Page of

A 

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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0001

A2RAs

Uses

Angiotensin II receptor antagonists (A2RAs) are used in the treatment of:

  1. 1. essential and renovascular hypertension

  2. 2. diabetic nephropathy

  3. 3. congestive cardiac failure, and

  4. 4. in patients intolerant of angiotensin-converting enzyme inhibitors (ACEIs).

Chemical

A2RAs belong to the tetrazoles group.

Presentation

A2RAs are available in tablet, capsule, liquid, and a powder form as an oral suspension. A number of commercially available types are available, including losartan, irbesartan, candesartan, and valsartan. The drug may also be combined with a thiazide diuretic.

Main actions

Antihypertensive.

Mode of action

A2RAs selectively block the G-protein-coupled angiotensin II receptor AT1, therefore preventing the physiological effects of angiotensin II via the renin–angiotensin–aldosterone system. The drug does not affect bradykinin-induced vasodilatation.

Routes of administration/doses

A2RAs are available for oral administration. The specific dose and frequency of an agent administered are dependent on the clinical indication, age of the patient, and particular agent being used.

Effects

CVS

A reduction in the systemic vascular resistance occurs, leading to a fall in the systolic and diastolic blood pressures.

GU

A2RAs cause a significant increase in the renal blood flow.

Toxicity/side effects

A2RAs are generally well tolerated. Dizziness secondary to hypotension may occur. Angio-oedema occurs rarely. The development of a dry cough (cf. ACE inhibitors) is not associated with A2RAs. Hyperkalaemia can occur.

Kinetics

Data are incomplete.

Absorption

A2RAs are generally well absorbed from the gastrointestinal tract. Bioavailability for some A2RAs are as follows: losartan (33%), irbesartan (60–80%), candesartan (15%), and valsartan (23%).

Distribution

The percentage of drug bound to plasma proteins (predominantly albumin) is high: losartan (99.7%), irbesartan (90%), candesartan (>99%), and valsartan (94–97%). The volume of distribution (VD) of A2RAs is highly variable: losartan (34 l), irbesartan (53–93 l), candesartan (9.1 l), and valsartan (17 l).

Metabolism

A2RA metabolism varies widely. Losartan undergoes extensive hepatic metabolism, generating an active metabolite. Irbesartan undergoes hepatic glucuronide conjugation and oxidation to inactive metabolites. Candesartan is a pro-drug presented as candesartan cilexetil, which undergoes rapid ester hydrolysis in the intestinal wall to the active drug candesartan. Valsartan undergoes minimal hepatic metabolism.

Excretion

Losartan is excreted 35% in the urine, and 60% in faeces. It has a half-life of 2 hours for the parent drug, and 69 hours for its active metabolite. Irbesartan has a half-life of 1115 hours. Candesartan is excreted 75% unchanged in the urine and faeces, with a half-life of 9 hours. Valsartan is excreted 80% unchanged (83% in faeces and 13% in the urine), with a half-life of 59 hours.

ACE inhibitors

Uses

ACEIs are used in the treatment of:

  1. 1. essential and renovascular hypertension

  2. 2. congestive cardiac failure, and

  3. 3. diabetic nephropathy.

Chemical

ACEIs are derived from peptides originally isolated from the venom of the pit viper Bothrops jararaca.

Presentation

ACEIs are available in tablet or capsule form, and a number of commercially available types are available, including captopril, enalapril, perindopril, lisinopril, and ramipril.

Main action

Antihypertensive.

Mode of action

ACEIs inhibit angiotensin-converting enzyme (with an affinity many times greater than that of angiotensin I), so preventing the formation of angiotensin I from angiotensin II. Part of their action may also be exerted through the modulation of sympathetic tone or the kallikrein–kinin–prostaglandin system.

Routes of administration/doses

ACEIs are only currently available for oral administration. The specific dose and frequency of an agent administered are dependent on the clinical indication, age of the patient, and particular agent being used.

Effects

CVS

The systemic vascular resistance decreases, leading to a decrease in the systolic and diastolic blood pressures; the cardiac output may increase by up to 25%, especially in the presence of cardiac failure.

GU

ACEIs cause an increase in the renal blood flow, although the glomerular filtration rate remains unchanged. Natriuresis may ensue, but there is little overall effect on the plasma volume.

Toxicity/side effects

ACEIs are generally well tolerated; hypotension, dizziness, fatigue, dry cough (due to an accumulation of bradykinin), gastrointestinal upsets, and rashes may occur. Renal function may deteriorate in patients with renovascular hypertension.

Kinetics

Data are incomplete.

Absorption

ACEIs are reasonably well absorbed from the gastrointestinal tract. Bioavailability for individual drugs is as follows: captopril (75%), enalapril (40%), perindopril (75%), lisinopril (25%), ramipril (50–60%).

Distribution

The percentage of drug bound to plasma proteins is variable: captopril (30%), enalapril (50%), perindopril (76%), ramipril (73%).

Metabolism

Captopril undergoes metabolism to a disulfide dimer and cysteine disulfide. Enalapril and perindopril are pro-drugs that are metabolized to their respective active forms. ACEIs undergo minimal metabolism in man.

Excretion

ACEIs have markedly variable half-lives and clearance data. The half-life of captopril is 1.9 hours, whereas that of lisinopril is 12 hours, enalapril 35 hours, perindopril 30–120 hours, and ramipril >50 hours. Captopril has a low clearance, compared to enalapril and perindopril which have plasma clearance values of approximately 300 ml/min.

Special points

The hypotensive effects of ACEIs are additive with that of anaesthetic agents. However, they do not necessarily protect against the cardiovascular responses to laryngoscopy.

There is an increased risk of renal failure with the co-administration of ACEIs and non-steroidal anti-inflammatory drugs (NSAIDs) in the presence of hypovolaemia.

Acetazolamide

Uses

Acetazolamide is used in the treatment of:

  1. 1. glaucoma

  2. 2. petit mal epilepsy

  3. 3. Ménière’s disease

  4. 4. familial periodic paralysis and

  5. 5. the prophylaxis and treatment of altitude sickness.

Chemical

A sulfonamide.

Presentation

As 250 mg tablets of acetazolamide and in vials containing 500 mg of the sodium salt of acetazolamide for reconstitution with water prior to injection.

Main action

Diuresis and a decrease in the intraocular pressure.

Mode of action

Acetazolamide is a reversible, non-competitive inhibitor of carbonic anhydrase situated within the cell cytosol and on the brush border of the proximal convoluted tubule. This enzyme catalyses the conversion of bicarbonate and hydrogen ions into carbonic acid and then carbonic acid to carbon dioxide (CO2) and water. Under normal circumstances, sodium ions (Na+) are reabsorbed in exchange for hydrogen ions in the proximal and distal renal tubules; acetazolamide decreases the availability of hydrogen ions, and therefore Na+ and bicarbonate ions remain in the renal tubule, leading to a diuresis.

Routes of administration/doses

The adult oral and intravenous dose is 250–1000 mg daily.

Effects

RS

Acetazolamide produces a compensatory increase in ventilation in response to the metabolic acidosis and increased tissue CO2 that the drug causes.

CNS

Acetazolamide has demonstrable anticonvulsant properties, possibly related to an elevated CO2 tension within the central nervous system (CNS). The drug decreases the pressure of both the cerebrospinal fluid (CSF) and the intraocular compartment by decreasing the rate of formation of the CSF and aqueous humour (by 50–60%).

AS

The drug inhibits gastric and pancreatic secretion.

GU

Acetazolamide produces a mild diuresis, with retention of Na+ and a subsequent increase in plasma Na+ concentration. The drug also decreases renal excretion of uric acid.

Metabolic/other

The excretion of an alkaline urine results in the development of a hyperchloraemic metabolic acidosis in response to the administration of acetazolamide. The drug also interferes with iodide uptake by the thyroid.

Toxicity/side effects

Occur rarely and include gastrointestinal and haemopoietic disturbances, rashes, renal stones, and hypokalaemia.

Kinetics

Absorption

Acetazolamide is rapidly and well absorbed when administered orally; the bioavailability by this route is virtually 100%.

Distribution

The drug is 70–90% protein-bound in the plasma.

Metabolism

Acetazolamide is not metabolized in man.

Excretion

The drug is excreted unchanged in the urine; the clearance is 2.7 l/hour, and the elimination-half-life is 1.7–5.8 hours.

Special points

The use of acetazolamide is contraindicated in the presence of hepatic or renal failure, as the drug will worsen any metabolic acidosis and may also cause urolithiasis. Pre-treatment with the drug will obtund the increase in intraocular pressure produced by the administration of suxamethonium; however, the use of acetazolamide is of dubious value during eye surgery, as it simultaneously increases the intrachoroidal vascular volume. Acetazolamide has been used effectively for the correction of metabolic alkalosis in the critically ill.

Acetazolamide is removed by haemodialysis.

Aciclovir

Uses

Aciclovir is used in the treatment of:

  1. 1. Herpes simplex infections of the skin and eye

  2. 2. Herpes simplex encephalitis

  3. 3. recurrent varicella-zoster virus infections, and

  4. 4. for the prophylaxis of herpes simplex infections in immunocompromised patients.

Chemical

An analogue of the nucleoside 2′-deoxyguanosine.

Presentation

As 200/400/800 mg tablets, a suspension containing 40 mg/ml, a white lyophilized powder in vials containing 250 mg of aciclovir sodium which is reconstituted prior to injection in water, and as a 3% ophthalmic ointment and 5% w/w cream for topical application.

Main action

Aciclovir is an antiviral agent, active against herpes simplex (I and II) and varicella-zoster virus.

Mode of action

Aciclovir is activated within the viral cell via phosphorylation by a virus-coded thymidine kinase and thus has a low toxicity for normal cells. Aciclovir triphosphate inhibits viral deoxyribonucleic acid (DNA) polymerase by becoming incorporated into the DNA primer template, effectively preventing further elongation of the viral DNA chain.

Routes of administration/doses

The adult oral dose is 200–400 mg 2–5 times daily, initially for a period of 5 days. The corresponding intravenous dose is 5–10 mg/kg 8-hourly, infused over a period of 1 hour. A higher dose is used for zoster than for simplex infections. Topical application should be performed 5 times daily, again for an initial period of 5 days.

Effects

Metabolic/other

Increases in plasma levels of urea and creatinine may occur if the drug is administered intravenously too rapidly.

Toxicity/side effects

Aciclovir is generally well tolerated. CNS disturbances (including tremors, confusion, and seizures) and gastrointestinal upset may occur. Precipitation of the drug in the renal tubules leading to renal impairment may occur if the drug is administered too rapidly or if an adequate state of hydration is not maintained. The drug is an irritant to veins and tissues.

Kinetics

Absorption

Oral absorption of the drug is erratic; the bioavailability by this route is 15–30%.

Distribution

The drug is 9–33% protein-bound in the plasma; the VD is 0.32–1.48 l/kg.

Metabolism

The major metabolite is 9-carboxymethoxymethyl guanine which is inactive.

Excretion

The drug is excreted by active tubular secretion in the urine, 45–80% unchanged. The elimination half-life is 2–3 hours.

Special points

A reduced dose should be used in the presence of renal impairment; haemodialysis removes 60% of the drug.

Adenosine

Uses

Adenosine is used in the diagnosis and treatment of paroxysmal supraventricular tachycardia.

Chemical

A naturally occurring nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles, in addition to being components of DNA and ribonucleic acid (RNA).

Presentation

As a clear, colourless solution containing 3 mg/ml adenosine in saline.

Main action

Depression of sinoatrial and atrioventricular (AV) nodal activity and slowing of conduction. The drug also antagonizes cyclic adenosine monophosphate (cAMP)-mediated catechol stimulation of ventricular muscle. Both actions result in negative chronotropic and inotropic effects.

Mode of action

Adenosine acts as a direct agonist at specific cell membrane receptors, classified into A1 and A2 subsets. A1 receptors are coupled to potassium channels by a guanine nucleotide-binding protein in supraventricular tissue.

Routes of administration/doses

Adenosine is administered as a rapid intravenous bolus, followed by a saline flush. The initial adult dose is 3 mg, followed, if necessary, by a 6 mg and then a 12 mg bolus at 1- to 2-minute intervals until an effect is observed. The paediatric dose is 0.0375–0.25 mg/kg. The drug acts within 10 seconds and has a duration of action of 10–20 seconds.

Effects

CVS

Depression of sinoatrial and AV nodal activity leads to the termination of paroxysmal supraventricular tachycardia. Atrial dysrhythmias are revealed by AV nodal block, leading to a transient slowing of the ventricular response. Adenosine has no clinically important effects on the blood pressure when administered as a bolus. A continuous high-dose infusion may result in a decrease in the systemic vascular resistance and decreased blood pressure. When administered as an infusion, adenosine causes a dose-dependent reflex tachycardia and an increase in the cardiac output. The drug also causes a dose-dependent increase in myocardial blood flow, secondary to coronary vasodilation mediated via endothelial A2 receptors. Adenosine decreases the pulmonary vascular resistance (PVR) in patients with pulmonary hypertension.

RS

Bolus administration of adenosine leads to an increase in both the depth and rate of respiration, probably mediated by A2 receptor stimulation in the carotid body. Infusion of the drug results in a fall in PaCO2. Bronchospasm may occur.

CNS

Infusion of adenosine results in increased cerebral blood flow. Low-dose adenosine induces neuropathic pain, hyperalgesia, and ischaemic pain. Adenosine itself is a neurotransmitter.

GU

Hypotensive doses of adenosine stimulate A2 receptors, resulting in renal and hepatic arterial vasoconstriction, although low doses have no effect on the glomerular filtration rate or sodium excretion.

Metabolic/other

Adenosine inhibits lipolysis and stimulates glycolysis.

Toxicity/side effects

The commonest side effects are transient facial flushing, dyspnoea, and chest discomfort. Bronchospasm has also been reported. The induced bradycardia predisposes to ventricular excitability and may result in ventricular fibrillation. Profound bradycardia requiring pacing may occur.

Kinetics

Absorption

Adenosine is inactive when administered orally.

Metabolism

Exogenous adenosine is absorbed from the plasma into red blood cells and the vascular endothelium where it is phosphorylated to adenosine monophosphate (AMP) or deaminated to inosine and hypoxanthine. The plasma half-life is <10 seconds.

Special points

No dose adjustment is necessary in the presence of renal or hepatic impairment. Adenosine has been used to induce hypotension perioperatively.

Intraoperative use of adenosine decreases the minimal alveolar concentration (MAC) of isoflurane and decreases post-operative analgesic requirements.

Adrenaline

Uses

Adrenaline is used in the treatment of:

  1. 1. anaphylactic and anaphylactoid shock

  2. 2. asystole

  3. 3. low cardiac output states

  4. 4. glaucoma and

  5. 5. as a local vasoconstrictor, and

  6. 6. is added to local anaesthetic solutions to prolong their duration of action.

Chemical

A catecholamine.

Presentation

As a clear solution for injection containing 0.1/1 mg/ml of adrenaline hydrochloride, a 1% ophthalmic solution, and as an aerosol spray delivering 280 micrograms metered doses of adrenaline acid tartrate.

Main action

Sympathomimetic.

Mode of action

Adrenaline is a directly acting sympathomimetic amine that is an agonist of alpha- and beta-adrenoreceptors; it has approximately equal activity at both alpha- and beta-receptors.

Routes of administration/doses

The drug may be administered intravenously either as an intravenous bolus in doses of 0.1–1 mg for the treatment of asystole or as an infusion at the rate of 0.01–0.1 micrograms/kg/min, titrated according to response; low doses tend to produce predominantly beta-effects, whilst higher doses tend to produce predominantly alpha-effects. The dose by the subcutaneous route is 0.1–0.5 mg. Adrenaline may be administered by inhalation; a maximum daily dose of 10–20 metered doses is recommended.

Effects

CVS

Adrenaline is both a positive inotrope and a positive chronotrope, and therefore causes an increase in the cardiac output and myocardial oxygen consumption. The drug causes an increase in the coronary blood flow. When administered as an intravenous bolus, adrenaline markedly increases the peripheral vascular resistance, producing an increase in the systolic blood pressure with a less marked increase in the diastolic blood pressure. When administered as an intravenous infusion, the peripheral vascular resistance (a direct beta-2 effect) and diastolic blood pressure both tend to decrease. The heart rate initially increases and subsequently decreases due to a vagal reflex. The plasma volume decreases as a result of the loss of protein-free fluid into the extracellular fluid. Adrenaline increases platelet adhesiveness and blood coagulability (by increasing the activity of factor V).

RS

Adrenaline is a mild respiratory stimulant and causes an increase in both the tidal volume and respiratory rate. The drug is a potent bronchodilator but tends to increase the viscosity of bronchial secretions.

CNS

Adrenaline only penetrates the CNS to a limited extent but does have excitatory effects. The drug increases the cutaneous pain threshold and enhances neuromuscular transmission. Adrenaline has little overall effect on the cerebral blood flow. It has weak mydriatic effects when applied topically to the eye.

AS

The drug decreases the intestinal tone and secretions; the splanchnic blood flow is increased.

GU

Adrenaline decreases the renal blood flow by up to 40%, although the glomerular filtration rate remains little altered. The bladder tone is decreased and the sphincteric tone increased by the drug, which may lead to difficulty with micturition. Adrenaline inhibits the contractions of the pregnant uterus.

Metabolic/other

The drug has profound metabolic effects; it decreases insulin secretion whilst increasing both glucagon secretion and the rate of glycogenolysis, resulting in elevation of the blood sugar concentration. The plasma renin activity is increased by the drug (a beta-1 effect), and the plasma concentration of free fatty acids is increased by the activation of triglyceride lipase. The serum potassium concentration transiently rises (due to release from the liver), following the administration of adrenaline; a more prolonged decrease in potassium concentration follows. Adrenaline administration increases the basal metabolic rate by 20–30%; in combination with the cutaneous vasoconstriction that the drug produces, pyrexia may result.

Toxicity/side effects

Symptoms of CNS excitation, cerebral haemorrhage, tachycardia, dysrhythmias, and myocardial ischaemia may result from the use of adrenaline.

Kinetics

Data are incomplete.

Absorption

The drug is inactivated when administered orally. Absorption is slower after subcutaneous than intramuscular administration. The drug is well absorbed from the tracheal mucosa.

Metabolism

Exogenous adrenaline is predominantly first metabolized by catechol-O-methyl transferase, predominantly in the liver, to metadrenaline and normetadrenaline (uptake-2); some is metabolized by monoamine oxidase within adrenergic neurones (uptake-1). The final common products of adrenaline metabolism are 3-methoxy 4-hydroxyphenylethylene and 3-methoxy 4-hydroxymandelic acid (which are inactive).

Excretion

The inactive products appear predominantly in the urine.

Special points

The dose of adrenaline should be limited to 1 microgram/ kg/30 min in the presence of halothane and to 3 micrograms/kg/ 30 min in the presence of enflurane or isoflurane, in an attempt to prevent the appearance of serious ventricular dysrhythmias. Infiltration of adrenaline-containing solutions should be avoided in regions of the body supplied by end arteries.

Alfentanil

Uses

Alfentanil is used:

  1. 1. to provide the analgesic component in general anaesthesia

  2. 2. in sedation regimens for intensive care, and

  3. 3. to obtund the cardiovascular responses to laryngoscopy.

Chemical

A synthetic phenylpiperidine derivative.

Presentation

As a clear, colourless solution for injection containing 0.5/5 mg/ml of alfentanil hydrochloride. The pKa of alfentanil is 6.5; alfentanil is 89% unionized at a pH of 7.4 and has a relatively low lipid solubility. Despite the low lipid solubility of the drug (octanol:water partition coefficient of 128.1), it has a faster onset of action, compared to fentanyl which has a much higher lipid solubility due to its low pKa and consequently large amount of unionized drug available to cross lipid membranes.

Main actions

Analgesia and respiratory depression.

Mode of action

Alfentanil is a highly selective mu-opioid (MOP) agonist; the MOP receptor appears to be specifically involved in the mediation of analgesia. Opioids appear to exert their effects by interacting with pre-synaptic Gi protein receptors, leading to a hyperpolarization of the cell membrane by increasing potassium conductance. Inhibition of adenylate cyclase, leading to a reduced production of cAMP and closure of voltage-sensitive calcium channels, also occurs. The decrease in membrane excitability that results may decrease both pre- and post-synaptic responses.

Routes of administration/doses

Alfentanil is administered intravenously in boluses of 5–50 micrograms/kg. The drug may be administered by intravenous infusion at a rate of 0.5–1 micrograms/kg/min. Alfentanil acts rapidly, with the peak effect occurring within 90 seconds of intravenous administration, and the duration of effect is 5–10 min. Administration of alfentanil reduces the amount of hypnotic/volatile agents required to maintain anaesthesia.

Effects

CVS

The most significant cardiovascular effect that alfentanil demonstrates is bradycardia of vagal origin; cardiac output, mean arterial pressure, pulmonary and systemic vascular resistance, and pulmonary capillary wedge pressure are unaffected by the administration of the drug. Doses of 5 micrograms/kg increase left ventricular contractility and cardiac output in animal models. Alfentanil obtunds the cardiovascular responses to laryngoscopy and intubation.

RS

Alfentanil is a potent respiratory depressant, causing a decrease in both the respiratory rate and tidal volume; it also diminishes the ventilatory response to hypoxia and hypercarbia. The drug is a potent antitussive agent. Chest wall rigidity (the ‘wooden chest’ phenomenon) may occur after the administration of alfentanil—this may be an effect of the drug on MOP receptors located on GABA-ergic interneurones. Alfentanil causes minimal histamine release; bronchospasm is thus rarely produced by the drug.

CNS

Alfentanil is 10–20 times more potent an analgesic than morphine and has little hypnotic or sedative activity. Miosis is produced as a result of stimulation of the Edinger–Westphal nucleus. Alfentanil reduces the intraocular pressure by approximately 45%. The drug causes an increase in the amplitude of the encephalogram (EEG) and reduces its frequency.

AS

The drug decreases gastrointestinal motility and gastric acid secretion; it also doubles the common bile duct pressure by causing spasm of the sphincter of Oddi.

GU

Alfentanil increases the tone of the ureters, bladder detrusor muscle, and vesicular sphincter.

Metabolic/other

High doses of alfentanil will obtund the metabolic ‘stress response’ to surgery; the drug appears to be even more effective than fentanyl in this respect. Unlike morphine, alfentanil does not increase the activity of antidiuretic hormone (ADH).

Toxicity/side effects

Respiratory depression, bradycardia, nausea, vomiting, and dependence may also complicate the use of the drug.

Kinetics

Distribution

Alfentanil is 85–92% bound to plasma proteins, predominantly to alpha-1 acid glycoprotein; the VD is 0.4–1 l/kg. Alfentanil crosses the placenta.

Metabolism

Alfentanil is predominantly metabolized in the liver by N-dealkylation to noralfentanil; the remainder of the drug is metabolized by a variety of pathways, including aromatic hydroxylation, demethylation, and amide hydrolysis followed by acetylation. The major phase II pathway is by conjugation to glucuronide. Cytochrome P450 3A3 and 3A4 play a predominant role in alfentanil metabolism and may be subject to competitive inhibition by the co-administration of midazolam, which may lead to a prolongation of alfentanil and midazolam drug effects. Metabolism of the drug may also be prolonged when other CYP3A4 inhibitors are used concomitantly.

Excretion

90% of an administered dose is excreted in the urine (<1% as unchanged drug). The clearance of alfentanil is 3.3–8.3 ml/kg/min, and the elimination half-life range is 90–111 min. The relatively brief duration of action of a single dose of alfentanil, in comparison to that of fentanyl, is due to the smaller VD and shorter elimination half-life of the former.

Special points

Alfentanil decreases the apparent MAC of co-administered volatile agents. The concomitant use of erythromycin, cimetidine, fluconazole, ketoconazole, ritonavir, and diltiazem may significantly inhibit the clearance of alfentanil.

The half-life of the drug is prolonged in the elderly and debilitated patients and those with significant hepatic and renal impairment.

It is unknown whether alfentanil is removed by haemodialysis.

Allopurinol

Uses

Allopurinol is used:

  1. 1. in the prophylaxis of gout

  2. 2. to prevent renal stone formation in patients with xanthinuria, and

  3. 3. in the prophylaxis of the tumour lysis syndrome.

Chemical

A hypoxanthine analogue.

Presentation

As 100/300 mg tablets of allopurinol.

Main action

Xanthine oxidase inhibitor and free-radical scavenger.

Mode of action

Allopurinol and its active metabolite oxipurinol inhibit xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine and xanthine to uric acid. Allopurinol also facilitates the incorporation of hypoxanthine and xanthine into DNA and RNA, further reducing serum uric acid concentrations. The drug has no anti-inflammatory, analgesic, or uricosuric actions.

Routes of administration/doses

The adult oral dose is 100–900 mg daily, adjusted according to the serum uric acid level. The serum urate levels begin to decrease 24–48 hours after the initiation of treatment; the maximum effect is observed after 1–3 weeks.

Toxicity/side effects

A skin rash may be followed by more severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions, as well as Stevens–Johnson syndrome, and/or generalized vasculitis, irreversible hepatotoxicity, and rarely death.

Kinetics

Absorption

Allopurinol is well absorbed when administered orally; the bioavailability by this route is 80–90%.

Distribution

The drug is not protein-bound in the plasma; the VD is 0.6 l/kg.

Metabolism

Allopurinol is rapidly converted to an active metabolite oxipurinol.

Excretion

Occurs predominantly in the urine for both allopurinol and oxipurinol; some 20% is excreted in faeces. The clearance of allopurinol is 680 ml/min/kg, and the elimination half-life is 1–3 hours.

Special points

An adequate urine output should be ensured during treatment with the drug; the dose of allopurinol should be reduced in the presence of severe renal impairment.

Allopurinol may protect against stress-induced gastric mucosal injury by scavenging oxygen-derived free radicals.

The drug and its metabolites are removed by haemodialysis.

Amiloride

Uses

Amiloride is used in the treatment of:

  1. 1. oedema of cardiac, renal, or hepatic origin

  2. 2. hypertension, and

  3. 3. in combination with loop or thiazide diuretics to conserve potassium.

Chemical

A pyrazinoylguanidine.

Presentation

As 5 mg tablets of amiloride hydrochloride and in various fixed-dose combinations with thiazide or loop diuretics.

Main action

Diuretic.

Mode of action

Amiloride selectively blocks sodium reabsorption in the distal convoluted tubule. As a result of the inhibition of Na+ transport, the electrical potential across the tubular epithelium decreases, and potassium ion (K+) excretion is inhibited. The net result is a slight increase in renal Na+ excretion and a decrease in excessive K+ excretion. Amiloride has been shown to decrease the enhanced urinary excretion of magnesium which occurs when a thiazide or loop diuretic is used alone.

Routes of administration/doses

The adult oral dose is 10–20 mg daily. The diuretic effect commences within 2 hours and lasts 24 hours.

Effects

CVS

With chronic use, amiloride causes a slight decrease in the systolic and diastolic blood pressures, probably due to a reduction in the Na+ content of arteriolar smooth muscle, producing a decrease in the systemic vascular resistance.

GU

The principal effect is diuresis, with an increased rate of Na+ and bicarbonate ion excretion and a decreased rate of K+, calcium (Ca2+), and ammonium and hydrogen ion excretion. The drug has no effect on free water clearance.

Metabolic/other

The inhibition of hydrogen ion excretion leads to a slight alkalinization of the urine; serum uric acid concentrations are also increased, following the administration of amiloride. A metabolic acidosis may occur.

Toxicity/side effects

The most significant side effect of the drug is hyperkalaemia; other reported side effects, although rare, occur infrequently. These include nausea and vomiting, abdominal pain, diarrhoea, rashes, cramps, CNS and haemopoietic disturbances, impotence, and interstitial nephritis.

Kinetics

Absorption

Amiloride is incompletely absorbed when administered orally; the bioavailability by this route is 50%.

Distribution

The drug is 5% protein-bound in the plasma; the VD is 5 l/kg.

Metabolism

No metabolism of the drug occurs in man.

Excretion

50% of the dose is excreted unchanged in the urine, the remainder in faeces. The clearance is 264–372 ml/min, and the elimination half-life is 18–24 hours (this is prolonged to 140 hours in the presence of renal failure).

Special points

Amiloride inhibits the excretion of co-administered digoxin; concurrent NSAID therapy tends to obtund the diuretic and antihypertensive effects of the drug.

Aminoglycosides

Uses

Aminoglycosides are used in the treatment of:

  1. 1. respiratory tract infections

  2. 2. urinary tract infections

  3. 3. skin and soft tissue infections

  4. 4. ocular infections

  5. 5. intra-abdominal sepsis

  6. 6. septicaemia

  7. 7. neutropenic sepsis

  8. 8. severe neonatal infections

  9. 9. CNS sepsis, and

  10. 10. as surgical prophylaxis.

Chemical

Aminocyclitol ring derivatives bound to amino sugars.

Presentation

Aminoglycosides in clinical use include gentamicin, amikacin, streptomycin, and neomycin. Gentamicin is available in a liquid form for topical use (ear/eye drops), in an intravenous form, and in a form suitable for intrathecal or intraventricular administration. Amikacin is available for intravenous use only. Neomycin is available in topical formulations combined with steroid (eye/ear/nasal drops; creams/ointments) or in tablet form. Streptomycin is available for intramuscular injection.

Main action

Aminoglycosides are active against:

  1. 1. Gram-positive bacteria (limited activity against streptococci spp.)

  2. 2. Gram-negative bacteria.

These agents are not active against anaerobic bacteria. Acquired resistance is common due to plasmid translocation. Streptomycin is active against Mycobacterium tuberculosis. Neomycin is a bowel-sterilizing agent when administered orally.

Mode of action

Aminoglycosides bind irreversibly to specific bacterial ribosomal proteins (30S subunit) and inhibit protein synthesis by interfering with the initiation of the polypeptide chain and by inducing misreading of messenger RNA (mRNA).

Routes of administration/doses

Aminoglycosides may be administered topically as eye, ear, or nasal drops, as creams or ointments, orally (neomycin), intravenously, or via the intrathecal/intraventricular route. The specific dose, route, and frequency of an agent administered is dependent on the clinical indication, age of the patient, and particular agent being used. Doses should be reduced in patients with renal impairment. Drug doses should be modified using drug level monitoring and trends in renal function.

Toxicity/side effects

Ototoxicity (with vestibular and auditory components) and nephrotoxicity (a form of acute tubular necrosis occurring 5–7 days after exposure) are the most serious side effects of the drug, and both are correlated with high trough concentrations of aminoglycosides. Headaches, nausea and vomiting, rashes, and abnormalities of liver function tests have also been reported in association with the use of these agents.

Kinetics

Absorption

Aminoglycosides are not significantly absorbed when administered orally due to their low lipid solubility; approximately 3% of neomycin is absorbed. The drugs are not inactivated within the gastrointestinal tract.

Distribution

The VD for gentamicin is 0.14–0.7 l/kg, and that for amikacin is 0.34 l/kg. The percentage of drug bound to plasma proteins is 70–85% for gentamicin and <20% for amikacin. High concentrations are found within the renal cortex. The CSF is poorly penetrated by these agents. Streptomycin penetrates tuberculous cavities well.

Metabolism

Aminoglycosides undergo minimal metabolism in man.

Excretion

Aminoglycosides are excreted unchanged almost completely by glomerular filtration. The clearance of gentamicin is 1.18–1.32 ml/kg/min, and that of amikacin is 1.42 ml/kg/min. The half-life of gentamicin and amikacin is 2–3 hours (which markedly increases as the renal function deteriorates).

Special points

Monitoring of drug levels of gentamicin and amikacin should follow local guidelines. Trough samples are taken immediately before a dose, and peak levels an hour after drug administration. Gentamicin and amikacin are removed by haemofiltration and dialysis.

Direct administration of gentamicin into the CSF via an indwelling extraventricular drain can be undertaken in the treatment of ventriculitis.

Neomycin has been used in the treatment of hepatic coma.

Aminoglycosides prolong the action of non-depolarizing muscle relaxants by inhibiting pre-synaptic acetylcholine release and stabilizing the post-synaptic membrane at the neuromuscular junction. This effect may be reversed by the administration of intravenous calcium. These agents should be used with caution in patients with myasthenia gravis.

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

Aminoglycosides exhibit synergy with other antibiotics, e.g. in the treatment of pneumonia and subacute bacterial endocarditis.

Aminophylline

Uses

Aminophylline is used in the treatment of:

  1. 1. asthma

  2. 2. chronic obstructive airways disease, and

  3. 3. heart failure.

Chemical

The ethylenediamine salt of theophylline (a methylated xanthine derivative).

Presentation

As tablets containing 100/225/350 mg of aminophylline, as 180/360 mg suppositories, and as a clear solution for injection containing 25 mg/ml of aminophylline.

Main action

Bronchodilatation associated with an increased ventilatory response to hypoxia and hypercapnia. It has been shown to improve diaphragmatic contractility.

Mode of action

Aminophylline acts by inhibiting a magnesium-dependent phosphodiesterase, the enzyme responsible for the degradation of cAMP. The drug has a synergistic effect with those catecholamines which directly activate adenylate cyclase and lead to an increase in the intracellular concentration of cAMP. In addition, aminophylline interferes with the influx of Ca2+ into smooth muscle cells and stabilizes mast cells by antagonizing the action of adenosine.

Routes of administration/doses

The adult daily oral dose is 900 mg, administered in 2–3 divided doses, and the rectal dose 360 mg daily, titrated according to response. The loading dose by the intravenous route is 5 mg/kg over 10–15 minutes; this may be followed by a maintenance infusion of 0.5 mg/kg/hour. An intravenous loading dose should be administered with extreme caution to patients already receiving oral or rectal aminophylline. The therapeutic range is narrow (10–20 micrograms/ml), and estimations of the plasma concentration of aminophylline are valuable during chronic therapy.

Effects

CVS

The drug has mild positive inotropic and chronotropic effects, producing an increase in the cardiac output and a decrease in the systemic vascular resistance, thus leading to a decrease in the arterial blood pressure. The left ventricular end-diastolic pressure and pulmonary capillary wedge pressure tend to decrease with the use of the drug. Aminophylline is arrhythmogenic at the upper extremes of its therapeutic range; it is synergistic with halothane in this respect.

RS

Aminophylline causes bronchodilatation, leading to an increase in the vital capacity. It also increases the sensitivity of the respiratory centre to CO2 and increases diaphragmatic contractility. Intravenous administration of the drug inhibits hypoxic pulmonary vasoconstriction and necessitates the administration of oxygen during therapy.

GU

Aminophylline increases the renal blood flow and glomerular filtration rate and decreases renal tubular sodium absorption, leading to a diuretic effect.

Metabolic/other

Hypokalaemia may occur, secondary to the diuretic effect and also to increased cellular uptake of potassium. Abnormalities of liver function tests and inappropriate ADH secretion are also recognized effects of the drug.

Toxicity/side effects

Gastrointestinal and CNS disturbances (including convulsions after rapid intravenous administration) and cardiac dysrhythmias (including ventricular fibrillation) may occur, especially with plasma concentrations in excess of 20 micrograms/ml.

Kinetics

Absorption

Aminophylline is rapidly absorbed when administered orally and has a bioavailability by this route of 88–96%. Rectal absorption is slow and erratic.

Distribution

The drug is 50–60% protein-bound in the plasma; the VD is 0.4–0.5 l/kg.

Metabolism

Occurs in the liver by demethylation and oxidation; a 3-methyl xanthine derivative is active.

Excretion

Demethylated metabolites are excreted in the urine; 10–13% of the dose is excreted unchanged. The clearance is 0.83–1.16 ml/min/kg; this is decreased in the presence of heart failure, liver disease, and in the elderly. Saturation of the metabolic pathways occurs near the therapeutic range; whilst obeying zero-order kinetics, the elimination half-life varies with the dose. Under conditions of first-order kinetics, the elimination half-life is 8 hours.

Special points

Co-administration of cimetidine, propranolol, or erythromycin will elevate plasma concentrations of aminophylline; conversely, co-administration of barbiturates, alcohol, or phenytoin will decrease plasma concentrations of aminophylline. The site of these interactions is at cytochrome P450. In high concentrations, the drug will antagonize non-depolarizing neuromuscular blockade.

Aminophylline infusion shortens the recovery time from enflurane–nitrous oxide (N2O) anaesthesia.

Amiodarone

Uses

Amiodarone is used in the treatment of:

  1. 1. tachydysrhythmias inappropriate for, or resistant to, other drugs and

  2. 2. those associated with the Wolff–Parkinson–White syndrome.

Chemical

An iodinated benzofuran derivative.

Presentation

As 100/200 mg tablets of amiodarone hydrochloride and in ampoules and prefilled syringes containing 30/50 mg/ml of amiodarone hydrochloride for injection.

Main action

A class III antiarrhythmic agent.

Mode of action

Amiodarone acts by partial antagonism of alpha- and beta-agonists by reducing the number of receptors or by inhibiting the coupling of receptors to the regulatory subunit of the adenylate cyclase system. In addition, the drug has a direct action in isolated myocardial preparations to decrease the delayed slow outward potassium current and, in higher doses, additionally depresses the fast and slow inward currents which are due to sodium and calcium, respectively.

Routes of administration/doses

The initial intravenous dose is 5 mg/kg, administered by infusion diluted in 250 ml of 5% glucose over 20–120 minutes via a central vein (the drug carrier is highly irritant). Most patients respond to an intravenous loading dose within 1 hour. Subsequently, 15 mg/kg/day may be administered intravenously if oral administration is not desirable or feasible. The adult oral dose is initially 200 mg 8-hourly, reducing to 100–200 mg daily after 1 week. The therapeutic level is 0.1 micrograms/ml.

Effects

CVS

Sinus rhythm is slowed by 15%, secondary to a reduction in the slow diastolic depolarization in nodal cells after the administration of amiodarone. AV nodal automaticity is depressed, and AV nodal conduction is slowed by 25% in the face of atrial tachycardia due to a decreased speed of depolarization of cells and an increase in the duration of the action potential. Amiodarone has no effect on conduction in the His bundle or ventricular myocardium. After oral administration, little effect is seen on the blood pressure or left ventricular contractility; the systemic vascular resistance decreases, and coronary sinus blood flow increases. After intravenous administration, left ventricular contractility may decrease; the effects are otherwise similar to those observed after oral administration.

Metabolic/other

Abnormalities of liver function tests occur in up to 50% of patients; abnormalities of thyroid function tests may also occur due to inhibition of triiodothyronine and enhancement of reverse triiodothyronine production.

Toxicity/side effects

Almost all patients receiving amiodarone develop corneal microdeposits, and one-third develop signs of CNS toxicity. Pneumonitis, cirrhosis, peripheral neuropathy, photosensitivity, and gastrointestinal upsets are well-recognized complications. Hypotension, cardiovascular collapse, and AV block have been reported after intravenous injection. Other dysrhythmias may arise, especially in the presence of hypokalaemia.

Kinetics

Absorption

The drug is incompletely absorbed after oral administration and has a bioavailability of 22–86%.

Distribution

Amiodarone is 96–98% protein-bound in the plasma; the VD is 1.3–65.8 l/kg, according to the dose.

Metabolism

The metabolic pathways of amiodarone have not been fully elucidated; it appears to be extensively metabolized in the liver, the major metabolite being desethyl-amiodarone which has antiarrhythmic properties and is cumulative.

Excretion

1–5% of the dose appears in the urine; the drug appears to be extensively excreted in the bile and faeces. The clearance is 0.14–0.6 l/min, and the elimination half-life has been estimated at 4 hours to 52 days, depending on the dose and route of administration.

Special points

Modification of the dose is not required in the presence of renal impairment; amiodarone is not removed by haemodialysis. The actions of digoxin, calcium antagonists, oral anticoagulants, and beta-adrenergic antagonists may be potentiated by amiodarone due to displacement from plasma proteins. Bradycardia, and complete and AV heart block resistant to atropine, adrenaline, and noradrenaline have been reported in patients receiving amiodarone undergoing general anaesthesia; it has been suggested that such patients may require temporary pacing in the perioperative period.

The drug is contraindicated in porphyria.

Amitriptyline

Uses

Amitriptyline is used for the treatment of:

  1. 1. depression

  2. 2. nocturnal enuresis, and

  3. 3. can be used as an adjunct in the treatment of chronic pain syndromes, including chronic tension headache, post-herpetic neuralgia, painful neuropathies, and chronic spinal syndromes.

Chemical

A dibenzocycloheptadiene derivative.

Presentation

As tablets containing 10/25/50 mg and a clear, colourless solution for injection containing 10 mg/ml of amitriptyline hydrochloride. A syrup containing 2 mg/ml of amitriptyline embonate is also available.

Main actions

Antidepressant, sedative, and analgesic.

Mode of action

Tricyclic antidepressants potentiate the action of biogenic amines within the CNS by inhibiting the pre-synaptic reuptake of noradrenaline and serotonin. They also antagonize muscarinic cholinergic, alpha-1 adrenergic, and H1 and H2 histaminergic receptors.

Routes of administration/doses

The adult oral dose is initially 75–150 mg/day, decreasing to 50–100 mg/day for maintenance. The corresponding parenteral dose is 10–20 mg 6-hourly. The drug takes from 3 to 30 days to become fully effective.

Effects

CVS

In high doses, amitriptyline may cause postural hypotension, tachycardia, dysrhythmias, and an increase in the conduction time through the AV node.

RS

The drug may cause respiratory depression when administered in toxic doses.

CNS

The predominant effect of the drug is an antidepressant action which may take several weeks to develop; sedation, weakness, and fatigue are also commonly produced.

Toxicity/side effects

A wide spectrum of cardiovascular, CNS, gastrointestinal, and haematological disturbances may complicate the use of amitriptyline. Anticholinergic side effects (blurred vision, dryness of the mouth, constipation, and urinary retention) tend to predominate.

Kinetics

Absorption

The drug is rapidly absorbed when administered orally; the bioavailability is 45% by this route.

Distribution

Amitriptyline is 95% protein-bound in the plasma; the VD is 18–22 l/kg.

Metabolism

Occurs by N-demethylation and hydroxylation, with subsequent conjugation to glucuronide and sulfate. Nortriptyline is an intermediate active metabolite.

Excretion

The conjugates are excreted in the urine. The clearance is 9.7–15.3 ml/min/kg, and the elimination half-life is 12.9–36.1 hours.

Special points

Hyoscine and the phenothiazines displace tricyclic antidepressants from their binding sites on plasma proteins and thus increase the activity of the latter; barbiturates increase the rate of hepatic metabolism of tricyclic antidepressants and decrease their activity. Amitriptyline accentuates the cardiovascular effects of adrenaline; care should be exercised when local anaesthetic agents containing adrenaline are used in patients receiving the drug. Amitriptyline also increases the likelihood of dysrhythmias and hypotension occurring during general anaesthesia.

Amoxicillin

Uses

Amoxicillin is used in the treatment of:

  1. 1. ear, nose, and throat, and respiratory tract infections

  2. 2. urinary tract infections, including gonorrhoea

  3. 3. septicaemia

  4. 4. gastroenteritis

  5. 5. endocarditis, and

  6. 6. meningitis.

Chemical

An aminopenicillin derivative of ampicillin.

Presentation

Amoxicillin is available in the following formulations:

  1. 1. in vials containing 250/500/1000 mg of amoxicillin sodium

  2. 2. in sachets containing 3 g of amoxicillin trihydrate for reconstitution

  3. 3. in capsules containing 250/500 mg of amoxicillin trihydrate

  4. 4. as a suspension containing 125 mg of amoxicillin trihydrate per 1.25 ml

  5. 5. as a syrup containing 125 mg/5 ml and 250 mg/5 ml of amoxicillin trihydrate.

The drug is also available in a variety of formulations in combination with the beta-lactamase inhibitor clavulanic acid as co-amoxiclav.

Main actions

Amoxicillin is bactericidal against a wide range of organisms, including some strains of the Gram-negative Haemophilus influenzae and Escherichia coli (benzylpenicillin showing lower activity against these species), Proteus mirabilis, Bordetella pertussis, and Neisseria, Salmonella, and Shigella spp. The drug is nearly always effective against the Gram-positive Streptococcus and Clostridium spp. (not Clostridium difficile). Ninety percent of staphylococci are resistant. It is ineffective against Pseudomonas and Klebsiella spp. and penicillinase-producing organisms. The addition of clavulanic acid reduces the minimum inhibitory concentration (MIC) against the following organisms: Staphylococcus aureus, Escherichia coli, Haemophilus influenzae, and Klebsiella spp.

Mode of action

Amoxicillin acts in the manner typical of penicillins; it binds to penicillin-binding proteins (PBPs) in the bacterial cell wall and inhibits pentapeptide cross-linking during its formation, resulting in cell wall disruption.

Route of administration/doses

The adult oral dose is 250–500 mg 8-hourly, and the corresponding parenteral dose is 500 mg 8-hourly, increased to 1 g 6-hourly in severe infections. Drug dosage and frequency may be modified on an individual patient basis in the treatment of severe infections.

Toxicity/side effects

Allergic phenomena, gastrointestinal upsets, interstitial nephritis, and haemopoietic disturbances may complicate the use of the drug. Amoxicillin and clavulanic acid use are associated with the late development of cholestatic jaundice.

Kinetics

Absorption

The drug is rapidly absorbed when administered orally; the bioavailability by this route is 72–94%. The bioavailability of clavulanic acid is approximately 60%, although it exhibits marked variability between individuals.

Distribution

Amoxicillin is 17–20% protein-bound in the plasma, predominantly to albumin; the VD is 0.3–0.4 l/kg. Clavulanic acid is 22% protein-bound; the VD is 0.2 l/kg.

Metabolism

30% is metabolized in the liver. Clavulanic acid undergoes 50–70% hepatic metabolism.

Excretion

The clearance of amoxicillin is 250–370 ml/min, and the elimination half-life is 61.3 min. Forty percent of clavulanic acid undergoes renal elimination (18–35% as unchanged drug). It has a clearance of 260 ml/min and an elimination half-life of approximately 1 hour.

Special points

A reduced dosing frequency should be considered in patients with severe renal impairment. Both amoxicillin and clavulanic acid are removed by haemodialysis.

Amphotericin

Uses

Amphotericin is used in the treatment of life-threatening systemic fungal infections, especially disseminated candidosis, coccidiomycosis, histoplasmosis, aspergillosis, and cryptococcosis. Amphotericin may also be administered orally for selective decontamination of the gut.

Chemical

Amphotericin is a mixture of two polyene macrolides (amphotericin A and B) produced by Streptomyces nodosus.

Presentation

As 100 mg tablets and a yellow powder in vials containing 50 000 units of amphotericin (with sodium deoxycholate which solubilizes amphotericin); the mixture forms a colloidal suspension in water; as a yellow opaque suspension of 5 mg/ml of amphotericin B complexed with two phospholipids in a 1:1 drug-to-lipid molar ratio with a ribbon-like structure, pH 5–7; as liposomal amphotericin, a lyophilized 50 mg product presentation where the 100-nm liposomes are created, so that the amphotericin is intercalated within the unilamellar bilayer structure; as an elongated disc structure, 100 nm in diameter, in a 1:1 molar ratio of amphotericin B and cholesteryl sulfate in 50 and 100 mg vials, presented in lyophilized powder for reconstitution to form a colloidal dispersion.

Main actions

Amphotericin is a fungistatic antibiotic which is active against a wide range of yeasts and yeast-like fungi, including Candida albicans.

Mode of action

The drug binds to cell membrane sterols, leading to altered membrane permeability to univalent ions, water, and small non-electrolyte molecules. Leakage of intracellular components occurs; cell growth is inhibited, and cell death may result. Amphotericin binds preferentially to sterols (especially ergosterol) in fungal cell membranes, although it does bind to sterols (especially cholesterol) in animal cell membranes where it exerts similar effects.

Routes of administration/doses

Amphotericin is administered by slow intravenous infusion (via a dedicated vein), diluted in 5% glucose, over 6 hours; the daily dose is 0.25–1.5 mg/kg, and treatment will usually be required for a period of several weeks. Intrathecal, topical, and nebulized administrations of the drug have also been described.

Effects

GU

Deterioration of renal function leading to hypokalaemia, renal tubular acidosis, or nephrocalcinosis occurs in >80% of patients who receive the drug; this is usually reversible but may need renal replacement therapy.

Metabolic/other

The drug may decrease serum magnesium levels. Amphotericin may alter immune function (especially that of T cells and monocytes) and thereby potentiate host defences.

Toxicity/side effects

The list of side effects reported with the use of amphotericin is lengthy. Gastrointestinal upsets (anorexia, nausea and vomiting, loss of weight), haematological impairment (anaemia, thrombocytopenia, leucopenia), and disturbances of the CNS (headache, muscle pains, vision disturbances, hearing loss, convulsions, peripheral neuropathy) may occur. The drug may also cause fever and phlebitis; acute dysrhythmias have also been reported.

Kinetics

The assay only distinguishes amphotericin B.

Absorption

The drug is poorly absorbed when administered orally.

Distribution

Amphotericin is 90–95% bound in the plasma to lipoproteins; the VD is 3.6–4.4 l/kg.

Metabolism

The metabolic pathway of amphotericin has not been established; the liver appears to be the principal site of metabolism.

Excretion

The drug is predominantly excreted in the urine, 2–5% unchanged. The dose should be reduced in the presence of renal impairment, as continued use of the drug may lead to further renal impairment. The clearance is 0.35–0.51 ml/min/kg, and the elimination half-life is 15 days. The high clearance and large VD indicate tissue uptake, and the long half-life indicates slow redistribution from tissues. Non-linear behaviour occurs with increasing dosage.

Special points

Liposomal encapsulation or incorporation into a lipid complex can substantially affect the action of amphotericin, compared to the free drug. There is a theoretical risk of amphotericin enhancing the effect of non-depolarizing relaxants and digoxin, secondary to the hypokalaemia that the former produces. Liposomal amphotericin (amphotericin incorporated into unilamellar liposomes) is safe, effective, and better tolerated, but may cause disordered liver function tests. The drug is poorly dialysable.

Aspirin

Uses

Aspirin is used:

  1. 1. for the treatment of pain of mild to moderate severity and severe bone pain

  2. 2. as an anti-inflammatory agent, e.g. in rheumatoid arthritis and osteoarthritis

  3. 3. as an antipyretic

  4. 4. for the prevention of recurrence after myocardial infarction

  5. 5. for the prevention of graft occlusion after coronary artery surgery

  6. 6. in the treatment of pre-eclampsia

  7. 7. for the prevention of transient ischaemic attacks, and

  8. 8. deep vein thrombosis (DVT) prophylaxis post-fractured neck of femur.

Chemical

An aromatic ester of acetic acid.

Presentation

As 75/100/300/600 mg tablets of aspirin and in a variety of fixed-dose combinations.

Main actions

Antipyretic, analgesic, and anti-inflammatory.

Mode of action

Aspirin acetylates, and thereby inhibits, the enzyme cyclo-oxygenase (COX) which converts arachidonic acid to cyclic endoperoxides, thus preventing the formation of prostaglandins and thromboxanes. Prostaglandins are involved in the sensitization of peripheral pain receptors to noxious stimuli. It may also inhibit the lipo-oxygenase pathway by an action on hydroperoxy fatty acid peroxidase. The drug inhibits cyclo-oxygenase irreversibly in platelets, but not in the endothelium.

Routes of administration/doses

The adult oral dose is 300–900 mg, 6- to 8-hourly; aspirin is not recommended for use in children under 12 years of age.

Effects

CVS

Aspirin has minimal haemodynamic effects at normal doses; however, platelet aggregation is inhibited, and bleeding time is increased by a decrease in thromboxane A2 production (with large doses, the concentration of prothrombin is decreased).

RS

Therapeutic doses of aspirin increase oxygen consumption and CO2 production by uncoupling oxidative phosphorylation. Overdosage may lead to hyperventilation (by a direct action of the drug on the respiratory centre), pulmonary oedema, and respiratory failure.

CNS

The analgesic effect of the drug appears to be exerted by both central and peripheral mechanisms; the antipyretic effect may be a manifestation of inhibition of prostaglandin synthesis at the hypothalamic level.

AS

Aspirin increases gastric acid production.

GU

The drug may cause proteinuria and an increase in the number of renal tubular casts appearing in the urine. Aspirin is uricosuric in high doses but paradoxically decreases urate excretion at low doses.

Metabolic/other

Blood sugar tends to decrease with low doses and increase with high doses of aspirin. Transient elevation of serum urea concentrations and elevation of liver enzymes may occur. Lipogenesis is decreased; very large doses of aspirin stimulate steroid secretion.

Toxicity/side effects

Gastrointestinal upsets occur in 2–6%; haemorrhage and gastric ulceration occur in about 1 in 10 000 of habitual users of aspirin. Large doses of the drug taken over a prolonged period may cause hepatic impairment and renal papillary necrosis, leading to chronic renal failure. Allergic response (including bronchospasm), CNS disturbances, and aplastic anaemia may also occur. The use of aspirin is associated with the development of Reye’s syndrome in children.

Kinetics

Absorption

Aspirin is rapidly and completely absorbed from the upper gastrointestinal tract and has a bioavailability of 70% due to an extensive first-pass metabolism.

Distribution

Aspirin is rapidly hydrolysed to salicylic acid; the pharmacokinetics are of this compound. Salicylic acid is 80–90% protein-bound in the plasma, primarily to albumin. The VD is 9.6–12.71. The drug has only a limited ability to cross the blood–brain barrier.

Metabolism/excretion

At therapeutic doses, 50% of salicylic acid is metabolized to salicylurate in the liver via a saturable enzyme pathway. A further 20% is metabolized to salicylphenolic glucuronide which is also a saturable pathway. First-order kinetics occurs with the metabolic pathways of salicylacyl glucuronide (10%) and gentisic acid (5%) production and with the urinary excretion of salicylic acid (15%). Due to the two saturable metabolic pathways, the elimination of salicylic acid obeys non-linear kinetics, i.e. the half-life varies with the dose administered.

Special points

Salicylates may increase the effect of co-administered oral anticoagulants and sulfonylureas due to displacement from plasma proteins.

Overdosage with aspirin has a mortality of 1–2% and may result in respiratory alkalosis or metabolic acidosis, according to the age of the patient and the time of ingestion. Alkalization of the urine increases the excretion of free salicylic acid; the fraction of free drug may increase from 5 to 85%. This principle is used in forced alkaline diuresis, and aspirin is removed by haemodialysis. A normal bleeding time should be demonstrated before embarking upon spinal or epidural anaesthesia in patients receiving aspirin.

Preoperative ingestion of aspirin is associated with increased blood loss during open heart surgery and prostatectomy.

Atenolol

Uses

Atenolol is used in the treatment of:

  1. 1. hypertension

  2. 2. angina

  3. 3. tachydysrhythmias, and

  4. 4. in the acute phase of myocardial infarction and prevention of reinfarction.

Chemical

A phenoxypropanolamine.

Presentation

As 25/50/100 mg tablets (and in fixed-dose combinations with nifedipine, amiloride, and chlortalidone), a 0.5% syrup, and as a clear, colourless solution for injection containing 0.5 mg/ml of atenolol.

Main action

Atenolol is negatively inotropic and chronotropic, leading to a fall in myocardial oxygen consumption; it also has antihypertensive and antiarrhythmic properties.

Mode of action

Atenolol acts by reversible, competitive blockade of cardiac beta-1 receptors and also has some action at beta-2 receptors.

Routes of administration/doses

The adult oral dose is 50–100 mg daily. Intravenously, 2.5–10 mg may be administered at a rate of 1 mg/min until the desired effect is achieved.

Effects

CVS

Sinus node automaticity and AV nodal conduction are decreased. The effective refractory periods of the atrial and AV nodes are all increased by the administration of atenolol. No effect is seen on conduction in the His–Purkinje system or the effective refractory period of the ventricles. The ensuing negative inotropic and chronotropic effects lead to a decrease in myocardial oxygen consumption. Atenolol has no intrinsic sympathomimetic activity. The drug has a prolonged antihypertensive effect and can lead to regression of left ventricular hypertrophy in hypertensive patients.

RS

Little effect is seen on lung function due to the cardioselectivity of atenolol.

CNS

Poor CNS penetration means that little effect is seen; however, sleep disturbances and vivid dreams have been reported.

GU

A clinically insignificant elevation in serum urea or creatinine may be produced by the drug.

Metabolic/other

The plasma triglyceride levels may increase, and high-density lipoprotein (HDL) cholesterol levels may decrease, following the use of atenolol.

Toxicity/side effects

The side effects are predictable manifestations of the pharmacological effects of the drug: exacerbation of peripheral vascular disease, bronchospasm, masking of the signs of hypoglycaemia, depression, impotence, and altered bowel habit. The precipitation of heart failure by atenolol is rare.

Kinetics

Absorption

The oral bioavailability is 50%.

Distribution

Atenolol is 3% protein-bound in the plasma; the VD is 0.7 l/kg.

Metabolism

<10% is metabolized in the liver.

Excretion

The drug is excreted largely unchanged in the urine. The clearance is 77 ml/min/kg (which is decreased in the presence of renal failure), and the elimination half-life is 6–9 hours.

Special points

The dosage should be reduced in renal failure if the glomerular filtration is <35 ml/min; the drug is readily dialysable.

Beta-blockade should be continued throughout the perioperative period; a single preoperative dose of atenolol may be as valuable as chronic treatment in the anaesthetic management of patients with borderline hypertension and in decreasing the hypertensive response to intubation and subsequent dysrhythmias. Beta-blockade may improve perioperative mortality from cardiovascular events.

Atracurium

Uses

Atracurium is used to facilitate intubation and controlled ventilation.

Chemical

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

Presentation

As a clear, colourless or pale yellow solution for injection available in 2.5 ml, 5 ml, and 25 ml vials, containing 10 mg/ml of atracurium besilate (equivalent to atracurium 7.5 mg/ml), needing to be stored at 2–8°C. It has a pH of between 3.25 and 3.65.

Main action

Competitive, non-depolarizing neuromuscular blockade.

Mode of action

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

Routes of administration/doses

The drug is administered intravenously. The ED95 of atracurium is estimated to be 0.23 mg/kg. An initial dose of 0.3–0.6 mg/kg is recommended, providing muscle relaxation for between 15 and 35 minutes. Endotracheal intubation can be achieved within 90–120 seconds of an intravenous dose of 0.5–0.6 mg/kg, with maximal resultant neuromuscular blockade achieved within 3–5 minutes following administration. Ninety-five percent recovery of the twitch height occurs within approximately 35 minutes. Maintenance of neuromuscular blockade may be achieved with bolus doses of 0.1–0.2 mg/kg. Atracurium may be administered by intravenous infusion at a rate of 0.3–0.6 mg/kg/hour, although there is wide inter-patient variability in dosage requirements, particularly in patients on ventilation in intensive care. Induced hypothermia to a temperature of approximately 25°C reduces the rate of metabolism of atracurium. Consequently, neuromuscular block can be maintained with approximately half the original infusion rate. The drug is non-cumulative with repeated or continuous administration. Ninety-five percent recovery of twitch height, following a single dose of atracurium, occurs within 35 minutes.

Effects

CVS

Atracurium has minimal cardiovascular effects; there is a change of <5% in the heart rate, mean arterial pressure, systemic vascular resistance, central venous pressure, and pulmonary capillary wedge pressure, following administration of the drug. The incidence of transient hypotension ranges from 1% to 14% in clinical trial data using doses of 0.3–0.6 mg/kg or greater.

RS

Bronchospasm may occasionally occur, secondary to histamine release, in approximately 0.2% of patients.

CNS

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

AS

Lower oesophageal sphincter pressure is unaffected by administration of atracurium.

Toxicity/side effects

Histamine release may occur (by up to 92%) if doses >0.6 mg/kg are used, leading to cutaneous flushing (2–3%), hypotension, and bronchospasm. Bradycardia has been reported, following the administration of atracurium. There have been rare reports of fatal anaphylactoid reactions with the administration of atracurium. Cross-sensitivity may exist with vecuronium, rocuronium, and pancuronium. Administration of atracurium by intravenous infusion to critically ill patients on intensive care has been associated with the development of a critical illness neuropathy/myopathy.

Kinetics

Distribution

Atracurium is 82% protein-bound in the plasma; the VD is 0.16–0.18 l/kg. The drug does not cross the blood–brain barrier. Atracurium does cross the placenta, but not in clinically significant amounts.

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 monoacrylate. 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 neuromuscular-blocking (NMB) activity.

Excretion

The clearance is 5.1–6.1 ml/kg/min, and the elimination half-life is 17–21 minutes; these parameters are little altered by renal or hepatic impairment, and no alteration in dose is necessary in these patients.

Special points

The duration of action of atracurium, 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 (isoflurane increases the activity by up to 35%), induction agents (including ketamine), fentanyl, suxamethonium, diuretics, calcium channel blockers, alpha- and beta-adrenergic antagonists, protamine, lidocaine, metronidazole, and the aminoglycoside antibiotics. Patients with burns may develop resistance to the effect of atracurium. The onset of neuromuscular blockade is likely to be lengthened and the duration of action shortened in patients receiving chronic anticonvulsant therapy. The use of atracurium appears to be safe in patients susceptible to malignant hyperpyrexia.

Laudanosine (in concentrations >17 micrograms/ml) has been shown to cause seizures in animal models and becomes measurable in patients who have received atracurium by infusion for 6 days; the clinical significance of this is unclear. Haemofiltration has a minimal effect on plasma levels of atracurium or laudanosine. The stereoisomer cisatracurium causes less histamine release and is available commercially. Atracurium, due to its acidic pH, should not be mixed with alkaline solutions (e.g. barbiturates).

Atropine

Uses

Atropine is used:

  1. 1. traditionally to dry secretions prior to ether or chloroform anaesthesia (nowadays when a dry airway is desirable, especially in children under 1 year of age)

  2. 2. to counter bradycardia due to increased vagal tone

  3. 3. to counter the muscarinic effects of anticholinergic agents

  4. 4. during cardiopulmonary resuscitation

  5. 5. as a cycloplegic

  6. 6. as a constituent of cold cures, and

  7. 7. in the treatment of organophosphorus poisoning and

  8. 8. tetanus.

Chemical

An alkaloid from Atropa belladona; atropine is a tertiary amine which is the ester of tropic acid and tropine. Commercial atropine is the racemic mixture of D- and I-hyoscyamine (I-form is active).

Presentation

As a clear, colourless solution for injection containing 0.5/0.6 mg/ml and 3 mg in 10 ml of atropine sulfate; it is also available as 0.6 mg tablets.

Main action

Anticholinergic.

Mode of action

Atropine exerts its effects by competitive antagonism of acetylcholine at muscarinic receptors (having little effect at nicotinic receptors, except at high doses).

Routes of administration/doses

Atropine may be administered intramuscularly or intravenously in a dose of 0.015–0.02 mg/kg. The adult oral dose is 0.2–0.6 mg. A total of 3 mg is needed for complete vagal blockade in adults.

Effects

CVS

In low doses, atropine may produce an initial bradycardia (Bezold–Jarisch reflex), followed by tachycardia (the usual effect). The cardiac output is increased, but there is little effect on the blood pressure. Atropine decreases the AV conduction time and may produce dysrhythmias. Dilatation of facial capillaries may occur with the use of high doses.

RS

Atropine produces bronchodilation with an increase in the physiological dead space. Bronchial secretions are reduced by the drug. The respiratory rate is increased, and a decreased incidence of laryngospasm has been reported following the administration of the drug.

CNS

Central excitation or depression may occur (central anticholinergic syndrome). The syndrome is characterized by somnolence, confusion, amnesia, agitation, hallucinations, dysarthria, ataxia, or delirium. Atropine also has antiemetic and anti-parkinsonian actions.

AS

The drug reduces salivation, the volume of gastric secretions, and tone and peristalsis throughout the gut. Atropine has a mild antispasmodic action on the biliary tree. The lower oesophageal tone is reduced by the drug.

GU

Tone and peristalsis in the urinary tract are decreased.

Metabolic/other

Cycloplegia, mydriasis, and an increase in intraocular pressure may be produced by the drug. Sweating is inhibited, and the basal metabolic rate is increased. The drug suppresses ADH secretion. Atropine has local anaesthetic properties.

Toxicity/side effects

Atropine is painful when injected intramuscularly, and the sensation of a dry mouth is unpleasant. The central anticholinergic syndrome may occur in the elderly, and inhibition of sweating may lead to hyperpyrexia in children. Urinary retention may be precipitated by the drug. Glaucoma may result from ocular (but not intravenous or intramuscular) administration.

Kinetics

Absorption

Atropine is rapidly absorbed from the gut; the bioavailability by oral route is 10–25%.

Distribution

Atropine is 50% protein-bound in the plasma, the VD is 2.0–4.0 l/kg. The drug crosses the placenta and blood–brain barrier.

Metabolism

Atropine is hydrolysed in the liver and tissues to tropine and tropic acid.

Excretion

94% of the dose is excreted in the urine in 24 hours, some unchanged. The clearance is 70 l/hour, and the elimination half-life is 2.5 hours.

Special points

Atropine reduces the incidence and morbidity of oculocardiac crises.

Copyright © 2021. All rights reserved.