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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0018

Teicoplanin

Uses

Teicoplanin is used in the parenteral treatment of severe infections:

  1. 1. complicated skin and soft tissue infections

  2. 2. bone and joint infections

  3. 3. hospital-acquired pneumonia

  4. 4. community-acquired pneumonia

  5. 5. urinary tract infections

  6. 6. infective endocarditis

  7. 7. peritonitis associated with continuous ambulatory peritoneal dialysis and

  8. 8. may be used orally as an alternative for Clostridium difficile infection- associated diarrhoea and colitis.

Commonly susceptible species are aerobic Gram-positive bacteria—Corynebacterium jeikeium, Enterococcus faecalis, Staphylococcus aureus (including MRSA), Streptococcus agalactiae, Streptococcus dysgalactiae, groups C and G streptococci, Streptococcus pneumoniae, Streptococcus pyogenes, streptococci in the viridans group; and aerobic Gram-positive bacteria Clostridium difficile, Peptostreptococcus spp. All Gram-negative organisms are resistant.

Chemical

Teicoplanin is a glycopeptide antibiotic from cultures of Actinoplanes teichomyceticus, comprising five major components differentiated by a specific fatty acid.

Presentation

As 200/400 mg powder for injection/infusion or oral solution with sodium chloride and sodium hydroxide (for pH adjustment). The solution is reconstituted by adding 3.14 ml of water for injection to the 200 mg and 400 mg powder vial. The water is slowly added to the vial which should be rotated until all the powder is dissolved to avoid foaming. If foam develops, stand for approximately 15 minutes. Only clear and yellowish solutions should be used. It then can be further diluted. Chemical and physical stability of the reconstituted solution prepared as recommended has been demonstrated for 24 hours at 2–8°C.

Main actions

Teicoplanin has a limited spectrum of antibacterial activity (Gram-positive) and may not be suitable for use as a single agent for the treatment of some infections, unless the pathogen is already documented and known to be susceptible.

Mode of action

Teicoplanin inhibits the growth of susceptible organisms by interfering with cell wall biosynthesis at a site different from that affected by beta-lactams. Peptidoglycan synthesis is blocked by specific binding to D-alanyl-D-alanine residues.

Teicoplanin antimicrobial activity depends essentially on the duration of time during which the substance level is higher than the MIC of the pathogen.

Routes of administration/doses

Due to its long half-life, loading doses is required of 400/800 mg 12-hourly for 3–5 administrations, then a daily maintenance of 400/600 mg. The dose needs to be adjusted according to the infection, organism, and presence of renal failure.

Effects

CNS

Teicoplanin does not readily penetrate into the CSF.

Metabolic/other

It is unknown whether teicoplanin is excreted in human milk. Teicoplanin is not removed by haemodialysis and only slowly by peritoneal dialysis.

Toxicity/side effects

Teicoplanin must be administered with caution in patients with known hypersensitivity to vancomycin, as cross-hypersensitivity reactions, including fatal anaphylactic shock, may occur. A previous history of ‘red man syndrome’ with vancomycin is not a contraindication to the use of teicoplanin. Life-threatening, or even fatal, cutaneous reactions have been reported. Increases in transaminase, alkaline phosphatase, and creatinine have all been recorded. Infusion-related reactions have been reported.

Kinetics

Absorption

When administered by the oral route, teicoplanin is not absorbed from the gastrointestinal tract. Bioavailability after intramuscular injection is approximately 90%.

Distribution

Teicoplanin is mainly bound to human serum albumin, and plasma protein binding ranges from 87.6 to 90.8%. The VDss varies from 0.7 to 1.4 ml/kg (>8 days). Teicoplanin is distributed mainly in the lungs, myocardium, and bone tissues, with tissue:serum ratios superior to 1.

Metabolism

Minimal two metabolites are formed probably by hydroxylation and represent 2–3% of the administered dose.

Excretion

Unchanged teicoplanin is mainly excreted by the urinary route (80% within 16 days), whilst 2.7% of the administered dose is recovered in faeces (via bile excretion) within 8 days after administration. The elimination half-life of teicoplanin varies from 100 to 170 hours. Teicoplanin has a low total clearance in the range of 10 to 14 ml/hour/kg, and a renal clearance in the range of 8 to 12 ml/hour/kg, indicating that teicoplanin is mainly excreted by renal mechanisms.

Special points

The dose has to be decreased in renal failure.

During maintenance treatment, teicoplanin trough serum concentrations monitoring is recommended at least once a week to ensure concentrations are stable and appropriate.

Resistance to teicoplanin can be based on the following mechanisms:

  1. 1. modified target structure: this form of resistance has occurred particularly in Enterococcus faecium. The modification is based on exchange of the terminal D-alanine-D-alanine function of the amino acid chain in a murein precursor with D-Ala-D-lactate, thus reducing the affinity to vancomycin. The responsible enzymes are a newly synthesized D-lactate dehydrogenase or ligase

  2. 2. the reduced sensitivity of staphylococci to teicoplanin is due to the overproduction of murein precursors to which the antibiotic is bound.

Cross-resistance between teicoplanin and the glycoprotein vancomycin may occur, but a number of vancomycin-resistant enterococci are sensitive to teicoplanin (Van-B phenotype).

Temazepam

Uses

Temazepam is used:

  1. 1. as a hypnotic and

  2. 2. for anaesthetic premedication.

Chemical

A 3-hydroxy benzodiazepine which is a minor metabolite of diazepam.

Presentation

As tablets containing 10/20 mg and an elixir containing 2 mg/ml of temazepam.

Main actions

Temazepam has anxiolytic, hypnotic, anticonvulsant, and muscle relaxant properties.

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

Temazepam is administered orally; the adult dose is 10–60 mg.

Effects

CVS

Benzodiazepines have minimal effects on cardiovascular parameters; an insignificant decrease in blood pressure may occur. Benzodiazepines can dilate coronary blood vessels, whilst simultaneously reducing myocardial oxygen consumption.

RS

High doses (40 mg) decrease the ventilatory response to hypercapnia.

CNS

The drug causes muscular relaxation, sedation, hypnosis, and anxiolysis; it also has anticonvulsant properties.

Metabolic/other

High doses (40 mg) cause a slight fall in temperature.

Toxicity/side effects

Temazepam is normally well tolerated; gastrointestinal upsets, headaches, dreams, paraesthesiae, and a ‘hangover effect’ (in 10–15%) may occur. 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

Absorption of oral temazepam is virtually complete; antacids delay the absorption of benzodiazepines.

Distribution

Temazepam is 76% protein-bound in vivo. The VD is 0.8 l/kg.

Metabolism

The drug is predominantly metabolized in the liver by direct conjugation to glucuronide; active metabolites are not formed to any great extent.

Excretion

80% of an administered dose appears in the urine as inactive conjugates; 12% is excreted in the faeces. The clearance is 6.6 l/hour, and the elimination half-life is 5–11 hours.

Special points

The drug is not removed by haemodialysis. Temazepam is a drug of abuse and has controlled drug status.

Terbutaline

Uses

Terbutaline is used in the treatment of:

  1. 1. asthma

  2. 2. chronic obstructive airways disease and

  3. 3. uncomplicated preterm labour.

Chemical

An alcohol.

Presentation

As 5 mg tablets, a syrup containing 0.3 mg/ml, a clear solution for injection containing 0.5 mg/ml, a respirator solution containing 2.5/10 mg/ml, and as an inhaler delivering 0.5 micrograms per actuation of terbutaline sulfate. It can be administered intravenously or subcutaneously 250–500 micrograms 6-hourly, and by infusion at a rate up to 5 micrograms/min in adults.

Main actions

Bronchodilatation and uterine relaxation.

Mode of action

Terbutaline is a beta-adrenergic agonist (with a more pronounced effect at beta-2 than beta-1 receptors) that acts by stimulation of membrane-bound adenylate cyclase in the presence of magnesium ions to increase intracellular cAMP concentrations.

Routes of administration/doses

The adult oral dose is 2.5–5 mg 8-hourly; the subcutaneous, intramuscular, and intravenous dose is 0.25–0.5 mg once or twice a day. Terbutaline may be administered by intravenous infusion diluted in glucose or saline at the rate of 1.5– 5 micrograms/min for 8–10 hours. The dose by inhalation is 0.25–0.5 micrograms 4-hourly or 2–5 mg 8- to 12-hourly if nebulized.

Effects

CVS

When used in large doses, terbutaline has positive inotropic and chronotropic effects.

RS

Bronchodilatation, leading to an increased PEFR and FEV1, occurs after administration of the drug. This is additive to the bronchodilatation produced by phosphodiesterase inhibitors. The drug interferes with the mechanism of hypoxic pulmonary vasoconstriction; an adequate inspired oxygen concentration should be ensured when terbutaline is used.

GU

Terbutaline relaxes uterine musculature. An increased tendency to bleeding has been reported in association with Caesarean sections.

Metabolic/other

Hyperinsulinaemia, leading to hypoglycaemia and hypokalaemia, may follow administration of the drug. Antepartum administration of terbutaline stimulates release of surface-active material into the alveolar space of the fetus, improving the function of the neonatal lung.

Toxicity/side effects

Tremor, palpitations, cramps, anxiety, and headache occur uncommonly after the administration of terbutaline.

Kinetics

Absorption

The drug is incompletely absorbed after oral administration; the bioavailability is 7–26%. Less than 10% is absorbed after inhalation, the remainder being swallowed.

Distribution

Terbutaline is 25% protein-bound in the plasma; the VD is 1.6 l/kg.

Metabolism

Terbutaline has an extensive first-pass metabolism; the drug is predominantly metabolized to a sulfate conjugate.

Excretion

60–70% is excreted unchanged in the urine, the remainder as the sulfated conjugate. The clearance is 1.75–2.75 ml/min/kg, and the elimination half-life is 11.5–23 hours.

Tetracycline

Uses

Tetracycline is used in the treatment of infections of:

  1. 1. the respiratory, gastrointestinal, and urinary tracts

  2. 2. ear, nose, and throat

  3. 3. soft tissues and in the treatment of

  4. 4. venereal diseases, including non-specific urethritis

  5. 5. typhus fever

  6. 6. psittacosis

  7. 7. cholera

  8. 8. acne rosacea and for

  9. 9. the treatment of recurrent pleural effusions and

  10. 10. the prophylaxis of subacute bacterial endocarditis.

Chemical

A napthacenecarboxamide derivative.

Presentation

As 250 mg tablets, a syrup containing 25 mg/ml, in vials containing 100 mg (with procaine) for intramuscular injection, and 250/500 mg (with ascorbic acid) for intravenous injection of tetracycline hydrochloride. An ointment for topical use is also available.

Main actions

Tetracycline is a broad-spectrum bacteriostatic antibiotic which is active against Gram-positive and Gram-negative bacteria, including Clostridium, Streptococcus, Neisseria, Brucella, and Vibrio spp., Haemophilus influenzae, Yersinia pestis, and Rickettsiae, Mycoplasma, Chlamydia, Leptospira, and Treponema spp.

Mode of action

Tetracycline inhibits bacterial protein synthesis by binding to bacterial 30S ribosomes (in the same manner as do aminoglycosides) and preventing the access of aminoacyl transfer RNA (tRNA) to the mRNA–ribosome complex, thereby preventing further elongation of the polypeptide chain.

Routes of administration/doses

The adult oral dose is 250–500 mg 6-hourly. The corresponding intramuscular dose is 100 mg 4- to 8-hourly, and the intravenous dose is 0.5–1 g 12-hourly. The intrapleural dose is 500 mg (of the intravenous preparation). Intramuscular injection of the drug is painful.

Effects

CVS

Tetracycline may increase the intracranial pressure.

Metabolic/other

The drug may cause an increase in the plasma urea concentration and decrease the plasma prothrombin activity.

Toxicity/side effects

Occur in 1–5% of patients. The drug may cause renal and hepatic impairment, gastrointestinal and haematological disturbances, moniliasis, rashes, photosensitivity, and thrombophlebitis. Tetracycline may also cause tooth staining in infancy.

Kinetics

Absorption

Tetracycline is incompletely absorbed when administered orally (it chelates with iron, calcium, and aluminium in the gut). The bioavailability is 77% by the oral route.

Distribution

The drug is widely distributed and exhibits good tissue penetration. The drug is 62–68% protein-bound in the plasma; the VD is 0.75–1.37 l/kg.

Metabolism

5% of the dose is metabolized to epitetracycline; the remainder is excreted unchanged.

Excretion

95% of the dose is excreted unchanged; 60% is excreted in the urine by glomerular filtration, the remainder in the faeces. The clearance is 1.43–1.91 ml/min/kg, and the half-life is 10–16 hours. A decreased dose should be used in the presence of renal failure.

Special points

Tetracycline has been demonstrated to increase the action of non-depolarizing relaxants. It is pharmaceutically incompatible with a host of other drugs, including thiopental, sodium bicarbonate, and autologous blood.

Tigecycline is a glycylcycline antibacterial structurally related to the tetracyclines with similar side effects. It is used for complicated intra-abdominal and skin and soft tissue infections. It is active against MRSA and VRE.

Thiopental

Uses

Thiopental is used:

  1. 1. for the induction of anaesthesia

  2. 2. in the management of status epilepticus and has been used

  3. 3. for brain protection.

Chemical

A thiobarbiturate.

Presentation

As a hygroscopic yellow powder, containing thiopental sodium and 6% sodium carbonate, stored under an atmosphere of nitrogen. The drug is reconstituted in water prior to use to yield a 2.5% solution with a pH of 10.8 and pKa of 7.6, which is stable in solution for 24–48 hours.

Main actions

Hypnotic and anticonvulsant.

Mode of action

Barbiturates are thought to act primarily at synapses by depressing post-synaptic sensitivity to neurotransmitters and by impairing pre-synaptic neurotransmitter release. Multi-synaptic pathways are depressed preferentially; the reticular activating system is particularly sensitive to the depressant effects of barbiturates. The action of barbiturates at the molecular level is unknown. They may act in a manner analogous to that of local anaesthetic agents by entering cell membranes in the unionized form, subsequently becoming ionized and exerting a membrane-stabilizing effect by decreasing Na+ and K+ conductance, decreasing the amplitude of the action potential, and slowing the rate of conduction in excitable tissue. In high concentrations, barbiturates depress the enzymes involved in glucose oxidation, inhibit the formation of ATP, and depress calcium-dependent action potentials. They also inhibit calcium-dependent neurotransmitter release and enhance chloride ion conductance in the absence of GABA.

Routes of administration/doses

The dose by the intravenous route is 2–7 mg/kg; following bolus administration, thiopental acts in one arm–brain circulation time and lasts for 5–15 minutes; it is cumulative with repeated administration. The drug may also be administered rectally in a dose of 1 g/22 kg body weight when it acts within 15 minutes.

Effects

CVS

Thiopental is a negative inotrope and decreases the cardiac output by approximately 20%; the blood pressure usually decreases as a result of both this effect and a decrease in systemic vascular resistance.

RS

Thiopental is a potent respiratory depressant; following intravenous administration, a period of apnoea may occur, followed by a more prolonged period of respiratory depression with a decrease in the ventilatory response to hypercapnia. Laryngeal spasm is occasionally seen in association with the administration of thiopental; the drug may also produce a degree of bronchoconstriction.

CNS

Thiopental produces a smooth, rapid induction of anaesthesia. Cerebral blood flow, intracranial pressure, and intraocular pressure are all decreased after the administration of the drug. As with all barbiturates, thiopental has anticonvulsant properties. The drug is antanalgesic when used in small doses. The characteristic EEG changes observed after thiopental administration are initially a fast activity which is subsequently replaced by synchronized low-frequency waves.

AS

The drug causes some depression of intestinal activity and constriction of the splanchnic vasculature.

GU

Thiopental decreases renal plasma flow and increases ADH secretion, leading to a decrease in the urine output. It has no effect on the tone of the gravid uterus.

Metabolic/other

A slight transient decrease in the serum potassium concentration may occur, following the administration of thiopental.

Toxicity/side effects

Severe anaphylactoid reactions may occur with the use of the drug, with a reported incidence of 1 in 20 000. Extravasation of the drug may lead to tissue necrosis; inadvertent intra-arterial injection may lead to arterial constriction and thrombosis. The treatment of the latter includes the administration of analgesia and alpha-adrenergic antagonists, sympathetic blockade of the limb, and anticoagulation.

Kinetics

Absorption

Thiopental is absorbed when administered orally or rectally.

Distribution

The drug is 65–86% protein-bound in the plasma, predominantly to albumin; 40% is sequestered in red blood cells; the VD is 1.96 l/kg. The rapid onset of action of the drug is due to:

  1. 1. the high blood flow to the brain

  2. 2. the lipophilicity of the drug and

  3. 3. its low degree of ionization—only the non-ionized fraction crosses the blood–brain barrier (thiopental is 61% non-ionized at pH 7.4; hyperventilation increases the non-bound fraction and increases the anaesthetic effect).

The relatively brief duration of anaesthesia following a bolus of thiopental is due to redistribution to muscle and later to fat.

Metabolism

Occurs in the liver by side-arm oxidation, oxidation to pentobarbital, and ring cleavage to form urea and 3-carbon fragments. Fifteen percent of the dose of the drug is metabolized per hour; 30% may remain in the body 24 hours after administration.

Excretion

Occurs predominantly in the urine as inactive metabolites; 0.5% is excreted unchanged. The clearance is 2.7–4.1 ml/kg/min, and the elimination half-life is 3.4–22 hours.

Special points

Volatile agents and surgery have no effect on the VD or clearance of thiopental; morphine increases the hypnotic effect of the drug and increases its brain half-life. The drug may induce acute clinical and biochemical manifestations in patients with porphyria. Thiopental should be used with caution in patients with fixed cardiac output states, hepatic or renal dysfunction, myxoedema, dystrophia myotonica, myasthenia gravis, familial periodic paralysis, and in the elderly or in patients who are hypovolaemic.

Thiopental is not removed by dialysis.

Drug structure

For the drug structure, please see Fig. 9.


Fig. 9 Drug structure of thiopental.

Fig. 9 Drug structure of thiopental.

Thrombolytics

Uses

Thrombolytic agents are used:

  1. 1. in the treatment of acute myocardial infarction

  2. 2. in the treatment of acute ischaemic cerebrovascular events (alteplase only)

  3. 3. for the intravascular dissolution of thrombi and emboli (e.g. DVT and massive pulmonary embolism (alteplase only)) and

  4. 4. in the treatment of acute or subacute occlusion of peripheral arteries.

Chemical

Thrombolytic agents are (glyco)protein structures that are either obtained from bacteria or genetically engineered. Streptokinase is a highly purified enzyme derived from beta-haemolytic streptococci of Lancefield Group C. Alteplase, reteplase, and tenecteplase are derived from Chinese hamster ovary cell lines using recombinant DNA technology.

Presentation

Streptokinase, alteplase, reteplase, and tenecteplase are all presented in a powder form requiring subsequent dissolving prior to intravenous injection and/or infusion, depending on the specific agent.

Main action

Fibrinolysis.

Mode of action

Alteplase, reteplase, and tenecteplase are recombinant human tissue plasminogen activators (rtPA) that are fibrin-specific. These agents bind to fibrin within the thrombus, with subsequent conversion of thrombus-bound plasminogen to plasmin, leading to fibrin degradation. Streptokinase acts indirectly on plasmin; the first phase is the formation of a streptokinase–plasminogen activator complex, which then converts further plasminogen molecules to active plasmin. Plasmin then digests fibrin to produce lysis of thrombi.

Routes of administration/doses

Thrombolytic agents are administered intravenously. This may be by bolus injection only, followed by further boluses and/or an intravenous infusion, depending on the type of agent being used and the regimen being followed. Streptokinase is administered by intravenous infusion. Alteplase is administered by a bolus, followed by infusion using either an ‘accelerated’ or a ‘standard’ regimen for acute myocardial infarction. For the treatment of pulmonary embolism, alteplase is administered as a 10 mg bolus over 1–2 minutes, followed by 90 mg over 2 hours. For the treatment of acute ischaemic stroke, alteplase is given over 1 hour at a dose of 0.9 mg/kg (maximum dose of 90 mg), with 10% of the dose given as a bolus. Tenecteplase is administered by a single weight-adjusted bolus, and reteplase is administered as two boluses 30 minutes apart.

Effects

CVS

Transient hypotension and reperfusion arrhythmias may occur, following administration of thrombolytic agents.

Metabolic/other

Fibrinolysis is produced by the action of the drug on plasmin. Following administration of streptokinase, anti-streptokinase antibodies are produced.

Toxicity/side effects

Excessive haemorrhage may complicate the use of any thrombolytic agent; if serious, this should be treated by cessation of drug administration, resuscitation, and possible treatment with intravenous tranexamic acid. The risk of a haemorrhagic cerebrovascular event is 0.5–1%. Pyrexia occurs commonly, following administration of streptokinase. Allergic reactions are common with the use of streptokinase, which can be minimized with the administration of antihistamines and corticosteroids.

Kinetics

Data are incomplete.

Distribution

The VD of thrombolytic agents are low: streptokinase 1.1 l, alteplase 2.8–4.6 l, reteplase 6 l, and tenecteplase 4.2–6.3 l.

Metabolism

Thrombolytic agents undergo hepatic metabolism. Tenecteplase binds to specific hepatic receptors prior to conversion into small peptides.

Excretion

The terminal elimination half-life of streptokinase is 83 minutes. Alteplase, reteplase, and tenecteplase undergo biphasic elimination. Alteplase is rapidly cleared from the plasma, with a plasma clearance of 550–680 ml/min. Reteplase and tenecteplase are cleared more slowly, with plasma clearance data of approximately 120 ml/min.

Special points

Heparin is administered with all thrombolytic agents, apart from streptokinase. Due to the bolus-dose administration of reteplase and tenecteplase, these agents are used in pre-hospital thrombolysis, in addition to in-hospital use.

The current National Service Framework for thrombolysis for myocardial infarction states a ‘call-to-needle’ time of 60 minutes and a ‘door-to-needle time’ of 20 minutes. If the ‘call-to-hospital’ time is >30 minutes, then pre-hospital thrombolysis should be considered. Thrombolytic agents should not be administered to patients with contraindications to thrombolysis, as detailed in national guidelines and/or local policies.

Tramadol

Uses

Tramadol is used in the management of moderate to severe pain.

Chemical

A synthetic opioid of the aminocyclohexanol group. The drug is a racemic mixture of two enantiomers (+) and (−) tramadol.

Presentation

As a clear aqueous solution for injection containing 50 mg/ml and tablets containing 50/100/150/200/300/400 mg of tramadol hydrochloride.

Main action

Centrally mediated analgesia.

Mode of action

Tramadol is a non-selective agonist at mu-, kappa-, and delta-opioid receptors (with a higher relative affinity for mu-receptors). It also inhibits neuronal reuptake of noradrenaline and enhances serotonin (5HT) release; inhibition of pain perception partly involves the activation of descending serotonergic and noradrenergic pathways.

Routes of administration/doses

Tramadol may be administered orally, intramuscularly, or by slow intravenous injection or infusion. The adult dose is 50–100 mg 4- to 6-hourly for all routes of administration. The paediatric dose is 1–2 mg/kg 4- to 6-hourly.

Effects

CVS

Tramadol has no clinically significant cardiovascular effects after intravenous administration.

RS

The respiratory rate, minute volume, and PaCO2 remain essentially unchanged, following intravenous administration of therapeutic doses of the drug.

CNS

Tramadol has an analgesic potency equivalent to pethidine. The analgesic effect is only partially (30%) reversed by naloxone.

AS

Tramadol has no demonstrable effect on bile duct sphincter activity. Constipation occurs uncommonly.

Toxicity/side effects

The principal side effects of tramadol are nausea, dizziness, sedation, and diaphoresis. The potential for tolerance and dependence appears to be low.

Kinetics

Absorption

The bioavailability following oral administration of the drug is 68–100%.

Distribution

The drug is 20% protein-bound in the plasma; the VD is 2.9–4.37 l/kg. Eighty percent of an administered dose crosses the placenta.

Metabolism

85% of an administered dose is metabolized by demethylation in the liver. One metabolite (O-desmethyltramadol) is active.

Excretion

90% of the dose is excreted in the urine, and 10% in the faeces. The clearance is 6.7–10.1 ml/kg/min, and the elimination half-life is 270–450 minutes. The elimination half-life is doubled in patients with impaired renal or hepatic function.

Special points

The use of tramadol is not recommended in patients with end-stage renal failure; the dosage interval should be increased to 12 hours in patients with renal or hepatic impairment.

The drug is not licensed for intraoperative use, as it may enhance intraoperative recall during enflurane/N2O anaesthesia.

Tramadol appears to be effective in the treatment of post-operative shivering.

The drug precipitates when mixed with diazepam or midazolam. The drug is only slowly removed by haemodialysis or haemofiltration.

Trichloroethylene

Uses

Trichloroethylene is used:

  1. 1. for the induction and maintenance of general anaesthesia and has been used

  2. 2. for pain relief during labour.

Chemical

A halogenated hydrocarbon.

Presentation

As a blue liquid (that should be protected from light) that is coloured with waxoline blue to enable differentiation from chloroform. The commercial preparation contains 0.01% thymol, which prevents decomposition on exposure to light; it is non-flammable in normal anaesthetic concentrations. The molecular weight of trichloroethylene is 131.4, the boiling point 67°C, and the saturated vapour pressure 8 kPa at 20°C. The MAC of trichloroethylene is 0.17, the oil/water solubility coefficient 400, and the blood/gas solubility coefficient 9.

Main action

General anaesthesia (reversible loss of both awareness and recall of noxious stimuli) and analgesia.

Mode of action

The mechanism of general anaesthesia remains to be fully elucidated. General anaesthetics appear to disrupt synaptic transmission (especially in the area of the ventrobasal thalamus). This mechanism may include potentiation of the GABAA and glycine receptors and antagonism at NMDA receptors. Their mode of action at the molecular level appears to involve the expansion of hydrophobic regions in the neuronal membrane, either within the lipid phase or within hydrophobic sites in cell membranes.

Routes of administration/doses

Trichloroethylene is administered by inhalation, conventionally via a calibrated vaporizer. The concentration used for the induction and maintenance of anaesthesia is 0.2–2%.

Effects

CVS

Trichloroethylene is noted for its cardiovascular stability; the heart rate, blood pressure, and cardiac output are little altered by the administration of the drug. Trichloroethylene has a marked propensity to cause dysrhythmias and sensitizes the myocardium to the effects of circulating catecholamines.

RS

The drug is moderately irritant to the respiratory tract and characteristically causes tachypnoea associated with a decreased tidal volume, which may lead to both hypoxia and hypercapnia.

CNS

The principal effect of trichloroethylene is general anaesthesia; the drug also has a marked analgesic effect. The drug increases cerebral blood flow, leading to an increase in intracranial pressure. A slight decrease in skeletal muscle tone results from the use of trichloroethylene.

AS

Nausea and vomiting occur commonly with the use of the drug.

GU

Trichloroethylene reduces the tone of the pregnant uterus when used in concentrations of 0.5%.

Toxicity/side effects

Trichloroethylene may provoke the appearance of myocardial dysrhythmias, particularly in the presence of hypoxia, hypercapnia, or excessive catecholamine concentrations.

Kinetics

Absorption

The major factors affecting the uptake of volatile anaesthetic agents are solubility, cardiac output, and the concentration gradient between the alveoli and venous blood. Trichloroethylene is relatively soluble in blood; the alveolar concentration therefore reaches inspired concentration relatively slowly, resulting in a slow induction of anaesthesia. An increase in the cardiac output increases the rate of alveolar uptake and slows the induction of anaesthesia. The concentration gradient between the alveoli and venous blood approaches zero at equilibrium; a large concentration gradient favours the onset of anaesthesia.

Distribution

The drug is initially distributed to organs with a high blood flow (brain, heart, liver, and kidney) and later to less well-perfused organs (muscles, fat, and bone).

Metabolism

20% of an administered dose is metabolized in the liver to yield trichloroacetic acid, monochloroacetic acid, and trichloroethanol (which is subsequently conjugated with glucuronide), and inorganic chloride.

Excretion

80% is exhaled unchanged; the metabolites are excreted in the urine over several days.

Special points

Trichloroethylene should not be used in a closed circuit with soda lime, since it decomposes in the presence of heat and alkali to form hydrochloric acid, carbon monoxide, dichloroacetylene, and phosgene, all of which are toxic.

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