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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0016

Ranitidine

Uses

Ranitidine is used in the treatment of:

  1. 1. peptic ulcer disease

  2. 2. reflux oesophagitis

  3. 3. the Zollinger–Ellison syndrome and

  4. 4. for the prevention of stress ulceration in critically ill patients and

  5. 5. prior to general anaesthesia in patients at risk of acid aspiration, especially during pregnancy and labour.

Chemical

A furan derivative.

Presentation

As a clear solution for intravenous or intramuscular injection containing 25 mg/ml, as 150/300 mg tablets, and as a syrup containing 15 mg/ml of ranitidine hydrochloride.

Main actions

Inhibition of gastric acid secretion.

Mode of action

Ranitidine acts via competitive blockade of histaminergic H2 receptors. Histamine appears to be necessary to potentiate the action of gastrin and acetylcholine on the gastric parietal cell, as well as act directly as a secretagogue.

Routes of administration/doses

Ranitidine may be administered by slow intravenous or intramuscular injection, the dose being 50 mg 6- to 8-hourly. The oral dose is 150 mg twice daily.

Effects

CVS

No effect is seen with normal clinical dosages.

RS

The drug has no effect on respiratory parameters.

AS

Ranitidine profoundly inhibits gastric acid secretion, reducing the volume, and hydrogen ion and pepsin content. The drug has a longer duration of anti-secretory activity than cimetidine. Ranitidine has been reported to cause a dose-related increase in lower oesophageal sphincter tone.

Metabolic/other

Ranitidine does not show anti-androgenic or anti-dopaminergic effects, nor does it affect cytochrome P450-mediated metabolism that are associated with cimetidine. The drug crosses the placenta, but no adverse effects on fetal well-being have been demonstrated.

Toxicity/side effects

Reversible abnormalities of liver function tests, rashes, and anaphylactoid reactions have been reported, following the use of ranitidine. Reversible confusion, thrombocytopenia, and leucopenia occur rarely after administration of the drug.

Kinetics

Absorption

Ranitidine has an oral bioavailability of 50–60%.

Distribution

The drug is approximately 15% protein-bound in the plasma; the VD is 1.2–1.8 l/kg.

Metabolism

A small fraction of the drug is metabolized by oxidation and methylation.

Excretion

Ranitidine is predominantly excreted unchanged by the kidney. The clearance is 10 ml/min/kg, and the elimination half-life is 1.6–2.5 hours.

Special points

A reduced dosage of the drug should be used in patients with renal failure; the drug is removed by haemodialysis.

Ranitidine may be associated with an increase in nosocomial pneumonia in ventilated critically ill patients.

Remifentanil

Uses

Remifentanil is used:

  1. 1. to provide the analgesic component in general anaesthesia

  2. 2. to provide analgesia/sedation in intensive care

  3. 3. to provide analgesia during labour when regional anaesthesia is not in use

  4. 4. to provide analgesia/sedation during ‘awake’ fibreoptic intubation.

Chemical

A synthetic phenylpiperidine derivative of fentanyl.

Presentation

As a white lyophilized powder to be reconstituted before use, containing remifentanil hydrochloride in a glycine buffer in 1/2/5 mg vials for dilution prior to infusion. It has a pKa of 7.1 and is 68% unionized at a pH of 7.4.

Main actions

Analgesia and respiratory depression.

Mode of action

Remifentanil is a pure mu-agonist (or MOP agonist); the mu-opioid receptor (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 occur. The decrease in membrane excitability that results may decrease both pre- and post-synaptic responses.

Routes of administration/doses

Remifentanil is licensed for intravenous administration only. The drug may be given by slow bolus injection of 1 microgram/kg over at least 30 seconds or by TCI with an approved infusion device incorporating, for example, the ‘Minto’ pharmacokinetic model with covariates for age and lean body mass. A manual infusion technique may also be used, titrated to response. The drug may be infused at a rate of 0.0125–1 microgram/kg/min, depending on the level of sedation and analgesia required. The peak effect of the drug occurs within 1– 3 minutes. The offset is rapid and predictable, even after prolonged infusion, typically occurring within 5–10 minutes of discontinuation of the infusion. Administration of remifentanil reduces the amount of hypnotic/volatile agent required to maintain anaesthesia.

Effects

CVS

Remifentanil decreases the mean arterial pressure and heart rate by 20%. Myocardial contractility and cardiac output may also decrease.

RS

Remifentanil is a potent respiratory depressant, causing a decrease in both the respiratory rate and tidal volume; it also diminishes the ventilatory response to hypoxia and hypercarbia. Chest wall rigidity (the ‘wooden chest’ phenomenon) may occur after the administration of remifentanil—this may be an effect of the drug on mu-receptors located on GABA-ergic interneurones. The drug does not cause histamine release.

CNS

Remifentanil has a centrally mediated vagal activity. It has an analgesic potency similar to fentanyl and possesses minimal hypnotic or sedative activity. It produces EEG effects similar to those of other opioids—high-amplitude, low-frequency activity. Miosis is produced as a result of stimulation of the Edinger–Westphal nucleus.

AS

The drug decreases gastrointestinal motility. There is a relatively low incidence of nausea and vomiting associated with its use.

Toxicity/side effects

Respiratory depression, bradycardia, nausea, and vomiting may all complicate the use of remifentanil. Because of its short duration of action, post-operative discomfort may be pronounced if remifentanil is used as a sole analgesic agent perioperatively.

Kinetics

Distribution

Remifentanil is 70% bound to plasma proteins, two-thirds to alpha-1 acid glycoprotein. The drug has a low lipid solubility, compared to other mu opioids, with a low VD of 0.1 l/kg, and distributes into peripheral tissues with a volume of distribution at steady state (VDSS) of 0.25–0.4 l/kg. Remifentanil crosses the placenta and may cause respiratory depression in the neonate. In children aged 1–12 years, the VD decreases with increasing age. The VD in neonates is twice that of adults.

Metabolism

Remifentanil undergoes rapid ester hydrolysis by non-specific plasma and tissue esterases to a carboxylic acid derivative remifentanil acid, which is 4600-fold less potent than remifentanil. The context-sensitive half-time of remifentanil of 3–5 minutes is fixed, due to the quantity of the above esterases, and does not increase with the duration of the infusion, unlike other opioids. The drug is not metabolized by plasma cholinesterases and is unaffected by its deficiency or by the administration of anticholinesterase drugs.

Excretion

The clearance of remifentanil is 4.2–5 l/min and independent of renal and hepatic function. The elimination half-life is 5–14 minutes and is unaltered with renal and hepatic dysfunction. Approximately 95% of an administered dose is excreted in the urine as remifentanil acid which has an elimination half-life of 1.5–2 hours. In children aged 1–12 years, the clearance of remifentanil decreases with increasing age. The clearance in neonates is twice that of adults, although the elimination half-life is approximately the same. The pharmacokinetics of remifentanil acid are similar in children, compared to those seen in adults.

Special points

The clearance of the metabolite remifentanil acid is prolonged in patients with renal impairment and may increase to 268 hours. The concentration of the metabolite may increase by 100-fold in intensive care patients with moderate or severe renal impairment at steady state, although there is no evidence that clinically significant mu-opioid effects are seen, even following remifentanil infusions lasting 3 days.

Intravenous lines must be flushed at the end of the infusion due to the risk of respiratory depression by the residual drug in the line dead space.

There is no evidence that remifentanil is extracted during renal replacement therapy.

Remifentanil acid is extracted during haemodialysis by 25–35%.

Patients with hepatic impairment are more sensitive to the respiratory depressant effects of remifentanil.

The lean body weight should be used when using the drug in morbidly obese patients as part of a TCI protocol.

Rivaroxaban

Uses

Rivaroxaban is used for the prevention of venous thromboembolism in patients undergoing elective knee and hip replacement surgery.

Chemical

An oxazolidinone derivative.

Presentation

As 10 mg tablets containing rivaroxaban. Each tablet also contains 27.9 mg lactose monohydrate.

Main actions

Direct factor Xa inhibitor.

Mode of action

Rivaroxaban directly inhibits factor Xa in a dose-dependent manner, leading to interruption of both the intrinsic and extrinsic coagulation pathways. The drug does not inhibit thrombin and has no effect on platelet function.

Routes of administration/doses

The drug is administered orally at a dose of 10 mg. The first dose should be given 6–10 hours after surgery. Treatment should continue for 5 weeks following hip surgery, and 2 weeks following knee surgery. No dose adjustment is required for patients with mild or moderately impaired renal function. The drug should be used with caution in patients with severe renal impairment.

Effects

Metabolic/other

The main effect of the drug is its anticoagulation effect. Rivaroxaban does not affect platelet function.

Toxicity/side effects

Excessive bleeding is the commonest reported side effect. The use of neuroaxial blocks in patients receiving the drug must be carefully considered, and the timing of block/catheter insertion/removal and commencement/withholding/discontinuation of rivaroxaban must be appropriately timed to minimize the risk of spinal/epidural haematoma formation. It is recommended that, following a dose of rivaroxaban, an epidural catheter should not be removed before 18 hours has elapsed, and any subsequent dose to be delayed by a further 6 hours following catheter removal.

Kinetics

Absorption

Rivaroxaban is rapidly absorbed following oral administration, with Cmax occurring within 2–4 hours of ingestion. The bioavailability of the drug is 80–100%.

Distribution

The drug is 92–95% protein-bound; the VD is approximately 50 l.

Metabolism

Two-thirds of an administered dose undergoes oxidative degradation and hydrolysis via CYP450 3A4, CYP450 2J2, and CYP-independent mechanisms. The morpholinone moiety and amide bonds are the main metabolic targets.

Excretion

Following hepatic metabolism, 50% of the metabolic products of the drug are renally excreted, whilst the remaining 50% are excreted in the faeces. Unchanged drug is excreted renally. The terminal elimination half-life of a 1 mg dose is 4.5 hours, increasing to 7–11 hours following a 10 mg dose due to absorption rate-limited elimination. The systemic clearance is approximately 10 l/hour.

Special points

In vitro studies demonstrate that the drug is a substrate of the transporter proteins P-glycoprotein and BCRP (breast cancer resistance protein).

Drug plasma levels may be reduced when rivaroxaban is administered to patients receiving CYP450 3A4 inducers such as rifampicin, phenytoin, carbamazepine, and St John’s Wort.

Drug plasma levels may increase when rivaroxaban is administered to patients receiving CYP450 3A4 and P-glycoprotein inhibitors such as ketoconazole, itraconazole, voriconazole, and HIV protease inhibitors.

There is no antidote currently available for rivaroxaban.

The drug is unlikely to be removed by haemodialysis due to high plasma protein binding.

Rocuronium

Uses

Rocuronium is used:

  1. 1. to facilitate tracheal intubation during routine and modified rapid sequence induction

  2. 2. for controlled ventilation.

Chemical

An aminosteroid which is structurally related to vecuronium.

Presentation

As a clear, colourless solution containing 10 mg/ml of rocuronium bromide. The drug is available in 5 and 10 mg ampoules.

Main action

Competitive neuromuscular blockade.

Mode of action

Rocuronium acts by competitive antagonism of acetylcholine at nicotinic (N2) receptors at the post-synaptic membrane of the neuromuscular junction; it also has some pre-junctional activity.

Routes of administration/doses

Rocuronium is administered intravenously; the normal intubating dose is 0.6 mg/kg, with subsequent doses of 0.15 mg/kg. This intubating dose equates to twice the ED90 for rocuronium (ED90 0.3 mg/kg) and results in ‘excellent’ intubating conditions in 80% of cases within 60 seconds. A dose of 1 mg/kg is recommended when rocuronium is used during modified rapid sequence induction, resulting in intubating conditions within 60 seconds in 93–96%. The increased speed of onset relates to the low potency of rocuronium. As a result of giving an increased dose (increased number of drug molecules), the concentration gradient at the neuromuscular junction is increased, leading to a faster diffusion of drug molecules and a reduction in drug onset time. The duration of action relates to the dose given, and, as a result, the usual recovery index of 8–17 minutes with a normal intubating dose is increased to nearly an hour when 1.0 mg/kg is used. The drug may also be infused at a rate of 300–600 micrograms/kg/hour. The drug is non-cumulative with repeated administration.

Effects

CVS

Rocuronium has minimal cardiovascular effects; with large doses, a mild vagolytic effect leads to a slight (9%) increase in the heart rate and an increase in the mean arterial pressure of up to 16%.

RS

Neuromuscular blockade leads to apnoea. Rocuronium causes an insignificant release of histamine; bronchospasm is extremely uncommon.

Toxicity/side effects

There have been very rare reports of fatal anaphylactoid reactions with the administration of rocuronium. Cross-sensitivity may exist with other aminosteroid compounds (vecuronium, pancuronium). Pain on injection occurs in 16% of subjects when rocuronium is used in combination with propofol, compared with 0.5% of subjects when thiopental is used.

Kinetics

Distribution

The drug is 30% protein-bound in the plasma; the VD is 0.27 l/kg.

Metabolism

No metabolites of rocuronium have been found in the plasma or urine.

Excretion

Rocuronium is excreted primarily by hepatic uptake and hepatobiliary excretion. 30 to 40% of the dose is excreted unchanged in the bile, 13–31% in the urine. After administration of a bolus dose, the plasma concentration time course runs in three exponential phases. In adults, the mean elimination half-life is 73 (66–80) minutes, with a plasma clearance of 3.7 (3.5–3.9) ml/kg/min. The pharmacokinetics of rocuronium are not significantly altered in the presence of renal failure. The mean elimination half-life is prolonged by 30 minutes, and the mean plasma clearance is reduced by 1 ml/kg/min in the presence of hepatic dysfunction; the duration of action is correspondingly increased.

Special points

The duration of action of rocuronium, in common with other non-depolarizing relaxants, may be prolonged by hypokalaemia, hypocalcaemia, hypothermia, hypermagnesaemia, hypoproteinaemia, dehydration, acidosis, and hypercapnia. The following drugs, when co-administered with non-depolarizing relaxants, increase the effect of the latter: volatile and induction agents, fentanyl, suxamethonium, diuretics, lithium, calcium antagonists, alpha- and beta-adrenergic antagonists, protamine, metronidazole, and the aminoglycoside antibiotics.

Rocuronium is physically incompatible with thiopental, methohexital, dexamethasone, erythromycin, trimethoprim, vancomycin, and diazepam. In animal studies, rocuronium does not appear to be a triggering factor for malignant hyperpyrexia.

Rocuronium causes significantly less rise in intraocular pressure, compared with suxamethonium.

Reversal of NMB activity by rocuronium may be achieved using neostigmine (in combination with glycopyrrolate), but only after four twitches have returned on the train-of-four count. The alpha-cyclodextrin sugammadex may be used to reverse rocuronium-induced neuromuscular blockade by encapsulating rocuronium molecules within the plasma, thereby creating a concentration gradient favouring the movement of remaining rocuronium molecules from the neuromuscular junction back into the plasma.

The ideal body weight should be used to calculate drug dosage in morbidly obese individuals.

Ropivacaine

Uses

Ropivacaine is used as a local anaesthetic.

Chemical

An amino amide which is member of the pipecoloxylidide group of local anaesthetics.

Presentation

As a clear, colourless solution containing racemic ropivacaine hydrochloride monohydrate (S- and R-enantiomers) in concentrations of 0.2/0.75/1.0% equivalent to 2.0, 7.5, and 10 mg/ml, respectively, of ropivacaine hydrochloride. A pure S-ropivacaine preparation is also available. It is not available in combination with a vasoconstrictor, as this does not alter its tissue uptake or the duration of action. The pKa of ropivacaine is 8.1, and it is 15% unionized at pH 7.4. The heptane:buffer partition coefficient is 2.9. The preparation also contains sodium hydroxide equivalent to 3.7 mg of sodium per ml.

Main action

Local anaesthetic.

Mode of action

Local anaesthetics diffuse in their uncharged base form through neural sheaths and the axonal membrane to the internal surface of cell membrane Na+ channels; here they combine with hydrogen ions to form a cationic species which enters the internal opening of the Na+ channel and combines with a receptor. This produces blockade of the Na+ channel, thereby decreasing Na+ conductance and preventing depolarization of the cell membrane.

S-ropivacaine is more potent and less cardiotoxic than R-ropivacaine.

Routes of administration/doses

Ropivacaine may be administered topically, by infiltration, or epidurally; the drug is not currently intended for use in spinal anaesthesia. The maximum recommended dose of ropivacaine is 3 mg/kg. Sensory blockade is similar in time course to that produced by bupivacaine; motor blockade is slower in onset and shorter in duration than that after an equivalent dose of bupivacaine. Alkalinization of 0.75% ropivacaine significantly increases the duration of action of epidural blockade.

Effects

CVS

Ropivacaine is less cardiotoxic than bupivacaine; in toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse. Ropivacaine has a biphasic vascular effect, causing vasoconstriction at low, but not at high, concentrations.

CNS

The principal effect of ropivacaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNS. Initially, excitation (light-headedness, dizziness, visual and auditory disturbances, and seizure activity) occurs due to inhibition of inhibitory interneurone pathways in the cortex. With increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNS depression (drowsiness, disorientation, and coma). Local anaesthetic agents block neuromuscular transmission when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible conductance.

GU

Ropivacaine does not compromise uteroplacental circulation.

Toxicity/side effects

Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above.

Kinetics

Absorption

The absorption of local anaesthetic agents is related to:

  1. 1. the site of injection (intercostal > caudal > epidural > brachial plexus > subcutaneous)

  2. 2. the dose—a linear relationship exists between the total dose and the peak blood concentrations achieved and

  3. 3. the presence of vasoconstrictors which delay absorption.

Distribution

Ropivacaine is 94% protein-bound in the plasma, predominantly to alpha-1 acid glycoprotein; the VD is 52–66 l. The drug demonstrates a biphasic absorption profile from the epidural space, with half-lives of 14 minutes and 4 hours in adults.

Metabolism

Ropivacaine is metabolized in the liver by aromatic hydroxylation via cytochrome CYP1A2 to 3-hydroxy-ropivacaine, the major metabolite, 4-hydroxy-ropivacaine, and 4-hydroxy-dealkylated-ropivacaine. Co-administration of a CYP1A2 inhibitor (e.g. fluvoxamine, enoxacin) may reduce plasma clearance of the drug by up to 77% in vitro. The isoenzyme CYP3A4 is also involved in the metabolism of ropivacaine, as administration of a CYP3A4 inhibitor (e.g. fluconazole) reduces the plasma clearance of the drug by 15% in vitro, although this is unlikely to cause a clinically significant effect. Ropivacaine has an intermediate hepatic extraction ratio of approximately 0.4. There is no evidence of in vivo racemization of ropivacaine.

Excretion

The clearance is 0.44–0.82 l/min, and the terminal elimination half-life is 59–173 minutes. Eighty-six percent of the dose is excreted in the urine, 1% unchanged; 37% of 3-hydroxy-ropivacaine is excreted in the urine, predominantly conjugated. The elimination half-life is longer after epidural (4.2 hours) than after intravenous administration due to the biphasic absorption from the former, as described above.

Special points

The onset and duration of conduction blockade are related to the pKa, lipid solubility, and the extent of protein binding. A low pKa and high lipid solubility are associated with a rapid onset time; a high degree of protein binding is associated with a long duration of action. Local anaesthetic agents significantly increase the duration of action of both depolarizing and non-depolarizing relaxants.

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