N
- DOI:
- 10.1093/med/9780198768814.003.0013
Uses
Nalbuphine is used:
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1. for premedication and
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2. as an analgesic in the treatment of moderate to severe pain.
Presentation
As a clear, colourless solution for injection containing 10 mg/ml of nalbuphine hydrochloride.
Mode of action
Nalbuphine is an agonist at kappa-opioid receptors and an antagonist at MOP receptors; it thus produces analgesia (a kappa effect), whilst antagonizing both the respiratory depressant effects and the potential for dependency that are associated with the mu-receptor.
Routes of administration/doses
The drug may be administered intravenously, intramuscularly, or subcutaneously in an adult dose of 10–20 mg. Nalbuphine acts within 2–3 minutes when administered intravenously and within 15 minutes when administered intramuscularly. The duration of action is 3–6 hours.
Effects
CVS
Nalbuphine has little significant effect on the heart rate, mean arterial pressure, systemic or pulmonary vascular resistance, or cardiac output.
RS
The drug has a respiratory depressant effect equal to that of morphine but demonstrates a ceiling effect at a dose of 0.5 mg/kg. It will antagonize the respiratory depressant effects of co-administered pure mu-agonists, whilst adding to the analgesic effect of the latter.
Toxicity/side effects
Sedation, dizziness, vertigo, dry mouth, and headache may complicate the use of nalbuphine. The drug causes less nausea and vomiting, psychotomimetic effects, and dependence than does morphine.
Kinetics
Absorption
The bioavailability by the oral route is 12–17% due to a significant first-pass hepatic metabolism. The bioavailability is 80% by the intramuscular and subcutaneous routes.
Metabolic/other
Occurs predominantly in the liver to two inactive conjugates which are secreted into the bile.
The metabolites are predominantly excreted (with some unchanged nalbuphine) via the faeces. A small fraction is excreted unchanged in the urine. The clearance is 0.8–2.3 l/min, and the elimination half-life is 110–160 minutes. Care should be exercised during the use of the drug in patients with renal or hepatic impairment.
Uses
Naloxone is used for:
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1. the reversal of respiratory depression due to opioids
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2. the diagnosis of suspected opioid overdose and has been used in the treatment of
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3. clonidine overdose.
Main actions
Reversal of MOP receptor effects such as sedation, hypotension, respiratory depression, and the dysphoric effects of partial agonists. The drug will precipitate acute withdrawal symptoms in opiate addicts.
Mode of action
Naloxone is a competitive antagonist at mu-, delta-, kappa-, and sigma-opioid receptors.
Routes of administration/doses
For the reversal of opioid-induced respiratory depression, the drug should be administered intravenously in small incremental doses, until the desired end point of reversal of respiratory depression without reversal of analgesia is reached; in adults, 0.1– 0.2 mg will normally achieve this effect. In the treatment of known or suspected opioid overdose, 0.4–2.0 mg may be administered intravenously, intramuscularly, or subcutaneously. The drug acts within 2 minutes when administered intravenously and has a duration of effect (approximately 20 minutes) that may be shorter than the opioid whose effects it is desired to counteract. It may therefore be necessary to administer additional doses of naloxone intravenously or intramuscularly.
Effects
CVS
The drug has no effect at normal doses. In doses of 0.3 mg/kg, the blood pressure may increase. Naloxone has been shown to reverse the hypotension associated with endotoxic and hypovolaemic shock in some animal studies.
Toxicity/side effects
Serious ventricular dysrhythmias occurring in patients with irritable myocardia after the administration of naloxone have been reported.
Uses
Neostigmine is used:
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1. for the reversal of non-depolarizing neuromuscular blockade and in the treatment of
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2. myasthenia gravis
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3. paralytic ileus and
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4. urinary retention.
Presentation
As 15 mg tablets of neostigmine bromide and as a clear, colourless solution for injection containing 2.5 mg/ml of neostigmine metilsulfate. A fixed-dose combination containing 0.5 mg of glycopyrronium bromide and 2.5 mg of neostigmine metilsulfate per ml is also available.
Mode of action
Neostigmine is a reversible, acid-transferring cholinesterase inhibitor which binds to the esteratic site of acetylcholinesterase and is hydrolysed by the latter, but at a much slower rate than is acetylcholine. The accumulation of acetylcholine at the neuromuscular junction allows the competitive antagonism of any non-depolarizing relaxant that may be present.
Routes of administration/doses
The adult oral dose is 15–50 mg 2- to 4-hourly. The intravenous dose for the reversal of non-depolarizing neuromuscular blockade is 0.05–0.07 mg/kg, administered slowly and in combination with an appropriate dose of an anticholinergic agent. The peak effect of the drug when administered intravenously occurs at 7–11 minutes; a single dose of neostigmine has a duration of action of 40–60 minutes.
Effects
CVS
The effects of neostigmine on the CVS are variable and depend upon the prevailing autonomic tone. The drug may cause bradycardia, leading to a fall in cardiac output; it decreases the effective refractory period of cardiac muscle and increases conduction time in conducting tissue. In high doses, neostigmine may cause hypotension, secondary to a central effect.
CNS
In small doses, the drug has a direct action on skeletal muscle, leading to muscular contraction. In high doses, neostigmine may block neuromuscular transmission by the combination of a direct effect and by allowing the accumulation of acetylcholine. Miosis and failure of accommodation may be precipitated by the administration of the drug.
Toxicity/side effects
The side effects are manifestations of its pharmacological actions, as described above. Cardiac arrest has been reported after the use of neostigmine.
Kinetics
Absorption
Neostigmine is poorly absorbed when administered orally; the bioavailability by this route is 1–2%.
Distribution
The drug is highly ionized and therefore does not cross the blood–brain barrier to any significant extent. Neostigmine is 6–10% protein-bound in the plasma; the VD is 0.4–1 l/kg.
Uses
Nifedipine is used in the treatment of:
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1. angina
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2. mild to severe hypertension (including pregnancy-induced hypertension)
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3. Raynaud’s phenomenon and
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4. coronary artery spasm occurring during coronary angiography or angioplasty.
Presentation
As 5/10 mg capsules and a slow-release preparation containing 10/20/30/60 mg per tablet. A fixed-dose combination with atenolol is also available.
Mode of action
Nifedipine causes competitive blockade of cell membrane slow calcium channels, leading to decreased influx of Ca2+ into cells. This produces electromechanical decoupling, inhibition of contraction, and relaxation of cardiac and smooth muscle fibres, and leads to a negative inotropic effect and vasodilatation. It may also act by increasing red cell deformability and preventing platelet clumping and thromboxane release.
Routes of administration/doses
The adult oral dose of nifedipine is 10–20 mg 8-hourly (20–40 mg 12-hourly for the slow-release preparation); 100–200 micrograms may be infused via a coronary catheter over 2 minutes.
Effects
CVS
The mean arterial pressure decreases by 20–33%; this effect is more pronounced in hypertensive patients. This is accompanied by a reflex increase in the heart rate by up to 28%. The systemic and pulmonary vascular resistance and left ventricular end-diastolic and pulmonary artery pressures all decrease. Cardiac output is increased; nifedipine also causes a sustained relaxation of epicardial conductance vessels, leading to increased coronary blood flow in patients with ischaemic heart disease. Nifedipine is 3–10 times more effective in inhibiting contraction in coronary artery smooth muscle than in myocardial contractile cells. The drug may also protect the myocardium during reperfusion after cardiac bypass.
RS
Nifedipine demonstrates no intrinsic bronchodilator effect in most studies. The drug appears to inhibit hypoxic pulmonary vasoconstriction.
CNS
The drug causes a marginal increase in the cerebral blood flow due to vasodilatation of large cerebral vessels.
AS
Contractility throughout the gut and lower oesophageal pressure are decreased by nifedipine. The hepatic blood flow is increased.
Toxicity/side effects
Occur in 20% of patients; headache, flushing, and dizziness (secondary to vasodilatation) are common; oedema of the legs, eye pain, and gum hyperplasia have been reported.
Kinetics
Special points
Nifedipine is a safe and effective drug for the treatment of post-surgical hypertension; the reduction in mean arterial pressure is associated with an increase in the cardiac index and systemic oxygen transport.
All volatile agents in current use decrease Ca2+ release from the sarcoplasmic reticulum and decrease Ca2+ flux into cardiac cells; the negatively inotropic effects of nifedipine are thus additive with those of the volatile agents. When used in combination with isoflurane, the negative inotropic effects of the drugs are additive and may result in a profound decrease in cardiac output.
Experiments in animals have demonstrated an increased risk of sinus arrest if volatile agents and calcium antagonists are used concurrently. If withdrawn acutely (especially in the post-operative period) after chronic oral use, severe rebound hypertension may result.
Calcium channel antagonists may also:
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1. reduce the MAC of volatile agents by up to 20% and
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2. increase the efficacy of NMB agents.
Administration of nifedipine immediately prior to induction appears to aggravate redistribution hypothermia. The drug is not removed by dialysis.
Uses
Nimodipine is used:
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1. in the prevention and treatment of cerebral vasospasm secondary to subarachnoid haemorrhage and may be of use in the management of
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2. migraine
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3. acute cerebrovascular accidents and
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4. drug-resistant epilepsy.
Presentation
As an intravenous infusion containing 200 micrograms/ml of nimodipine containing ethanol 20% and macrogol ‘400’ 17%, and as 30 mg tablets.
Mode of action
Nimodipine is a calcium antagonist that binds to specific sites in the cell membranes of vascular smooth muscle and prevents Ca2+ influx through ‘slow’ Ca2+ channels, leading to vasodilatation; the drug has a relatively specific action on cerebral arterioles.
Routes of administration/doses
The drug should be administered into a running crystalloid infusion via a central vein at the rate of 1 mg/hour for the first 2 hours and thereafter at the rate of 2 mg/hour for 5–14 days. The oral dose is 60 mg every 4 hours, starting within 4 days of subarachnoid haemorrhage.
Effects
Toxicity/side effects
Side effects occur infrequently, although flushing, headache, nausea, hypotension, and reversible abnormalities of liver function tests may complicate the use of the drug.
Kinetics
Absorption
Nimodipine is rapidly and well absorbed when administered orally but has a bioavailability by this route of only 3–28% due to a significant first-pass metabolism.
Nimodipine is initially demethylated and dehydrogenated to an inactive pyridine analogue which subsequently undergoes further degradation.
Excretion
Half of the dose appears as metabolites in the urine, and a third in the faeces. The clearance is 420–520 l/hour, and the elimination half-life is 0.9–7.2 hours (dependent upon the route of administration). The clearance is decreased by hepatic impairment; the effect of renal impairment is unclear.
Special points
Nimodipine has some effect in obtunding the cardiovascular responses to intubation and surgical stimulation; the peak blood pressures post-intubation and post-incision are consistently 10–15% lower in patients receiving the drug than those recorded in untreated patients.
The drug is adsorbed onto polyvinyl chloride tubing and is also light-sensitive; however, it remains stable in diffuse daylight for up to 10 hours.
Presentation
In aluminium cylinders containing 100/800 ppm of NO and nitrogen; the cylinders may contain either 353 l at standard temperature and pressure (STP) of NO in nitrogen or 1963 l at STP. Pure NO is toxic and corrosive. NO can also be supplied via stainless steel medical gas piping.
Mode of action
NO is produced in vivo by NO synthase which uses the substrate L-arginine. NO diffuses to the vascular smooth muscle layer and stimulates guanylate cyclase; the cyclic guanosine monophosphate (cGMP) produced activates a phosphorylation cascade which leads to smooth muscle relaxation and vasodilatation.
Routes of administration/doses
NO is administered by inhalation in a dose of 5–20 ppm; the drug can either be injected into the patient limb of the inspiratory circuit of a ventilator during inspiration only or administered using a continuous-flow system which delivers NO throughout the respiratory cycle. The former technique reduces a ‘bolus’ effect seen with a continuous-flow technique, in addition to reducing nitrogen dioxide formation. This latter effect is achieved by decreasing the time allowed for oxygen and NO to mix. The delivery system is designed to minimize the oxidation of NO to nitrogen dioxide. Monitoring of NO concentrations can be achieved by a chemiluminescence monitor or electrochemical detector.
Effects
CVS
NO is a potent vasodilator that mediates the hypotension and significant vascular leak characteristic of septic shock. Inhaled NO is a selective pulmonary vasodilator, since it is avidly bound to haemoglobin and thereby inactivated before reaching the systemic circulation. NO released from the vascular endothelium inhibits platelet aggregation and attenuates platelet and white cell adhesion.
RS
NO inhibits hypoxic pulmonary vasoconstriction and preferentially increases blood flow through well-ventilated areas of the lung, thereby improving ventilation:perfusion relationships.
CNS
NO increases the cerebral blood flow and appears to have a physiological role as a neurotransmitter within the autonomic and central nervous systems.
Exposure to 500–2000 ppm of NO results in methaemoglobinaemia and pulmonary oedema. Contamination by nitrogen dioxide can similarly lead to pneumonitis and pulmonary oedema.
Kinetics
Special points
Prolonged inhalation (up to 27 days) of the gas appears safe and is not associated with tachyphylaxis.
Abrupt cessation of NO can cause a profound decrease in PaO2 and increase in pulmonary artery pressure, possibly via downregulation of endogenous NO production or guanylate cyclase activity. The dose should be reduced slowly to avoid this from occurring, even in patients who may not have clinically responded to NO therapy. During treatment, concentrations of nitrogen dioxide must be monitored.
NO therapy is contraindicated in neonates known to have circulations dependent on a right-to-left shunt or significant left-to-right shunts.
Development of methaemoglobinaemia usually rapidly resolves on discontinuation of treatment over several hours. Persistent methaemoglobinaemia can be treated using methylthioninium chloride.
Mortality does not appear to be affected by the administration of NO in ARDS.
The occupational exposure limits are 25 ppm for NO and 3 ppm for nitrogen dioxide.
Uses
N2O is used:
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1. as an adjuvant to the induction and maintenance of general anaesthesia
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2. as an analgesic during labour and other painful procedures
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3. in cryosurgery as a refrigerant
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4. as a gas of recreational use.
Presentation
As a liquid in cylinders at a pressure of 44 bar at 15ºC; the cylinders are French blue and are available in six sizes (C–J, containing 450–18 000 l, respectively), following manufacture by heating ammonium nitrate to 250ºC. The gauge pressure does not correlate with the cylinder content, until all N2O is in the gaseous phase. It is a sweet-smelling, colourless gas; it is non-flammable but supports combustion. It has a molecular weight of 44, specific gravity of the gas of 1.53, a boiling point of −88.5ºC, a critical temperature of 36.5ºC, and a critical pressure of 71.7.atmospheres. Due to the critical temperature being close to the ambient temperature, the filling ratio of the cylinder is 0.75 in temperate regions, but reduced to 0.67 in tropical regions. The MAC of N2O is 105, the oil:water partition coefficient 3.2, and the blood:gas partition coefficient 0.47 (compared to 0.015 for nitrogen). There are trace amounts of CO2, carbon monoxide, and NO/nitrogen dioxide present in cylinders of N2O at the following maximum amounts: 300 vpm, 10 vpm, 2 vpm, respectively.
Entonox® is the trade name given to a 50/50 mixture of oxygen and N2O and is produced by bubbling oxygen through liquid N2O. It is available in cylinders which are French blue, with white and blue shoulders in the following four sizes: SD, D, F, G, containing 440–5000 l, respectively. The cylinder pressure is 137 bar at 15°C. At normal temperatures, both of the components of Entonox® are present in pressurized cylinders in the gaseous phase (due to the Poynting effect); below its pseudocritical temperature of −7ºC, liquefaction of N2O occurs, resulting in the separation of the two components.
N2O is also available commercially as small cannisters.
Mode of action
The mode of action of the anaesthetic action of N2O is via non-competitive inhibition of the NMDA-subtype of glutamate receptors (N-methyl-D-aspartate)—this provides the predominant analgesic component of N2O. It may also act via the two-pore domain potassium channels (e.g. TREK-1) which increase potassium conductance and subsequent neurone hyperpolarization. It appears to have minimal effect at GABAA receptors. The analgesic action of N2O occurs via supraspinal activation of opioid receptors and GABA-ergic interneurones in the periaqueductal grey matter, and noradrenergic neurones in the locus coeruleus. The latter activation pathway appears to be triggered by the hypothalamic release of corticotrophin-releasing factor, mediated by N2O antagonism at the NMDA receptor.
N2O is administered by inhalation; a concentration of 70% in oxygen is conventionally used as an adjunct to general anaesthesia. Entonox® is used to provide analgesia for a range of painful procedures.
Effects
CVS
N2O decreases myocardial contractility in vitro; in vivo, the mean arterial pressure is usually well maintained by a reflex increase in the peripheral vascular resistance. Deterioration in left ventricular function occurs when N2O is added to a high-dose opioid–oxygen anaesthetic sequence, volatile agents, or a propofol infusion.
RS
The gas causes a slight depression in respiration, with a decrease in the tidal volume and an increase in the respiratory rate. N2O is non-irritant and does not cause bronchospasm.
Toxicity/side effects
15% of patients receiving N2O will experience nausea and vomiting. The gas is 35 times more soluble than nitrogen in the blood; N2O will therefore cause an increase in the size of air-filled spaces (e.g. pneumothorax, intestines, air cysts in the middle ear) in the body. A further manifestation of this physical property of the gas is the Fink effect (diffusion hypoxia); when N2O is discontinued, the ingress of the gas into the alveoli lowers the alveolar oxygen concentration. The prolonged use of high concentrations of N2O (>6 hours) leads to oxidation of the cobalt ion of cobalamin (vitamin B12). The resulting cobalt cation prevents cobalamin from acting as a coenzyme for methionine synthetase. This cytosolic enzyme is involved in the synthesis of DNA, RNA, myelin, and catecholamines. The resultant clinical syndrome is akin to pernicious anaemia, megaloblastic anaemia, and pancytopenia. Twenty percent of elderly patients are deficient in cobalamin. N2O may decrease the proliferation of human peripheral blood mononuclear cells and alter neutrophil chemotaxis. Prolonged use/abuse of the gas may lead to altered mental state, paraesthesiae, ataxia, lower limb weakness, and spasticity. Subacute combined degeneration of the cord may occur and may be irreversible. In neonatal rats, N2O exacerbates isoflurane-induced apoptotic neuronal death. N2O is teratogenic in animals when administered during early pregnancy. The maximum exposure to N2O in the UK is 100 ppm.
Kinetics
Absorption
N2O diffuses freely across the normal alveolar epithelium. The rate of uptake of the gas is increased by a decreased cardiac output, an increased concentration, and increased alveolar ventilation. Due to its relative insolubility, the alveolar concentration of the gas approaches the inspired concentration rapidly; 90% equilibration occurs within 15 minutes, and 100% equilibration within 5 hours.
Special points
N2O exhibits the following two effects. The ‘concentration effect’ implies that the greater the inspired anaesthetic concentration, the more rapid the rise in the alveolar concentration. The ‘second gas effect’ refers to the ability of one gas administered in a high concentration (e.g. N2O) to accelerate the uptake of another gas (e.g. halothane) that is co-administered. Sixty-six percent of N2O in oxygen decreases the MAC of halothane to 0.29, of enflurane to 0.6, of isoflurane to 0.5, of sevoflurane to 0.66, and of desflurane to 2.8. The use of N2O is safe in patients susceptible to malignant hyperpyrexia.
Presentation
As a clear, colourless solution containing 2 mg/ml of noradrenaline acid tartrate for dilution prior to infusion.
Mode of action
Noradrenaline is a directly and indirectly acting sympathomimetic amine that exerts its action predominantly at alpha-adrenergic receptors, with a minor action at beta-receptors.
Routes of administration/doses
Noradrenaline is administered through a central vein as an infusion in glucose or saline in a concentration of 40 micrograms/ml (expressed as the base) at a rate titrated according to the response desired. The drug has a duration of action of 30–40 minutes; tachyphylaxis occurs with prolonged administration.
Effects
CVS
Noradrenaline increases the peripheral vascular resistance, leading to an increase in the systolic and diastolic blood pressures; the cardiac output remains unchanged or decreases slightly. Reflex vagal stimulation leads to a compensatory bradycardia. The drug produces coronary vasodilatation, leading to a marked increase in coronary blood flow. The circulating blood volume is reduced by noradrenaline due to loss of protein-free fluid to the extracellular fluid. Noradrenaline may also cause nodal rhythm, AV dissociation, and ventricular dysrhythmias.
RS
The drug causes a slight increase in the minute volume, accompanied by a degree of bronchodilatation.
CNS
The cerebral blood flow and oxygen consumption are decreased by the administration of noradrenaline; mydriasis also occurs.
Toxicity/side effects
Anxiety, headache, photophobia, pallor, sweating, gangrene, and chest pain may occur with the use of the drug. Extravasation of noradrenaline may lead to sloughing and tissue necrosis.
Kinetics
Absorption
Noradrenaline undergoes significant first-pass metabolism and is inactive when administered orally.
Metabolism
Exogenous noradrenaline is metabolized by two pathways: by oxidative deamination to the aldehyde by mitochondrial monoamine oxidase (in the liver, brain, and kidney) and by methylation by cytoplasmic catechol-O-methyl transferase to normetanephrine. The predominant metabolite appearing in the urine is 3-methoxy, 4-hydroxymandelic acid (vanillylmandelic acid, VMA).
Special points
The use of noradrenaline during halothane anaesthesia may lead to the appearance of serious cardiac dysrhythmias; if co-administered with MAOIs or tricyclic antidepressants, serious hypertensive episodes may be precipitated.
The drug is pharmaceutically incompatible with barbiturates and sodium bicarbonate.
