Pharmacy Blog – Dr Vibore

In a double-blind study in psychiatric patients it was found that chlorpromazine 400 to 800mg daily,a dose that normally produced plasma levels of 100 to 300 nanograms/mL, only produced levels of 0 to 70 nanograms/mL when lithium carbonate was also given (See reference number 1).

Other studies confirm that normal therapeutic levels of lithium carbonate reduce plasma chlorpromazine levels (See reference number 2,3). The peak serum levels and AUC of chlorpromazine were reduced by 40 % and 26%,respectively, in healthy subjects given lithium carbonate (See reference number 2).

A paranoid schizophrenic taking chlorpromazine 200 to 600mg daily for 5 years with no extrapyramidal symptoms developed stiffness of his face,arms and legs, and parkinsonian tremor of both hands within one day of starting to take lithium 900mg daily. His lithium blood level after 3 days was 0.5 mmol/L. He was later given lithium 1.8 g daily (blood level 1.17 mmol/L),chlorpromazine 200mg daily and benzatropine 2mg daily, which improved his condition, but he still complained of stiffness and had a persistent hand tremor.(See reference number 4)

A number of other reports describe emergence of severe extrapyramidal adverse effects when chlorpromazine was given with lithium (See reference number 5-7). Ventricular fibrillation,thought to be caused by chlorpromazine toxicity, occurred in a patient taking lithium when both drugs were suddenly withdrawn (See reference number 8). Severe neurotoxicity has also been seen in a handful of other patients taking lithium and chlorpromazine (See reference number 9,10).

A large-scale retrospective study of literature over period 1966 to 1996 using Medline database identified 41 cases of neurotoxic adverse effects in 41 patients with low therapeutic concentrations of lithium. Of these patients,10 were taking haloperidol (See reference number 9).

Another retrospective study using both Medline and spontaneous reporting system of FDA in US, over period 1969 to 1994, identified 237 cases of severe neurotoxicity involving lithium, of which 59 also involved concurrent use of haloperidol (See reference number 11,12).

Other reports describe encephalopathic syndromes (lethargy,fever, tremulousness, confusion, extrapyramidal and cerebellar dysfunction),(See reference number 13)neuromuscular symptoms, impaired consciousness and hyperthermia,(See reference number 14)delirium, severe extrapyramidal symptoms and organic brain damage in patients taking haloperidol with lithium (See reference number 15-26). In one study it was found that of 13 patients who were taking haloperidol, 5 developed neurotoxic reactions, and they were receiving higher doses of haloperidol (average dose was 59 mg) than 8 patients who did not develop such symptoms (average dose was 34.9 mg) (See reference number 27). The sudden emergence of extrapyramidal or other adverse effects with lithium and haloperidol has also been described in other studies (See reference number 9,15,28).

In contrast to reports cited above, there are others describing successful and uneventful use (See reference number 13,29-32). A retrospective search of Danish hospital records found that 425 patients had taken both drugs and none of them had developed serious adverse reactions (See reference number 33).

A small rise in serum lithium levels occurs in presence of haloperidol, but it is almost certainly of little or no clinical significance (See reference number 34).

A large-scale retrospective study of literature over period 1966 to 1996 using Medline database identified 41 cases of neurotoxic adverse effects in 41 patients with low, therapeutic concentrations of lithium. Of these patients,51.2 % were also taking at least one antipsychotic drug (See reference number 9). Another retrospective study using both Medline and spontaneous reporting system of FDA in US, over period 1969 to 1994, identified 237 cases of severe neurotoxicity involving lithium, with 188 involving lithium with antipsychotics (See reference number 11,12). The sudden emergence of extrapyramidal or other adverse effects has also been described in other studies. The antipsychotics implicated in this interaction with lithium are

thioridazine,,trifluoperazine,zuclopenthixol (See reference number 9). Examples of some cases are cited in a little more detail below.

A study of 10 patients taking fluphenazine, haloperidol or tiotixene found that addition of lithium worsened their extrapyramidal symptoms (See reference number 43). Neurotoxicity (tremor,rigidity, ataxia, tiredness, vomiting, confusion) attributed to an interaction between lithium and fluphenazine has been described in another patient. He previously took haloperidol and later took chlorpromazine with lithium,without problem (See reference number 44). Irreversible brain damage has been reported in a patient taking fluphenazine decanoate and lithium (See reference number 45). Severe neurotoxic complications (seizures,encephalopathy, delirium, abnormal EEGs) developed in 4 patients taking thioridazine 400mg daily or more and lithium. Serum lithium levels remained below 1 mmol/L. Lithium and other phenothiazines had been taken by 3 of them for extended periods without problems, and fourth subsequently took lithium and fluphenazine without problems (See reference number 46). In one study concurrent use of lithium and chlorpromazine, perphenazine, or thioridazine was associated with sleep-walking episodes in 9 % of patients (See reference number 47). Somnolence,confusion, delirium, creatinine phosphokinase elevation and fever occurred in a man taking lithium when risperidone was given (See reference number 48). A retrospective review of 39 patients with a diagnosis of neurotoxicity caused by treatment with lithium and an antipsychotic,found that

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the onset of symptoms varied from 24 hrs to 3 months after taking two drugs together, with an average delay of 12.7 days (See reference number 28).

Not understood. One suggestion to account for reduced serum levels of chlorpromazine, which is based on animal studies,(See reference number 50,51) is that chlorpromazine can be metabolised in gut. Therefore, if lithium delays gastric emptying, more chlorpromazine will be metabolised before it reaches circulation. Just why severe neurotoxicity and other adverse effects sometimes develop in patients taking lithium and antipsychotics is not understood. It is subject of considerable discussion and debate (See reference number 9,11,12,52,53).

Information about reduction in chlorpromazine levels caused by lithium is limited, but it would seem to be an established interaction of clinical importance. Serum chlorpromazine levels below 30 nanograms/mL have been shown to be ineffective, whereas clinical improvement is usually associated with levels within 150 to 300 nanogram/mL range (See reference number 54). Thus a fall in levels to below 70 nanograms/mL,as described in one study, would be expected to result in a reduced therapeutic response to chlorpromazine. Therefore effects of concurrent use should be closely monitored and chlorpromazine dosage increased if necessary.

The development of severe neurotoxic or severe extrapyramidal adverse effects with combinations of antipsychotics and lithium appears to be uncommon and unexplained but be alert for any evidence of toxicity if lithium is given with any of these drugs. One recommendation is that onset of neurological manifestations, such as excessive drowsiness or movement disorders, warrants electroencephalography without delay and withdrawal of drugs, especially as irreversible effects have been seen. A review(See reference number 55) suggests that concurrent use of haloperidol seems to be safe if lithium levels are below 1 mmol/L. It is not known whether this also applies to other antipsychotics.

At moment there seems to be no way of identifying apparently small number of patients who are particularly at risk, but possible likely factors include a previous history of extrapyramidal reactions with antipsychotics and use of large doses of antipsychotic.

For interactions of atypical antipsychotics with lithium see amisulpride,; aripiprazole, ; clozapine, ; olanzapine, ; quetiapine, ; and ziprasidone, .

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Loudon JB,Waring H. Toxic reactions to lithium and haloperidol. Lancet (1976) ii, 1088.

Juhl RP,Tsuang MT, Perry PJ. Concomitant administration of haloperidol and lithium carbonate in acute mania. Dis Nerv Syst (1977) 38, 675.

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Menes C,Burra P, Hoaken PCS. Untoward effects following combined neuroleptic-lithiumtherapy. Can J Psychiatry (1980) 25, 573–6.

Keitner GI,Rahman S. Reversible neurotoxicity with combined lithium-haloperidol administration. J Clin Psychopharmacol (1984) 4, 104–5.

Thomas CJ. Brain damage with lithium/haloperidol. Br J Psychiatry (1979) 134,552.

Thomas C,Tatham A, Jakubowski S. Lithium/haloperidol combinations and brain damage.Lancet (1982) i, 626.

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Biederman J,Lerner Y, Belmaker H. Combination of lithium and haloperidol in schizo-affective disorder. A controlled study. Arch Gen Psychiatry (1979) 36, 327–33.

Baastrup PC,Hollnagel P, Sørensen R, Schou M. Adverse reactions in treatment with lithiumcarbonate and haloperidol. JAMA (1976) 236, 2645–6.

Schaffer CB,Batra K, Garvey MJ, Mungas DM, Schaffer LC. The effect of haloperidol onserum levels of lithium in adult manic patients. Biol Psychiatry (1984) 19, 1495–9.

West A. Adverse effects of lithium treatment. BMJ (1977) 2,642.

Sachdev PS. Lithium potentiation of neuroleptic-related extrapyramidal side effects. Am J Psychiatry (1986) 143,942.

de la Gandara J,Dominguez RA. Lithium and loxapine: a potential interaction. J Clin Psychiatry (1988) 49, 126.

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Rivera-Calimlim L,Castañeda L, Lasagna L. Significance of plasma levels of chlorpromazine. Clin Pharmacol Ther (1973) 14, 144.

Batchelor DH,Lowe MR. Reported neurotoxicity with the lithium/haloperidol combinationand other neuroleptics—a literature review. Hum Psychopharmacol (1990) 5, 275–80.

The interactions where effects of antipsychotic, anxiolytic and hypnotic drugs are affected are covered in this section but there are other monographs elsewhere in this publication where effects of other drugs are altered by a benzodiazepine or antipsychotic.

The antipsychotics are represented by chlorpromazine (and other phenothiazines), haloperidol (and other butyrophenones) and thioxanthenes, and atypical, or newer, antipsychotic drugs, such as clozapine and risperidone. Their major use is in treatment of psychoses such as schizophrenia and mania. These are listed in table 1 below,(below). Some of antipsychotics are also used as antiemetics, and for motor tics and hiccups.

The majority of interactions between older antipsychotics are pharmacodynamic, relating to their effect on dopamine, whilst several of newer atypical antipsychotics are metabolised to a significant extent by cytochrome P450 isoenzymes. The concurrent use of other drugs which are inhibitors or inducers of these isoenzymes may result in large changes in plasma levels. In particular, tobacco smoking and caffeine can have an effect on pharmacokinetics of some of these drugs, leading to adverse effects or lack of therapeutic effect following lifestyle changes.

The anxiolytics include benzodiazepines and related drugs, cloral hydrate and other drugs used to treat psychoneuroses such as anxiety and tension, and are intended to induce calm without causing drowsiness and sleep. Some of benzodiazepines and related drugs are also used as antiepileptics and hypnotics. table 1 below, (below) contains a list of benzodiazepines and related drugs. Many benzodiazepines undergo phase I metabolism by N-dealkylation and hydroxylation and many of metabolites are active. They may then undergo phase II conjugation,mainly to form glucuronides before being excreted. For example,diazepam is metabolised to nordazepam (desmethyldiazepam), temazepam and oxazepam. The metabolism of diazepam in liver is also mediated by cytochrome P450 isoenzymes, particularly CYP2C19, and diazepam is excreted mainly as free or conjugated metabolites.

The triazolo-and related benzodiazepines,such as alprazolam, midazolam and triazolam, are mainly metabolised by hydroxylation, mediated by CYP3A4, to active compounds, which then rapidly undergo glucuronide conjugation.

Benzodiazepines such as lorazepam,oxazepam and temazepam, which are mainly conjugated without prior phase I metabolism, are unlikely to be involved in interactions with inhibitors or inducers of cytochrome P450. Benzodiazepines themselves do not significantly induce cytochrome P450 isoenzymes,so interactions involving enhanced metabolism of other drugs are not usual.

Zaleplon,zolpidem and zopiclone are metabolised by several cytochrome CYP450 isoenzymes and it has been suggested that because of this, other drugs which affect a particular isoenzyme such as CYP3A4, may have less effect on their metabolism. However, their pharmacokinetics are affected by potent inducers such as rifampicin and by inhibitors such as azole antifungals. Buspirone undergoes CYP3A4-mediated metabolism in liver.

table 1 below Antipsychotics,anxiolytics, and hypnotics

Amisulpride,Aripiprazole, Clozapine, Olanzapine, Quetiapine, Risperidone, Sertindole, Ziprasidone, Zotepine

Butaperazine,Chlorpromazine, Fluphenazine, Levomepromazine, Mesoridazine, Pericyazine, Perphenazine, Prochlorperazine, Promazine, Thioridazine, Trifluoperazine

Benperidol,Bromperidol, Droperidol, Haloperidol

Chlorprothixene,Flupentixol, Tiotixene, Zuclopenthixol

Loxapine,Molindone, Pimozide, Sulpiride

Alprazolam,Bromazepam, Brotizolam, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Clotiazepam, Diazepam, Flunitrazepam, Flurazepam, Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Midazolam, Nitrazepam, Oxazepam, Oxazolam, Quazepam, Temazepam, Triazolam

Buspirone,Clomethiazole, Cloral betaine, Cloral hydrate, Eszopiclone, Glutethimide, Hydroxyzine, Meprobamate, Promethazine, Triclofos, Zaleplon, Zolpidem, Zopiclone

Table 1 Antipsychotics, anxiolytics, and hypnotics
Group	Drugs
Antipsychotics
Atypical antipsychotics	Amisulpride, Aripiprazole, Clozapine, Olanzapine, Quetiapine, Risperidone, Sertindole, Ziprasidone, Zotepine
Phenothiazines	Butaperazine, Chlorpromazine, Fluphenazine, Levomepromazine, Mesoridazine, Pericyazine, Perphenazine, Prochlorperazine, Promazine, Thioridazine, Trifluoperazine
Butyrophenones	Benperidol, Bromperidol, Droperidol, Haloperidol
Thioxanthenes	Chlorprothixene, Flupentixol, Tiotixene, Zuclopenthixol
Miscellaneous	Loxapine, Molindone, Pimozide, Sulpiride
Anxiolytics and hypnotics
Benzodiazepines	Alprazolam, Bromazepam, Brotizolam, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Clotiazepam, Diazepam, Flunitrazepam, Flurazepam, Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Midazolam, Nitrazepam, Oxazepam, Oxazolam, Quazepam, Temazepam, Triazolam
Miscellaneous	Buspirone, Clomethiazole, Cloral betaine, Cloral hydrate, Eszopiclone, Glutethimide, Hydroxyzine, Meprobamate, Promethazine, Triclofos, Zaleplon, Zolpidem, Zopiclone

Table 2 Antipsychotics, anxiolytics, and hypnotics
Group	Drugs
Antipsychotics
Atypical antipsychotics	Amisulpride, Aripiprazole, Clozapine, Olanzapine, Quetiapine, Risperidone, Sertindole, Ziprasidone, Zotepine
Phenothiazines	Butaperazine, Chlorpromazine, Fluphenazine, Levomepromazine, Mesoridazine, Pericyazine, Perphenazine, Prochlorperazine, Promazine, Thioridazine, Trifluoperazine
Butyrophenones	Benperidol, Bromperidol, Droperidol, Haloperidol
Thioxanthenes	Chlorprothixene, Flupentixol, Tiotixene, Zuclopenthixol
Miscellaneous	Loxapine, Molindone, Pimozide, Sulpiride
Anxiolytics and hypnotics
Benzodiazepines	Alprazolam, Bromazepam, Brotizolam, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Clotiazepam, Diazepam, Flunitrazepam, Flurazepam, Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Midazolam, Nitrazepam, Oxazepam, Oxazolam, Quazepam, Temazepam, Triazolam
Miscellaneous	Buspirone, Clomethiazole, Cloral betaine, Cloral hydrate, Eszopiclone, Glutethimide, Hydroxyzine, Meprobamate, Promethazine, Triclofos, Zaleplon, Zolpidem, Zopiclone

Table 3 Antipsychotics, anxiolytics, and hypnotics
Group	Drugs
Antipsychotics
Atypical antipsychotics	Amisulpride, Aripiprazole, Clozapine, Olanzapine, Quetiapine, Risperidone, Sertindole, Ziprasidone, Zotepine
Phenothiazines	Butaperazine, Chlorpromazine, Fluphenazine, Levomepromazine, Mesoridazine, Pericyazine, Perphenazine, Prochlorperazine, Promazine, Thioridazine, Trifluoperazine
Butyrophenones	Benperidol, Bromperidol, Droperidol, Haloperidol
Thioxanthenes	Chlorprothixene, Flupentixol, Tiotixene, Zuclopenthixol
Miscellaneous	Loxapine, Molindone, Pimozide, Sulpiride
Anxiolytics and hypnotics
Benzodiazepines	Alprazolam, Bromazepam, Brotizolam, Chlordiazepoxide, Clobazam, Clonazepam, Clorazepate, Clotiazepam, Diazepam, Flunitrazepam, Flurazepam, Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Midazolam, Nitrazepam, Oxazepam, Oxazolam, Quazepam, Temazepam, Triazolam
Miscellaneous	Buspirone, Clomethiazole, Cloral betaine, Cloral hydrate, Eszopiclone, Glutethimide, Hydroxyzine, Meprobamate, Promethazine, Triclofos, Zaleplon, Zolpidem, Zopiclone

No adverse reactions normally occur in patients taking betablockers who undergo dipyridamole–thallium-201 scintigraphyand echocardiography,but case reports suggest that very rarelybradycardia and asystole can occur.

A 71-year-old woman taking nadolol 120mg daily and bendroflumethiazide,with a 3-week history of chest pain, was given a 300mg dose of oral dipyridamole as part of a diagnostic dipyridamole-thallium imaging test for coronary artery disease. She was given thallium-201 intravenously, 50 minutes after dipyridamole, but 3 minutes later, while exercising, she complained of chest pain and then had a cardiac arrest. She was given cardiopulmonary resuscitation and a normal cardiac rhythm was obtained after she was given intravenous aminophylline (See reference number 1).

Adverse interactions occurred in another 2 patients taking beta blockers during diagnostic dipyridamole-thallium stress testing. One patient, who was taking atenolol, developed bradycardia then asystole, which was treated with aminophylline and atropine, and other patient, who was taking metoprolol, developed bradycardia, which resolved after she was given aminophylline (See reference number 2).

These reports need to be set in a broad context. A very extensive study of high-dose dipyridamole echocardiography (10 451 tests in 9 122 patients) noted significant adverse effects in only 96 patients,with major adverse reactions occurring in just 7 patients. Three of 7 developed asystole and two of these patients were taking unnamed beta blockers (See reference number 3).

One possible explanation is that both drugs have negative chronotropic effects on heart

The value and safety of dipyridamole perfusion scintigraphy and echocardiography have been very extensively studied in very large numbers of patients,and reports of bradycardia and asystole, attributed to an interaction between dipyridamole and beta blockers, are sparse. It would therefore appear to be a relatively rare interaction (if such it is).

Blumenthal MS,McCauley CS. Cardiac arrest during dipyridamole imaging. Chest (1988) 93, 1103–4.

Roach PJ,Magee MA, Freedman SB. Asystole and bradycardia during dipyridamole stresstesting in patients receiving beta blockers. Int J Cardiol (1993) 42, 92–4.

Picano E et al. on behalf of the Echo-Persantine International Cooperative Study Group. Safetyof intravenous high-dose dipyridamole echocardiography. Am J Cardiol (1992) 70,252–8.

A study in 25 patients who had been given streptokinase for treatment of acute myocardial infarction, found that 12 weeks later, 24 patients had enough anti-streptokinase antibodies in circulation to neutralise an entire

1.5 million unit dose of streptokinase. After 4 to 8 months,18 out of 20 still had enough antibodies to neutralise half of a 1.5 million unit dose of streptokinase (See reference number 1). Further study has suggested that after streptokinase use,anti-streptokinase antibodies fall within 24 hours, but then increase gradually and are significantly raised by 4 days after treatment. The antibody titres reach a peak (approximately 200 times that of pretreatment levels) after 2 weeks and then subsequently decline,but remain above baseline values for at least one year (See reference number 2). Antibody titres may remain high enough to neutralise effects of streptokinase for several years after a dose,(See reference number 3,4) and high titres persisting for up to 7.5 years have been reported (See reference number 5). However, in contrast, another study found that neutralising antibody titres had returned to control levels by 2 years (See reference number 6). Increased titres of streptokinase antibodies have also been seen in patients receiving topical streptokinase for wound care,(See reference number 7)intrapleural streptokinase for pleural effusions,(See reference number 8) and following streptococcal infections (See reference number 9). Apart from reduced thrombolytic effect, repeated dosing(See reference number 10) or high pre-treatment anti-streptokinase antibody titres(See reference number 11) may increase risk of allergic reactions.

Anistreplase,like its parent drug streptokinase, has been shown to be neutralised by anti-streptokinase antibodies (See reference number 12,13).

Of 6 patients given urokinase 1.5 million units infused over 30 minutes for recurrent myocardial infarction,rigors occurred in 4 patients and 2 of these also had bronchospasm; they had all previously received streptokinase (See reference number 14).

Streptokinase use causes production of anti-streptokinase antibodies. These persist in circulation so that clot-dissolving effects of another dose of streptokinase given many months later may be ineffective, or less effective, because it becomes bound and neutralised by antibodies. Many people already have a very low titre of antibodies resulting from previous streptococcal infections,yet this does not usually appear to influence thrombolysis (See reference number 15).

The interaction that results in neutralisation of thrombolytics is established and clinically important. One author(See reference number 16)says that clinically,therapy is not repeated within a year as it would not work. Given that it has been suggested that effects may be very persistent, it would seem prudent, if a second use is needed, to use a thrombolytic with less antigenic effects such as alteplase. The British National Formulary says that streptokinase should not be used again beyond 4 days of first use of either streptokinase or anistreplase (See reference number 17). In addition, manufacturer recommends avoidance of streptokinase in patients who have had recent streptococcal infections that have produced high anti-streptokinase titres, such as acute rheumatic fever or acute glomerulonephritis (See reference number 9).

Little is known about increased risk of hypersensitivity reactions

1. Jalihal S,Morris GK. Antistreptokinase titres after intravenous streptokinase. Lancet (1990) 335, 184–5.

Lynch M,Littler WA, Pentecost BL, Stockley RA. Immunoglobulin response to intravenousstreptokinase in acute myocardial infarction. Br Heart J (1991) 66, 139–42.

Elliott JM,Cross DB, Cederholm-Williams SA, White HD. Neutralizing antibodies to streptokinase four years after intravenous thrombolytic therapy. Am J Cardiol (1993) 71, 640–5.

Lee HS,Cross S, Davidson R, Reid T, Jennings K. Raised levels of antistreptokinase antibodyand neutralization titres from 4 days to 54 months after administration of streptokinase or anistreplase. Eur Heart J (1993) 14, 84–9.

Squire IB,Lawley W, Fletcher S, Holme E, Hillis WS, Hewitt C, Woods KL. Humoral andcellular immune responses up to 7.5 years after administration of streptokinase for acute myocardial infarction. Eur Heart J (1999) 20, 1245–52.

McGrath K,Hogan C, Hunt D, O’Malley C, Green N, Dauer R, Dalli A. Neutralising antibodies after streptokinase treatment for myocardial infarction: a persisting puzzle. Br Heart J (1995) 74, 122–3.

Green C. Antistreptokinase titres after topical streptokinase. Lancet (1993) 341,1602–3.

Laisaar T,Pullerits T. Effect of intrapleural streptokinase administration on antistreptokinaseantibody level in patients with loculated pleural effusions. Chest (2003) 123, 432–5.

Streptase (Streptokinase). CSL Behring UK Ltd. UK Summary of product characteristics,March 2007.

White HD,Cross DB, Williams BF, Norris RM. Safety and efficacy of repeat thrombolytictreatment after acute myocardial infarction. Br Heart J (1990) 64, 177–81.

Lee HS,Yule S, McKenzie A, Cross S, Reid T, Davidson R, Jennings K. Hypersensitivityreactions to streptokinase in patients with high pre-treatment antistreptokinase antibody andneutralisation titres. Eur Heart J (1993) 14, 1640–3.

Binette MJ,Agnone FA. Failure of APSAC thrombolysis. Ann Intern Med (1993) 119, 637.

Brugemann J,van der Meer J, Bom VJJ, van der Schaaf W, de Graeff PA, Lie KI. Anti-streptokinase antibodies inhibit fibrinolytic effects of anistreplase in acute myocardial infarction.Am J Cardiol (1993) 72, 462–4.

Matsis P,Mann S. Rigors and bronchospasm with urokinase after streptokinase. Lancet (1992) 340, 1552.

Fears R,Hearn J, Standring R, Anderson JL, Marder VJ. Lack of influence of pretreatmentantistreptokinase antibody on efficacy in a multicenter patency comparison of intravenousstreptokinase and anistreplase in acute myocardial infarction. Am Heart J (1992) 124, 305–

14.

Moriarty AJ. Anaphylaxis and streptokinase. Hosp Update (1987) 13,342.

British National Formulary. 53(See reference number rd)ed. London: The British Medical Association and The Pharmaceutical Press; 2007. p. 132.

Glyceryl trinitrate may reduce thrombolytic efficacy of alteplase, but this is not thought to be clinically relevant.

Clinical evidence,mechanism, importance and management

In a randomised study,60 patients with acute anterior myocardial infarction were given intravenous alteplase 100mg over 3 hours, as well as heparin and aspirin. In addition, 27 of patients were also given intravenous glyceryl trinitrate 100 micrograms/minute for 8 hours. Patients receiving both alteplase and glyceryl trinitrate had signs of reperfusion less often (56%) than patients who received alteplase alone (76%). In combined treatment group time to reperfusion was also longer (37.8 versus 19.6 minutes) and incidence of coronary artery re-occlusion was higher (53% versus 24%). Giving alteplase with glyceryl trinitrate produced plasma levels of tissue plasminogen activator (tPA) antigen that were about two-thirds lower than when alteplase was given alone (See reference number 1). Impaired thrombolysis has been found in another study(See reference number 2) and also in an earlier study in dogs (See reference number 3).

It was postulated that glyceryl trinitrate increased hepatic blood flow and therefore increased metabolism of alteplase, which resulted in reduced plasma tPA levels (See reference number 1). However, an in vitro study found that glyceryl trinitrate enhanced degradation of alteplase, and therefore a mechanism other than increased hepatic blood flow seems likely to be involved (See reference number 4). It has been suggested that this interaction may not be clinically important,(See reference number 5) and current evidence is too sparse to warrant changing current practice.

Romeo F,Rosano GMC, Martuscelli E, De Luca F, Bianco C, Colistra C, Comito M, Cardona N, Miceli F, Rosano V, Mehta JL. Concurrent nitroglycerin administration reduces the efficacyof recombinant tissue-type plasminogen activator in patients with acute anterior wall myocardial infarction. Am Heart J (1995) 130, 692–7.

Nicolini FA,Ferrini D, Ottani F, Galvani M, Ronchi A, Behrens PH, Rusticali F, Mehta JL. Concurrent nitroglycerin therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction. Am J Cardiol (1994) 74, 662–6.

Mehta JL,Nicolini FA, Nichols WW, Saldeen TGP. Concurrent nitroglycerin administrationdecreases thrombolytic potential of tissue-type plasminogen activator. J Am Coll Cardiol (1991) 17, 805–11.

White CM,Fan C, Chen BP, Kluger J, Chow MSS. Assessment of the drug interaction betweenalteplase and nitroglycerin: an in vitro study. Pharmacotherapy (2000) 20, 380–2.

Boehringer Ingelheim. Personal communication,March 1999.

Platelets usually circulate in plasma in an inactive form, but following injury to blood vessels they become activated and adhere to site of injury. Platelet aggregation then occurs, which contributes to haemostatic plug. Platelet aggregation involves binding of fibrinogen with a glycoprotein IIb/IIIa receptor on platelet surface. The activated platelets secrete substances such as adenosine diphosphate (ADP) and thromboxane A2 that result in additional platelet aggregation and also cause vasoconstriction. Finally a number of platelet derived factors stimulate production of thrombin and hence fibrin through coagulation cascade (see The blood clotting process, ). Opposing this process is fibrinolysis pathway, which is initiated during clot formation by a number of mediators such as tissue plasminogen activator (tPA) and urokinase. These proteins convert plasminogen to plasmin, which in turn degrades fibrin, main component of clot.

Antiplatelet drugs (see table 1 below,(below)) reduce platelet aggregation and are used to prevent thromboembolic events. They act through a wide range of mechanisms including:

prevention of thromboxane A2 synthesis or inhibition of thromboxane receptors e.g. aspirin inhibits platelet cyclo-oxygenase,preventing synthesis of thromboxane A2

• interference in final step in platelet aggregation by stopping fibrinogen binding with glycoprotein IIb/IIIa receptor on platelet surface

Therefore some antiplatelet drugs can have beneficial additive effects with other antiplatelet drugs that act via different mechanisms. Furthermore,other drugs such as dextrans, heparin, some prostaglandins and sulfinpyrazone also have some antiplatelet activity.

Thrombolytics (see table 1 below, (below)) are used in treatment of thromboembolic disorders. Thrombolytics activate plasminogen to form plasmin, which is a proteolytic enzyme that degrades fibrin and therefore produces clot dissolution.

This section is primarily concerned with those interactions where activities of antiplatelet drugs or thrombolytics are changed by presence of another drug. Note that interactions of high-dose aspirin are covered under analgesics

Cilostazol,Dipyridamole

Aspirin,Indobufen, Triflusal

Abciximab,Eptifibatide, Tirofiban

Clopidogrel,Ticlopidine

Ditazole,Trapidil

Alteplase,Anistreplase, Defibrotide, Reteplase, Streptokinase, Tenecteplase, Urokinase

Table 1 Antiplatelet drugs and thrombolytics
Group	Drugs
Antiplatelet drugs
Adenosine reuptake inhibitors/Phosphodiesterase inhibitors	Cilostazol, Dipyridamole
Cyclo-oxygenase inhibitors	Aspirin, Indobufen, Triflusal
Glycoprotein IIb/IIIa-receptor antagonists	Abciximab, Eptifibatide, Tirofiban
Thienopyridines (inhibitors of adenosine diphosphate mediated platelet aggregation)	Clopidogrel, Ticlopidine
Thromboxane receptor antagonists	Picotamide
Miscellaneous	Ditazole, Trapidil
Thrombolytics
Thrombolytics	Alteplase, Anistreplase, Defibrotide, Reteplase, Streptokinase, Tenecteplase, Urokinase

Table 2 Antiplatelet drugs and thrombolytics
Group	Drugs
Antiplatelet drugs
Adenosine reuptake inhibitors/Phosphodiesterase inhibitors	Cilostazol, Dipyridamole
Cyclo-oxygenase inhibitors	Aspirin, Indobufen, Triflusal
Glycoprotein IIb/IIIa-receptor antagonists	Abciximab, Eptifibatide, Tirofiban
Thienopyridines (inhibitors of adenosine diphosphate mediated platelet aggregation)	Clopidogrel, Ticlopidine
Thromboxane receptor antagonists	Picotamide
Miscellaneous	Ditazole, Trapidil
Thrombolytics
Thrombolytics	Alteplase, Anistreplase, Defibrotide, Reteplase, Streptokinase, Tenecteplase, Urokinase

No significant pharmacokinetic interaction occurs between selegiline and cabergoline,pramipexole or ropinirole.

Clinical evidence,mechanism, importance and management

Dostert P,Benedetti MS, Persiani S, La Croix R, Bosc M, Fiorentini F, Deffond D, Vernay D,Dordain G. Lack of pharmacokinetic interaction between the selective dopamine agonist cabergoline and the MAO-B inhibitor selegiline. J Neural Transm (1995) 45 (Suppl), 247–57.

Mirapexin (Pramipexole). Boehringer Ingelheim Ltd. UK Summary of product characteristics,August 2006.

SmithKline Beecham. Personal Communication,September 1996.

Ferrous sulfate can reduce bioavailability of levodopa andcarbidopa, and may possibly reduce control of Parkinson’sdisease.

A study in 9 patients with Parkinson’s disease found that a single 325mg dose of ferrous sulfate reduced AUC of levodopa by 30 % and reduced AUC of carbidopa by more than 75%. There was a trend towards an increase in disability,suggesting a worsening of disease, but this did not reach statistical significance. Some, but not all of patients had some deterioration in control of their disease(See reference number 1)

In another study, 8 healthy subjects were given a single 250mg dose of levodopa, with and without a single 325mg dose of ferrous sulfate, and plasma levodopa levels were measured for following 6 hours. Peak plasma levodopa levels and levodopa AUC were reduced by 55 % and AUC was reduced by 51%. Those subjects who had highest peak levels and greatest absorption when given levodopa alone, showed greatest reductions when additionally given ferrous sulfate (See reference number 2).

Ferrous iron rapidly oxidises to ferric iron at pH values found in gastrointestinal tract

Information appears to be limited to these single-dose and in vitro studies. The importance of this interaction in patients taking both drugs long-term awaits further study but extent of reductions in absorption (30 to 50%), and hint of worsening control,(See reference number 1) suggests that this interaction may be of clinical importance. Be alert for any evidence of this. Separating administration of iron and levodopa as much as possible is likely to prove effective, as this appears to be an absorption interaction. More study is needed.

Campbell NRC,Rankine D, Goodridge AE, Hasinoff BB, Kara M. Sinemet-ferrous sulphateinteraction in patients with Parkinson’s disease. Br J Clin Pharmacol (1990) 30, 599–605.

Campbell NRC,Hasinoff B. Ferrous sulfate reduces levodopa bioavailability: chelation as apossible mechanism. Clin Pharmacol Ther (1989) 45, 220–5.

Campbell RRA,Hasinoff B, Chernenko G, Barrowman J, Campbell NRC. The effect of ferroussulfate and pH on L-dopa absorption. Can J Physiol Pharmacol (1990) 68, 603–7.

Greene RJ,Hall AD, Hider RC. The interaction of orally administered iron with levodopa andmethyldopa therapy. J Pharm Pharmacol (1990) 42, 502–4.

Clinical evidence,mechanism, importance and management

A 66-year-old man with idiopathic Parkinson’s disease and AIDS was free of dyskinesias when taking levodopa with a dopa-decarboxylase inhibitor,although he had unpredictable fluctuations. After 1 month of starting indinavir 2400mg daily, lamivudine and zidovudine, he developed severe peak-dose dyskinesias, and on periods lasted all day, with no fluctuations. The antivirals were stopped and dyskinesias improved within 5 days. Each antiviral was then given separately for 2 weeks. Only indinavir induced dyskinesias,which started after 3 days of treatment.(See reference number 1)

The mechanism of this interaction is uncertain, but may be related to inhibition of cytochrome P450 by protease inhibitors such as indinavir (See reference number 1).

This appears to be only report of this possible interaction. Bear in mind possibility that levodopa dose may need to be decreased if a protease inhibitor such as indinavir is required

1. Caparros-Lefebvre D,Lannuzel A, Tiberghien F, Strobel M. Protease inhibitors enhance levodopa effects in Parkinson’s disease. Mov Disord (1999) 14, 535.

Limited evidence suggests that clonidine may oppose effects oflevodopa. Be aware that,as with all antihypertensives, additivehypotensive effects may occur.

5mg daily for 10 to 24 days) caused a worsening of parkinsonism (an exacerbation of rigidity and akinesia). The concurrent use of antimuscarinic drugs reduced effects of this interaction (See reference number 1)

Another report on 10 hypertensive and 3 normotensive patients with Parkinson’s disease, 9 of them taking levodopa and 4 of them not, claimed that concurrent treatment with clonidine did not affect control of parkinsonism. However, 2 patients stopped taking clonidine because of an increase in tremor and gait disturbance (See reference number 2).

A suggestion is that clonidine opposes antiparkinson effects by stimulating alpha-receptors in brain

Be alert for a reduction in control of Parkinson’s disease during concurrent use

ing used (See reference number 1). Also note,that as with all antihypertensives, additive hypotensive effects may occur.

Shoulson I,Chase TN. Clonidine and the anti-parkinsonian response to L-dopa or piribedil.Neuropharmacology (1976) 15, 25–7.

Tarsy D,Parkes JD, Marsden CD. Clonidine in Parkinson disease. Arch Neurol (1975) 32, 134–6.