Page of

M 

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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0012

Macrolides

Uses

Macrolides are used in the treatment of:

  1. 1. respiratory tract infections

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

  3. 3. ocular, ear, and oral infections

  4. 4. gastrointestinal infections

  5. 5. GU infections

  6. 6. as surgical prophylaxis and

  7. 7. for the prophylaxis of subacute bacterial endocarditis

  8. 8. and have been used as a prokinetic in intensive care.

Chemical

A macrocyclic lactone ring to which deoxy sugars are attached.

Presentation

Macrolides in clinical use include erythromycin, clarithromycin, and azithromycin. Erythromycin is available in a form for topical use as a treatment for acne vulgaris, as a powder for oral suspension, in tablet and capsule formulations, and as an intravenous formulation. Clarithromycin is available as an oral preparation or for intravenous use. The drug is also available in combination with other agents for Helicobacter pylori eradication therapy. Azithromycin is available in tablet, oral suspension, or intravenous formulations.

Main action

Macrolides are bactericidal/bacteriostatic antibiotics that are active predominantly against:

  1. 1. Gram-positive bacteria

  2. 2. some Gram-negative bacteria (particularly with azithromycin)

  3. 3. Gram-positive and negative anaerobes

  4. 4. obligate intracellular parasites (Legionella, Mycoplasma).

Mode of action

Macrolides bind to specific bacterial ribosomal proteins (50S subunit) and inhibit peptide translocase, thereby preventing the formation of polymerized peptides.

Routes of administration/doses

Macrolides may be administered topically as creams or ointments, orally or intravenously, or via the intrathecal/intraventricular route. The specific dose, route, and frequency of an agent administered are dependent on the clinical indication, age of the patient, and particular agent being used. Doses should be reduced in patients with renal impairment.

Effects

AS

Erythromycin has a prokinetic effect on gut motility.

Toxicity/side effects

Common side effects include nausea, vomiting, and diarrhoea. Hepatic dysfunction, allergic phenomena, and ototoxicity have also been reported.

Kinetics

Absorption

Macrolides are absorbed to varying degrees, depending on the specific agent: erythromycin (10–60%), clarithromycin (50%), azithromycin (37%). Erythromycin undergoes first-pass metabolism.

Distribution

The VD for erythromycin is 0.34–1.22 l/kg, and for azithromycin 0.44 l/kg. The percentage of drug bound to plasma proteins is 81–87% for erythromycin, 8% for clarithromycin, and 12–50% for azithromycin. High concentrations are found within the lung tissue. The CSF is poorly penetrated by these agents.

Metabolism

Macrolides undergo hepatic metabolism in man. Erythromycin undergoes demethylation; clarithromycin is converted to 14-hydroxyclarithromycin as part of first-pass metabolism. This metabolite is microbiologically active. Clarithromycin is also metabolized in the liver via N-dealkylation. Azithromycin is metabolized via hepatic N- and O-demethylation to inactive metabolites.

Excretion

Erythromycin and clarithromycin are excreted renally. The clearance of erythromycin is 5–13.2 ml/min/kg; the half-life is 1.6 hours, with 2–15% of the drug being excreted unchanged in the urine. The clearance of clarithromycin is unknown, as it exhibits non-linear kinetics; the half-life is 5–6 hours, with 33% of the drug being excreted unchanged in the urine and 11% as the 14-hydroxyclarithromycin metabolite. Ten percent of an administered dose of clarithromycin is excreted via the bile. Azithromycin has a clearance of 10.18 ml/kg/min, a prolonged half-life of 68 hours, with 12% of the drug being excreted unchanged in the urine. The major excretion pathway for azithromycin is via the bile.

Special points

Erythromycin and clarithromycin may cause QT prolongation in the critically ill. All macrolides inhibit CYP450 3A4, which may lead to increased drug levels of the following agents if administered concurrently to a patient: methylprednisolone, warfarin, phenytoin, ciclosporin, theophylline, sodium valproate, tacrolimus, midazolam, digoxin.

Erythromycin and clarithromycin are not removed by haemofiltration or dialysis, and, therefore, the dose should be halved in patients receiving renal replacement therapy. No dose adjustment is necessary for azithromycin.

Erythromycin should be avoided in patients with suspected or confirmed porphyria.

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

Magnesium

Uses

Magnesium has been used in the management of:

  1. 1. pre-eclampsia and eclampsia

  2. 2. hypomagnesaemia associated with malabsorption syndromes (especially chronic alcoholism), diuretics, and critical illness

  3. 3. premature labour (as a tocolytic)

  4. 4. acute myocardial infarction

  5. 5. torsades de pointes and other ventricular dysrhythmias

  6. 6. barium poisoning

  7. 7. asthma

  8. 8. cerebral oedema

  9. 9. spasms occurring with tetanus

  10. 10. autonomic hyperreflexia secondary to chronic spinal cord injury and is

  11. 11. a component of cardioplegic solutions.

Chemical

An inorganic sulfate.

Presentation

A clear, colourless solution of magnesium sulfate containing 2.03 mmol/ml of ionic magnesium 50%.

Main actions

Magnesium is an essential cofactor in over 300 enzyme systems. It is also essential for the production of ATP, DNA, RNA, and protein function.

Mode of action

The precise mechanism of the anticonvulsant activity of magnesium remains unknown; it produces a dose-dependent pre-synaptic inhibition of acetylcholine release at the neuromuscular junction.

Routes of administration/doses

Magnesium sulfate may be administered intravenously or intramuscularly. A number of dose regimes have been described for the use of magnesium sulfate in the management of pre-eclampsia, e.g. 16 mmol administered intravenously over 20 minutes followed by an infusion of 4–8 mmol/hour. Serum concentrations should be monitored repeatedly, and the dose adjusted correspondingly. Loss of deep tendon reflexes is a useful clinical sign of impending toxicity.

Effects

CVS

Magnesium acts peripherally to cause vasodilation and may cause hypotension when used in high doses. The drug slows the rate of sinoatrial node impulse formation and prolongs sinoatrial conduction time, the PR interval, and AV nodal effective refractory period. Magnesium attenuates both the vasoconstrictor and arrhythmogenic actions of adrenaline.

RS

Magnesium is an effective bronchodilator and attenuates hypoxic pulmonary vasoconstriction.

CNS

The drug is a CNS depressant and exhibits anticonvulsant properties. High concentrations inhibit catecholamine release from adrenergic nerve terminals and the adrenal medulla.

AS

Magnesium sulfate acts as an osmotic laxative when administered orally.

GU

The drug exerts a renal vasodilator and diuretic effect. It decreases uterine tone and contractility; placental perfusion may increase, secondary to a decrease in uterine vascular resistance. Magnesium crosses the placenta and may cause neonatal hypotonia and neonatal depression.

Metabolic/other

Magnesium prolongs the clotting time of whole blood, decreases thromboxane B2 synthesis, and inhibits thrombin-induced platelet aggregation.

Toxicity/side effects

Minor side effects include warmth, flushing, nausea, headache, and dizziness. Dose-related side effects include somnolence, areflexia, AV and intraventricular conduction disorders, progressive muscular weakness, and cardiac arrest. The toxic effects can be reversed by the administration of calcium. Intramuscular injection of magnesium sulfate is painful.

Kinetics

Absorption

25–65% of ingested magnesium is absorbed.

Distribution

Magnesium is 30% protein-bound in the plasma.

Excretion

More than 50% of an exogenous magnesium load is excreted in the urine, even in the presence of significant magnesium deficiency.

Special points

Magnesium enhances the effects of other CNS depressants and NMB agents; 30–50% of the normal dose of non-depolarizing relaxants should be used to maintain neuromuscular blockade in the presence of magnesium sulfate. Acute administration of magnesium sulfate prior to the use of suxamethonium appears to prevent potassium release and may reduce the incidence and severity of muscle pains.

Magnesium deficiency is present in 20–65% of patients receiving intensive care.

Mannitol

Uses

Mannitol is used:

  1. 1. to reduce the pressure and volume of CSF

  2. 2. to preserve renal function during the perioperative period in jaundiced patients and in those undergoing major vascular surgery

  3. 3. in the short-term management of patients with acute glaucoma

  4. 4. for bowel preparation prior to colorectal procedures

  5. 5. to initiate a diuresis in transplanted kidneys, and

  6. 6. in the treatment of rhabdomyolysis.

Chemical

An alcohol, derived from Dahlia tubers.

Presentation

As sterile, pyrogen-free solutions of 10% and 20% mannitol in water; crystallization may occur at low temperatures.

Main actions

Osmotic diuresis and antioxidant.

Mode of action

Mannitol is a low-molecular-weight (182 daltons) compound and is thus freely filtered at the glomerulus and not reabsorbed, nor does it cross the intact blood–brain barrier. Its action as a diuretic rests upon the fact that it increases the osmolality of the glomerular filtrate and tubular fluid, increasing urinary volume by an osmotic effect. Mannitol decreases CSF volume and pressure by:

  1. 1. decreasing the rate of CSF formation and

  2. 2. by withdrawing brain extracellular water across the blood–brain barrier into the plasma; if the barrier is disrupted, mannitol passes into the brain extravascular space and is ineffective.

Mannitol also acts as a hydroxyl radical scavenger.

Routes of administration/doses

For the reduction of elevated intracranial pressure, a dose of 1 g/kg is infused intravenously over 15 minutes prior to operative treatment. Subsequently, intermittent doses of 0.25–0.5 g/kg may be used for the treatment of persistently elevated intracranial pressure. The diuretic dose is 0.5–1 g/kg. Mannitol acts within a few minutes and lasts 1–4 hours.

The oral dose for bowel preparation is 100 ml of the 20% solution—care should be taken to maintain adequate hydration.

Effects

CVS

The acute administration of mannitol increases the cardiac output; blood pressure increases by 5–10 mmHg.

CNS

Mannitol induces a significant reduction in intracranial pressure with preservation of cerebral blood flow in patients with intact autoregulation; in patients with defective autoregulation, a minimal reduction in intracranial pressure with an increase in cerebral blood flow occurs.

GU

Renal blood flow is increased, and the rate of renin secretion decreases; mannitol washes out the medullary interstitial gradient, leading to a decreased ability to produce concentrated urine. Diuresis occurs 1–3 hours after administration.

Metabolic/other

The plasma sodium and potassium concentrations may fall and that of urea increase with the use of high doses of mannitol.

Toxicity/side effects

Circulatory overload and rebound increases in intracranial pressure may occur, following the use of mannitol. Allergic responses are rare; the drug is irritant to tissues and veins. Mannitol may have toxic effects on the distal convoluted tubule and collecting duct cells, causing vacuolization.

Kinetics

Absorption

After oral administration, approximately 17.5% is absorbed in the small bowel.

Distribution

The drug shows a biphasic distribution to plasma and extracellular water; complex fluid shifts occur in response to this. The VD is 0.47 l/kg.

Metabolism

Mannitol is not metabolized in man.

Excretion

The drug is excreted unchanged in the urine; the clearance is 7 ml/min/kg, and the elimination half-life is 72 minutes.

Special points

Blood should not be co-administered with mannitol. A total dose exceeding 3 g/kg/day may produce a serum osmolality >320 mOsm/l. Rebound increases in intracranial pressure may occur after the cessation of mannitol therapy.

Metaraminol

Uses

Metaraminol is used as an adjunct in the treatment of hypotension occurring during general or neuroaxial anaesthesia.

Chemical

A synthetic sympathomimetic amine.

Presentation

As a clear solution containing 10 mg/ml of metaraminol tartrate.

Main action

Peripheral vasoconstriction.

Mode of action

Metaraminol is a direct- and indirect-acting sympathomimetic agent that has agonist effects mainly at alpha-1 adrenoceptors, but also has some beta-adrenoceptor activity. The drug also causes noradrenaline to be released from intracytoplasmic stores, in addition to causing adrenaline release.

Routes of administration/doses

The adult dose by intravenous infusion of metaraminol diluted in saline or glucose should be titrated according to response; bolus doses of 0.5–5 mg may be administered intravenously with extreme caution. The corresponding intramuscular or subcutaneous dose for the prevention of hypotension is 2–10 mg. The onset of effect after intravenous administration occurs within 1–2 minutes, with maximum effect at 10 minutes, and lasts 20–60 minutes. The onset of effect after intramuscular or subcutaneous administration occurs within 10 minutes and lasts 1–1.5 hours.

Effects

CVS

Metaraminol causes a sustained increase in the systolic and diastolic blood pressures due to an increase in the systemic vascular resistance; it also increases PVR. A reflex bradycardia occurs. The drug has positive inotropic properties, although the cardiac output may fall due to the increase in systemic vascular resistance. Coronary blood flow is increased by metaraminol by an indirect mechanism.

RS

The drug causes a slight decrease in the respiratory rate and an increase in the tidal volume.

CNS

The cerebral blood flow is decreased by the administration of metaraminol.

GU

The renal blood flow is decreased by metaraminol, and the drug causes contraction of the pregnant uterus and reduces uterine artery blood flow via its effect at alpha-adrenoceptors.

Metabolic/other

Metaraminol increases glycogenolysis and inhibits insulin release, leading to hyperglycaemia. Lipolysis is increased, and the concentration of free fatty acids may become elevated. The drug may increase oxygen consumption and elevate body temperature.

Toxicity/side effects

Headaches, dizziness, tremor, nausea, and vomiting may occur with the use of the drug. Rapid and large increases in blood pressure resulting in left ventricular failure and cardiac arrest have been reported after the administration of metaraminol. Extravascular injection of the drug may lead to tissue necrosis and abscess formation at the injection site.

Excessive hypertension may occur when metaraminol is administered to patients with hyperthyroidism or those receiving MAOIs.

Kinetics

There are limited quantitative data available. The effect starts 1–2 minutes after intravenous injection, 10 minutes after intramuscular injection, and 5–20 minutes after subcutaneous injection. It is reportedly 45% protein-bound.

The drug does not cross the blood–brain barrier.

Metformin

Uses

Metformin is used in the treatment of non-insulin-dependent (type II) diabetes mellitus.

Chemical

A biguanide.

Presentation

As 500/850 mg tablets of metformin hydrochloride.

Main action

Hypoglycaemia.

Mode of action

Biguanides have no effect in the absence of circulating insulin; they do not alter insulin concentration but do enhance its peripheral action. They appear to act by inhibiting the intestinal absorption of glucose and decreasing the peripheral utilization of glucose, both by increasing the rate of anaerobic glycolysis and by decreasing the rate of gluconeogenesis.

Routes of administration/doses

The adult oral dose is 1.5–3 g daily in divided doses. Metformin has a duration of action of 8–12 hours.

Effects

CVS

Metformin reduces the intestinal absorption of glucose, folate, and vitamin B12; it has no effects on gastric motility. The drug may also increase the intestinal utilization of glucose and cause weight loss.

Metabolic/other

Metformin increases the sensitivity to the peripheral actions of insulin by increasing the number of low-affinity binding sites for insulin in red blood cells, adipocytes, hepatocytes, and skeletal muscle cells. The drug does not cause hypoglycaemia in diabetic subjects receiving metformin monotherapy. Metformin inhibits the metabolism of lactate and causes a decrease in the plasma triglyceride, cholesterol, and pre-beta lipoprotein concentrations.

Toxicity/side effects

Metformin is normally well tolerated; gastrointestinal disturbances may occur. Lactic acidosis may complicate the use of the drug rarely.

Kinetics

Absorption

The drug is slowly absorbed from the small intestine; the oral bioavailability is 50–60%.

Distribution

Metformin is not protein-bound in the plasma.

Metabolism

No metabolites of the drug have been detected in man.

Excretion

The drug is excreted essentially unchanged in the urine. The clearance exceeds the glomerular filtration rate, implying active tubular secretion. The elimination half-life is 1.7–4.5 hours. The drug is not recommended for use in patients with renal impairment.

Methohexital

Uses

Methohexital is used for the induction and maintenance of anaesthesia.

Chemical

A methylated oxybarbiturate.

Presentation

As a white, crystalline powder in vials containing 0.1/ 0.5 g of methohexital sodium mixed with sodium carbonate; this is dissolved in water before administration to yield a clear, colourless solution with a pH of 11 and a pKa of 7.9, which is stable in solution for 6 weeks.

Main action

Hypnotic.

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 drug is usually administered intravenously in a dose of 1–1.5 mg/kg; it acts in one arm–brain circulation time, and awakening occurs in 2–3 minutes. The drug may also be administered intramuscularly in a dose of 6.6 mg/kg or rectally in a dose of 15–20 mg/kg.

Effects

CVS

Methohexital has negatively inotropic effects and decreases the systemic vascular resistance; it may also depress transmission in autonomic ganglia and thus lead to hypotension.

RS

Methohexital is a more powerful respiratory depressant than thiopental and obtunds the ventilatory response to both hypoxia and hypercarbia. The drug may cause pronounced coughing and hiccuping.

CNS

At low doses, methohexital may cause paradoxical excitement. Induction of anaesthesia with the drug is associated with an increased incidence of excitatory phenomena when compared to thiopental. Methohexital decreases both the cerebral blood flow and intracranial pressure. The drug may cause epileptiform EEG patterns; abnormal muscle movements may also occur due to neurotransmitter release.

AS

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

GU

Methohexital 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

The drug decreases the production of superoxide anions by polymorphonuclear leucocytes.

Toxicity/side effects

Methohexital causes pain on injection in up to 80% of patients. It is less irritant than thiopental when extravasation occurs but, when administered intra-arterially, may lead to arterial constriction and thrombosis. Anaphylactoid reactions occur with a frequency similar to that observed with thiopental. Nausea and vomiting may complicate the use of methohexital.

Kinetics

Distribution

The drug is 51–65% protein-bound in the plasma, predominantly to albumin; 20% is sequestered in red blood cells; the VD is 1.13 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 (methohexital is 75% 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 methohexital is due to redistribution to muscle and later to fat. Methohexital has a shorter duration of action than thiopental due to its very short distribution half-life and a high clearance which is four times greater than that of thiopental.

Metabolism

Occurs in the liver, primarily to a 4-hydroxy metabolite.

Excretion

The metabolites are excreted in the urine; 1% of the dose is excreted unchanged. The clearance is 7.9–13.9 ml/min/kg, and the elimination half-life is 1.8–6 hours.

Special points

The drug may induce acute clinical and biochemical manifestations in patients with porphyria and is also not recommended for use in epileptics. Methohexital 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.

Methoxamine

Uses

Methoxamine is used for:

  1. 1. the correction or prevention of hypotension during spinal or general anaesthesia and cardiopulmonary bypass and

  2. 2. the treatment of supraventricular tachycardias.

Chemical

A synthetic sympathomimetic amine.

Presentation

As a clear solution containing 20 mg/ml of methoxamine hydrochloride.

Main actions

Peripheral vasoconstriction and bradycardia.

Mode of action

Methoxamine is a selective alpha-1 adrenergic agonist.

Routes of administration/doses

Methoxamine is administered intravenously at a rate of 1 mg/min to a total dose of 5–10 mg in an adult; it acts within 1–2 minutes and has a duration of action of 1 hour. The corresponding intramuscular dose is 5–20 mg when the onset of action is 15– 20 minutes, and the duration of effect is 90 minutes.

Effects

CVS

Methoxamine commonly produces a reflex and intrinsic bradycardia, accompanied by an increase in the systolic and diastolic blood pressures and central venous pressure. The drug has no effect on the cardiac output but prolongs the effective refractory period and slows AV conduction.

RS

The drug has no effect on respiratory function.

AS

Contraction of gastrointestinal sphincters follows the administration of methoxamine.

GU

The drug produces renal arterial vasoconstriction, leading to a fall in the glomerular filtration rate. Contraction of the pregnant uterus and a decrease in uterine blood flow may occur.

Metabolic/other

Mydriasis, piloerection, and diaphoresis are produced by the drug. Glycogenolysis and gluconeogenesis are stimulated; this is accompanied by a decrease in insulin secretion.

Toxicity/side effects

Headaches, projectile vomiting, sensations of coldness, and the desire to urinate have been reported in association with the use of methoxamine.

Kinetics

There are no data available.

Special points

The drug may precipitate severe hypertension in patients with uncontrolled hyperthyroidism or who are receiving MAOIs or tricyclic antidepressants.

Methyldopa

Uses

Methyldopa is used in the treatment of:

  1. 1. hypertension and

  2. 2. pre-eclampsia.

Chemical

A phenylalanine derivative.

Presentation

As 125/250/500 mg tablets and a suspension containing 50 mg/ml of methyldopa. A solution for intravenous administration containing 50 mg/ml of methyldopa hydrochloride is also available.

Main actions

Antihypertensive.

Mode of action

Methyldopa is metabolized to alpha-methyl noradrenaline which is stored in adrenergic nerve terminals within the CNS; the latter is a potent agonist at alpha-2 (pre-synaptic) nerve terminals and reduces central sympathetic discharge, thereby lowering the blood pressure (cf. clonidine).

Routes of administration/doses

The adult oral dose is 0.5–3 g/day in 2–3 divided doses.

Effects

CVS

Methyldopa decreases the systemic vascular resistance, with little accompanying change in either the cardiac output or heart rate. Postural hypotension occurs uncommonly with the use of the drug.

GU

Methyldopa has little effect on the renal or uteroplacental blood flow, the glomerular filtration rate, or filtration fraction.

Metabolic/other

Plasma renin activity and noradrenaline concentrations decrease after administration of the drug.

Toxicity/side effects

The reported side effects after the administration of methyldopa are numerous. CVS disturbances that may result from the use of the drug include orthostatic hypotension, bradycardia, and peripheral oedema. CNS disturbances may also occur, including sedation, depression, weakness, paraesthesiae, and dizziness. Gastrointestinal, dermatological, and haematological disturbances, including thrombocytopenia, a positive Coombs’ test (in 10–20%), and haemolytic anaemia, have also been reported. Methyldopa may also cause hepatic damage.

Kinetics

Absorption

Methyldopa has a variable absorption when administered orally; the bioavailability is 8–62% by this route due to a significant first-pass metabolism.

Distribution

The drug is 50% protein-bound in the plasma; the VD is 0.21–0.37 l/kg.

Metabolic/other

Methyldopa is conjugated to sulfate, as it traverses the intestinal mucosa and is metabolized in the liver to a variety of poorly characterized metabolites.

Excretion

20–40% of an administered dose is excreted in the urine, two-thirds of this unchanged. The clearance is 2.2–4 ml/min/kg, and the elimination half-life is 2.1–2.8 hours.

Special points

The hypotension effects of the drug are additive with those produced by volatile anaesthetic agents; methyldopa also decreases the apparent MAC of the latter.

The action of the drug is prolonged in the presence of renal failure; it is removed by haemodialysis.

Methyldopa commonly produces nasal congestion; care should be exercised during nasal intubation in patients receiving the drug.

Methylphenidate

Uses

Methylphenidate is used for the treatment of:

  1. 1. attention-deficit/hyperactivity disorder (ADHD)

  2. 2. narcolepsy and has been used for the treatment of

  3. 3. post-anaesthetic shivering

  4. 4. hiccuping during general anaesthesia

  5. 5. depression and

  6. 6. brain injury.

Chemical

A piperidine derivative.

Presentation

As 5/10/20 mg tablets of methylphenidate hydrochloride and a range of extended-release formulations.

Main actions

Central nervous stimulation.

Mode of action

Methylphenidate binds to the dopamine transporter in pre-synaptic cell membranes, blocking its reuptake, thereby increasing extracellular dopamine levels. It also affects noradrenaline reuptake and binds weakly to 5-hydroxytryptamine (5HT) receptors.

Routes of administration/doses

The drug is administered orally to a maximum of 60 mg/day in divided doses.

Effects

CVS

The drug causes dose-dependent hypertension and tachycardia.

CNS

Methylphenidate causes generalized CNS stimulation.

Metabolic/other

Methylphenidate decreases growth velocity.

Toxicity/side effects

Insomnia, nervousness, anorexia, hypertension, and tachycardia occur relatively frequently. The drug has significant potential for abuse.

Kinetics

Absorption

Methylphenidate is almost completely absorbed after oral administration.

Distribution

The drug exhibits a low degree of protein binding.

Metabolism

Occurs primarily by de-esterification to ritalinic acid.

Excretion

60–80% of the dose is administered in the urine. The elimination half-life is 2.5 hours.

Metoclopramide

Uses

Metoclopramide is used in the treatment of:

  1. 1. digestive disorders, e.g. hiatus hernia, reflux oesophagitis, and gastritis

  2. 2. nausea and vomiting due to a variety of causes, e.g. drugs (general anaesthetic agents, opiates, and cytotoxic gents), radiotherapy, hepatic and biliary disorders

  3. 3. diagnostic radiology of the gastrointestinal tract

  4. 4. migraine, and

  5. 5. post-operative gastric hypotonia.

Chemical

A chlorinated procainamide derivative.

Presentation

As 10 mg tablets, a syrup containing 1 mg/ml, and as a clear, colourless solution for injection containing 5 mg/ml of metoclopramide hydrochloride.

Main actions

Increased gastrointestinal motility and antiemetic.

Mode of action

The effects of metoclopramide on gastrointestinal motility appear to be mediated by:

  1. 1. antagonism of peripheral dopaminergic (D2) receptors

  2. 2. augmentation of peripheral cholinergic responses, and

  3. 3. direct action on smooth muscle to increase tone.

The antiemetic effects of the drug appear to be mediated by:

  1. 1. central dopaminergic (D2) blockade, leading to an increased threshold for vomiting at the chemoreceptor trigger zone and

  2. 2. decrease in the sensitivity of visceral nerves supplying afferent information to the vomiting centre.

Routes of administration/doses

Metoclopramide may be administered orally, intravenously, or intramuscularly; the adult dose by all routes is 10 mg 8-hourly. A dose of 1–2 mg/kg is recommended for the treatment of nausea and vomiting associated with cisplatin treatment.

Effects

CVS

There have been occasional reports of hypotension during general anaesthesia and cardiac arrest, dysrhythmias, and hypertension in patients with phaeochromocytoma following the administration of metoclopramide.

CNS

Metoclopramide raises the threshold for vomiting at the chemoreceptor trigger zone and prevents apomorphine-induced vomiting in man. The drug has neuroleptic effects (including an antipsychotic action), as would be expected of a centrally acting dopamine antagonist.

AS

Metoclopramide increases the tone of the lower oesophageal sphincter by about 17 mmHg, accelerates gastric emptying and the amplitude of gastric contractions, and accelerates small intestinal transit time. Its effects on large bowel motility are variable. The drug has no effect on gastric secretion.

GU

The drug may increase ureteric peristaltic activity.

Metabolic/other

Metoclopramide stimulates prolactin release and also causes a transient increase in aldosterone secretion.

Toxicity/side effects

Occur in 11% of patients receiving the drug; drowsiness, dizziness, faintness, and bowel disturbances are the most frequently reported side effects. Extrapyramidal side effects occur; the commonest manifestations are akathisia and oculogyric crises; extrapyramidal effects occur more frequently with higher doses, and in patients with renal impairment and the elderly. The neuroleptic malignant syndrome has been reported in association with metoclopramide.

Kinetics

Absorption

The drug is rapidly absorbed after oral administration and has a bioavailability by this route of 32–97%. This wide variability is due primarily to first-pass conjugation to sulfate.

Distribution

Metoclopramide is 13–22% protein-bound in the plasma; the VD is 2.2–3.4 l/kg.

Metabolism

Occurs primarily in the liver; the major metabolite is a sulfate derivative. Two other metabolites have been identified in man.

Excretion

80% of an oral dose is excreted in the urine within 24 hours; 20% of this is unchanged, and the remainder appears as non-metabolized drug conjugated to a sulfate or glucuronide and as the sulfated metabolite. The clearance is 8.8–11.6 ml/min/kg, and the elimination half-life is 2.6–5 hours.

Metoclopramide is not significantly removed by haemodialysis.

Metronidazole

Uses

Metronidazole is used for:

  1. 1. the treatment and prophylaxis of infections due to anaerobic bacteria, especially Bacteroides fragilis and Clostridia spp., and the treatment of

  2. 2. protozoal infections such as amoebiasis, giardiasis, and trichomoniasis

  3. 3. acute dental infections, and

  4. 4. pseudomembranous colitis.

Chemical

A synthetic imidazole derivative.

Presentation

As 200/400/500 mg tablets; 500 mg or 1 g suppositories; as an oral suspension of 200 mg/5 ml; and as a clear, colourless 0.5% solution for intravenous injection of metronidazole.

Main actions

Metronidazole is an antimicrobial agent with a high degree of activity against anaerobes and protozoa.

Mode of action

The drug acts via a reactive intermediate which reacts with bacterial DNA, so that the resultant DNA complex can no longer function as an effective primer for DNA and RNA polymerases—all nucleic acid synthesis is thus effectively terminated.

Routes of administration/doses

The adult oral dose is 200–800 mg, and the corresponding rectal dose is 1 g 8-hourly. The intravenous dose is 500 mg 8-hourly, administered at a rate of 5 ml/min.

Effects

Metabolic/other

Metronidazole decreases the cholesterol content of bile.

Toxicity/side effects

Unpleasant taste, nausea and vomiting, gastrointestinal disturbances, rashes, and darkening of urine have been reported. Peripheral neuropathy and leucopenia may occur with chronic use of the drug.

Kinetics

Absorption

The bioavailability of oral metronidazole is 80% and by the rectal route is 75%.

Distribution

Metronidazole is distributed in virtually all tissues and body fluids in concentrations that do not differ markedly from their serum levels. Approximately 10% is protein-bound in the plasma. The VD is 0.75 l/kg.

Metabolism

Occurs by oxidation and glucuronidation in the liver.

Excretion

60% of the dose is excreted unchanged in the urine; the drug does not usually accumulate in renal failure. The clearance is 1.22 ml/kg/min, and the elimination half-life is 6–10 hours.

Special points

Metronidazole increases the anticoagulant effect of warfarin and exhibits a disulfiram-like interaction with alcohol, producing an acute confusional state and vomiting.

Prolongation of the action of vecuronium by the co-administration of the drug has been demonstrated in animals.

Metronidazole may cause reddish brown discoloration of the urine.

Metronidazole is removed by haemodialysis.

Midazolam

Uses

Midazolam is used:

  1. 1. for induction of anaesthesia

  2. 2. for sedation during endoscopy and procedures performed under local anaesthesia and during intensive care

  3. 3. as a hypnotic

  4. 4. for premedication prior to general anaesthesia and may be of use

  5. 5. in the treatment of chronic pain, including deafferentation syndromes.

Chemical

A water-soluble imidazobenzodiazepine.

Presentation

As a clear, colourless solution of midazolam hydrochloride containing 1/2/5 mg/ml.

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. Midazolam has kappa-opioid agonist activity in vitro, which may explain the mechanism of benzodiazepine-induced spinal analgesia.

Routes of administration/doses

The intramuscular dose (used for premedication) is 0.07–0.08 mg/kg; the intravenous dose for sedation is 0.07–0.1 mg/kg, titrated according to response. The end point for sedation is drowsiness and slurring of speech; response to commands is, however, maintained. The drug may also be administered intrathecally in an adult dose of 0.3–2 mg or epidurally in a dose of 0.1–0.2 mg/kg.

Effects

CVS

Systolic blood pressure decreases by 5% and diastolic pressure by 10%, and the systemic vascular resistance falls by 15–33%, following the administration of the drug; the heart rate increases by 18%. Midazolam in combination with fentanyl obtunds the pressor response to intubation to a greater extent than thiopental in combination with fentanyl.

RS

Midazolam decreases the tidal volume, but this is offset by an increase in the respiratory rate; the minute volume is thus little changed. Apnoea occurs in 10–77% of patients when midazolam is used as an induction agent. The drug impairs the ventilatory response to hypercapnia.

CNS

The drug produces hypnosis, sedation, and anterograde amnesia. There have been no studies of the anticonvulsant activity of midazolam in man. The cerebral oxygen consumption and cerebral blood flow are decreased in a dose-related manner, but a normal relationship is maintained between the two. When administered intrathecally or epidurally, the drug has anti-nociceptive effects.

AS

A midazolam–fentanyl induction sequence is associated with a lower incidence of post-operative vomiting than with a thiopental–fentanyl sequence. The drug reduces hepatic blood flow.

GU

Midazolam decreases renal blood flow.

Metabolic/other

Midazolam decreases the adrenergic, but not the cortisol and renin, response to stress. The drug causes significant inhibition of phagocytosis and leucocyte bactericidal activity.

Toxicity/side effects

Side effects are confined to occasional discomfort at the site of injection. Withdrawal phenomena may occur in children after prolonged infusion.

Kinetics

Absorption

The bioavailability when administered by the oral route is 44% and by the intramuscular route is 80–100%.

Distribution

The drug is 96% protein-bound in the plasma; the VD is 0.8– 1.5 l/kg. The VD may increase to 3.1 l/kg in the critically ill.

Metabolism

Midazolam is virtually completely metabolized in the liver to hydroxylated derivatives which are then conjugated to a glucuronide. Metabolites bind to CNS benzodiazepine receptors and are pharmacologically active.

Excretion

Occurs in the urine, predominantly as the hydroxylated derivatives; renal impairment thus has little effect. The clearance is 5.8–9 ml/min/kg, and the elimination half-life is 1.5–3.5 hours. The elimination half-life may increase to 5.4 hours in the critically ill.

Special points

The short duration of action of midazolam is due to its high lipophilicity, high metabolic clearance, and rapid rate of elimination. However, this may not be the case after prolonged dosing on intensive care.

The use of midazolam in premedication decreases the MAC of volatile agents by approximately 15%.

The clinical effects of the drug can be reversed by physostigmine, glycopyrronium bromide, and flumazenil.

Milrinone

Uses

Milrinone is used in the acute management of:

  1. 1. severe treatment-resistant congestive cardiac failure and in

  2. 2. low cardiac output states following cardiac surgery.

Chemical

Milrinone is a bipyridine molecule.

Presentation

As a clear, colourless to pale yellow solution for injection in 10 and 20 ml glass ampoules containing 1 mg/ml of milrinone lactate. The pKa of milirone is 9.67, and the pH is 6.35.

Main actions

Positive inotropism and vasodilatation.

Mode of action

Milrinone acts by selective inhibition of type III cAMP phosphodiesterase in cardiac and vascular muscle. This causes an increase in intracellular ionized calcium and contractile force in cardiac muscle. It also causes cAMP-dependent protein phosphorylation and subsequent vascular muscle relaxation. It does not have beta-adrenergic agonist activity. The drug improves left ventricular diastolic relaxation.

Routes of administration/doses

Milrinone is administered intravenously. In adult patients, a loading dose of 50 micrograms/kg administered over 10 minutes is recommended, followed by a continuous infusion of between 0.375 micrograms/kg/min and 0.75 micrograms/kg/min, titrated to haemodynamic response. In paediatric patients, a loading dose of between 50 and 75 microgram/kg is administered over 30–60 minutes, followed by a continuous infusion of between 0.25 and 0.75 micrograms/kg/min.

Effects

CVS

Milrinone has a positive inotropic action and leads to an increase in the cardiac output. The cardiac index increases by 25–30%. Pulmonary capillary wedge pressure decreases by 20%, together with a decrease in the systemic vascular resistance and mean arterial pressure. The drug may increase AV nodal conductance which may lead to an increase in ventricular response in patients with atrial fibrillation or atrial flutter.

GU

The urine output and glomerular filtration rate may increase, secondary to an increase in the cardiac output and renal perfusion.

Toxicity/side effects

Commonly reported side effects include ventricular ectopics, arrhythmias, and hypotension. Arrhythmias are often associated with an underlying cause (e.g. pre-existing arrhythmia, electrolyte abnormality).

Kinetics

Distribution

Milrinone is 70–80% protein-bound. The VD is 0.38 l/kg following a loading dose, and 0.45 l/kg following a continuous intravenous infusion.

Metabolism

12% of an administered dose undergoes hepatic metabolism to an O-glucuronide metabolite.

Excretion

83% of milrinone is excreted renally. Following a loading dose, the half-life is 2.3 hours, with a clearance of 0.13 l/kg/hour. Following a continuous infusion, the half-life is 2.4 hours, with a clearance of 0.14 l/kg/hour.

Special points

The infusion rate should be decreased in patients with severe renal impairment, as the half-life is prolonged in the presence of a reduced glomerular filtration rate.

Mivacurium

Uses

Mivacurium is used to facilitate intubation and controlled ventilation.

Chemical

A benzylisoquinolinium which is a mixture of three stereoisomers: trans–trans (57%), cis–trans (36%), cis–cis (4–8%). The cis–cis isomer is estimated to have <5% of the neuromuscular-blocking potency of the other two stereoisomers.

Presentation

As a clear, pale yellow aqueous solution in 5 and 10 ml ampoules containing 2.14 mg/ml of mivacurium hydrochloride. It has a pH of approximately 4.5.

Main action

Competitive, non-depolarizing neuromuscular blockade.

Mode of action

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

Routes of administration/doses

Mivacurium is administered by intravenous injection; in adults, the mean dose to reach the ED95 is 0.07 mg/kg. The recommended intubating dose in adults is 0.2 mg/kg administered over 30 seconds or a dose of 0.25 mg/kg administered as a divided dose (0.15 mg/kg, followed 30 seconds later by 0.1 mg/kg), which provides good to excellent intubating conditions within 2–2.5 minutes and 1.5–2 minutes (following completion of the first divided dose), respectively. Maintenance doses of 0.1 mg/kg are required at approximately 15-minute intervals in adults and children. Continuous infusion of mivacurium in adults may also be administered at a rate of 8–10 micrograms/kg/min (0.5– 0.6 mg/kg/hour). The ED95 in infants and children is 0.07 mg/kg and 0.1 mg/kg, respectively. The corresponding recommended doses for tracheal intubation are 0.15 mg/kg for infants and 0.2 mg/kg for children, with times to maximal neuromuscular block of 1.4 and 1.7 minutes, respectively. Average infusion rates to maintain 89–99% neuromuscular block are 11–14 micrograms/kg/min for children aged 2 months to 12 years old (0.7–0.9 mg/kg/hour). The duration of neuromuscular blockade is related to the bolus dose; doses in adults of 0.07, 0.15, 0.2, and 0.25 mg/kg produce clinically effective block for approximately 13, 16, 20, and 25 minutes, respectively. Spontaneous recovery after a continuous infusion is independent of the duration of infusion and is similar to recovery reported for single doses. Tachyphylaxis or cumulative neuromuscular blockade is not associated with continuous infusion of mivacurium. Significant train-of-four fade is not seen during the onset of block with mivacurium, and intubation of the trachea may be possible before the train-of-four count has been abolished.

Effects

CVS

Mivacurium has minimal CVS effects; a slight (7%) transient decrease in the blood pressure and a slight (7%) increase in the heart rate may occur after rapid intravenous injection. The drug has no significant vagal or ganglion-blocking properties in the normal dosage range.

RS

Neuromuscular blockade leads to apnoea; bronchospasm may occur, secondary to histamine release.

Toxicity/side effects

Transient cutaneous flushing occurs in approximately 16% of patients and is the commonest side effect. Hypotension, tachycardia, bronchospasm, erythema, and urticaria may all occur, with an incidence of <1%, and are attributed to histamine release. There have been rare reports of fatal anaphylactoid reactions with the administration of mivacurium. Cross-sensitivity may occur with vecuronium, rocuronium, and pancuronium.

Kinetics

Distribution

The VD of the trans–trans isomer is 147 ml/kg, that of the cis–trans isomer is 276 ml/kg, and that of the cis–cis isomer is 335 ml/kg.

Metabolism

The primary mechanism of metabolism of the trans–trans and cis–trans stereoisomers is enzymatic hydrolysis by plasma cholinesterases to yield a quaternary alcohol and a quaternary monoester metabolite which appear to be inactive. Some hydrolysis by liver esterases also occurs. The clearance of the cis–cis isomer is independent of plasma cholinesterase.

Excretion

The metabolites are excreted in the bile and urine, together with some unchanged drug. The clearance of the trans–trans isomer is 53 ml/kg/min, that of the cis–trans isomer is 99 ml/kg/min, and that of the cis–cis isomer is 4.6 ml/kg/min. The elimination half-life of the trans–trans isomer is 2.0 minutes, that of the cis–trans isomer is 1.8 minutes, and that of the cis–cis isomer is 53 minutes. The clearance of the trans–trans and cis–trans stereoisomers in elderly patients may decrease to 32 and 47 ml/kg/min, respectively, resulting in prolongation of action by approximately 20–30%. Renal impairment increases the clinical duration of action of mivacurium by a factor of 1.5, and hepatic impairment increases it by a factor of 3.

Special points

The duration of action of mivacurium is prolonged by isoflurane and enflurane, and it is recommended that the initial dose be reduced by 25%. Concomitant use of halothane causes minimal prolongation of action of the drug, and dosage reduction is not required. Data suggest that sevoflurane may reduce the mivacurium infusion rate requirement in children by up to 70%. Mivacurium is metabolized by plasma cholinesterase and, as such, its duration of activity prolonged in individuals possessing a genetic abnormality of plasma cholinesterase or an acquired reduction in its activity. The following drugs may reduce plasma cholinesterase activity: oral contraceptives, glucocorticoids, MAOIs, ketamine, lithium, ester local anaesthetic agents, metoclopramide, ecothiopate, trimetaphan, and edrophonium. Acquired conditions associated with a reduced activity of plasma cholinesterase include: malignancy, renal impairment, hepatic impairment, cardiac failure, pregnancy, thyrotoxicosis. The following drugs enhance the neuromuscular effects of mivacurium: aminoglycoside antibiotics, propranolol, calcium channel blockers, diuretics, and magnesium and lithium salts.

In patients who are obese, the ideal body weight should be used for dose calculation.

Mivacurium can be reversed using neostigmine (together with an inhibitor of vagal activity). Administration of between 0.03 and 0.06 mg/kg of neostigmine at 10% recovery from neuromuscular block produces 95% recovery of muscle twitch response and a T4:T1 ratio of >75% in approximately 10 minutes.

Mivacurium does not act as a trigger agent for malignant hyperpyrexia in animal models.

The drug is physically incompatible with alkaline solutions (e.g. barbiturates).

Morphine

Uses

Morphine is used:

  1. 1. for premedication

  2. 2. as an analgesic in the management of moderate to severe pain

  3. 3. in the treatment of left ventricular failure

  4. 4. to provide analgesia during terminal care, and

  5. 5. in combination with kaolin in the symptomatic treatment of diarrhoea.

Chemical

A phenanthrene derivative.

Presentation

As 5/10/30/60/100/200 mg tablets, as a syrup containing 2/10/20 mg/ml, as 15/30 mg suppositories, and as a clear, colourless solution for injection containing 10/15/30 mg/ml of morphine sulfate; preservative-free morphine must be used for epidural/spinal use.

Main actions

Analgesia and respiratory depression.

Mode of action

Morphine is an agonist at mu- and kappa-opioid receptors. Opioids appear to exert their effects by increasing intracellular calcium concentration which, in turn, increases potassium conductance and hyperpolarization of excitable cell membranes. The decrease in membrane excitability that results may decrease both pre- and post-synaptic responses.

Routes of administration/doses

The initial adult oral dose is 5– 20 mg 4-hourly, increased as required. The dose by the rectal route is 15– 30 mg 4-hourly. The corresponding intramuscular or subcutaneous dose is 0.1–0.2 mg/kg, and the intravenous dose is 0.05–0.1 mg/kg 3- to 4-hourly. Morphine may also be administered intrathecally; an adult dose of 0.2–1 mg has been recommended. The drug has a peak analgesic effect 30–60 minutes after intramuscular injection and has a duration of effect of 3–4 hours.

Effects

CVS

Morphine has minimal effects on the CVS; the predominant effect is that of orthostatic hypotension, secondary to a decrease in the systemic vascular resistance, at least part of which is mediated by histamine release. The drug may also cause bradycardia when administered in high doses.

RS

The principal effect of the drug is respiratory depression with a decreased ventilatory response to hypoxia and hypercapnia. Morphine also has a potent antitussive action. Bronchoconstriction may occur with the use of high doses of the drug.

CNS

Morphine is a potent analgesic agent and may also cause drowsiness, relief of anxiety, and euphoria. Miosis is produced by the drug as a result of stimulation of the Edinger–Westphal nucleus. Seizures and muscular rigidity may occur with the use of high doses of morphine.

AS

Morphine decreases gastrointestinal motility and decreases gastric acid, biliary, and pancreatic secretions; it also increases the common bile duct pressure by causing spasm of the sphincter of Oddi. The drug may also cause nausea, vomiting, and constipation.

GU

The drug increases the tone of the ureters, bladder detrusor muscle, and sphincter, and may precipitate urinary retention.

Metabolic/other

Mild diaphoresis and pruritus may result from histamine release. Morphine increases the secretion of ADH and may therefore lead to impaired water excretion and hyponatraemia. The drug causes a transient decrease in adrenal steroid secretion.

Toxicity/side effects

Respiratory depression, nausea and vomiting, hallucinations, and dependence may complicate the use of morphine. Pruritus may occur after epidural or spinal administration of the drug.

Kinetics

Absorption

Morphine is well absorbed when administered orally; the bioavailability by this route is 15–50% due to an extensive first-pass metabolism.

Distribution

The drug is 20–40% protein-bound in the plasma, predominantly to albumin; the VD is 3.4–4.7 l/kg. Morphine equilibrates slowly between the plasma and CSF; there is no clear correlation between the degree of analgesia and the plasma concentration of the drug.

Metabolism

Occurs in the liver to morphine-3-glucuronide, morphine-6-glucuronide, and normorphine. In animal models, morphine-6-glucuronide has analgesic effects, and morphine-3-glucuronide has effects on arousal. Enterohepatic cycling of the metabolites probably does not occur.

Excretion

Occurs predominantly in the urine as the glucuronide conjugates; 7–10% appears in the faeces as conjugated morphine. The clearance is 12–23 ml/min/kg, and the elimination half-life is 1.7–4.5 hours. Cumulation of morphine-6-glucuronide occurs in the presence of renal failure; a reduction in the dose of the drug is necessary under these circumstances.

Special points

Morphine should be used with caution in the presence of hepatic failure, as the drug may precipitate encephalopathy. Similarly, the use of the drug in patients with hypopituitarism may precipitate coma. In common with other opioids, morphine decreases the apparent MAC of co-administered volatile agents. The actions of the drug are all reversed by naloxone, although the analgesia afforded by the epidural administration of morphine is well preserved after the administration of naloxone.

Morphine is not removed by haemodialysis or by peritoneal dialysis.

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