Nitrates

Chemistry and Pharmacodynamics

Chemistry

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

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

Physiologic effects

• Preload Preload Cardiac Mechanics reduction:
  • Primary mechanism to ↓ myocardial O₂ demand
  • Nitrates relax vascular smooth muscle → venodilation Venodilation Venous Function → ↓ cardiac preload Preload Cardiac Mechanics:
    • ↓ Myocardial wall stress
    • ↓ Myocardial O₂ demand
    • ↓ BP
    • Can produce 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 due to ↓ BP
  • Indirectly improves subendocardial blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure:
    • ↓ Left end-diastolic pressure as a result of systemic venodilation Venodilation Venous Function
    • Epicardium Epicardium Heart: Anatomy to endocardium Endocardium The innermost layer of the heart, comprised of endothelial cells. Heart: Anatomy blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure ↑
• 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:
  • Opens myocardial vascular bed:
    • Due to smooth muscle relaxation of the coronary artery Coronary Artery Truncus Arteriosus
    • Large coronary 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 are dilated primarily.
    • Benefits the ischemic zone the most
  • Enhances collateral coronary artery Coronary Artery Truncus Arteriosus blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure
  • Beneficial in coronary artery Coronary Artery Truncus Arteriosus vasospasm:
    • Relaxes or prevents coronary artery Coronary Artery Truncus Arteriosus spasm
    • ↑ O₂ supply
    • Does not ↓ O₂ demand
• 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 Platelet 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. Hemostasis

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:
    • 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:
  • Patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes
  • Onset: 40‒60 minutes
  • Peak effect: 60‒180 minutes
  • Duration: 18‒24 hours
• 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

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 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 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 Stenosis Hypoplastic Left Heart Syndrome (HLHS): 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:
  • Nitrates induce cerebral vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs.
  • ↑ Cerebral blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure
  • Compromises intracranial perfusion
• 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:
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with right ventricular dysfunction are preload Preload Cardiac Mechanics dependent.
  • Nitrates cause venous pooling and ↓ preload Preload Cardiac Mechanics
• 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