Page of

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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0011

Labetalol

Uses

Labetalol is used in the treatment of:

  1. 1. all grades of hypertension

  2. 2. hypertensive emergencies and has been used

  3. 3. to produce controlled hypotension during anaesthesia

  4. 4. for the control of the reflex cardiovascular responses to intubation and

  5. 5. in the management of acute myocardial infarction.

Chemical

A synthetic salicylamide derivative.

Presentation

As a clear solution for injection containing 5 mg/ml and as 50/100/200/400 mg tablets of labetalol hydrochloride.

Main action

Antihypertensive.

Mode of action

Labetalol acts by selective antagonism of alpha-1, beta-1, and beta-2 adrenoceptors (the ratio of alpha:beta effects is 1:3 when administered orally, and 1:7 when administered intravenously). The drug has some intrinsic sympathomimetic activity at beta-2 adrenoceptors and may cause some vasodilation directly by stimulation of beta-2 receptors in vascular smooth muscle.

Routes of administration/doses

The adult oral dose is 100–800 mg 12-hourly. The drug may also be administered intravenously as a 5–20 mg bolus injected over 2 minutes, with subsequent increments to a maximum adult dose of 200 mg, or by infusion (diluted in glucose or glucose saline) at the rate of 20–160 mg/hour. When administered intravenously, labetalol acts in 5–30 minutes and has a mean duration of action of 50 minutes.

Patients should remain supine, whilst receiving the drug via the intravenous route, and subsequently assume the upright position cautiously, as profound postural hypotension may occur.

Effects

CVS

Intravenous labetalol causes a 20% (greater in hypertensive patients) decrease in the systolic and diastolic blood pressure; the heart rate and cardiac output may decrease by 10%. The drug reduces the systemic vascular resistance by 14%; limb blood flow increases, and coronary vascular resistance may decrease. Labetalol inhibits platelet aggregation in vitro.

RS

With single doses, the drug has no effect on forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), or specific airways resistance in patients with obstructive airways disease. Chronic use of the drug has no clinically significant effect on respiratory function.

CNS

Labetalol has no effect on cerebral blood flow; autoregulation is well maintained.

GU

Labetalol decreases renal vascular resistance by 20%, leading to an increase in the renal blood flow. The glomerular filtration rate, however, remains unchanged.

Metabolic/other

The concentrations of adrenaline, noradrenaline, and prolactin increase acutely in hypertensive patients given labetalol intravenously. The drug may also decrease plasma renin activity and the concentration of angiotensin II. The erythrocyte sedimentation rate (ESR) and serum transaminase concentration may increase, following the administration of the drug; labetalol has no effect on plasma lipid concentration.

Toxicity/side effects

The side effects of beta-blockade (asthma, Raynaud’s phenomenon, heart failure, cramps, nightmares, etc.) occur less frequently during the use of labetalol than do the side effects of alpha-blockade (dizziness, formication, nasal congestion, etc.). Gastrointestinal disturbances may also complicate the use of labetalol.

Kinetics

Absorption

Labetalol is rapidly absorbed when administered orally, but, due to a significant first-pass metabolism, the bioavailability shows an 8-fold variation (11–86%).

Distribution

The drug is 50% protein-bound in the plasma; the VD is 2.5–15.7 l/kg.

Metabolism

Labetalol is extensively metabolized in the liver (and possibly in the gut wall) to several inactive conjugates.

Excretion

Occurs predominantly as inactive conjugates in the urine (5% is excreted unchanged), with some appearing in the faeces. The clearance is 13–31 ml/min/kg, and the elimination half-life is 3–8 hours. Renal impairment has no effect on the kinetics of labetalol; the dose should be reduced in the presence of hepatic impairment.

Special points

In the presence of concentrations of halothane 3%, labetalol causes a significant decrease in cardiac output, stroke volume, mean arterial pressure, and central venous pressure.

Haemodialysis will remove 1% of a dose of labetalol.

Levetiracetam

Uses

Levetiracetam is used:

  1. 1. as a single agent for partial seizures

  2. 2. as an adjuvant therapy in the treatment of myoclonic epilepsy and generalized epilepsy.

Chemical

A pyrrolidone derivative.

Presentation

Levetiracetam is available as tablets containing 250, 500, 750, or 1000 mg. The drug is also available as an oral solution containing 100 mg/ml. An intravenous concentrate is available at a concentration of 100 mg/ml presented in a glass vial. The latter must be further diluted into 100 ml of compatible fluid prior to administration.

Main actions

Antiepileptic.

Mode of action

Levetiracetam acts in a different way to other antiepileptic medications. The mode of action remains to be fully elucidated, but the drug appears to reduce intracellular calcium release. In a rodent model, the drug binds to synaptic vesicle protein 2A, which is involved in excitatory neurotransmitter release. The interaction of levetiracetam and this protein may also contribute to its antiepileptic properties.

Routes of administration/doses

Levetiracetam may be administered orally or by intravenous infusion. The recommended adult dose is 500 mg twice daily. The maximum dose is 1500 mg twice daily.

Effects

CNS

Somnolence and headache occur in 10% of patients.

AS

Levetiracetam causes nasopharyngitis in up to 10% of patients.

Toxicity/side effects

Tremors, dizziness, and cutaneous rashes have been reported.

Kinetics

Absorption

Very high bioavailability approaching 100%.

Distribution

Data incomplete. Very little of the drug is protein-bound.

Metabolism

24% of an administered does undergoes hepatic hydrolysis of the acetamide group to an inactive metabolite.

Excretion

95% of an administered dose is excreted in the urine. The half-life of levetiracetam is 7 hours.

Special points

A dose reduction is recommended for patients with moderate to severe renal failure. Levetiracetam does not interact with the cytochrome P450 enzyme system.

Levosimendan

Uses

Levosimendan is used in the treatment of acute heart failure syndromes resulting from a variety of aetiologies.

Chemical

A propanedinitrile derivative.

Presentation

As a clear, yellow, or orange solution for injection containing 2.5 mg/ml of levosimendan in 5 and 10 ml ampoules which needs to be diluted prior to administration.

Main action

Positive inotrope and vasodilatation.

Mode of action

Levosimendan increases calcium sensitivity by binding to myocardial troponin C, leading to stabilization and increased duration of calcium binding. This results in increased myocardial contractility, without impairment of myocardial relaxation or increased oxygen demand. The drug also stimulates ATP-sensitive K+ channels, leading to vasodilatation, in addition to myocardial anti-stunning/ischaemic effects.

Routes of administration/doses

Levosimendan is administered by intravenous infusion either by peripheral or central routes. An initial loading dose of 6–12 micrograms/kg should be administered over a 10-minute period, followed by an intravenous infusion at a rate of 0.1–0.2 micrograms/kg/min.

Effects

CVS

The primary action of levosimendan is to increase myocardial contractility via increased calcium sensitivity, without a corresponding increase in myocardial oxygen demand. The drug also causes coronary and peripheral vasodilatation. This may lead to anti-stunning and anti-ischaemia myocardial effects.

GU

The urine output and glomerular filtration rate increase, secondary to the increase in cardiac output.

Metabolic/other

Human data have demonstrated a reduction in lactate concentrations, following administration of the drug in patients with septic shock.

Toxicity/side effects

Hypotension, headache, nausea, and vomiting are the commonest side effects reported, secondary to the vasodilatory effects of the drug. Hypokalaemia and arrhythmias have also been reported in small numbers of patients.

Kinetics

Distribution

Levosimendan is 97–98% bound to albumin; the VD at steady state is 0.2 l/kg.

Metabolism

95% of an administered dose undergoes hepatic conjugation to cyclic or N-acetylated cysteinylglycine and cysteine conjugates. Five percent of administered levosimendan undergoes intestinal reduction to aminophenylpyridazinone (OR-1855), followed by reabsorption into the plasma where further metabolism occurs by N-acetyltransferase to the active metabolite OR-1896. The rate of metabolism of the drug is genetically determined, although there is no evidence that any clinically significant therapeutic effect occurs between individuals who are rapid or slow acetylators. Levosimendan does not induce or inhibit the cytochrome P450 isoenzyme system.

Excretion

54% of an administered dose is renally excreted, and 44% is found in the faeces. The elimination half-life is approximately 3 hours, and the clearance is 3 ml/kg/hour. Less than 0.05% of levosimendan is excreted unchanged in the urine. The circulating metabolites (OR-1855 and OR-1896) are formed and excreted in a delayed pharmacokinetic profile, reaching a peak plasma concentration approximately 2 days after termination of an infusion of the drug. The metabolites of levosimendan have a half-life of 75–80 hours and are excreted predominantly in the urine.

Special points

The drug is not removed by haemodialysis.

Levosimendan may produce a clinical improvement which continues beyond the termination of the treatment period.

There are human data to suggest that administration of the drug may lead to reduced levels of circulating pro-inflammatory cytokines (interleukin-6, IL-6) and soluble apoptosis mediators, in addition to lower concentrations of B-type natriuretic peptide.

Levothyroxine

Uses

Thyroid hormones are used in the treatment of:

  1. 1. hypothyroidism

  2. 2. myxoedema coma, and

  3. 3. goitre.

Chemical

Both hormones are iodine-containing amino acid derivatives of thyronine.

Presentation

Levothyroxine is presented as tablets containing 25/50/100 micrograms of levothyroxine sodium. Triiodothyronine is presented as 20 micrograms tablets and a white lyophilized powder for reconstitution in water containing 20 micrograms of triiodothyronine.

Main action

Modulation of growth and metabolism.

Mode of action

The thyroid hormones, probably predominantly triiodothyronine, combine with a ‘receptor protein’ within the cell nucleus and thereby activate the DNA transcription process, leading to an increase in the rate of RNA synthesis and a generalized increase in protein synthesis.

Routes of administration/doses

The adult oral dose of levothyroxine is 25–300 micrograms daily in divided doses, titrated according to the clinical response and results of thyroid function tests. The corresponding dose of triiodothyronine is 10–60 micrograms daily; the dose by the intravenous route is 5–20 micrograms 4- to 12-hourly; close monitoring is essential during intravenous administration. There is a 24-hour latency period, before the effects of levothyroxine are manifested; the peak effect occurs in 6–7 days. Triiodothyronine acts in 6 hours, and the peak effect is observed within 24 hours.

Effects

CVS

The thyroid hormones are positively inotropic and chronotropic; these effects may be mediated by an increase in the number of myocardial beta-adrenergic receptors. The systolic blood pressure is increased by 10–20 mmHg; the diastolic blood pressure decreases, and the mean arterial pressure remains unchanged. Vasodilation results from the increase in peripheral oxygen consumption; the circulating blood volume also increases slightly.

RS

The thyroid hormones increase the rate and depth of respiration, secondary to the increase in the basal metabolic rate.

CNS

The hormones have a stimulatory effect on CNS function; tremor and hyperreflexia may result. Their physiological function also includes mediation of negative feedback on the release of thyroid-stimulating hormone from the pituitary.

AS

Appetite is increased, following the administration of levothyroxine or triiodothyronine; the secretory activity and motility of the gastrointestinal tract are also increased.

GU

The thyroid hormones are involved in the control of sexual function and menstruation.

Metabolic/other

Thyroid hormones promote gluconeogenesis and increase the mobilization of glycogen stores. Lipolysis is stimulated, leading to an increase in the concentration of free fatty acids; hypercholesterolaemia may result from increased cholesterol turnover. The rate of protein synthesis is enhanced.

Toxicity/side effects

Excessive administration of the thyroid hormones results in the clinical state of thyrotoxicosis.

Kinetics

Absorption

Both levothyroxine and triiodothyronine are completely absorbed when administered orally.

Distribution

Both hormones are bound to thyroid-binding globulin and thyroid-binding pre-albumin in the plasma; levothyroxine is 99.97% bound, and triiodothyronine is 99.5% bound. The VD of levothyroxine is 0.2 l/kg, and that of triiodothyronine is 0.5 l/kg.

Metabolism

35% of levothyroxine is converted to triiodothyronine in the periphery (predominantly in the liver and kidney), and some to inactive reverse T3. Both levothyroxine and triiodothyronine undergo conjugation to glucuronide and sulfate, and are excreted in the bile; some enterohepatic circulation occurs.

Excretion

20–40% of an administered dose is excreted in the faeces unchanged. The clearance of levothyroxine is 1.7 ml/min, and the elimination half-life is 6–7 days; the clearance of triiodothyronine is 17 ml/min, and the elimination half-life is 2 days.

Special points

The thyroid hormones increase the anticoagulant activity of co-administered warfarin. Beta-adrenergic antagonists interfere with the conversion of levothyroxine to triiodothyronine and lead to a relative increase in the inactive reverse T3 fraction.

Lidocaine

Uses

Lidocaine is used:

  1. 1. as a local anaesthetic and

  2. 2. in the treatment of ventricular tachydysrhythmias, acting as a class Ib antiarrhythmic.

Chemical

A tertiary amine which is an amide derivative of diethylaminacetic acid.

Presentation

As a clear, colourless solution in concentrations of 0.5/1/1.5/2% solution of lidocaine hydrochloride (with or without 1:200 000 adrenaline); a gel containing of 21.4 mg/ml of lidocaine hydrochloride (with or without chlorhexidine gluconate); a 5% ointment, a 10% spray, and a 4% aqueous solution for topical application; and as a cream/suppositories (in combination with hydrocortisone) for rectal administration. The 1% and 2% preparations are available with or without the preservatives methylhydroxybenzoate (1.7 mg/ml) and propylhydroxybenzoate (0.3 mg/ml). Hydrochloric acid and sodium hydroxide are also present in some formulations (the latter to a maximum of 1%). The pKa of lidocaine is 7.7 and is 25% unionized at a pH of 7.4. The heptane:buffer partition coefficient is 2.9.

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.

Routes of administration/doses

Lidocaine may be administered topically, by infiltration, intrathecally, or epidurally; the toxic dose of lidocaine is 3 mg/kg (7 mg/kg with adrenaline). The maximum dose is 300 mg (500 mg with adrenaline). The adult intravenous dose for the treatment of acute ventricular dysrhythmias is a bolus injection of 1 mg/kg, administered over 2 minutes. A second dose may be administered according to the response of the patient. This is normally followed by an infusion at a rate of 20–50 micrograms/kg/min. Lidocaine acts in 2–20 minutes (dependent on the rate of administration and the presence of vasoconstrictors and the concentrations used). The speed of onset of lidocaine may be increased by the addition of bicarbonate to increase the pH of the solution, thereby increasing the unionized fraction of drug. The pH of the drug is approximately 6.4.

Effects

CVS

In low concentrations, lidocaine decreases the rate of rise of phase 0 of the cardiac action potential by blockade of inactivated sodium channels.

This results in a rise in the threshold potential, with the duration of the action potential and effective refractory period being shortened. It has few haemodynamic effects when used in low doses, except to cause a slight increase in the systemic vascular resistance, leading to a mild increase in the blood pressure. In toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse.

RS

The drug causes bronchodilatation at subtoxic concentrations. Respiratory depression occurs in the toxic dose range.

CNS

The principal effect of lidocaine 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.

AS

Local anaesthetics depress contraction of the intact bowel.

Metabolic/other

Lidocaine may have some anticholinergic and antihistaminergic activity.

Toxicity/side effects

Lidocaine is intrinsically less toxic than bupivacaine. 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. Methaemoglobinaemia may occur if doses in excess of 600 mg are used and is caused by the metabolite O-toluidine, although this condition may occur at lower doses in patients suffering from anaemia or a haemoglobinopathy or in patients receiving therapy known to also precipitate methaemoglobinaemia (sulfonamides). Use of lidocaine for paracervical block or pudendal nerve block in obstetric patients is not recommended, as this may give rise to methaemoglobinaemia in the neonate, as the erythrocytes are deficient in methaemoglobin reductase.

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

Lidocaine is 64–70% protein-bound in the plasma, predominantly to alpha-1 acid glycoprotein; the VD is 0.7–1.5 l/kg.

Metabolism

Lidocaine is metabolized in the liver by N-dealkylation, with subsequent hydrolysis to monoethylglycine and xylidide. Monoethylglycine is further hydrolysed, whilst xylidide undergoes hydroxylation to 4-hydroxy-2,6-xylidine which is the main metabolite and excreted in the urine. Metabolites of lidocaine may lower the fit threshold, thereby potentiating seizure activity, whilst others have some antiarrhythmic properties.

Excretion

Less than 10% of the dose is excreted unchanged in the urine. The clearance is 6.8–11.6 ml/min/kg, and the elimination half-life is 90– 110 minutes. The clearance is reduced in the presence of cardiac and hepatic failure.

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.

Due to the narrow therapeutic index of lidocaine, the plasma concentrations of the drug need to be monitored in patients with cardiac and hepatic impairment.

Lidocaine is not removed by haemodialysis.

Intravenous administration of lidocaine decreases N2O and halothane requirements by 10% and 28%, respectively.

EMLA® (Eutectic Mixture of Local Anaesthetics) is a white cream used to provide topical anaesthesia prior to venepuncture and has also been used to provide anaesthesia for split skin grafting. It contains 2.5% prilocaine and 2.5% lidocaine in an oil–water emulsion. When applied topically under an occlusive dressing, local anaesthesia is achieved after 1–2 hours and lasts for up to 5 hours. The preparation causes temporary blanching and oedema of the skin; detectable methaemoglobinaemia may also occur in the presence of excessive O-toluidine plasma levels as a metabolite of prilocaine.

Linezolid

Uses

Linezolid is used in the treatment of:

  1. 1. nosocomial and community-acquired pneumonia

  2. 2. complex skin and soft tissue infections, and

  3. 3. MRSA infection and vancomycin-resistant Enterococcus (VRE).

Chemical

An oxazolidinone.

Presentation

As 600 mg tablets and a solution for intravenous administration containing 2 mg/ml of linezolid.

Main action

Antibacterial active against a wide range of Gram-positive organisms, particularly Enterococcus, Streptococcus, and staphylococcal spp., and Gram-positive anaerobes, including Clostridium perfringens.

Mode of action

Linezolid inhibits bacterial protein synthesis by binding specifically to the 50S ribosomal subunit, thereby preventing initiation complex formation.

Routes of administration/doses

The adult oral and intravenous dose is 600 mg 12-hourly.

Toxicity/side effects

Headache, abnormalities of liver function tests, taste alteration, and gastrointestinal disturbances are common. Fertility may be affected reversibly. Skin and bleeding disorders, phlebitis, and pancreatitis may also occur.

Kinetics

Absorption

Linezolid is rapidly absorbed after oral administration and has an oral bioavailability approaching 100%.

Distribution

The drug is 31% protein-bound in the plasma; the VD is 0.64 l/kg.

Metabolism

Linezolid is metabolized by oxidation to two inactive carboxylic acid metabolites.

Excretion

30% is excreted unchanged in the urine; the metabolites are excreted in the urine and faeces. The elimination half-life is 5 hours, and the clearance 120 ml/min.

Special points

Linezolid is a reversible non-selective MAOI. It enhances the effects of ephedrine on the blood pressure.

Lithium

Uses

Lithium is used in the treatment of:

  1. 1. mania and hypomania and in the prophylaxis of

  2. 2. recurrent bipolar depression

  3. 3. recurrent affective disorders, and

  4. 4. as an adjunct in the treatment of chronic pain of non-malignant origin.

Chemical

An alkali metal.

Presentation

As tablets containing 200/250/400/450 mg of lithium carbonate.

Main action

Antipsychotic.

Mode of action

The precise mode of action of lithium is unknown; it may act by stabilization of membranes or by alteration of central neurotransmitter function.

Routes of administration/doses

The adult oral dose is 0.4–1.2 g/day; serum levels should be monitored within 1 week of starting lithium and regularly thereafter, as the drug has a narrow therapeutic index. The therapeutic level is 0.5–1.5 mmol/l.

Effects

CVS

Prolonged lithium therapy may lead to reversible ECG changes, especially T-wave depression.

CNS

The drug has no effect on CNS function in normal subjects, although an increase in muscle tone occurs commonly. Lithium appears to lower the seizure threshold in epileptics.

GU

Over one-third of patients receiving lithium develop polyuria and polydipsia due to antagonism of the effects of ADH.

Metabolic/other

With prolonged use of lithium, retention of sodium (secondary to an increase in aldosterone secretion) may occur, as may hypercalcaemia and hypermagnesaemia. The drug has mild insulin-like effects on carbohydrate metabolism.

Toxicity/side effects

At therapeutic serum levels, disturbances of thyroid function, weight gain, tremor, pretibial oedema, and allergic phenomena may occur. Excessive serum concentrations may result in nausea and vomiting, abdominal pain, diarrhoea, ataxia, convulsions, coma, dysrhythmias, and death. Nephrogenic diabetes insipidus occurs in 5–20% of patients on long-term lithium treatment.

Kinetics

Absorption

The drug is rapidly absorbed when administered orally; the bioavailability is 100%.

Distribution

Lithium exhibits no demonstrable protein binding in the plasma; the VD is 0.45–1.13 l/kg.

Excretion

95% of a dose of lithium is excreted in the urine, the remainder in sweat. The clearance is 0.24–0.46 ml/min/kg, and the elimination half-life is 14–30 hours.

Special points

Renal, cardiac, and thyroid function should be monitored regularly during lithium therapy. Co-administration of lithium and diazepam has been reported to lead to hypothermia; the drug may also increase the duration of action of both depolarizing and non-depolarizing relaxants.

The drug is removed by haemodialysis.

Lorazepam

Uses

Lorazepam is used:

  1. 1. in the short-term treatment of anxiety

  2. 2. as a hypnotic

  3. 3. in premedication and

  4. 4. for the treatment of status epilepticus.

Chemical

A hydroxybenzodiazepine.

Presentation

As 1/2.5 mg tablets and as a clear, colourless solution for injection containing 4 mg/ml of lorazepam.

Main actions

  1. 1. Hypnosis

  2. 2. Sedation

  3. 3. Anxiolysis

  4. 4. Anterograde amnesia

  5. 5. Anticonvulsant, and

  6. 6. Muscular relaxation.

Mode of action

Benzodiazepines are thought to act via specific benzodiazepine receptors found at synapses throughout the CNS, but concentrated especially in the cortex and midbrain. Benzodiazepine receptors are closely linked with GABA receptors and appear to facilitate the activity of the latter. Activated GABA receptors open chloride ion channels which then either hyperpolarize or short-circuit the synaptic membrane.

Routes of administration/doses

The adult oral or sublingual dose is 1–4 mg/day in divided doses. The intravenous or intramuscular dose is 0.025–0.05 mg/kg; intramuscular injection is painful.

Effects

CVS

Lorazepam appears to have no direct cardiac effects.

RS

Mild respiratory depression occurs, following the administration of the drug, which is of clinical significance only in patients with lung disease.

CNS

The drug produces sedation, anterograde amnesia, and an anticonvulsant effect.

AS

Lorazepam has no effect on basal gastric acid secretion but decreases pentagastrin-stimulated gastric acid secretion by 25%.

Metabolic/other

Circulating cortisol and glucose levels fall when lorazepam is used in premedication, probably secondarily to its anxiolytic effect.

Toxicity/side effects

Drowsiness, sedation, confusion, and impaired coordination occur in a dose-dependent fashion. Paradoxical stimulation has been reported and occurs more frequently when hyoscine is administered concurrently. Tolerance and dependence may occur with prolonged use of benzodiazepines; acute withdrawal of benzodiazepines in these circumstances may produce insomnia, anxiety, confusion, psychosis, and perceptual disturbances.

Kinetics

Absorption

Lorazepam has a bioavailability of 90% when administered by the oral or intramuscular route.

Distribution

The drug is 88–92% protein-bound in the plasma; the VD is 1 l/kg. Lorazepam is less extensively distributed than diazepam and thus has a longer duration of action despite the shorter elimination half-life of lorazepam.

Metabolism

Lorazepam is conjugated directly in the liver to glucuronide to form an inactive water-soluble metabolite.

Excretion

80% of an orally administered dose appears in the urine as the glucuronide. The clearance is 1 ml/min/kg, and the elimination half-life is 8–25 hours—this is unaffected by renal disease.

Special points

The co-administration of cimetidine does not impair the metabolic clearance of lorazepam.

The drug is not removed by haemodialysis.

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