The bupropion .It a drug with antidepressant effect, chemically related to phenylethylamines, set of molecules with antidepressant, psychostimulant appetite depressant and of (properties venlafaxine , amphetamines , fenproporex , fenfluramine , amfepramone , etc).
Bupropion is a selective neuronal reuptake inhibitor of catecholamines ( norepinephrine and dopamine ) with minimal effect on indolamine ( serotonin ) reuptake and does not inhibit the action of any monoamine oxidase. The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown. However, it is assumed that noradrenergic and / or dopaminergic mechanisms are involved in this action.
Although the mechanism of action of the antidepressant action has not been clarified, it is suggested that it is mediated by the inhibition of the reuptake of norepinephrine and dopamine.
Bupropion is a weak inhibitor of neuronal reuptake of norepinephrine and dopamine, although inhibition of reuptake occurs at doses higher than those required for the antidepressant effects of bupropion.
Hydroxybupropion, an active metabolite of bupropion, exhibits weak norepinephrine reuptake blocking activity, but reaches concentrations high enough to produce clinically significant blocking of antidepressant effects.
Animal studies have suggested that the antidepressant activity of bupropion can be measured through noradrenergic pathways that span the locus ceruleus.
Bupropion and hydroxybupropion reduce the flash rates of noradrenergic neurons at the locus ceruleus in a dose-dependent manner: this action is similar to that of tricyclic antidepressants. this drug shows little affinity for the serotonergic transport system and does not inhibit monoamine oxidase. It has the following IUPAC Nomenclature : (RS) -3-chloro-N-tert-butyl-β-keto-amphetamineChemical structure of the drug.
C 13 H 18 ClNO
Bupropion is primarily metabolized to hydroxybupropion by the isoenzyme CYP2B6, therefore concurrent use with drugs that affect its metabolism, such as orphenadrine and cyclophosphamide, may increase its pharmacological effects. Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
- Alcohol: Concurrent use or cessation of chronic use of alcohol during therapy can lower the threshold for seizures and increase the risk of their production; Patients should be advised to minimize alcohol consumption or avoid its use altogether.
- Tricyclic antidepressants or clozapine , or fluoxetine , or haloperidol , or lithium , or loxapine , or maprotiline , or molindone , or phenothiazines , or thioxanthenes , or trazodone : Concurrent use of these medications with bupropion may lower the threshold for seizures and increase the risk of major motor attacks; in addition, changes in the treatment regimen, such as abrupt discontinuation of a benzodiazepine, can precipitate an attack.
- Liver enzyme inducers: Concurrent use with bupropion may increase its metabolism. A study in patients receiving chronic carbamazepine therapy showed a significant decrease in peak plasma bupropion and AUC concentration and an increase in peak hydroxybupropion concentration and AUC. A study in cigarette smokers showed no effect of smoking on the pharmacokinetics of bupropion.
- Liver enzyme inhibitors: This medication can inhibit liver microsomal enzymes by decreasing metabolism and increasing serum concentrations of bupropion, increasing the risk of seizures.
A study in patients who received valproic acid chronically showed no change in bupropion concentrations but increased peak hydroxybupropion concentration and AUC.
- Nicotine : Although the transdermal nicotine system can be used concurrently with bupropion in the treatment of nicotine dependence, this combination may be associated with hypertension; blood pressure should be monitored in patients receiving this combination.
- Rinotavir : Although there is no experience with this combination, rinotavir has a high affinity for various isoenzymes of cytochrome P450 and may increase plasma concentrations of bupropion and thus increase the risk of seizures.
- Levodopa : Concurrent use with bupropion may result in a higher incidence of adverse effects; small initial doses of bupropion and small gradual increases are recommended during concurrent therapy.
- Monoamine oxidase (MAO) inhibitors including procarbazine , selegiline, and furazolidone : Concurrent use of bupropion with these medications may increase the risk of acute bupropion toxicity and is contraindicated; a medication-free interval of at least 2 weeks must elapse between discontinuation of the MAO inhibitor and initiation of bupropion therapy.
- Absorption: Following oral administration of 150 mg (prolonged-release tablet) to healthy volunteers, peak plasma concentrations (Cmax) of 100 nanograms / ml were observed at 2.5 to 3 hours.
The total drug exposure (AUC) and Cmax values for hydroxybupropion are approximately 3 and 14 times higher, respectively, than the Cmax and AUC values for bupropion.
The Cmax of threohydrobupropion is comparable to the Cmax of bupropion, while the AUC of threohydrobuporpion is approximately 5 times greater than that of bupropion.
Peak plasma levels of hydroxybupropion and treohydrobupropion are reached approximately 6 hours after administration of a single dose of bupropion. Steady state of bupropion and its metabolites is reached in 5-8 days. The absolute bioavailability is unknown; although at least 87% of the dose is absorbed.
Oral absorption is not significantly affected when taken from food.
- Distribution: It is widely distributed, with an apparent volume of distribution of 2000 l. Bupropion, hydroxybupropion, and treohydrobupropion are moderately bound to plasma proteins (84%, 77%, and 42%, respectively). Bupropion and its active metabolites are excreted in human milk.
In animal studies, bupropion and its active metabolites have been shown to cross the blood-brain barrier and the placenta .
- Metabolism: It is extensively metabolized in the liver , with the formation of three pharmacologically active metabolites in plasma: hydroxybupropion and the aminoalcoholic isomers treohydrobupropion and erythrobupropion. These may be of clinical importance, since their plasma concentrations are as high or higher than those of bupropion. Active metabolites are metabolized to inactive metabolites (some of which have not been fully characterized but may include conjugates) and excreted in urine.
In vitro studies indicate that bupropion is metabolized to its main active metabolite, bupropion, primarily by CYP (cytochrome P450) 2B6 and, to a lesser extent, by CYP1A2, 2A6, 2C9, 3A4, and 2E1. In contrast, the formation of threohydrobupropion involves a carbonyl reduction process, in which the isoenzymes of cytochrome P450 are not involved. Bupropion and hydroxybupropion are inhibitors of the isoenzyme CYP2D6. After oral administration of a single 150 mg dose, there was no difference in Cmax, half-life, time taken to reach maximum concentration (Tmax), AUC, or clearance of bupropion or its major metabolites between smokers and non-smokers. .
Bupropion has been shown to induce its own metabolism in animals, after subchronic administration. In humans, there is no evidence of enzyme induction in patients receiving recommended doses of amphebutamone hydrochloride for 10 to 45 days.
- Elimination: 87% and 10% of the radioactive dose was recovered in urine and faeces, respectively. The fraction of the dose that was excreted unchanged was only 0.5%. Less than 10% of this dose was collected in the urine as inactive metabolites.
The mean apparent clearance is approximately 200 l / h and the elimination half-life of bupropion is approximately 20 hours. The elimination half-life of hydroxybupropion is approximately 20 hours. The elimination half-lives of treobupropion and erythrohydrobupropion are longer (37 and 33 hours, respectively).
- Tobacco dependence: together with motivational support, it is indicated to help quit smoking in patients with nicotine dependence.
Bupropion is contraindicated in patients with conditions that present seizures. It is also contraindicated in patients diagnosed with bulimia or anorexia nervosa because of the high incidence of seizures noted in these patients when treated with bupropion.
Concurrent use of bupropion and an MAOI is contraindicated. At least 14 days should be allowed to elapse between the discontinuation of an MAOI and the initiation of treatment with bupropion. This medicine is contraindicated in patients with hypersensitivity to any of its active ingredients.
- Allergic reactions: Anaphylactoid reactions characterized by symptoms such as pruritus , urticaria , angioedema and dyspnea requiring medical treatment have been reported in a percentage of about 1-3% in clinical trials. In addition, spontaneous reports have been rarely presented in after-sales studies of erythema multiforme , Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion.
- Insomnia: Depressive patients treated with bupropion have developed insomnia. In dose-dependent smoking cessation trials, 29% of patients treated with bupropion 150 mg / day and 35% of patients treated with bupropion 300 mg / day experienced insomnia compared to 21% of patients treated with placebo. They were forced to discontinue treatment in 0.6% of the bupropion-treated patients and in none of the placebo-treated patients.
Insomnia can be minimized by avoiding taking the dose at bedtime and, if necessary, reducing the dose.
- Psychosis , confusion, and other neuropsychiatric phenomena: In clinical trials with bupropion in non-depressed smokers, the incidence of neuropsychiatric side effects was generally comparable to placebo. Depressive patients treated with bupropion in depression trials demonstrated a variety of neuropsychiatric signs and symptoms including delirium, hallucinations, psychosis, concentration disorder, paranoia, and confusion. In some cases, these symptoms decreased with dose reduction and / or discontinuation of treatment.
- Activation of psychosis and / or mania: Antidepressants can precipitate manic episodes in patients with bipolar disorders during the depressive phase of their illness and can activate latent psychosis in other susceptible individuals. There were no reports of activation of psychosis or mania in bupropion clinical trials conducted in non-depressed smokers.
- Use in patients with systemic disease: There is no clinical experience establishing the safety of bupropion in patients with a recent history of myocardial infarction or unstable heart disease. Consequently, if it is used in these groups, care should be taken with its administration. Orthostatic hypotension with third-degree block is possible .
- CNS tumor, or head trauma, or spontaneous seizures: History of increased risk of major motor attacks.
- Drug abuse: Patients with a history of amphetamine or stimulant abuse may be attracted to bupropion due to its mild amphetamine-like activity, especially at higher doses; however the risk of attacks has prevented a more adequate test.
Since bupropion hydrochloride and its metabolites are almost completely excreted by the kidneys and the metabolites are likely to undergo conjunctions in the liver prior to urinary excretion, treatment of patients with renal or hepatic dysfunction should be started with reduced doses as the bupropion and its metabolites can accumulate in such patients to a greater degree than usual. The patient must be carefully monitored to evaluate possible toxic effects of elevated tissue and blood levels of the drug and its metabolites.
- Dry mouth, gastrointestinal disturbances including nausea and vomiting, abdominal pain, constipation.
- Insomnia, tremor, impaired concentration, headache , dizziness, depression, agitation, anxiety. –
- Rash, itching , sweating.
- Hypersensitivity reactions such as hives.
- Alterations in the sense of taste.
- Chest pain , asthenia .
- Tachycardia , increased blood pressure (sometimes severe), flushing.
- Vasodilation , postural hypotension , syncope .
- Anorexia .
- Tinnitus , vision disturbance.
- More serious hypersensitivity reactions including angioedema , dyspnea / bronchospasm, and anaphylactic shock. Arthralgia , myalgia and fever have also been reported along with “rash” and other symptoms suggestive of delayed hypersensitivity. These symptoms can resemble serum sickness. Erythema multiforme and Stevens Johnson syndrome have also been reported .
- Seizures: The incidence of seizures is approximately 0.1% (1 / 1,000). The most common type of seizure is generalized tonic-clonic seizures, a type of seizure that can lead in some cases to post-seizure confusion or memory impairment.
- Keep this medicine in its container, tightly closed and out of the reach of children.
- Store it at room temperature and away from excessive heat and humidity (not in the bathroom).
- Throw away any medicine that is out of date or no longer used.