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Author(s):

Sathiji Nageshwaran

, Heather C Wilson

, Anthony Dickenson

, and David Ledingham

DOI:
10.1093/med/9780199664368.003.0021
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date: 20 February 2020

3,4-diaminopyridine (amifampridine)

3,4-DAP was first used in clinical practice in the 1980s and is now the mainstay of symptomatic treatment for LEMS. Unlicensed preparations were widely used, before amifampridine phosphate (Firdapse®) was licensed in Europe in 2010. They differ from Firdapse® only by minor alterations in chemical structure and are still used in many regions where the cost of Firdapse® is considered prohibitive.

Uses

Licensed uses

In the UK

  • LEMS: Firdapse® is licensed for symptomatic treatment in individuals aged 18 years and older.

No 3,4-DAP formulation is licensed in the USA.

Off-licence uses

  • Congenital myasthenic syndrome and DBN.

Presentation

  • Trade name: Firdapse®. Generic amifampridine is not widely available.

  • Formulation: oral scored tablets, 10mg.

Mechanism of action

3,4-DAP prolongs presynaptic cell membrane depolarization by blockade of presynaptic voltage-gated potassium channels. This increases the influx of calcium into nerve endings and facilitates exocytosis of acetylcholine-containing vesicles. This action overcomes the effect of VGCC blockade in LEMS, resulting in successful neuromuscular transmission. In DBN, the same mechanism is believed to result in increased excitability of the Purkinje cells of the cerebellum, which may restore their inhibitory function on deep cerebellar and vestibular nuclei.

Toxicity and side effects

  • Commoncardiovascular: arrhythmias, palpitations. Gastrointestinal: non-specific GI upset. Neurological: anxiety, blurred vision, chorea, dizziness, drowsiness, fatigue, headache, myoclonia, oral paraesthesiae, sleep disorders, weakness. Respiratory: exacerbation of asthma.

Contraindications

  • Absolute: epilepsy (3,4-DAP lowers seizure threshold), uncontrolled asthma, and congenital long QT syndromes.

  • Relative: in renal and hepatic impairment, the manufacturer recommends a smaller starting dose of 5–10mg and gradual uptitration.

Uses in special populations

  • Elderly: no separate data on safety and efficacy in this group, but this group has an age-related decline in renal and hepatic function, and reduced doses may be required.

  • Pregnancy/lactation: no safety data. The manufacturer advises avoidance and effective contraception for men and women during treatment with 3,4-DAP.

Efficacy

  • DBN: a prospective, placebo-controlled study evaluated the effect of a single dose of 3,4-DAP (20mg) on DBN (n = 17, of various aetiologies). Mean peak slow-phase velocity was reduced from 7.2 (SD: 4.2) degrees/s before treatment to 3.1 (SD: 2.5) degrees/s 30min after treatment (p <0.001). Subjects reported less oscillopsia and felt more stable, while standing and walking. Recently, 3,4-DAP (10mg) and 4-AP (10mg) were compared in a double-blind, prospective cross-over study (n = 8) for the treatment of DBN. 4-AP was shown to be more effective at 45 and 90min, as shown by significant reductions in slow-phase velocity.

  • LEMS: four randomized, placebo-controlled trials of 3,4-DAP have been undertaken, showing an improvement on a validated myasthenia score of 2.44 points (95% CI 1.22–3.6) when measured between 3 and 8 days of treatment, and of CMAP amplitude by 1.36mV (95% CI 0.99–1.72) when compared with placebo. Clinical improvement lasts for up to 8 weeks.

Dosing and monitoring

Dosing

  • DBN: as 3,4-DAP is an expensive drug, an observed test dose is often given first where patients are given either the medication or a placebo, and then the degree of nystagmus, gait, and dynamic visual acuity are assessed pre- and post-dosing. If the test dose is successful, then treatment can be started at 10mg od, and increased by 10mg every 1–2 weeks, as required/tolerated, up to 20mg tds.

  • LEMS: 15mg od; 5mg increments every 4–5 days, up to a maximum of 60mg/day in 3–4 divided doses.

Monitoring

Perform an ECG at baseline. Commonly, the first test dose is given, while the patient is attached to a cardiac monitor, to assess for the presence of arrhythmia.

Pharmacokinetics and interactions

Pharmacokinetics

Well-absorbed orally, with a bioavailability of 93–100%. Peak plasma concentration by 0.6–1.3h. Absorption is affected by food, with a 2-fold increase in Tmax. Time to steady state has not been described in the manufacturer’s literature. Metabolized to an inactive 3-N-acetylated metabolite. Half-life is around 2.5h. Amifampridine is fully renally excreted within 24h, 19% as the parent molecule and 81% as the metabolite.

Interactions

See Table A.45.

Table A.45 Interactions of 3,4-DAP (amifampridine)

Pharmacodynamic interactions

  • With medications which prolong the QT interval, e.g. sultopride: risk of ventricular arrhythmias

  • With medications which reduce seizure threshold: increased risk of seizures

References

Kalla R, Spiegel R, Claassen J, et al. Comparison of 10-mg doses of 4-aminopyridine and 3, 4-diaminopyridine for the treatment of downbeat nystagmus. J Neuroophthalmol 2011;31(4):320–5.Find this resource:

Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev 2011;2:CD003279.Find this resource:

Lundh H, Nilsson O, Rosén I. Novel drug of choice in Eaton-Lambert syndrome. J Neurol Neurosurg Psychiatry 1983;46(7):684–5.Find this resource:

Strupp M, Schuler O, Krafczyk S, et al. Treatment of downbeat nystagmus with 3, 4-diaminopyridine. A placebo-controlled study. Neurology 2003;61(2):165–70.Find this resource:

Acetazolamide

Acetazolamide was first marketed in the UK as an AED in 1953. It can be used as a broad-spectrum AED (predominantly as an adjunct) and is also commonly used in the management of idiopathic intracranial hypertension. It benefits from a rapid onset of action and few pharmacological interactions. Its usefulness in epilepsy is limited by tolerance which can develop within 1–6 months of initiating therapy.

Uses

Licensed uses

In the UK

  • Epilepsy: acetazolamide is licensed for treatment as an adjunct of atonic, atypical absence, myoclonic, tonic, and generalized tonic–clonic seizures in individuals of all ages.

Acetazolamide is not licensed for use in the treatment of epilepsy in the USA.

Off-licence uses

  • Catamenial seizures, episodic ataxias, idiopathic intracranial hypertension, and periodic paralyses.

Presentation

  • Trade names: Diamox® and Diamox® SR. Generics are available.

  • Formulations: Diamox® is available as a modified-release capsule, a powder for reconstitution, IM or IV injection (as a sodium salt), and as a tablet. Modified-release capsule: 250mg. Powder for reconstitution: 500mg per vial. Tablet: 250mg.

Mechanism of action

  • Epilepsy: acetazolamide is a carbonic anhydrase inhibitor. The exact mechanism of action in epilepsy is unclear. Its action may be mediated by inhibition of cerebral carbonic anhydrase enzymes or by systemic lowering of the pH, resulting in lowering of intracellular pH and suppression of neuronal activity. When used as an adjunct, a proportion of its effect may be due to increased tissue absorption of other AEDs such as phenytoin and phenobarbital.

  • Idiopathic intracranial hypertension: acetazolamide is believed to reduce the formation of CSF by inhibiting the action of choroid plexus carbonic anhydrase activity.

Toxicity and side effects

Carbonic anhydrase inhibitors reduce intracellular pH, resulting in an increased incidence of hypokalaemia, metabolic acidosis, nephrolithiasis, paraesthesiae, polydipsia, and polyuria.

  • Commondermatological: allergic rash. Endocrine: reduced libido. Gastrointestinal: anorexia, diarrhoea, nausea, and parageusia. Neurological: dizziness, headache, and paraesthesiae.

  • Seriousdermatological: Stevens–Johnson syndrome and toxic epidermal necrolysis have been reported. Haematological: rarely blood dyscrasias and bone marrow suppression.

Contraindications

  • Absolute: pre-existing adrenocortical insufficiency due to its tendency for potassium loss, cirrhosis due to its predisposition for hyperammonaemia, pre-existing metabolic acidosis, and severe renal impairment. In addition, it should be avoided in patients treated with high-dose aspirin, as the combination has been reported to result in tachypnoea, loss of appetite, coma, and even death.

  • Relative: the dose should be lowered in mild to moderate renal impairment (eGFR <60mL/min/1.73m2). It should be used with caution in patients with hyponatraemia, hypokalaemia, a history of sulfonamide-induced allergic rash, and those with a previous history of nephrolithiasis or on treatments predisposing to stone formation, including topiramate and zonisamide. It should not be given to patients who are undergoing sustained treatment for chronic angle-closure glaucoma.

Uses in special populations

  • Elderly: the elderly have an age-related deterioration in their renal and hepatic function, and benefit from lower dosing regimens. Co-prescription of other medications is also more likely in the elderly, and hence the risk of pharmacokinetic interactions is high.

  • Pregnancy: some animal studies have demonstrated teratogenic effects; however, there are no controlled studies in humans. Use in pregnancy involves weighing up the potential benefits and side effects. Most would use alternative means of controlling CSF pressure in IIH, including weight control, regular lumbar puncture, or a neurosurgical procedure. The pharmacokinetics of acetazolamide during pregnancy have not been adequately studied.

  • Lactation: acetazolamide is present in breast milk. Infant’s plasma levels are 4–9% of maternal plasma levels, and this is thought to be too low to be harmful. If used, infants should be monitored for potential side effects. They should be switched to alternative methods of feeding if these are identified.

Efficacy

  • Epilepsy: there is little good-quality evidence available as to the clinical efficacy of acetazolamide in epilepsy. What evidence there is comes from the 1950s and suggests that acetazolamide is a broad-spectrum AED, prone to the development of tolerance after 1–6 months. The tolerance is eliminated by intermittent use, making it useful if an AED is needed for short periods, e.g. catamenial epilepsy.

  • Idiopathic intracranial hypertension: For discussion of the evidence base for use in IIH, please see the IIH section, pp. [link][link].

Dosing and monitoring

Dosing

  • Epilepsy: the PO and IV dosages are between 0.25g and 1g daily in divided doses.

  • Idiopathic intracranial hypertension: acetazolamide can be started at 250–500mg bd for BIH (or 15–25mg/kg/day in 2–3 divided doses), and increased according to response. Suggested dose increments are 15–25mg/kg at weekly intervals. Doses of up to 2–4g/day may be used. Side effects are dose-related, and higher doses may not be tolerated by some patients.

Routine monitoring

Not recommended routinely. Serum bicarbonate can be monitored, if necessary.

Therapeutic drug monitoring

Optimum seizure control occurs at plasma acetazolamide levels of 10–14mg/L.

Pharmacokinetics and interactions

Pharmacokinetics

Acetazolamide has good oral absorption, with bioavailability >90%. It reaches maximum plasma concentrations (Tmax) at 2–4h, and steady state in 2 days. It does not undergo hepatic metabolism. Hundred per cent of the dose is ultimately excreted unchanged by the kidneys. The half-life is 10–15h.

Interactions

See Table A.46.

Table A.46 Interactions of acetazolamide

Medications whose plasma levels are altered by acetazolamide

Pharmacodynamic interactions

  • Levels increased: carbamazepine, ciclosporin, phenobarbital, and phenytoin

  • Levels decreased: lithium and primidone

  • With other carbonic anhydrase inhibitors and bicarbonate: increased risk of nephrolithiasis

  • With high-dose aspirin: risk of tachypnoea, anorexia, sedation, and even death

References

Ball A, Howman A, Wheatley K, et al. A randomized controlled trial of treatment for idiopathic intracranial hypertension. J Neurol 2011;258(5):874–81.Find this resource:

Celebisoy N, Gokcay F, Sirin H, et al. Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta Neurol Scand 2007;116(5):322–7.Find this resource:

Foldvary-Schaefer N, Falcone T. Catamenial epilepsy: pathophysiology, diagnosis and management. Neurology 2003;61(6 Suppl 2):S2–15.Find this resource:

Katayama F, Miura H, Takanashi S. Long-term effectiveness and side effects of acetazolamide in the treatment of refractory epilepsies. Brain Dev 2002;24(3):150–4.Find this resource:

Aciclovir

Aciclovir has been used in the management of herpes virus infections since the 1980s. It is most effective against HSV 1 and 2, to a lesser extent herpes zoster, and has only minimal effectiveness against CMV and EBV. It needs to be started without delay if herpes encephalitis is suspected, and continued for at least 2–3 weeks, potentially longer in the immunosuppressed.

Uses

Licensed uses

In the UK/USA

  • Viral encephalitis: IV aciclovir is licensed for the treatment of herpes encephalitis in individuals of all ages. In the USA, the IV licence only includes herpes simplex encephalitis.

Off-licence uses

  • None.

Presentation

  • Trade names: Zovirax®. Generics are available.

  • Formulations: aciclovir is available as multiple enteral and parenteral formulations. For the purposes of herpes encephalitis, only the IV form should be used. This is available as a powder for reconstitution and IV infusion and as a sterile concentrate. Powder for reconstitution and IV infusion: 250mg. Sterile concentrate: 10mL, 20mL, and 40mL at 25mg/mL.

Mechanism of action

Aciclovir is a purine nucleoside analogue. It specifically interacts with the viral thymidine kinase enzyme, leading to the creation of aciclovir triphosphate, a false substrate for viral DNA polymerase, which, when incorporated into a new DNA chain, results in termination, thereby preventing DNA replication.

Toxicity and side effects

  • Commondermatological: allergic rash, phlebitis with IV infusion, photosensitivity, pruritus, and urticaria. Gastrointestinal: abdominal pain, diarrhoea, nausea, reversible changes in hepatic enzymes, and vomiting. Neurological: fatigue and headache. Renal: deranged renal function.

  • Seriousdermatological: severe local inflammatory reactions, potentially resulting in necrosis, may occur with tissue extravasation during IV infusion. Anaphylaxis and angio-oedema are rare. Gastroenterological: hepatitis. Haematological: anaemia, leucopenia, and thrombocytopenia have been reported. Neurological: severe neurological reactions, including ataxia, convulsions, tremors, and even coma can occur. Psychiatric: psychosis can occur. Renal: acute kidney injury, particularly with IV infusions—this can be minimized by slow IV infusions and ensuring adequate hydration.

Contraindications

  • Absolute: hypersensitivity to aciclovir, its excipients, or valciclovir.

  • Relative: use with caution in patients with underlying neurological abnormalities or previous neurological reactions to cytotoxic drugs, or who are co-prescribed IFN or intrathecal methotrexate, as these groups may be more prone to neurological side effects.

In renal impairment, the dose will need to be reduced.

  • For the IV formulation: if CrCl is 25–50mL/min, give 5–10mg/kg bd, rather than tds; if CrCl is 10–25mL/min, give 5–10mg/kg od. Consult the product literature if CrCl is <10mL/min.

  • For the oral formulation: if the eGFR is <10mL/min/1.73m2, use the 800mg bd for herpes zoster infections; if the eGFR is 10–25mL/min/1.73m2, use 800mg tds.

No dose adjustments are required in hepatic impairment, although it should be used with caution in severe impairment.

Uses in special populations

  • Elderly: the elderly have an age-related deterioration in their renal function and may benefit from lower dosing regimens. The elderly are also more likely to get neuropsychiatric side effects and worsening renal function; hence urea and electrolytes (U&Es) should be frequently monitored.

  • Pregnancy: limited data are available regarding the use of aciclovir in pregnancy. Small registries of human births and animal studies have not shown teratogenicity. However, aciclovir does cross the placenta, so the manufacturers advise against use, unless the benefits outweigh the risks.

  • Lactation: aciclovir enters breast milk. The manufacturer advises against use by nursing mothers, unless the benefits outweigh the risks.

Efficacy

Compared to historic controls before the use of effective antivirals, aciclovir cuts the mortality rate from herpes simplex encephalitis by approximately two-thirds (from 70% to 20% case-based mortality). Increasing duration of symptoms prior to initiation of treatment is strongly associated with poorer outcome. Neurological sequelae occur in 70%, but these are of variable severity and functional impact. Approximately half of patients return to a normal life. For herpes zoster encephalitis, aciclovir is used on the basis of case study evidence and expert consensus; there are no controlled studies.

Dosing and monitoring

Dosing

For the treatment of herpes encephalitis, administer 10mg/kg tds for a minimum of 14–21 days for herpes simplex, and 14 days for herpes zoster. The need for ongoing treatment should be guided by the presence or absence of positive viral CSF PCR results, following a standard treatment course, and clinical response. Immunocompromised patients may need longer courses.

Routine monitoring

Renal function, FBC, and liver function should be monitored frequently during treatment.

Pharmacokinetics and interactions

Pharmacokinetics

The terminal plasma half-life of aciclovir after IV infusion is ~3h; this can be prolonged to 20h in chronic renal failure. CSF levels reach 50% of corresponding plasma levels. Protein binding is 10–30%. Aciclovir is mainly eliminated via the renal tract, 75–80% as unchanged drug and 10–15% as the major metabolite 9-carboxymethoxymethylguanine.

Interactions

See Table A.47.

Table A.47 Interactions of aciclovir

Medications whose plasma levels are altered by aciclovir

Medications whose plasma levels are altered by aciclovir

Pharmacodynamic interactions

Levels increased: cimetidine, mycophenolate mofetil (metabolite), probenecid, tenofovir, and theophylline

Levels increased: mycophenolate mofetil (metabolite)

  • With nephrotoxics: increased risk of acute kidney injury

  • With herpes zoster vaccine: may diminish the effect of the vaccine

References

McGrath N, Anderson NE, Croxson M, et al. Herpes simplex encephalitis treated with aciclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 1997;63(3):321–6.Find this resource:

Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults—Association of British Neurologists and British Infection Association National Guidelines. J Infect 2012;64(4):347–73.Find this resource:

Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008;47(3):303–27.Find this resource:

Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus aciclovir therapy in herpes simplex encephalitis. N Engl J Med 1986;314(3):144–9.Find this resource:

Alemtuzumab

This drug, initially marketed as Campath®, was developed to treat B-cell chronic lymphocytic leukaemia. It was licensed for treatment of RRMS in the UK in 2014.

Uses

Licensed uses

In the UK/USA

  • MS: alemtuzumab is licensed for the treatment of highly active RRMS in individuals aged 18 years and older.

Off-licence uses

  • None.

Presentation

  • Trade name: Lemtrada®. Generics are not available.

  • Formulation: a concentrate for IV infusion (10mg/mL): 12mg.

Mechanism of action

Alemtuzumab is a humanized IgG1-kappa monoclonal antibody specific for the protein CD52 on the cell surface of B and T lymphocytes. It mediates cell lysis by complement fixation and cell-mediated cytotoxicity. This induces a prolonged depletion of circulating lymphocytes. B cells recover rapidly, but T cells can take up to 5 years to return to baseline levels.

Toxicity and side effects

  • Commonendocrine: thyroid dysfunction. Psychiatric: anxiety and insomnia.

  • Seriouscardiovascular: arrhythmia, cardiac failure, and MI. Haematological: anaemia, immune thrombocytopenic purpura (ITP), lymphopenia, and neutropenia. Immunological: ITP and thyroid dysfunction. Anaphylaxis infusion reactions (dyspnoea, fever, hypotension, rash, tachycardia, and urticaria) and opportunistic infections. Renal: autoimmune-related kidney disease, including anti-glomerular basement membrane disease. Respiratory: acute respiratory distress syndrome.

Contraindications

  • Absolute: hypersensitivity to alemtuzumab (or murine proteins), active systemic infections, HIV, and active malignancy.

  • Relative: the effects on patients with renal or hepatic impairment have not been studied, and caution is advised.

Use in special populations

  • Elderly: alemtuzumab has not been studied in the elderly.

  • Pregnancy: the teratogenicity of this drug is not known, but it is contraindicated in pregnancy. Active contraception should be used during, and for 6 months after, treatment.

  • Lactation: breastfeeding should be avoided.

Efficacy

The CARE-MS I trial compared alemtuzumab 12mg/day to SC IFN-β‎-1a in patients who had not previously been treated with DMTs. The relapse rate over 2 years was 22% with alemtuzumab, compared to 40% with Interferon Beta-1a (P<0.0001). With no significant effect on 6-month disability progression. The CARE-MS II trial again compared alemtuzumab 12mg/day or 24mg/day to SC IFN-β‎-1a. The relapse rate over 2 years was 49% lower, compared to IFN, and the risk of 6-month sustained accumulation of disability was reduced by 42% (p = 0.0098).

Over a median 7-year follow-up, most (52%) patients received just two cycles; 36% required three cycles, 8% four, and 1% five. Disease stabilization was seen in the majority of patients, with 67.8% showing improved or unchanged 6-month sustained disability, compared with baseline, and 59.8% showing overall improvement or stabilization of disability using an area under the curve analysis. Secondary autoimmunity was the most frequently observed side effect, occurring in 47.7% patients, commonly involving the thyroid gland.

Dosing and monitoring

Dosing

IV infusion of 12mg each day for 5 consecutive days, followed by 12mg each day for 3 days after 1 year.

Routine monitoring

Patients should be pre-treated with corticosteroids (1g methylprednisolone for the first 3 days of the treatment course), antihistamines, and oral aciclovir (200mg bd for 1 month) to prevent herpes zoster infections. Patients should be observed for infusion reactions, which can be severe. Prophylaxis against Pneumocystis jiroveci pneumonia (PCP) is used for a minimum of 2 months and until the CD4 count exceeds 200 × 106/L. There is a significant risk of thrombocytopenia and neutropenia during treatment. FBC should be measured before, and at regular intervals (current recommendation is monthly) during, treatment. If platelet counts fall below 25 × 109/L or neutrophil counts fall below 0.25 × 109/L, alemtuzumab should be withheld. The drug should be permanently discontinued if autoimmune thrombocytopenia or anaemia develops. Thyroid function tests (TFTs) and urinalysis should also be monitored regularly during treatment.

Pharmacokinetics and interactions

Pharmacokinetics

Clearance decreases with repeated doses, due to the reducing numbers of CD52 receptors in the periphery. With accumulation in the plasma, the rate of elimination reaches zero-order kinetics. The half-life is 8h following the initial dose and increases up to 6 days after repeated doses.

Interactions

Patients should only ever receive irradiated blood products following treatment, due to the risk of transfusion-associated graft-versus-host disease. Patients should not receive live vaccines for 12 months following treatment.

References

Cohen JA, Coles AJ, Arnold DL, et al; CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012;380(9856):1819–28.Find this resource:

Coles AJ, Fox E, Vladic A, et al; Alemtuzumab more effective than interferon beta-1-a at 5 year follow up of CAMMS223 clinical trial. Neurology 2012;78(14):1069–78.Find this resource:

Coles AJ, Twyman CL, Arnold DL, et al; CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled phase 3 trial. Lancet 2012;380(9856):1829–39.Find this resource:

Tuohy O, Costelloe L, Hill-Cawthorne D, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry 2015;86(2):208–15.Find this resource:

Alteplase

Alteplase is a parenteral fibrinolytic agent, which is the only agent of its class to be licensed in the management of acute ischaemic stroke. It was first approved for acute ischaemic stroke in the UK in the late 1990s. Fibrinolytic therapy has the potential to restore cerebral blood flow and markedly improve neurological outcome when used in the first hours post-acute ischaemic stroke.

Uses

Licensed uses

In the UK/USA

Alteplase is licensed for the treatment of acute ischaemic stroke if treatment is within 4.5h of symptom onset (USA: 3h after symptom onset), and intracranial haemorrhage is excluded by imaging, in individuals aged 18 years and older.

Off-licence uses

  • None.

Presentation

  • Trade name: Actilyse®. Generics are not available.

  • Formulations: alteplase is available as a powder for reconstitution and injection or infusion in 10mg, 20mg, and 50mg vials.

Mechanism of action

Alteplase is a tissue plasminogen activator (t-PA) which converts plasminogen to plasmin. Plasmin is an enzyme that degrades fibrin clots. The aim is to reduce the impact of ischaemia by restoring blood flow through the occluded artery.

Toxicity and side effects

  • Commoncardiovascular: hypotension. Gastrointestinal: nausea and vomiting. Haematological: iron deficiency anaemia. Immunological: allergic reaction, injection site reaction.

  • Seriouscardiovascular: recurrent ischaemia or angina, heart failure, reperfusion arrhythmias. Gastrointestinal: haemorrhage (occasionally major). Neurological: intracranial haemorrhage. Respiratory: pulmonary oedema.

Contraindications

  • Absolute: alteplase is contraindicated in cases where there is a high risk of haemorrhage; according to the product licence, this includes:

    1. 1. significant bleeding at any time within the past 6 months;

    2. 2. known haemorrhagic diathesis;

    3. 3. patients receiving effective oral anticoagulant treatment;

    4. 4. known history of, or suspected, intracranial/subarachnnoid haemorrhage;

    5. 5. any history of CNS damage, e.g. neoplasm, aneurysm, surgery;

    6. 6. traumatic external heart massage, obstetric delivery, puncture of a non-compressible blood vessel (e.g. subclavian or jugular vein) within the last 10 days;

    7. 7. elevated BP—systolic >185mmHg or diastolic >110mmHg;

    8. 8. bacterial endocarditis or pericarditis;

    9. 9. acute pancreatitis;

    10. 10. ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, or arterial/venous malformations;

    11. 11. neoplasm with increased bleeding risk;

    12. 12. severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices), and active hepatitis;

    13. 13. major surgery or significant trauma within the past 3 months;

    14. 14. CT evidence of multilobar infarction;

    15. 15. blood glucose <2.7mmol/L or >22.2mmol/L (<50 or >400mg/day);

    16. 16. platelet count <100 000/mm3.

In the USA, the American Stroke Association recommends additional contraindications to alteplase use in the management of acute stroke when considered 3–4.5h post-onset of symptoms:

  1. 1. age >80 years;

  2. 2. patients taking oral anticoagulants (irrespective of INR);

  3. 3. a baseline National Institutes of Health Stroke Scale (NIHSS) score of >25;

  4. 4. ischaemic injury occupying more than one-third of the MCA territory;

  5. 5. patients with both a prior stroke and diabetes.

In the experienced stroke physician’s hands, some of the contraindications listed may not be absolute in practice, and, in complex cases, careful consideration of the balance of risk and benefit is required.

  • Relative:

    1. 1. seizures at onset of stroke with post-ictal residual neurological impairments;

    2. 2. pregnancy;

    3. 3. minor or rapidly improving stroke symptoms;

    4. 4. acute MI within the previous 3 months.

Uses in special populations

  • Elderly: in the elderly, no dose adjustment is required. However, the benefits of therapy should be carefully weighed up against the risk of adverse events such as bleeding.

  • Pregnancy: should be used with caution and only if benefits outweigh risks. Its use may lead to premature separation of the placenta in the first 18 weeks of pregnancy. It additionally confers an increased risk of maternal haemorrhage throughout pregnancy and post-partum, while also having the theoretical risk of fetal haemorrhage throughout pregnancy.

  • Lactation: there are no data available, and hence it should be used with caution.

Efficacy

Early trials of alteplase use within the first 3h post-symptom onset in acute ischaemic stroke showed that patients were at least 30% more likely to have minimal or no disability at 3 months, when compared to placebo (NINDSr-tPA). The ECASS III RCT suggested that favourable outcomes could be obtained when alteplase was used up to 4.5h post-symptom onset. However, other similar small studies suggested there was no benefit in giving alteplase after 3h (ATLANTIS and ECASS II).

Ultimately, a much larger study the IST-3 trial was run to clarify whether alteplase should be used in situations where benefit was uncertain, e.g. >3h from onset, >80 years. It was a large (n = 3035, of whom 1617 were older than 80 years of age) randomized, open-label trial, which ascertained that patients thrombolysed within 6h of symptom onset had improved functional outcomes, a benefit that extended to the population aged >80. However, no benefit was conferred with regard to mortality.Those who were thrombolysed faced an increased number of deaths within the first 7 days (7% vs 1%), while those who were not had a higher mortality rate between 7 days and 6 months.

Dosing and monitoring

Dosing

The total dose is 900 micrograms/kg (maximum 90mg). The first 10% of the dose is given by IV injection over 60s, then the remainder by IV infusion over 60min.

Monitoring

It is recommended that, when alteplase is administered, standard resuscitation equipment should be available. Due to an increased haemorrhagic risk, antiplatelet agents should not be started until 24h after administration of alteplase.

Pharmacokinetics and interactions

Pharmacokinetics

When administered IV, alteplase is inactive in the circulatory system, until it binds to the fibrin clot where it is subsequently activated, inducing the conversion of plasminogen to plasmin and leading to the dissolution of the fibrin clot. Alteplase is cleared rapidly from the circulating blood and metabolized mainly by the liver, with a half-life of ~5min. Fibrinolytic activity is present for a further hour following cessation of the infusion.

Interactions

See Table A.48.

Table A.48 Interactions of alteplase

Pharmacodynamic interactions

  • With abciximab, aspirin, clopidogrel, heparin, NSAIDs, ticlopidine, vitamin K antagonists, warfarin: increased risk of bleeding

  • With ACE inhibitors: increased risk of angio-oedema

References

Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359(13):1317–29.Find this resource:

Sandercock P, Wardlaw JM, Lindley RJ, et al. (2012). The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379(9834):2352–63.Find this resource:

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333(24):1581–7.Find this resource:

Wechsler LR. Intravenous thrombolytic therapy for acute ischemic stroke. N Engl J Med 2011;364(22):2138–214.Find this resource:

Amantadine

Amantadine was first marketed in the 1960s for the treatment of influenza. It was serendipitously found to have a beneficial effect on the symptoms of PD in patients treated for influenza in 1968. It can be used as monotherapy or as an adjunct to levodopa, particularly in those with troublesome dyskinesias.

Uses

Licensed uses

In the UK/USA

  • PD: amantadine is licensed for the treatment of PD in individuals aged 10 years and older in the UK, and 1 year and older in the USA.

In the USA

  • Drug-induced extrapyramidal syndrome: amantadine is also licensed for the treatment of drug-induced extrapyramidal side effects in individuals aged 1 year and older.

Off-licence uses

  • Chorea and MS-related fatigue.

Presentation

  • Trade names: Lysovir® and Symmetrel®. Generics are available.

  • Formulations: amantadine is available as a capsule and a syrup. Capsule: 100mg. Syrup: 50mg/5mL in a 150mL bottle.

Mechanism of action

The exact mechanism of action in the treatment of PD is unknown; proposed mechanisms include: inhibition of dopamine reuptake and enhanced dopamine release at the presynaptic membrane, post-synaptic upregulation of D2 receptors, antimuscarinic activity, and non-competitive NMDA receptor antagonism (NMDA receptor blockade has been shown to reduce the severity of levodopa-induced dyskinesias in monkey models of PD).

Toxicity and side effects

  • Commoncardiovascular: orthostatic hypotension and peripheral oedema. Dermatological: livedo reticularis. Gastrointestinal: anorexia, constipation, diarrhoea, dry mouth, and nausea. Neurological: ataxia, dizziness, dream abnormality, fatigue, headache, insomnia, somnolence. Psychiatric: agitation, anxiety, confusion, delirium, depression, and hallucinations.

  • Serioushaematological: agranulocytosis. Neurological: lowered seizure threshold and NMS (related to dosage reduction or sudden withdrawal). Ophthalmological: corneal oedema. Psychiatric: mania, psychosis, and suicide.

Contraindications

  • Absolute: known hypersensitivity to amantadine, severe renal impairment (CrCl <15mL/min).

  • Relative: use with caution in angle-closure glaucoma, underlying neuropsychiatric disorders, cardiovascular disorders, and known seizure disorder (lowers seizure threshold). No dose alteration in hepatic impairment. In renal impairment, reduce the dose to 100mg every 2–3 days if CrCl is 15–35mL/min.

Uses in special populations

  • Elderly: the elderly experience an age-related reduction in renal function and are more prone to side effects, including orthostatic hypotension; hence a lower dosing regimen may be appropriate.

  • Pregnancy: teratogenicity noted in animal studies and case reports in humans; use in pregnancy is contraindicated.

  • Lactation: amantadine is present in milk; its manufacturers advise avoidance in nursing mothers.

Efficacy

A randomized, placebo-controlled trial of amantadine (300mg/day) was conducted in advanced PD patients with motor fluctuations and dyskinesias treated with levodopa. Amantadine treatment was superior to placebo in suppressing dyskinesias, with an average duration of effect of 4.9 vs 1.3 months with placebo (p <0.001). There was an increase in ‘on’ time and a decrease in ‘off’ time; however, neither was significant. Another placebo-controlled study of 17 patients treated with amantadine found the anti-dyskinetic effect to be maintained at 1 year.

Dosing and monitoring

Dosing

Start treatment at 100mg od, and increase to 100mg bd at 1 week. This is the usual maintenance dose, although amantadine can be further uptitrated by 100mg a week to a maximum dose of 400mg/day, if required. Onset of effect may be seen after 1–2 days but often is lost after a few months. Avoid giving the second dose in the evening, due to risk of insomnia.

Pharmacokinetics and interactions

Pharmacokinetics

Oral bioavailability is 66–100%. Tmax is 3–4h. Steady state is reached at 3 days. Sixty-seven per cent is protein-bound (plasma proteins and red blood cells). Amantadine undergoes minimal metabolism by N-acetylation. The elimination half-life is 90%; the predominant mechanism is renal secretion, ~90% as unchanged drug.

Interactions

See Table A.49.

Table A.49 Interactions of amantadine

Medications which alter amantadine plasma levels

Pharmacodynamic interactions

Levels increased: drugs which impair renal clearance (e.g. thiazide diuretics, and trimethoprim)

  • With anticholinergics: can enhance the anticholinergic effects of amantadine

  • With CNS depressants, e.g. alcohol: may increase CNS toxicity

References

Fox S, Katzenschlager R, Lim S, et al. The Movement Disorder Society Evidence-Based Medicine Review Update: treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2011;26(Suppl 3):S2–41.Find this resource:

Metman L, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999;56(11):1383–6.Find this resource:

Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Onofrj M. Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004;75(1):141–3.Find this resource:

Ammonium tetrathiomolybdate

Ammonium tetrathiomolybdate, an unlicensed agent previously used to treat copper toxicosis in animals, is emerging as a potential new chelating treatment in WD. Its improved side effect profile, in particular the reduced incidence of neurological deterioration on initiation of treatment (compared to the existing chelating therapies available for WD) and the encouraging results from short-term clinical efficacy studies have promoted its off-licence use.

Uses

Licensed uses

In the UK/USA

  • Ammonium tetrathiomolybdate has no licensed uses.

Off-licence uses

  • WD.

Presentation

  • Trade names: it is not yet commercially available.

  • Formulations: in clinical trials, it has been given via the oral route.

Mechanism of action

Ammonium tetrathiomolybdate acts to reduce total body copper in two ways; firstly, it binds copper from both food and endogenously secreted intestinal copper, to form a complex which prevents intestinal copper absorption. Secondly, when absorbed, tetrathiomolybdate complexes available copper with albumin, thereby preventing cellular absorption and increasing systemic copper removal.

Toxicity and side effects

  • Commongastrointestinal/hepatic: a mild elevation of aminotransferase enzymes has been observed in some clinical studies (~5% of patients). This effect occurs much less frequently if the daily dose does not exceed 120mg and is quickly responsive to a drug holiday and/or dose reduction.

  • Serioushaematological: the predominant adverse effect observed in clinical studies is mild bone marrow suppression, producing anaemia, leucopenia, and occasionally thrombocytopenia. This is probably because the bone marrow requires copper for cellular proliferation. It is a dose-related effect; it occurs much less frequently if the daily dose does not exceed 120mg and is quickly responsive to a drug holiday and/or dose reduction. Neurological: deterioration of the neurological manifestations of WD occurs in ~4%, i.e. a lower rate than with alternative copper-chelating agents.

Contraindications

  • Absolute: hypersensitivity to ammonium tetrathiomolybdate.

  • Relative: studies have not been performed in patients with hepatic or renal impairment; hence no guidance with regard to dose adjustment can be recommended—use with caution.

Uses in special populations

  • Elderly/pregnancy/lactation: there are no data on the safety and efficacy of tetrathiomolybdate in patients above 65 years of age, those who are pregnant, or nursing mothers; use with caution.

Efficacy

An open-label study of 55 patients presenting with neurological symptoms of WD treated with tetrathiomolybdate showed that the neurological symptoms worsened in only 4% of patients (two of 55) during the 8 weeks of tetrathiomolybdate treatment, as indicated by serial quantitative neurology and speech scores.

When comparing tetrathiomolybdate with trientine, a double-blind RCT of 48 patients with neurological symptoms of WD demonstrated that deterioration of these neurological symptoms occurred in only 4% of patients (one of 25), compared to 26% in the trientine arm (p <0.05). Furthermore, at a 3-year period, patients initially treated with tetrathiomolybdate recovered an average of 81% of their neurological function.

Dosing and monitoring

Dosing

In the RCT by Brewer and colleagues, patients received tetrathiomolybdate in doses of 20mg tds with meals and 20mg tds in between meals.

Routine monitoring

Regular monitoring of the FBC and liver profile should be undertaken.

Pharmacokinetics and interactions

Pharmacokinetics

  • Pharmacokinetic studies have not been carried out.

Interactions

  • None as yet reported.

References

Brewer GJ, Askari F, Lorincz MT, et al. Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch Neurol 2006;63(4):521–7.Find this resource:

Brewer GJ, Hadera P, Kluin KJ, et al. Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 2003;60(3):379–85.Find this resource:

Apixaban

Apixaban was first marketed in the UK in 2012. It is an effective anticoagulant, which can be used when there is poor INR control despite compliance with warfarin therapy, or in patients who are allergic to, or unable to tolerate, warfarin.

Uses

Licensed uses

In the UK/USA

  • Prevention of stroke: apixaban is licensed for the prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation in individuals aged 18 years and older. In the UK, patients need to score at least 1 point on the CHADS2 VASc score.

Off-licence uses

  • None.

Presentation

  • Trade name: Eliquis®. Generics are not available.

  • Formulations: apixaban is available as a 2.5mg tablet.

Mechanism of action

Apixaban is a potent, oral, reversible, direct, and highly selective active site inhibitor of factor Xa. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Apixaban has no direct effects on platelet aggregation but indirectly inhibits platelet aggregation induced by thrombin.

Toxicity and side effects

  • Commondermatological: bruising. Gastrointestinal: nausea. Haematological: anaemia.

  • Seriousgastrointestinal: intra-abdominal haemorrhage. Haematological: haemorrhage. Neurological: ICH.

Contraindications

  • Absolute: hypersensitivity to apixaban or its excipients. Active bleeding, conditions associated with an increased risk of bleeding, e.g. peptic ulcer disease, ICH, etc. Severe hepatic impairment or any degree of hepatic disease with coagulopathy and a risk of bleeding. Severe renal impairment: CrCl <15mL/min. Metallic heart valves (apixaban has not been trialled in this setting).

  • Relative: in those with CrCl from 15 to 29mL/min and lesser degrees of hepatic impairment, apixaban should be used with caution.

Uses in special populations

  • Elderly: dose adjustment may be necessary in the elderly population. The elderly experience an age-related decline in hepatic and renal function; hence these parameters should be regularly monitored, while on treatment.

  • Pregnancy: should only be used if the benefit outweighs the potential increased risk of bleeding

  • Lactation: avoid in those who are breastfeeding—animal studies have demonstrated that it is excreted at high levels in breast milk.

Efficacy

In the ARISTOTLE trial, 18 201 AF patients with intermediate risk of clinical thromboembolic stroke (mean CHADS2 score of 2.1) were randomly assigned to either apixaban (5mg bd) or warfarin (target INR 2.0–3.0). The primary composite endpoint of stroke and systemic embolism was significantly reduced (0.33% per year) in the apixaban group. The hazard ratio with apixaban was 0.79 (95% CI 0.66–0.95; p <0.001 for non-inferiority and p = 0.01 for superiority).

Dosing and monitoring

Dosing

For the prevention of stroke in non-valvular AF, the recommended dose is 5mg bd. Halve the dose to 2.5mg bd if two or more of age >80 years, body weight <60kg, or serum creatinine ≥133micromol/L are present.

Monitoring

There is no need for monitoring of coagulation parameters during treatment with apixaban in routine clinical practice. However, if clinically indicated, the Rotachrom® anti-FXa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery.

Pharmacokinetics and interactions

Pharmacokinetics

The absolute bioavailability of apixaban is ~50% for doses up to 10mg. Tmax occurs at 3–4h after dosing. Apixaban demonstrates linear pharmacokinetics, with dose-proportional increases in exposure for oral doses up to 10mg. It is predominantly metabolized by CYP3A4, but CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2 play minor roles in its metabolism. Apixaban is also a substrate for the p-glycoprotein transport protein. It has multiple routes of elimination; ~25% is recovered as metabolites, with the majority recovered in faeces. Renal excretion of apixaban accounts for ~27% of total clearance. Apixaban has a half-life of ~12h.

Interactions

See Table A.50.

Table A.50 Interactions of apixaban

Medications which alter apixaban plasma levels

Pharmacodynamic interactions

  • Levels decreased: rifampacin

  • Levels increased: HIV protease inhibitors, e.g. indinavir, and azole antifungals, e.g. itraconazole and ketoconazole

With anticoagulants, antiplatelets, IV diclofenac, and sulfinpyrazone: increased risk of bleeding

References

Easton JD, Lopes RD, Bahit MC, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol 2012;11(6):503–11.Find this resource:

Granger CB, Alexander JH, McMurray JV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981–92.Find this resource:

Aspirin

Aspirin is a salicylic ester of acetic acid. It has a wide range of clinical uses, owing to its analgesic, antipyretic, anti-inflammatory, and antithrombotic properties. It was first marketed in the UK in 1939.

Uses

Licensed uses

In the UK

  • Cerebrovascular disease: aspirin is licensed for the secondary prevention of thrombotic cerebrovascular disease in individuals aged 16 years and older.

In the USA

  • Cerebrovascular disease: aspirin is licensed for the prevention and treatment of acute stroke and TIA in individuals aged 12 years and older.

Off-licence uses

  • Prevention of stroke in patients with AF, treatment of thrombotic complications of neuro-Behçet’s and SLE, and treatment of cortical venous sinus thrombosis.

Presentation

Aspirin is available in combination with multiple other agents, including caffeine, codeine, and dipyridamole. Only formulations containing aspirin alone are discussed further.

  • Trade names: Disprin®, Nu-Seals®, and Resprin®.Generics are available.

  • Formulations: aspirin is available as a dispersible tablet, enteric-coated tablet, standard tablet, and suppository. Tablets: 75mg, 81mg (USA), 300mg, 325mg (USA), 500mg (USA), and 650mg (USA) doses. Suppository: 300mg and 600mg.

Mechanism of action

Aspirin irreversibly inhibits COX enzymes. This reduces the formation of the pro-aggregatory molecule thromboxane A2 by platelets, thus reducing the rate of further clot formation.

Toxicity and side effects

  • Commongastrointestinal: gastrointestinal irritation. Haematological: iron deficiency anaemia. Immunological: allergic reaction. Neurological: tinnitus. Respiratory: bronchospasm.

  • Seriousgastrointestinal: major haemorrhage. Immunological: angio-oedema.

Contraindications

  • Absolute: active peptic ulceration, haemophilia and other bleeding disorders, pregnancy (third trimester), gout, severe hepatic impairment. History of hypersensitivity to aspirin or any other NSAID which includes attacks of asthma, angio-oedema, urticardia, or rhinitis. Severe renal (CrCl <10mL/min) and severe hepatic impairment.

  • Relative: concurrent use of NSAIDs or anticoagulants, poorly controlled hypertension (increased risk of intracranial bleeding), in those aged <21 due to increased risk of Reye’s syndrome. Use with caution in mild to moderate renal impairment, as it can cause further deterioration in renal function, and the risk of gastrointestinal bleed may be increased.

Uses in special populations

  • Elderly: use with caution, as the elderly are at an increased risk of gastrointestinal bleeding.

  • Pregnancy: aspirin is associated with anaemia and intrauterine growth retardation, and may increase fetal mortality. It should be used only if benefits outweigh the risk and ideally stopped in the third trimester to reduce the risk of bleeding during delivery.

  • Lactation: aspirin is present in breast milk and should be avoided due to the possible risk of Reye’s syndrome to an infant.

Efficacy

Most national guidelines recommend the acute treatment of stroke with aspirin as soon as possible after brain imaging has excluded haemorrhage. Systematic reviews of large trials (CAST, IST) have clearly established that starting aspirin therapy within the first 48h of acute ischaemic stroke avoids death or disability at 6 months for ~10 per 1000 patients treated. The benefit of aspirin is not dependent on aspirin dosages, although maximal thromboxane inhibition may only be achieved at high doses; hence current practice in the UK is to load aspirin for 2 weeks at 300mg following an acute stroke, then to switch to clopidogrel or drop the aspirin dose to 75mg to reduce the risk of gastric side effects.

Dosing and monitoring

Dosing

In acute stroke, use 300mg of aspirin od for 2 weeks. For prevention of strokes (including secondary to AF), use 75mg od long-term. Proton pump inhibitors may be commenced, in addition to aspirin, if dyspepsia is reported. If the patient has dysphagia, use an enteral tube or a suppository.

Monitoring

FBC and renal function monitoring should be performed regularly in patients at risk of bleeding or renal impairment, respectively.

Pharmacokinetics and interactions

Pharmacokinetics

Aspirin is largely absorbed in the small intestines; a small amount of the ionized form is absorbed by the stomach. Bioavailability is 50–75%. Tmax is 1–2h. Aspirin is rapidly hydrolysed to salicylate predominantly by the gastrointestinal mucosa and red blood cells. 50–80% of salicylate is bound to plasma proteins. It is predominantly metabolized hepatically by conjugation with glycine. The half-life of salicylate is 3h at doses of 300mg—this increases markedly at higher doses. Excretion is predominantly renal—75% as salicyluric acid.

Interactions

See Table A.51.

Table A.51 Interactions of aspirin

Medications which alter aspirin plasma levels

Medications whose plasma levels are altered by aspirin

Pharmacodynamic interactions

  • Levels decreased: corticosteroids and kaolin

  • Levels increased: metoclopramide

Levels increased: methotrexate and zafirlukast

  • With acetazolamide: increased risk of toxicity with high-dose aspirin

  • With clopidogrel, corticosteroids, coumarins, iloprost, NSAIDs, SSRIs, and venlafaxine: increased risk of bleeding

  • Probenecid, spironolactone, sulfinpyrazole: aspirin antagonizes their effects

  • With valproate and phenytoin: aspirin enhances their effects

  • Varicella-zoster vaccines: possible increased risk of Reye’s syndrome

References

CAST (Chinese Acute Stroke Trial) Collaborative. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischemic stroke. Lancet 1997;349(9066):1641–9.Find this resource:

Chen Z, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke: A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000;31(6):1240–9.Find this resource:

International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both or neither among 19435 patients with acute ischemic stroke. Lancet 1997;349(9065):1569–81.Find this resource:

Sandercock P, Gubitz G, Foley P, et al. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2008;3:CD000029.Find this resource:

Azathioprine

Azathioprine was developed in the 1950s as a chemotherapeutic agent and was subsequently used in the 1960s as one of the early immunosuppressants for transplantation. It is currently used in a wide range of autoimmune neurological diseases.

Uses

Azathioprine is usually indicated in immunosuppressive regimens as an adjunct to basic immunosuppression with corticosteroids, which form the mainstay of therapy. It may also be used in patients who are intolerant to corticosteroids. Common neurological uses are given below:

  • autoimmune limbic encephalitis;

  • Behçet’s (first-line, chronic);

  • GCA (second-line, chronic);

  • IBM;

  • LEMS (first-line, chronic);

  • MG (first-line, chronic);

  • neurolupus (first-line, chronic);

  • NMO (first-line, chronic);

  • PM/DM (first-line, chronic);

  • Sjögren’s syndrome (first-line, chronic);

  • Susac’s syndrome;

  • vasculitis.

Presentation

  • Trade names: Azamune®, Azasan®, and Imuran®. Generics are available.

  • Formulations: azathioprine is available as oral tablets (Azamune® and Azasan®) and vials of powder for IV infusion (Imuran®). Oral tablet: 25, 50, 75, and 100mg. Vial: 50mg.

Mechanism of action

Azathioprine is metabolized into 6-mercaptopurine, which acts both as a purine antimetabolite inhibiting nucleic acid synthesis and as an alkylating agent. This allows the drug to modulate immunological responses by limiting leucocyte proliferation. It also exhibits antineoplastic effects.

Toxicity and side effects

The principal side effect is a dose-related suppression of bone marrow function.

  • Commongastrointestinal: nausea and vomiting. Haematological: anaemia, leucopenia, and thrombocytopenia. Immunological: increased risk of infection.

  • Seriousdermatological: Kaposi’s sarcoma, squamous cell carcinoma, and Stevens–Johnson syndrome. Gastrointestinal: gastric ulceration, hepatic impairment (including veno-occlusive disease), and pancreatitis. Gynaecological: cervical and vulval cancer. Haematological: acute myeloid leukaemia, bone marrow failure, myelodysplastic syndromes, and non-Hodgkin’s lymphoma. Immunological: hypersensitivity reactions (including acute kidney injury, anaphylaxis, and vasculitis). Respiratory: interstitial pneumonitis (reversible).

Contraindications

  • Absolute: hypersensitivity, severe infections, severe hepatic impairment, bone marrow failure, pancreatitis, and concurrent live vaccination.

  • Relative: patients with renal disease or mild to moderate hepatic impairment should be given doses at the lower end of the normal range.

Use in special populations

  • Elderly: this drug has not been studied in the elderly; however, the elderly experience an age-related decline in hepatic and renal function and should be given doses at the lower end of the normal range.

  • Pregnancy: azathioprine is teratogenic in animals and should be avoided, where possible, in pregnancy.

  • Lactation: breastfeeding is contraindicated.

Efficacy

See under separate conditions in the relevant chapters.

Dosing and monitoring

Dosing

An oral dose of 1–3mg/kg daily is typically used in autoimmune conditions. A usual starting dose is between 25 and 50mg/day. This should be taken with meals. The dose is then gradually increased over weeks, with close monitoring, to achieve optimum symptomatic control (usually around 150mg/day).

Routine monitoring

Thiopurine methyltransferase (TPMT) metabolizes azathioprine and has reduced enzyme activity in up to 10% of the population. TMPT levels should be measured in all patients prior to treatment initiation. Regular FBC monitoring is required during treatment. This should be weekly for the first 2 months and can then be done at least every 3 months thereafter. Patients should be advised to seek help if they develop a fever, sore throat, bruising, bleeding, or signs of infection. They should also be warned about the increased risk of skin cancer, and the skin should be examined at regular intervals. Withdrawal of this drug can lead to severe relapses in disease and should be done gradually. Chickenpox can be fatal in the immunocompromised, and patients should be advised to seek medical help if they are not immune and become exposed.

Pharmacokinetics and interactions

Pharmacokinetics

The bioavailability of azathioprine is highly variable: 30–90%. Plasma levels peak within 2h of administration. The drug is rapidly distributed, with a maximum of 30% binding to plasma proteins. Azathioprine is a prodrug; it is metabolized by both the liver and kidneys to the principal active metabolite 6-mercaptopurine. The plasma half-life of azathioprine is 30–80min, and that of 6-mercaptopurine 3–5h. 6-mercaptopurine is subsequently metabolized by several different enzymes, including TMPT and xanthine oxidase, into inactive metabolites. Around 50% of a given dose is excreted in the urine in the first 24h, and 12.6% can be found in the stool at 48h. Only a small amount of <2% is excreted as unchanged drug.

Interactions

See Table A.52.

Table A.52 Interactions of azathioprine

Medications which alter azathioprine plasma levels

Medications whose plasma levels are altered by azathioprine

Pharmacodynamic interactions

Increased levels: allopurinol

Decreased levels: warfarin

  • With ACE inhibitors, aminosalicylates, NSAIDs, ribavirin, sulfamethoxazole, and trimethoprim: the myelosuppressive effects are increased

  • With febuxostat: the manufacturer advises against concomitant use