Pharmacotherapy of Obesity (eBook)

Contents 6
List of contributors 7
Preface 8
Why drugs? 10
Introduction 10
Historical context 11
Why use a drug? 12
Risk/benefit ratio 13
Weight change effects on energy balance 14
Energy expenditure changes 14
Ingestive behavior 15
What kind of a drug are we looking for? 15
Are there new potential drugs being developed? 16
The herd versus the individual 16
Should the search for new drugs be encouraged? 16
References 17
Some historical aspects of drug treatment for obesity 20
Introduction 20
Thyroid extract 20
Dinitrophenol 22
Amphetamine 22
Norepinephrine reuptake inhibitors 24
Serotonergic agents 25
Fenfluramine/phentermine 25
Summary 27
References 27
Regulation of energy balance – towards rational drug design in obesity 29
CNS regulation of energy balance and metabolism 29
Neuroanatomy of energy homeostasis 29
Hypothalamic pathways and neurotransmitters 31
How does the hypothalamus sense energy requirements? 41
Concluding remarks 46
References 46
Intestinal lipase inhibitors 55
Introduction 55
Pharmacology 55
Toxicology 56
Clinical pharmacology 57
Pharmacokinetics 57
Drug interactions 58
Therapeutic use 58
Efficacy – obesity clinical trials 58
Efficacy in obesity with co-morbidity 60
Use in children and adolescents 61
Adverse reactions 63
Cetilistat 63
References 64
Sibutramine 66
Introduction 66
Pharmacology 66
Clinical pharmacology 67
Adverse effects 67
Clinical efficacy 69
Therapeutic use 69
Efficacy in clinical trials 70
Efficacy in obesity and co-morbidity 71
Sibutramine in children and adolescents 72
Long-term outcomes of weight loss with sibutramine: The SCOUT study 73
References 73
The endocannabinoid system as a target for obesity treatment 76
Introduction 76
The endocannabinoid system 77
Rimonabant – a CB1 receptor antagonist 78
Clinical trials in obesity 79
Adverse effects of rimonabant 83
Long-term outcome studies 85
References 87
Using the body’s natural signals – gut hormones 88
Introduction 88
General principles 88
Central circuits of appetite control 90
Gut hormones that signal satiety 90
Gut hormones that signal hunger 100
Co-administration and combination therapy 100
Conclusions 101
References 101
Influencing energy expenditure and substrate utilisation 107
Introduction 107
Rationale for thermogenic drugs 107
Biochemistry and endocrinology of thermogenesis 109
Hormone mimetics 111
Intracellular targets for thermogenic drugs 113
Inhibition of lipid synthesis 115
Hypothalamic energy metabolism 117
Conclusion 118
References 118
Index 122
The MDT-Series Milestones in Drug Therapy 126
Forthcoming titles 126
Published volumes 126

The endocannabinoid system as a target for obesity treatment (p. 69-70)

Muhammad Khan and John P.H. Wilding

Diabetes and Endocrinology Clinical Research Group, University Hospital Aintree, Clinical Sciences Centre, 3rd Floor, Lower Lane, Liverpool L9 7AL, UK

Introduction

During the past 30 years the prevalence of obesity has risen substantially in most developed countries. Across the world obesity is becoming one of the most preventable and modifiable metabolic disorders. There is evidence linking obesity to an increased risk of more than 30 medical conditions, raising an appropriate concern that this alarming trend will have major health consequences [1]. Serious conditions such as increased risk of type 2 diabetes mellitus (DM), coronary heart disease, hypertension, obstructive sleep apnoea and cancer, higher overall mortality rate and decreased lifespan have been associated with obesity [2, 3]. Morbid obesity can cause a decrease in life expectancy among young adults by as much as 5–20 years [4]. In addition to being a chief health concern, obesity is also becoming a major economic problem with significant consequences for health services worldwide. During the last 20 years beneficial trends have been evident in many cardiovascular disease risk factors including smoking, relative saturated fat intakes and cholesterol levels. Unfortunately, the parallel increase in adverse factors such as increased energy density of foods and reduced exercise, resulting in obesity, has counterbalanced or may have overwhelmed these benefits causing a growing prevalence of obesity-associated cardiometabolic disease [5].

The awareness of the health consequences of overweight and obesity, the benefits of modest weight loss and the frequent failure of lifestyle interventions for both weight loss and weight loss maintenance has led to the search for effective anti-obesity treatment. Evidence suggests that most obese individuals have an inappropriate control of their food intake rather than a metabolic defect in energy expenditure. This concept has turned attention toward drugs which reduce appetite or enhance satiety and so decrease energy intake as compared to thermoregulatory agents which increase energy expenditure.

The endocannabinoid system

Since the discovery of the first cannabinoid receptor together with its endogenous ligand in the early 1990s, the molecular basis for this novel neuromodulatory system has become better understood. The endocannabinoid system is now known to comprise a range of molecules, synthesised on demand from arachidonic acid precursors that regulate synaptic neurotransmission, together with their associated receptors [6]. This system acts as a neuromodulatory system affecting many physiological functions, not only in the central nervous system (CNS), but also in endocrine, reproductive, gastrointestinal, cardiovascular and immune systems. There are now known to be two types of endocannabinoid receptors, known as CB1 and CB2. Their natural ligands were identified as anandamide, monoacyl glycerol, 2-arachidonylglycerol and other fatty acid ethanolamides. The two most extensively studied endocannabinoids are anandamide and 2-arachidonylglycerol, both are synthesised from arachidonic acid and are lipid in nature. Interestingly, endocannabinoids are produced post-synaptically but act on pre-synaptic release of neurotransmitters, mainly causing inhibition of their release [6].