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Anaesthetic relevance of drugs used to treat cancer
PHARMACOLOGY
Anaesthetic relevance of drugs used to treat cancer
Cytotoxics: site of action DNA
Alex Pleuvry Alkylators
Intercalators/topos
The probability of cancer patients presenting for surgery is increasing as the incidence of cancer increases combined with the greater availability of new treatments, earlier treatments and combinations of treatments. Some of these patients will be receiving active anti-cancer treatment at the time of surgery and others will have recently completed a course of therapy. Hormonal anti-cancer agents have relatively mild toxicity (see Anaesthesia and Intensive Care Medicine 3:9: 353) and are most commonly used as monotherapies. Cytotoxic drugs are extremely reactive molecules; they are often used in combinations, in the treatment of cancer patients at various stages in the disease, and may be used preoperatively, perioperatively or postoperatively. The sites of action of the most commonly used cytotoxic drugs are briefly summarized in Figure 1. They tend to attack all rapidly dividing cells (not only cancer cells) resulting in a range of major toxicities. The toxic effects of the commonly used cytotoxic drugs are summarized in Figures 2 and 3. Immunological anti-cancer agents (e.g. interleukins, interferons) are less commonly used, but new generations of more selective agents are coming into use, such as monoclonal antibodies (e.g. rituximab, trastuzumab, bevacizumab), signal transduction inhibitors (e.g. imatinib, gefitinib) and proteosome inhibitors (e.g. bortezomib). In addition, a variety of supportive (or ancillary) agents is needed to support the patient’s symptoms (e.g. analgesics, bisphosphonates) and to alleviate the toxicity of cytotoxic drugs (e.g. 5HT3 antagonists for nausea and vomiting, Colony Stimulating Factors such as filgrastim for myelosuppression, loperamide for diarrhoea).
DNA synthesis
Antimetabolites
Spindle poisons
Proteins
Microtubules/ Mitosis
Enzymes
Cell division
1
Many cytotoxic drugs are given in complex combinations, therefore it is not always clear which component is the cause of an interaction. Knowledge of the mechanism of action of a cytotoxic drug seems to have poor predictive power for drug interactions. It is difficult to find data relating to anti-cancer or anaesthetic interactions in paediatrics. This is partially explained by the elderly accounting for such a high proportion of all cancer patients (only 0.5% of new cancer diagnoses are in children under 14 years). The new agents (monoclonal antibodies, signal transduction inhibitors) have been available for clinical use for a short time and little information on their interactions with anaesthetic agents is available. Analgesic and anti-emetic drugs are used in cancer therapy and in anaesthetic management, so there is a potential for ‘doubledosing’ the patient. Cytotoxic and general anaesthetic drugs have immunodepressant properties, therefore concomitant use could compromise the patient’s immune status.
Problems with evaluating interactions between anti-cancer agents and drugs used in anaesthesia There are few well-controlled studies; most are case reports, animal or in vitro studies. Data on cytotoxic drugs are further confused by the high incidence of toxicity, the high incidence of treatment failure, the consequential development of advanced cancer symptoms, and incomplete information on dose (often empirical), schedule and patient status. In particular, information on time between the last dose of the anti-cancer agent, the clearance time for that treatment, and induction of anaesthesia is hard to find.
Observed drug interactions with anti-cancer agents Because cytotoxics are such reactive molecules, there are many potentially hazardous interactions with other cytotoxic and nonanaesthetic drugs. However, there are few potentially hazardous interactions with anaesthetic agents (as defined by the BNF) and these are summarized in Figure 4.
Alex Pleuvry is an Independent Pharmaceutical Consultant. He qualified in pharmacy from the University of London, and spent most of his career in the pharmacuetical industry. His particular area of interest is the chemotherapy and hormone therapy of cancer.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:6
RNA
General anaesthetics: halothane, isoflurane, ketamine and propofol do not appear to be involved in serious interactions with 189
© 2006 Elsevier Ltd
PHARMACOLOGY
Examples of major toxic effects of common cytotoxics Bone marrow suppression
Gastrointestinal (see Figure 3)
Alopecia
Major organ toxicity
• Cyclophosphamide
++
+
++
• Ifosfamide
++
+
++
Bladder/renal, cardiac, respiratory, neurotoxicity Bladder
• Methotrexate
++
+
+
Liver, respiratory, renal
• Fluorouracila • Capecitabine • Tegafur/UFT
++
+
0
Mucosa, cardiotoxicity, neurotoxicity
• Gemcitabine
++
+
• Doxorubicin
++
++
++
Cardiotoxicity
• Epirubicin
++
+
++
Cardiotoxicity
• Mitoxantrone
++
+
+
Cardiotoxicity
• Mitomycin
+
+
+/-
Necrosis, lung, renal
• Bleomycin
0
+
+
Lung, hypersensitivity
• Carboplatin
+
+
• Cis-platinum
++
++
• Oxaliplatin
++
++
• Vinblastine
++
+
+
Neurotoxicity
• Vincristine
+
+
+
Neurotoxicity
• Vinorelbine
++
+
+
Neurotoxicity
• Irinotecan (Top-1)
++
++
+
• Topotecan (Top-1)
++
+
+
• Etoposide (Top-2)
++
+
++
Hypersensitivity
• Docetaxel
++
+
++
• Paclitaxel
++
+/-
++
Neurotoxicity, oedema, cardiac, hypersensitivity Neurotoxicity, cardiac, liver, renal, hypersensitivity
Alkylating agents
Anti-metabolites
Liver
Cytotoxic antibiotics and anthracyclines (intercalators)
Platinum analogues Liver +
Renal, ototoxicity Neurotoxicity, renal, ototoxicity
Spindle poisons
Topoisomerase-1 and -2 inhibitors
Tubulin inhibitors (taxanes)
This table is not intended to be exhaustive Key: 0 absent/rare; + mild/not usually dose-limiting; ++ common and usually dose-limiting a capecitabine and tegafur are pro-drugs of fluorouracil
2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:6
190
© 2006 Elsevier Ltd
PHARMACOLOGY
anti-cancer agents. However, Huettemann et al.1 found that pretreatment of children with the cytotoxics doxorubicin and cyclophosphamide could enhance the myocardial depressant activity of isoflurane, even in patients with normal preoperative cardiac function. Other anthracyclines are also cardiotoxic so may also exhibit this tendency, especially epirubicin, since it is an isomer of doxorubicin. Similarly, breast cancer patients pretreated with anthracyclines show more prolongation of the QTc interval during isoflurane anaesthesia than non-anthracycline-treated patients. Animal data suggest increased mortality in mice treated with cyclophosphamide and halothane but no serious problems have been reported clinically.
Examples of major gastrointestinal toxicities of some common cytotoxics Mucositis Cyclophosphamide Methotrexate Fluorouracil Paclitaxel Doxorubicin Cis-platinum Mitomycin Bleomycin Vincristine Irinotecan
+ ++ ++ + ++ 0 + + +
Nausea and vomiting + + + +/++ ++ + +/0
Diarrhoea 0 + + +/+ 0 0 +/0 ++
Medical gases: in patients who have received high cumulative doses of bleomycin, the pulmonary toxicity is enhanced by higher concentrations of inspired oxygen, and some bleomycin-treated patients have experienced similar problems with high-dose nitrous oxide anaesthesia. A potentially hazardous interaction can occur when methotrexate is given within 6 hours of nitrous oxide anaesthesia, when the antifolate effect is increased; this combination should be avoided.
Key: 0 absent/rare; + mild/not usually dose-limiting; ++ common and usually dose-limiting
3
Potentially hazardous interactions between drugs used in anaesthesia and cancer therapy O2
N2O
Barbiturates β-blockers
Anticonvulsants
NSAIDs
Lidocaine
Anticoagulants
Antihistamines
Cancer therapy Cytotoxics • Bleomycin
A
• Fluorouracil
B
• Ifosfamide
B C
• Mercaptopurine • Methotrexate
D
E
Hormonal anti-cancers C
• Aminoglutethimide
F
• Bicalutamide B
• Flutamide • Progestogens
G
G
C
• Tamoxifen
B
• Toremifene
B
Tyrosine kinase inhibitors H
• Imatinib Ancillary/supportive therapy
K
• Aprepitant • Dolasetron • Opioid analgesics
I
I J
B
Key: A increased pulmonary toxicity; B increased anticoagulant effect; C decreased anticoagulant effect; D increased antifolate activity; E decreased excretion of methotrexate leading to increased risk of toxicity; F avoid concomitant use of bicalutamide with terfenadine; G increased metabolism of progestins; H phenytoin reduces imatinib plasma concentration; I increased risk of ventricular arrhythmias; J carbamazepine activity enhanced by dextropropoxyphene; K avoid concomitant use of aprepitant with terfenadine
4
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:6
191
© 2006 Elsevier Ltd
PHARMACOLOGY
Barbiturates interact with a variety of anti-cancer agents including docetaxel, doxorubicin, etoposide, methotrexate, toremifene and the anti-emetics tropisetron and aprepitant (aprepitant is a neurokinin-1 receptor antagonist used for the prevention of nausea and vomiting in platinum-treated patients). Phenobarbital induces cytochrome CYP3A4, which may result in enhanced activation of ifosfamide, leading to greater toxicity but enhanced clearance of vincristine, etoposide and irinotecan, resulting in reduced anticancer efficacy. Although barbiturates induce liver enzymes leading to pharmacokinetic changes in cyclophosphamide handling, this has not been found to be a serious clinical problem in terms of toxicity or reduced efficacy. However, doxorubicin efficacy may be decreased. Barbiturates can reduce plasma concentrations of the anti-emetic drugs tropisetron and aprepitant. A potentially hazardous interaction can occur when barbiturates are co-administered with progestogens, resulting in increased metabolism of the latter and thus reduced efficacy.
effect on tropisetron. A potentially serious interaction between anticonvulsants and opioid analgesics can result in reduced plasma concentrations of the latter. However, the effects of dextropropoxyphene can be enhanced by carbamazepine Anticoagulants: interactions with drugs used in cancer therapy are many and varied but without obvious explanatory mechanisms. The anticoagulant effects of warfarin can be increased by many non-steroidal anti-inflammatory drug (NSAID) analgesics, the hormonal anti-cancers (flutamide, bicalutamide and tamoxifen) and many cytotoxics, including fluorouracil, ifosfamide, carboplatin and cyclophosphamide. The mechanism in many cases is the displacement of warfarin from protein binding sites. Conversely, anticoagulant effects can be decreased by the anti-emetic aprepitant, progestogens, aminoglutethimide and mercaptopurine, although mercaptopurine does appear to activate the synthesis of prothrombin. Many of these interactions are classified as potentially hazardous. In the case of patients treated with the tyrosine kinase inhibitor imatinib it is advisable to use heparin as an anticoagulant instead of warfarin. Gefitinib, a tyrosine kinase inhibitor available in the USA and Japan, but not in Europe, has recently been associated with interactions involving warfarin.
Neuromuscular agents: the alkylating agent, cyclophosphamide, has pseudocholinesterase inhibitor properties that persist for 3–4 weeks after the last dose. This can reduce the breakdown of suxamethonium, resulting in protracted postoperative apnoea. A similar reaction can occur with another alkylating agent, thiotepa.
NSAIDs: many patients who received methotrexate and NSAID analgesics (e.g. aspirin, ibuprofen, diclofenac, naproxen) experienced no problems; however, life-threatening toxicity has occurred in a few patients. The main mechanism appears to be a rise in serum methotrexate concentrations caused by reduced renal perfusion due to inhibition of PGE2 prostaglandin synthesis by the NSAID.
β-blockers: both propranolol and the anthracycline, doxorubicin, inhibit cardiac enzymes. Animal data, unconfirmed clinically, have suggested a potential increase in cardiotoxicity. The interleukin aldesleukin can enhance the hypotensive effects of β-blockers. The risk of ventricular arrhythmias is increased in the presence of β-blocker and the anti-emetic drug tropisetron (caution is advised), while a similar but potentially hazardous interaction can occur with β-blockers and dolasetron. However, the mechanism of this interaction is not clear and there does not seem to be a problem with the longer, established 5HT3 antagonists, ondansetron and granisetron.
Local anaesthetics: concomitant use of lidocaine with the antiemetic dolasetron can produce an increased risk of ventricular arrhythmias. Animal data suggest the concentration of local anaesthetics achievable in the clinic could increase doxorubicin cardiotoxicity, but clinical data are sparse.
Anti-epileptics: anticonvulsant serum concentrations of phenytoin, carbamazepine and valproate can decrease, which may result in seizures, during cytotoxic treatments with numerous agents, including cisplatin, carboplatin, bleomycin, carmustine, methotrexate, temozolamide, cyclophosphamide, paclitaxel, docetaxel, thiotepa and vinca alkaloids. Anticonvulsant serum concentrations can increase when patients are treated with the anti-metabolites fluorouracil or tegafur, and acute phenytoin intoxication has been reported. Phenytoin induces cytochrome CYP3A4, which may result in enhanced activation of ifosfamide, leading to greater toxicity but enhanced clearance of vincristine, etoposide and irinotecan, resulting in reduced anti-cancer efficacy. Phenytoin increases the antifolate effect of methotrexate. Valproic acid can inhibit glucuronysyl transferase, resulting in decreased clearance of the active metabolite of irinotecan, leading to greater toxicity. Potentially hazardous interactions have been reported with the hormonal anti-cancers, since phenytoin increases the metabolism of progestogens, resulting in decreased efficacy. Also, phenytoin reduces the plasma concentration of the tyrosine kinase inhibitor imatinib, therefore this combination should be avoided. Plasma concentrations of the anti-emetic aprepitant can be reduced by carbamazepine or phenytoin, and primidone has a similar
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:6
Antihistamines: manufacturers advise against concomitant use of terfenadine with the anti-androgen bicalutamide or the anti-emetic aprepitant.
KEY REFERENCE 1 Huettemann E, Junker T, Chatzinikolaou K et al. The influence of anthracycline therapy on cardiac function during anesthesia. Anesth Analg 2004; 98: 941–7. FURTHER READING Beijnen J, Schellens J. Drug interactions in oncology. Lancet Oncol 2004; 5: 489–96. British National Formulary. 50th ed, Appendix 1. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2005. Kvolik S, Glavas-Obrovac L, Sakic K, Margaretic D, Karner I. Anaesthetic implications of anticancer chemotherapy. Eur J Anaesthesiol 2003; 20: 859–71. Stockley I H. Drug interactions. 6th ed. London: Pharmaceutical Press, 2002.
192
© 2006 Elsevier Ltd
Anaesthetic relevance of drugs used to treat cancer
Cytotoxics: site of action DNA
Alex Pleuvry Alkylators
Intercalators/topos
The probability of cancer patients presenting for surgery is increasing as the incidence of cancer increases combined with the greater availability of new treatments, earlier treatments and combinations of treatments. Some of these patients will be receiving active anti-cancer treatment at the time of surgery and others will have recently completed a course of therapy. Hormonal anti-cancer agents have relatively mild toxicity (see Anaesthesia and Intensive Care Medicine 3:9: 353) and are most commonly used as monotherapies. Cytotoxic drugs are extremely reactive molecules; they are often used in combinations, in the treatment of cancer patients at various stages in the disease, and may be used preoperatively, perioperatively or postoperatively. The sites of action of the most commonly used cytotoxic drugs are briefly summarized in Figure 1. They tend to attack all rapidly dividing cells (not only cancer cells) resulting in a range of major toxicities. The toxic effects of the commonly used cytotoxic drugs are summarized in Figures 2 and 3. Immunological anti-cancer agents (e.g. interleukins, interferons) are less commonly used, but new generations of more selective agents are coming into use, such as monoclonal antibodies (e.g. rituximab, trastuzumab, bevacizumab), signal transduction inhibitors (e.g. imatinib, gefitinib) and proteosome inhibitors (e.g. bortezomib). In addition, a variety of supportive (or ancillary) agents is needed to support the patient’s symptoms (e.g. analgesics, bisphosphonates) and to alleviate the toxicity of cytotoxic drugs (e.g. 5HT3 antagonists for nausea and vomiting, Colony Stimulating Factors such as filgrastim for myelosuppression, loperamide for diarrhoea).
DNA synthesis
Antimetabolites
Spindle poisons
Proteins
Microtubules/ Mitosis
Enzymes
Cell division
1
Many cytotoxic drugs are given in complex combinations, therefore it is not always clear which component is the cause of an interaction. Knowledge of the mechanism of action of a cytotoxic drug seems to have poor predictive power for drug interactions. It is difficult to find data relating to anti-cancer or anaesthetic interactions in paediatrics. This is partially explained by the elderly accounting for such a high proportion of all cancer patients (only 0.5% of new cancer diagnoses are in children under 14 years). The new agents (monoclonal antibodies, signal transduction inhibitors) have been available for clinical use for a short time and little information on their interactions with anaesthetic agents is available. Analgesic and anti-emetic drugs are used in cancer therapy and in anaesthetic management, so there is a potential for ‘doubledosing’ the patient. Cytotoxic and general anaesthetic drugs have immunodepressant properties, therefore concomitant use could compromise the patient’s immune status.
Problems with evaluating interactions between anti-cancer agents and drugs used in anaesthesia There are few well-controlled studies; most are case reports, animal or in vitro studies. Data on cytotoxic drugs are further confused by the high incidence of toxicity, the high incidence of treatment failure, the consequential development of advanced cancer symptoms, and incomplete information on dose (often empirical), schedule and patient status. In particular, information on time between the last dose of the anti-cancer agent, the clearance time for that treatment, and induction of anaesthesia is hard to find.
Observed drug interactions with anti-cancer agents Because cytotoxics are such reactive molecules, there are many potentially hazardous interactions with other cytotoxic and nonanaesthetic drugs. However, there are few potentially hazardous interactions with anaesthetic agents (as defined by the BNF) and these are summarized in Figure 4.
Alex Pleuvry is an Independent Pharmaceutical Consultant. He qualified in pharmacy from the University of London, and spent most of his career in the pharmacuetical industry. His particular area of interest is the chemotherapy and hormone therapy of cancer.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:6
RNA
General anaesthetics: halothane, isoflurane, ketamine and propofol do not appear to be involved in serious interactions with 189
© 2006 Elsevier Ltd
PHARMACOLOGY
Examples of major toxic effects of common cytotoxics Bone marrow suppression
Gastrointestinal (see Figure 3)
Alopecia
Major organ toxicity
• Cyclophosphamide
++
+
++
• Ifosfamide
++
+
++
Bladder/renal, cardiac, respiratory, neurotoxicity Bladder
• Methotrexate
++
+
+
Liver, respiratory, renal
• Fluorouracila • Capecitabine • Tegafur/UFT
++
+
0
Mucosa, cardiotoxicity, neurotoxicity
• Gemcitabine
++
+
• Doxorubicin
++
++
++
Cardiotoxicity
• Epirubicin
++
+
++
Cardiotoxicity
• Mitoxantrone
++
+
+
Cardiotoxicity
• Mitomycin
+
+
+/-
Necrosis, lung, renal
• Bleomycin
0
+
+
Lung, hypersensitivity
• Carboplatin
+
+
• Cis-platinum
++
++
• Oxaliplatin
++
++
• Vinblastine
++
+
+
Neurotoxicity
• Vincristine
+
+
+
Neurotoxicity
• Vinorelbine
++
+
+
Neurotoxicity
• Irinotecan (Top-1)
++
++
+
• Topotecan (Top-1)
++
+
+
• Etoposide (Top-2)
++
+
++
Hypersensitivity
• Docetaxel
++
+
++
• Paclitaxel
++
+/-
++
Neurotoxicity, oedema, cardiac, hypersensitivity Neurotoxicity, cardiac, liver, renal, hypersensitivity
Alkylating agents
Anti-metabolites
Liver
Cytotoxic antibiotics and anthracyclines (intercalators)
Platinum analogues Liver +
Renal, ototoxicity Neurotoxicity, renal, ototoxicity
Spindle poisons
Topoisomerase-1 and -2 inhibitors
Tubulin inhibitors (taxanes)
This table is not intended to be exhaustive Key: 0 absent/rare; + mild/not usually dose-limiting; ++ common and usually dose-limiting a capecitabine and tegafur are pro-drugs of fluorouracil
2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:6
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© 2006 Elsevier Ltd
PHARMACOLOGY
anti-cancer agents. However, Huettemann et al.1 found that pretreatment of children with the cytotoxics doxorubicin and cyclophosphamide could enhance the myocardial depressant activity of isoflurane, even in patients with normal preoperative cardiac function. Other anthracyclines are also cardiotoxic so may also exhibit this tendency, especially epirubicin, since it is an isomer of doxorubicin. Similarly, breast cancer patients pretreated with anthracyclines show more prolongation of the QTc interval during isoflurane anaesthesia than non-anthracycline-treated patients. Animal data suggest increased mortality in mice treated with cyclophosphamide and halothane but no serious problems have been reported clinically.
Examples of major gastrointestinal toxicities of some common cytotoxics Mucositis Cyclophosphamide Methotrexate Fluorouracil Paclitaxel Doxorubicin Cis-platinum Mitomycin Bleomycin Vincristine Irinotecan
+ ++ ++ + ++ 0 + + +
Nausea and vomiting + + + +/++ ++ + +/0
Diarrhoea 0 + + +/+ 0 0 +/0 ++
Medical gases: in patients who have received high cumulative doses of bleomycin, the pulmonary toxicity is enhanced by higher concentrations of inspired oxygen, and some bleomycin-treated patients have experienced similar problems with high-dose nitrous oxide anaesthesia. A potentially hazardous interaction can occur when methotrexate is given within 6 hours of nitrous oxide anaesthesia, when the antifolate effect is increased; this combination should be avoided.
Key: 0 absent/rare; + mild/not usually dose-limiting; ++ common and usually dose-limiting
3
Potentially hazardous interactions between drugs used in anaesthesia and cancer therapy O2
N2O
Barbiturates β-blockers
Anticonvulsants
NSAIDs
Lidocaine
Anticoagulants
Antihistamines
Cancer therapy Cytotoxics • Bleomycin
A
• Fluorouracil
B
• Ifosfamide
B C
• Mercaptopurine • Methotrexate
D
E
Hormonal anti-cancers C
• Aminoglutethimide
F
• Bicalutamide B
• Flutamide • Progestogens
G
G
C
• Tamoxifen
B
• Toremifene
B
Tyrosine kinase inhibitors H
• Imatinib Ancillary/supportive therapy
K
• Aprepitant • Dolasetron • Opioid analgesics
I
I J
B
Key: A increased pulmonary toxicity; B increased anticoagulant effect; C decreased anticoagulant effect; D increased antifolate activity; E decreased excretion of methotrexate leading to increased risk of toxicity; F avoid concomitant use of bicalutamide with terfenadine; G increased metabolism of progestins; H phenytoin reduces imatinib plasma concentration; I increased risk of ventricular arrhythmias; J carbamazepine activity enhanced by dextropropoxyphene; K avoid concomitant use of aprepitant with terfenadine
4
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:6
191
© 2006 Elsevier Ltd
PHARMACOLOGY
Barbiturates interact with a variety of anti-cancer agents including docetaxel, doxorubicin, etoposide, methotrexate, toremifene and the anti-emetics tropisetron and aprepitant (aprepitant is a neurokinin-1 receptor antagonist used for the prevention of nausea and vomiting in platinum-treated patients). Phenobarbital induces cytochrome CYP3A4, which may result in enhanced activation of ifosfamide, leading to greater toxicity but enhanced clearance of vincristine, etoposide and irinotecan, resulting in reduced anticancer efficacy. Although barbiturates induce liver enzymes leading to pharmacokinetic changes in cyclophosphamide handling, this has not been found to be a serious clinical problem in terms of toxicity or reduced efficacy. However, doxorubicin efficacy may be decreased. Barbiturates can reduce plasma concentrations of the anti-emetic drugs tropisetron and aprepitant. A potentially hazardous interaction can occur when barbiturates are co-administered with progestogens, resulting in increased metabolism of the latter and thus reduced efficacy.
effect on tropisetron. A potentially serious interaction between anticonvulsants and opioid analgesics can result in reduced plasma concentrations of the latter. However, the effects of dextropropoxyphene can be enhanced by carbamazepine Anticoagulants: interactions with drugs used in cancer therapy are many and varied but without obvious explanatory mechanisms. The anticoagulant effects of warfarin can be increased by many non-steroidal anti-inflammatory drug (NSAID) analgesics, the hormonal anti-cancers (flutamide, bicalutamide and tamoxifen) and many cytotoxics, including fluorouracil, ifosfamide, carboplatin and cyclophosphamide. The mechanism in many cases is the displacement of warfarin from protein binding sites. Conversely, anticoagulant effects can be decreased by the anti-emetic aprepitant, progestogens, aminoglutethimide and mercaptopurine, although mercaptopurine does appear to activate the synthesis of prothrombin. Many of these interactions are classified as potentially hazardous. In the case of patients treated with the tyrosine kinase inhibitor imatinib it is advisable to use heparin as an anticoagulant instead of warfarin. Gefitinib, a tyrosine kinase inhibitor available in the USA and Japan, but not in Europe, has recently been associated with interactions involving warfarin.
Neuromuscular agents: the alkylating agent, cyclophosphamide, has pseudocholinesterase inhibitor properties that persist for 3–4 weeks after the last dose. This can reduce the breakdown of suxamethonium, resulting in protracted postoperative apnoea. A similar reaction can occur with another alkylating agent, thiotepa.
NSAIDs: many patients who received methotrexate and NSAID analgesics (e.g. aspirin, ibuprofen, diclofenac, naproxen) experienced no problems; however, life-threatening toxicity has occurred in a few patients. The main mechanism appears to be a rise in serum methotrexate concentrations caused by reduced renal perfusion due to inhibition of PGE2 prostaglandin synthesis by the NSAID.
β-blockers: both propranolol and the anthracycline, doxorubicin, inhibit cardiac enzymes. Animal data, unconfirmed clinically, have suggested a potential increase in cardiotoxicity. The interleukin aldesleukin can enhance the hypotensive effects of β-blockers. The risk of ventricular arrhythmias is increased in the presence of β-blocker and the anti-emetic drug tropisetron (caution is advised), while a similar but potentially hazardous interaction can occur with β-blockers and dolasetron. However, the mechanism of this interaction is not clear and there does not seem to be a problem with the longer, established 5HT3 antagonists, ondansetron and granisetron.
Local anaesthetics: concomitant use of lidocaine with the antiemetic dolasetron can produce an increased risk of ventricular arrhythmias. Animal data suggest the concentration of local anaesthetics achievable in the clinic could increase doxorubicin cardiotoxicity, but clinical data are sparse.
Anti-epileptics: anticonvulsant serum concentrations of phenytoin, carbamazepine and valproate can decrease, which may result in seizures, during cytotoxic treatments with numerous agents, including cisplatin, carboplatin, bleomycin, carmustine, methotrexate, temozolamide, cyclophosphamide, paclitaxel, docetaxel, thiotepa and vinca alkaloids. Anticonvulsant serum concentrations can increase when patients are treated with the anti-metabolites fluorouracil or tegafur, and acute phenytoin intoxication has been reported. Phenytoin induces cytochrome CYP3A4, which may result in enhanced activation of ifosfamide, leading to greater toxicity but enhanced clearance of vincristine, etoposide and irinotecan, resulting in reduced anti-cancer efficacy. Phenytoin increases the antifolate effect of methotrexate. Valproic acid can inhibit glucuronysyl transferase, resulting in decreased clearance of the active metabolite of irinotecan, leading to greater toxicity. Potentially hazardous interactions have been reported with the hormonal anti-cancers, since phenytoin increases the metabolism of progestogens, resulting in decreased efficacy. Also, phenytoin reduces the plasma concentration of the tyrosine kinase inhibitor imatinib, therefore this combination should be avoided. Plasma concentrations of the anti-emetic aprepitant can be reduced by carbamazepine or phenytoin, and primidone has a similar
ANAESTHESIA AND INTENSIVE CARE MEDICINE 7:6
Antihistamines: manufacturers advise against concomitant use of terfenadine with the anti-androgen bicalutamide or the anti-emetic aprepitant.
KEY REFERENCE 1 Huettemann E, Junker T, Chatzinikolaou K et al. The influence of anthracycline therapy on cardiac function during anesthesia. Anesth Analg 2004; 98: 941–7. FURTHER READING Beijnen J, Schellens J. Drug interactions in oncology. Lancet Oncol 2004; 5: 489–96. British National Formulary. 50th ed, Appendix 1. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2005. Kvolik S, Glavas-Obrovac L, Sakic K, Margaretic D, Karner I. Anaesthetic implications of anticancer chemotherapy. Eur J Anaesthesiol 2003; 20: 859–71. Stockley I H. Drug interactions. 6th ed. London: Pharmaceutical Press, 2002.
192
© 2006 Elsevier Ltd