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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0006

Fentanyl

Uses

Fentanyl is used:

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

  2. 2. in combination with a major tranquillizer to produce neuroleptanalgesia

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

  4. 4. as an agent used for patient-controlled analgesia

  5. 5. in premedication and

  6. 6. for palliative care.

Chemical

A tertiary amine which is a synthetic phenylpiperidine derivative.

Presentation

As a clear, colourless solution for injection containing 50 micrograms/ml fentanyl citrate; as transdermal patches which deliver 12/25/50/75/100 micrograms/hour over a 72-hour period; as sublingual tablets containing 100/200/400/600/800 micrograms; as lozenges containing 200/400/600/800/1200/1600 micrograms; and as fentanyl hydrochloride in an iontophoretic transdermal system. The pKa of fentanyl is 8.4, is 9% unionized at a pH of 7.4, has a molecular weight of 286, and is highly lipid-soluble, having an octanol:water partition coefficient of 717.

Main actions

Analgesia and respiratory depression.

Mode of action

Fentanyl is a highly selective mu-agonist (or MOP agonist); 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 occur. The decrease in membrane excitability that results may decrease both pre- and post-synaptic responses.

Routes of administration/doses

The adult dose for premedication by the intramuscular route is 50–100 micrograms. For the induction or supplementation of general anaesthesia, an intravenous dose of 1– 100 micrograms/kg may be used. The drug may be administered by intravenous infusion. Fentanyl may also be administered via the epidural route—a dose of 50–100 micrograms is usually employed—or via the spinal route at doses of 5–25 micrograms. The drug acts rapidly in 2–5 minutes due to its high lipid solubility when administered intravenously; a small dose has a duration of action of 30–60 minutes, whereas high (>50 micrograms/kg) doses may be effective for 4–6 hours. Following application of a transdermal patch, serum fentanyl concentrations only increase gradually, with equilibrium occurring at between 12 and 24 hours. Transdermal fentanyl patches should be replaced every 72 hours, whilst iontophoretic transdermal system devices should be replaced or stopped after 24 hours. Administration of fentanyl reduces the amount of hypnotic/volatile agent required to maintain anaesthesia.

Effects

CVS

The most significant cardiovascular effect of fentanyl is bradycardia of vagal origin; cardiac output, mean arterial pressure, pulmonary and systemic vascular resistance, and pulmonary capillary wedge pressure are unaffected by the administration of the drug. Fentanyl obtunds the cardiovascular responses to laryngoscopy and intubation.

RS

Fentanyl 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. The drug is a potent antitussive agent. Chest wall rigidity (the ‘wooden chest’ phenomenon) may occur after the administration of fentanyl—this may be an effect of the drug on mu-receptors located on GABA-ergic interneurones. Fentanyl causes minimal histamine release; bronchospasm is thus rarely produced by the drug.

CNS

Fentanyl is 50–80 times more potent an analgesic than morphine and has little hypnotic or sedative activity. Miosis is produced as a result of stimulation of the Edinger–Westphal nucleus. There have been several reports of seizure-like motor activity occurring in patients receiving fentanyl; however, no epileptic spike-wave patterns are demonstrable on the EEG (although beta activity is initially decreased, and alpha activity is increased; subsequently alpha activity disappears, and delta activity predominates).

AS

The drug decreases gastrointestinal motility and decreases gastric acid secretion; it also doubles the common bile duct pressure by causing spasm of the sphincter of Oddi.

GU

Fentanyl increases the tone of the ureters, bladder detrusor muscle, and vesicular sphincter.

Metabolic/other

High doses of fentanyl will obtund the metabolic ‘stress response’ to surgery, although the drug has no effect on white cell function. Unlike morphine, fentanyl does not increase the activity of ADH.

Toxicity/side effects

Respiratory depression may occur post-operatively, possibly related to the appearance of a secondary peak in the plasma fentanyl concentration due to elution from muscle. Nausea, vomiting, and dependence may also complicate the use of the drug.

Kinetics

There is large inter-individual variability in pharmacokinetics.

Absorption

Fentanyl is absorbed orally and has a bioavailability of 33%. Orally administered fentanyl may become highly ionized in the stomach (99.9%), leading to slow absorption in the alkaline small bowel and subsequent first-pass metabolism. Transdermal delivery produces 47% absorption at 24 hours, 88% at 48 hours, and 94% by 72 hours. Drug delivery continues after patch removal.

Distribution

Fentanyl is 81–94% bound to plasma proteins; the VD is 0.88–4.41 l/kg. The short duration of action of a single dose of the drug is due to redistribution (cf. thiopental), whereas continuous administration leads to saturation of tissues and a significantly prolonged duration of action. Fentanyl is more lipid-soluble than morphine and thus crosses the blood–brain barrier more easily; it thus has a more rapid onset of action than morphine. Additionally, intrathecal fentanyl does not cause delayed respiratory depression, unlike morphine, as, due to its high lipid solubility, it is rapidly absorbed into the spinal cord.

Metabolism

Fentanyl appears to be metabolized primarily by N-dealkylation to norfentanyl, with subsequent hydroxylation of this and the parent compound to hydroxypropionyl derivatives. The drug may also undergo hydroxylation and amide hydrolysis. Cytochrome P450 3A4 plays the predominant role in fentanyl metabolism. As well as the liver, this is also found in the human intestine. Some enterosystemic cycling of the drug may occur as does first-pass metabolism (see above). The metabolites are not pharmacologically active.

Excretion

10% of an administered dose is excreted in the urine. The clearance of fentanyl is 13 ml/kg/min, and the elimination half-life range is 141–853 minutes. Halothane decreases the clearance of fentanyl by 48%; a similar effect occurs with enflurane. The clearance of fentanyl is decreased in surgical patients with renal impairment and in patients with hepatic impairment. Oral ritonavir (a potent CYP3A4 inhibitor) prolongs the clearance of intravenously administered fentanyl by two-thirds.

Special points

Fentanyl decreases the apparent MAC of co-administered volatile agents and increases the effect of non-depolarizing muscle relaxants to a similar extent as does halothane. The drug is pharmacologically incompatible with thiopental or methohexital.

It is unknown whether fentanyl is removed by haemodialysis.

The physical and chemical properties of fentanyl make it a suitable agent for transdermal administration. The fentanyl iontophoretic transdermal system works by generating a low-intensity electrical current (activated by the patient) which causes positively charged fentanyl molecules held within a positively charged hydrogel reservoir to be repelled and delivered transdermally into the systemic circulation.

Flecainide

Uses

Flecainide is an antiarrhythmic agent used:

  1. 1. for the suppression of irritable foci, e.g. ventricular tachycardia and ventricular ectopics

  2. 2. in the treatment of re-entry dysrhythmias, e.g. the Wolff–Parkinson–White syndrome and

  3. 3. in the treatment of symptomatic paroxysmal atrial fibrillation intolerant of other medication.

Chemical

An amide type local anaesthetic.

Presentation

As 50/100 mg tablets and as a 10 mg/ml solution of flecainide acetate for intravenous administration.

Main action

A class Ic antiarrhythmic.

Mode of action

Flecainide reduces the maximum rate of depolarization in heart muscle and thereby slows conduction, particularly in the His–Purkinje system. It has a profound effect on conduction in accessory pathways, especially on retrograde conduction, and markedly suppresses ventricular ectopic foci. It is a local anaesthetic agent which depresses membrane responsiveness and conduction velocity, with no effect on the duration of the action potential.

Routes of administration/doses

The adult oral dose is 100–200 mg 12-hourly. Intravenously, flecainide may be administered as a bolus dose of 2 mg/kg over 10 minutes, followed by an infusion of 1.5 mg/kg/hour for 1 hour, reducing to 0.25 mg/kg/hour.

Effects

CVS

Flecainide is generally well tolerated; the blood pressure and heart rate usually remain unchanged. The drug has negative inotropic potential.

CNS

Visual disturbances may occur and are probably a central effect of the drug.

Toxicity/side effects

Reversible liver damage, dizziness, paraesthesiae, headaches, and nausea may complicate the use of the drug.

Kinetics

Absorption

Flecainide is rapidly and completely absorbed after oral administration; the bioavailability is 85–90%.

Distribution

Flecainide is 37–58% protein-bound in the plasma; the VD is 5.8–10 l/kg.

Metabolism

Occurs in the liver to two major metabolites—meta- O-dealkylated flecainide and its lactam.

Excretion

10–50% of the dose is excreted unchanged in the urine. The clearance is 10 ml/min/kg, and the elimination half-life is 7–15 hours after intravenous administration and 12–27 hours after oral administration.

Special points

Flecainide increases plasma digoxin levels by 15% when the two drugs are administered concurrently. Hypokalaemia reduces the effectiveness of the drug; a reduced dose should be used in renal or hepatic failure.

Flecainide is not removed by haemodialysis.

Flucloxacillin

Uses

Flucloxacillin is used in the treatment of:

  1. 1. respiratory tract infections as an adjunct

  2. 2. skin and soft tissue infections

  3. 3. osteomyelitis

  4. 4. staphylococcal endocarditis and for

  5. 5. prophylaxis during surgery.

Chemical

A semi-synthetic isoxazolyl penicillin.

Presentation

As 250/500 mg capsules, in vials containing 250/500/ 1000 mg of flucloxacillin sodium, and as a syrup containing 25/50 mg/ml of flucloxacillin magnesium.

Main action

Flucloxacillin is an acid-stable, penicillinase-resistant, narrow- spectrum bactericidal antibiotic active against Staphylococcus aureus, group A beta-haemolytic streptococci, and pneumococci.

Mode of action

Flucloxacillin acts in a manner typical of penicillins, by binding to a cell wall PBP, and thereby interfering with the activity of the enzymes which are involved in the cross-linking of bacterial cell wall peptidoglycans.

Routes of administration/doses

The adult oral and intramuscular dose is 250–500 mg 6-hourly; the corresponding intravenous dose is 250 mg to 2 g 6-hourly.

Toxicity/side effects

Gastrointestinal and CNS disturbances, rashes, sore throat, and glossitis may complicate the use of the drug. Flucloxacillin may cause both pseudomembranous colitis and jaundice in the critically ill.

Kinetics

Absorption

Flucloxacillin is 50–70% absorbed when administered orally.

Distribution

The drug is 95% protein-bound in the plasma; the VD is 6.8–9.4 l.

Metabolism

8–13% is metabolized to an active form 5-hydroxymethyl-flucloxacillin, and 4% is hydrolysed in the liver to penicilloic acid which is inactive.

Excretion

Excretion of the drug occurs by glomerular filtration and tubular secretion, 35–75% of the dose appearing in the urine, according to the dose and route of administration. The clearance is 3 ml/min/kg, and the elimination half-life is 46 minutes.

Special points

Reduction of the dose of flucloxacillin should be considered if the creatinine clearance is 10 ml/min; the drug is not significantly removed by haemodialysis.

Precipitation occurs if flucloxacillin is co-administered with an aminoglycoside.

Flucloxacillin is not active against MRSA.

Flumazenil

Uses

Flumazenil is used:

  1. 1. as an aid to weaning and neurological assessment of ventilated patients who have received benzodiazepine sedation during intensive care

  2. 2. as part of the ‘wake-up’ test during scoliosis surgery

  3. 3. to reverse oversedation after endoscopy and

  4. 4. for diagnosis of, and assessment after, benzodiazepine overdose.

Chemical

An imidazobenzodiazepine.

Presentation

As a clear, colourless solution containing 100 micrograms/ml of flumazenil.

Main action

Reversal of the actions of benzodiazepines.

Mode of action

Flumazenil is a competitive antagonist at central benzodiazepine receptors.

Routes of administration/doses

Flumazenil is administered intravenously, titrated in 100 micrograms increments to a total maximum adult dose of 1 mg. It acts in 30–60 seconds and lasts 15–140 minutes. It may also be infused intravenously at 100–400 micrograms/hour.

Toxicity/side effects

Hypertension, dysrhythmias, dizziness, nausea and vomiting, facial flushing, anxiety, and headache have been described. Resedation after prior administration of a benzodiazepine and convulsions in epileptics have also been reported.

Kinetics

Absorption

Flumazenil is well absorbed when administered orally but undergoes significant first-pass hepatic metabolism.

Distribution

The drug is 50% protein-bound in the plasma; the VD is 0.9 l/kg.

Metabolism

Flumazenil is extensively metabolized in the liver to a carboxylic acid and glucuronide, both of which are inert.

Excretion

95% is excreted in the urine, 0.1% unchanged. The clearance is 700–1100 ml/min, and the elimination half-life is 53 minutes.

Special points

Flumazenil improves the quality of emergence from anaesthesia and reduces post-operative shivering.

Fluoroquinolones

Uses

Fluoroquinolones are used in the treatment of infections of:

  1. 1. the respiratory tract

  2. 2. skin, soft tissue, bone, and joints

  3. 3. ocular, ear, nose, and oral infections

  4. 4. gastrointestinal infections

  5. 5. GU infections

  6. 6. pelvic and intra-abdominal infections

  7. 7. gonorrhoea

  8. 8. septicaemia and

  9. 9. in the prophylaxis/treatment of organisms with the potential for use in bioterrorism.

Chemical

Fluorinated quinolones derived from nalidixic acid.

Presentation

Fluoroquinolones in clinical use include ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin, and all are available for intravenous administration aside from norfloxacin. Ciprofloxacin is available as eye drops and as an eye ointment, as a powder for oral suspension, and in tablet formulations. Ofloxacin is available in an eye drop preparation.

Main action

Fluoroquinolones are bactericidal antibiotics that are active against:

  1. 1. Gram-positive bacteria

  2. 2. Gram-negative bacteria

  3. 3. Gram-positive and negative anaerobes.

There is emerging resistance to fluoroquinolones from a number of species, including Escherichia coli, Shigella, Neisseria gonorrhoeae, Acinetobacter, and Pseudomonas spp.

Mode of action

Fluoroquinolones act by inhibiting bacterial DNA gyrase, topoisomerase IV, and type II topoisomerases, thereby inhibiting bacterial DNA replication.

Routes of administration/doses

Fluoroquinolones may be administered topically as ointments, orally, or intravenously. The specific dose, route, and frequency of an agent administered are dependent on the clinical indication, age of the patient, and particular agent being used.

Toxicity/side effects

Common side effects include abdominal pain, nausea, and vomiting. Neuropsychiatric disturbances have been reported, including anxiety, insomnia, seizures, and hallucinations. Fluoroquinolone use is associated with Achilles tendon rupture, particularly when co-administered with corticosteroids. Allergic reactions, photosensitivity, and transient elevations of liver enzymes have all been reported. The use of these antibiotics is associated with an increased risk of Clostridium difficile and MRSA infection.

Kinetics

Absorption

Fluoroquinolones are generally well absorbed, depending on the specific agent: ciprofloxacin (70–80%), levofloxacin (100%), moxifloxacin (91%). Norfloxacin has a lower bioavailability of 30–40%. Ciprofloxacin undergoes first-pass metabolism. Co-administration of sucralfate or calcium/magnesium/iron salts reduces the amount of drug absorbed.

Distribution

Protein binding of 30–40% is typical of this group of drugs. Norfloxacin has lower protein binding of <15%. The VD for ciprofloxacin is 2–3 l/kg. Fluoroquinolones demonstrate high CSF and tissue penetration.

Metabolism

Fluoroquinolones undergo little hepatic metabolism in man.

Excretion

The majority of fluoroquinolones undergo renal excretion. Ciprofloxacin undergoes active tubular secretion, as demonstrated by a higher clearance rate of 416–650 ml/min, compared to other fluoroquinolones: moxifloxacin (179–246 ml/min) and norfloxacin (275 ml/min). The half-life for these drugs are as follows: ciprofloxacin (3–6.9 hours), levofloxacin (6–8 hours), moxifloxacin (12 hours), norfloxacin (3–4 hours).

Special points

Dose reduction is required in severe renal impairment. 25–30% of an administered dose of ciprofloxacin is removed during haemodialysis.

Ciprofloxacin significantly increases the half-life of co-administered theophylline, necessitating monitoring of plasma concentrations of the latter.

Ciprofloxacin is used in combination therapy in the treatment of Bacillus anthracus infection and as a single agent against Yersinia pestis. The drug is also used for post-exposure prophylaxis to the following potential bioterrorism organisms: Bacillus anthracus (anthrax), Yersinia pestis (plague), and Francisella tularensis (tularaemia).

Antimicrobial agents should always be administered, following consideration of local pharmacy and microbiological policies.

Fondaparinux

Uses

Fondaparinux is used in the treatment of:

  1. 1. acute pulmonary embolism

  2. 2. acute DVT, and

  3. 3. in the prophylaxis of DVT.

Chemical

Synthetic and specific inhibitor of activated factor X (Xa)

Presentation

Fondaparinux sodium solution is provided in a single-dose, sterile, preservative-free prefilled syringes with an automatic needle protection system, containing 2.5/5/7.5/10 mg. The packaging (needle guard) contains latex.

Main action

Prevention of thrombus formation.

Mode of action

The antithrombotic activity of fondaparinux is the result of antithrombin III (ATIII)-mediated selective inhibition of factor Xa. By selectively binding to ATIII, fondaparinux potentiates (about 300 times) the innate neutralization of factor Xa by ATIII. Neutralization of factor Xa interrupts the blood coagulation cascade and so inhibits thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin (activated factor II), has no effect on platelet function, and does not affect fibrinolytic activity or bleeding time.

Routes of administration/dose

2.5/5/7.5/10 mg dose. It is administered by subcutaneous injection, according to the patient’s weight and desired treatment.

Effects

Metabolic/other

May be excreted in breast milk.

Toxicity/side effects

Fondaparinux should be used with extreme caution in conditions with an increased risk of haemorrhage—rates of 1–2% of bleeding if the risk is low, and thrombocytopenia (moderate 3% and severe 1%) are reported. Local irritation (injection site bleeding, rash, and pruritus) may occur, following subcutaneous injection. Asymptomatic increases in AST and ALT have been described.

Kinetics

Absorption

Fondaparinux administered by subcutaneous injection is rapidly and completely absorbed; bioavailability is 100%, with a maximum plasma concentration at 2 hours.

Distribution

It distributes mainly in blood and, only to a minor extent, in extravascular fluid; hence, the VD is 7–11 l. Fondaparinux is >94% protein-bound to ATIII.

Metabolism

This has not been investigated, as it is excreted unchanged in the urine.

Excretion

In healthy individuals up to 75 years of age, up to 77% of a single fondaparinux dose is eliminated in the urine as unchanged drug in 72 hours. The elimination half-life is 17–21 hours.

Special points

Routine coagulation tests, such as prothrombin time and activated partial thromboplastin time (APTT), are relatively insensitive measures of the activity of fondaparinux. Fondaparinux increases the risk of bleeding in patients with impaired renal function due to reduced clearance and should not be used with a creatinine clearance of <30 ml/min.

Epidural or spinal haematomas may occur in patients who are anticoagulated with LMWHs, heparinoids, or fondaparinux. These haematomas may result in long-term or permanent paralysis. Factors that can increase the risk of developing epidural or spinal haematomas include:

  1. 1. use of indwelling epidural catheters

  2. 2. concomitant use of other drugs that affect haemostasis such as NSAIDs, platelet inhibitors, or other anticoagulants

  3. 3. history of traumatic or repeated epidural or spinal puncture

  4. 4. history of spinal deformity or spinal surgery

  5. 5. the optimal timing between the administration of fondaparinux and neuraxial procedures is not known.

Patients need to be monitored frequently for signs and symptoms of neurologic impairment, and, if discovered, urgent treatment is necessary.

Furosemide

Uses

Furosemide is used in the treatment of:

  1. 1. oedema of cardiac, renal, or hepatic origin

  2. 2. chronic renal insufficiency

  3. 3. hypertension

  4. 4. raised intracranial pressure

  5. 5. symptomatic hypercalcaemia, and

  6. 6. conversion of oliguric to polyuric renal failure.

Chemical

An anthranilic acid (sulfonamide) derivative.

Presentation

As a clear solution (which must be protected from light) for injection containing 10 mg/ml and as 20/40/500 mg tablets of furosemide. A syrup containing 20/40/50 mg in 5 ml is available. A number of fixed-dose combinations with amiloride, triamterene, spironolactone, and potassium chloride are also available.

Main action

Diuresis.

Mode of action

Furosemide acts by inhibition of active chloride ion reabsorption in the proximal tubule and ascending limb of the loop of Henle—by reducing the tonicity of the renal medulla, a hypotonic or isotonic urine is produced. The mechanism of action at a cellular level may be exerted via inhibition of Na+K+ATPase or by inhibition of glycolysis.

Routes of administration/doses

The adult oral dose is 20–2000 mg daily; the intramuscular dose is 20–50 mg. Intravenous administration is titrated according to response—a range of 10–1000 mg is recommended. The infusion rate should not exceed 4 mg/min, as ototoxicity may result.

Effects

CVS/RS

Pulmonary and systemic vasodilation occur, leading to symptomatic relief of breathlessness prior to diuresis.

GU

A diuresis occurs within a few minutes and lasts 2 hours when furosemide is administered intravenously; correspondingly, diuresis starts 1 hour after oral administration and lasts 4–6 hours. Free water clearance is increased by the drug. The renal blood flow is increased and redistributed in favour of inner corticomedullary flow. Oxygen consumption in the loop of Henle is reduced to basal levels and may protect the kidney from ischaemia.

Metabolic/other

The drug causes a metabolic alkalosis and may be diabetogenic; the serum urate concentrations are increased.

Toxicity/side effects

Hypokalaemia, hypocalcaemia, hypomagnesaemia, and metabolic alkalosis may occur after the administration of furosemide. Transient auditory nerve damage, pancreatitis, skin rashes, and bone marrow depression have been reported. Furosemide causes interstitial nephritis in high doses; this is a common cause of acute renal failure when co-administered with an aminoglycoside—the two drugs are synergistic in this respect. Deafness is also more likely to result when furosemide and an aminoglycoside are co-administered.

Kinetics

Absorption

Furosemide is 60–70% absorbed after oral administration; the bioavailability by this route is 43–71%.

Distribution

The drug is 96% protein-bound in the plasma, almost exclusively to albumin. The VD is 0.11–0.13 l/kg.

Metabolism

Furosemide appears to be metabolized primarily in the kidney to a glucuronide.

Excretion

80% is excreted in the urine as unchanged and glucuronidated furosemide; the rest appears in the faeces. The clearance is 2.2 ml/min/kg, and the elimination half-life is 45–92 minutes.

Special points

The effects of non-depolarizing muscle relaxants may be enhanced by furosemide, probably due to hypokalaemia. The response to concurrently administered vasopressors may be diminished and that to vasodilators enhanced, both phenomena being manifestations of a contracted circulating blood volume.

The drug is not removed by haemodialysis.

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