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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0002

Bendroflumethiazide

Uses

Bendroflumethiazide is used in the treatment of:

  1. 1. hypertension

  2. 2. oedema due to heart failure or the nephrotic syndrome

  3. 3. diabetes insipidus

  4. 4. renal tubular acidosis

  5. 5. hypercalciuria, and

  6. 6. for the inhibition of lactation.

Chemical

A thiazide.

Presentation

As 2.5/5 mg tablets of bendroflumethiazide and in a variety of fixed-dose combinations with beta-adrenergic antagonists.

Main actions

Diuretic and antihypertensive.

Mode of action

Thiazide diuretics inhibit sodium chloride co-transport in the distal convoluted tubule. They inhibit Na+ reabsorption, which results in an increased urinary excretion of sodium, potassium, and water.

Routes of administration/doses

The adult oral dose is 2.5–10 mg daily. Bendroflumethiazide has a duration of action of 12–18 hours.

Effects

CVS

Bendroflumethiazide exerts its antihypertensive effect by decreasing the plasma volume and as a vasodilator. It also causes a slight decrease in the cardiac output.

CNS

In toxic doses, the drug causes depression of the CNS.

GU

Bendroflumethiazide decreases the renal blood flow and may also cause a reduction in the glomerular filtration rate. The drug decreases the urinary excretion of calcium and increases that of sodium, potassium, and magnesium.

Metabolic/other

Thiazide diuretics may increase the blood sugar concentration by enhancing glycogenolysis and decreasing the rate of glycogenesis and insulin secretion. They may also increase serum urate, triglyceride, and cholesterol concentrations and give rise to a hypochloraemic acidosis.

Toxicity/side effects

CNS and haemopoietic disturbances, rashes, impotence, and acute pancreatitis may complicate the use of the drug. Bendroflumethiazide may interfere with diabetic control and produce hypercholesterolaemia and gout, and it may aggravate renal or hepatic insufficiency.

Kinetics

Absorption

Bendroflumethiazide is completely absorbed when administered orally.

Distribution

Bendroflumethiazide is completely absorbed when administered orally.

Metabolism

The drug is 94% protein-bound in the plasma; the VD is 1.18 l/kg.

Excretion

Occurs predominantly in the urine, 30% unchanged. The clearance is 3.68 ml/min/kg, and the elimination half-life is 2.7–4.1 hours.

Special points

The drug may cause hypokalaemia and hypercalcaemia, which may precipitate digoxin toxicity, potentiate the effect of non-depolarizing muscle relaxants, and increase the likelihood of dysrhythmias occurring during general anaesthesia.

The hypotension occurring secondary to the administration of opioids, barbiturates, and halothane is reportedly exaggerated in patients receiving thiazide diuretics.

Bupivacaine

Uses

Bupivacaine is used as a local anaesthetic.

Chemical

An amide which is a structural homologue of mepivacaine.

Presentation

As a clear, colourless solution containing racemic bupivacaine (S- and R-enantiomers) in concentrations of 0.25% (2.64 mg/ml equivalent to bupivacaine hydrochloride anhydrous 2.5 mg/ml) and 0.5% (5.28 mg/ml equivalent to bupivacaine hydrochloride anhydrous 5.0 mg/ml). The 0.25/0.5% solutions are available combined with 1:200 000 adrenaline, which contain the preservative sodium metabisulfite. A 0.5% (‘hyperbaric’ or ‘heavy’) solution containing 80 mg/ml of glucose (with a specific gravity of 1.026) is also available. Bupivacaine 0.1% is available as a mixture with 2 micrograms/ml of fentanyl for epidural use. The S-enantiomer is available as levobupivacaine hydrochloride in the following concentrations: 2.5 mg/ml, 5 mg/ml, and 7.5 mg/ml. Levobupivacaine is also available for epidural use in the following concentrations: 0.625 mg/ml and 1.25 mg/ml. The pKa of bupivacaine is 8.1, and it is 15% unionized at a pH of 7.4. The heptane:buffer partition coefficient is 27.5.

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+ channels, thereby decreasing Na+ conductance and preventing the depolarization of the cell membrane.

Routes of administration/doses

Bupivacaine may be administered topically, by infiltration, intrathecally, or epidurally; the toxic dose of bupivacaine is 2 mg/kg (with or without adrenaline). The maximum dose is 150 mg. The drug acts within 10–20 minutes and has a duration of action of 5–16 hours.

Effects

CVS

Bupivacaine is markedly cardiotoxic; it binds specifically to myocardial proteins, in addition to blocking cardiac sodium channels and decreasing the rate of increase of phase 0 during the cardiac action potential. In toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse. K+ and Ca2+ channels may also be affected at toxic doses. Levobupivacaine-induced cardiotoxicity requires a greater dose to be administered, compared with racemic bupivacaine.

CNS

The principal effect of bupivacaine 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. Levobupivacaine produces less motor blockade, but longer sensory blockade, following epidural administration.

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. The use of the drug for intravenous regional blockade is no longer recommended, as refractory cardiac depression, leading to death, has been reported when it is used for this purpose.

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.

The addition of adrenaline to bupivacaine solutions does not influence the rate of systemic absorption, as:

  1. 1. the drug is highly lipid-soluble, and therefore its uptake into fat is rapid, and

  2. 2. the drug has a direct vasodilatory effect.

Distribution

Bupivacaine is 95% protein-bound in the plasma to albumin and alpha-1 acid glycoprotein; the VD is 21–103 l. An in vitro study of levobupivacaine protein binding in man demonstrated plasma protein binding to be >97% at concentrations between 0.1 and 1.0 micrograms/ml.

Metabolism

Occurs in the liver by N-dealkylation, primarily to pipecoloxylidide. N-desbutyl bupivacaine and 4-hydroxy bupivacaine are also formed. There is no evidence of in vivo racemization of levobupivacaine. In vitro studies of levobupivacaine demonstrate that CYP3A4 and CYP1A2 are responsible for its metabolism to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively.

Excretion

5% of the dose is excreted in the urine as pipecoloxylidide; 16% is excreted unchanged. The clearance is 0.47 l/min, and the elimination half-life (after intravenous administration) is 0.31–0.61 hours.

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. In infants under 6 months of age, the low level of albumin and alpha-1 acid glycoprotein results in an increase in the free fraction of bupivacaine. Local anaesthetic agents significantly increase the duration of action of both depolarizing and non-depolarizing relaxants. Levobupivacaine may precipitate if diluted in alkaline solutions. Clonidine (8.4 micrograms/ml), morphine (0.05 mg/ml), and fentanyl (4 micrograms/ml) have been shown to be compatible with levobupivacaine.

Buprenorphine

Uses

Buprenorphine is used:

  1. 1. in the treatment of moderate to severe pain and has been used

  2. 2. in sequential analgesia.

Chemical

A synthetic derivative of the alkaloid thebaine.

Presentation

As a clear, colourless solution containing 300 micrograms/ml of buprenorphine hydrochloride, 200/400 micrograms tablets, and various strengths of transdermal patches.

Main actions

Analgesia.

Mode of action

The mode of action of buprenorphine remains to be fully elucidated. The drug acts as a partial agonist at MOP receptors but dissociates slowly from the latter, leading to prolonged analgesia. Buprenorphine appears also to have a high affinity for (but a low intrinsic activity at) kappa-opioid receptors. One unusual property of buprenorphine hydrochloride observed in vitro is its very slow rate of dissociation from its receptor. This may explain its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence.

Routes of administration/doses

The adult intramuscular and intravenous dose is 0.3–0.6 mg 6- to 8-hourly; the corresponding sublingual dose is 0.2–0.4 mg 6- to 8-hourly. The drug is also effective when administered by the epidural route; a dose of 0.3 mg has been recommended. The dose for transdermal delivery should be evaluated after 24–72 hours and adjusted according to instructions, due to the slow rise in plasma levels. Buprenorphine has a significantly longer latency period and duration of action than morphine.

Effects

CVS

Buprenorphine has minimal cardiovascular effects; the heart rate may decrease (by up to 25%) and the systolic blood pressure may fall by 10%, following administration of the drug.

RS

The drug produces respiratory depression and an antitussive effect, similar to that produced by morphine. Buprenorphine may cause histamine and tryptase release from lung parenchymal mast cells and may increase the PVR.

CNS

The drug is 25 times as potent an analgesic as morphine. In common with other opioids, buprenorphine produces miosis. The drug decreases cerebral glucose metabolism by up to 30%.

GU

The drug has been shown to reduce the rate of urine output in animals.

Metabolic/other

Buprenorphine decreases the release of luteinizing hormone and increases the release of prolactin.

Toxicity/side effects

Side effects are similar in nature and incidence to those produced by morphine. Drowsiness, dizziness, headache, confusion, dysphoria, and nausea and vomiting may be produced by the drug. Buprenorphine appears to be less liable to produce dependence than pure mu-agonists.

Kinetics

Absorption

The drug is absorbed when administered orally but undergoes a significant first-pass metabolism, and the sublingual route is therefore preferred. The bioavailability is 40–90% when administered intramuscularly and 44–94% when administered sublingually.

Distribution

Only unchanged buprenorphine appears to reach the CNS. The drug is 96% protein-bound in vitro; the VD is 3.2 l/kg.

Metabolism

Occurs in the liver by dealkylation with subsequent conjugation to glucuronide; the polar conjugates then appear to be excreted in the bile and hydrolysed by bacteria in the gastrointestinal tract.

Excretion

Occurs predominantly via the faeces as unchanged buprenorphine; the remainder is excreted in the urine as conjugated buprenorphine and dealkylated derivatives. The clearance is 934 ml/min (this is decreased by 30% under general anaesthesia), and the elimination half-life is 5 hours.

Special points

Being a partial agonist, buprenorphine antagonizes the effects of morphine and other opioid agonists and may precipitate abstinence syndromes in opiate-dependent subjects. The respiratory depressant effects of the drug are not completely reversed by even large doses of naloxone; doxapram, however, will do so. Severe respiratory depression has occurred when benzodiazepines have been co-administered with buprenorphine.

Buprenorphine is not removed by haemodialysis.

The addition of buprenorphine to local anaesthesia for brachial plexus blockade triples the length of post-operative analgesia, compared to local anaesthesia alone.

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