Pharmacology
Cardiovascular
Regarding nitrates, which of the following statements is INCORRECT:
Answer:
Initial metabolism of these drugs releases nitrite ions, which undergoes intracellular conversion to nitric oxide (NO). Nitric oxide then activates guanylyl cyclase, causing an increase in the intracellular concentration of cGMP in the vascular smooth muscle cells. cGMP activates protein kinase G, an enzyme that ultimately causes vascular smooth muscle relaxation.Nitrates
Pharmacology / Cardiovascular
Last Updated: 17th April 2019
Nitrates are useful in the management of angina. Although they are potent coronary vasodilators, the main benefit derives from a reduction in venous return which in turn reduces left ventricular effort, decreasing oxygen demands and relieving anginal pain.
Vasodilators can also act in heart failure by arteriolar dilatation which reduces both peripheral vascular resistance and left ventricular pressure during systole resulting in improved cardiac output. They can also cause venous dilatation which results in dilatation of capacitance vessels, increase of venous pooling, and diminution of venous return to the heart (decreasing left ventricular end-diastolic pressure).
Mechanism of Action
Initial metabolism of these drugs releases nitrite ions, which undergoes intracellular conversion to nitric oxide (NO). Nitric oxide then activates guanylyl cyclase, causing an increase in the intracellular concentration of cGMP in the vascular smooth muscle cells. cGMP activates protein kinase G, an enzyme that ultimately causes vascular smooth muscle relaxation.
Type Examples
Sublingual glyceryl trinitrate (GTN) is one of the most effective drugs for providing rapid relief of angina, although its effects only last for 20 - 30 minutes. It may be administered as sublingual tablets or by sublingual administration using aerosol spray.
If sublingual glyceryl trinitrate is required more than twice a week, then combined therapy is required, where beta-blockers or calcium-channel blockers are taken in addition to nitrates which are reserved for acute attacks. If necessary, a long-acting nitrate is added.
Long-acting nitrates are more stable and may be effective for several hours, depending on the drug and the preparation (sublingual, oral, modified release). Isosorbide dinitrate is widely used; duration of action of up to 12 hours is claimed for modified-release preparations. The use of isosorbide mononitrate, which is the main active metabolite of the dinitrate, avoids the variable absorption and unpredictable first-pass metabolism of the dinitrate.
Glyceryl trinitrate or isosorbide dinitrate may be tried by intravenous injection when the sublingual form is ineffective in patients with chest pain due to myocardial infarction or severe ischaemia. Intravenous injections are also useful in the treatment of congestive heart failure.
Side Effects
Side effects such as dizziness, flushing, tachycardia, throbbing headache and postural hypotension may limit therapy, especially when angina is severe or when patients are unusually sensitive to the effects of nitrates. Prolonged high dosage may cause methaemoglobinaemia as a result of oxidation of haemoglobin.
Contraindications
Nitrates should not be used in people with:
- Acute myocardial infarction (MI) with low filling pressure, acute circulatory failure, (shock, vascular collapse), or very low blood pressure
- Hypertrophic obstructive cardiomyopathy (HOCM), constrictive pericarditis, cardiac tamponade, low cardiac filling pressures, or aortic/mitral valve stenosis
- Diseases associated with a raised intracranial pressure (for example following a head trauma, including cerebral haemorrhage)
- Severe anaemia
- Closed angle glaucoma
- Severe hypotension, or hypovolaemia
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
