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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0003

Carbamazepine

Uses

Carbamazepine is used in the treatment of:

  1. 1. epilepsy, especially temporal lobe and tonic–clonic seizures

  2. 2. trigeminal neuralgia, and

  3. 3. prophylaxis of bipolar disorder.

Chemical

An iminostilbene derivative structurally related to the tricyclic antidepressants.

Presentation

As 100/200/400 mg tablets, 125/250 mg suppositories, and as a white syrup containing 20 mg/ml of carbamazepine.

Main actions

Anticonvulsant and analgesic.

Mode of action

The mode of action of carbamazepine is unknown; it may act via alterations in adenosine disposition within the CNS. It does not appear to act in the same manner as tricyclic antidepressants.

Routes of administration/doses

The adult oral dose is 100–1600 mg daily in divided doses.

Effects

CVS

Carbamazepine has antiarrhythmic properties and depresses AV conduction.

CNS

The drug is more effective than phenytoin in raising the threshold for minimal electroshock seizures. Carbamazepine also has analeptic properties.

GU

Carbamazepine has an antidiuretic effect that may lead to water intoxication.

Toxicity/side effects

Diplopia, nausea and vomiting, drowsiness, and ataxia are relatively common side effects of the drug. Rashes occur in 3% of patients. Carbamazepine may also cause renal and liver damage. Mild neutropenia occurs commonly; fatal aplastic anaemia is extremely rare.

Kinetics

Absorption

The drug is well absorbed when administered orally; the bioavailability by this route is nearly 100%.

Distribution

Carbamazepine is 75% protein-bound in the plasma; the VD is 1 l/kg.

Metabolism

Occurs via oxidation in the liver to an epoxide which is active. With chronic use, the drug induces its own metabolism.

Excretion

The drug is predominantly excreted in the urine as unconjugated metabolites; the clearance is 20 ml/kg/hour, and the elimination half-life is 16–36 hours.

Special points

Sodium valproate and calcium antagonists may increase the plasma concentrations of free carbamazepine if administered concurrently. The efficacy of both pancuronium and vecuronium is reportedly decreased in patients receiving carbamazepine. Regular liver function tests and estimation of white cell counts need to be performed during chronic carbamazepine therapy.

The drug is not removed by haemodialysis.

Carbapenems

Uses

Carbapenems are used in the treatment of:

  1. 1. respiratory tract infections

  2. 2. urinary tract infections

  3. 3. infections of bone, joint, skin, and soft tissues

  4. 4. intra-abdominal sepsis

  5. 5. gynaecological sepsis

  6. 6. meningitis

  7. 7. septicaemia

  8. 8. neutropenic sepsis, and

  9. 9. as surgical prophylaxis.

Chemical

Beta-lactam derivatives.

Presentation

Imipenem, meropenem, and ertapenem are presented as a dry powder. Imipenem is presented in an ampoule containing 500 mg of imipenem monohydrate and 500 mg of cilastatin sodium, which blocks renal imipenem metabolism. Meropenem is presented in ampoules containing 500 mg and 1 g as meropenem trihydrate. Ertapenem is presented in vials containing 1 g of ertapenem (as ertapenem sodium). Each 1 g dose of ertapenem contains approximately 137 mg of sodium.

Main action

Carbapenems are broad-spectrum antibiotics with activity against:

  1. 1. Gram-positive bacteria (not meticillin-resistant Staphylococcus aureus (MRSA) or Enterococcus faecalis)

  2. 2. Gram-negative bacteria (not Stenotrophomonas maltophilia)

  3. 3. Anaerobic bacteria

  4. 4. Extended-spectrum beta-lactamase (ESBL)-producing organisms.

Mode of action

Carbapenems act by binding to PBPs on the bacterial cytoplasmic membrane, thereby blocking peptidoglycan synthesis and thus cell wall formation. Cilastatin sodium, presented with imipenem, is a competitive, reversible inhibitor of dehydropeptidase-1, which mediates the renal metabolism of imipenem. The drug itself has no intrinsic antibacterial activity.

Routes of administration/doses

Carbapenems are administered intravenously. The specific dose and frequency of an agent administered are dependent on the clinical indication, age of the patient, and particular agent being used. Doses should be reduced in patients with renal impairment.

Toxicity/side effects

Hypersensitivity reactions, diarrhoea, vomiting, a positive Coombs’ test, and pseudomembranous colitis have been reported, following the administration of carbapenems. Patients with underlying CNS disorders and/or renal impairment may develop CNS side effects.

Kinetics

Distribution

The VD for imipenem is 16 l, for meropenem 12.5–20 l, and for ertapenem 8 l. The percentage of drug bound to plasma proteins is 20% for imipenem, 2% for meropenem, and 85–95% for ertapenem.

Metabolism

Imipenem is combined with cilastatin, which prevents renal hydrolysis of the beta-lactam ring. However, 20–25% of an administered dose undergoes non-renal systemic metabolism that remains to be fully elucidated. Meropenem is metabolized to an inactive metabolite. Ertapenem is metabolized to a ring-open derivative, following hydrolysis mediated by dehydropeptidase-1.

Excretion

The clearance of imipenem is 225 ml/min (reduced to 194 ml/min when administered with cilastatin), and it has a half-life of 62 minutes. The clearance of meropenem is equivalent to the creatinine clearance, and it has a half-life of 60 minutes. Seventy percent of an administered dose of meropenem is excreted unchanged in the urine. The clearance of ertapenem is 207 ml/min, and it has a half-life of 4 hours. Eighty percent of an administered dose is excreted in the urine (38% unchanged, 37% as the inactive metabolite) and 10% in faeces.

Special points

Imipenem is cleared by dialysis, and the dose should be halved and the dose interval doubled. Meropenem and ertapenem are unaffected by hepatic dysfunction. No data are available regarding the use of imipenem in patients with hepatic dysfunction.

Co-administration of imipenem and ganciclovir may lead to focal seizures. Carbapenems may reduce sodium valproate levels, leading to seizure activity.

Carbapenemase-producing organisms, such as Klebsiella pneumoniae, have been isolated.

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

Carbon dioxide

Uses

CO2 is used:

  1. 1. to reverse apnoea due to passive hyperventilation

  2. 2. to facilitate the inhalational induction of anaesthesia and blind nasal intubation

  3. 3. to speed the onset of action of local anaesthetics

  4. 4. to increase cerebral blood flow during carotid artery surgery

  5. 5. for the insufflation of body cavities during endoscopy

  6. 6. for cryotherapy, and

  7. 7. in the treatment of hiccups.

Chemical

An organic gas.

Presentation

As a liquid in cylinders at a pressure of 50 bar at 15°C; the cylinders are grey and are available in three sizes (C–E, containing 450–1800 l, respectively). CO2 is a colourless gas with a pungent smell in high concentrations; it is non-flammable and does not support combustion. The specific gravity of the gas is 1.98, the critical temperature 31°C, and the critical pressure 73.8 atmospheres.

Main action

Respiratory and sympathetic stimulation.

Routes of administration/doses

The gas is generally administered by inhalation but may be insufflated into, for example, the peritoneal cavity. Any concentration that is desired may be employed; concentrations of up to 5% are generally administered by inhalation.

Effects

CVS

In vitro, the gas has negative inotropic and chronotropic effects; in vivo, these effects are offset by sympathetic stimulation. The overall effect of the administration of 5% CO2 is to increase the heart rate, systolic and diastolic blood pressures, and cardiac output. Dysrhythmias may occur in vivo, although, in vitro, the gas increases the threshold for catecholamine-induced dysrhythmias. The peripheral vascular resistance is decreased in vivo; CO2 is a potent coronary arterial vasodilator.

RS

CO2 (in a concentration of 5%) stimulates respiration by an action on the respiratory centre and peripheral chemoreceptors, leading to an increase in the tidal volume and respiratory rate; bronchodilatation is also produced. At high concentrations, respiratory depression occurs. The presence of an increased partial pressure of CO2 in the blood shifts the oxygen dissociation curve to the right (the Bohr effect).

CNS

A PaCO2 of 8–11 kPa will increase the cerebral blood flow by 100% and lead to an increase in the intracranial pressure and progressive narcosis. A PaCO2 of 3.5 kPa will reduce the cerebral blood flow by 30%.

Metabolic/other

The administration of exogenous CO2 causes a respiratory acidosis which may, in turn, lead to hyperkalaemia. The plasma concentrations of adrenaline, noradrenaline, angiotensin, and 15-hydroxy-corticosteroid are increased by the administration of CO2.

Toxicity/side effects

When administered in concentrations of 10%, the gas may cause dyspnoea, headache, dizziness, restlessness, paraesthesiae, diaphoresis, and dysrhythmias.

Kinetics

Absorption

The gas is freely permeable through normal alveolar tissue.

Distribution

CO2 is transported in the blood in solution, in the form of bicarbonate ions, and in combination with plasma proteins and haemoglobin.

Metabolism

The gas is transformed in the blood to the forms described above.

Excretion

Predominantly by exhalation and some as renally excreted bicarbonate.

Special points

A respiratory acidosis may alter drug action by altering both the degree of ionization and protein binding of drugs; an increased dose of thiopental and a decreased dose of tubocurarine are required in the face of an uncompensated respiratory acidosis.

Caspofungin

Uses

Caspofungin is used for:

  1. 1. treatment of invasive candidiasis

  2. 2. treatment of invasive aspergillosis, and

  3. 3. empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropenic patients.

Chemical

Semi-synthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis.

Presentation

As off-white powder in 50 mg and 70 mg vials containing 35.7 mg and 50 mg of sucrose, respectively—store in a refrigerator at 2–8°C. It is reconstituted with 10.5 ml of water to make a clear solution and should be used immediately. Stability data show the concentrate solution for infusion can be stored for up to 24 hours when the vial is stored at 25°C. It contains no preservatives. Diluted patient infusion solution should be used immediately, diluted with 100 ml or 250 ml of 0.9/0.45% sodium chloride solution or lactated Ringer’s solution. Stability data have shown that this can be used within 24 hours when stored at 25°C or less, or within 48 hours when the intravenous infusion bag is stored refrigerated at 2–8°C.

Main actions

Fungicidal activity with lysis and death of hyphal apical tips and branch points where cell growth and division occur. Caspofungin is active against Aspergillus fumigatus/flavus/niger/terreus/candidus and Candida spp. (Candida albicans/dubliniensis/glabrata/guilliermondii, kefyr, krusei, lipolytica, lusitaniae, parapsilosis, rugosa, and tropicalis), including isolates with multiple resistance transport mutations and those with acquired or intrinsic resistance to fluconazole, amphotericin B, and 5-flucytosine.

Mode of action

Caspofungin acetate inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of many filamentous fungi and yeast. Beta (1,3)-D-glucan is not present in mammalian cells.

Route of administration/doses

A single 70 mg intravenous loading dose is given on day 1, followed by 50 mg daily thereafter. In patients weighing >80 kg, after the initial 70 mg loading dose, caspofungin 70 mg daily is recommended. After reconstitution and dilution, the solution should be administered by slow intravenous infusion over approximately 1 hour. The duration of treatment is unknown and should be based on the patient (duration of clinical response to empirical therapy), up to 72 hours after the resolution of neutropenia (absolute neutrophil count, ANC ≥500): fungal infections for a minimum of 14 days, and continue for at least 7 days after both neutropenia and clinical symptoms are resolved; invasive candidiasis after symptoms have resolved, and antifungal therapy should continue for at least 14 days after the last positive culture; invasive aspergillosis is based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. In general, treatment should continue for at least 7 days after the resolution of symptoms.

Effects

GU

Caspofungin is not an inhibitor of cytochrome P450 (CYP).

Metabolic/other

Hypokalaemia, decreased haemoglobin level, decreased haematocrit, and decreased white blood cell count.

Toxicity/side effects

Anaphylaxis, histamine-mediated adverse reactions, including rash, facial swelling, angio-oedema, pruritus, sensation of warmth, or bronchospasm have been reported.

Kinetics

Absorption

Poor oral bioavailability.

Distribution

Caspofungin is 97% protein-bound to albumin. Peak concentrations occur in tissues at 1.5–2 days where 92% of the dose is distributed. Only a small fraction of caspofungin taken up into tissues returns to the plasma, so a true estimate of the VD of caspofungin is impossible to calculate.

Metabolism

It undergoes spontaneous degradation to an open ring compound, with further peptide hydrolysis and N-acetylation. Two intermediate products form covalent adducts to plasma proteins, resulting in a low-level, irreversible binding.

Excretion

Elimination from the plasma is slow, with a clearance of 10–12 ml/min. Plasma concentrations of caspofungin decline in a polyphasic manner, following single 1-hour intravenous infusions. A short alpha-phase occurs immediately post-infusion, followed by a beta-phase with a half-life of 9–11 hours. An additional gamma-phase also occurs with a half-life of 45 hours. Distribution is the dominant mechanism influencing the plasma clearance. Approximately 41% of the dose is excreted in the urine, and 34% in faeces. Caspofungin displays moderate non-linear pharmacokinetics.

Special points

No dosage adjustment is needed for renal or liver impairment; there is little knowledge about severe liver impairment. Weight was found to influence caspofungin pharmacokinetics; the plasma concentrations decrease with increasing weight with 23% AUC, hence a higher dose for patients weighing >80 kg. Less common non-Candida yeasts and non-Aspergillus moulds may not be covered by caspofungin. Close monitoring of liver enzymes should be considered if caspofungin and ciclosporin are used concomitantly due to elevation of aspartate transaminase (AST) and alanine transaminase (ALT). This product contains sucrose, so patients with rare hereditary problems of fructose intolerance or sucrase–isomaltase insufficiency should not have caspofungin.

Cephalosporins

Uses

Cephalosporins are used in the treatment of:

  1. 1. respiratory tract infections

  2. 2. urinary tract infections

  3. 3. infections of bone, joint, and soft tissues

  4. 4. intra-abdominal, gynaecological, and obstetric sepsis

  5. 5. meningitis

  6. 6. septicaemia, and

  7. 7. as surgical prophylaxis.

Chemical

Derivatives of penicillin containing a beta-lactam and a hydrothiazine ring.

Presentation

Cephalosporins are divided into first (cefradine), second (cefuroxime), and third (cefotaxime, ceftazidime, ceftriaxone) generations.

Main action

Cephalosporins are broad-spectrum bactericidal antibiotics that are variably resistant to hydrolysis by beta-lactamase. The drugs are effective against Gram-positive organisms. Gram-negative cover improves with each subsequent generation of cephalosporin (cefradine < cefuroxime < cefotaxime/ceftazidime/ceftriaxone), although this is at the expense of reduced activity against Gram-positive bacteria. Ceftazidime is active against the following organisms: Pseudomonas, Klebsiella, Proteus, Salmonella, Shigella, Neisseria spp., Haemophilus influenzae, and Escherichia coli.

Mode of action

Cephalosporins act by binding to PBPs on the bacterial cytoplasmic membrane, thereby blocking peptidoglycan synthesis and thus cell wall synthesis.

Routes of administration/doses

Cefradine is available in capsule form, as a syrup, or as a powder for dissolving in solution for intravenous use. Cefuroxime is available as a tablet, as granules for use as an oral suspension, or as a powder for dissolving in solution for intravenous administration. Third-generation cephalosporins are presented for intravenous use only. The specific dose and frequency of an agent administered are dependent on the clinical indication, age of the patient, and particular agent being used.

Toxicity/side effects

Cephalosporins are generally well tolerated. Rashes, hypersensitivity reactions, fever, diarrhoea, transient haematological disturbances (including a positive Coombs’ text), and abnormalities of liver function tests may occur with the use of these drugs. If administered in high doses to patients concurrently receiving other nephrotoxic drugs, further deterioration in renal function may result. Clostridium difficile infection may complicate the administration of these agents. The development of a ‘Jarisch–Herxheimer’ reaction may complicate the use of cephalosporins in the treatment of Lyme disease.

Kinetics

Absorption

Cefradine is well absorbed from the gastrointestinal tract. The bioavailability of cefuroxime is 36–52%.

Distribution

Cephalosporins exhibit variable degrees of protein binding: cefradine 8–17%, cefuroxime and cefotaxime 35–50%, ceftazidime <10%, ceftriaxone 95%. The drugs are widely distributed, and third-generation agents penetrate inflamed tissues well.

Metabolism

Most cephalosporins are not metabolized, apart from cefotaxime which is partially metabolized to the active metabolite desacetyl-cefotaxime. The half-life for these agents are short (1–2 hours), compared with ceftriaxone which has a half-life of 8 hours.

Excretion

Cephalosporins are predominantly renally excreted unchanged in the urine. Forty percent of ceftriaxone is excreted in the bile and faeces, 60% in the urine.

Special points

Cephalosporins are removed by haemodialysis.

Cephalosporins are associated with an increased potential for Clostridium difficile infection.

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

Chloroprocaine

Uses

Chloroprocaine is used for spinal anaesthesia for surgical procedures lasting no longer than 40 minutes.

Chemical

An ester of aminobenzoic acid.

Presentation

As a clear, colourless solution containing 5 ml of chloroprocaine hydrochloride in a glass ampoule at a concentration of 10 mg/ml. The pH of the solution is 3–4. The pKa is 8.96.

Main actions

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.

Route of administration/doses

Chloroprocaine is licensed for intrathecal administration. The duration of action of the drug is dose-dependent. For example, a sensory block to T10 can be achieved with 40 mg of the drug lasting 80 minutes, or 50 mg of the drug lasting 100 minutes.

Effects

CVS

Chloroprocaine is 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.

CNS

The principal effect of chloroprocaine 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.

Toxicity/side effects

The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above.

Kinetics

Limited data are available.

Metabolism

Chloroprocaine is rapidly metabolized by plasma pseudocholinesterase, producing the metabolites beta-diethylaminoethanol and 2-chloro-4-aminobenzoic acid.

Excretion

The metabolites of chloroprocaine are excreted in the urine.

Chlorphenamine

Uses

Chlorphenamine is used in the treatment of:

  1. 1. allergic rhinitis

  2. 2. urticaria

  3. 3. pruritus, and

  4. 4. anaphylactic and anaphylactoid reactions.

Chemical

An alkylamine.

Presentation

As 4 mg tablets, a syrup containing 0.4 mg/ml, and a clear, colourless solution for injection containing 10 mg/ml of chlorphenamine maleate.

Main action

Antihistaminergic (H1 receptors) and anticholinergic.

Mode of action

Chlorphenamine acts by reversible competitive antagonism of histamine H1 receptors.

Routes of administration/doses

The adult oral dose is 4 mg 6- to 8-hourly. The drug may also be administered intravenously (over a period of 1 min), intramuscularly, or subcutaneously as a stat dose of 10 mg.

Effects

CVS

The drug inhibits histamine-induced vasodilation and increased capillary permeability.

RS

Chlorphenamine decreases bronchial secretions; it does not completely reverse anaphylactic bronchospasm in man, since leukotrienes are involved in the mediation of allergic bronchoconstriction.

CNS

The drug has a sedative effect and local anaesthetic properties.

Metabolic/other

Chlorphenamine has anticholinergic properties.

Toxicity/side effects

The predominant side effect of the drug is drowsiness, but it may also produce gastrointestinal disturbances (including nausea and vomiting) and anticholinergic side effects.

Kinetics

Absorption

The drug is slowly absorbed when administered orally; the bioavailability by this route is 25–50% due to an extensive first-pass metabolism in the gut wall and liver.

Distribution

The drug is 70% protein-bound in the plasma; the VD is 7.51–7.65 l/kg.

Metabolism

Occurs via demethylation and oxidative deamination in the liver.

Excretion

The mono- and di-desmethyl derivatives are excreted pre- dominantly in the urine; 1–27% (dependent upon the urinary pH) of an administered dose is excreted unchanged in the urine. The clearance is 4.4–7.92 ml/min/kg, and the elimination half-life is 2–43 hours.

Special points

The sedative effect of the drug is additive with that produced by anaesthetic agents.

The drug is not removed by dialysis.

Chlorpromazine

Uses

Chlorpromazine is used in the treatment of:

  1. 1. schizophrenia and related psychoses

  2. 2. nausea and vomiting associated with terminal illness, and

  3. 3. intractable hiccup.

Chemical

A phenothiazine (with an aliphatic side chain).

Presentation

As 10/25/50/100 mg tablets, a syrup containing 5 mg/ml, 100 mg suppositories, and as a straw-coloured solution for injection containing 25 mg/ml of chlorpromazine hydrochloride.

Main action

Antipsychotic, antiemetic, and sedative.

Mode of action

The antiemetic and neuroleptic effects of the drug appear to be mediated by central dopaminergic (D2) blockade, leading to an increased threshold for vomiting at the chemoreceptor trigger zone. The other pharmacological effects are mediated by antagonism of serotonergic, histaminergic, muscarinic cholinergic, and alpha-adrenergic receptors.

Routes of administration/doses

The adult oral dose is 10–50 mg 6- to 8-hourly; the corresponding dose by the intramuscular route is 25–50 mg 6- to 8-hourly.

Effects

CVS

Chlorpromazine is negatively inotropic; in combination with the decrease in the systemic vascular resistance mediated by alpha-adrenergic blockade that it produces, postural hypotension with a reflex tachycardia are the main effects observed. The drug increases the coronary blood flow and has a mild quinidine-like action on the heart. Chlorpromazine may produce electrocardiographic (ECG) changes, including prolongation of the PR and QT intervals, T-wave flattening, and ST-segment depression.

RS

The drug is a respiratory depressant; it also diminishes bronchial secretions.

CNS

The main central effect of the drug is neurolepsis, but sedation and anxiolysis are also produced. Chlorpromazine enhances the effect of co-administered analgesics and lowers the seizure threshold; it also has local anaesthetic properties. The drug causes skeletal muscle relaxation via a central effect. Miosis occurs due to alpha-adrenergic blockade. It increases sleep time but decreases the time spent in the rapid eye movement (REM) phase. The characteristic EEG changes associated with the use of chlorpromazine are slowing with an increase in theta- and delta-wave activity and a decrease in alpha- and beta-wave activity, associated with some increase in burst activity.

AS

Chlorpromazine increases appetite and may cause weight gain; it tends to decrease salivation, gastric secretion, and gastrointestinal motility.

GU

The drug increases renal blood flow and has a weak diuretic action. Ejaculation and micturition may be inhibited, secondary to the anticholinergic effect of the drug.

Metabolic/other

Chlorpromazine impairs temperature regulation by both central and peripheral mechanisms; anaesthetized subjects receiving the drug show a tendency to become poikilothermic. The phenothiazines increase prolactin secretion and tend to decrease adrenocorticotrophic and ADH release. Insulin release, and thus glucose tolerance, may also be impaired by the drug.

Toxicity/side effects

Chlorpromazine is generally a well-tolerated and safe drug, despite its panoply of effects. The drug may produce a variety of extrapyramidal syndromes, including the rare neuroleptic malignant syndrome (a complex of symptoms that include catatonia, cardiovascular lability, hyperthermia, and myoglobinaemia) which has a mortality in excess of 10%. A variety of anticholinergic effects, jaundice, blood dyscrasias, and allergic phenomena may also complicate the use of the drug.

Kinetics

Absorption

Chlorpromazine is well absorbed when administered orally but has a bioavailability by this route of 30% due to an extensive first-pass metabolism in the liver and gut wall.

Distribution

The drug is 95–98% protein-bound in the plasma; the VD is 12–30 l/kg.

Metabolism

Chlorpromazine is extensively metabolized in the liver by oxidation, dealkylation, demethylation, and hydroxylation, with subsequent conjugation to glucuronide; at least 168 metabolites have been described, many of which are active.

Excretion

Occurs in equal quantities in the urine and faeces; <1% is excreted unchanged. The clearance is 5.7–11.5 ml/min/kg, and the elimination half-life is 30 hours.

Special points

The depressant effects of chlorpromazine are additive with those produced by general anaesthetic agents.

The drug is not removed by haemodialysis.

Cisatracurium

Uses

Cisatracurium is used to facilitate intubation and controlled ventilation.

Chemical

A benzyl isoquinolinium ester which is one of ten stereoisomers of atracurium due to the presence of four chiral centres.

Presentation

As a clear, colourless or pale yellow solution for injection available in 5, 10, and 20 ml vials containing 6.7 mg/ml of cisatracurium besilate (equivalent to cisatracurium 5 mg/ml), needing to be stored at 2–8°C. It contains no antimicrobial preservative. It has a pH of between 3.25 and 3.65.

Main action

Competitive, non-depolarizing neuromuscular blockade.

Mode of action

Cisatracurium acts by competitive antagonism of acetylcholine at nicotinic (N2) receptors at the post-synaptic membrane of the neuromuscular junction.

Routes of administration/doses

The drug is administered intravenously. The ED95 of cisatracurium is estimated to be 0.05 mg/kg during opioid anaesthesia. An initial dose of 0.15 mg/kg is recommended, providing good to excellent intubating conditions in 120 seconds. The time to 90% T1 suppression following this dose is 2.6 minutes; the time to maximal T1 suppression is 3.5 minutes, and the time to 25% spontaneous T1 recovery is 55 minutes. Maintenance of neuromuscular blockade may be achieved with bolus doses of 0.03 mg/kg (0.02 mg/kg in paediatric patients) which will provide approximately 20 minutes of additional neuromuscular blockade (approximately 9 minutes in paediatric patients). Once recovery from neuromuscular blockade has started, the rate of recovery is independent of the dose of cisatracurium administered. Cisatracurium may be administered by intravenous infusion at an initial rate of 3 micrograms/kg/min (0.18 mg/kg/hour), although there is wide inter-patient variability in dosage requirements, particularly in patients ventilated on intensive care. This infusion rate should result in T1 suppression of between 89 and 99%. After an initial period of stabilization of neuromuscular block, a rate of 1–2 micrograms/kg/min (0.06–0.12 mg/kg/min) is recommended to maintain adequate blockade (0.03–0.06 mg/kg/min in patients ventilated on intensive care). Following long-term continuous infusion of cisatracurium (<6 days), the median time to full spontaneous recovery was approximately 50 minutes. When used in conjunction with isoflurane maintenance, the infusion rate may be reduced by up to 40%. The use of cisatracurium in patients undergoing induced hypothermia (25–28°C) has not been studied.

Effects

CVS

Cisatracurium has fewer cardiovascular effects than atracurium. There is no change in the mean arterial pressure or heart rate following rapid bolus doses of 0.1–0.4 mg/kg in healthy adults and patients with severe cardiovascular disease. Bradycardia (0.4%), hypotension (0.2%), and cutaneous flushing (0.2%) have all been reported.

RS

Bronchospasm following the administration of cisatracurium has been occasionally reported (approximately 0.2%).

CNS

The drug has no effect on the intracranial or intraocular pressure.

AS

Lower oesophageal sphincter pressure is unaffected by administration of cisatracurium.

Toxicity/side effects

There is no dose-dependent increase in histamine release following the administration of cisatracurium at doses of 0.1–0.4 mg/kg. There have been rare reports of fatal anaphylactoid reactions with the administration of atracurium. The administration of cisatracurium by intravenous infusion to critically ill patients on intensive care has been associated with the development of a critical illness neuropathy/myopathy.

Kinetics

Distribution

The binding of cisatracurium has not been determined due to its rapid degradation at physiological pH. The VD at steady state is 0.12–0.16 l/kg.

Metabolism

Occurs by two pathways; the major pathway is via Hofmann degradation (cleavage of the link between the quaternary nitrogen ion and the central chain) to laudanosine and a quaternary monacrylate. Laudanosine is cleared primarily by the liver. The minor degradative pathway is via hydrolysis by non-specific esterases in the blood to a quaternary alcohol and a quaternary acid. The metabolites have insignificant NMB activity.

Excretion

The clearance is 4.7–5.7 ml/kg/min, and the elimination half-life is 22–29 minutes; these parameters are little altered by renal or hepatic impairment, and no alteration in dose is necessary in these patients. A study in healthy adults demonstrated that 95% of the dose of cisatracurium is excreted in the urine (mostly as conjugated metabolites) and 4% in the faeces. Between 10% and 15% of an administered dose is excreted unchanged in the urine.

Special points

The duration of action of cisatracurium, in common with other non-depolarizing relaxants, is prolonged by hypokalaemia, hypocalcaemia, hypermagnesaemia, hypoproteinaemia, dehydration, acidosis, and hypercapnia. The following drugs, when co-administered with atracurium, increase the effect of the latter: volatile anaesthetic agents, ketamine, other non-depolarizing NMB agents, diuretics (furosemide, mannitol, acetazolamide), calcium channel blockers, propranolol, lidocaine, aminoglycoside antibiotics, and magnesium and lithium salts. A decreased effect may be seen in patients receiving chronic anticonvulsant therapy.

The Cmax values of laudanosine are lower in patients receiving intravenous infusions of cisatracurium, compared with those receiving a continuous atracurium infusion. No dose alteration is required in patients with renal or hepatic impairment, although the half-life values of metabolites are prolonged in patients with renal impairment.

Cisatracurium, due to its acidic pH, should not be mixed with alkaline solutions (e.g. barbiturates). It is not compatible with propofol or ketorolac. The drug is compatible with the following agents: alfentanil, fentanyl, sufentanil, and midazolam.

Porcine studies indicate that cisatracurium does not trigger malignant hyperthermia, although the drug has not been studied in susceptible humans.

Clomethiazole

Uses

Clomethiazole is used:

  1. 1. in the management of alcohol withdrawal states

  2. 2. as an anticonvulsant (emergency use only)

  3. 3. as a hypnotic for the elderly

  4. 4. in the treatment of eclampsia and pre-eclampsia, and

  5. 5. for sedation in patients undergoing surgery under regional blockade or intensive care.

Chemical

A thiamine derivative.

Presentation

As a clear, aqueous solution containing 8 mg/ml of clomethiazole edisylate, and in 192 mg capsule and 50 mg/ml syrup form.

Main action

Anticonvulsant, sedative, and anxiolytic.

Mode of action

The anticonvulsant and sedative actions are due to enhancement of central GABA-ergic transmission and possibly inhibition of central dopaminergic transmission.

Routes of administration/doses

For the control of convulsions in adults, 40–100 ml of the 0.8% solution are infused intravenously over 5–10 minutes; subsequently, the infusion rate is tailored to the response. For sedation, 25 ml/min are administered intravenously for 1–2 minutes, followed by a maintenance infusion of 1–4 ml/min. As a hypnotic, 1–2 capsules or 5–10 ml of the syrup are administered orally.

Effects

CVS

Tachycardia and hypotension are the only clinically significant effects of the drug. It is also powerfully amnesic.

RS

No effects are seen with the use of clomethiazole, but, at high doses, airway obstruction may occur.

CNS

Clomethiazole has anticonvulsant, sedative, and hypnotic properties.

Toxicity/side effects

Nasal and conjunctival irritation, headache, and increased bronchial secretions may occur. Prolonged intravenous infusion of clomethiazole may lead to volume overload and electrolyte abnormalities due to the water load involved. Renal failure has been reported after prolonged use associated with hypotension. Physical dependence and withdrawal states have been reported, following chronic use of the drug.

Kinetics

Absorption

Clomethiazole is well absorbed when administered orally; the bioavailability by this route is 25–34% due to a high hepatic clearance.

Distribution

The drug is 65–70% protein-bound in the plasma, predominantly to albumin; the VD is 3–5 l/kg.

Metabolism

Occurs predominantly by oxidation in the liver; there is an extensive first-pass effect. Ten to 20% is metabolized in the lung; there may also be some renal extraction of the drug.

Excretion

0.1% is excreted unchanged in the urine. The clearance is 2.1 l/min, and the elimination half-life is 1–6 hours.

Special points

Clomethiazole is absorbed by plastic giving-sets.

It is removed by haemodialysis, but this may not significantly affect the degree of sedation.

Clonidine

Uses

Clonidine is used in the treatment of:

  1. 1. all grades of essential and secondary hypertension

  2. 2. hypertensive crises and in the management of

  3. 3. migraine

  4. 4. menopausal flushing and may be of use in

  5. 5. chronic pain

  6. 6. during opiate and alcohol withdrawal, and

  7. 7. for intravenous regional analgesia for chronic regional pain syndromes.

Chemical

An aniline derivative.

Presentation

As 0.1/0.25/0.3 mg tablets and as a clear, colourless solution for injection containing 0.15 mg/ml of clonidine hydrochloride.

Main action

Antihypertensive, analgesic, sedative, and anxiolytic.

Mode of action

Clonidine acts acutely by stimulating alpha-2 (pre-synaptic) adrenoceptors, thereby decreasing noradrenaline release from sympathetic nerve terminals and consequently decreasing sympathetic tone; it also increases vagal tone. The drug acts chronically by reducing the responsiveness of peripheral vessels to vasoactive substances and to sympathetic stimulation. The analgesic effects are also mediated by activation of alpha-2 adrenoceptors in the dorsal horn of the spinal cord.

Routes of administration/doses

The adult oral dose is 0.05–0.6 mg 8-hourly; the corresponding intravenous dose is 0.15–0.3 mg. When administered by the epidural route, a dose of 0.15 mg has been used. The drug acts within 10 minutes and lasts for 3–7 hours when administered intravenously.

Effects

CVS

When administered intravenously, clonidine causes a transient increase in the blood pressure (due to the stimulation of vascular alpha-1 receptors), followed by a sustained decrease. The heart rate and venous return may decrease slightly; the drug has no effect on cardiac contractility, and the cardiac output is well maintained. The coronary vascular resistance is decreased by clonidine; the systemic vascular resistance is decreased with long-term treatment.

CNS

Clonidine decreases the cerebral blood flow and intraocular pressure. It exerts a depressant effect on both spontaneous sympathetic outflow and afferent A delta- and C-fibre-mediated somatosympathetic reflexes.

AS

Clonidine decreases gastric and small bowel motility and is an antisialogogue.

GU

Clonidine reduces renovascular resistance; however, little alteration in the glomerular filtration rate occurs.

Metabolic/other

The drug causes a decrease in plasma catecholamine concentrations and plasma renin activity. Blood sugar concentration may increase, secondary to alpha-adrenergic stimulation.

Toxicity/side effects

Drowsiness and a dry mouth may occur in up to 50% of patients who receive the drug. CNS disturbances, fluid retention, impotence, and constipation have also been reported. Rapid withdrawal of the drug may lead to life-threatening rebound hypertension and tachycardia.

Kinetics

Absorption

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

Distribution

Clonidine is very lipid-soluble and penetrates the CNS. The drug is 20% protein-bound in the plasma; the VD is 1.7–2.5 l/kg.

Metabolism

Less than half of an administered dose is metabolized in the liver to inactive metabolites.

Excretion

65% of the dose of clonidine is excreted unchanged in the urine; some 20% is excreted in the faeces. The clearance is 1.9–4.3 ml/min/kg, and the elimination half-life is 6–23 hours. The latter is markedly increased in the presence of renal impairment; the dose of clonidine should be reduced if the glomerular filtration rate is 10 ml/min.

Special points

Clonidine decreases the MAC of co-administered volatile agents. It decreases the incidence of post-anaesthetic shivering and post-operative nausea and vomiting (PONV).

Clonidine decreases the propofol dose needed for laryngeal mask airway (LMA) insertion.

It obtunds tourniquet-induced hypertension.

Clonidine decreases post-operative agitation in children undergoing sevoflurane anaesthesia.

It prolongs the duration of local anaesthesia when co-administered for neural and retrobulbar blockade.

The drug is not removed by haemodialysis.

Clopidogrel

Uses

Clopidogrel is used in the treatment of:

  1. 1. acute coronary syndrome

  2. 2. recent myocardial infarction

  3. 3. recent stroke and transient ischaemic attacks

  4. 4. established peripheral vascular disease, and

  5. 5. as part of revascularization procedures to reduce the incidence of thrombotic events.

Chemical

Clopidogrel is a thienopyridine.

Presentation

As 75/300 mg tablets.

Main actions

Inhibitor of platelet activation and aggregation; prolongation of bleeding time.

Mode of action

Clopidogrel is a pro-drug and a class inhibitor of P2Y12 adenosine diphosphate (ADP) platelet receptors. The active metabolite of clopidogrel selectively and irreversibly inhibits the binding of ADP to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. It acts by irreversibly modifying the platelet ADP receptor. Platelets exposed to clopidogrel are affected for their lifespan. Dose-dependent inhibition of platelet aggregation can be seen 2 hours after a single oral dose.

Route of administration/doses

Orally 75 mg once daily in combination with aspirin, with or without thrombolytic agents. For acute coronary syndromes and prevascularization procedures, use a 300 mg loading dose orally, then continue at 75 mg once daily.

Effects

CVS

No effect is seen with normal clinical dosages.

RS

The drug has no effect on respiratory parameters.

AS

No effect is seen with normal clinical dosages.

Metabolic/other

Interaction with other drugs affecting platelet function, thus enhancing the potential for bleeding.

Toxicity/side effects

Minor bleeding (5%); major bleeding, including intracranial, gastrointestinal, and retroperitoneal, 4%; life-threatening bleeding, 2%; agranulocytosis, aplastic anaemia/pancytopenia, thrombotic thrombocytopenic purpura, usually in the first 2 weeks of treatment.

If undergoing routine surgery and antiplatelet effect is not desired, discontinue clopidogrel 5 days prior. If an emergency surgery is needed or trauma has been sustained with the attendant risk of bleeding, platelet transfusion may be used.

Kinetics

Absorption

Clopidogrel is rapidly absorbed. Bioavailability is 50%.

Distribution

The drug and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The data for VD are incomplete.

Metabolism

Clopidogrel is a pro-drug and is extensively metabolized in the liver, undergoing rapid hydrolysis to carboxylic acid derivative (active). The metabolic pathway is the cytochrome P450 (CYP) system.

Excretion

50% is excreted in the urine, and approximately 46% in faeces, over the 5 days post-dosing. After a single oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 8 hours.

Kinetics

Clopidogrel at recommended doses in patients who are CYP2C19-poor metabolizers forms less of the active metabolite and so has a smaller effect on platelet function. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses exhibit higher cardiovascular morbidity. It is possible to identify the CYP2C19 genotype.

The risk of bleeding may be increased with aspirin. NSAIDs, anticoagulants, and proton pump inhibitors decrease its efficacy. Bleeding during surgery is increased.

Cocaine

Uses

Cocaine is used as a topical vasoconstrictor.

Chemical

An ester of benzoic acid (a naturally occurring alkaloid derived from the leaves of Erythroxylon coca).

Presentation

As 1–4% solutions and as a non-proprietary paste of varying concentration.

Main action

Local anaesthesia, vasoconstriction, and euphoria.

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. Cocaine also produces blockade of the uptake-1 pathway of noradrenaline and dopamine, leading to vasoconstriction and CNS excitation.

Routes of administration/doses

Cocaine is administered topically; the toxic dose is 3 mg/kg. The drug has a duration of action of 20– 30 minutes.

Effects

CVS

The usual effect of cocaine is to produce hypertension and tachycardia due to a combination of central sympathetic stimulation and the blockade of noradrenaline reuptake at peripheral adrenergic nerve terminals, leading to intense peripheral vasoconstriction. Large doses produce myocardial depression and may precipitate ventricular fibrillation.

RS

Therapeutic concentrations of the drug cause stimulation of the respiratory centre and an increase in ventilation.

CNS

The principal effect of cocaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNS. Initially, excitation (euphoria, light-headedness, dizziness, visual and auditory disturbances, and fitting) occurs due to the blockade of inhibitory pathways in the cortex; with increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNS depression (drowsiness, disorientation, and coma). Cocaine may also cause hyperreflexia, mydriasis, and an increase in the intraocular pressure.

AS

The drug produces hyperdynamic bowel sounds and marked nausea and vomiting (a central effect).

Metabolic/other

Cocaine causes a marked increase in body temperature due to increased motor activity combined with cutaneous vasoconstriction and a direct effect of the drug on the hypothalamus.

Toxicity/side effects

Allergic phenomena occur occasionally with the use of cocaine. The side effects are predominantly correlated with excessive plasma concentrations of the drug. These include confusion, hallucinations, seizures, cerebral haemorrhage and infarction, and medullary depression leading to respiratory arrest. Chest pain is common; myocardial infarction, pulmonary oedema, gut infarction, rhabdomyolysis, and disseminated intravascular coagulation (DIC) may also occur. Cocaine is a drug of dependence; maternal use may result in neonatal dependence. Nasal septum necrosis is reported.

Kinetics

Absorption

The drug is well absorbed from mucosae, including that of the gut. The bioavailability when administered intranasally is 0.5%.

Distribution

Cocaine is 98% protein-bound in the plasma; the VD is 0.9–3.3 l/kg.

Metabolism

In common with the other ester-type local anaesthetic agents, cocaine is predominantly degraded by plasma esterases, predominantly to benzoylecgonine.

Excretion

The metabolites are excreted in the urine, 10% unchanged. The clearance is 26–44 ml/min/kg, and the elimination half-life is 25–60 minutes.

Codeine

Uses

Codeine is used for the treatment of:

  1. 1. pain of mild to moderate severity

  2. 2. diarrhoea and excessive ileostomy output and

  3. 3. as an antitussive agent and

  4. 4. traditionally to provide analgesia for head-injured patients.

Chemical

A naturally occurring phenanthrene alkaloid which is a methylated morphine derivative.

Presentation

As 15/30/60 mg tablets, a syrup containing 5 mg/ml, and as a clear, colourless solution for injection containing 60 mg/ml of codeine phosphate. A number of fixed-dose preparations containing paracetamol, ibuprofen, or aspirin in combination with codeine phosphate are also available.

Main action

Analgesic, antitussive, and a decrease in gastrointestinal motility.

Mode of action

Codeine has a very low affinity for opioid receptors; 10% of the drug is metabolized to morphine, and the analgesic and constipating effects are due to the morphine metabolite. The antitussive effects of codeine appear to be mediated by specific high-affinity codeine receptors.

Routes of administration/doses

The adult oral and intramuscular dose is 30–60 mg 4- to 6-hourly. Rectal administration in a dose of 1 mg/kg can be used in paediatrics. It should not be given intravenously due to hypotension probably due to histamine release.

Effects

RS

The principal effect of the drug is an antitussive effect; it also produces some respiratory depression with a decreased ventilatory response to hypoxia and hypercapnia.

CNS

Codeine is ten times less potent an analgesic, compared to morphine, and produces few of the central effects associated with opioids.

AS

The drug markedly inhibits gastrointestinal motility, leading to constipation.

Toxicity/side effects

Nausea and vomiting, dizziness, and excitatory phenomena may complicate the use of the drug; cardiovascular collapse may occur when codeine is taken in overdose or administered intravenously. Bowel perforation, secondary to decreased gastrointestinal transit, has been reported. Codeine has a low propensity to cause dependence.

Kinetics

Absorption

Codeine phosphate is well absorbed when administered orally and rectally; the bioavailability by these routes is 60–70%, as little first-pass metabolism of the drug occurs. Absorption is faster after intramuscular absorption (0.5 hours). Peak concentration occurs at 1 hour.

Distribution

Codeine is 7% protein-bound in the plasma; the VD is 5.4 l/kg.

Metabolism

Codeine is extensively metabolized in the liver by three methods: principally (10–20%) by glucuronidation to codeine-6-glucuronide, by N-demethylation (10–20%) to norcodeine, and by O-demethylation to morphine (5–15%).

Other minor metabolites (normorphine and norcodeine-6-glucuronide) have been found.

Genetic variability occurs with the cytochrome P450 enzyme CYP2D6 which causes conversion to morphine, so ‘fast’ metabolizers produce more morphine.

Excretion

Occurs predominantly in the urine as free and conjugated codeine, norcodeine, and morphine; 17% of the dose is excreted unchanged. The clearance is 98 l/hour after oral administration, and the elimination half-life is 2.8 hours. The dose should be reduced in the presence of renal failure.

Special points

There are no published data to support the use of codeine in the management of head-injured patients. The drug has traditionally been used in these circumstances due to its low potency and consequent relative lack of respiratory and neurological depressant effects.

Co-trimoxazole

Uses

Co-trimoxazole should be used in the treatment of:

  1. 1. Pneumocystis carinii infections

  2. 2. toxoplasmosis, and

  3. 3. nocardiasis.

Chemical

(trimethoprim + sulfamethoxazole) Trimethoprim is a diaminopyrimidine, and sulfamethoxazole is a sulfonamide.

Presentation

All preparations contain trimethoprim and sulfamethoxazole in the ratio of 1:5. The tablets contain 20/80/160 mg of trimethoprim in a fixed-dose combination with 100/400/800 mg of sulfamethoxazole, respectively. A suspension for oral administration is also available. A pale yellow preparation of co-trimoxazole is available for intravenous use and contains 16 mg of trimethoprim and 80 mg of sulfamethoxazole per ml. The intramuscular preparation contains 160 mg of trimethoprim and 800 mg of sulfamethoxazole in 3 ml.

Main action

Co-trimoxazole is bactericidal against a broad spectrum of Gram-positive and Gram-negative aerobic bacteria, including the Gram-positive Staphylococcus and Streptococcus spp., the Gram-negative Proteus, Salmonella, Shigella, and Klebsiella spp., and Escherichia coli. It is also effective against some protozoa, Chlamydia spp., and some anaerobic species. Bacterial resistance to the drug is widespread.

Mode of action

Co-trimoxazole inhibits the synthesis of tetrahydrofolic acid which is needed for the synthesis of nucleic acids and amino acids. The two components of the drug act at separate stages in the biosynthetic pathway of tetrahydrofolic acid; sulfamethoxazole inhibits the synthesis of dihydrofolic acid, and trimethoprim is a competitive inhibitor of dihydrofolate reductase. Mammalian dihydrofolate reductase is minimally affected by co-trimoxazole; in any case, mammalian cells utilize preformed folate derived from the diet.

Routes of administration/doses

The adult oral dose is 2–3 of the 80/400 mg tablets 12-hourly. The corresponding dose by the intravenous or intramuscular route is 160/800 to 240/1200 mg 12-hourly. The intravenous preparation should be diluted in a crystalloid prior to use and infused over a period of 90 minutes.

Effects

Metabolic/other

Serum creatinine concentrations may increase with the use of the drug, due to competition for tubular secretory mechanisms and an effect on the assay of creatinine. The plasma concentration of thyroid hormone may also decrease.

Toxicity/side effects

The use of co-trimoxazole may be complicated by allergic phenomena, and gastrointestinal and haematological disturbances, especially neutropenia. Patients known to be deficient in vitamin B12 or folate are at increased risk for the latter complication.

Kinetics

Absorption

Both components of the drug are well absorbed; the bioavailability of both sulfamethoxazole and trimethoprim is 100%.

Distribution

The plasma ratio of trimethoprim:sulfamethoxazole is 1:20, which appears to be optimal for synergistic activity. Trimethoprim is 45% protein-bound in the plasma; its VD is 1.6–2.0 l/kg. Sulfamethoxazole is 66% protein-bound in the plasma; its VD is 0.19–0.23 l/kg.

Metabolism

5–15% of the dose of trimethoprim is metabolized to inactive products; sulfamethoxazole is extensively metabolized, the major metabolite being an acetyl derivative.

Excretion

Both components are excreted predominantly in the urine; 80% of the dose of trimethoprim is excreted unchanged, whereas sulfamethoxazole is excreted predominantly as inactive metabolites. The clearance of trimethoprim is 1.6–2.8 ml/min/kg, and the elimination half-life is 11 hours. The clearance of sulfamethoxazole is 0.28–0.36 ml/min/kg, and the elimination half-life is 9 hours. The dose of co-trimoxazole should be reduced if the creatinine clearance is 30 ml/min; hepatic impairment has no effect on the kinetics of the drug.

Special points

Co-trimoxazole potentiates the anticoagulant effect of co-administered warfarin and the hypoglycaemic effect of co-administered sulfonylureas. The drug has a theoretically synergistic action with N2O on folic acid metabolism. Both components of the drug are haemodialysable.

Cyclizine

Uses

Cyclizine is used in the treatment of nausea and vomiting due to:

  1. 1. opioid or general anaesthetic agents

  2. 2. motion sickness

  3. 3. radiation sickness, and

  4. 4. Ménière’s disease.

Chemical

A piperazine derivative.

Presentation

As tablets containing 50 mg of cyclizine hydrochloride and as a clear, colourless solution for injection containing 50 mg/ml of cyclizine lactate which should be protected from light. Fixed-dose combinations with morphine, caffeine, ergotamine, and dipipanone are available. It has a pH of 3.2.

Main action

Antiemetic.

Mode of action

Cyclizine is a competitive antagonist of histamine at H1 receptors and has anticholinergic activity at the muscarinic M1, M2, and M3 receptors. The antiemetic effect is mediated via blockade of central histamine and muscarinic receptors within the vomiting area of the chemoreceptor trigger zone. Cyclizine produces its antiemetic effect within 2 hours and lasts approximately 4 hours.

Route of administration/doses

Cyclizine may be given orally or by intramuscular or intravenous injection. Given the low pH of the parenteral preparation, injection by either route may be painful. The maximum daily dose is 150 mg. The paediatric dose is 1 mg/kg.

Effects

CVS

The drug has mild anticholinergic action and can produce tachycardia and hypotension due to alpha-blockade.

RS

Cyclizine, although it has antihistaminergic properties, does not completely reverse anaphylactic bronchospasm, as leukotrienes are involved in the mediation of allergic bronchoconstriction.

CNS

The principal effect of the drug is antiemetic, with a slight degree of sedation. Cyclizine reduces the sensitivity of the labyrinthine apparatus and depresses vestibular stimulation.

AS

Cyclizine increases the tone of the lower oesophageal sphincter.

Toxicity/side effects

The predominant side effects are anticholinergic, including drowsiness, dryness of the mouth, and blurred vision. Restlessness, nervousness, insomnia, and auditory and visual hallucinations have been reported. Confusion in the elderly is common.

Kinetics

Data are incomplete.

Absorption

The drug is well absorbed when administered orally; the bioavailability by this route is 80%. Following oral administration of 50 mg of cyclizine, peak plasma concentrations of 70 ng/ml occur at approximately 2 hours.

Metabolism

Cyclizine is metabolized in the liver by N-demethylation to norcyclizine. Norcyclizine has little antihistamine activity.

Excretion

The elimination half-life is 10–20 hours. Limited data suggest that only 1% of the total administered dose is excreted unchanged in the urine.

Special points

Cyclizine appears to be as effective as perphenazine in counteracting the nausea and vomiting associated with the use of opioids. The sedative effect of the drug is additive with that produced by anaesthetic agents.

The drug should be used with caution in patients with severe heart failure, as a fall in cardiac output may occur following the administration of cyclizine, secondary to increases in the heart rate, mean arterial pressure, and pulmonary capillary wedge pressure.

The drug should be avoided in patients with porphyria.

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