The Pharmacology of Obesity

CH 31

LEARNING OBJECTIVES Epidemic of obesityEpidemic of obesity Why treat obesity?Why treat obesity? Pathophysiology of ObesityPathophysiology of Obesity Pharmacology of obesityPharmacology of obesity

Pharmacology of drugs currently approved for Pharmacology of drugs currently approved for treatment of obesitytreatment of obesity

Pharmacology of investigational agentsPharmacology of investigational agents Non pharmacological methodsNon pharmacological methods

Dietary and nutritional recommendationsDietary and nutritional recommendations

Physical activity and other lifestyle changesPhysical activity and other lifestyle changes

Surgical options for weight lossSurgical options for weight loss

The Epidemic of Obesity

Obesity Trends* Among U.S. AdultsObesity Trends* Among U.S. AdultsBRFSS, 1985BRFSS, 1985

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Obesity Trends* Among U.S. AdultsObesity Trends* Among U.S. AdultsBRFSS, 2001BRFSS, 2001

Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

Prevalence of ObesityPrevalence of Obesity

More than 30% of adults in More than 30% of adults in the US are overweight or the US are overweight or

obese, and this percentage obese, and this percentage is rising.is rising.

Percentage of people with BMI ≥ 30 in the US in 2005

CDC’s Behavioral Risk Factor Surveillance System.

Why Treat Obesity?

300,000 deaths a year, making it 2nd only to smoking as a cause of death

Contributes or causes to many other health problems including: Type 2 Diabetes Mellitus Coronary Artery Disease Degenerative Joint Disease Certain Types of Cancer

Pathophysiology of Obesity of Obesity

The role of peripheral hormones and other mediators in the regulation of energy balance and fat stores

. The primary level of hypothalamic control is vested in two groups of neurons, with opposing actions, in the arcuate nucleus (ARC). In one group, the peptides neuropeptide Y (NPY) and agouti-related protein (AgRP) are co-localised; the other contains the polypeptides prepro-opiomelanocortin (POMC) and cocaine- and amphetamine-related transcript (CART), which release α-melanocyte-stimulating hormone (MSH). Blood-borne hormones arising from the gastrointestinal (GI) tract or adipose tissue are sensed by receptors on vagal and other afferents and are relayed through the nucleus tractus solitarius to modify the activity of these neuronal circuits. The influence of hormones on each neuronal group is indicated. Hormones (e.g. leptin) arise from the peripheral blood and influence the ARC neurons directly or indirectly through neuronal signals; mediators (e.g. 5HT, orexin) originate within the central nervous system itself. Activation of the NPY/AgRP group by, for example, a fall in leptin or an increase in ghrelin levels results in increased food intake and decreased energy expenditure. In the POMC/CART group of neurons, increased leptin or other hormone levels triggered by overfeeding produces a predominately inhibitory effect on feeding behaviour. A number of other hormones such as cholecystokinin (CCK) and amylin also alter the properties of the ARC neurons although the mechanism is not clear. GLP-1, glucagon-like peptide-1.

Obesity

Obesity is a multifactorial disorder of energy balance, in which long-term calorie intake exceeds energy output.

It is characterized by an excessive body mass index (BMI; weight in kg divided by the square of height in m).

A subject with a BMI of 18.5-25 kg/m2 is considered as having a healthy body weight, one with a BMI of 25-30 kg/m2 as overweight, and one with a BMI > 30 kg/m2 as obese.

A BMI of 40 or above indicates that a person is morbidly obese. This can increases a person's risk of death from any cause by 50% to 150%.

Obesity is a growing problem in most rich nations; the incidence-at present approximately 30% in the USA and 15-20% in Europe-is increasing.

A BMI > 30 kg/m2 significantly increases the risk of type 2 diabetes, hypercholesterolaemia, hypertension, ischaemic heart disease, gallstones and some cancers.

BMI 25-29.9 (Grade 1, overweight) BMI 30-39.9 (Grade 2, obese) BMI > 40 (Grade 3, Morbidly obese) Increased visceral fat

Waist > 94 cm in men (waist-to-hip > 0.95)

Waist > 80 cm in women (waist-to-hip >0.8)

Pharmacology of Obesity Potential Strategies for Anti-Obesity Drug Action Indication C.I Pharmacology of Drugs Currently Approved for

Treatment of Obesity Pharmacology of investigational agents

Potential Strategies for Anti-Obesity Drug Action

Reducing food intake.Reducing food intake. Either amplify effects of signals/factors that Either amplify effects of signals/factors that inhibit food intake or block signals/factors that augment food intake inhibit food intake or block signals/factors that augment food intake

Blocking nutrient absorptionBlocking nutrient absorption (especially fat or carbohydrates) in the (especially fat or carbohydrates) in the intestine. intestine.

Increasing thermogenesis.Increasing thermogenesis. Either increase metabolism and dissipate food Either increase metabolism and dissipate food energy as heat or increase energy expenditure through the enhancement of energy as heat or increase energy expenditure through the enhancement of physical activity. physical activity.

Modulating fat metabolism/storageModulating fat metabolism/storage.. Regulate fat synthesis/breakdown by Regulate fat synthesis/breakdown by making appropriate adjustments to food intake or energy expenditure. making appropriate adjustments to food intake or energy expenditure.

Modulating the central regulation of body weight.Modulating the central regulation of body weight. Either alter the Either alter the internal set point or modulate the signals presented regarding fat stores. internal set point or modulate the signals presented regarding fat stores.

INDICATIONS FOR USE OF OBESITY DRUGS

•A combined intervention of behavior therapy, dietary changes and increased physical activity should be maintained for at least 6 months before considering pharmacotherapy.

CONTRAINDICATIONS OR CAUTIONS TO THE USE OF OBESITY DRUGS

Pregnancy or lactation Unstable cardiac disease Uncontrolled hypertension (SBP >180, DBP > 110 mmHg) Unstable severe systemic illness Unstable psychiatric disorder or history of anorexia Other drug therapy, if incompatible (eg MAO inhibitors,

migraine drugs, adrenergic agents, arrhythmic potential) Closed angle glaucoma (caution) General anesthesia

General Drug therapy

Appetite suppressants Adrenergic agents (e.g. amphetamine,

methamphetamine, phenylpropanol amine, phentermine)

Serotonergic agents (e.g. fenfluramine, dexfenfluramine, SSRIs like sertraline, fluoxetine)

Thermogenic agents ephedrine, caffeineNew ones Sibutramine ; Orlistat

Clinical uses of antiobesity drugs

The main treatment of obesity is a suitable diet and increased exercise.

Orlistat , which causes fat malabsorption, is considered for severely obese individuals, especially with additional cardiovascular risk factors (e.g. diabetes mellitus, hypertension).

Many centrally acting appetite suppressants have been withdrawn because of addiction, pulmonary hypertension or other serious adverse effects. Sibutramine is one possible adjunctive treatment of severely obese individuals.

Drugs removed from Drugs removed from marketmarket

FenfluramineDexfenfluraminePhenylpropanolamine

Pharmacology of Drugs Currently Approved for Treatment of

Obesity

Sibutramine

Non-selective inhibitor of neuronal reuptake of

serotonin and norepinephrine: appetite

suppressant

Sibutramine Blocks Neuronal Sibutramine Blocks Neuronal Monoamine (Serotonin, Norepinephrine, Monoamine (Serotonin, Norepinephrine,

Dopamine) ReuptakeDopamine) Reuptake

XXXX

= Monoamine

S

S = Sibutramine

Mechanism of ActionMechanism of Action

Sympathomimetic amine-Appetite Suppressant

-Centrally acting neurotransmitter reuptake inhibitor- serotonin, norepinephrine and dopamine

-Early satiety-Increase in energy expenditure

Sibutramine,

originally intended as an antidepressant, has shown promise in the treatment of obesity.

The drug inhibits the reuptake of serotonin and noradrenaline at the hypothalamic sites that regulate food intake.

Its main effects are to reduce food intake and cause dose-dependent weight loss

Sibutramine enhances satiety and is reported to produce a reduction in waist circumference (i.e. a reduction in visceral fat), a decrease in plasma triglycerides and very low-density lipoproteins, but an increase in high-density lipoproteins.

Causes a beneficial effects on hyperinsulinaemia a

There is some evidence that the weight loss is associated with higher energy expenditure, possibly through an increase in thermogenesis mediated by the sympathetic nervous system.

Sibutramine Indications

Among obese patients who should undergo drug therapy, sibutramine works best for those who:

Experience difficulty controlling food intake Do not feel full Think about food a lot Do not have increased cardiovascular disease risk or

multiple risk factors Are younger

Sibutramine is taken once daily with or without food.

Side Effects Sibutramine increases heart rate ,tachycardia and

blood pressure. Regular monitoring of these parameters is essential, and the drug is C.I if C.V. disease is present or if the systolic or diastolic pressure is raised by 10 mmHg or more.

dry mouth, constipation and insomnia, anxiety, headache, depression, risk of serotonin syndrome in combination with other CNS drugs.

Should take in the morning to avoid insomnia Interactions with drugs that are metabolised by

one of the P450 isoenzymes can occur.

SibutramineSibutramineAdverse EffectsAdverse Effects ContraindicationContraindication

ssIncrease BP, HRIncrease BP, HR History of CAD, CHF, History of CAD, CHF,

CVA, glaucoma CVA, glaucoma

Palpitations, prolong Palpitations, prolong QTQT

Tachyarrhythmia Tachyarrhythmia (rare)(rare)

History of arrhythmiaHistory of arrhythmia

ThrombocytopeniaThrombocytopenia Predisposition to Predisposition to bleedingbleeding

P450 metabolismP450 metabolism Severe liver or renal Severe liver or renal diseasedisease

Serotonin syndromeSerotonin syndrome MAOIs, SSRIsMAOIs, SSRIs

HA, insomnia, Sz HA, insomnia, Sz (rare)(rare)

History of seizureHistory of seizure

GI disturbanceGI disturbance

OrlistatOrlistat

Pancreatic lipase inhibitor: fat Pancreatic lipase inhibitor: fat malabsorptionmalabsorption

M.O.A Orlistat reacts with serine residues at the

active sites of gastric and pancreatic lipases, irreversibly inhibiting the enzymes and thereby preventing the breakdown of dietary fat to fatty acids and glycerols.

It therefore causes a dose-related decrease in fat absorption and a corresponding increase in faecal fat excretion that plateaus at some 30% of dietary fat.

Given with a low-calorie diet in obese individuals, it produces a modest but consistent loss of weight compared with in placebo-treated control subjects.

Orlistat Indications

Among obese patients who meet the criteria for anti-obesity drug therapy, orlistat is most likely to benefit those who: Do not feel hungry Are not preoccupied with food Eat out or order-in often Have increased cardiovascular disease risk

or multiple cardiovascular risk factors Are older Take multiple medications

Orlistat is taken 3 times daily with meals

Orlistat is also reported to be

effective in patients suffering from type 2 diabetes and other complications of obesity

to reduce leptin levels to reduce blood pressure to protect against weight loss-induced changes

in biliary secretion to delay gastric emptying and gastric secretion to improve several important metabolic

parameters and not to interfere with the release or action

of thyroid and other important hormones It does not induce changes in energy

expenditure.

Unwanted effects Abdominal cramps, flatus with discharge

and faecal incontinence can occur, as can intestinal borborygmi (rumbling) and oily spotting. Surprisingly, in view of the possibility of these antisocial effects occurring the drug is well tolerated.

Supplementary therapy with fat-soluble vitamins may be needed, and there has been a report of decreased absorption of contraceptive pills.

No significant drug interactions have been noted, except in the case of ciclosporin , where reduced absorption of the latter drug has been reported

Metformin

hepatic gluconeogenesis and glucose production; hepatic insulin sensitivity

food intake fat stores ,improves lipid profiles 25 % reduction in cumulative 3 yr incidence

of T2DM in adults; CV morbidity & mortality in adults w/ T2DM

Side effects

Transient abdominal discomfort or diarrhea

Lactic acidosis (rare) in adults with chronic cardiac, hepatic, renal or GI disease.

Urinary losses of B vitamins: use daily MVI in all metformin patients

**Approved for obesity +Type 2 **Approved for obesity +Type 2 diabetes mellitus; not yet approved diabetes mellitus; not yet approved for obesityfor obesity

New FDA approved

lorcaserin hydrochloride to treat some overweight or to treat some overweight or obese adultsobese adults

Acts by activating the serotonin 2C receptor in the Acts by activating the serotonin 2C receptor in the brain. Activation of this receptor may help a person eat brain. Activation of this receptor may help a person eat less and feel full after eating smaller amounts of food.less and feel full after eating smaller amounts of food.

The most common side effects in non-diabetic patients The most common side effects in non-diabetic patients are headache, dizziness, fatigue, nausea, dry mouth, are headache, dizziness, fatigue, nausea, dry mouth, and constipation, and in diabetic patients are low blood and constipation, and in diabetic patients are low blood sugar (hypoglycemia), headache, back pain, cough, and sugar (hypoglycemia), headache, back pain, cough, and fatigue.fatigue.

Pharmacology of investigational agents

THC

Δ9-tetrahydrocannabinol (THC) is the active principle of cannabis, and took off with the discovery of

1-specific cannabinoid receptors-termed CB receptors

2- endogenous ligands (endocannabinoids),

Cannabis Main active constituent is Δ9-tetrahydrocannabinol (THC) Actions on the central nervous system include both depressant

and psychotomimetic effects. Causes euphoria and a feeling of relaxation, with sharpened

sensory awareness. Leads to impairment of learning, memory and motor

performance, including impaired driving ability. THC also shows analgesic and antiemetic activity, as well as

causing catalepsy and hypothermia in animal tests. Peripheral actions include vasodilatation, reduction of

intraocular pressure and bronchodilatation. Cannabinoids are less liable than opiates, nicotine or alcohol to

cause dependence but may have long-term psychological effects.

The endocannabinoid system  Cannabinoid receptors (CB1, CB2) are G-protein coupled

Activation of CB1 inhibits adenylyl cyclase and calcium channels, and activates potassium channels, inhibiting synaptic transmission.

The peripheral receptor (CB2) is expressed mainly in cells of the immune system. .

Endogenous ligands for CB receptors are known as endocannabinoids. They are eicosanoid mediators

The best-established endocannabinoids are anandamide and 2-arachidonoyl glycerol (2-AG), which have many roles, including functioning as 'retrograde' mediators passing information from postsynaptic to presynaptic neurons.

The main enzyme that inactivates anandamide is fatty acid amide hydrolase (FAAH).

A putative 'endocannabinoid membrane transporter' may transport cannabinoids from postsynaptic neurons, where they are synthesised, to the synaptic cleft, where they access CB1 receptors, and into presynaptic terminals, where 2-AG is metabolised.

FAAH 'knockout' mice have an increased brain content of anandamide and an increased pain threshold; selective inhibitors of FAAH have analgesic and anxiolytic properties, implicating endocannabinoids in nociception and anxiety.

Rimonabant, an antagonist at CB1 receptors, causes sustained weight loss and may promote abstinence from tobacco.

Pharmacology of investigational agents

Rimonabant

Cannabinoid-1 receptor blocker Reduces over activation of the central & peripheral

endocannabinoid system 3045 pts with BMI>27 and HTN or dyslipidemia Most common side effect was nausea

It was licensed in Europe for treating obesity, but was withdrawn because of psychiatric problems including depression.

Potential and actual clinical uses of cannabinoid agonists and antagonists

Cannabinoid agonists and antagonists are undergoing evaluation for a wide range of possible indications, including the following. Agonists: - glaucoma (to reduce pressure in the eye) - nausea/vomiting associated with cancer chemotherapy - cancer and AIDS (to reduce weight loss) - neuropathic pain - head injury - Tourette's syndrome - Parkinson's disease (to reduce involuntary movements caused as an

adverse effect of L-dopa Antagonists:

- obesity - tobacco dependence - drug addiction - alcoholism.

Non pharmacological Non pharmacological methodsmethods

Weight Loss SurgeryWeight Loss SurgeryOption for limited number of patients Option for limited number of patients with clinically severe obesity. with clinically severe obesity.

• BMI BMI >>40 or 40 or >>35 with comorbid 35 with comorbid conditionsconditions

• Reserved for patients in whom medical Reserved for patients in whom medical therapy has failed therapy has failed

• Gastric restriction or gastric bypass Gastric restriction or gastric bypass

Integrated program must be in place Integrated program must be in place before and after surgery.before and after surgery.

Gastric BypassGastric Bypass

•Gastrojejunostomy impairs rapid gastric emptying•Create 15-30 ml gastric pouch

AdvantagesAdvantages::

Significant weight loss or lower BMI Significant weight loss or lower BMI (~33%) one year post-op; generally (~33%) one year post-op; generally sustainable (14 yearsustainable (14 year

Deterrence to carbohydrate Deterrence to carbohydrate ingestioningestion

Enhanced satietyEnhanced satiety

RisksRisks::

Perioperative death (0.5%) Perioperative death (0.5%) Other: intestinal leakage, Other: intestinal leakage,

thromboembolic disease, incisional thromboembolic disease, incisional hernia, cholelithiasis, hernia, cholelithiasis,

Micronutrient deficiencies: Fe, Ca, Micronutrient deficiencies: Fe, Ca, BB11, B, B12, 12, folatefolate

Late deaths also reported (up to 6 Late deaths also reported (up to 6 years post-op)years post-op)

Late weight regain? Late weight regain? (up to 15% of pts)(up to 15% of pts)

Laparoscopic Adjustable Gastric Laparoscopic Adjustable Gastric BandBand

Adjustable Gastric BandingAdjustable Gastric Banding

Advantages:Advantages:

Minimally invasive placement Minimally invasive placement (laparoscopic)(laparoscopic)

Less nutrient effectLess nutrient effect Adjustable (by MD – encourages)Adjustable (by MD – encourages) RemovableRemovable

DisadvantagesDisadvantages::

? Slower weight loss (max at 2-3 yr p-? Slower weight loss (max at 2-3 yr p-op)op)

Finite lifetime (needs to be replaced)Finite lifetime (needs to be replaced) Long term results are unknown (only Long term results are unknown (only

available for <10 years)available for <10 years) Not yet approved by FDA for <18 Not yet approved by FDA for <18

Comparison of ProceduresComparison of Procedures