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PubMed1999

Use of transdermal amitriptyline gel in a patient with chronic pain and depression.

A man with severe inflammatory bowel disease suffered from chronic abdominal pain and depression. A transdermal amitriptyline gel preparation was compounded since he was unable to take drugs orally Serum concentrations of amitriptyline and its active metabolite nortriptyline were measured over 24 hours. Symptoms of depression were monitored before starting transdermal therapy and at the end of 6 weeks. Pain symptoms and amitriptyline adverse drug events were monitored daily Steady-state serum concentrations of drug and metabolite were within the therapeutic range over 24 hours. The patient reported that his mood was improved but his abdominal pain remained unchanged. Transdermal amitriptyline gel was well tolerated and is an alternative delivery system in patients unable to take drugs orally.

Administration, Cutaneous↗

PubMed2007

Identifying drugs needing pharmacogenetic monitoring in a Korean hospital.

PURPOSE: A decision matrix for identifying drugs for which pharmacogenetic drug monitoring (PDM) provides the greatest benefit in a Korean setting is described. SUMMARY: We developed a decision matrix including the ethnic frequency of clinically relevant polymorphic cytochrome P-450 (CYP) enzymes, and the metabolic profiles and adverse drug reactions of drugs. Using the developed decision matrix based on the population allele frequencies of CYP enzymes, we identified potential candidates for PDM among the most commonly used drugs at Seoul National University Hospital (SNUH). Collectively, 17 of these drugs were largely metabolized by at least one polymorphic CYP enzyme. Pharmacogenetic information was used to identify CYP2C9, CYP2C19, and CYP2D6 as the major CYP enzymes of clinical importance for pharmacologic effect and safety in Koreans. The frequencies of poor and intermediate metabolizers among Koreans were 0% and 2.3-12% for CYP2C9, 12% and 42% for CYP2C19, and 0.44% and 28% for CYP2D6, respectively. The frequency of ultrarapid metabolizers of CYP2D6 was 2.28%. The decision matrix and pharmacogenetic information were used to identify seven drugs for PDM: warfarin, glimepiride, diazepam, amitriptyline, nortriptyline, codeine, and oxycodone. This approach can be applied to other institutional hospitals or other ethnic populations and would be helpful for advancing pharmacy practice. Further work is required to assess the practical and potential clinical relevance of pharmacogenetic variations on drugs of interest before the implementation of PDM. CONCLUSION: A decision matrix helped identify drugs for which PDM provides the greatest potential benefit at one Korean hospital.

Alleles↗

PubMed1993

Antidepressant drugs and the emergence of suicidal tendencies.

Although antidepressant medications represent the cornerstone of treatment for patients with moderate to severe clinical depression, they also carry serious risks. There is evidence which suggests that antidepressants can, in rare instances, induce or exacerbate suicidal tendencies. Nine clinical mechanisms have been proposed through which this may occur. These are: (a) energizing depressed patients to act on pre-existing suicidal ideation; (b) paradoxically worsening depression; (c) inducing akathisia with associated self-destructive or aggressive impulses; (d) inducing panic attacks; (e) switching patients into manic or mixed states; (f) producing severe insomnia or interfering with sleep architecture; (g) inducing an organic obsessional state; (h) producing an organic personality disorder with borderline features; and (i) exacerbating or inducing electroencephalogram (EEG) or other neurological disturbances. Epidemiological and controlled studies also provide data on the association between antidepressant drugs and suicidal ideation, attempts and fatalities. These include studies which: (a) suggest that electroconvulsive therapy may be more effective than antidepressant drugs in reducing the frequency of suicide attempts; (b) indicate that antidepressants may differ in their capacity to reduce the frequency of suicide attempts; (c) find that more overdose attempts were made by patients receiving maprotiline than placebo; and (d) suggest that fluoxetine may be associated with a greater risk of inducing de novo suicidal ideation. Evidence suggests that antidepressants may vary by at least 15-fold in the number of fatal overdoses per million prescriptions. Estimated overdose proclivity rates were derived after adjusting the fatal toxicity data by the therapeutic index of the drug. These rates were very consistent between agents with the same pharmacological properties, and correlated well with known overdose risk rates for amitriptyline, mianserin and maprotiline. Estimated overdose proclivity rates suggest that the highly selective noradrenaline (norepinephrine) uptake inhibitors (desipramine, nortriptyline, maprotiline) may be associated with a greater risk for overdose than more mixed uptake inhibitors and monoamine oxidase inhibitors (MAOIs). Antidepressants are not uniformly neutral in regard to suicidal ideation and attempts. Data clearly demonstrate that antidepressants ameliorate suicidal ideation more effectively than placebo in patients with depression. Although antidepressants diminish suicidal ideation in many recipients, about as many patients experience worsening suicidal ideation on active medication as they do on placebo. Furthermore, at least as many patients attempted suicide on fluoxetine and tricyclic antidepressants as on placebo, and more patients attempted to overdose on maprotiline than placebo. These observations suggest that antidepressants may redistribute suicide risk, attenuating risk in some patients who respond well, while possible enhancing risk in others who respond more poorly.(ABSTRACT TRUNCATED AT 400 WORDS)

Antidepressive Agents↗

PubMed1998

Systemic antifungal agents. Drug interactions of clinical significance.

There are 3 main classes of systemic antifungals: the polyene macrolides (e.g. amphotericin B), the azoles (e.g. the imidazoles ketoconazole and miconazole and the triazoles itraconazole and fluconazole) and the allylamines (e.g. terbinafine). Other systemic antifungals include griseofulvin and flucytosine. Most drug-drug interactions involving systemic antifungals have negative consequences. The interactions of amphotericin B, flucytosine, griseofulvin, terbinafine and azole antifungals can be divided into the following categories: (i) additive dangerous interactions; (ii) modifications of antifungal kinetics by other drugs; and (iii) modifications of the kinetics of other drugs by antifungals. Amphotericin B and flucytosine mainly interact with other agents pharmacodynamically. Clinically important drug interactions with amphotericin B cause nephrotoxicity, hypokalaemia and blood dyscrasias. The most important drug interaction of flucytosine occurs with myelotoxic agents. Hypokalaemia can precipitate the long QT syndrome, as well as potentially lethal ventricular arrhythmias like torsade de pointes. Synergism is likely to occur when either QT interval-modifying drugs (e.g. terfenadine and astemizole) and drugs that induce hypokalaemia (e.g. amphotericin B) are coadministered. Induction and inhibition of cytochrome P450 enzymes at hepatic and extrahepatic sites are the mechanisms that underlie the most serious pharmacokinetic drug interactions of the azole antifungals. These agents have been shown to notably decrease the catabolism of numerous drugs: histamine H1 receptor antagonists, warfarin, cyclosporin, tacrolimus, digoxin, felodipine, lovastatin, midazolam, triazolam, methylprednisolone, glibenclamide (glyburide), phenytoin, rifabutin, ritonavir, saquinavir, nevirapine and nortriptyline. Non-antifungal drugs like carbamazepine, phenobarbital (phenobarbitone), phenytoin and rifampicin (rifampin) can induce the metabolism of azole antifungals. The bioavailability of ketoconazole and itraconazole is also reduced by drugs that increase gastric pH, such as H2 receptor antagonists, proton pump inhibitors, sucralfate and didanosine. Griseofulvin is an enzymatic inducer of coumarin-like drugs and estrogens, whereas terbinafine seems to have a low potential for drug interactions. Despite important advances in our understanding of the mechanisms underlying pharmacokinetic drug interactions during the 1990s, at this time they still remain difficult to predict in terms of magnitude in individual patients. This is because of the large interindividual and intraindividual variations in the catalytic activity of those metabolising enzymes that can either be induced or inhibited by various drugs. Notwithstanding these variations, increasing clinical experience is allowing pharmacokinetic interactions to be used to advantage in order to improve the tolerability of some drugs, as recently exemplified by the use of a fixed combination of ketoconazole and cyclosporin.

Antifungal Agents↗

PubMed2001

Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions.

Drug-drug interactions can be associated with patient morbidity due to either increased toxicity or a potentially ineffective concentration. Because interactions cannot always be anticipated during drug development and actual patients receiving a drug for therapeutic use often differ from those included in clinical trials, postmarketing surveillance is essential. Therapeutic drug monitoring (TDM) databases offer a unique opportunity in this respect. Prerequisites for TDM databases to provide valid information in a pharmacoepidemiological perspective include the following: precise description of exposure to the potentially interacting drugs; measurement of parent compound and active metabolites through accurate and precise analytical techniques; documentation of relevant patient characteristics that may act as confounding factors (e.g. gender, age, smoking habits); repeated assessments over time if possible; and sound pharmacokinetic framework for data selection, analysis and interpretation. The contribution of TDM to the documentation of drug-drug interactions takes advantage of different possible study designs, discussed on the basis of recently published studies. The single case report plays an important role as an alert signal. It is illustrated for a patient on long-term treatment, who displayed an unexpectedly high clozapine concentration after the introduction of ciprofloxacin comedication. The prospective on and off comedication panel study shows advantages in terms of carefully selected inclusion criteria and control of treatment modalities. A study of the thioridazine-fluvoxamine interaction is presented, with patients followed on thioridazine monotherapy, after introduction of fluvoxamine and after its discontinuation. The main advantage of the retrospective large-scale TDM database screen is representativeness of patients actually treated, whereas drawbacks are related to quality of data and suitability for valid interpretation. Such an approach is illustrated by a review of data collected over 10 years of routine TDM that allowed documenting induction of nortriptyline metabolism by carbamazepine and inhibition by several phenothiazines. Finally, population pharmacokinetics is well suited to observational data collected for TDM purpose, provided quality is ascertained. Focus is placed on interindividual variability and relationship between pharmacokinetic parameters and patient characteristics, including comedication. The population approach is discussed with respect to a study that documented a 32% increase of haloperidol clearance associated with anticonvulsant comedication, in addition to effects of age and bodyweight. Among factors to consider for improved effectiveness in the use of TDM databases for postmarketing surveillance of drug-drug interactions, integration of efficacy and safety data in future studies and communication of expert recommendations to prescribing physicians are essential.

Databases, Factual↗

PubMed2004

Current use of selective serotonin reuptake inhibitors and risk of acute myocardial infarction.

BACKGROUND: It has been suggested that increased platelet activation increases the risk of acute myocardial infarction (AMI) in patients with depression. Selective serotonin reuptake inhibitors (SSRIs) may attenuate platelet activation by serotonin depletion in platelets. Observational studies have shown discrepant results of AMI risk associated with the use of SSRIs. OBJECTIVE: The aim of this study was to evaluate the association of exposure to different groups of antidepressants, including SSRIs, and the risk of AMI. The study also assessed in more detail the influence of timing of the exposure to antidepressants in a general adult population (<90 years of age), with or without diagnosed risk factors for AMI. STUDY DESIGN/METHODS: We conducted a population-based case-control analysis on the UK General Practice Research Database (GPRD). The study included 8688 patients (<90 years of age), with a first-time AMI between 1995 and 2001, and 33 923 controls, who were matched by age, sex, calendar time, and general practice. Conditional logistic regression was used to estimate odds ratios (ORs). RESULTS: Current use of an antidepressant was defined as a supply of the last prescription for an antidepressant that lasted up to the index date or beyond. Recent past use was defined as a supply of the last prescription for an antidepressant that ended 1-29 days before the index date. SSRIs investigated were citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. Non-SSRIs investigated were amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nefazodone, trazodone and trimipramine. Other antidepressants included were amoxapine, desipramine, lithium, maprotiline, mianserin, moclobemide, nortriptyline and protriptyline. Adjusted ORs (with 95% CI) for the current use of SSRIs, non-SSRIs, or other antidepressants, compared with non-use of antidepressants, were 0.63 (95% CI 0.43, 0.91; p=0.02), 0.92 (95% CI 0.77, 1.09; p=0.32) and 0.59 (95% CI 0.29, 1.20; p=0.14), respectively. The adjusted OR of recent past use of SSRIs compared with non-use of SSRIs was 1.42 (95% CI 1.02, 1.97; p=0.04). CONCLUSION: The present analysis provides further evidence that the current use of SSRIs is associated with a slightly decreased risk for AMI.

Age Distribution↗

PubMed2001

Chronic depression in the elderly: approaches for prevention.

Depression in old age frequently follows a chronic and/or relapsing course, related to medical comorbidity, cognitive impairment and depletion of psychosocial resources. As endorsed by the US National Institutes of Health (NIH) Consensus Development Conference on the Diagnosis and Treatment of Late Life Depression, a major goal of treatment is to prevent relapse, recurrence and chronicity. We believe that most, if not all, elderly patients with major depressive episodes are appropriate candidates for maintenance therapy, because of the vulnerability to relapse and recurrence and because of the favourable benefit to risk ratio of available treatments. Antidepressant pharmacotherapy is the mainstay of this therapeutic goal, but psychosocial approaches (especially interpersonal psychotherapy) have also been shown to contribute significantly to prevention of a chronic depressive illness and to prevention of the disability that attends depression. Studies published to date have established the long term or maintenance efficacy of the tricyclic antidepressant nortriptyline. Current, ongoing studies are addressing the maintenance efficacy of paroxetine and citalopram to prolong recovery in depression associated with old age. These studies are focusing particularly on patients aged 70 years and above, who are at high risk of recurrence, and on patients in primary care settings, where under-recognition and under-treatment of depression in the elderly have been costly from a public health perspective in terms of increased medical utilisation, burden to patients and families, and high rates of suicide. Depression in old age is a major contributor to the global burden of illness-related disability, but it is extremely treatable if appropriate pharmacotherapy is prescribed and accepted by patients and their caregivers.

Aged↗

PubMed2003

Demographics, assessment and management of pain in the elderly.

The prevalence of pain increases with each decade of life. Pain in the elderly is distinctly different from pain experienced by younger individuals. Cancer is a leading cause of pain; however, other conditions that cause pain such as facet joint arthritis (causing low back pain), polymyalgia rheumatica, Paget's disease, neuropathies, peripheral vascular disease and coronary disease most commonly occur in patients over the age of 50 years. Poorly controlled pain in the elderly leads to cognitive failure, depression and mood disturbance and reduces activities of daily living. Barriers to pain management include a sense of fatalism, denial, the desire to be 'the good patient', geographical barriers and financial limitations. Aging causes physiological changes that alter the pharmacokinetics and pharmacodynamics of analgesics, narrowing their therapeutic index and increasing the risk of toxicity and drug-drug interactions. CNS changes lead to an increased risk of delirium. Assessment among the verbal but cognitively impaired elderly is satisfactorily accomplished with the help of unidimensional and multidimensional pain scales. A comprehensive physical examination and pain history is essential, as well as a review of cognitive function and activities of daily living. The goal of pain management among the elderly is improvement in pain and optimisation of activities of daily living, not complete eradication of pain nor the lowest possible drug dosages. Most successful management strategies combine pharmacological and nonpharmacological (home remedies, massage, topical agents, heat and cold packs and informal cognitive strategies) therapies. A basic principle of the pharmacological approach in the elderly is to start analgesics at low dosages and titrate slowly. The WHO's three-step guideline to pain management should guide prescribing. Opioid choices necessitate an understanding of pharmacology to ensure safe administration in end-organ failure and avoidance of drug interactions. Adjuvant analgesics are used to reduce opioid adverse effects or improve poorly controlled pain. Adjuvant analgesics (NSAIDs, tricyclic antidepressants and antiepileptic drugs) are initiated prior to opioids for nociceptive and neuropathic pain. Preferred adjuvants for nociceptive pain are short-acting paracetamol (acetaminophen), NSAIDs, cyclo-oxygenase-2 inhibitors and corticosteroids (short-term). Preferred drugs for neuropathic pain include desipramine, nortriptyline, gabapentin and valproic acid. Drugs to avoid are pentazocine, pethidine (meperidine), dextropropoxyphene and opioids that are both an agonist and antagonist, ketorolac, indomethacin, piroxicam, mefenamic acid, amitriptyline and doxepin. The type of pain, and renal and hepatic function, alter the preferred adjuvant and opioid choices. Selection of the appropriate analgesics is also influenced by versatility, polypharmacy, severity and type of pain, drug availability, associated symptoms and cost.

Acetaminophen↗

PubMedDate not supplied

Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose.

Strong correlations have been reported between drug concentrations at steady-state and a single drug concentration determined sometime after an initial dose for lithium, nortriptyline, imipramine, desipramine, choramphenicol and theophylline. The mathematical basis of these relationships suggests that a one point method for predicting steady-state drug concentrations and individual dosing requirements should be widely applicable to most drugs and should be valid for patients having a wide range of drug half-lives. A method is presented for evaluating the optimum time of blood sampling to determine a drug concentration in serum of plasma that best correlates with steady-state levels and for defining the range of drug half-lives beyond which the predictive approach is likely to give poor results.

Antidepressive Agents, Tricyclic↗

PubMedDate not supplied

Circadian changes of drug disposition in man.

Circadian (approximately equal to 24 hours) and other endogenous biological rhythms, detectable at all levels of organisation, constitute a temporal structure in all animal species, including man. Circadian, circannual, and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical and chemical agents, including medications and foods, are rather common phenomena. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of three complementary concepts: the chronopharmacokinetics of a drug (rhythmic changes in its pharmacokinetics), the chronesthesy (rhythmic changes in susceptibility of target biosystems to the drug), and the chronergy (the drug-integrated overall effects). The chronopharmacokinetics of many drugs have been evaluated in man including sodium salicylate, aspirin, indomethacin, paracetamol (acetaminophen), phenacetin, amidopyrine, theophylline, digitalis, propranolol, clorazepate, hexobarbitone (hexobarbital), lithium, phenytoin (diphenylhydantoin), nortriptyline, ethanol, erythromycin, ampicillin, sulfasymazine, sulphanilamide, cisplatin (cis-diammine dichloroplatinum), d-xylose, ferrous sulphate, potassium chloride, hydrocortisone and prednisolone, among others. The roles presumably played by circadian rhythms in drug metabolising liver enzymes and kidney function are summarized, and the practical implications of chronopharmacokinetics, aiming both to improve in a quantitative manner the metabolic fate of a drug and its effectiveness, are discussed.

Adolescent↗

PubMed1987

The relationship between antidepressant response and tricyclic antidepressant plasma concentrations. A retrospective analysis of the literature using logistic regression analysis.

The relationship between the antidepressant effect of the tricyclic antidepressants and their plasma concentrations was reviewed. Logistic regression was utilised as an analytical tool to facilitate the evaluation. The currently available literature allowed the construction of 4 tricyclic data sets of sufficient size to warrant statistical analysis. Inspection of the distribution of the data and the logistic regression analyses resulted in several conclusions regarding the existence of 'therapeutic windows' for these drugs. Firstly, no relationship between amitriptyline plasma concentrations and therapeutic response was apparent. Secondly, curvilinear relationships were apparent for 2 of the other tricyclic antidepressants studied. The currently recommended therapeutic range of 60 to 150 micrograms/L for nortriptyline was found to be the range most likely to produce a positive antidepressant effect. Desipramine concentrations between 108 and 158 micrograms/L were most commonly associated with beneficial therapeutic responses. Finally, a linear relationship was noted for imipramine in which an imipramine therapeutic plasma concentration threshold of 244 micrograms/L and above was most commonly associated with a beneficial response to the drug.

Animals↗

PubMed1989

Recent developments in the study of the effects of cigarette smoking on clinical pharmacokinetics and clinical pharmacodynamics.

With the ever-increasing population of cigarette smokers, the potential for cigarette smoke to affect drug therapy both pharmacokinetically and pharmacodynamically is significant. The overriding pharmacokinetic effect is increased drug metabolism through the induction of liver enzymes. The constituents of tobacco smoke, primarily nicotine, have their own pharmacological effects which may potentiate or antagonise the desired pharmacological effect of a particular drug, thereby affecting its efficacy. Furthermore, end-organ responsiveness may also be altered by tobacco. These latter 2 aspects constitute altered clinical pharmacodynamics. Approximately 30 drugs have been evaluated in terms of cigarette smoking. Induction of liver enzymes has been shown to increase the metabolism of imipramine, meprobamate, oestrogens, pentazocine, phenylbutazone, theophylline and warfarin. Nicotine has been shown to inhibit diuresis, alter ulcer healing, impair subcutaneous absorption, affect protein binding and stimulate catecholamine release; these effects have been evaluated in terms of therapy with frusemide (furosemide), histamine H2-antagonists, insulin, lignocaine (lidocaine) and beta-blockers, respectively. The interactions have not been correlated with clinical significance in all cases. Diminished end-organ responsiveness may account for reduced drowsiness in smokers receiving chlorpromazine and benzodiazepines, compared with non-smokers. Smoking has been associated with diminished pain tolerance, requiring increased dosages of morphine, pethidine (meperidine) and propoxyphene. Enzyme-inducers such as carbamazepine, phenytoin and phenobarbitone appear to be minimally affected by cigarette smoke, perhaps because hepatic enzymes are already maximally stimulated. Codeine, corticosteroids and nortriptyline do not appear to be affected by cigarette smoke. The bioavailability of glutethimide is higher in smokers, but this has not been associated with greater efficacy. The effect of smoking on paracetamol (acetaminophen) has been variable, depending on the extent of smoking, and does not appear to be of clinical significance.

Animals↗

PubMed1993

Clinical pharmacokinetics of antidepressants in the elderly. Therapeutic implications.

The prevalence of depression in the elderly suggests that a substantial number of older patients will be treated with an antidepressant medication such as one of the tricyclics, trazodone, fluoxetine or lithium. The physiological changes that accompany aging raise the possibilities of altered pharmacokinetics, patterns of efficacy and adverse effect profiles. The literature addressing the subject of antidepressant use in the elderly has not provided a clear, consistent picture of how these drugs behave in this population in comparison with younger patients. Particularly in the case of the tricyclic antidepressants (TCAs), a large degree of interindividual variation in drug clearance (CL) confounds attempts to find differences attributable to age per se. Study design, however, is also a problem in that very few investigators include a young control group, choosing instead to compare their data with previously reported outcomes. Designations of statistical significance and positive correlation also differ among investigators, and the clinical significance of any finding is not always addressed. The available data suggest that imipramine CL is reduced in the elderly and that amitriptyline CL may be reduced. Desipramine CL does not appear to be affected by age, although decreased renal function in the elderly may lead to accumulation of the hydroxylated metabolite, the clinical importance of which is not known. Nortriptyline is the most thoroughly studied TCA in the elderly. CL seems decisively lower only in elderly patients with concurrent medical illness. The hydroxylated metabolite probably accumulates with diminishing renal function. Not enough data are available on doxepin to make a conclusion. Trazodone CL is diminished somewhat in elderly men. Lithium CL appears to diminish with the declining renal function associated with aging. Fluoxetine data are sparse. Available data do not show any decrease in CL of the parent drug; more information is needed on the metabolite norfluoxetine. Although knowledge of CL changes with aging can help the clinician more accurately achieve the desired steady-state concentration of a drug during long term therapy, much work is still needed to evaluate the relationships among drug concentrations at steady-state, efficacy and adverse effects in the elderly.

Aged↗

PubMed1993

Pharmacokinetic optimisation of tricyclic antidepressant therapy.

Pharmacokinetics has greatly contributed to the elucidation of the variability in clinical response to antidepressants in terms of differences in plasma concentrations due to genetic constitution, age, associated diseases and drug interactions. Despite no general agreement, therapeutic and toxic concentrations have been suggested for some tricyclic antidepressants (TCAs) [amitriptyline, nortriptyline, imipramine, desipramine]. Predictive techniques may be implemented on the basis of which starting TCA dosages may be selected to reach more rapidly those concentrations at which efficacy is more probable. Therapeutic drug monitoring may thereafter assist the clinician in refining the individualisation of the dosage regimen.

Adult↗

PubMed2000

Effects of the antifungal agents on oxidative drug metabolism: clinical relevance.

This article reviews the metabolic pharmacokinetic drug-drug interactions with the systemic antifungal agents: the azoles ketoconazole, miconazole, itraconazole and fluconazole, the allylamine terbinafine and the sulfonamide sulfamethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or small intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controlled pharmacokinetic interaction studies in patients or healthy volunteers are reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isoforms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Methods used for in vitro drug interaction studies and in vitro-in vivo scaling are then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drug-metabolising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin, tacrolimus, alprazolam, triazolam, midazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, terfenadine or astemizole can result in clinically significant drug interactions, some of which can be life-threatening. The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor is much lower. Thus, clinical interactions of CYP3A substrates with this azole derivative are of lesser magnitude, and are generally observed only with fluconazole dosages of > or =200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan with fluconazole results in clinically significant drug interactions. Fluconazole is a potent inhibitor of CYP2C19 in vitro, although the clinical significance of this has not been investigated. No clinically significant drug interactions have been predicted or documented between the azoles and drugs that are primarily metabolised by CYP1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions with coadministered substrates of this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. On the basis of the existing in vitro and in vivo data, drug interactions of terbinafine with substrates of other CYP isoforms are unlikely.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Comprehensive survey of the relationship between serum concentration and therapeutic effect of amitriptyline in depression.

The relationship between serum concentration (C(s)) of amitriptyline and its therapeutic effect in depression has been investigated frequently over the last 3 decades; however, the results were controversial and no consensus was reached. Therefore, we have performed a comprehensive survey and meta-analysis of the subject. All relevant literature was included, and the design of studies on the serum concentration-therapeutic effect relationship (SCTER) of amitriptyline was evaluated. Pooled original data from SCTER studies with adequate design were analysed by various statistical methods: regression analysis of therapeutic effect and C(s); comparison of the mean therapeutic effect in various ranges of C(s); dichotomisation of outcome and analysis according to sensitivity of receiver operation curves; frequency of responders and nonresponders in ranges determined by points of sensitivity; analysis of the distribution of C(s) in responders and nonresponders; logistic regression of responders and nonresponders with C(s) and other independent variables; calculation of effect size (g) and mean effect size (g(m)). Forty-five SCTER studies of amitriptyline were identified, and 27 studies met the minimum criteria of adequate study design. Inadequate study design predicted the finding of no SCTER. Analysis of the pooled data from studies with adequate design confirmed a therapeutic window of the sum of C(s) of amitriptyline and its active metabolite nortriptyline of about 80 to 200 microg/L. A moderate and significant positive g(m) (0.538, 95% confidence interval 0.167 to 0.909) was calculated for treatment with C(s) within the therapeutic window in comparison with treatment with C(s) outside the therapeutic window (19 studies with adequate design and original data available, n = 583). In conclusion, the evidence for a biphasic SCTER of amitriptyline in depression is considerably improved, and the results may help to find a consensus in the future. However, the clinical benefit of therapeutic drug monitoring of amitriptyline can only be demonstrated in a controlled and randomised study. Furthermore, the results provide further evidence that antidepressants at optimum C(s) are superior to placebo in the treatment of depression.

Amitriptyline↗

PubMed2004

Pharmacokinetic interactions of topiramate.

Topiramate is a new antiepileptic drug (AED) that has been approved worldwide (in more than 80 countries) for the treatment of various kinds of epilepsy. It is currently being evaluated for its effect in various neurological and psychiatric disorders. The pharmacokinetics of topiramate are characterised by linear pharmacokinetics over the dose range 100-800 mg, low oral clearance (22-36 mL/min), which, in monotherapy, is predominantly through renal excretion (renal clearance 10-20 mL/min), and a long half-life (19-25 hours), which is reduced when coadministered with inducing AEDs such as phenytoin, phenobarbital and carbamazepine. The absolute bioavailability, or oral availability, of topiramate is 81-95% and is not affected by food. Although topiramate is not extensively metabolised when administered in monotherapy (fraction metabolised approximately 20%), its metabolism is induced during polytherapy with carbamazepine and phenytoin, and, consequently, its fraction metabolised increases. During concomitant treatment with topiramate and carbamazepine or phenytoin, the (oral) clearance of topiramate increases 2-fold and its half-life becomes shorter by approximately 50%, which may require topiramate dosage adjustment when phenytoin or carbamazepine therapy is added or discontinued. From a pharmacokinetic standpoint, topiramate is a unique example of a drug that, because of its major renal elimination component, is not subject to drug interaction due to enzyme inhibition, but nevertheless is susceptible to clinically relevant drug interactions due to induction of its metabolism. Unlike old AEDs such as phenytoin and carbamazepine, topiramate is a mild inducer and, currently, the only interaction observed as a result of induction by topiramate is that with ethinylestradiol. Topiramate only increases the oral clearance of ethinylestradiol in an oral contraceptive at high dosages (>200 mg/day). Because of this dose-dependency, possible interactions between topiramate and oral contraceptives should be assessed according to the topiramate dosage utilised. This paper provides a critical review of the pharmacokinetic interactions of topiramate with old and new AEDs, an oral contraceptive, and the CNS-active drugs lithium, haloperidol, amitriptyline, risperidone, sumatriptan, propranolol and dihydroergotamine. At a daily dosage of 200 mg, topiramate exhibited no or little (with lithium, propranolol and the amitriptyline metabolite nortriptyline) pharmacokinetic interactions with these drugs. The results of many of these drug interaction studies with topiramate have not been published before, and are presented and discussed for the first time in this article.

Anticonvulsants↗

PubMed1990

Clomipramine. An overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder.

During the 20 years that have elapsed since clomipramine (chlorimipramine) was first marketed, it has become well established in the treatment of depressive illness, particularly treatment-resistant depression. However, in addition to its role as an antidepressant, attention is being focused on the use of clomipramine in 2 other areas of psychiatry: obsessive compulsive disorder and panic disorder. Short term clinical trials have shown that clomipramine is generally more effective than amitriptyline, imipramine, desipramine, nortriptyline or clorgiline in reducing obsessive compulsive symptoms. Clomipramine appears to produce some short term benefit with exposure therapy in patients with obsessive compulsive disorder. However, the efficacy of the drug after long term follow-up has not been fully investigated. The antiobsessional efficacy of clomipramine appears to be independent of its antidepressant activity. In patients with panic disorder with or without agoraphobia (DSM-IIIR), clomipramine reduces the frequency and severity of panic attacks within 7 to 21 days of beginning treatment and efficacy is maintained for at least 12 months. Clomipramine is more effective than imipramine, the generally accepted standard treatment for patients with panic disorder after 2 weeks' treatment, but after 6 or 10 weeks both drugs are similarly effective. Other double-blind studies have shown that clomipramine is more effective than placebo and at least as effective as fluvoxamine and oxitriptan (5-hydroxytryptophan) in reducing panic attacks and associated anxiety. Adverse effects associated with clomipramine treatment are mild to moderate in nature and are predominantly a result of the drug's anticholinergic activity. The incidence of seizures is dose related, occurring in 0.48% of all patients receiving clomipramine less than or equal to 250 mg/day and 2.1% of patients receiving greater than or equal to 300 mg/day. In conclusion, the available data indicate that clomipramine is a worthwhile addition to the limited treatments available for obsessive compulsive disorder and panic disorder, two psychiatric disorders which have previously been difficult to manage pharmacologically.

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