dinitrate and isosorbide mononitrates in man. Arzneimittel-Forschung. 1983; [PubMed PMID: 6684933]|
|||Abshagen UW, Pharmacokinetics of isosorbide mononitrate. The American journal of cardiology. 1992 Nov 27; [PubMed PMID: 1449102]|
|||Thadani U,Whitsett T, Relationship of pharmacokinetic and pharmacodynamic properties of the organic nitrates. Clinical pharmacokinetics. 1988 Jul; [PubMed PMID: 3135973]|
|||Sisenwine SF,Ruelius HW, Plasma concentrations and urinary excretion of isosorbide dinitrate and its metabolites in the dog. The Journal of pharmacology and experimental therapeutics. 1971 Feb; [PubMed PMID: 5568780]|
|||Boden WE,Finn AV,Patel D,Peacock WF,Thadani U,Zimmerman FH, Nitrates as an integral part of optimal medical therapy and cardiac rehabilitation for stable angina: review of current concepts and therapeutics. Clinical cardiology. 2012 May; [PubMed PMID: 22528319]|
|||Parker JD,Parker JO, Nitrate therapy for stable angina pectoris. The New England journal of medicine. 1998 Feb 19; [PubMed PMID: 9468470]|
|||Echols MR,Yancy CW, Isosorbide dinitrate-hydralazine combination therapy in African Americans with heart failure. Vascular health and risk management. 2006; [PubMed PMID: 17323596]|
|||Thadani U,Rodgers T, Side effects of using nitrates to treat angina. Expert opinion on drug safety. 2006 Sep; [PubMed PMID: 16907656]|
|||Christiansen I,Iversen HK,Olesen J, Headache characteristics during the development of tolerance to nitrates: pathophysiological implications. Cephalalgia : an international journal of headache. 2000 Jun; [PubMed PMID: 11037739]|
|||Inal ME,Egüz AM, The effects of isosorbide dinitrate on methemoglobin reductase enzyme activity and antioxidant states. Cell biochemistry and function. 2004 Mar-Apr; [PubMed PMID: 15027102]|
|||Khaybullina D,Patel A,Zerilli T, Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. P [PubMed PMID: 25395817]|
|||do Nascimento TS,Pereira RO,de Mello HL,Costa J, Methemoglobinemia: from diagnosis to treatment. Revista brasileira de anestesiologia. 2008 Nov-Dec; [PubMed PMID: 19082413]|
|||Münzel T,Steven S,Daiber A, Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Vascular pharmacology. 2014 Dec; [PubMed PMID: 25446162]|
|||Kośmicki M,Sadowski Z,Szwed H,Kowalik I, What intervals in oral therapy of isosorbide dinitrate in various doses are sufficient to prevent nitrate tolerance? Medical science monitor : international medical journal of experimental and clinical research. 2000 Jul-Aug; [PubMed PMID: 11208406]|