Clinical Pharmacology and Toxicology of Sibutramine - Assignment Example

? Sibutramine (Meridia®/Reductil Sibutramine (Meridia®/Reductil Introduction Sibutramine hydrochloride monohydrate is an oral, medical agent administered for the purpose of treating obesity. The active ingredient is chemically a racemic mixture of the positive (+) and negative (-) enantiomers of cyclobutanemethanamine, 1-(4-chlorophenyl)-N, N-dimethyl-?-(2-methylpropyl)-, hydrochloride, monohydrate (1). 1. Structural formula is sibutramine Clinical Pharmacology and Toxicology of Sibutramine Mode of Action Sibutramine works by causing reuptake inhibition of dopamine, serotonin and norepinephrine. The drug and its main and pharmacologically active metabolites M1 and M2 do not act through monoamines release. Pharmacodynamics Sibutramine hydrochloride monohydrate acts as a neurotransmitter reuptake inhibitor, which decreased the reuptake of dopamine, norepinephrine and serotonin by 16%, 54% and 53% respectively. The inhibition of reuptake of these substances ensures that their levels increase within synaptic clefts and thereby increasing the levels of satiety. The serotenergic action, which results reuptake inhibition is particularly thought to influence appetite dynamics. The drug also has mechanism of action akin to tricyclic antidepressants, but it has not demonstrated antidepressant properties in animal studies already carried out. The pharmacological action of the drug is exerted via its secondary (M2) and primary (M1) amine metabolites. The parent compound is a powerful inhibitor of norepinephrine and serotonin in vivo, but not in vitro. On the other hand, the metabolites M2 and M1 cause the reuptake inhibition of serotonin and norepinephrine both in vivo and in vitro. The M1 and M2 metabolites also inhibit the reuptake of dopamine in vitro within the brain, but this happens at a lower potency than that of the inhibition on the other two neurotransmitters-norepinephrine and serotonin. The secondary and primary metabolites of sibutramine and sibutramine itself are not neurotransmitters’ releasing agents (1, 2). Chronic administration of the drug in animal models has shown no depletion of brain monoamines. Pharmacokinetics Absorption: sibutramine is absorbed through the gastrointestinal tract after one hour from oral administration. The drug undergoes first pass extensive metabolism within the liver to form di-desmethyl and mono-desmethyl metabolites (M2 and M1), which are pharmacologically active. Peak concentrations in the plasma are attained within 3 to 4 hours. Mass balance studies have shown that at least 77% of one oral dose of the drug is absorbed. Absolute bioavailability of the drug is not yet known (1, 2). Distribution: studies of radiolabeled sibutramine show extensive and rapid distribution in tissues, with the highest concentration being detected in the kidney and liver, which act as eliminating organs. In vitro M2, M1 and sibutramine are bound to human plasma proteins at rates of 94%, 94% and 97% respectively (2). Metabolism: Principal metabolism of the drug performed by cytochrome P450 (3A4) isoenzyme, which forms the desmethyl metabolites (M2 and M1). The M2 and M1 metabolites, which are active, are further converted via conjugation and hydroxylation to inactive metabolites M6 and M5. The peak radiolabeled material found in the plasma is accounted for by M6 (27%), M5 (52%), M2 (12%), M1 (6%) and unchanged sibutramine (3%). The plasma concentrations of M2 and M1 metabolites reached a state of steadiness in four days after dosing (1, 2). Excretion: an estimated 68% to 95% of the radiolabeled drug from a single dose was excreted through faeces and urine over two weeks. A majority of the excretion was through urine by approximately 77%. The main metabolites excreted through urine were M6 and M5. M2, M1 and the unchanged drug portions were not detected in urine. Hepatic metabolism is the primary excretory route for M2 and M1, whereas; M6 and M5 are excreted primarily from the kidney (2). Indications Sibutramine is indicated for weight loss and the general management of obesity and maintenance of weight loss. Sibutramine is effectively used in conjunction with exercise and a low calorie diet. The drug is recommended for obese individuals with a BMI (body mass index) of ? 30 kg/m?, or ? 27 kg/m? (3). Dosage and Administration 10 mg per day is the recommendable sibutramine dosage and this can be administered with or without food. The dosage may be titrated to a total of 15mg after four weeks if the attained weight loss is inadequate (4). A dose of 5 mg is recommended as a reserve for patients that cannot tolerate the 10mg and 15 mg dose. Contraindications Sibutramine is contraindicated for people with various conditions including: Patients taking monoamine oxidase (MAO) inhibitors Patients with a history of heart-related conditions such as tachycardia, stroke, arrhythmia, angina, transient ischemic attack, arterial occlusive disease and congestive heart failure. Patients using centrally acting obesity control drugs other than sibutramine. Patients with eating disorders such as bulimia nervosa or anorexia nervosa. Patients above 65 years of age or those below 16 years of age. Patients with hyperthyroidism Patients with closed angle glaucoma Lactating and pregnant women Patients with prostate gland enlargement and urinary retention Patients with seizure disorders. Drug Interactions Central Nervous System (CNS) Active Drugs The use of sibutramine with other central nervous system-active drugs, especially serotonergic agents has not undergone systematic evaluation. Therefore, extra caution is advised whenever there is concomitant administration of sibutramine alongside other CNS-active drugs. There have been reports of serious and at times fatal reactions among patient populations using serotonergic agents (including venlafaxine, sertraline, paroxetine, fluvoxamine or fluoxetine) in combination with monoamine oxidase inhibitors (MAOI) such as selegiline and phenalzine (6). These serious and at times fatal reactions are a result of the ‘serotonin syndrome.’ Sibutramine has an inhibitory effect on serotonin reuptake, and as such MAOI should not be administered concomitantly with the drug. As a matter of recommendation two weeks should elapse between the discontinuation of MAOI to the initiation of sibutramine treatment and vice-versa (6). Serotonin syndrome has also been observed in concomitant use of agents of migraine treatment (including dihydroergotamine and sumatriptan succinate, serotonin reuptake inhibitors and specific opioids such as tryptophan, meperidine and dextromethorphan. Serotonin syndrome also occurs when two serotonin reuptake inhibitors are used concomitantly. Due to the ability of sibutramine to inhibit serotonin reuptake, it should not be administered concomitantly with other serotonergic agents (7, 10). Serotonin syndrome requires prompt medical attention. Drugs that raise heart rate or blood pressure There has been no evaluation of the concomitant use of agents that raise blood pressure or heart rate and sibutramine. These agents may include certain allergy medications which contain pseudoephedrine and ephedrine as well as decongestants. The lack of knowledge on these concomitant indications calls for caution in administration of sibutramine to patients already using such drugs (5). Sibutramine’s Side Effects/Adverse Effects Common side effects, which characterize sibutramine use, include muscle/joint pain, flushing, headache, menstrual cramps/pain, drowsiness, dizziness, trouble sleeping, constipation, upset stomach, nausea, strange taste in the mouth, a paradoxically increased appetite and dry mouth. A high number of cardiovascular conditions have also been reported in patients using sibutramine versus a control study group by 11.4% versus 10% respectively (9). The US Food and Drug Administration noted clinical concerns that the drug increases the risk of strokes and heart attack among patients with a history of cardiovascular conditions (10, 11). Additionally, sibutramine can increase the heart rate and blood pressure significantly in patients with controlled hypertension. Therefore careful monitoring of such patients is necessary. These are the main reasons why the FDA and TGA (Therapeutic Goods Administration) had to ban the use of the drug because it posed more harm than good for patients using it. There are also infrequent side effects, which however require immediate attention. These side effects include paresthesia, mood and mental changes (suicidal ideation, depression, confusion, restlessness and excitement), cardiac arrhythmias, shortness of breath, uneven heartbeats, very stiff muscles, hallucinations, tremors, fever, dilated pupils and overactive reflexes. Reasons of Sibutramine Withdrawal by the TGA According to the Australian Adverse Reaction Bulletin, Sibutramine has been implicated in a number of adverse reactions, which have led to its withdrawal from the market. To date ADRAC has gotten 138 reports-404 adverse reactions-associated with sibutramine use (13). The commonest adverse reactions are consistent with sibutramine information and are listed in the table below. At both extremes of the spectrum psychiatric reactions have been reported, and specifically mania and depression. Sibutramine was found to be the sole suspect in 11 out of the 12 cases of depression. The use and time to onset was ranging between 1 to 13 days, and most users recovered after ending the use of sibutramine. The 12 reports included 2 of suicide attempt and 2 of suicidal ideation (13). Sibutramine was also the sole suspect in 2 out of 3 reports of mania, and both patients recovered after stopping the use of sibutramine. The other case of mania occurred in a patient that had a history of previous cases of bipolar disorder. Reported cases of cardiovascular adverse reactions include chest pain, palpitations and cardiac rhythm disorders. Sibutramine was the sole suspect in 27 of the cases. The most serious reactions caused myocardial infarction, cardiac arrest and ventricular fibrillation (13). There were also 8 reports of high blood pressure. Serotonin syndrome adverse reaction reports occurred in five cases. The time to onset after sibutramine use was 1 to 22 days. Sibutramine was the sole medication in 2 cases and was used with sertraline in 1 case and with tramadol in 2 other cases. Common side effects, which characterize sibutramine use, include muscle/joint pain, flushing, headache, menstrual cramps/pain, drowsiness, dizziness, trouble sleeping, constipation, upset stomach, nausea, strange taste in the mouth, a paradoxically increased appetite and dry mouth. A high number of cardiovascular conditions have also been reported in patients using sibutramine versus a control study group by 11.4% versus 10% respectively (9). The US Food and Drug Administration noted clinical concerns that the drug increases the risk of strokes and heart attack among patients with a history of cardiovascular conditions (10, 11). Additionally, sibutramine can increase the heart rate and blood pressure significantly in patients with controlled hypertension. Therefore careful monitoring of such patients is necessary. These are the main reasons why the FDA and TGA (Therapeutic Goods Administration) had to ban the use of the drug because it posed more harm than good for patients using it. References 1. Ryan DH, Kaiser P & Bray GA. Sibutramine: a novel new agent for obesity treatment. Obesity Research 1995; 3(Suppl.4): 553S-559S 2. Hanotin C, Thomas F. & Jones SP. Efficacy and tolerability of sibutramine in obese patients: a dose-ranging study. Int J Obesity 1998; 22:32-36 3. Stock MJ. Sibutramine: A review of the pharmacology of a novel anti-obesity agent. Int J Obesity 1997; 21 (suppl. 1):S25-S29 4. Brown TM, Skop BP & Mareth TR. Pathophysiology and management of the serotonin syndrome. Ann Pharmacotherapy 1996; 30:527-533 5. Gillman PK. Ecstasy, serotonin syndrome and the treatment of hyperpyrexia (letter). MJA 1997; 167:109-111 6. Nojimoto, D. F. Piffer, C. R. Kiguti, R.L. Lameu, C. Camargo, A.C.M. Pereira, O.C.M. et al. Multiple effects of sibutramine on ejaculation and on vas deferens and seminal vesicle contractility. Journal of Toxicology and Applied Pharmacology, 2009; 239 (3): 233–240 7. Heal DJ, Prow MR & Gosden J. A comparison of various antidepressant drugs demonstrates rapid desensitisation of a2-adrenoceptors exclusively by sibutramine hydrochloride. Psychopharmacol 1992; 107: 497-502 8. King DJ & Devaney N. Clinical pharmacology of sibutramine hydrochloride (BTS 54524), a new antidepressant, in healthy volunteers. Br J Clin Pharmacol 1988; 26:607-611. 9. Weintraub M, Rubio A. & Golik A. Sibutramine in weight control: A dose- ranging, efficacy study. Clin Pharmacol Ther 1991; 50:330-337. 10. Lean MEJ. Sibutramine--a review of clinical efficacy. Int J Obesity 1997; 21(suppl. 1):S30-S36 11. Luscombe GP, Slater NA, Lyons MB et al: Effect on radiolabelled-monoamine uptake in vitro of plasma taken from healthy volunteers administered the antidepressant sibutramine HCl. Psychopharmacology 1990; 100:345-349. 12. Sternbach H. The serotonin syndrome. Am J Psychiatr 1992; 149:1410-1411 13. Therapeutic Goods Administration (TGA). Australian Adverse Drug Reactions Bulletin, Vol.25, No 3 Read More