Name | Nitric oxide | Epoprostenol |
Class | Inhaled pulmonary vasodilator | Inhaled pulmonary vasodilator |
Chemistry | A free radical with the formula NO | Synthetic analogue of the naturally occurring eicosanoid prostacyclin (prostaglandin I2 or PGI2) |
Routes of administration | Administered as part of inspired gas mixture, usually as an admixture fraction measured in tens of ppm, via a proprietary system (INOMax) | Can be intravenous, but usually nebulised as a part of a solution with a glycine buffer, using a continuous ultrasonic nebuliser |
Absorption | Absorbs rapidly into the pulmonary circulation via the lungs | Absorbs rapidly into the pulmonary circulation via the lungs |
Solubility | As it dissociates in water, nitric oxide produces nitric acid (HNO3) which has a pKa of -1.3 | Natural pKa is 4.4; requires a diluent which contains glycine and sodium hydroxide. The pH of the reconstituted drug mixture has a pH of around 12, because the drug tends to spontaneously hydrolyse in aqueous solution at a normal pH |
Distribution | VOD is impossible to measure, but is potentially very large. NO reacts with oxygen and water to produce nitrogen dioxide and nitrites, which then bind to haemoglobin and produce either nitrosylhaemoglobin or methaemoglobin, i.e. it can be described as "highly protein bound". | 0.357L/kg |
Target receptor | Soluble guanylyl cyclase (which is induced by NO) | Activates G protein-coupled PGE receptors on platelets and endothelial cells, which activates adenlyl cyclase and increases cAMP |
Mechanism of action | Inhibits vasoconstriction by increasing the amount of cyclic GMP (cGMP) in the cytosol, thus decreasing the amount of cytosolic calcium ions available to sustain smooth muscle contraction | Increased cyclic AMP leads to decreased platelet activation and activates PKA, which phosphorylates and inhibits myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation |
Metabolism | One way or another, nitric oxide ends up as methaemoglobin and nitrate. Either it reacts with lung water, becoming nitrite (which reacts with oxyhemoglobin and generates methaemoglobin and nitrate) or it combines directly with oxyhaemoglobin, with the same results. If it encounters hypoxic blood, it can combine with deoxyhaemoglobin to create nitrosyl-haemoglobin, which then rapidly becomes methaemoglobin when it contacts oxygen. | Degrades spontaneously as well as enzymatically into about sixteen major and minor metabolites |
Elimination | Nitrates are eliminated mainly in urine whereas methaemoglobin is metabolised in several hours into haemoglobin by endogenic reductases. The nitrates excreted in urine represent over 70% of the inhaled NO dose. |
Half-life is about six minutes |
Time course of action | Onset of effect is seen within seconds | Platelet inhibition effects last up to 2 hrs; smooth muscle vasodilation is very shortlived (comparable with half-life) |
Clinical effects | Apart from pulmonary vasodilation, there is methemoglobinaemia, hypotension (maybe some of it does leak into the systemic circulation, or maybe this the effect of depressed LV function, rebound hypoxia after abrupt withdrawal, thrombocytopenia (in as many as 10% of patients) and increased susceptibility to pulmonary infections probably due to NO2 formation and associated lung injury. | Vasodilation (pulmonary as well as systemic); inhibition of platelet aggregation; facial flushing, tachycardia, bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying |
Single best reference for further information | TGA (AusPAR) product information | Flolan PI by GlaxoSmithCline |
Name | Oxygen |
Class | Vital ingredient of multicellular life |
Chemistry | Diatomic gas |
Routes of administration | Inhaled; also as intravenous or intra-arterial infusion of well-oxygenated blood (i.e. ECMO), and can be given externally (as in hyperbaric oxygen therapy) |
Absorption | Absorbs rapidly into the pulmonary circulation via the lungs (250ml/min with 21% FiO2, at rest) |
Solubility | Poor solubility in water |
Distribution | Widely distributed- total body oxygen content is 64% by weight. Highly protein-bound (to haemoglobin) |
Target receptor | Cytochrome c mitochondrial enzymes |
Mechanism of action | Increases ATP by acting a substrate for aerobic metabolism of glucose |
Metabolism | Metabolised in all tissues (mainly brain, heart and skeletal muscle) Mainly metabolised by cytochrome c mitochondrial enzymes (90%) Zero-order clearance kinetics, roughly 200ml/minute |
Elimination | Rapidly eliminated by metabolism into CO2 and water |
Time course of action | Minutes |
Clinical effects | Drying of mucous membranes and inspissation of secretions Inflammatory tracheobronchitis Decreased central respiratory drive (minimally) Hypecapnoea in "CO2 retainers" mainly by virtue of V/Q mismatch and Haldane effect Absorption atelectasis Increased left-to-right shunting in ASDs Increased peripheral vascular resistance Cerebral and coronary vasoconstriction Euphoria Retrolental fibroplasia of the newborn Decreased erythropoiesis |
Single best reference for further information | Haim Bitterman's 2009 article, "Bench-to-bedside review: oxygen as a drug" |
Name | Sildenafil | Tadalafil | Milrinone |
Class | Pulmonary vasodilator | Pulmonary vasodilator | Ino-dilator |
Chemistry | Pyrazolopyrimidine | Pyrazinopyridoindole | Biperidine |
Routes of administration | Oral, but also available as an attractive buccal spray | Oral | IV; but can also be administed as a nebulised aerosol, and had initially been marked as an oral preparation |
Absorption | Rapidly absorbed after oral administration, with a mean absolute bioavailability of 41%; a high-fat meal reduces absorption | Appears to have a high oral bioavailability | Well absorbed orally; 92% oral bioavailability |
Solubility | Basic drug, with a pKa value of 8.7; highly (96%) protein-bound | Acidic drug, pKa ~ 3.5; highly protein bound (94%) | pKa 4.6 and 8.5; good solublity at physiological pH |
Distribution | Very large VOD: 105 L/kg; i.e extensively distrbuted into tissues | very large VOD: 64 L/kg | 0.38L/kg; 70% protein bound |
Target receptor | Phosphodiesterase 5 | Phosphodiesterase 5 | Phosphodiesterase 3 |
Mechanism of action | Increases cyclic GMP by inhibiting phosphodiesterase 5, which is responsible for cGMP catabolism. Selective for vascular smooth muscle. | Increases cyclic GMP by inhibiting phosphodiesterase 5, which is responsible for cGMP catabolism. Selective for vascular smooth muscle. | Increases cyclic AMP by inhibiting phosphodiesterase 3, which is responsible for cAMP catabolism. Selective for vascular smooth muscle and cardiac muscle. |
Metabolism | Cleared predominantly by the liver: metablised by CYP3A into an active metabolite which itself has about 50% of th PDE5-inhibiting potency of the parent drug | Hepatic clearance is the main mode; metabolised by CYP 3A4 into a totally inactive metabolite | Mostly cleared renally; of the free fraction some undergoes hepatic metabolism into an inactive o-glucouronide, and the rest is excreted unchanged at a rate which varies depending on renal blood flow |
Elimination | Half life of sildenafil and its major metabolite is about 4 hours. | Half-life is 17.5 hrs | Half life is 2.3 hours in patients with heart failure, slightly less in normal healthy adults and longer in patients with renal dysfunction |
Time course of action | Vasodilation is maximal approximately 1-2 hours after dosing | Effects are maximal ~ 2 hours following oral administration | Onset of action is usually within 5-15 minutes |
Clinical effects | Pulmonary vasodilation, systemic vasodilation with hypotension, reflex tachycardia in reponse to this; priapism; headache | Pulmonary vasodilation, systemic vasodilation with hypotension, reflex tachycardia in reponse to this; priapism; headache | Improved vntricular contractility; decreased systemic vascular resistance; decreased pulmonary vascular resistance; tachycardia; propensity to arrhythmias. |
Single best reference for further information | REVATIO product pamphlet (sildenafil citrate) | TGA product information for Cialis, by Eli Lily | Canadian (Novopharm) product pamphlet for milrinone lactate |
For completeness, the following table contains details about the two most popular endothelin-1 receptor antagonists. There is no possible way this could ever be viewed as core material even by the most deranged examiners. The only halfway interesting thing to remember about these drugs is the fact that, unlike the vast majority of drugs, they are excreted almost exclusively via the bile.
Name | Bosentan | Ambrisentan |
Class | Pulmonary vasodilator | Pulmonary vasodilator |
Chemistry | Pyrimidine derivative | Propionic acid |
Routes of administration | Oral | Oral |
Absorption | 50% oral bioavailability | 90% oral bioavailability |
Solubility | pKa 5.8; highly protein-bound (98%); | 99% protein bound; this drug is a carboxylic acid with a pKa of 4 |
Distribution | Large VOD, 28L/kg | Large VOD, 40L/kg |
Target receptor | Endothelin receptor types ETA and ETB | Endothelin receptor types ETA and ETB |
Mechanism of action |
Bosentan is a non-selective ETA and ETB receptor antagonist. By competitive inhbition, bosentan prevents binding of endothelin to its ETA receptor, which would usually produce smooth muscle contraction (vasoconstriction). ETA are G-protein coupled receptors; activating them leads to an increase in cAMP and an increased availability of intracellular calcium which gives rise to vasoconstriction. |
Ambrisentan is a selective ETA receptor antagonist. By competitive inhbition, ambrisentan prevents binding of endothelin to its ETA receptor, which would usually produce smooth muscle contraction (vasoconstriction). ETA are G-protein coupled receptors; activating them leads to an increase in cAMP and an increased availability of intracellular calcium which gives rise to vasoconstriction. |
Metabolism | Hepatic metabolism and almost completely biliary elimination; only 3% of the dose is recovered from the urine. Only of the metabolites is effective and probably contributes 10-20% of the total drug effect | Ambrisentan is excreted largely unchanged (45.6% of the dose); excretion is biliary. The rest is glucouronidated and oxidised by CYP3A4 into relatively inactive metabolites |
Elimination | Terminal elimination half-life is about 5 hours in healthy adult subjects | In humans, the terminal half-life following oral administration was determined to be approximately 15 hours |
Time course of action | Effects are maximal ~ 1 hour following oral administration | Maximum plasma concentrations (Cmax) of ambrisentan typically occur around 1.5 hours post dose |
Clinical effects | Pulmonary vasodilation, fluid retention, pulmonary veno-occlusive disease, foetal toxicity, anaemia | Pulmonary vasodilation, fluid retention, pulmonary veno-occlusive disease, foetal toxicity, anaemia, LFT derangedment ("transaminitis"), |
Single best reference for further information | FDA information on the TRACLEER brand of bosentan | TGA information pamphlet for the VOLIBRIS brand of ambrisentan |
Roberts, David H., et al. "Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension." Chest 120.5 (2001): 1547-1555.
Siobal, Mark S. "Pulmonary vasodilators." Respiratory care 52.7 (2007): 885-899.