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PubMed1987

Valproate monotherapy in the management of generalized and partial seizures.

For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.

Clinical Trials as Topic↗

PubMed1987

Hepatic considerations in the use of antiepileptic drugs.

Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10-38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.

Anticonvulsants↗

PubMedDate not supplied

Associations between risk factors for valproate hepatotoxicity and altered valproate metabolism.

The effects of three risk factors for valproate (VPA) hepatotoxicity (i.e., young age, polypharmacy, and high VPA serum level) on the metabolism of VPA to its monounsaturated metabolites [2-en-VPA (2-en), 3-en-VPA (3-en) and 4-en-VPA (4-en)] were investigated in 106 patients treated with VPA (56 cases of monotherapy and 50 cases of polytherapy). In the monotherapy group, there was a significant negative correlation between age and 4-en/VPA ratio. In the same group, the 4-en/VPA ratio showed a significant positive correlation with serum VPA level, while 3-en/VPA and 2-en/VPA ratios showed significant negative correlations. In patients greater than 10 years, the 4-en/VPA ratio was significantly higher, while the 2-en/VPA ratio was significantly lower in the polytherapy group than in the monotherapy group. Our results indicate that all three risk factors clearly increase the metabolic conversion of VPA to 4-en, the most toxic VPA metabolite, and that polytherapy and high VPA serum level result in the inhibited beta-oxidative metabolism of VPA to 2-en. These altered VPA metabolic profiles are strikingly similar to the abnormal VPA metabolism previously reported in cases with fatal hepatic failure. Although VPA-induced fatal hepatotoxicity has been regarded as an idiosyncratic reaction, it is possible that these three factors enhance susceptibility to VPA hepatotoxicity by altering the metabolism of VPA.

Age Factors↗

PubMed1992

Cognitive function--victim of disease or hostage to treatment?

In persons suffering from epilepsy, cognitive functioning may be compromised for various reasons, including--first and foremost--the learning and behavioral effects of the conditions causing the epilepsy. In addition, the epilepsy itself may cause changes in the nervous system through the metabolic and excitotoxic effects of the seizures and the neurotransmitter elements involved at the membrane level. The effect of the treatment modality, be it pharmacologic or surgical, may also play havoc with cognitive function. The neurobehavioral effects of antiepileptic drugs, although probably less important with the newer agents than in the past, must be considered, especially in polypharmacy, as recent reports have indicated. With increasing data, the effects of various surgical procedures on the cognitive elements of human behavior are becoming better recognized.

Anticonvulsants↗

PubMedDate not supplied

Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities.

Since our last report on valproate (VPA)-related hepatotoxicity in 1988, 8 other children have died of VPA-associated liver failure in Germany and Switzerland. We compared the clinical course of these children with that of 6 children with a reversible outcome of severe hepatotoxicity related to VPA. Thirty-five percent of patients with fatal liver failure were normally developed, 23.5% were receiving VPA monotherapy, and 35.3% were aged < or = 2 years. The initial clinical symptoms of VPA-related hepatotoxicity were nausea, vomiting, apathy or coma, and increasing seizures in more than 50% of patients, in combination with febrile infections at onset of symptoms. As compared with the series of German patients reported in 1988, one third of the fatalities occurred after the first 6 months of therapy as compared with 6% in the 1988 series. Clinical symptoms and laboratory findings were the same in patients with reversible and with fatal outcome. Early or immediate withdrawal of VPA after the first signs of VPA-associated hepatotoxicity may be responsible for the increased number of children who recovered after VPA-related severe liver failure. The pathogenesis of liver failure during VPA treatment remains unknown; metabolic defects and cofactors such as polypharmacy or infections have become increasingly likely to contribute by depleting intracellular CoA. Worldwide, 132 patients have died of VPA-associated liver failure and/or pancreatitis. Because a group at risk for fatalities with VPA cannot be defined precisely, patients treated with VPA and their families must be made well aware of the clinical symptoms of hepatotoxicity such as apathy, vomiting, or increased seizure frequency, especially in the presence of febrile infections. Laboratory tests and clinical controls during the first 6 months of therapy should not be neglected.

Adult↗

PubMed1995

The effect of age on pharmacokinetics of antiepileptic drugs.

Management of epilepsy in the elderly requires understanding of the unique biochemical and pharmacologic characteristics of this patient population. Accurate assessment of seizures and identification of epilepsy syndromes, thorough neurologic assessment to define etiology, and comprehensive evaluation of the patient's health and living situation are necessary for informed management decisions. Challenges to treatment include concomitant diseases, polypharmacy with accompanying drug interactions, and changes in physiology, such as changes in renal clearance and hepatic function than alter drug absorption, protein binding, metabolism, and elimination. Elderly patients with declining intellectual function, motor impairment, or altered sensory function may be especially susceptible to dose-related CNS side effects of antiepileptic drugs (AEDs). Drugs prescribed for concomitant illnesses such as hypertension, cardiovascular disease, infections, behavioral problems, and gastrointestinal disturbances may alter absorption, distribution, and metabolism of AEDs, with an adverse impact on efficacy and increased occurrence of adverse effects. The AEDs may induce metabolism of other drugs, resulting in decline in target response. Addition of an AED to an elderly patient's medical regimen requires careful review of all prescribed drugs. Optimal care of elderly patients with epilepsy includes use of free drug levels to monitor AED concentrations, careful dose selection, and sensitivity to the social problems that may occur in this population.

Adult↗

PubMed1997

The problem of intractability: the continuing need for new medical therapies in epilepsy.

Treatment of epilepsy, one of the most common neurologic disorders, has evolved from "institutional" polytherapy to "dogmatic" monotherapy, and, most recently, to "rational" polypharmacy. The introduction of bromides for the treatment of epilepsy was followed first by phenobarbital and then by phenytoin as therapeutic options. Although attempts to combine medications were legion, none was supported by studies that demonstrated the benefit of such combinations. The issue of adverse effects became a principal argument in favor of monotherapy. Monotherapy, using newly developed drugs, avoided problems due to drug interactions but was ineffective in 20-30% of patients. A greater understanding of basic disease mechanisms and developments in molecular biology have led to an increased number of effective drugs for the estimated 6-12% of patients with epilepsy whose condition is intractable. Clinical research continues to build on the work of basic scientists in attempting to develop treatments based on a desire to move beyond the palliative and to affect the causative mechanisms of the disease. Novel medical approaches now under exploration include the use of drugs with complementary mechanisms of action, stimulation of various components of the nervous system, biochemical manipulations, focal intracerebral drug perfusion, and gene therapy.

Anticonvulsants↗

PubMed1998

Antiepileptic drugs as a cause of worsening seizures.

PURPOSE: Although the paradoxical ability of antiepileptic drugs (AEDs) to increase seizure activity has been recognized for decades, the underlying mechanisms are poorly understood and few systematic studies have addressed this problem. This article is intended to provide a critical review of available literature on this topic. METHODS: Information was collected by means of computerized literature searches, screening of journals and textbooks, and consultation with colleagues. Mechanisms which potentially might precipitate underlying drug-induced exacerbation of seizures were considered based on available pharmacologic and clinical knowledge. RESULTS: The reviewed information suggests that a paradoxical increase in seizure frequency may occur as a result of at least two separate mechanisms. The first appears to involve a nonspecific manifestation of drug intoxication; seizure-worsening in this context is usually reversible by dosage reduction or elimination of unnecessary polypharmacy. Conversely, the other mechanism may involve a distinct adverse primary action of the drug in specific seizure types or in syndromic forms. Carabamazepine, in particular, has been reported to precipitate or exacerbate a variety of seizures, most notably absence, atonic, or myoclonic seizures in patients with generalized epilepsies characterized by bursts of diffuse and bilaterally synchronous spike-and-wave EEG activity. Phenytoin and vigabatrin also have been implicated in worsening of seizures, particularly generalized seizures, whereas gabapentin has been associated repeatedly with precipitation of myoclonic jerks. Benzodiazepines occasionally have been reported to precipitate tonic seizures, especially when given intravenously to control other seizure types in patients with Lennox-Gastaut syndrome. Seizure deterioration has been reported also with other drugs; though in most cases evidence is still insufficient for meaningful conclusions to be drawn. CONCLUSIONS: Drug-induced exacerbation of seizures is a serious and common clinical problem that is often unrecognized or overlooked by the treating physician. Its occurrence appears to be related to three possible causes: an incorrect diagnosis of seizure type or syndromic form, lack of knowledge about certain drugs that are contraindicated in specific types of epilepsies, or to prescription of excessive drug dosages and drug combinations. Further studies are required to evaluate the prevalence of this phenomenon of drug-induced exacerbation of seizures, to investigate its mechanisms in greater detail and to characterize additional prognostic factors that may be used for early identification of patients at risk.

Acute Disease↗

PubMed1999

The pharmacologic basis of antiepileptic drug action.

The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever-growing armentarium of AEDs, necessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action.

Animals↗

PubMed1978

Depression in the elderly. II. Possible drug etiologies; differential diagnostic criteria.

Drugs for the treatment of various medical or psychiatric disorders may sometimes cause or exacerbate depression in the elderly. Drug interactions due to polypharmacy (a common method of prescribing for aged patients) may also play a role the genesis of depression. The roles of specific drugs and of drug interactions are reviewed. Criteria for the diagnosis of depression in the elderly, as well as differential diagnostic guidelines, are presented and constructive suggestions offered.

Aged↗

PubMed1979

Drug utilization and prescribing patterns in a skilled nursing facility: the need for a rational approach to therapeutics.

A study was made of 50 patients drawn at random from a Skilled Nursing Facility (SNF) attended by seven physicians. For 59 percent of these patients, polypharmacy was practiced but no substantiating diagnoses were recorded. Approximately half of the drugs were administered pro re nata. More drugs were prescribed in potentially toxic dosages than in subtherapeutic dosages. The risk of an adverse drug reaction (ADR) was most often associated with anticholinergic agents, sedative-hypnotic drugs, and neuroleptics (thioridazine and chlorpromazine), particularly when prescribed concurrently. Risk of an ADR was highest when a drug was prescribed without recording a definite diagnostic indication. Lack of consistency by individual physicians in their approaches to the therapy of similar disease entities in comparable patients tended to support the concept of peer review in SNFs and also the need for teaching a rational approach to therapeutics in SNFs based on clinical pharmacology as applied to the elderly.

Aged↗

PubMed1982

The management of cardiovascular disease in the elderly.

Elevated blood pressure (either isolated systolic levels above 1150-160 mm Hg, or diastolic/systolic elevations), left ventricular hypertrophy, and possibly decreased high-density lipoproteins (HDL) and increased low-density lipoprotein (LDL) are significant risk factors for cardiovascular disease in the elderly. Treatment of other precursors, such as total cholesterol or triglycerides, is probably not warranted in this group. For the management of hypertension, administration of diuretics with the judicious use of adrenergic inhibitors and vasodilators is indicated. In treating patients who have congestive heart failure, dosages of agents such as digoxin must be carefully adjusted. Antiarrhythmics are generally not well tolerated by the elderly. Whenever possible, polypharmacy should be avoided to prevent adverse interactions.

Aged↗

PubMed1984

Drug disposition in the elderly: a review of the critical factors.

There are meaningful direct correlations between increasing patient age, the incidence of multiple pathologic conditions, and the implementation of polypharmacy regimens. The latter practice culminates in a significant increase in the incidence of adverse drug reactions in these patients. However, the reason the elderly often respond less favorably to many drugs in comparison with young or mature subjects remains unresolved, although the literature is replete with clinical studies that document this phenomenon. This paper presents the state of our knowledge to date.

Adult↗

PubMed1985

Comparison of admission and discharge medications in two geriatric populations.

Drug usage patterns were determined from a chart review of two groups of the elderly upon admission to and discharge from the hospital. A comparison was made between a United States group (N = 60) and a Scotland group (N = 60). The most common drugs noted in both groups were cardiovascular drugs (primarily diuretics) and vitamins and minerals. The mean number of drugs per patient in both groups was approximately four, with minimal change in number between admission and discharge. The number of drugs decreased with male sex and increasing age in the United States group and increased with male sex and increasing age in the Scotland group. The Scotland group was on more short-acting benzodiazepines, more bowel medications, more antidepressants, more antiparkinson agents, and fewer respiratory drugs than the United States group. Although both groups tended to have certain drugs deleted, Scotland patients were more likely to have narcotics discontinued and bowel medications added before discharge. These drug usage patterns demonstrate substantial polypharmacy in the elderly and the importance of selecting appropriate drugs in the elderly.

Age Factors↗

PubMed1989

Influence of hospitalization on drug therapy in the elderly.

In order to determine whether acute hospitalization leads to changes in the medications used by the elderly after discharge, we studied the medications used at admission and discharge for 197 elderly subjects admitted to one hospital. We found that 40% of all admission medications were discontinued by discharge and 45% of all discharge medications were newly started during the hospitalization. Although the number of drugs used did not increase significantly from admission to discharge (4.50 to 4.80, P = .128), the number of narcotics, laxatives, and antibiotics increased significantly. For those elderly subjects admitted to the hospital taking less than the average number of medications, the overall use of medication increased from admission to discharge (2.89 to 3.75, P less than .0001). These "low users" were discharged on more benzodiazepines, narcotics, laxatives, antibiotics, and cardiac medications. Our data suggest that during hospitalization admission medications are discontinued and new medications are started in large numbers and that these changes are accompanied by a tendency towards the increased use of certain categories of medications. These changes may place the elderly patient at increased risk of polypharmacy and its complications.

Aged↗

PubMed1989

Drug-induced illness as a cause for admission to a community hospital.

To assess the rate of occurrence of drug-induced illness as a cause for admission to the general medicine service of a community hospital, charts were reviewed retrospectively of all patients admitted to the service over two randomly selected one-month periods. Statistical analysis was performed on patients over and under the age of 65, and on iatrogenic and noniatrogenic admissions. Twenty-three of 244 patients (9.4%) were admitted with drug-induced illness. Patients with drug-induced illness had 5.7 medications as compared to 3.2 medications per patient admitted for other reasons (P less than .05). A single drug was responsible for 61% of all drug-induced illness admissions. Aspirin and other nonsteroidal anti-inflammatory agents were most often implicated. Eighteen of 155 elderly patients (11.7%) were admitted with drug-induced illness. These patients were on an average of 6.3 medications as compared with 3.8 medications per elderly patient admitted for other causes (P less than .005). Polypharmacy and a preponderantly elderly population may explain the substantial number of admissions caused by adverse drug reactions. Further research to assess the role of patient age and the number and type of medications involved in the event of drug-induced illness requires standardization of definition and diagnostic criteria.

Adult↗

PubMed1994

A medical unit for the acute care of the elderly.

Older patients often experience a loss of independent physical functioning during the course of an acute illness requiring hospitalization. This functional decline is associated with serious sequelae including prolonged hospital stay, nursing home placement, and mortality. Elements of hospitalization may contribute to the progression or persistence of functional decline. The Unit for Acute Care of the Elderly (ACE Unit) at University Hospitals of Cleveland is an acute care general medical service that is designed to foster the independent functioning of patients. The Prehab Program of Patient Centered Care on the ACE Unit is a multifaceted intervention that integrates geriatric assessment into the optimal medical and nursing care of patients in an interdisciplinary environment. The Prehab Program has several key elements tailored to each individual patient's needs: a prepared environment, patient-centered care, multidimensional assessment and nonpharmacologic prescriptions, medical care review, and home planning. Standards of care serve to reduce the risk of iatrogenic illness resulting from polypharmacy, use of physical restraints, and diagnostic procedures. Nurse-initiated guidelines contribute to prevention of functional decline and to restoration of independent patient functioning. The effectiveness of the ACE Unit is being evaluated in a randomized clinical trial.

Acute Disease↗

PubMed1995

Occult caffeine as a source of sleep problems in an older population.

OBJECTIVE: To evaluate the impact of caffeine in medication on sleep complaints in a community population of persons aged 67 or older. DESIGN: Cross-sectional analysis. SETTING: Iowa 65+ Rural Health Study. PARTICIPANTS: Those who completed their own interview, including a section on the use of medications, during the third annual in-person follow-up in 1984-1985. MEASUREMENTS MAIN OUTCOMES: trouble falling asleep or other sleep complaints. Covariates: use of caffeine-containing medication, spasmolytic, or sympathomimetic drug; number of drugs used; depressive symptoms; self-perceived health; comorbidity, hip fracture, arthritis, ulcer of stomach or intestines; and consumption of caffeinated beverages. RESULTS: The prevalence of caffeinated medication use by participants was 5.4%. Those reporting the use of any caffeine-containing medication were at an increased risk of having trouble falling asleep (Odds Ratio [OR] = 1.79, 95% confidence interval [CI] = 1.19-2.68). There was no significant risk of other reported nighttime or daytime sleep problems associated with use of caffeine-containing drugs. Even after adjusting for other factors that could interfere with initiation of sleep, such as painful disease, depressive symptoms, polypharmacy, use of specific medications known to interfere with sleep, and coffee consumption, the use of caffeine-containing medication still presented a significantly increased risk of having trouble falling asleep (OR = 1.60, CI = 1.04-2.46). Although those participants using over-the-counter analgesic medication containing caffeine had an increased risk of trouble falling asleep (OR = 1.88, CI = 1.22-2.90), there was no significant risk of trouble falling asleep for those who took similar noncaffeinated OTC analgesic drugs (OR = 1.26, CI = 0.87-1.83). CONCLUSIONS: The use of caffeine-containing medication is associated with sleep problems. Healthcare providers should be aware of potential problems associated with over-the-counter medications containing caffeine and should counsel patients about the potential of sleep problems. Older patients should be encouraged to read the label on medications and to select drugs that are caffeine-free when that is possible.

Aged↗