PHARMACOKINETICS -THER A PE UTICS
Clin. Pharmacokinet. 23 (2): 147-160. 1992 0312-5963/92/0008-0147/$07.00/0 © Adis International Limited. All rights reserved. CPK1205
Pharmacokinetic Optimisation of Antiemetic Therapy Mark Campbell and D. Nicolas Bateman Northern Regional Drug and Therapeutics Centre, Newcastle upon Tyne, England
Contents 147 148 148 148 149 151 151 151 152 152 152 152 153 153 153 154 154 154 154 155 155 155 156 156
Summary
Summary I. Concentration-Effect Relationships 2. Non-Phenothiazine Dopamine Antagonists 2.1 Domperidone 2.2 Metoclopramide 2.3 Haloperidol 3. Phenothiazines 3.1 Prochlorperazine 3.2 Chlorpromazine 4. Corticosteroids 4.1 Methylprednisolone 4.2 Dexamethasone 5. Nabilone 6. Benzodiazepines 6.1 Lorazepam 6.2 Diazepam 6.3 Concentration-Effect 7. Serotonin Antagonists 8. Antihistamines 8.1 Promethazine 8.2 Cinnarizine 8.3 Diphenhydramine 9. Scopolamine (Hyoscine) 10. Conclusions
Antiemetic drugs are used to treat nausea and vomiting due to a variety of causes and have a wide range of pharmacological properties. The choice of drug will, therefore, depend in part on the condition being treated. The drugs can be classified as dopamine antagonists (including phenothiazines and nonphenothiazines), corticosteroids, cannabinoids, benzodiazepines, serotonin antagonists, antihistamines and anticholinergics. There is very little evidence of a relationship between plasma drug contentrations and either their efficacy or the incidence of adverse effects with most antiemetic drugs. With drugs for which concentration-effect studies have been performed, e.g. the benzodiazepines and antihistamines, the effects monitored have not been directly relevant to their use as antiemetics. Antiemetics are used widely, for example, in cancer chemotherapy. Nonetheless, apart from
Clin. Pharmacokinet. 23 (2) 1992
148
metoc!opramide, little work has been done on the influence of indicators of systemic disease on the pharmacokinetics of antiemetic drugs.
The symptoms of nausea and vomiting are frequent in clinical practice. They arise from many different aetiologies, ranging from the mundane (food poisoning) to the exotic (space travel). The physiological control pathways that are believed to be involved in the control of emesis contain a wide range of neurotransmitters (Borison et al. 1981; Mitchelson 1992). Although nausea and vomiting are frequently self-limiting, drugs which are claimed to have antiemetic properties are widely used. The physician has a wide range of therapies available which are claimed to have antiemetic properties (table I). These can be selected for therapeutic use either on the basis of the likely mechanisms involved in the production of the symptoms, for example motion sickness, or, in some cases where mechanisms are less clear, on the basis of clinical trial data, for example corticosteroid therapy m cytotoxic-induced vomiting.
1. Concentration-Effect Relationships For the knowledge of pharmacokinetic properties of a drug to be of most use to practising clinicians there needs to be evidence of some relationship between plasma concentration and efficacy or adverse effects. Study of this relationship is made more difficult in that animal models of vomiting are variable, and not directly applicable to humans. Furthermore, except perhaps in chemotherapy-induced vomiting or experimental studies of motion sickness where there can be confidence that a standard stimulus has been administered, doseranging and plasma-concentration response studies are very difficult to perform in practice. Since in chemotherapy-induced emesis it is now common to use multiple therapy, the difficulties in data interpretation will be obvious. In this article we address what is known of the pharmacokinetics of the antiemetic drugs in table II and highlight the evidence for any relationships
that have been demonstrated between plasma concentration and effect. A large number of antiemetics possess dopamine antagonist activity and are believed to act on the chemoreceptor trigger zone, which is outside the blood-brain barrier. It might then be expected that a close relationship would be drawn between blood concentrations and efficacy for these drugs. Since most drugs in this category have other pharmacological properties, for example antihistamine or serotonin3 [5-hydroxytryptamine3 (5-HT3)] antagonist action, which may be relevant to clinical efficacy (Peroutka & Snyder 1982), it becomes immediately apparent that dose-response relationships will be confused. Perhaps the most obvious example is metoclopramide, which at low concentrations causes a maximal rise in prolactin production (an indication of dopamine receptor blockade) but at high concentrations, such as those attained in 'high dose' therapy for vomiting associated with cancer chemotherapy, is more likely acting primarily as a 5-HT receptor antagonist. Few studies have addressed the issue of plasma concentration-effect relationships for this class of compounds. Since antiemetic drugs belong to a variety of drug groups they will be discussed separately. Doses and routes of administration for some antiemetic drugs discussed in this article are listed in table III.
2. Non-Phenothiazine Dopamine Antagonists 2.1 Domperidone Domperidone is available for oral and rectal administration, the parenteral preparation having been withdrawn by the manufacturer after concern regarding cardiac dysrrhythmias in patients receiving the drug intravenously. There are no studies relating the efficacy of domperidone to its plasma concentration, but its
149
Pharmacokinetics of Antiemetics
pharmacokinetics are well established (Meuldermans et al. 1981). The most salient feature seems to be the relatively low bioavailability of the drug after oral or rectal administration. This did not appear to be taken into account when drug was initially marketed with similar parenteral and oral dosage recommendations. 2.2 Metoclopramide The pharmacokinetics of metoclopramide were extensively studied (Bateman 1983) before Gralla and colleagues (1981) introduced their high dose regimen for cytotoxic drug-induced vomiting. Subsequent work extended knowledge of the handling
of the drug at higher plasma concentrations and investigated the relationship between these concentrations and antiemetic effects in cancer patients. From a practical perspective the value of pharmacokinetic studies with this drug has been to establish the appropriate dosage regimen to produce a desired plasma concentration. The reasons for desiring the attainment of any particular blood concentration have been less easy to define. Metoclopramide has linear pharmacokinetics at the dosages studied, with most investigators finding a plasma half-life (t'l~) of 4 to 6h, a mean clearance (CL) of between 0.4 and 0.5 L/kg· h, and a volume of distribution (Vd) of 3 to 4 L/kg. These appear to hold from single doses of 5mg to a total
Table I. Common situations in which antiemetics are used Condition
Drug(s) of choice
Notes
Cytotoxic-induced vomiting
Phenothiazines Haloperidol Benzodiazepines Metoclopramide Corticosteroids Ondansetron
Motion sickness
Scopolamine (hyoscine)
Triozzi & Laszlo (1987) Often used in combination or in unusually high doses (e.g. dexamethasone, metoclopramide) 5HT3 antagonists (e.g. ondansetron) may be a genuine advance in highly emetic regimens, such as those containing cisplatin Mechanism of emetic response Editorial (1989) includes imbalance in cholinergic neurones Commonly causes side effects, even after transdermal administration Cinnarizine (an antihistamine) may be less sedative Short term treatment only, especially Grahame-Smith & Aronson (1984) in the elderly, who are susceptible to hypotensive effects and druginduced parkinsonism Has both central and direct action in promoting gastric emptying and therefore increase the rate of absorption of oral analgesics Palazzo & Strunin (1984)
Antihistamines
Labyrinthitis
Prochlorperazine or similar phenothiazine
Migraine
Metoclopramide
Postoperative nausea and vomiting Pregnancy
Metoclopramide Phenothiazines Phenothiazines Metoclopramide Antihistamines
Reasonable evidence that e.g. promethazine, prochlorperazine, metoclopramide, cyclizine are free of major teratogenic risk
Reference
Sidle (1987)
Clin. Pharmacokinet. 23 (2) 1992
150
Table II. Selected pharmacokinetic parameters of drugs used as antiemetics F(%)
Vd (L/kg)
tv. (h)
CL (L/h)
Route(s) of Special elimination situations
References
Dopamine antagonists Prochlorperazine V
?
Clin. Pharmacokinet. 23 (2): 147-160. 1992 0312-5963/92/0008-0147/$07.00/0 © Adis International Limited. All rights reserved. CPK1205
Pharmacokinetic Optimisation of Antiemetic Therapy Mark Campbell and D. Nicolas Bateman Northern Regional Drug and Therapeutics Centre, Newcastle upon Tyne, England
Contents 147 148 148 148 149 151 151 151 152 152 152 152 153 153 153 154 154 154 154 155 155 155 156 156
Summary
Summary I. Concentration-Effect Relationships 2. Non-Phenothiazine Dopamine Antagonists 2.1 Domperidone 2.2 Metoclopramide 2.3 Haloperidol 3. Phenothiazines 3.1 Prochlorperazine 3.2 Chlorpromazine 4. Corticosteroids 4.1 Methylprednisolone 4.2 Dexamethasone 5. Nabilone 6. Benzodiazepines 6.1 Lorazepam 6.2 Diazepam 6.3 Concentration-Effect 7. Serotonin Antagonists 8. Antihistamines 8.1 Promethazine 8.2 Cinnarizine 8.3 Diphenhydramine 9. Scopolamine (Hyoscine) 10. Conclusions
Antiemetic drugs are used to treat nausea and vomiting due to a variety of causes and have a wide range of pharmacological properties. The choice of drug will, therefore, depend in part on the condition being treated. The drugs can be classified as dopamine antagonists (including phenothiazines and nonphenothiazines), corticosteroids, cannabinoids, benzodiazepines, serotonin antagonists, antihistamines and anticholinergics. There is very little evidence of a relationship between plasma drug contentrations and either their efficacy or the incidence of adverse effects with most antiemetic drugs. With drugs for which concentration-effect studies have been performed, e.g. the benzodiazepines and antihistamines, the effects monitored have not been directly relevant to their use as antiemetics. Antiemetics are used widely, for example, in cancer chemotherapy. Nonetheless, apart from
Clin. Pharmacokinet. 23 (2) 1992
148
metoc!opramide, little work has been done on the influence of indicators of systemic disease on the pharmacokinetics of antiemetic drugs.
The symptoms of nausea and vomiting are frequent in clinical practice. They arise from many different aetiologies, ranging from the mundane (food poisoning) to the exotic (space travel). The physiological control pathways that are believed to be involved in the control of emesis contain a wide range of neurotransmitters (Borison et al. 1981; Mitchelson 1992). Although nausea and vomiting are frequently self-limiting, drugs which are claimed to have antiemetic properties are widely used. The physician has a wide range of therapies available which are claimed to have antiemetic properties (table I). These can be selected for therapeutic use either on the basis of the likely mechanisms involved in the production of the symptoms, for example motion sickness, or, in some cases where mechanisms are less clear, on the basis of clinical trial data, for example corticosteroid therapy m cytotoxic-induced vomiting.
1. Concentration-Effect Relationships For the knowledge of pharmacokinetic properties of a drug to be of most use to practising clinicians there needs to be evidence of some relationship between plasma concentration and efficacy or adverse effects. Study of this relationship is made more difficult in that animal models of vomiting are variable, and not directly applicable to humans. Furthermore, except perhaps in chemotherapy-induced vomiting or experimental studies of motion sickness where there can be confidence that a standard stimulus has been administered, doseranging and plasma-concentration response studies are very difficult to perform in practice. Since in chemotherapy-induced emesis it is now common to use multiple therapy, the difficulties in data interpretation will be obvious. In this article we address what is known of the pharmacokinetics of the antiemetic drugs in table II and highlight the evidence for any relationships
that have been demonstrated between plasma concentration and effect. A large number of antiemetics possess dopamine antagonist activity and are believed to act on the chemoreceptor trigger zone, which is outside the blood-brain barrier. It might then be expected that a close relationship would be drawn between blood concentrations and efficacy for these drugs. Since most drugs in this category have other pharmacological properties, for example antihistamine or serotonin3 [5-hydroxytryptamine3 (5-HT3)] antagonist action, which may be relevant to clinical efficacy (Peroutka & Snyder 1982), it becomes immediately apparent that dose-response relationships will be confused. Perhaps the most obvious example is metoclopramide, which at low concentrations causes a maximal rise in prolactin production (an indication of dopamine receptor blockade) but at high concentrations, such as those attained in 'high dose' therapy for vomiting associated with cancer chemotherapy, is more likely acting primarily as a 5-HT receptor antagonist. Few studies have addressed the issue of plasma concentration-effect relationships for this class of compounds. Since antiemetic drugs belong to a variety of drug groups they will be discussed separately. Doses and routes of administration for some antiemetic drugs discussed in this article are listed in table III.
2. Non-Phenothiazine Dopamine Antagonists 2.1 Domperidone Domperidone is available for oral and rectal administration, the parenteral preparation having been withdrawn by the manufacturer after concern regarding cardiac dysrrhythmias in patients receiving the drug intravenously. There are no studies relating the efficacy of domperidone to its plasma concentration, but its
149
Pharmacokinetics of Antiemetics
pharmacokinetics are well established (Meuldermans et al. 1981). The most salient feature seems to be the relatively low bioavailability of the drug after oral or rectal administration. This did not appear to be taken into account when drug was initially marketed with similar parenteral and oral dosage recommendations. 2.2 Metoclopramide The pharmacokinetics of metoclopramide were extensively studied (Bateman 1983) before Gralla and colleagues (1981) introduced their high dose regimen for cytotoxic drug-induced vomiting. Subsequent work extended knowledge of the handling
of the drug at higher plasma concentrations and investigated the relationship between these concentrations and antiemetic effects in cancer patients. From a practical perspective the value of pharmacokinetic studies with this drug has been to establish the appropriate dosage regimen to produce a desired plasma concentration. The reasons for desiring the attainment of any particular blood concentration have been less easy to define. Metoclopramide has linear pharmacokinetics at the dosages studied, with most investigators finding a plasma half-life (t'l~) of 4 to 6h, a mean clearance (CL) of between 0.4 and 0.5 L/kg· h, and a volume of distribution (Vd) of 3 to 4 L/kg. These appear to hold from single doses of 5mg to a total
Table I. Common situations in which antiemetics are used Condition
Drug(s) of choice
Notes
Cytotoxic-induced vomiting
Phenothiazines Haloperidol Benzodiazepines Metoclopramide Corticosteroids Ondansetron
Motion sickness
Scopolamine (hyoscine)
Triozzi & Laszlo (1987) Often used in combination or in unusually high doses (e.g. dexamethasone, metoclopramide) 5HT3 antagonists (e.g. ondansetron) may be a genuine advance in highly emetic regimens, such as those containing cisplatin Mechanism of emetic response Editorial (1989) includes imbalance in cholinergic neurones Commonly causes side effects, even after transdermal administration Cinnarizine (an antihistamine) may be less sedative Short term treatment only, especially Grahame-Smith & Aronson (1984) in the elderly, who are susceptible to hypotensive effects and druginduced parkinsonism Has both central and direct action in promoting gastric emptying and therefore increase the rate of absorption of oral analgesics Palazzo & Strunin (1984)
Antihistamines
Labyrinthitis
Prochlorperazine or similar phenothiazine
Migraine
Metoclopramide
Postoperative nausea and vomiting Pregnancy
Metoclopramide Phenothiazines Phenothiazines Metoclopramide Antihistamines
Reasonable evidence that e.g. promethazine, prochlorperazine, metoclopramide, cyclizine are free of major teratogenic risk
Reference
Sidle (1987)
Clin. Pharmacokinet. 23 (2) 1992
150
Table II. Selected pharmacokinetic parameters of drugs used as antiemetics F(%)
Vd (L/kg)
tv. (h)
CL (L/h)
Route(s) of Special elimination situations
References
Dopamine antagonists Prochlorperazine V
?
