D
- DOI:
- 10.1093/med/9780198768814.003.0004
Uses
Dabigatran is used for the primary prevention of:
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1. venous thromboembolic events post-elective total hip replacement and
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2. venous thromboembolic events post-elective total knee replacement surgery.
Mode of action
Dabigatran etexilate is a pro-drug. Following oral administration, it undergoes plasma and hepatic esterase-catalysed hydrolysis to dabigatran which acts as a direct thrombin inhibitor. Inhibition of thrombin prevents cleavage of fibrinogen to fibrin. The drug also inhibits:
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1. free thrombin
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2. fibrin-bound thrombin, and
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3. thrombin-induced platelet aggregation.
Routes of administration/doses
Dabigatran is available in 75 and 110 mg capsules as dabigatran mesilate. The recommended dose for prevention of venous thromboembolism following elective knee replacement surgery is 110 mg, taken 1–4 hours after surgery, followed by 220 mg once daily for 10 days. The recommended dose following elective hip replacement surgery is the same, but treatment is continued for 28–35 days. The dose should be reduced in the elderly and in patients with moderate renal impairment to 75 mg, taken 1–4 hours after surgery, followed by 150 mg once daily.
Toxicity/side effects
Excessive bleeding is the most common reported side effect (14% of patients). The colourant ‘sunset yellow’ is present within capsules of dabigatran, which has been associated with allergic reactions. The use of neuroaxial blocks in patients receiving the drug must be carefully considered, and the timing of lock/catheter insertion/removal and commencement/withholding/discontinuation of dabigatran must be appropriately timed to minimize the risk of spinal/epidural haematoma formation.
Kinetics
Absorption
Dabigatran is rapidly converted from its etexilate form to the active drug via esterase hydrolysis. The bioavailability of the drug is 6.5%. Following oral administration, Cmax is reached within 0.5–2 hours.
Metabolism
Dabigatran is metabolized by conjugation to active acylglucuronides. Four isomers may exist: 1-O-, 2-O-, 3-O-, and 4-O-acylglucuronide, accounting for <10% of total drug in the plasma.
The drug is excreted predominantly unchanged in the urine at a rate proportional to the glomerular filtration rate. Plasma levels of the drug demonstrate a bi-exponential decline, with a terminal elimination half-life of 12–14 hours. Six percent of an administered dose is excreted in faeces. Renal impairment increases the time of drug exposure. Consequently, the dose should be reduced in moderate renal impairment, and the drug should be avoided in patients with severe renal impairment. Limited data from patients with hepatic impairment did not demonstrate increased time of drug exposure following the administration of dabigatran.
Special points
The use of unfractionated heparin, low-molecular-weight heparins (LMWHs), fondaparinux, desirudin, thrombolytic agents, glycoprotein IIb/IIIa receptor antagonists, clopidogrel, ticlopidine, dextran, sulfinpyrazone, and vitamin K antagonists is not recommended in patients concurrently receiving dabigatran.
The time of drug exposure is increased when dabigatran is administered to patients concurrently receiving amiodarone, and the daily dose should be reduced to 150 mg of dabigatran daily. The mechanism of this interaction has not been fully elucidated. However, amiodarone is an inhibitor of the efflux transporter P-glycoprotein of which dabigatran is a substrate. Strong inhibitors of P-glycoprotein include verapamil and clarithromycin. The drug should be used with caution in patients receiving these drugs. Dabigatran should not be administered to patients also receiving the P-glycoprotein inhibitor quinidine.
The time of drug exposure may be reduced when dabigatran is administered to patients concurrently receiving P-glycoprotein inducers such as rifampicin and Hypericum perforatum (St John’s wort).
There is no antidote currently available for dabigatran.
The drug may be removed by haemodialysis.
Uses
Dantrolene is used in the treatment of:
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1. malignant hyperthermia and the neuroleptic malignant syndrome
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2. heat stroke, and
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3. muscle spasticity and may be of use
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4. as an adjunct in the treatment of tetanus.
Presentation
As 25 or 100 mg capsules of dantrolene sodium, as a lyophilized orange powder which contains 20 mg of dantrolene sodium and 3 g of mannitol (to improve the solubility), together with sodium hydroxide in each vial; this is reconstituted prior to use with 60 ml of water. A solution of pH 9.5 is produced.
Mode of action
Dantrolene acts within skeletal muscle fibres to inhibit Ca2+ release through the inhibition of ryanodine receptors in the sarcoplasmic reticulum to cause a reduction in muscular contraction to a given electrical stimulus. Part of its action may be due to a marked GABA-ergic effect.
Routes of administration/doses
For the treatment of acute hyperthermia, 1–10 mg/kg administered intravenously (either via a central vein or into a fast-running infusion), as required—an average of 2.5 mg/kg is required. For the prophylaxis of malignant hyperthermia, 4–8 mg/kg/day are given for 1–2 days prior to surgery in 3–4 divided doses; the role of this regime is controversial. The oral adult dose used for the prevention of spasticity is 25–100 mg 6-hourly. Therapeutic effects are observed within 15 minutes; the mean duration of action is 4–6 hours.
Effects
Toxicity/side effects
The drug is highly irritant if extravasated. With chronic use, muscular weakness, drowsiness, and gastrointestinal disturbances may occur. Hepatic dysfunction occurs in up to 2% of patients which is reversible.
Special points
There are no controlled trials of the effectiveness of dantrolene in the treatment of malignant hyperthermia or the malignant neuroleptic syndrome in man; however, >80% of patients with prodromal signs of the syndromes improve after receiving dantrolene. It has also been used successfully in the management of ‘Ecstasy’ toxicity.
Verapamil and dantrolene administered concurrently in animals may cause hyperkalaemia, leading to ventricular fibrillation; these drugs are not recommended for use together in man.
Presentation
As a clear, colourless liquid that should be protected from light. The commercial preparation contains no additives and is flammable at a concentration of 17%. The molecular weight of desflurane is 168; the boiling point is 22.8°C, and the saturated vapour pressure is 88.5 kPa at 20°C. The MAC of desflurane is age-dependent and ranges from 5.17 ± 0.65% to 10.65% (1.67 ± 0.4% to 7.75% in the presence of 60% N2O); the blood:gas partition coefficient is 0.45, and the fat:blood partition coefficient is 29. Desflurane is stable in the presence of moist soda lime.
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 gamma-amino-butyric acid (GABA) type A (GABAA) and glycine receptors and antagonism at N-methyl-D-aspartate (NMDA) receptors. Their mode of action at the molecular level appears to involve expansion of hydrophobic regions in the neuronal membrane, either within the lipid phase or within hydrophobic sites in cell membranes.
Routes of administration/dose
Desflurane is administered by inhalation. Because of the high saturated vapour pressure, desflurane must be administered by a specific pressurized and heated vaporizer. The concentration used for induction of anaesthesia is quoted as 4–11%, although induction is usually achieved using a different agent. Maintenance of anaesthesia is usually achieved by using between 2% and 6%.
Effects
CVS
Desflurane causes a decrease in myocardial contractility, but the sympathetic tone is relatively well preserved. The cardiac index and left ventricular ejection fraction are well preserved in man. Desflurane causes a dose-dependent decrease in the systemic vascular resistance and mean arterial pressure; the heart rate may increase via an indirect autonomic effect, particularly at inspired concentrations of 9% or greater. The drug does not appear to cause the ‘coronary steal’ phenomenon in man. Desflurane does not sensitize the myocardium to the effects of catecholamines.
RS
Desflurane is a respiratory depressant, causing dose-dependent decreases in the tidal volume and an increase in the respiratory rate. The drug depresses the ventilatory response to CO2. Desflurane is markedly irritant to the respiratory tract in concentrations >6%.
The principal effect of desflurane is general anaesthesia. The drug causes cerebral vasodilation, leading to an increase in the cerebral blood flow; the effects on the intracranial pressure are unclear. As with other volatile anaesthetic agents, desflurane may increase the intracranial pressure in patients with space-occupying lesions. Desflurane decreases cerebral oxygen consumption and is not associated with epileptiform activity. A centrally mediated decrease in the skeletal muscle tone results from the use of desflurane.
Toxicity/side effects
There is a high incidence of airway irritation and reactivity during the use of high concentrations of desflurane, making it unsuitable for use during gaseous induction. It is not recommended for induction in children, as airway irritation may be severe. Desflurane is a trigger agent for the development of malignant hyperthermia. Desflurane may cause PONV.
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. Due to the low blood:gas partition coefficient of desflurane, it is exceptionally insoluble in blood; the alveolar concentration therefore reaches inspired concentration very rapidly (fast wash-in rate), 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 the alveoli and venous blood approaches zero at equilibrium; a large concentration gradient favours the onset of anaesthesia.
Special points
Desflurane potentiates the action of co-administered depolarizing and non-depolarizing muscle relaxants.
Due to the physical characteristics of desflurane, a specific vaporizer is used to administer the drug. The vaporizer comprises an electrically heated vaporization chamber in which desfludrane is heated to 39°C at a pressure of 1550 mmHg. A percentage control dial controls the flow of desflurane vapour into the fresh gas flow (1% graduations from 0% to 10%; 2% graduations from 10% to 18%). A fixed restriction in the fresh gas flow path and the use of a differential pressure transducer allow the vaporizer to match the pressure of desflurane vapour upstream of the control valve, with the pressure of the fresh gas flow at the fixed restriction.
As with other volatile anaesthetic agents, the co-administration of N2O, benzodiazepines, or opioids lowers the MAC of desflurane.
Desflurane may be used safely in patients breathing spontaneously via a laryngeal mask.
Uses
Dexamethasone is used:
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1. as replacement therapy in congenital adrenocortical deficiency states and in the treatment of
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2. allergic disorders
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3. asthma
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4. many autoimmune and rheumatologic disorders
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5. eczema and contact sensitivity syndromes and
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6. leukaemia and lymphoma chemotherapy regimes and
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7. immunosuppression after organ transplantation
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8. palliative treatment of tumours
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9. prevention of post-operative and chemotherapy-induced nausea and vomiting
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10. ophthalmic inflammatory diseases
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11. acute exacerbations of inflammatory bowel disease
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12. acute severe skin diseases
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13. cerebral oedema
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14. bacterial meningitis—prevents hearing loss
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15. tests for Cushing’s syndrome
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16. hypercalcaemia of malignancy, sarcoidosis, and vitamin D toxicity
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17. antenatal use in preterm labour
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18. myasthenia gravis
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19. autoimmune renal disease and
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20. has been used for epidural injection.
Presentation
As 0.5/2 mg tablets of dexamethasone, an oral solution and in vials as dexamethasone (sodium phosphate) 3.8 mg/mL, and as a variety of topical creams, some of which are fixed-dose combinations.
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. Dexamethasone has approximately a seven-times higher anti-inflammatory potency than prednisolone and 30 times that of hydrocortisone. Adrenocorticoids act on the hypothalamic–pituitary–adrenal axis at specific receptors on the plasma membrane. In other tissues, the adrenocorticoids diffuse across cell membranes and form complexes with specific cytoplasmic receptors which enter the cell nucleus and stimulate protein synthesis. Adrenocorticoids have anti-allergic, antitoxic, antishock, antipyretic, and immunosuppressive properties.
Routes of administration/doses
For oral administration, the initial dosage of dexamethasone varies from 0.75 to 9 mg daily, depending on the disease being treated.
CVS
In the absence of corticosteroids, the capillary wall permeability increases; small blood vessels demonstrate an inadequate motor response, and the 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. They prevent oedema formation.
CNS
Corticosteroids increase the excitability of the CNS; the absence of glucocorticoids leads to apathy, depression, and irritability. In the CSF, they reduce the inflammatory response to anti-infective released bacterial endotoxins and cell wall components, including reduction of the release of cytokines (e.g. interleukin-1 (IL-1) beta, tumour necrosis factor (TNF)).
AS
Dexamethasone increases the likelihood of peptic ulcer disease; it also decreases the gastrointestinal absorption of calcium.
GU
The urinary excretion of calcium is increased by the drug, and it increases the glomerular filtration rate and stimulates tubular secretory activity. Dexamethasone has only minor mineralocorticoid activities and does not induce water and sodium retention.
Metabolic/other
Dexamethasone 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, resulting in a negative nitrogen balance.
Dexamethasone 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. It decreases inflammation by stabilizing leucocyte lysosomal membranes, preventing the release of destructive acid hydrolases from leucocytes, or reducing leucocyte adhesion to the capillary endothelium. The drug antagonizes histamine activity and the release of kinin, and decreases immunoglobulin and complement concentrations and the passage of immune complexes through basement membranes. It depresses the reactivity of tissues to antigen–antibody interactions.
Corticosteroids stimulate erythroid cells of the bone marrow and increase neutrophil and red cell numbers, whilst causing eosinopenia and lymphocytopenia and reducing the activity of lymphoid tissue. It prolongs the survival time of erythrocytes and platelets.
Dexamethasone inhibits pituitary corticotropin (adrenocorticotrophin hormone, ACTH) release and decreases the output of endogenous corticosteroids.
It reduces fibroblast proliferation, collagen deposition, and subsequent scar tissue formation.
Short-course intramuscular therapy is used in selected women with preterm labour to hasten fetal maturation (e.g. lungs, cerebral blood vessels), including preterm premature rupture of membranes, pre-eclampsia, or third-trimester haemorrhage. It reduces the incidence and/or severity of neonatal respiratory distress syndrome (RDS), causing a reduction in the need for neonatal ventilatory support and surfactant therapy; these beneficial effects are additive with the surfactant. The combined effects on multiple organ maturation reduce neonatal mortality, with the beneficial effects extending over a wide range of gestational age (24–34 weeks).
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. Neuropsychiatric symptoms, including psychosis, are well described.
Kinetics
Absorption
After intravenous administration, dexamethasone sodium phosphate is rapidly hydrolysed to dexamethasone. After an intravenous dose of 20 mg dexamethasone, plasma levels peak within 5 minutes.
Distribution
Dexamethasone is bound (up to 77%) by plasma proteins, mainly albumin. There is a high uptake of dexamethasone by the liver, kidney, and adrenal glands.
Metabolism
Metabolism in the liver is slow, and excretion is mainly in the urine, largely as unconjugated steroids.
Excretion
The plasma half-life is 3.5–4.5 hours, but, as the effects outlast the significant plasma concentrations of steroids, the plasma half-life is of little relevance, and the use of the biological half-life is more applicable. The biological half-life of dexamethasone is 36–54 hours; therefore, dexamethasone is especially suitable in conditions where continuous glucocorticoid action is desirable.
Special points
It has been recommended that perioperative steroid cover be given:
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1. to patients who have received high-dose steroid replacement therapy for 2 weeks in the preceding year prior to surgery
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2. to patients undergoing pituitary or adrenal surgery.
Glucocorticoids antagonize the effects of anticholinesterase drugs.
Injection of corticosteroids into the epidural space of the spine may result in rare, but serious, adverse events, including loss of vision, stroke, paralysis, and death.
Uses
Dexmedetomidine is used as a sedative for post-surgical patients requiring mechanical ventilation.
Presentation
As a clear, colourless isotonic solution containing 100 g/ml of dexmedetomidine base and 9 mg/ml of sodium chloride in water. The solution is preservative-free and contains no additives.
Mode of action
Dexmedetomidine is a specific alpha-2 adrenoceptor agonist that acts via post-synaptic alpha-2 receptors primarily in the locus coeruleus to increase conductance through K+ channels.
Routes of administration/dose
The drug is administered by intravenous infusion, commencing at 1 g/kg for 10 minutes, then at 0.2–0.7 g/kg/hour. The duration of use should not exceed 24 hours. Dexmedetomidine has also been administered transdermally and intramuscularly.
Effects
RS
Dexmedetomidine causes a slight increase in PaCO2 and a decrease in minute ventilation, with minimal change in the respiratory rate—these effects are not clinically significant.
Toxicity/side effects
Hypotension, bradycardia, nausea, and a dry mouth are the most commonly reported side effects of the drug.
Kinetics
Special points
The drug shows a pharmacodynamic interaction with volatile agents and analgesic agents. The clearance is decreased in hepatic impairment, although renal impairment does not significantly alter its pharmacokinetics. Dexmedetomidine is currently licensed for use in the United States of America (USA), but not Europe.
Uses
Dextrans are used:
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1. for plasma volume replacement in haemorrhage, burns, or excessive fluid and electrolyte loss and
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2. in the prophylaxis of post-operative thromboembolism.
Chemical
Dextrans are polysaccharide derivatives of sucrose by the action of the bacterium Leuconostoc mesenteroides; the preparation is then further processed by hydrolysis and fractionation.
Presentation
Dextrans are available as dextran 40 and dextran 70. Both agents are presented as clear, colourless solutions in either 5% glucose or 0.9% saline. Dextran 40 is a 10% solution containing molecules with an average molecular weight of 40 000; 90% of molecules have a molecular weight within the range of 10 000–75 000. Dextran 70 is a 6% solution containing molecules with an average molecular weight of 70 000; 90% of molecules have a molecular weight within the range of 20 000–115 000.
Mode of action
Each gram of dextran in the circulation will retain approximately 20 ml of water by its osmotic effect; an infusion of 500 ml of dextran 40 will maximally increase the circulating plasma volume by approximately 1000 ml. An infusion of 500 ml of dextran 70 will increase the circulating plasma volume by approximately 750 ml. Molecules above the renal threshold for dextran elimination of 55 000 daltons are generally retained within the intravascular space, whereas those below 20 000 daltons have access to the interstitial space. Dextrans exert their antithrombotic action by reducing ADP-induced platelet aggregation and by decreasing the activating effect of thrombin on platelets. These agents also alter fibrinogen binding.
Routes of administration/doses
The specific dose of an agent administered is dependent on the clinical indication, haemodynamic status of the patient, and particular agent being used. When used in the prophylaxis of post-operative thrombosis, the adult dose is 500 ml infused over 4–6 hours in the immediate post-operative period, repeated on the next day. For high-risk cases, this may be continued on alternate days for up to 2 weeks.
Effects
CVS
The haemodynamic effects of dextrans are proportional to the prevailing circulating volume. The duration of action of these agents depends on the type of dextran used.
Severe hypersensitivity reactions occur in 1 in 3300—this is probably due to a cross-reaction with antibodies to a recent pneumococcal infection. Overtransfusion may lead to pulmonary oedema. Increased capillary oozing due to improved perfusion pressure and capillary flow may be noted perioperatively. Acute renal failure may complicate the use of dextran 40 when it is used in the management of profound hypovolaemia.
Uses
Diamorphine is used:
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1. for premedication
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2. as an analgesic in the management of moderate to severe pain
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3. in the treatment of left ventricular failure
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4. as an antitussive agent, and
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5. to provide analgesia for palliative care.
Presentation
As tablets containing 10 mg and as a lyophilized white powder in ampoules containing 5/10/30/100/500 mg of diamorphine hydrochloride for reconstitution with water. A number of non-proprietary elixirs and suppositories are also available.
Mode of action
Diamorphine is a pro-drug; it does not possess an unsubstituted phenolic hydroxyl group at the 3-position and acts via active derivatives (6-O-acetylmorphine and morphine) which are MOP receptor agonists. Opioids appear to exert their effects by increasing intracellular calcium concentration which, in turn, increases potassium conductance and hyperpolarization of excitable cell membranes. The decrease in membrane excitability that results may decrease both pre-and post-synaptic responses.
Routes of administration/doses
The average adult dose by the intravenous or intramuscular route is 5–10 mg. The corresponding intrathecal or epidural dose is 2.5–5 mg. Due to its higher lipid solubility, the drug has a more rapid onset of action than morphine and has a duration of action of 90 minutes after intramuscular administration.
Effects
CVS
Diamorphine has little effect on the CVS when used in normal doses. In high doses, it may cause bradycardia due to a combination of increased vagal activity and decreased sympathetic activity; hypotension resulting from a decrease in the systemic vascular resistance may occur.
RS
The principal effect of the drug is respiratory depression in opioid-naive subjects, with a decreased ventilatory response to hypoxia and hypercapnia. Diamorphine also has a potent antitussive action. Bronchoconstriction may occur with the use of high doses of the drug.
CNS
Diamorphine is 1.5–2 times as potent an analgesic agent as morphine. The drug tends to cause marked euphoria; there is a clinical impression that it causes less nausea and vomiting than morphine. Miosis is produced as a result of stimulation of the Edinger–Westphal nucleus. Seizures may occur with the use of high doses of the drug.
Diamorphine decreases gastrointestinal motility and gastric acid, biliary, and pancreatic secretions; it also increases the common bile duct pressure by causing spasm of the sphincter of Oddi. There is a clinical impression that the drug causes less constipation than does an equipotent dose of morphine.
Toxicity/side effects
Respiratory depression, nausea and vomiting, hallucinations, and dependence may complicate the use of diamorphine. Pruritus may occur after epidural or spinal administration of the drug.
Kinetics
Data are incomplete due to the instability of the drug in vivo and difficulties in the assay methodology.
Absorption
Diamorphine is extensively absorbed when administered orally; the bioavailability appears to be low due to an extensive first-pass metabolism.
Metabolism
Diamorphine undergoes rapid enzymatic hydrolysis in the plasma and in association with red blood cells, probably via pseudocholinesterase and at least three esterases located within red blood cells. The initial metabolic product is 6-O-acetylmorphine (which is the active form of the drug) which is, in turn, further metabolized to morphine, with subsequent glucuronidation.
Uses
Diazepam is used:
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1. in the short-term treatment of anxiety
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2. in the treatment of status epilepticus
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3. for muscle spasm in tetanus and other spastic conditions
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4. for alcohol withdrawal, and for
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5. premedication and
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6. sedation during endoscopy and procedures performed under local anaesthesia.
Presentation
As tablets containing 2/5/10 mg, a syrup containing 0.4/1 mg/ml, as 10 mg suppositories, and as a solution for rectal administration containing 2/4 mg/ml of diazepam. The drug is also supplied as a clear, yellow solution and as a white oil-in-water emulsion for injection containing 5 mg/ml.
Main actions
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1. Hypnosis
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2. Sedation
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3. Anxiolysis
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4. Anterograde amnesia
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5. Anticonvulsant, and
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6. Muscular relaxation.
Mode of action
Benzodiazepines are thought to act via specific benzodiazepine receptors found at synapses throughout the CNS, but concentrated especially in the cortex and midbrain. Benzodiazepine receptors are closely linked with GABA receptors and appear to facilitate the activity of the latter. Activated GABA receptors open chloride ion channels which then either hyperpolarize or short-circuit the synaptic membrane.
Diazepam has kappa-opioid agonist activity in vitro, which may explain the mechanism of benzodiazepine-induced spinal analgesia.
Routes of administration/doses
The adult oral dose is 2–60 mg/day in divided doses; the initial intravenous dose is 10–20 mg, increasing according to clinical effect.
Effects
CVS
A transient decrease in the blood pressure and a slight decrease in the cardiac output may occur, following the intravenous administration of diazepam. The coronary blood flow is increased, secondary to coronary arterial vasodilation; a decrease in myocardial oxygen consumption has also been reported.
Toxicity/side effects
Depression of the CNS, including drowsiness, ataxia, and headache, may complicate the use of diazepam. Rashes, gastrointestinal upsets, and urinary retention have also been reported. Tolerance and dependence may occur with prolonged use of benzodiazepines; acute withdrawal of benzodiazepines in these circumstances may produce insomnia, anxiety, confusion, psychosis, and perceptual disturbances. Intravenous diazepam is highly irritant to veins; the oil-in-water preparation is less so.
Kinetics
Absorption
Diazepam is rapidly absorbed after oral administration; the bioavailability is 86–100%. Absorption after intramuscular administration is slow and erratic.
Special points
Diazepam decreases the MAC of volatile agents and potentiates non-depolarizing muscle relaxants. Cimetidine decreases the clearance of co-administered diazepam and thereby increases the plasma levels of the latter. Diazepam is adsorbed onto plastic.
The drug is not removed by dialysis.
Uses
Diclofenac is used in the treatment of:
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1. rheumatoid arthritis and osteoarthritis
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2. musculoskeletal disorders
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3. soft tissue injuries
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4. ankylosing spondylitis
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5. acute gout
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6. renal and biliary colic
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7. dysmenorrhoea
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8. minor post-surgical pain and as an adjunct to systemic opioid therapy
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9. as an antipyretic, and
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10. to inhibit perioperative miosis and post-operative inflammation in cataract surgery.
Presentation
As 25/50/100 mg tablets, 12.5/25/50/100 mg suppositories, and in ampoules containing either 25 mg/ml or 75 mg/2ml of diclofenac sodium for injection, depending on the nature of the preparation. An emulsified gel as diethylammonium and eye drops as a 0.1% solution of diclofenac sodium are also available. Modified-release/slow-release preparations are also available for oral administration, in addition to a dispersible formulation. Depending on the intravenous preparation, the following additives may be present: mannitol, sodium metabisulfite, benzyl alcohol, propylene glycol, sodium hydroxide, or hydroxypropylbetadex (a solubilizing agent).
Mode of action
Diclofenac is a non-specific inhibitor of COX (COX-2:COX-1 ratio = 1:1) which converts arachidonic acid to cyclic endoperoxidases, thus preventing the formation of prostaglandins, thromboxanes, and prostacylin. Prostaglandins are involved in the sensitization of peripheral pain receptors to noxious stimuli. The drug may also inhibit the lipo-oxygenase pathway by an action on hydroperoxy fatty acid peroxidase.
Route of administration/doses
The adult oral dose is 75–150 mg/day in divided doses; the rectal dose is 100 mg, usually administered at night with further suppositories or tablets up to a maximum dose of 150 mg per 24 hours; it may also be given pre- or perioperatively. The intramuscular dose is 75 mg once or twice daily. The paediatric dose is 1 mg/kg three times a day. The intravenous dose is 25–75 mg, up to a maximum daily dose of 150 mg. Depending on the intravenous preparation, a bolus administration may or may not be recommended. Some preparations require dilution in 100–500 ml of 0.9% sodium chloride or 5% glucose solutions, with subsequent buffering with sodium bicarbonate solution.
AS
Diclofenac causes less gastrointestinal damage than aspirin or indometacin. Dyspepsia, nausea, bleeding from gastric and duodenal vessels, mucosal ulceration, perforation, and diarrhoea are expected COX-1 effects. The drug may lead to disease exacerbation in patients with Crohn’s disease or ulcerative colitis. Diclofenac may cause a rise in ALT in up to 15% of patients.
Toxicity/side effects
Occur in 12%; complications are related to the duration of therapy, and risks increase markedly after >5 days of continuous therapy, especially in the elderly.
Disturbances of the gastrointestinal system and CNS occur occasionally.
Rashes and hepatic, renal, and haematological impairment have been reported.
As with other NSAIDs, prolonged use may lead to analgesic nephropathy, characterized by papillary necrosis and interstitial fibrosis. Acute renal failure may be precipitated when NSAIDs are administered to patients who have renal perfusion dependent on prostaglandin production (i.e. when there are high levels of circulating vasoconstrictors or hypovolaemia).
Intramuscular injection may be painful, and sterile abscesses have been reported.
The drug may inhibit uterine contraction.
Kinetics
Absorption
The drug is well absorbed when administered by all routes. The oral bioavailability is 60%.
Distribution
Diclofenac is 99.5% protein-bound in the plasma, predominantly to albumin. The VD is 0.12–0.17 l/kg. The drug crosses the placenta in animal models. Diclofenac enters the synovial fluid and reaches maximum concentration 2–4 hours after peak plasma concentrations have been achieved. Drug levels within the synovial fluid may remain high for up to 12 hours, before being eliminated with a half-life of 3–6 hours.
Metabolism
Diclofenac undergoes significant first-pass metabolism, principally in the liver by hydroxylation and methoxylation to phenolic metabolites, with subsequent conjugation to inactive glucuronide and sulfate metabolites. Two phenolic metabolites have biological activity, although much reduced, compared with the parent drug.
Special points
Renal and hepatic impairment have little effect on the plasma concentration of diclofenac. The drug may increase plasma concentrations of co-administered digoxin and lithium by reducing renal clearance.
Diclofenac may increase the effect of co-administered oral anticoagulants, heparin, and sulfonylureas due to displacement from plasma proteins.
NSAIDs antagonize the antihypertensive effects of ACEIs via the inhibition of vasodilatory prostaglandin synthesis. The risk of renal impairment increases if NSAIDs and ACEIs are co-administered. NSAIDs inhibit the activity of diuretics.
Diclofenac should not be administered to aspirin-sensitive asthmatics.
In patients with severe renal impairment, the excipient hydroxypropylbetadex is subject to renal elimination and may accumulate if present in the intravenous preparation. The clinical relevance of this in man is unclear.
Uses
Digoxin is used in the treatment of:
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1. atrial fibrillation and flutter
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2. heart failure and may be of use
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3. in the prevention of supraventricular dysrhythmias following thoracotomy.
Presentation
As 0.0625/0.125/0.25 mg tablets, an elixir containing 0.05 mg/ml, and as a clear, colourless solution for injection containing 0.25 mg/ml of digoxin.
Mode of action
Digoxin acts both directly and indirectly; its direct action is exerted by binding to, and inhibiting the action of, Na+K+ATPase within the sarcolemma cell membrane. This produces an increase in the intracellular Na+ concentration and a decrease in the intracellular K+ concentration. The increase in the intracellular Na+ concentration causes displacement of bound intracellular Ca2+. This increased availability of Ca2+ results in a positive inotropic action. The decrease in the intracellular K+ concentration leads to slowing of AV conduction and of the pacemaker cells. The drug also acts indirectly by modifying autonomic activity and increasing efferent vagal activity.
Routes of administration/doses
The loading dose by both oral and parenteral routes is 10–20 micrograms/kg 6-hourly until the desired effect is achieved. Intravenous injection must be slow (at a rate not exceeding 0.025 mg/min)—the peak effects are observed 2 hours after intravenous administration. The maintenance dose is 10–20 micrograms/kg/day in divided doses; therapy should be adjusted according to response, guided (where appropriate) by measurement of serum levels of the drug. The therapeutic range is 1–2 micrograms/ml.
Effects
CVS
The main action of digoxin is to increase the force of cardiac contraction; automaticity and contractility also increase. The heart rate is slowed due to a combination of improved haemodynamics, depression of sinus node discharge, slowing of AV nodal conduction, an increase in the AV nodal refractory period, and an indirect vagotonic effect. Rapid intravenous administration of digoxin may cause vasoconstriction, leading to hypertension and decreased coronary blood flow. The characteristic ECG changes produced by the drug include prolongation of the PR interval, ST-segment depression, T-wave flattening, and shortening of the QT interval.
Side effects are common with digoxin, especially if the therapeutic range is exceeded. The gastrointestinal side effects include anorexia, nausea and vomiting, diarrhoea, and abdominal pain. The neurological side effects of the drug include headache, drowsiness, confusion, visual disturbances, muscular weakness, and coma. Digoxin may cause any form of dysrhythmia, especially junctional bradycardia, ventricular bigemini, and second- or third-degree heart block. Rashes and gynaecomastia occur uncommonly. Digoxin-specific antibody fragments are available for the treatment of digoxin toxicity.
Kinetics
Absorption
Absorption from the gastrointestinal tract is highly variable, and the bioavailability by this route varies from 60% to 90%. Absorption after intramuscular injection is erratic.
Distribution
Digoxin is 20–30% protein-bound in the plasma; the VD is 5–11 l/kg. The concentrations achieved at steady state in cardiac tissue are 15–30 times that of plasma.
Metabolism
Less than 10% of the dose undergoes hepatic metabolism via stepwise cleavage of the sugar moieties.
Excretion
50–70% of an administered dose of digoxin is excreted unchanged in the urine as a result of glomerular filtration and active tubular secretion. The clearance is dependent on renal function and may be calculated from the formula:
The elimination half-life is 1.6 days. The dose interval should be increased in the presence of renal impairment.
Special points
Patients receiving suxamethonium, pancuronium, or beta-adrenergic agonists concurrently with digoxin may exhibit an increased incidence of dysrhythmias.
The following states increase the likelihood of digoxin toxicity: hypokalaemia, hypernatraemia, hypercalcaemia, hypomagnesaemia, acid–base disturbances, hypoxaemia, and renal failure. Co-administered verapamil, nifedipine, amiodarone, and diazepam also increase plasma digoxin concentrations.
Digoxin is not removed by dialysis.
Uses
Diltiazem is recommended for use:
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1. in the treatment of stable and variant angina and may be of use in the treatment of:
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2. hypertension
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3. supraventricular tachycardias
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4. Raynaud’s phenomenon
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5. migraine, and
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6. oesophageal motility disorders.
Main action
Diltiazem increases myocardial oxygen supply and decreases myocardial oxygen demand by coronary artery dilation, possibly aided by direct and indirect haemodynamic alterations.
Mode of action
Diltiazem acts via dose-dependent inhibition of the slow inward calcium current in normal cardiac tissue.
Effects
CVS
Diltiazem is a potent peripheral and coronary arterial vasodilator, leading to a decrease in the systemic and pulmonary vascular resistances; the cardiac output increases due to a reduction in afterload. Little effect on the heart rate occurs in man; bradycardia tends to occur with chronic use. AV nodal conduction is decreased by the drug; diltiazem is thus of use in the treatment of supraventricular tachycardias.
AS
A significant reduction in lower oesophageal pressure is produced in patients with achalasia, although no effect is seen in normal subjects.
Toxicity/side effects
Occur in 2–10% and include headaches, flushing, peripheral oedema, and bradycardia.
Kinetics
Absorption
90% of an oral dose is absorbed; the bioavailability by this route is 33–40% due to a significant first effect.
Special points
Caution should be used if the drug is administered concurrently with a beta-adrenergic antagonist, as serious bradycardias may arise. All volatile agents in current use decrease Ca2+ release from the sarcoplasmic reticulum and decrease Ca2+ flux into cardiac cells; the negative inotropic effects of diltiazem are thus additive with those of the volatile agents. Experiments in animals have demonstrated an increased risk of sinus arrest if volatile agents and calcium antagonists are used concurrently. If withdrawn acutely (especially in the post-operative period) after chronic oral use, severe rebound hypertension may result. Calcium antagonists may also:
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1. reduce the MAC of volatile agents by up to 20% and
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2. increase the efficacy of NMB agents.
Diltiazem may increase the plasma concentration of co-administered digoxin by 20–60%. It also increases the toxicity of bupivacaine in animal models.
Uses
Dobutamine is used to provide inotropic support in patients with a low cardiac output, secondary to:
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1. myocardial infarction
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2. cardiac surgery
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3. cardiomyopathy
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4. positive end-expiratory pressure ventilation
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5. in septic shock to increase oxygen transport to the tissues and
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6. cardiac stress testing.
Presentation
Dobutamine is presented in vials which hold a solution for injection containing 12.5/50 mg/ml of dobutamine hydrochloride, which needs to be diluted prior to infusion.
Mode of action
Dobutamine acts directly on catecholamine receptors to activate adenylate cyclase, which catalyses the conversion of adenosine triphosphate (ATP) to cAMP. This results in increased cell membrane permeability to Ca2+ which are necessary for depolarization and completion of the contractile process.
Routes of administration/doses
Dobutamine is infused intravenously, diluted in a suitable crystalloid to a volume of at least 50 ml. The dose range is 0.5–40 micrograms/kg/min, titrated against response; the drug acts within 1–2 minutes. Solutions should be used within 24 hours.
Effects
CVS
The primary action of dobutamine is to increase cardiac contractility by a direct action on cardiac beta-1 adrenoceptors. Sinoatrial nodal automaticity is increased, leading to an increased heart rate; AV nodal conduction velocity is also increased by the drug. Dobutamine also has activity at alpha- and beta-2 adrenoceptors, and thus tends to have only moderate effect on the systemic vascular resistance. Myocardial perfusion may increase. The drug leads to a decrease in both the left ventricular end-diastolic pressure and systemic vascular resistance, and thus to an increase in the cardiac index in patients with severe congestive cardiac failure.
Toxicity/side effects
Are uncommon at dose ranges below 10 micrograms/kg/min. Dysrhythmias, excessive tachycardia and hypertension, fatigue, nervousness, headache, and chest pain may occur. Allergic phenomena have been reported.
Distribution
Due to a half-life of 2 minutes, steady-state concentrations occur within 8–10 minutes when the drug is given at a fixed rate. The VD is 0.2 l/kg.
Presentation
As tablets containing 10 mg and a suspension containing 1 mg/ml of domperidone; 30 mg suppositories are also available.
Mode of action
The effects of domperidone on gastrointestinal mobility appear to be mediated by antagonism of peripheral dopaminergic (D2) receptors. Little else is known of the mechanism of action of the drug.
Routes of administration/doses
The adult oral dose is 10–20 mg, and the rectal dose 60 mg 4- to 8-hourly.
Effects
CVS
Domperidone has no significant effects on the cardiac output, heart rate, blood pressure, or conduction.
CNS
The drug does not readily cross the blood–brain barrier and is thus essentially devoid of central effects.
AS
The drug increases the lower oesophageal sphincter tone and the rate of gastric emptying. It has an antiemetic effect indistinguishable from that of metoclopramide in the prevention of post-operative vomiting but appears to be more effective in the treatment of established post-operative vomiting.
Toxicity/side effects
Domperidone is generally very well tolerated; there are occasional reports of extrapyramidal reactions occurring with the use of the drug. Galactorrhoea and gynaecomastia have also been reported.
Uses
Dopamine has been used in the management of:
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1. low cardiac output states
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2. septicaemic shock, and
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3. impending renal failure to promote diuresis.
Presentation
As a clear, colourless solution for injection containing 40/160 mg/ml of dopamine hydrochloride.
Mode of action
In low doses (1–5 micrograms/kg/min), dopamine acts upon specific dopaminergic receptors, of which at least two types are recognized. D1 receptors are a form of adenylate cyclase; D2 receptors are not linked to adenylate cyclase and are involved in the central modulation of behaviour and movement. At higher dose ranges, the drug acts via direct and indirect stimulation of beta- and alpha-adrenergic receptors; at an infusion rate of 5–10 micrograms/kg/min, beta stimulation predominates, whereas, at infusion rates exceeding 15 micrograms/kg/min, alpha effects predominate.
Routes of administration/doses
Dopamine is administered by intravenous infusion, diluted in glucose/saline or Hartmann’s solution. A dedicated central vein is preferred for the administration of the drug. A dose of 1–20 micrograms/kg/min may be used, titrated according to response. The drug acts within 5 minutes and has a duration of action of 10 minutes.
Effects
CVS
The cardiovascular effects of dopamine depend upon the rate of infusion. At low doses (5 micrograms/kg/min), beta-adrenergic effects predominate, leading to a positive inotropic effect, increased automaticity, and an increase in the cardiac output and coronary blood flow; the drug has little effect on the heart rate. Systolic and diastolic blood pressures may decrease slightly due to a decrease in the systemic vascular resistance (a beta-2 effect). With the use of high doses (15 micrograms/kg/min), peripheral vasoconstriction (an alpha-adrenergic effect) occurs, leading to an increased venous return and systolic blood pressure. Dopamine has variable effects on the PVR.
CNS
Dopamine is a central neurotransmitter involved in the modulation of movement; exogenous dopamine does not cross the blood–brain barrier, except in its laevorotatory form. The drug causes marked nausea due to a direct action on the chemosensitive trigger zone (which lies outside the blood–brain barrier). Increased intraocular pressure occurs with dopamine administration in critically ill patients.
The drug causes vasodilation of the splanchnic circulation by an effect on dopaminergic receptors and decreases gastroduodenal motility in the critically ill.
GU
In low doses (1–5 micrograms/kg/min), dopamine causes a marked decrease in the renal vascular resistance, with a corresponding increase in renal blood flow. Dopamine produces diuresis via the D1 receptors on the luminal and basal membranes of the proximal convoluted tubule. Natriuresis is produced by the inhibition of Na+K+ATPase. Creatinine clearance remains unaltered.
Toxicity/side effects
Tachycardia, dysrhythmias, angina, hypertension, and nausea and vomiting may all follow the administration of the drug. Extravasation of dopamine may cause ischaemic tissue necrosis and skin sloughing. An increase in perioperative cardiac events may occur.
Kinetics
Special points
As with all inotropes, correction of hypovolaemia should be ensured before use of the drug. A reduced dose should be used in patients who have recently received monoamine oxidase inhibitors (MAOIs). Halogenated volatile anaesthetic agents may increase the likelihood of dysrhythmias occurring during the concurrent use of dopamine. The dopaminergic stimulation is blocked by phenothiazines.
There is no evidence dopamine provides renal protection, and it may worsen renal ischaemia. It does not prevent the need for renal support nor does it delay the time for support.
The drug is inactivated by alkaline solutions (e.g. sodium bicarbonate).
Uses
Dopexamine is used in the treatment of:
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1. low cardiac output states (including those complicating cardiac surgery)
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2. acute heart failure
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3. to increase splanchnic blood flow and
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4. to prevent renal shutdown.
Presentation
As a clear solution containing 10 mg/ml of dopexamine hydrochloride; the solution should be discarded if it becomes discoloured.
Mode of action
Dopexamine is an agonist at dopaminergic D1 and D2 receptors and thus leads to relaxation of vascular smooth muscle in the renal, mesenteric, cerebral, and coronary arterial beds (D1 effects) and stimulation of sympathetic pre-junctional receptors, thereby decreasing noradrenaline release (a D2 effect). The drug also inhibits uptake-1 of noradrenaline and has potent beta-2 adrenergic agonist activity.
Route of administration/doses
Dopexamine should be diluted prior to administration in either glucose or saline and administered via a central vein using a controlled infusion device. The initial dose is 0.5 micrograms/kg/min which may be increased, as necessary, to a maximum dose of 6 micrograms/kg/min.
Effects
CVS
Dopexamine has positive inotropic and chronotropic effects, and thus increases the cardiac output. The drug causes arteriolar vasodilation, leading to a mild decrease in the diastolic blood pressure with a slight increase in the systolic blood pressure; the left and right ventricular afterload, left ventricular end-diastolic pressure, and pulmonary artery pressure decrease following the administration of the drug. Dopexamine also causes a slight increase in the coronary artery blood flow, with no attendant alteration in myocardial oxygen extraction. The drug has a low propensity to cause dysrhythmias.
CNS
The drug increases the cerebral blood flow, secondary to cerebral vasodilation. Nausea and vomiting may result from a weak D2 effect at the chemoreceptor trigger zone.
Uses
Doxapram is used:
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1. as a respiratory stimulant for the treatment of post-operative respiratory depression and acute-on-chronic respiratory failure and has been used
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2. in the treatment of laryngospasm
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3. to facilitate blind nasal intubation and
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4. in the treatment of post-operative shivering.
Presentation
As a clear, colourless solution containing 20 mg/ml and as a solution for infusion containing 2 mg/ml in 5% glucose of doxapram hydrochloride.
Mode of action
Doxapram acts primarily by stimulating the peripheral chemoreceptors and secondarily by a direct action on the respiratory centre.
Routes of administration/doses
The drug may be administered intravenously as a bolus of 1 mg/kg or as an infusion of 1.5–4 mg/min. Given intravenously, doxapram acts in 20–40 seconds; its peak effect is seen at 1–2 minutes, and the duration of action is 5–12 minutes, although pharmacological effects are detectable for 2 hours.
Effects
CVS
Doxapram causes an increase in the cardiac output, primarily due to an increase in the stroke volume. A slight increase in the blood pressure and heart rate may be produced by the drug.
RS
The minute volume is increased by doxapram due to an increase in the tidal volume; at higher doses, an increase in respiratory rate occurs. The CO2 response curve is displaced to the left by the drug. The work of breathing is increased.
CNS
The cerebral blood flow is increased, following the administration of doxapram; the drug has less convulsant activity than other analeptic agents.
Toxicity/side effects
Restlessness, dizziness, hallucinations, excessive sweating, and a sensation of perineal warmth have been described subsequent to the administration of doxapram.
Special points
Doxapram has been shown:
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1. to lead to a more rapid return to consciousness after inhalational anaesthesia
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2. to reverse opioid-induced respiratory depression without reversing analgesia and
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3. to prevent the necessity for mechanical ventilation in some patients.
The drug may possibly decrease the incidence of post-operative chest infections.
Oxygen must be given to patients receiving doxapram due to the increased metabolic rate and the increase in the work of breathing.
Uses
Droperidol is used:
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1. in premedication
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2. in the technique of neuroleptanalgesia
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3. in the treatment of nausea and vomiting occurring post-operatively or as a result of chemotherapy
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4. in the treatment of psychosis and has been used
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5. for the control of perioperative hiccuping.
Presentation
As 10 mg tablets, a syrup containing 1 mg/ml, and as a clear solution for injection containing 5 mg/ml of droperidol.
Mode of action
The antiemetic and neuroleptic effects of the drug appear to be mediated by:
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1. central dopaminergic (D2) blockade, leading to an increased threshold for vomiting at the chemoreceptor trigger zone and
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2. post-synaptic GABA antagonism.
Route of administration/doses
The adult oral or intramuscular dose is 5–10 mg, and the intravenous dose when used as a neuroleptic agent is 5–15 mg, although the drug appears to be an effective antiemetic in doses as low as 0.5 mg. The onset of action after intravenous administration is 3–20 minutes, and the drug may act for up to 12 hours.
Effects
CVS
Droperidol has minimal cardiovascular effects, but its antagonistic effects at alpha-adrenergic receptors may lead to hypotension in the presence of hypovolaemia.
RS
The drug causes small decreases in the minute volume, functional residual capacity, and airways resistance.
CNS
Droperidol induces neurolepsis, a state characterized by diminished motor activity, anxiolysis, and indifference to the external environment. The seizure threshold is raised by the drug.
Toxicity/side effects
Extrapyramidal effects occur in 1%. Gastrointestinal disturbances, abnormalities of liver function tests, and allergic phenomena have been reported after the use of droperidol. Malignant neuroleptic syndrome may be precipitated by droperidol.
Absorption
The drug is well absorbed after intramuscular administration. The pharmacokinetics of droperidol after oral administration has not been elucidated.
