[Axelrod et al. (1958)][1] first described the enzyme-catalyzed O- methylation of catecholamines and other catechols in the late 1950s. The enzyme responsible for the O- methylation, catechol- O -methyltransferase (COMT; EC[2.1.1.6][2]),2 was partly purified and characterized by the same group ([

Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors.

When peripheral decarboxylation is blocked by carbidopa or benserazide, the main metabolic pathway of levodopa is O-methylation by catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new potent, selective and reversible nitrocatechol-type COMT inhibitors. Animal studies have demonstrated that entacapone mainly has a peripheral effect whereas tolcapone also inhibits O-methylation in the brain. In human volunteers, both entacapone and tolcapone dose-dependently inhibit the COMT activity in erythrocytes, improve the bioavailability and decrease the elimination of levodopa, and inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is administered with every scheduled dose of levodopa whereas tolcapone is administered 3 times daily. The different administration regimens for these agents are based on their different pharmacokinetic and pharmacodynamic profiles. Both entacapone and tolcapone enhance and extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. They prolong the duration of levodopa effect. Clinical studies show that they increase the daily ON time by an average 1 to 3 hours, improve the activities of daily living and allow daily levodopa dosage to be decreased. Correspondingly, they significantly reduce the daily OFF time. No comparative studies between entacapone and tolcapone have been performed. Tolcapone also appears to have a beneficial effect in patients with nonfluctuating Parkinson's disease. The main adverse effects of the COMT inhibitors are related to their dopaminergic and gastrointestinal effects. Enhancement of dopaminergic activity may cause an initial worsening of levodopa-induced adverse effects, such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders and hallucinations. Levodopa dose adjustment is recommended to avoid these events. Tolcapone is associated with diarrhoea in about 16 to 18% of patients and entacapone in less than 10% of patients. Diarrhoea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the colour of COMT inhibitors and their metabolites. Elevated liver transaminase levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. The descriptions of acute, fatal fulminant hepatitis and potentially fatal neurological reactions, such as neuroleptic malignant syndrome and rhabdomyolysis, in association with tolcapone led to the suspension of its marketing authorisation in the European Community and Canada. In many other countries, the use of tolcapone is restricted to patients who are not responding satisfactorily to other therapies. Regular monitoring of liver enzymes is required if tolcapone is used. No such adverse reactions have so far been described for entacapone and no laboratory monitoring has been proposed. COMT inhibitors added to levodopa therapy are beneficial, particularly in patients with fluctuating disease. They may be combined with other antiparkinsonian drugs, such as dopamine agonists, selegiline and anticholinergics without adverse interactions. They provide a new treatment possibility in patients with Parkinson's disease who have problems with their present levodopa therapy.

Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease

New, Selective Catechol-O-Methyltransferase Inhibitors as Therapeutic Agents in Parkinson’s Disease

Common naturally occurring polymorphisms have been identified in the coding regions of the alpha(1A)-, alpha(2B)-, beta(1)- and beta(2)-adrenoceptor (AR) genes [alpha(1A)-AR R492C, alpha(2B)-AR insertion/deletion (I/D), beta(1)-AR R389G, beta(2)-AR G16R and beta(2)-AR Q27E] and are associated with modified in vivo and in vitro functionality. We tested their possible effects on the haemodynamic responses to intravenous adrenaline (20, 40, 80 and 160 ng/kg of body weight per min; 5 min for each infusion rate) before and after beta-blockade (propranolol) in 16 young healthy men. We monitored changes in heart rate, blood pressure (BP), ECG, coronary flow velocity and plasma adrenaline and noradrenaline. The Cys/Cys (CC) genotype of the alpha(1A)-AR R492C polymorphism was associated with a longer ECG PR interval before and during the adrenaline infusions. The deletion/deletion (D/D) genotype of the alpha(2B)-AR I/D polymorphism was associated with blunted coronary blood flow increases during the adrenaline infusion before beta-blockade. The beta(1)-AR R389G polymorphism was not associated with modified responses to infused adrenaline. Subjects carrying the Gly/Gly (GG) genotype of the beta(2)-AR G16R polymorphism demonstrated increases in diastolic BP upon adrenaline infusion, whereas diastolic BP was decreased in the other genotype groups. These results suggest that, upon acute adrenaline infusion, the alpha(2B)-AR D/D genotype confers increased vasoconstriction and that the beta(2)-AR GG genotype confers reduced vasodilatation.

Effects of common polymorphisms in the α1A-, α2B-, β1- and β2-adrenoreceptors on haemodynamic responses to adrenaline

According to the United States Food and Drug Administration web site, there are more than 15,000 currently approved prescription and over-the-counter drugs, diagnostics and intravenous supplementation products in the United States (78). Couple these with the hundreds of herbal and dietary supplements that undergo little if any scrutiny by the Food and Drug Administration (48), and it is no wonder that the potential for adverse drug interactions is a growing concern for all fields of patient care including dental medicine. To further complicate matters, common food products, such as grapefruit juice, that are consumed by many patients because of their reported cardiovascular and cancer-preventing benefits, have been involved in some of the most serious adverse drug interactions reported to date (19, 74, 158). There is no doubt that our patient population is consuming more and more drugs and herbal products. The geriatric dental population is increasing (75) and because of the presence of multiple disease states such as hypertension, congestive heart failure, diabetes, arthritis, and osteoporosis in these individuals, polypharmacy in this population is the norm (99, 182). In addition, decreases in cardiac output resulting in less blood flow and less drug being presented to the liver and kidney, decreases in hepatic and pre-hepatic drug metabolizing efficiency, decreases in renal excretory ability and increased receptor sensitivity to a variety of the central nervous system-acting drugs such as antidepressants, narcotics, and benzodiazepines, and a progressive decline in counter-regulatory (homeostatic) mechanisms make this population especially vulnerable to the adverse effects of drugs (232). Unlike 30 years ago, when many of these patients were coming to dental practices completely or partially edentulous, these patients are now maintaining their teeth longer and even when there is risk of tooth loss or there are edentulous spaces, many of these patients are opting for complex periodontal, implant, and restorative procedures over full or partial dentures (60). As a consequence, these patients need local anesthesia ⁄ vasoconstrictors, analgesics, anxiolytics, and antibiotics, which on occasion could adversely interact with a variety of the medications they are on. Even among young to middle-aged adults, the intake of certain prescription medications, especially those within the cardiovascular classes of drugs, is on the rise. With the new guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, patients with what was previously considered normal or borderline blood pressure are now being placed on a variety of antihypertensive agents (45). Patients with concomitant cardiovascular risk factors such as diabetes are being more aggressively treated, with multi-drug regimens often being recommended at the initiation of antihypertensive therapy. Classes of drugs that did not exist 20 years ago are being widely administered to young and old alike. On December 29, 1987, fluoxetine (Prozac ) became the first selective serotonin reuptake inhibitor approved by the Food and Drug Administration for the treatment of adult depression (233). Today there are five selective serotonin reuptake inhibitors in the top 100 prescribed drugs in the United States (229). In addition to adult depression, they are being prescribed for a variety of psychiatric conditions including childhood depression, social anxiety disorder, general anxiety disorder, panic attacks, and obsessive–compulsive disorder. Because of their more recent arrival on the market compared to other drug classes, our knowledge of potential adverse drug interactions with these agents is still evolving. Like the geriatric patient population, the pediatric dental patients have their own unique physiology and anatomy compared to young adult patients that

Adverse drug interactions in dentistry.

Background

Entacapone is a potent, selective catechol-O-methyltransferase (COMT) inhibitor. Entacapone could potentiate the hemodynamic effects of exogenously administered catecholamines, which are substrates of the COMT enzyme.



Design and methods

Originally, the study was to follow a placebo-controlled, randomized crossover design. Because of two cases of ventricular arrhythmia, a decision was made to terminate the study before its completion. Six subjects went through the isoproterenol and epinephrine infusions while taking placebo and five other subjects while taking entacapone. The actual design was thus one with two parallel groups with random allocation and double-blind drug administration. The subjects were given either a single dose of 400 mg entacapone or placebo 30 minutes before the start of isoproterenol or epinephrine infusions. Four dosages of epinephrine (1.5, 3, 6, or 12 μg/min) and isoproterenol (0.5, 1, 1.5, or 2 μg/min) were infused (5 minutes for each level). Heart rate and blood pressure were measured and ECG was monitored. The concentrations of isoproterenol and epinephrine in plasma were determined by HPLC.



Results

The maximal increase in heart rate during isoproterenol infusion after entacapone administration (40 ± 11 beats/min, mean ± SD) was statistically greater (p = 0.0496) than after placebo administration (27 ± 7 beats/min). The increase in heart rate during epinephrine infusion was 25 ± 13 beats/min after entacapone administration and 14 ± 9 beats/min after placebo administration (p = 0.127). There were no statistically significant differences between entacapone and placebo in blood pressure or in plasma concentrations of isoproterenol and epinephrine.



Conclusion

We conclude that entacapone may potentiate the chronotropic and arrhythmogenic effects of exogenously administered isoproterenol and epinephrine.



Clinical Pharmacology & Therapeutics (1995) 58, 221–227; doi:

Stig Sundberg

Papers

The effect of entacapone on the disposition and hemodynamic effects of intravenous isoproterenol and epinephrine