Page of

O 

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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0014

Omeprazole

Uses

Omeprazole is used in the treatment of:

  1. 1. peptic ulcer disease

  2. 2. peptic oesophagitis

  3. 3. the Zollinger–Ellison syndrome

  4. 4. prevention of NSAID-associated ulcers and

  5. 5. following endoscopic treatment of peptic ulcer bleeding.

Chemical

A substituted benzimidazole derivative.

Presentation

As capsules containing 10/20/40 mg of omeprazole and in 40 mg vials as a powder of the sodium salt of omeprazole.

Main actions

Inhibition of basal and stimulated gastric acid secretion.

Mode of action

Omeprazole acts via a derivative which binds irreversibly to parietal cell H-K-ATPase and non-competitively inhibits it. The activity of the parietal cell ‘proton pump’, which represents the final common pathway of hydrogen ion secretion, is thus inhibited.

Routes of administration/doses

The adult oral dose for the treatment of peptic ulcer disease is 20–40 mg daily for a period of 4–8 weeks; the corresponding dose for the treatment of the Zollinger–Ellison syndrome is 20–120 mg daily. The intravenous dose is administered over 5 minutes.

Effects

AS

Omeprazole significantly reduces the volume of gastric juice but has no effect on the rate of gastric emptying. A single 20 mg dose will effectively control acid secretion for 24 hours. In animals, orally administered omeprazole appears to confer protection against stress-induced gastric ulceration.

Metabolic/other

The drug has no demonstrable effect on endocrine function.

Toxicity/side effects

Omeprazole is usually well tolerated; rashes, nausea, headache, gastrointestinal disturbances, liver dysfunction, and arrhythmia may occur.

Kinetics

Absorption

Oral omeprazole is rapidly absorbed and has a bioavailability of 40–97%, dependent upon the formulation and dose. The drug may increase its own bioavailability, since degradation occurs under acidic conditions.

Distribution

The drug is 95–96% protein-bound in the plasma, predominantly to albumin and alpha-1-acid glycoprotein. The VD is 0.3–0.4 l/kg.

Metabolism

Omperazole is rapidly and completely metabolized by oxidation to a sulfone, reduction to a sulfide, and hydroxylation.

Excretion

80% of an oral dose is excreted in the urine, the remainder in the faeces. The clearance is 533–666 ml/min, and the elimination half-life is 0.5–1.5 hours.

Special points

Omeprazole is 2–10 times as potent as cimetidine; furthermore, it heals ulcers significantly more rapidly than conventional H2 antagonist regimes and may be effective in patients resistant to conventional therapy. Proton pump inhibitors reduce the risk of rebleeding from peptic ulcer disease and the need for surgery.

The pharmacokinetics of the drug are unaltered by renal impairment, and it is not removed by haemodialysis; no dose reduction is required in patients with renal or hepatic impairment. Omeprazole decreases the clearance of co-administered diazepam, phenytoin, and warfarin.

Administration of omeprazole (as with other proton pump inhibitors) is associated with ventilator-associated pneumonia in critically ill patients.

Ondansetron

Uses

Ondansetron is used:

  1. 1. in the management of nausea and vomiting induced by chemotherapy and radiotherapy and

  2. 2. in the prevention and treatment of PONV.

Chemical

A synthetic carbazole.

Presentation

As a clear, colourless aqueous solution in 2/4 ml ampoules containing 2 mg/ml ondansetron hydrochloride dihydrate. It is also available as 4/8 mg tablets, as a strawberry-flavoured lyophilizate (4/8 mg), and as a suppository containing 16 mg of ondansetron.

Main action

Antiemetic.

Mode of action

Ondansetron is a highly selective antagonist at 5HT3 receptors and acts both centrally and peripherally. Emetogenic stimuli appear to cause release of 5HT in the small intestine and initiate a vomiting reflex by activating vagal afferents via 5HT3 receptors; ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also result in the release of 5HT in the area postrema, promoting emesis via a central mechanism.

Routes of administration/doses

For prevention of chemotherapy- or radiotherapy-induced nausea and vomiting, the route of administration and dose of ondansetron should be flexible in the range of 8–32 mg/day. For prophylaxis against PONV, the drug may be administered as a single dose of 4 mg by intramuscular or slow intravenous injection. The paediatric dose is 0.1 mg/kg. Identical doses are recommended for treatment of established PONV.

Effects

CVS

Ondansetron has no demonstrable effects on the CVS.

RS

The drug has no effect on the ventilatory response to CO2.

CNS

Ondansetron has no sedative effects and does not impair performance in psychomotor tests.

AS

Ondansetron has no effect on gastric motility but does increase large bowel transit time.

Metabolic/other

Ondansetron has no effect on serum prolactin concentration or haemostatic function.

Toxicity/side effects

Constipation, headache, and flushing may occur. Bradycardia may occur, following rapid intravenous administration. Rare cases of anaphylaxis have been reported.

Kinetics

Absorption

Ondansetron is passively and completely absorbed, following oral administration, and undergoes first-pass metabolism. Oral bioavailability of the drug is 60–65%. Peak plasma concentrations of approximately 30 ng/ml are achieved in about 1.5 hours, following an 8 mg oral dose. Following intramuscular injection, peak plasma levels of 25 ng/ml are reached within 10 minutes, and, following a 4 mg intravenous dose, peak plasma levels of 65 ng/ml are achieved.

Distribution

The drug is 70–76% protein bound in the plasma; the VD is 2 l/kg.

Metabolism

Ondansetron is extensively metabolized in the liver by multiple hepatic cytochrome P450 enzymes (CYP3A4, CYP2D6, and CYP1A2). The drug is metabolized by hydroxylation or N-demethylation of the indole nucleus, followed by conjugation with glucuronic acid or sulfate. Due to the number of enzyme systems involved, inhibition or deficiency of one (e.g. CYP2D6 deficiency/debrisoquine polymorphism) is normally compensated by other enzymes, resulting in little or no significant change in ondansetron clearance or dose requirement. Patients receiving CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin) may have increased clearance of ondansetron, although this does not require dosage adjustment.

Excretion

Less than 5% of the drug is excreted unchanged in the urine. The clearance is 6.3 ml/kg/min, and the elimination half-life is 3 hours.

Special points

In patients with renal impairment, both the systemic clearance and VD are reduced, following intravenous administration of ondansetron, resulting in an increase in the elimination half-life (>4 hours). This increase is not clinically significant, and no alteration of dose is required in patients with renal impairment. Hepatic impairment significantly reduces the clearance of the drug, with prolonged elimination half-lives (15–32 hours) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism. As a result of these effects, the dose of ondansetron should be limited to 8 mg/day in patients with hepatic impairment.

The drug may reduce the analgesic effect of tramadol.

Ondansetron contains <23 mg of sodium per dose.

Ondansetron may reduce the incidence of post-anaesthetic shivering.

Ondansetron may be used in combination with dexamethasone in the treatment of PONV.

Oseltamivir

Uses

Oseltamivir is used in the treatment of:

  1. 1. influenza virus infections and

  2. 2. for the prophylaxis of influenza virus infections.

Chemical

A synthetic ethyl ester.

Presentation

As 30/45/75 mg capsules and as a granulate powder for oral suspension at a concentration of 12 mg/ml of oseltamivir phosphate.

Main action

Oseltamivir is an antiviral agent active against influenza virus.

Mode of action

Oseltamivir phosphate is a pro-drug and requires ester hydrolysis to convert it into the active component oseltamivir carboxylate. Oseltamivir carboxylate selectively inhibits influenza A and B neuraminidases in vitro, leading to inhibition of virus infection and replication.

Routes of administration/doses

The adult oral dose for treatment of influenza infection is 150 mg in divided doses for 5 days. The dose in children aged between 1 and 12 years old is dependent on the patient’s weight as follows: ≤15 kg (30 mg twice daily), >15–23 kg (45 mg twice daily), >23–40 kg (60 mg twice daily), >40 kg (75 mg twice daily), for 5 days. The dose for infants <12 months of age is 3 mg/kg (3–12 month olds), 2.5 mg/kg (1–3 month olds), 2 mg/kg (0–1 month old), twice daily for 5 days. The recommended dose for post-exposure prophylaxis is 75 mg once daily for 10 days in adults. The dose in children aged between 1 and 12 years old is dependent on the patient’s weight as follows: ≤15 kg (30 mg once daily), >15–23 kg (45 mg once daily), >23–40 kg (60 mg once daily), >40 kg (75 mg once daily), for 10 days. The dose for infants <12 months of age is 3 mg/kg (3–12 month olds), 2.5 mg/kg (1–3 month olds), 2 mg/kg (0–1 month old), once daily for 10 days. Efficacy has been demonstrated when treatment initiation occurs within 2 days of first onset of symptoms (for treatment) or within 2 days of exposure to an infected individual (for prophylaxis).

Toxicity/side effects

The most commonly reported side effects are nausea (11%) and vomiting (8%), following use of the drug in adults. The incidence of these effects is higher in paediatric patients.

Kinetics

Absorption

The drug is readily absorbed from the gastrointestinal tract. Oseltamivir phosphate is converted by hepatic esterases to oseltamivir carboxylate. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate.

Distribution

The drug is 3% protein-bound in the plasma; the VD at steady state is approximately 23 l.

Metabolic/other

Oseltamivir phosphate is extensively converted to oseltamivir carboxylate by hepatic esterases. It undergoes no further metabolism prior to elimination. Neither the pro-drug nor its active metabolite interacts with the hepatic cytochrome P450 system.

Excretion

Oseltamivir carboxylate is eliminated by renal excretion (>99%) via tubular secretion.

Special points

Dose reduction is recommended in patients with severe renal impairment. No dose adjustment is required in patients with hepatic impairment.

In vitro studies have demonstrated that virus isolates with reduced susceptibility to oseltamivir carboxylate can be recovered. Resistance to the drug is associated with mutations, resulting in amino acid substitutions in viral neuraminidase, haemagglutinin, or both. Resistant mutations are usually viral subtype-specific and may be naturally occurring (i.e. no prior exposure to oseltamivir required to cause resistance).

Oxycodone

Uses

Oxycodone is used for:

  1. 1. the treatment of moderate to severe pain in patients with cancer and post-operative pain and

  2. 2. in the treatment of severe pain requiring a strong opioid.

Chemical

A semi-synthetic opium alkaloid derivative.

Presentation

Oxycodone is available in immediate- and controlled-release preparations. The drug is available in 10 mg/ml and 50 mg/ml preparations for intravenous use; 5/10/20 mg capsules for oral use; and 1 mg/ml and 10 mg/ml as liquid formulations for oral use. The controlled-release preparation is available in 5/10/15/20/30/40/60/80/120 mg tablets.

Main actions

The drug has opioid agonist activity, producing analgesia and anxiolysis, together with antitussive and sedative effects.

Mode of action

Oxycodone has an affinity for mu-, kappa-, and delta-opioid receptors. The MOP receptor appears to be specifically involved in the mediation of analgesia. Opioids appear to exert their effects by interacting with pre-synaptic Gi-protein receptors, leading to hyperpolarization of the cell membrane by increasing K+ conductance. Inhibition of adenylate cyclase, leading to reduced production of cAMP and closure of voltage-sensitive calcium channels, also occurs. The decrease in membrane excitability that results may decrease both pre- and post-synaptic responses.

Routes of administration/doses

The drug may be administered orally, intravenously, or subcutaneously. The initial adult intravenous dose is 1–10 mg, administered slowly over 1–2 minutes and titrated to effect. The initial adult oral dose is 5 mg 4- to 6-hourly, titrated to effect. Ten mg of oral oxycodone is equivalent to 20 mg of oral morphine; 2 mg of oral oxycodone is equivalent to 1 mg of parenteral oxycodone. There are no data available on the use of oxycodone in children. Dose reductions are required in elderly patients and those with renal and hepatic impairment.

Effects

CVS

Oxycodone has minimal effects on the CVS; the predominant effect is that of orthostatic hypotension, secondary to a decrease in the systemic vascular resistance, partly mediated by histamine release.

RS

The principal effect of the drug is respiratory depression with a decreased ventilatory response to hypoxia and hypercapnia. Oxycodone also has an antitussive action. Bronchoconstriction may occur with high doses of the drug.

CNS

Oxycodone is a powerful analgesic agent and may also cause drowsiness, relief of anxiety, and euphoria. Miosis is produced by the drug as a result of stimulation of the Edinger–Westphal nucleus. Increased muscle tone and seizure activity may occur with the use of high doses of oxycodone.

AS

Oxycodone decreases gastrointestinal motility. The drug may also cause nausea, vomiting, and constipation.

GU

The drug increases the tone of the ureters, bladder detrusor muscle, and sphincter, and may precipitate urinary retention.

Metabolic/other

The drug may cause histamine release, resulting in pruritus.

Toxicity/side effects

Respiratory depression, nausea and vomiting, hallucinations, and dependence may complicate the use of oxycodone.

Kinetics

Absorption

The oral bioavailability of oxycodone is 60–87%. The time to Pmax is 1–1.5 hours, following administration of immediate-release oxycodone. The controlled-release preparation has the same bioavailability, but, due to a biphasic release pattern, the time to reach Pmax is 3 hours.

Distribution

The VD of oxycodone is 2.6 l/kg at steady state. Approximately 45% of the drug is bound to plasma proteins. The drug penetrates the placenta and is found in breast milk.

Metabolism

The drug undergoes extensive hepatic metabolism via CYP450 3A to noroxycodone and CYP450 2D6 to oxymorphone and various other conjugated glucuronides.

Excretion

Oxycodone and its metabolites undergo renal elimination. Up to 19% of free drug, up to 50% of conjugated oxycodone, and up to 14% of conjugated oxymorphone may be found in the urine. The elimination half-life of immediate-release oxycodone is 3 hours, and that of controlled release preparations 4.5 hours. Steady state is reached in approximately 24 hours. The clearance is 800 ml/min.

Special points

Oxycodone should be used with caution in the presence of hepatic failure, as the drug may precipitate encephalopathy. In common with other opioids, oxycodone decreases the apparent MAC of co-administered volatile agents. The actions of the drug are all reversed by naloxone.

Prochlorperazine is chemically incompatible with oxycodone. The drug is compatible with hyoscine, dexamethasone, haloperidol, midazolam, and metoclopramide.

There is no evidence to suggest that blockade of CYP450 2D6 and CYP450 3A4 results in clinically significant effects.

Oxygen

Uses

Oxygen is used:

  1. 1. in the management of all forms of hypoxia (other than histotoxic)

  2. 2. as an adjunct in the management of shock and in the treatment of

  3. 3. carbon monoxide poisoning

  4. 4. pneumatosis coli

  5. 5. decompression sickness and

  6. 6. anaerobic infections.

Chemical

A gaseous inorganic element.

Presentation

As a compressed gas in cylinders at a pressure of 137 bar (13 700 kPa) at 15°C; the cylinders are black with white shoulders and are available in several different sizes. Those cylinders commonly used in hospital are C–J containing 170–6800 l, respectively. Size J cylinders are used for cylinder manifolds. The AZ cylinder is MRI-compatible and contains 170 l. Oxygen is also available commercially in liquid form, one volume of liquid oxygen yielding 840 volumes of gaseous oxygen at 15°C and 1013 mb. Liquid oxygen is stored in a vacuum-insulated evaporator (VIE) which ranges in liquid capacity from 1600 to 18 675 l, depending on its size.

Oxygen is a colourless, odourless, tasteless gas which supports combustion and is explosive in the presence of grease. It has a molecular weight of 32, a specific gravity of 1.105, a critical temperature of −118.4°C, and a critical pressure of 50.8 atmospheres.

It is supplied at 99.5% purity with maximum amounts of carbon monoxide and CO2 of 5.0 vpm and 300.0 vpm, respectively. Liquid oxygen appears pale blue.

Main action

The essential role of oxygen is in the process of oxidative phosphorylation.

Mode of action

Elemental oxygen is combined with hydrogen ions via mitochondrial cytochrome oxidase; the energy released is used for the synthesis of ATP.

Routes of administration

Oxygen is administered by inhalation via fixed-performance or variable-performance devices. Depending on the device used, inspired concentrations of up to 100% may be achieved. Fixed-performance devices include anaesthetic breathing systems with a suitably large reservoir and Venturi-operated devices (also known as high airflow oxygen enrichment, or HAFOE, devices). Variable-performance devices include Hudson face masks, partial rebreathing masks, nasal cannulae, and nasal catheters. A number of factors determine the FiO2 delivered by a variable-performance device: gas flow rate, peak inspiratory flow rate, respiratory rate, and how tightly fitting the face mask is.

Effects

CVS

The administration of 100% oxygen causes a slight decrease in the heart rate (due to an effect on chemoreceptors), a slight increase in the diastolic blood pressure, and a decrease of 8–20% in the cardiac output due to myocardial depression. The coronary blood flow decreases, secondary to coronary arterial vasoconstriction. In contrast, the PVR and mean arterial pressure decrease.

RS

Mild respiratory depression (due to a decrease in sensitivity of the respiratory centre to CO2) results from the administration of 100% oxygen. Nitrogen is eliminated from the lungs within 2–3 minutes (leading to atelectasis subsequent to the loss of the ‘splinting’ effect of nitrogen), from the blood within 5 minutes, and from the body within 2 hours. The binding of oxygen with haemoglobin tends to displace CO2 from the blood (the Haldane effect).

CNS

The administration of 100% oxygen causes cerebrovascular constriction (due to an increased sensitivity to adrenergic agonists), resulting in a decrease in the cerebral blood flow.

Toxicity/side effects

The following toxic effects are associated with the use of high concentrations of oxygen:

  1. 1. CO2 retention in patients with respiratory failure who are predominantly dependent upon a hypoxic drive to respiration

  2. 2. retrolental fibroplasia in neonates

  3. 3. acute oxygen toxicity (the Paul–Bert effect) may occur if hyperbaric 100% oxygen is used; the symptoms are altered mood, vertigo, loss of consciousness, and convulsions

  4. 4. chronic oxygen toxicity may occur when concentrations >60% are used for prolonged periods at atmospheric pressure; the symptoms of this are tracheobronchial irritation, sore throat, and substernal pain, and the signs are pulmonary congestion, atelectasis, and a decreased vital capacity

  5. 5. prolonged administration of 100% oxygen may interfere with red blood cell formation.

Kinetics

Absorption

The gas is freely permeable through normal alveolar tissue.

Distribution

Oxygen is transported in the blood predominantly combined to haemoglobin; in addition, each 100 ml of plasma contains 0.3 ml of dissolved oxygen at normal atmospheric pressure and an FiO2 of 0.21. When 100% oxygen is administered at atmospheric pressure, each 100 ml of plasma contains approximately 1.7 ml of dissolved oxygen. If 100% oxygen is administered at 3 atmospheres, approximately 6 ml of dissolved oxygen is contained within each 100 ml of plasma.

Metabolism

Occurs within mitochondria to produce CO2 and water.

Excretion

As exhaled CO2 and metabolic water.

Oxytocin

Uses

Oxytocin is used:

  1. 1. for the induction and acceleration of labour

  2. 2. to promote lactation and in the management of

  3. 3. missed and incomplete abortion and

  4. 4. post-partum haemorrhage.

Chemical

A naturally occurring polypeptide from the posterior lobe of the pituitary gland.

Presentation

As a clear solution for injection containing 5/10 units/ml of synthetic oxytocin (which is free from vasopressin and extraneous animal protein) and in a fixed-dose combination for injection containing 5 units/ml of oxytocin and 500 micrograms of ergometrine maleate (which has a more sustained effect on the uterus than does oxytocin).

Main actions

Stimulation of uterine contraction.

Mode of action

Oxytocin is thought to act by binding to specific receptors on smooth muscle cells and increasing the permeability of the myometrial cell membrane to K+, thereby decreasing the membrane potential and increasing the excitability of the uterine smooth muscle.

Routes of administration/doses

Oxytocin is administered by intravenous infusion at a rate of 1.5–12 milliunits/min, titrated against the frequency and duration of uterine contractions. The intramuscular dose of the oxytocin–ergometrine preparation is 1 ml.

Effects

CVS

Bolus intravenous administration of oxytocin causes a decrease in the blood pressure that occurs within 30 seconds and lasts up to 10 minutes—this response is exaggerated in the anaesthetized subject. A reflex tachycardia and an increase in the cardiac output by up to 1.5 l/min occur. ECG changes, such as prolongation of the QT interval and T-wave flattening, may reflect poor coronary artery filling.

AS

Oxytocin has no effect on the lower oesophageal sphincter pressure during pregnancy.

GU

Infusions of oxytocin increase the renal blood flow in animal models.

Metabolic/other

Oxytocin has an antidiuretic effect (exerted by a direct action on the renal tubules) which may, when it is administered in high doses with large volumes of electrolyte-free fluid, lead to water intoxication. Oxytocin also causes milk ejection by causing contraction of modified smooth muscle within the mammary gland, forcing milk from alveolar channels into large sinuses.

Toxicity/side effects

Oxytocin may cause uterine spasm and rupture, leading to fetal asphyxia when infused too rapidly. Anaphylactoid reactions to the drug have also been reported. Water intoxication has been described above.

Kinetics

Data are incomplete.

Absorption

Oxytocin is active when administered by any parenteral route but is inactivated by chymotrypsin when administered orally.

Metabolism

Oxytocin is rapidly removed from the plasma by hydrolysis in the liver and kidney (by the action of oxytocinase).

Excretion

The elimination half-life is 1–7 minutes.

Special points

Oxytocin should not be infused through the same intravenous line as blood and plasma, as rapid inactivation of the polypeptide by plasma oxytocinase occurs. Infusions of oxytocin may alter the action of co-administered suxamethonium, leading to a decrease in the fasciculations caused by the latter and an increased dose requirement for suxamethonium.

Copyright © 2021. All rights reserved.