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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0009

Ibuprofen

Uses

Ibuprofen is used in the treatment of:

  1. 1. rheumatoid arthritis and osteoarthritis

  2. 2. musculoskeletal disorders

  3. 3. soft tissue injuries

  4. 4. ankylosing spondylitis

  5. 5. acute gout

  6. 6. renal and biliary colic

  7. 7. dysmenorrhoea

  8. 8. migraine

  9. 9. post-surgical pain as an adjunct to other analgesic agents, including opioids, and

  10. 10. as an antipyretic.

Chemical

A phenylpropanoic acid derivative.

Presentation

Ibuprofen is available in multiple forms, including capsules, tablets, suspensions, suppositories, and topical gels. It may be presented as a sole agent or in combination with other drugs. The drug is often a component in proprietary cold cures. It has a pKa of 4.91.

Main actions

Analgesic, anti-inflammatory, and antipyretic.

Mode of action

Ibuprofen is a non-specific inhibitor of COX which converts arachidonic acid to cyclic endoperoxidases, thus preventing the formation of prostaglandins, thromboxanes, and prostacyclin. Prostaglandins are involved in the sensitization of peripheral pain receptors to noxious stimuli.

Routes of administration/doses

The adult oral dose is 1200– 1800 mg daily in divided doses. In severe conditions, the daily dose may be increased to 2400 mg. The paediatric oral dose is 20 mg/kg in divided doses. The drug may be administered orally, rectally, or topically.

Effects

RS

Bronchoconstriction may occur in 20% of asthmatic patients.

AS

Dyspepsia, nausea, bleeding from gastric and duodenal vessels, mucosal ulceration, perforation, and diarrhoea are expected COX-1 effects. The drug may lead to disease exacerbation in patients with Crohn’s disease or ulcerative colitis.

Metabolic/other

Ibuprofen reduces platelet aggregation.

Toxicity/side effects

Disturbances of the gastrointestinal system occur commonly. Rashes, and hepatic, renal, and haematological impairment have been reported. As with other NSAIDs, prolonged use may lead to analgesic nephropathy, characterized by papillary necrosis and interstitial fibrosis. Acute renal failure may be precipitated when NSAIDs are administered to patients who have the renal perfusion dependent on prostaglandin production (i.e. when there are high levels of circulating vasoconstrictors or hypovolaemia).

Kinetics

Absorption

The bioavailability of the drug is 80%.

Distribution

Ibuprofen is 90–99% protein-bound in the plasma to albumin. The VD is 0.14 l/kg. The drug crosses the placenta.

Metabolism

Ibuprofen undergoes hepatic metabolism via oxidation to two inactive metabolites.

Excretion

The drug is excreted in the urine. The half-life of ibuprofen is 2 hours.

Special points

NSAIDs antagonize the antihypertensive effects of ACEIs via the inhibition of vasodilatory prostaglandin synthesis. The risk of renal impairment increases if NSAIDs and ACEIs are co-administered. NSAIDs inhibit the activity of diuretics. Ibuprofen may cause premature closure of the ductus arteriosus in the fetus when administered during the third trimester of pregnancy.

Imipramine

Uses

Imipramine is used for the treatment of:

  1. 1. depression and

  2. 2. nocturnal enuresis.

Chemical

A dibenzazepine derivative.

Presentation

As 10/25 mg tablets and a syrup containing 5 mg/ml of imipramine hydrochloride.

Main action

Antidepressant.

Mode of action

Tricyclic antidepressants may potentiate the action of biogenic amines within the CNS by preventing their reuptake at nerve terminals. They also antagonize muscarinic cholinergic, alpha-1 adrenergic, and H1 and H2 histaminergic receptors.

Routes of administration/doses

The adult oral dose is 25–50 mg 6- to 8-hourly.

Effects

CVS

Imipramine causes postural hypotension as a result of peripheral alpha-adrenergic blockade; a compensatory tachycardia may develop. The tricyclic antidepressants are also negatively inotropic; they also have characteristic effects on ECG morphology, including T-wave flattening and inversion.

RS

Imipramine has little effect on respiratory function when normal doses are used.

CNS

The predominant effect of the drug is an antidepressant action which may take several weeks to develop; sedation, weakness, and fatigue are also commonly produced.

AS

High doses of imipramine increase the gastric emptying time.

Metabolic/other

The drug may produce excessive sweating by an unknown mechanism.

Toxicity/side effects

Occur in 5% and include palpitations, dysrhythmias, tremor, confusion, mania, and hepatic dysfunction. Anticholinergic side effects (blurred vision, dryness of the mouth, constipation, and urinary retention) may also occur. Overdose of the drug may result in fits, coma, and fatal dysrhythmias.

Kinetics

Absorption

The drug is well absorbed when administered orally; the bioavailability is 19–35%.

Distribution

Imipramine is 95% protein-bound in the plasma; the VD is 15–31 l/kg.

Metabolism/other

The drug is demethylated to an active form desimipramine; this is inactivated by hydroxylation, with subsequent conjugation to glucuronide.

Excretion

The glucuronide conjugates are excreted in the urine. The clearance is 11–19 ml/min/kg, and the elimination half-life is 11–25 hours.

Special points

Hyoscine and the phenothiazines displace tricyclic antidepressants from their binding sites on plasma proteins and thus increase the activity of the latter; barbiturates increase the rate of hepatic metabolism of tricyclic antidepressants and decrease their activity.

Imipramine accentuates the cardiovascular effects of adrenaline; care should be exercised when local anaesthetic agents containing adrenaline are used in patients receiving the drug. Imipramine also increases the likelihood of dysrhythmias occurring during general anaesthesia.

Imipramine is not removed by haemodialysis.

Insulin

Uses

Insulin is used in the management of:

  1. 1. type I diabetes mellitus

  2. 2. diabetic emergencies

  3. 3. the perioperative control of blood sugar concentration

  4. 4. hyperkalaemia and

  5. 5. to improve glucose utilization during TPN and

  6. 6. in provocation tests for growth hormone.

Chemical

A polypeptide hormone. Human insulin is produced commercially by recombinant DNA techniques; bovine insulin differs by three, and porcine insulin by one, amino acid from human insulin.

Presentation

A wide variety of insulin preparations are available; the standard preparations contain 100 units/ml. The source may be human recombinant, bovine, or porcine, and each may be modified by the addition of zinc or protamine to retard absorption.

Main actions

Stimulation of carbohydrate metabolism, protein synthesis, and lipogenesis.

Mode of action

Insulin binds to and activates a specific membrane-bound receptor; the effects of this may be mediated by alterations in the intracellular concentrations of cyclic nucleotides. Insulin exerts a direct effect on lipoprotein lipase, increases the rate of transcriptional and translational events during protein synthesis, and controls membrane polarization and ion transport by activating Na+K+ATPase.

Routes of administration/doses

Insulin may be administered intravenously, intramuscularly, and subcutaneously in a dose titrated according to the blood sugar estimations. It may be diluted for intravenous infusion in saline/glucose. The apparent dose requirement is increased by 20% when bovine or porcine insulin is used in place of human insulin.

Rapidly acting insulins act within 1 hour and have a duration of action of 5–7 hours; slow-acting preparations act within 4 hours and have a duration of action of 18–36 hours.

Continuous insulin infusion devices are also available for patients.

Effects

Metabolic/other

Insulin has profound effects upon carbohydrate, fat, and protein metabolism. The drug increases the rate of diffusion of glucose into all cells and specifically into hepatocytes by enhancing the activity of glucokinase (which causes the initial phosphorylation of glucose, thereby ‘trapping’ glucose intracellularly). The drug increases the rate of glycogen synthesis by enhancing the activity of phosphofructokinase (which is involved in glucose phosphorylation) and glycogen synthetase (which polymerizes monosaccharides to form glycogen). Insulin simultaneously inhibits glycogenolysis by an action on phosphorylase and inhibits gluconeogenesis. It also facilitates diffusion of glucose into muscle cells.

Insulin causes fat deposition in adipose tissue by increasing the hepatic synthesis of fatty acids; these are utilized within the liver to form triglycerides which are released into the bloodstream; insulin simultaneously activates lipoprotein lipase in adipose tissue which splits triglycerides into fatty acids, enabling them to be absorbed into adipose tissue where they are stored. The drug also inhibits a hormone-sensitive lipase, thereby preventing hydrolysis of triglycerides, and facilitates glucose transport into fat cells, leading to an increased supply of glycerol which is used in the manufacture of storage triglycerides.

Insulin causes active transport of amino acids into cells and increases mRNA translation and DNA transcription; in addition, it inhibits the catabolism of proteins.

The drug also causes an increase in the rate of potassium and magnesium transport into cells.

Toxicity/side effects

The commonest acute side effect of insulin is hypoglycaemia. Chronic use may be complicated by localized allergic reactions, lipodystrophy, and insulin resistance due to antibody formation.

Kinetics

Absorption

Insulin is inactive when administered orally, since it is destroyed by gastrointestinal proteases.

Distribution

The drug exhibits little protein binding; the VD is 0.075 l/kg (0.146 l/kg in the diabetic subject).

Metabolism

Insulin is rapidly metabolized in the liver, muscle, and kidney by glutathione insulin transhydrogenase.

Excretion

The metabolites appear in the urine. The clearance is 33.3 ml/min/kg (18.5 ml/min/kg in the diabetic subject), and the elimination half-life is 1.6–3.4 minutes (5.3–7.8 minutes in the diabetic subject).

Special points

The co-administration of steroids, levothyroxine, thiazide diuretics, and sympathomimetic agents tends to counteract the effects of insulin on carbohydrate metabolism. Many regimes of insulin administration have been described for the perioperative management of diabetic patients.

Insulin is not removed by dialysis.

Tight blood sugar control in critical illness has been shown to decrease mortality, especially in surgical patients.

Intralipid ® 20%

Uses

Intralipid® 20% is used:

  1. 1. in the preparation of TPN mixtures

  2. 2. in the treatment of local anaesthetic toxicity with or without circulatory arrest and

  3. 3. in the prevention of essential fatty acid deficiency syndrome.

Chemical

A fat emulsion.

Presentation

As a white, oil–water emulsion containing 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin, sodium hydroxide, and water. It has a pH of approximately 8 and contains emulsified fat particles of 0.5 micrometres in size. Soybean oil consists of long-chain unsaturated fatty acids in the following proportions: linoleic (44–62%), oleic (19–30%), palmitic (7–14%), linolenic (4–11%), stearic (1.4–5.5%). Intralipid® 20% has an osmolality of approximately 350 mOsm/kg water equivalent to 260 mOsm/l of emulsion.

Main action

As an energy substrate. Intralipid® 20% appears to reverse local anaesthetic cardiotoxicity.

Mode of action

The mechanism of action remains to be fully elucidated but may involve the establishment of a concentration gradient away from the primary site of action of the local anaesthetic.

Routes of administration/doses

Intralipid® 20% is administered by intravenous infusion when given as part of TPN therapy. The various doses with regard to this indication are beyond the scope of this book. For the treatment of local anaesthetic toxicity with or without circulatory arrest, together with advanced life support measures as indicated, an initial intravenous bolus dose of 1.5 ml/kg should be administered over 1 minute, together with the commencement of an intravenous infusion at 15 ml/kg/hour. If cardiovascular stability has not been achieved or circulation deteriorates further, two subsequent bolus doses may be given 5 minutes apart. The continuous infusion rate should be doubled to 30 ml/kg/hour at any point after 5 minutes if identical criteria are met. The maximum cumulative dose is 12 ml/kg.

Effects

Metabolic/other

The principal effect of the drug is to act as an energy substrate, 2 kcal/ml, resulting in an increase in heat production and oxygen consumption.

Toxicity/side effects

Pancreatitis may occur, secondary to hyperlipidaemia, following administration of the drug. Hepatic dysfunction has been described after prolonged use.

Kinetics

Data are incomplete. The emulsified fat particles are cleared from the bloodstream by a mechanism thought to be similar to the removal of chylomicrons.

Special points

Following the administration of Intralipid® 20% (or another intravenous lipid emulsion) in the management of suspected local anaesthetic toxicity, serum amylase or lipase should be monitored for 2 days to assist in excluding the development of pancreatitis. Cases should be reported to the appropriate national regulatory organization governing patient safety (in the UK, this is the National Patient Safety Agency), and the use of lipid reported to the international registry at http://www.lipidrescue.org.

Ipratropium

Uses

Ipratropium is used in the treatment of asthma and chronic obstructive airways disease.

Chemical

A synthetic quaternary ammonium compound which is a derivative of atropine.

Presentation

As an isotonic solution of ipratropium bromide containing 0.25 mg/ml for nebulization or as a metered-dose aerosol delivering 200 micrograms/dose (18 micrograms of which is available to the patient).

Main action

Bronchodilatation.

Mode of action

Ipratropium acts by competitive inhibition of cholinergic receptors on bronchial smooth muscle, thereby blocking the bronchoconstrictor action of vagal efferent impulses. It may also inhibit acetylcholine enhancement of mediator release by blocking cholinergic receptors on the surface of mast cells.

Routes of administration/doses

The drug is administered by inhalation of a nebulized solution or aerosol in an adult dose of 100– 500 micrograms 6-hourly or 1–2 puffs 6-hourly, respectively. The maximum effect is achieved in 1.5–2 hours and lasts 4–6 hours.

Effects

CVS

No effect on cardiovascular function is observed after administration by inhalation. When administered intravenously, tachycardia with an increase in blood pressure and cardiac output and a fall in central venous pressure may result.

RS

Bronchodilatation is the principal effect of the drug. No effect is seen on the viscosity or volume of secretions or the effectiveness of mucociliary clearance. The oxygen saturation remains unaltered, following the administration of ipratropium.

CNS

The drug has no effect, since ipratropium is unable to cross the blood–brain barrier.

AS

When given orally in large doses, gastric secretion and salivation are decreased by the drug.

Toxicity/side effects

None of the typical anticholinergic side effects are observed if ipratropium is administered by inhalation. Twenty to 30% of patients receiving the drug experience transient local effects: dryness or unpleasant taste in the mouth. Local deposition of the nebulized drug on the eye may cause mydriasis and difficulty with accommodation.

Kinetics

Absorption

The bioavailability of the drug when administered orally is 3–30%, and 5% by the inhaled route.

Distribution

The VD is 0.4 l/kg.

Metabolism

Ipratropium is metabolized to eight inactive metabolites.

Excretion

Occurs in approximately equal proportions in the urine and faeces. The clearance is 11.8 l/hour, and the elimination half-life is 3.2– 3.8 hours.

Special points

Ipratropium is less effective than beta-adrenergic agonists in the treatment of asthma, although its effectiveness in the treatment of bronchitis appears to be equal to that of the beta-adrenergic agonists. An additive effect with the latter drugs is difficult to prove.

Isoflurane

Uses

Isoflurane is used:

  1. 1. for the induction and maintenance of general anaesthesia and has been used

  2. 2. for sedation during intensive care.

Chemical

A halogenated methyl ether which is a structural isomer of enflurane.

Presentation

As a clear, colourless liquid with a pungent smell, which is non-flammable; the commercial preparation contains no additives or stabilizers and is supplied in amber-coloured bottles. The molecular weight of isoflurane is 184.5, the boiling point 48.5°C, and the saturated vapour pressure 32 kPa at 20°C. The MAC of isoflurane is 1.15 (0.50 in 70% N2O), although it is age-dependent and ranges from 1.05 in elderly patients to 1.6 in neonates; the blood:gas partition coefficient is 1.4, and the fat:blood partition coefficient is 50. The oil:gas partition coefficient is 97.

Main action

General anaesthesia (reversible loss of both awareness and recall of noxious stimuli).

Mode of action

The mechanism of general anaesthesia remains to be fully elucidated. General anaesthetics appear to disrupt synaptic transmission (especially in the area of the ventrobasal thalamus). This mechanism may include potentiation of the GABAA and glycine receptors and antagonism at NMDA receptors. Their mode of action at the molecular level appears to involve the expansion of hydrophobic regions in the neuronal membrane, either within the lipid phase or within hydrophobic sites in cell membranes.

Routes of administration/dose

Isoflurane is administered by inhalation; the agent has a pleasant, non-irritant odour. The concentration used for induction of anaesthesia is quoted as 5–8%. Maintenance of anaesthesia is usually achieved using between 0.5 and 3%.

Effects

CVS

Isoflurane causes a dose-related decrease in myocardial contractility and mean arterial pressure; the systolic pressure decreases to a greater degree than the diastolic pressure. The drug does not affect the heart rate, and myocardial sensitization to catecholamines does not occur. The drug does not appear to cause the ‘coronary steal’ phenomenon in man.

RS

Isoflurane is a respiratory depressant, causing dose-dependent decreases in the tidal volume and an increase in the respiratory rate. The drug depresses the ventilatory response to CO2 and inhibits hypoxic pulmonary vasoconstriction. Isoflurane appears to relax bronchial smooth muscle constricted by histamine or acetylcholine.

CNS

The principal effect of isoflurane is general anaesthesia. The drug causes cerebral vasodilation, leading to an increase in cerebral blood flow; the cerebral metabolic rate is decreased. As with other volatile anaesthetic agents, isoflurane may increase the intracranial pressure in a dose-related manner. Isoflurane use is not associated with epileptiform activity.

GU

Isoflurane reduces renal blood flow and leads to an increase in fluoride ion concentrations (12 micromoles/l to 90 micromoles/l in anaesthesia lasting 1 to 6 hours, respectively). There is no evidence that isoflurane causes gross changes in human renal function. The drug causes uterine relaxation.

Metabolic/other

In animal models, the drug decreases liver synthesis of fibrinogen, transferrin, and albumin.

Toxicity/side effects

Isoflurane may cause PONV. Isoflurane is a trigger agent for the development of malignant hyperthermia. There are no reports of renal toxicity occurring in patients who have received the drug.

Kinetics

Absorption

The major factors affecting the uptake of volatile anaesthetic agents are solubility, cardiac output, and the concentration gradient between the alveoli and venous blood. Due to the low blood:gas partition coefficient of isoflurane, it is exceptionally insoluble in blood; the alveolar concentration therefore reaches inspired concentration very rapidly (fast wash-in rate), resulting in a rapid induction of (and emergence from) anaesthesia. An increase in the cardiac output increases the rate of alveolar uptake and slows the induction of anaesthesia. The concentration gradient between the alveoli and venous blood approaches zero at equilibrium; a large concentration gradient favours the onset of anaesthesia.

Distribution

The drug is initially distributed to organs with a high blood flow (brain, heart, liver, kidney) and later to less well-perfused organs (muscle, fat, bone).

Metabolism

0.2% of an administered dose undergoes hepatic metabolism, principally by oxidation and dehalogenation.

Excretion

Isoflurane is principally exhaled unchanged; 0.2% of an administered dose is excreted in the urine as non-volatile fluorinated compounds.

Special points

Isoflurane potentiates the action of co-administered depolarizing and non-depolarizing muscle relaxants to a greater extent than either halothane or enflurane.

As with other volatile anaesthetic agents, the co-administration of N2O, benzodiazepines, or opioids lowers the MAC of isoflurane.

Drug structure

For the drug structure, please see Fig. 4.


Fig. 4 Drug structure of isoflurane.

Fig. 4 Drug structure of isoflurane.

Isoprenaline

Uses

Isoprenaline is used in the treatment of:

  1. 1. complete heart block (whilst awaiting transvenous pacing)

  2. 2. asthma

  3. 3. torsades de pointes and is used to provide

  4. 4. inotropic support.

Chemical

A synthetic catecholamine.

Presentation

As a clear solution for injection containing 0.02/1 mg/ml of isoprenaline hydrochloride. An aerosol delivering 80/400 micrograms of isoprenaline sulfate per metered dose is also available.

Main actions

Positive inotropism, positive chronotropism, and broncho- dilatation.

Mode of action

Isoprenaline is a beta-adrenergic agonist; its actions are mediated by membrane-bound adenylate cyclase and the subsequent formation of cAMP.

Routes of administration/doses

Isoprenaline may also be administered as an infusion, diluted in water or 5% glucose, at the rate of 0.5–8 micrograms/min, according to response. The positive chronotropic effect becomes apparent after 20 minutes.

Effects

CVS

Isoprenaline is a powerful positive inotrope and chronotrope, and thus causes an increase in the cardiac output and systolic blood pressure. The drug causes a decrease in the peripheral vascular resistance (a beta-2 effect); as a result, the diastolic blood pressure tends to decrease. The drug increases automaticity and enhances AV nodal conduction; it also increases the coronary blood flow which tends to offset the increase in myocardial oxygen consumption that it produces.

RS

The drug is a potent bronchodilator, and increases anatomical dead space and ventilation/perfusion mismatching which may lead to hypoxia.

CNS

Isoprenaline is a CNS stimulant.

AS

Isoprenaline decreases gastrointestinal tone and motility; the mesenteric blood supply is increased by the drug.

GU

The administration of isoprenaline reduces the renal blood flow in normotensive subjects but may increase renal perfusion in shock states. The drug also reduces the uterine tone.

Metabolic/other

In common with adrenaline, isoprenaline increases the plasma concentration of free fatty acids and may cause hyperglycaemia. Isoprenaline inhibits antigen-induced histamine release and the formation of slow-releasing substance of anaphylaxis.

Toxicity/side effects

The use of isoprenaline may be complicated by excessive tachycardia, palpitations, angina, dysrhythmias, hypotension, and sweating. The use of isoprenaline inhalers by asthmatic patients has been associated with an excess mortality.

Kinetics

Quantitative data are lacking.

Absorption

The drug is well absorbed when administered orally but is subject to an extensive first-pass metabolism in the intestinal mucosa and liver.

Distribution

Isoprenaline is 65% protein-bound in the plasma.

Metabolism

Isoprenaline is a relatively poor substrate for the action of monoamine oxidase; the drug is predominantly metabolized by catechol-O-methyl transferase in the liver to sulfated conjugates.

Excretion

15–75% of an administered dose of isoprenaline is excreted unchanged in the urine, the remainder as sulfated conjugates. The plasma half-life is 1–7 minutes.

Special points

Hypoxia, hypercapnia, and the co-administration of halothane, trilene, or cyclopropane increase the likelihood of the development of dysrhythmias during the use of isoprenaline. Tachyphylaxis may occur with prolonged use.

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