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Source:
Drugs in Anaesthesia and Intensive Care (5 ed.)
Author(s):

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0013

Nalbuphine

Uses

Nalbuphine is used:

  1. 1. for premedication and

  2. 2. as an analgesic in the treatment of moderate to severe pain.

Chemical

A semi-synthetic phenanthrene derivative.

Presentation

As a clear, colourless solution for injection containing 10 mg/ml of nalbuphine hydrochloride.

Main action

Analgesia.

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.

CNS

Nalbuphine has an analgesic potency equivalent to that of morphine. It has no euphoriant effects.

AS

The drug causes less inhibition of gastrointestinal activity than other opioids.

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.

Distribution

Nalbuphine is 25–40% protein-bound in the plasma; the VD is 162–498 l.

Metabolic/other

Occurs predominantly in the liver to two inactive conjugates which are secreted into the bile.

Excretion

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.

Special points

Nalbuphine is ineffective in obtunding the cardiovascular responses to laryngoscopy and intubation. The drug will precipitate withdrawal symptoms in opiate addicts; its effects are reversed by naloxone.

Nalbuphine has been used in the management of post-operative shivering.

Naloxone

Uses

Naloxone is used for:

  1. 1. the reversal of respiratory depression due to opioids

  2. 2. the diagnosis of suspected opioid overdose and has been used in the treatment of

  3. 3. clonidine overdose.

Chemical

A substituted oxymorphone derivative.

Presentation

As a clear solution for injection containing 0.02/0.4 mg/ml of naloxone hydrochloride.

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.

CNS

Naloxone causes slight drowsiness at very high doses. Some forms of stress-induced analgesia are obtunded by naloxone; the drug also decreases the tolerance to pain in subjects with high pain thresholds.

AS

Naloxone reverses opioid-induced spasm of the sphincter of Oddi.

Toxicity/side effects

Serious ventricular dysrhythmias occurring in patients with irritable myocardia after the administration of naloxone have been reported.

Kinetics

Absorption

The drug is 91% absorbed when administered orally but has a bioavailability by this route of 2% due to an extensive first-pass metabolism.

Distribution

The drug is 46% protein-bound in adult plasma. The VD is 2 l/kg.

Metabolism

The drug is metabolized in the liver, primarily by conjugation to glucuronide.

Excretion

The clearance is 25 ml/min/kg, and the plasma half-life is 1.2 hours.

Special points

Naloxone is effective in alleviating the pruritus, nausea, and respiratory depression associated with the epidural or spinal administration of opioids.

Neostigmine

Uses

Neostigmine is used:

  1. 1. for the reversal of non-depolarizing neuromuscular blockade and in the treatment of

  2. 2. myasthenia gravis

  3. 3. paralytic ileus and

  4. 4. urinary retention.

Chemical

A quaternary amine which is an ester of an alkyl carbamic acid.

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.

Main actions

Cholinergic.

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.

RS

Neostigmine increases bronchial secretion and may cause broncho- constriction.

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.

AS

The drug increases salivation, lower oesophageal and gastric tone, gastric acid output, and lower gastrointestinal tract motility. Nausea and vomiting may occur.

GU

Neostigmine increases ureteric peristalsis and may lead to involuntary micturition.

Metabolic/other

Sweating and lacrimation are increased.

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

Data are incomplete.

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.

Metabolism

Neostigmine is predominantly metabolized by plasma esterases to a quaternary alcohol; some hepatic metabolism with subsequent biliary excretion may also occur.

Excretion

50–67% of an administered dose is excreted in the urine. The clearance is 5.7–11.1 ml/min/kg, and the elimination half-life is 15–80 minutes; the clearance is decreased, and the elimination half-life is increased in the presence of renal impairment.

Special points

Neostigmine prolongs the duration of action of suxamethonium. There is some evidence that the use of neostigmine to reverse neuromuscular blockade is associated with an increased incidence of gastrointestinal anastomotic breakdown.

Nifedipine

Uses

Nifedipine is used in the treatment of:

  1. 1. angina

  2. 2. mild to severe hypertension (including pregnancy-induced hypertension)

  3. 3. Raynaud’s phenomenon and

  4. 4. coronary artery spasm occurring during coronary angiography or angioplasty.

Chemical

A dihydropyridine derivative.

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.

Main actions

Relaxation of arterial smooth muscle in both the coronary and peripheral circulations.

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.

GU

Nifedipine has no marked effect on the renal blood flow or glomerular filtration rate. Uterine activity is decreased by the drug.

Metabolic/other

Plasma renin activity and catecholamines are increased; short-term use may decrease glucose tolerance. Platelet aggregation is impaired by the drug; thromboxane synthesis is inhibited, and nifedipine may thus decrease thromboxane-induced coronary artery spasm.

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

Absorption

Nifedipine is completely absorbed when administered orally; the bioavailability by this route is 45–68%.

Distribution

The drug is 92–98% protein-bound in the plasma, the VD is 0.62–1.12 l/kg.

Metabolism

95% of the dose is metabolized in the liver to three inactive metabolites.

Excretion

90% of the metabolites are excreted in the urine, the rest in the faeces. The clearance is 27–66 l/hour, and the elimination half-life is 1.3–11 hours, dependent upon the route of administration.

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:

  1. 1. reduce the MAC of volatile agents by up to 20% and

  2. 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.

Nimodipine

Uses

Nimodipine is used:

  1. 1. in the prevention and treatment of cerebral vasospasm secondary to subarachnoid haemorrhage and may be of use in the management of

  2. 2. migraine

  3. 3. acute cerebrovascular accidents and

  4. 4. drug-resistant epilepsy.

Chemical

A dihydropyridine.

Presentation

As an intravenous infusion containing 200 micrograms/ml of nimodipine containing ethanol 20% and macrogol ‘400’ 17%, and as 30 mg tablets.

Main action

Dilation of cerebral vessels, leading to improved cerebral perfusion.

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

CVS

In normal subjects, doses of 2 mg/hour decrease the systolic and diastolic blood pressures. In the anaesthetized patient, an infusion of 1 microgram/kg/min decreases the systemic vascular resistance by 10– 40% and increases the cardiac output by 25–45%.

CNS

Nimodipine increases the cerebral blood flow by up to 18%, with no demonstrable ‘steal’ effect in patients who have had a subarachnoid haemorrhage. The use of nimodipine in such patients leads to a significant reduction in mortality and morbidity.

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.

Distribution

The drug is 98% protein-bound in the plasma; the VD is 0.94–2.3 l/kg.

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.

Nitric oxide

Uses

Nitric oxide (NO) is used as a selective pulmonary vasodilator in pulmonary hypertension.

Chemical

An inorganic gas.

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.

Main actions

Vasodilatation.

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.

GU

NO may play a role in the regulation of renin production and sodium homeostasis in the kidney. It is the physiological mediator of penile erection.

Metabolic/other

NO released from macrophages reacts with superoxide ion to form the free radical peroxynitrite which is toxic to bacteria. Insulin release appears to be modulated by NO.

Toxicity/side effects

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

Absorption

NO is highly lipid-soluble and diffuses freely across cell membranes.

Metabolism

Following inhalation, NO combines with oxyhaemoglobin that is 60–100% saturated, producing methaemoglobin and nitrate. NO has a half-life of <5 seconds. During the first 8 hours of NO exposure, methaemoglobin concentrations increase.

Excretion

The main metabolite is nitrate (70%) which is excreted by the kidneys.

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.

Nitrous oxide

Uses

N2O is used:

  1. 1. as an adjuvant to the induction and maintenance of general anaesthesia

  2. 2. as an analgesic during labour and other painful procedures

  3. 3. in cryosurgery as a refrigerant

  4. 4. as a gas of recreational use.

Chemical

An inorganic gas.

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.

Main actions

Analgesia and depression of the CNS.

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.

Routes of administration/dose

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.

CNS

N2O is a CNS depressant and, when administered in a concentration of 80%, will cause loss of consciousness in most subjects. The gas is a powerful analgesic in concentrations of >20%. Its administration causes a rise in the intracranial pressure.

GU

N2O has no effect on the uterine tone.

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.

Metabolism

Little, if any, metabolism occurs in man.

Excretion

N2O is excreted unchanged through the lungs and skin.

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.

Noradrenaline

Uses

Noradrenaline is used in the treatment of refractory hypotension.

Chemical

A catecholamine.

Presentation

As a clear, colourless solution containing 2 mg/ml of noradrenaline acid tartrate for dilution prior to infusion.

Main action

Increased systemic vascular resistance.

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.

AS

The hepatic and splanchnic blood flow are decreased by the drug.

GU

Noradrenaline decreases the renal blood flow; the glomerular filtration rate is usually well maintained. The tone of the bladder neck is increased. Noradrenaline increases the contractility of the pregnant uterus; this may lead to fetal bradycardia and asphyxia.

Metabolic/other

Noradrenaline may decrease insulin secretion, leading to hyperglycaemia; the concentration of free fatty acids and the plasma renin activity may increase.

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.

Distribution

The VD is 0.09–0.4 l/kg.

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).

Excretion

5% of an administered dose of noradrenaline is excreted unchanged; the clearance is 27.9–100 ml/min/kg, and the half-life is 0.57–2.4 minutes.

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.

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