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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0008

Haloperidol

Uses

Haloperidol is used in the treatment of:

  1. 1. schizophrenia and related psychoses

  2. 2. nausea and vomiting

  3. 3. motor tics and hiccuping

  4. 4. acute confusional states and delirium in critical care and

  5. 5. for premedication and

  6. 6. palliative care.

Chemical

A butyrophenone derivative.

Presentation

As 0.5/1.5/5/10/20 mg tablets, 0.5 mg capsules, a syrup containing 2/10 mg/ml, and as a clear solution for injection containing 5 mg/ml of haloperidol. A depot preparation containing 50/100 mg/ml of haloperidol decanoate is also available.

Main action

Antiemetic and neuroleptic.

Mode of action

The antiemetic and neuroleptic 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. post-synaptic GABA antagonism.

Routes of administration/doses

The adult oral dose is 1–15 mg daily in divided doses. The initial intramuscular dose is 2–30 mg, with additional doses of 5 mg until the symptoms are controlled. The intravenous dose is 1–5 mg. The drug has a longer duration of action than droperidol.

Effects

CVS

Haloperidol has minimal cardiovascular effects, but its antagonistic effects at alpha-adrenergic receptors may lead to hypotension in the presence of hypovolaemia.

RS

The drug has minimal effect on respiration.

CNS

Haloperidol induces neurolepsis, a state characterized by diminished motor activity, anxiolysis, and indifference to the external environment. The seizure threshold is raised by the drug.

AS

The drug has a powerful antiemetic effect via a central effect at the chemosensitive trigger zone.

Metabolic/other

Haloperidol, in common with other dopamine antagonists, may cause hyperprolactinaemia.

Toxicity/side effects

Extrapyramidal effects occur relatively commonly during the use of haloperidol; these include the neuroleptic malignant syndrome (a complex of symptoms that include catatonia, cardiovascular lability, hyperthermia, and myoglobinaemia) which has a mortality in excess of 10%. Gastrointestinal and haemopoietic disturbances, abnormalities of liver function tests, and allergic phenomena have been reported after the use of the drug.

Kinetics

Absorption

The drug is well absorbed after oral administration; the bioavailability by this route is 50–88%.

Distribution

The drug is 92% protein-bound in the plasma; the VD is 18–30 l/kg.

Metabolism

Haloperidol is extensively metabolized in the liver; a reduced metabolite may be active.

Excretion

The clearance is 11.3 ml/min/kg, and the elimination half-life is 10–38 hours, dependent upon the route of administration.

Special points

Haloperidol is the preferred agent for the treatment of delirium in the critically ill adult. The sedative effects of the drug are additive with those of other CNS depressants administered concurrently. Hypotension resulting from the administration of the drug should not be treated using adrenaline, as a further decrease in the blood pressure may result.

Haloperidol is not removed by dialysis.

Halothane

Uses

Halothane is used for the induction and maintenance of general anaesthesia.

Chemical

A halogenated hydrocarbon containing bromine, chlorine, and fluorine.

Presentation

As a clear, colourless liquid (that should be protected from light) with a characteristic sweet smell. The commercial preparation contains 0.01% thymol which prevents decomposition on exposure to light; it is non-flammable at normal anaesthetic concentrations. The molecular weight of halothane is 197.4, the boiling point 50.2°C, and the saturated vapour pressure 32 kPa at 20°C. The MAC of halothane is 0.75 (0.29 in the presence of 70% N2O), the oil/water solubility coefficient 220, and the blood/gas solubility coefficient 2.5. The drug is readily soluble in rubber; it does not attack metals in the absence of water vapour but will attack brass, aluminium, and lead in the presence of water vapour.

Main actions

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

Mode of action

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

Routes of administration/doses

Halothane is administered by inhalation, conventionally via a calibrated vaporizer. The concentration used for the inhalational induction of anaesthesia is 2–4% and for maintenance 0.5–2%.

Effects

CVS

Halothane causes a dose-related decrease in myocardial contractility and cardiac output, with an attendant decrease in cardiac work and myocardial oxygen consumption, possibly by inhibition of Ca2+ flux within myocardial cells and of the interaction between Ca2+ and the contractile proteins. The heart rate decreases as a result of vagal stimulation; the systemic vascular resistance is decreased by 15–18%, leading to a decrease in systolic and diastolic blood pressures; halothane also obtunds the baroreceptor reflexes. The drug has little effect on coronary vascular resistance. The threshold potential and refractory period of myocardial cells are increased; the drug also decreases the rate of phase IV repolarization. Halothane causes marked sensitization of the myocardium to catecholamines, although it does not itself increase the concentration of circulating catecholamines.

RS

Halothane is a respiratory depressant, markedly decreasing the tidal volume, although the respiratory rate may increase. A slight increase in PaCO2 may result in spontaneously breathing subjects; the drug also decreases the ventilatory response to hypoxia and hypercapnia, and inhibits the mechanism of hypoxic pulmonary vasoconstriction. Halothane is non-irritant to the respiratory tract; it causes bronchodilatation by a direct effect on the bronchial smooth muscle and also inhibits histamine-induced bronchoconstriction. Bronchial secretions are reduced by the drug.

CNS

The principal effect of halothane is general anaesthesia; the drug has little, if any, analgesic effect. The drug causes cerebral vasodilation, leading to an increase in both the cerebral blood flow and intracranial pressure; it also decreases cerebral oxygen consumption. A centrally mediated decrease in the skeletal muscle tone results from the use of halothane.

AS

The drug decreases salivation and gastric motility; splanchnic blood flow decreases as a result of the hypotension the drug produces.

GU

Halothane decreases renal blood flow by 40% and the glomerular filtration rate by 50%; a small volume of concentrated urine results. The drug reduces the tone of the pregnant uterus.

Metabolic/other

Halothane decrease plasma noradrenaline concentration, whilst increasing the concentrations of thyroxine and growth hormone. It also inhibits leucocyte phagocytosis. The drug causes a fall in the body temperature, predominantly by cutaneous vasodilation. Halothane causes a significant decrease in NO synthase activity.

Toxicity/side effects

Halothane is a potent trigger agent for the development of malignant hyperthermia. The drug may also cause the appearance of myocardial dysrhythmias, particularly in the presence of hypoxia, hypercapnia, or excessive catecholamine concentrations. Shivering (‘halothane shakes’) may occur post-operatively. The most serious side effect halothane hepatitis occurs (rarely) after repeated use of the drug in the same individual. Halothane hepatitis is thought to be the result of an immune reaction to a metabolite formed by a reductive metabolic pathway. The risk of this complication is increased by obesity, perioperative hypoxaemia, and a short interval between consecutive exposures. It has been recommended that a period of at least 6 months should elapse prior to repeated administration of the drug to any individual.

Kinetics

Absorption

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

Distribution

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

Metabolism

20% of an administered dose is metabolized in the liver via cytochrome P450 2El, principally by oxidation and dehalogenation, to yield trifluoroacetic acid, trifluoroacetyl ethanolamide, chloro bromo difluoroethylene, and chloride and bromide radiscals.

Excretion

60–80% is exhaled unchanged; the metabolites are excreted in the urine. Excretion of metabolites may continue for up to 3 weeks after the administration of halothane.

Special points

Halothane potentiates the action of co-administered non-depolarizing relaxants. The dose of co-administered adrenaline should not exceed 10 ml of a 1:100 000 solution in a 10-minute period, to guard against the development of ventricular dysrhythmias.

Drug structure

For the drug structure, please see Fig. 3.


Fig. 3 Drug structure of halothane.

Fig. 3 Drug structure of halothane.

Hartmann’s solution

Uses

Hartmann’s solution is used:

  1. 1. in the treatment of dehydration

  2. 2. for the acute expansion of intravascular volume and

  3. 3. to provide maintenance fluid and electrolyte requirements in the perioperative period.

Chemical

Compound sodium lactate.

Presentation

As a clear, colourless sterile solution in 500/1000 ml bags containing 131 mmol of Na+, 111 mmol of chloride ions, 2 mmol of Ca2+, 5 mmol of K+, and 29 mmol of lactate ions (which are converted to bicarbonate ions in the liver) per litre. The pH of the solution is 6–7.3.

Main action

Intravascular volume expansion.

Routes of administration/doses

Hartmann’s solution is administered intravenously at a rate titrated against the patient’s clinical status.

Effects

CVS

The haemodynamic effects of Hartmann’s solution are proportional to the prevailing circulating volume and are short-lived.

GU

Renal perfusion is temporarily restored towards normal in hypovolaemic patients transfused with the crystalloid.

Metabolic/other

1 l of one-sixth molar sodium lactate is potentially equivalent to 290 ml of 5% sodium bicarbonate in its acid-neutralizing effect and to 600 ml of 5% glucose in its antiketogenic effect.

Toxicity/side effects

The predominant hazard is that of overtransfusion, leading to hypernatraemia, pulmonary oedema, and metabolic alkalosis.

Kinetics

Data are incomplete.

Distribution

Hartmann’s solution is initially distributed into the plasma but later equilibrates with the extracellular fluid.

Metabolism

The lactate component is oxidized in the liver to bicarbonate and glycogen over a period of about 2 hours. This is dependent on cellular oxidative activity, and the mechanism may be depressed by hypoxia and liver dysfunction.

Excretion

Via the urine.

Heparins

Uses

Heparin is used for:

  1. 1. the prevention of venous thromboembolic disease

  2. 2. the priming of haemodialysis and cardiopulmonary bypass machines and for maintaining the patency of indwelling lines and the treatment of

  3. 3. DIC

  4. 4. fat embolism, and

  5. 5. in the treatment of acute coronary syndromes.

Chemical

Commercial heparin is a mixture of acid mucopolysaccharides (molecular weight 3000–60 000 daltons) extracted from bovine lung or porcine intestinal mucosa.

Presentation

LMWHs are also available. These agents consist of short polysaccharide chains, which have an average molecular weight of <8000 daltons.

Main action

Anticoagulant.

Mode of action

The drug acts by binding reversibly to ATIII and enhancing its ability to inhibit certain proteases in the coagulation cascade (XIII, XII, XI, X, IX, plasmin, and thrombin). It also binds directly to several coagulation proteases and thereby facilitates their reaction with ATIII. LMWH acts via ATIII to inhibit factor Xa.

Routes of administration/dose

The intravenous dose of heparin is titrated (at approximately 1000 IU/hour) to maintain APTT at 1.5–2 times the control value. The subcutaneous dose is 5000 IU 8- to 12-hourly. One IU of heparin will prevent 1 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1:100 calcium chloride solution. Heparin sodium contains at least 120 IU/mg. LMWHs are available for subcutaneous and intravenous use. The dose and route of LMWH administration is dependent on the clinical indication and specific agent being used.

Effects

Metabolic/other

In addition to its anticoagulant effects, heparin inhibits platelet aggregation by fibrin. Heparin increases hepatic triglyceride and other lipase activities in plasma, leading to an increase in plasma free fatty acid concentration.

Toxicity/side effects

Excessive bleeding is the most commonly reported side effect; osteoporosis and aldosterone suppression have also been reported. Thrombocytopenia occurs in approximately 5% of patients who receive the drug and occurs more commonly when bovine heparin is used. Heparin-induced thrombocytopenia (HIT) predisposes to thrombosis, and, when thrombosis is identified, the condition is called heparin-induced thrombocytopenia and thrombosis (HITT). This may be asymptomatic or be associated with life-threatening arterial and venous thromboses, a condition which carries a mortality of 30%. HIT is caused by the formation of abnormal antibodies that activate platelets. HIT can be confirmed with specific blood tests. The treatment of HIT requires both protection from thrombosis and the choice of an agent that will not reduce the platelet count further.

Kinetics

Absorption

There are no data concerning oral administration. The bioavailability appears to be the same for intravenous or subcutaneous administration.

Distribution

One-third is bound in the plasma to ATIII, and the rest to albumin, fibrinogen, and proteases. The VD is 40–100 ml/kg.

Metabolism

Heparin appears to be desulfated and depolymerized (by heparinases) in the liver, kidneys, and reticulo-endothelial system.

Excretion

Small amounts are excreted unchanged in the urine; renal impairment has little effect on the pharmacokinetics of heparin. The clearance is 0.5–2 ml/kg/min, and the elimination half-life is 0.5–2.5 hours. Heparin elimination is markedly decreased during hypothermia, e.g. during cardiopulmonary bypass.

Special points

During heparin therapy, the thrombin time, whole blood clotting time, and APTT (kaolin cephalin time) are all prolonged. The bleeding time is unaffected by heparin, and the drug has no fibrinolytic activity. Specific antagonism of the effects of heparin may be achieved by the use of protamine (cf. protamine).

Neuroaxial anaesthesia and heparin therapy require careful consideration. Data suggest that at least 4 hours should elapse from the discontinuation of an unfractionated heparin infusion to the initiation of neuroaxial anaesthesia. If a patient has received LMWH for thromboembolism prophylaxis, then at least 12 hours should elapse prior to spinal/epidural insertion. If a treatment dose has been administered, then neuroaxial anaesthesia should be delayed by 24 hours.

LMWHs may be partially reversed using protamine (maximum effect <60%). Limited data suggest that, in the first 8 hours following administration of LMWH, 1 mg of protamine ‘reverses’ 1 mg of LMWH, up to the maximum dose of protamine that can be safely given. The effect of LMWH decreases over time, with a 50% reduction in effect by approximately 8 hours, and <33% effect after 12 hours.

LMWH has the apparent advantages of once-daily administration, safety during pregnancy, and causing thrombocytopenia less frequently.

Heparin is not removed by haemodialysis.

Human albumin solution

Uses

Human albumin solution (HAS) is used:

  1. 1. for plasma volume replacement in haemorrhage, burns, or excessive fluid and electrolyte loss

  2. 2. for the priming of extracorporeal circuits

  3. 3. in the treatment of hypoalbuminaemic states and

  4. 4. as a replacement fluid during therapeutic plasma exchange.

Chemical

A protein solution.

Presentation

As a clear, straw-coloured fluid for infusion containing 4.5/5/20/25% of protein (of which 96% is albumin); the solutions contain sodium carbonate, sodium bicarbonate, and/or acetic acid to adjust the pH to 6.4–7.4 and stabilizers, but no preservatives. The solutions are prepared from pooled venous plasma from healthy subjects who are hepatitis B surface antigen (HepBsAg)- and human immunodeficiency virus (HIV)-negative; the solutions are pasteurized at 60°C for 10 hours. The sodium content of HAS is 130–160 mmol/l.

Main actions

Plasma volume expansion and reversal of hypoal- buminaemia.

Mode of action

Albumin is intimately involved in the regulation of plasma volume due to its colloid oncotic pressure; 5% HAS is iso-oncotic, but 20/25% HAS will draw 3/3.5 times the administered volume into the circulation from the tissues within 15 minutes.

Routes of administration/doses

HAS is administered by intravenous infusion, according to clinical requirements; the haematocrit should be monitored and maintained above 25%—circulatory overload must be avoided.

Effects

CVS

The haemodynamic effects of HAS are proportional to the prevailing volaemic status; in the face of hypovolaemia, HAS infusion restores cardiovascular parameters towards normal. Myocardial depression has been reported with HAS. Although it contains no clotting factors, HAS does not interfere with the mechanism of blood clotting.

GU

Renal perfusion is restored towards normal in hypovolaemic subjects transfused with the colloid.

Toxicity/side effects

The major concern with the use of HAS is circulatory overload. Allergic reactions and aluminium toxicity occur infrequently.

Kinetics

Data are incomplete.

Metabolism

Exogenous albumin enters the amino acid pool and undergoes biotransformation within the liver.

Excretion

The elimination half-life is 16–18 days.

Special points

HAS does not inhibit endothelial activation in sepsis. There is little evidence to support the use of albumin to improve outcome in the critically ill. Its effects on plasma volume are not predictable, especially in pathological states associated with leaky capillary membranes.

Hydralazine

Uses

Hydralazine is used in the treatment of:

  1. 1. chronic moderate to severe hypertension

  2. 2. acute, severe hypertension

  3. 3. pre-eclampsia and

  4. 4. congestive heart failure.

Chemical

A phthalazine derivative.

Presentation

As 25/50 mg tablets of hydralazine hydrochloride, in ampoules containing 20 mg of hydralazine hydrochloride, as a white lyophilized powder which is reconstituted prior to use in water.

Main action

Peripheral vasodilation.

Mode of action

Hydralazine appears to act directly on vascular smooth muscle by interfering either with calcium entry into the cell or the release of calcium from intracellular stores; this leads to electromechanical decoupling and inhibition of contraction.

Routes of administration/doses

The adult oral dose is 50–200 mg/day in divided doses; the intravenous dose is 20–40 mg administered slowly. The drug takes 15–20 minutes to act when administered intravenously and has a duration of action of 2–6 hours.

Effects

CVS

Hydralazine causes predominantly arteriolar vasodilation, leading to a decrease in the systemic vascular resistance; a compensatory tachycardia develops, and the cardiac output increases.

CNS

Cerebral blood flow increases after the administration of hydralazine.

GU

The renal blood flow increases, secondary to the increased cardiac output; however, hydralazine usually produces sodium retention and a decrease in urine volume.

Metabolic/other

Plasma renin activity is increased by the drug.

Toxicity/side effects

Minor side effects, such as headache, flushing, sweating, nausea, and vomiting, are common. The drug may precipitate angina in patients with myocardial ischaemia. A lupus-like syndrome may occur when high doses are used. Peripheral neuropathies and blood dyscrasias occur rarely with the use of hydralazine.

Kinetics

Absorption

The bioavailability of oral hydralazine is dependent on the acetylator status and thus the extent of first-pass metabolism; average values are 16–35%.

Distribution

Hydralazine is 87% protein-bound in the plasma; the VD is 4.2 l/kg.

Metabolism

The drug is primarily metabolized by acetylation and oxidation, with subsequent conjugation. Phenotypically determined populations of fast and slow acetylators exist.

Excretion

50–90% is excreted in the urine, 1–2% unchanged. Up to 10% may appear in the faeces. The clearance is 1.4 l/kg/hour, and the elimination half-life is 0.67–3.6 hours.

Special points

The drug is commonly used in combination with a beta-adrenergic antagonist to obtund the compensatory tachycardia and increased plasma renin activity caused by hydralazine.

The hypotensive effects of volatile agents and hydralazine are additive. A dose of 0.4 mg/kg has been recommended 10 minutes prior to induction in order to obtund the pressor response to intubation.

The drug crosses the placenta and may produce fetal tachycardia when used in pregnancy or labour.

The addition of hydralazine to glucose solutions is not recommended.

Hydralazine is not removed by haemodialysis.

Hydrocortisone

Uses

Hydrocortisone is used:

  1. 1. as replacement therapy in adrenocortical deficiency states and in the treatment of

  2. 2. allergy and anaphylaxis

  3. 3. asthma

  4. 4. panoply of autoimmune disorders

  5. 5. eczema and contact sensitivity syndromes and

  6. 6. in leukaemia chemotherapy regimes and

  7. 7. for immunosuppression after organ transplantation.

Chemical

A glucocorticosteroid.

Presentation

As 10/20 mg tablets of hydrocortisone, in vials containing a white lyophilized powder which is diluted in water to yield a solution containing 100 mg of hydrocortisone sodium succinate, and as a variety of topical creams and retention enemas, some of which are fixed-dose combinations.

Main action

Anti-inflammatory.

Mode of action

Corticosteroids act by controlling the rate of protein synthesis; they react with cytoplasmic receptors to form a complex which directly influences the rate of RNA transcription. This directs the synthesis of lipocortins.

Routes of administration/doses

The adult dose by the intravenous route is 100–500 mg 6- to 8-hourly; the drug acts within 2–4 hours and has a duration of action of 8 hours when administered intravenously. The corresponding oral dose is 10–20 mg/day, using the lowest dose that is effective and on alternate days, if possible, to limit the development of side effects. The intra-articular dose is 5–50 mg daily.

Effects

CVS

In the absence of corticosteroids, vascular permeability increases; small blood vessels demonstrate an inadequate motor response, and cardiac output decreases. Steroids have a positive effect on myocardial contractility and cause vasoconstriction by increasing the number of alpha-1 adrenoreceptors and beta-adrenoreceptors and stimulating their function.

CNS

Corticosteroids increase the excitability of the CNS; the absence of glucocorticoids leads to apathy, depression, and irritability.

AS

Hydrocortisone increases the likelihood of peptic ulcer disease; it also decreases the gastrointestinal absorption of calcium.

GU

Hydrocortisone has weak mineralocorticoid effects and produces sodium retention and increased potassium excretion; the urinary excretion of calcium is also increased by the drug. The drug increases the glomerular filtration rate and stimulates tubular secretory activity.

Metabolic/other

Hydrocortisone exerts profound effects on carbohydrate, protein, and lipid metabolism. Glucocorticoids stimulate gluconeogenesis and inhibit the peripheral utilization of glucose; they cause a redistribution of body fat, enhance lipolysis, and also reduce the conversion of amino acids to protein. Hydrocortisone is a potent anti-inflammatory agent which inhibits all stages of the inflammatory process by inhibiting neutrophil and macrophage recruitment, blocking the effect of lymphokines, and inhibiting the formation of plasminogen activator. Corticosteroids increase red blood cell, neutrophil, and haemoglobin concentrations, whilst depressing other white cell lines and the activity of lymphoid tissue.

Toxicity/side effects

Consist of an acute withdrawal syndrome and a syndrome (Cushing’s) produced by prolonged use of excessive quantities of the drug. Cushing’s syndrome is characterized by growth arrest, a characteristic appearance consisting of central obesity, a moon face and buffalo hump, striae, acne, hirsutism, and skin and capillary fragility, together with the following metabolic derangements: altered glucose tolerance, fluid retention, a hypokalaemic alkalosis, and osteoporosis. A proximal myopathy, cataracts, and an increased susceptibility to peptic ulcer disease may also complicate the use of the drug.

Kinetics

Absorption

Hydrocortisone is well absorbed when administered orally or rectally; the oral bioavailability is 54%, and the rectal bioavailability is 30–90%.

Distribution

The drug is reversibly bound in the plasma to albumin (20%) and a specific corticosteroid-binding globulin (70%); the drug is 90% protein-bound at low concentrations, but only 60–70% protein-bound at higher concentrations. The VD is 0.3–0.5 l/kg, according to the dose.

Metabolism

Occurs in the liver to tetrahydrocortisone.

Excretion

The clearance of hydrocortisone is dose-dependent and ranges from 167 to 283 ml/min; the elimination half-life is 1.2–1.8 hours.

Special points

Cortisone and hydrocortisone (cortisol) are metabolically interconvertible; only the latter is active. The conversion of cortisone to hydrocortisone is rapid and extensive, and occurs as a first-pass effect in the liver. Hydrocortisone is one-quarter as potent as an anti-inflammatory agent as prednisolone. It has been recommended that perioperative steroid cover be given:

  1. 1. to patients who have received high-dose steroid replacement therapy for 2 weeks in the preceding year prior to surgery

  2. 2. to patients undergoing pituitary or adrenal surgery. Glucocorticoids antagonize the effects of anticholinesterase drugs.

Relative adrenal insufficiency is reported in the critically ill, and low-dose hydrocortisone and mineralocorticoid replacement have been shown to decrease the time to ‘shock’ reversal and may decrease mortality.

Hyoscine

Uses

Hyoscine is used:

  1. 1. in premedication

  2. 2. in the prophylaxis of motion sickness

  3. 3. as an antispasmodic and

  4. 4. in palliative care.

Chemical

Hyoscine is an alkaloid derived from Scopolia carniolica and is an ester of tropic acid and scopine. Scopolamine is l-hyoscine.

Presentation

Hyoscine hydrobromide is presented as a clear solution for injection containing 0.4 mg/ml and as a fixed-dose combination with papaveretum. Hyoscine butylbromide is presented as a clear solution containing 20 mg/ml and in 10 mg tablet form. A transdermal preparation delivering 1 mg/72 hours of hyoscine is also available.

Main actions

Anticholinergic with marked sedative effects.

Mode of action

The drug acts by competitive antagonism of acetylcholine at muscarinic receptors (hyoscine has little effect at nicotinic receptors).

Routes of administration/doses

Hyoscine may be administered intramuscularly, intravenously, subcutaneously, transdermally, or orally. The intramuscular dose for premedication is 8–15 micrograms/kg. The adult oral dose is 20 mg 6-hourly.

Effects

CVS

Hyoscine has less effect than atropine on cardiovascular parameters. When administered intravenously, an initial tachycardia may be followed by a bradycardia.

RS

The drug causes a marked decrease in bronchial secretions, mild bronchodilatation, and mild stimulation of respiration.

CNS

Hyoscine is a CNS depressant, causing ‘twilight sleep’ and amnesia. It has antanalgesic, antiemetic, and anti-parkinsonian properties. Hyoscine may also cause the central anticholinergic syndrome.

AS

A marked antisialogogue, hyoscine is also antispasmodic throughout the gut and biliary tree.

GU

The tone of the bladder and ureters is reduced, following administration of the drug.

Metabolic/other

Hyoscine has a more marked effect on the eye and sweat gland activity than atropine.

Toxicity/side effects

The central anticholinergic syndrome is the main side effect and may be prolonged, especially in the elderly; peripheral anticholinergic side effects may also occur, following the use of hyoscine.

Kinetics

Absorption

Hyoscine is poorly absorbed after oral administration; the bioavailability is 10% by this route. The drug is well absorbed, following subcutaneous or intramuscular administration.

Distribution

Hyoscine is 11% protein-bound in the plasma; the VD is 2.0 l/kg.

Metabolism

The drug is extensively metabolized in liver and tissues to scopine and scopic acid.

Excretion

2% of an oral dose is excreted unchanged in the urine, and 5% in the bile. The clearance is 45 l/hour, and the elimination half-life is 2.5 hours.

Special points

The drug may induce acute clinical and biochemical manifestations in patients with porphyria.

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