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Nitrates

Nitrates are a class of medications that cause systemic vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs ( veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins: Histology > arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries: Histology) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation Venodilation Venous Function causes pooling of blood, decreased preload Preload Cardiac Mechanics, and ultimately decreased myocardial O2 demand. At high doses, nitrates can decrease afterload Afterload Afterload is the resistance in the aorta that prevents blood from leaving the heart. Afterload represents the pressure the LV needs to overcome to eject blood into the aorta. Cardiac Mechanics and may be used in hypertensive crises. The main adverse effects include headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, and reflex tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children. Repeated use of nitrates leads to tolerance Tolerance Pharmacokinetics and Pharmacodynamics. Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation include concomitant therapy with PDE5 inhibitors, hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy, and suspected right ventricular infarction.

Last updated: Sep 1, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Chemistry and Pharmacodynamics

Chemistry

  • Nitrates are salts or esters of nitric acid.
  • Nitroglycerine is the prototype of this drug class.
Nitroglycerine chemical structure nitrates

Nitroglycerine chemical structure

Image: “Skeletal formula of zwitterionic nitroglycerin” by BartVL71. License: Public Domain

Mechanism of action

Exogenously administered nitrates are converted to NO after entering the cell:

  • NO is converted into S-nitrosothiols → stimulates guanylyl cyclase Guanylyl cyclase A mammalian enzyme composed of a heterodimer of alpha and beta subunits. Each subunit consists of four domains; N-terminal HNOX domain, PAS-like domain, a coiled-coil domain, and a C-terminal catalytic domain. All four domains are homologous proteins with a similar conformation of functional domains. Soluble guanylate cyclase catalyzes the formation of cyclic GMP from GTP, and is a key enzyme of the nitric oxide signaling pathway involved in the regulation of a variety of biological and physiological processes in mammals. Vascular Resistance, Flow, and Mean Arterial Pressure
  • Guanylyl cyclase Guanylyl cyclase A mammalian enzyme composed of a heterodimer of alpha and beta subunits. Each subunit consists of four domains; N-terminal HNOX domain, PAS-like domain, a coiled-coil domain, and a C-terminal catalytic domain. All four domains are homologous proteins with a similar conformation of functional domains. Soluble guanylate cyclase catalyzes the formation of cyclic GMP from GTP, and is a key enzyme of the nitric oxide signaling pathway involved in the regulation of a variety of biological and physiological processes in mammals. Vascular Resistance, Flow, and Mean Arterial Pressure converts cellular guanosine-5′-triphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate Guanosine monophosphate A guanine nucleotide containing one phosphate group esterified to the sugar moiety and found widely in nature. Purine and Pyrimidine Metabolism ( cGMP cGMP Guanosine cyclic 3. Phosphodiesterase Inhibitors) → relaxation of vascular smooth muscle cells: 
    • Primarily venous dilation 
    • Secondarily arterial dilation
Mechanism of action for nitrates

Mechanism of action for nitrates:
Stimulation of guanylyl cyclase Guanylyl cyclase A mammalian enzyme composed of a heterodimer of alpha and beta subunits. Each subunit consists of four domains; N-terminal HNOX domain, PAS-like domain, a coiled-coil domain, and a C-terminal catalytic domain. All four domains are homologous proteins with a similar conformation of functional domains. Soluble guanylate cyclase catalyzes the formation of cyclic GMP from GTP, and is a key enzyme of the nitric oxide signaling pathway involved in the regulation of a variety of biological and physiological processes in mammals. Vascular Resistance, Flow, and Mean Arterial Pressure induces the conversion of guanosine-5′-triphosphate (GTP) to cGMP cGMP Guanosine cyclic 3. Phosphodiesterase Inhibitors, resulting in vascular smooth muscle relaxation and vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs.

GMP: guanosine monophosphate Guanosine monophosphate A guanine nucleotide containing one phosphate group esterified to the sugar moiety and found widely in nature. Purine and Pyrimidine Metabolism

Image by Lecturio. License: CC BY-NC-SA 4.0

Physiologic effects

  • Preload Preload Cardiac Mechanics reduction:
  • Afterload Afterload Afterload is the resistance in the aorta that prevents blood from leaving the heart. Afterload represents the pressure the LV needs to overcome to eject blood into the aorta. Cardiac Mechanics reduction:
    • Secondary mechanism to ↓ myocardial O2 demand
    • Higher doses have arteriodilatory effects:
      • Afterload Afterload Afterload is the resistance in the aorta that prevents blood from leaving the heart. Afterload represents the pressure the LV needs to overcome to eject blood into the aorta. Cardiac Mechanics
      • ↓ Myocardial wall stress due to lowered resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing
      • ↓ O2 consumption
  • Effect of higher doses:
  • Antiplatelet properties:
    • Antithrombotic effects
    • Stimulation of platelet guanylyl cyclase Guanylyl cyclase A mammalian enzyme composed of a heterodimer of alpha and beta subunits. Each subunit consists of four domains; N-terminal HNOX domain, PAS-like domain, a coiled-coil domain, and a C-terminal catalytic domain. All four domains are homologous proteins with a similar conformation of functional domains. Soluble guanylate cyclase catalyzes the formation of cyclic GMP from GTP, and is a key enzyme of the nitric oxide signaling pathway involved in the regulation of a variety of biological and physiological processes in mammals. Vascular Resistance, Flow, and Mean Arterial Pressure 
    • Inhibits binding of fibrinogen Fibrinogen Plasma glycoprotein clotted by thrombin, composed of a dimer of three non-identical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides a and b, the proteolytic action of other enzymes yields different fibrinogen degradation products. Hemostasis to platelet IIb and IIIa receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors, which are essential components of platelet aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

  • Oral:
    • Sublingual:
      • Tablet
      • Onset of action: 1‒3 minutes
      • Peak effect: 4‒8 minutes
      • Duration: 30‒60 minutes
    • Translingual:
      • Spray
      • Onset of action: 2 minutes
      • Peak effect: 4‒10 minutes
      • Duration: 30‒60 minutes
    • Buccal:
      • Tablet
      • Onset of action: 2‒5 minutes
      • Peak effect: 4‒10 minutes
      • Duration: 2 hours
    • Sustained release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology:
      • Tablet
      • Onset of action: 20‒45 minutes
      • Peak effect: 45‒120 minutes
      • Duration: 4‒8 hours
  • Topical:
    • Ointment
    • Onset: 15‒60 minutes
    • Peak effect: 30‒120 minutes
    • Duration: 2‒12 hours
  • Transdermal:
  • IV:
    • Infusion
    • Onset: immediate
    • Peak effect: immediate
    • Duration: 3‒5 minutes

Distribution

  • The volume of distribution following IV administration is 3.3 L/kg.
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products drug concentrations range between 50 and 500 ng/mL:
    • Binding of nitroglycerin to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis is approximately 60%.
    • Binding of 1,2-dinitroglycerin to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis is 60%.
    • Binding of 1,3-dinitroglycerin to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis is 30%.
  • Highly water soluble

Metabolism

  • Hepatic organic nitrate reductase is the primary enzyme responsible for the metabolism of nitroglycerin:
    • Cleaves nitrate groups from the parent molecule → glycerol di- and mononitrate metabolites → ultimately to glycerol and organic nitrate
    • Drugs with a 1st-pass effect (e.g., oral nitroglycerin and isosorbide dinitrate) exhibit lower potency.
    • Drugs without a 1st-pass effect (e.g., sublingual forms):
      • Higher potency
      • Therapeutic drug levels in the blood are achieved faster.
  • 1,2-dinitroglycerin and 1,3-dinitroglycerin are the 2 major metabolites found in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products.
  • Glycerol mononitrate metabolites are biologically inactive.

Excretion

  • Metabolites are primarily excreted in the urine.
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products drug concentration decreases rapidly.
  • Average elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 2–3 minutes

Indications

Table: Comparison of nitrates
Medications Common formulations Indications Clinical pearls
Nitroglycerin
  • Sublingual
  • Oral
  • Transdermal
  • IV
  • Angina
  • Acute MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction (unless a right ventricular or inferior infarct Infarct Area of necrotic cells in an organ, arising mainly from hypoxia and ischemia Ischemic Cell Damage)
  • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
  • Variant angina Variant angina Vasospastic angina, also known as prinzmetal or variant angina, is an uncommon cause of chest pain due to transient coronary artery spasms. The pathophysiology is distinguished from stable or unstable angina secondary to atherosclerotic coronary artery disease (CAD). Vasospastic Angina
  • Hypertensive emergency Hypertensive emergency A condition of markedly elevated blood pressure with diastolic pressure usually greater than 120 mm hg. Malignant hypertension is characterized by widespread vascular damage, papilledema, retinopathy, hypertensive encephalopathy, and renal dysfunction. Uncontrolled Hypertension (off label)
  • Can dose sublingual nitroglycerin every 5 minutes, up to 3 doses
  • Can use IV nitroglycerin for angina
Isosorbide dinitrate Oral
  • Angina
  • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
  • Achalasia Achalasia Achalasia is a primary esophageal motility disorder that develops from the degeneration of the myenteric plexus. This condition results in impaired lower esophageal sphincter relaxation and absence of normal esophageal peristalsis. Patients typically present with dysphagia to solids and liquids along with regurgitation. Achalasia (off label)
  • Slower onset but longer duration of action than nitroglycerin
  • Good for chronic stable angina Stable angina Persistent and reproducible chest discomfort usually precipitated by a physical exertion that dissipates upon cessation of such an activity. The symptoms are manifestations of myocardial ischemia. Stable and Unstable Angina prophylaxis Prophylaxis Cephalosporins
Isosorbide mononitrate Oral
  • Angina
  • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
Active metabolite of isosorbide dinitrate (better bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics)
Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia nitroprusside IV
  • Hypertensive emergency Hypertensive emergency A condition of markedly elevated blood pressure with diastolic pressure usually greater than 120 mm hg. Malignant hypertension is characterized by widespread vascular damage, papilledema, retinopathy, hypertensive encephalopathy, and renal dysfunction. Uncontrolled Hypertension
  • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
Combines with hemoglobin to produce cyanide Cyanide Inorganic salts of hydrogen cyanide containing the -cn radical. The concept also includes isocyanides. It is distinguished from nitriles, which denotes organic compounds containing the -cn radical. Cyanide Poisoning and cyanmethemoglobin
Amyl nitrite Nitrite Salts of nitrous acid or compounds containing the group NO2-. The inorganic nitrates of the type mno2 (where m=metal) are all insoluble, except the alkali nitrites. The organic nitrites may be isomeric, but not identical with the corresponding nitro compounds. Kidney Function Tests Inhalation
  • Cyanide poisoning Cyanide Poisoning Hydrogen cyanide is an extremely poisonous, colorless, flammable liquid used in multiple industries and includes rubber, plastic, and household paints. Exposure to cyanide can occur via inhalation, dermal contact, or intestinal ingestion. Cyanide Poisoning
  • Angina
  • Oxidizes hemoglobin to methemoglobin
  • Methemoglobin binds with cyanide Cyanide Inorganic salts of hydrogen cyanide containing the -cn radical. The concept also includes isocyanides. It is distinguished from nitriles, which denotes organic compounds containing the -cn radical. Cyanide Poisoning to form cyanmethemoglobin.
  • As a drug of abuse, “poppers” produces euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy.
Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia nitrite Nitrite Salts of nitrous acid or compounds containing the group NO2-. The inorganic nitrates of the type mno2 (where m=metal) are all insoluble, except the alkali nitrites. The organic nitrites may be isomeric, but not identical with the corresponding nitro compounds. Kidney Function Tests IV Cyanide poisoning Cyanide Poisoning Hydrogen cyanide is an extremely poisonous, colorless, flammable liquid used in multiple industries and includes rubber, plastic, and household paints. Exposure to cyanide can occur via inhalation, dermal contact, or intestinal ingestion. Cyanide Poisoning Similar mechanism as that of amyl nitrite Nitrite Salts of nitrous acid or compounds containing the group NO2-. The inorganic nitrates of the type mno2 (where m=metal) are all insoluble, except the alkali nitrites. The organic nitrites may be isomeric, but not identical with the corresponding nitro compounds. Kidney Function Tests

Adverse Effects and Contraindications

Adverse effects

  • Common side effects:
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess (cerebral vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs)
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension (systemic vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs)
    • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children (reflex sympathetic activity)
    • Flushing (cutaneous vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs)
  • High blood concentrations may induce methemoglobinemia Methemoglobinemia Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia:
    • Nitrates oxidize ferrous (Fe2+) iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements to ferric (Fe3+) iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements.
    • Inducing methemoglobinemia Methemoglobinemia Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia may be used therapeutically to treat cyanide poisoning Cyanide Poisoning Hydrogen cyanide is an extremely poisonous, colorless, flammable liquid used in multiple industries and includes rubber, plastic, and household paints. Exposure to cyanide can occur via inhalation, dermal contact, or intestinal ingestion. Cyanide Poisoning.
    • Methemoglobin has a high binding affinity for cyanides.
  • Long-term infusion of sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia nitroprusside may lead to cyanide Cyanide Inorganic salts of hydrogen cyanide containing the -cn radical. The concept also includes isocyanides. It is distinguished from nitriles, which denotes organic compounds containing the -cn radical. Cyanide Poisoning toxicity Toxicity Dosage Calculation.

Tachyphylaxis and tolerance Tolerance Pharmacokinetics and Pharmacodynamics

  • Tachyphylaxis (↓ effect with rapid, repeated administration) 
  • Tolerance Tolerance Pharmacokinetics and Pharmacodynamics (requiring ↑ doses over time to achieve the same effect)
    • Major problem resulting from the chronic use of nitrates
    • With continued administration:
      • ↓ Hemodynamic and antianginal effects
      • Side effects also ↓
    • Incompletely understood
    • 3 proposed mechanisms:
      • ↓ Formation of NO as a result of impaired nitroglycerin conversion to 1,2-glyceryl dinitrate
      • Reduction in NO bioactivity
      • Vasoconstrictor activation of the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification and RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones due to nitrate-induced vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
    • Prevention:
      • Most effective: intermittent therapy with a nitrate-free interval of 8‒10 hours
      • Rebound angina can occur in the nitrate-free interval.

Drug interactions

PDE5 inhibitors

  • Can be fatal due to:
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension: due to increased vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
    • Inhibition of PDE5, which is responsible for the breakdown of cGMP cGMP Guanosine cyclic 3. Phosphodiesterase Inhibitors to GMP
    • cGMP cGMP Guanosine cyclic 3. Phosphodiesterase Inhibitors levels resulting from prevention of its breakdown
  • Examples:
    • Sildenafil Sildenafil A phosphodiesterase type-5 inhibitor; vasodilator agent and urological agent that is used in the treatment of erectile dysfunction and primary pulmonary hypertension. Phosphodiesterase Inhibitors (ViagraⓇ)
    • Vardenafil Vardenafil A piperazine derivative, phosphodiesterase 5 inhibitor and vasodilator agent that is used as a urological agent in the treatment of erectile dysfunction. Phosphodiesterase Inhibitors (LevitraⓇ)
    • Tadalafil Tadalafil A carboline derivative and phosphodiesterase 5 inhibitor that is used primarily to treat erectile dysfunction; benign prostatic hyperplasia and primary pulmonary hypertension. Phosphodiesterase Inhibitors (CialisⓇ)

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy: may induce or enhance outflow tract obstruction
  • Severe aortic stenosis Aortic stenosis Aortic stenosis (AS), or the narrowing of the aortic valve aperture, is the most common valvular heart disease. Aortic stenosis gradually progresses to heart failure, producing exertional dyspnea, angina, and/or syncope. A crescendo-decrescendo systolic murmur is audible in the right upper sternal border. Aortic Stenosis: potential severe hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration:
    • ↑ Risk of severe and uncontrollable hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Due to loss of compensatory mechanisms 
  • Increased intracranial pressure Intracranial Pressure Idiopathic Intracranial Hypertension
  • Right-sided (ventricular) MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension

References

  1. Fung, H. (1992). Do nitrates differ? British Journal of Clinical Pharmacology, 34, 5S-9S. https://europepmc.org/article/med/1633079
  2. Parker, J. (1989). Nitrate tolerance in angina pectoris. Cardiovascular Drugs and Therapy, 2(6): 823-829. https://europepmc.org/article/med/2488098
  3. Kannam, J., Gersh, B. (2021). Nitrates in the management of chronic coronary syndrome. In Kaski, J. (Ed.), UpToDate. Retrieved June 6, 2021, from https://www.uptodate.com/contents/nitrates-in-the-management-of-chronic-coronary-syndrome
  4. Reeder, G. (2021). Nitrates in the management of acute coronary syndrome. In Kaski, J. (Ed.), UpToDate. Retrieved June 6, 2021, from https://www.uptodate.com/contents/nitrates-in-the-management-of-acute-coronary-syndrome
  5. Parker, J.D., Parker, J.O. (1998). Nitrate therapy for stable angina pectoris. N Engl J Med; 338:520. https://pubmed.ncbi.nlm.nih.gov/9468470/https://pubmed.ncbi.nlm.nih.gov/9468470/
  6. Fihn, S.D., Gardin, J.M., Abrams, J., et al. (2012). ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation; 126:3097. https://pubmed.ncbi.nlm.nih.gov/23166210/
  7. Katzung, B.G. (2012). Vasodilators & the treatment of angina pectoris. In Katzung, B.G., Masters., and Trevor, A.J. (Eds). Basic & Clinical Pharmacology, 12th edition. (pp. 195-201). McGraw-Hill Companies, Inc.

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