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The Pharmacology of
Obesity
CH 31
LEARNING OBJECTIVES
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Epidemic of obesity
Why treat obesity?
Pathophysiology of Obesity
Pharmacology of obesity
 Pharmacology of drugs currently approved for
treatment of obesity
 Pharmacology of investigational agents
Non pharmacological methods
Dietary and nutritional recommendations
Physical activity and other lifestyle changes
Surgical options for weight loss
The Epidemic of Obesity
Obesity Trends* Among U.S. Adults
BRFSS, 1985
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16,
2001;286:10.
Obesity Trends* Among U.S. Adults
BRFSS, 2001
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16,
2001;286:10.
Prevalence of Obesity
More than 30% of adults in the US are
overweight or obese, and this
percentage is rising.
Percentage of people with BMI ≥ 30 in the US in 2005
CDC’s Behavioral Risk Factor Surveillance System.
Why Treat Obesity?
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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:
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Type 2 Diabetes Mellitus
Coronary Artery Disease
Degenerative Joint Disease
Certain Types of Cancer
Pathophysiology of Obesity
The role of peripheral hormones and other mediators in the regulation
of energy balance and fat stores
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. 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 αmelanocyte-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
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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 1520% 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.
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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)
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Pharmacology of Obesity
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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
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Reducing food intake. Either amplify effects of signals/factors that inhibit
food intake or block signals/factors that augment food intake
Blocking nutrient absorption (especially fat or carbohydrates) in the
intestine.
Increasing thermogenesis. Either increase metabolism and dissipate food
energy as heat or increase energy expenditure through the enhancement of
physical activity.
Modulating fat metabolism/storage. Regulate fat synthesis/breakdown by
making appropriate adjustments to food intake or energy expenditure.
Modulating the central regulation of body weight. Either alter the
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
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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
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Adrenergic agents (e.g. amphetamine,
methamphetamine, phenylpropanol amine,
phentermine)
Serotonergic agents (e.g. fenfluramine,
dexfenfluramine, SSRIs like sertraline, fluoxetine)
Thermogenic agents
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ephedrine, caffeine
New ones
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Sibutramine ; Orlistat
Clinical uses of antiobesity drugs
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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.
Snow, V. et. al. Ann Intern Med 2005;142:525 -531
Drugs removed from market
 Fenfluramine
 Dexfenfluramine
 Phenylpropanolamine
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 Monoamine (Serotonin,
Norepinephrine, Dopamine) Reuptake
X
S
= Monoamine
S = Sibutramine
Mechanism of Action
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Sympathomimetic amine-Appetite Suppressant
-Centrally acting neurotransmitter reuptake
inhibitor- serotonin, norepinephrine and
dopamine
-Early satiety
-Increase in energy expenditure
Sibutramine,
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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
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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:
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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
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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.
Sibutramine
Adverse Effects
Contraindications
Increase BP, HR
History of CAD, CHF,
CVA, glaucoma
History of arrhythmia
Palpitations, prolong QT
Tachyarrhythmia (rare)
Thrombocytopenia
Predisposition to bleeding
P450 metabolism
Severe liver or renal disease
Serotonin syndrome
MAOIs, SSRIs
HA, insomnia, Sz (rare)
History of seizure
GI disturbance
Orlistat
Pancreatic lipase inhibitor: fat
malabsorption
M.O.A
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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
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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
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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
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 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 diabetes
mellitus; not yet approved for obesity
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New FDA approved
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lorcaserin hydrochloride to treat some overweight
or obese adults
Acts by activating the serotonin 2C receptor in the
brain. Activation of this receptor may help a person
eat less and feel full after eating smaller amounts of
food.
The most common side effects in non-diabetic
patients are headache, dizziness, fatigue, nausea, dry
mouth, and constipation, and in diabetic patients are
low blood sugar (hypoglycemia), headache, back
pain, cough, and fatigue.
Pharmacology of
investigational agents
THC
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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
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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.
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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
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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
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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
methods
Weight Loss Surgery
Option for limited number of patients with
clinically severe obesity.
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BMI >40 or >35 with comorbid conditions
Reserved for patients in whom medical therapy
has failed
Gastric restriction or gastric bypass
Integrated program must be in place before and
after surgery.
Gastric Bypass
•Gastrojeju
nostomy
impairs
rapid
gastric
emptying
•Create 1530 ml
gastric
pouch
Advantages:
 Significant
weight loss or lower BMI (~33%)
one year post-op; generally sustainable (14 year
 Deterrence to carbohydrate ingestion
 Enhanced satiety
Risks:
 Perioperative
death (0.5%)
 Other: intestinal leakage, thromboembolic
disease, incisional hernia, cholelithiasis,
 Micronutrient deficiencies: Fe, Ca, B1, B12, folate
 Late deaths also reported (up to 6 years post-op)
 Late weight regain? (up to 15% of pts)
Laparoscopic Adjustable Gastric Band
Adjustable Gastric Banding
Advantages:
 Minimally
invasive placement (laparoscopic)
 Less nutrient effect
 Adjustable (by MD – encourages)
 Removable
Disadvantages:
?
Slower weight loss (max at 2-3 yr p-op)
 Finite lifetime (needs to be replaced)
 Long term results are unknown (only available for
<10 years)
 Not yet approved by FDA for <18
Comparison of Procedures