The Pharmacology of Obesity

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The Pharmacology of Obesity

• Dr. hanin osama

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Definition of Obesity

• BMI 25-29.9 (Grade 1, overweight)
• BMI 30-39.9 (Grade 2, obese)
• BMI gt 40 (Grade 3, Morbidly obese)
• Increased visceral fat
• Waist gt 94 cm in men (waist-to-hip gt 0.95)
• Waist gt 80 cm in women (waist-to-hip gt0.8)

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Why Treat Obesity?

• Contributes to approximately 300,000 deaths a
  year, making it 2nd only to smoking as a cause of
  death
• Contributes or causes to many other diseases
  including
• Type 2 Diabetes Mellitus
• Coronary Artery Disease
• Degenerative Joint Disease
• Certain Types of Cancer
• Nonalcoholic Steatohepatitis

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Indications for Drug Therapy in Obesity

• A combined intervention of behavior therapy,
  dietary changes and increased physical activity
  should be maintained for at least 6 months before
  considering pharmacotherapy.
• Failure of diet and exercise alone
• BMI of 30 kg/m² or more or a BMI of 27 kg/m² or
  more with comorbid condition
• Understand that drug therapy is adjunctive to
  lifestyle intervention
• Have realistic expectations about weight loss
  goals and outcomes
• Demonstrate readiness for change
• Are unable to lose/maintain weight with lifestyle
  change alone
• Comply with medication use
• Have no medical or psychiatric contraindications

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Potential Strategies for Anti-Obesity Drug Action

• Reducing food intake.
• Blocking nutrient absorption
• Increasing thermogenesis.
• Modulating fat metabolism/storage.
• Modulating the central regulation of body
  weight.

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ADDITIONAL CONSIDERATIONS WHEN USING ANTI-OBESITY
DRUGS

• Weight loss drugs should never be used without
  continued concomitant lifestyle modifications
  and as part of a comprehensive weight loss
  program.
• Continual assessment of drug therapy for efficacy
  and safety is necessary.
• If the drug is efficacious in helping the patient
  to lose and/or maintain weight loss and there are
  no serious adverse effects, it can be continued.
• If not, it should be discontinued.

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1. Sibutramine

• Mechanism of action
• Was developed originally as antidepressant
• Inhibit reuptake of serotonin and norepinephrine
  at nerve terminals increasing their concentration
  at postsynaptic receptors in the brain that
  affect food intake
• It is also thought to stimulate energy
  expenditure

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• Pharmacokinetics
• Rapidly absorbed from the GI
• Extensively metabolized by CYP 3A4 to active
  metabolites
• With dietary advise this drug is expected to
  cause loss 5-7 of the body weight but this tend
  to be regained after the drug is stopped

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• Indications and precautions
• Patients with BMI of 27 who have CVS disease or
  BMI gt30 with or without CVS disease
• It should be discontinued
• if weight loss at 3monts of starting the drug is
  lt5 of the initial weight
• the patient regained 3kg after previous weight
  loss
• Should not be given more than one year
• Sibutramine is taken once daily with or without
  food.

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• Contraindications and D/I
• sibutramine should not be used by patients who
  have
• uncontrolled hypertension
• coronary heart disease
• congestive heart failure
• Arrhythmias
• stroke
• severe renal or liver dysfunction
• obesity from endocrine disease
• Major eating or psychiatric disorder
• Should not be given with TCA because of CNS
  toxicity

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• Side Effects
• dry mouth, constipation, headache, insomnia,
  increased blood pressure, tachycardia, sweating,
  altered taste.
• Should monitor all patients twice weekly in the
  first 3 months for hypertension
• Should take in the morning to avoid insomnia

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2. Orlistat (Xenical)

• Mechanism of action
• Pancreatic lipase inhibitor that blocks the
  absorption of up to one third of ingested fat.
  (normally 5 of fat is not absorbed)
• Weight loss is due to calories loss but drug
  related adverse effects also contribute by
  diminishing the food intake
• Patients who adhere to a low calorie diet and
  take orlistat lost an average of 9-10kg after one
  year (compared to 6kg on placebo)

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• Orlistat is taken 3 times daily with meals, if
  the meal is missed or contain no fat the dose of
  orlistat should be omitted
• Treatment should be proceed beyond 3 month only
  if lost gt5 of the initial body weight and beyond
  6 month if lost gt10 should not normally exceed
  one year and never 2 years
• Indications
• Aged 18-75
• Who have lost 2.5kgbody weight by dieting and
  increasing physical activity in the previous
  month
• Patients with BMI of 27 who have CVS disease or
  BMI gt30 with or without CVS disease

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• Side effects
• Because it blocks intestinal absorption of fat it
  can result in diarrhea and steatorrhea (liquid
  oily stools), urgency, abdominal pain. This is
  minimized by maintaining a strict low fat diet
  (lt30 of diet)
• Mal-absorption of fat soluble vitamins
• C/I
• Chronic intestinal malabsorption
• Cholestasis

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Investigational Agents for Treatment of Obesity
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1. Topiramate

• Topiramate is antiepileptic drug approved by the
  FDA as an antiseizure medication.
• When reports surfaced that patients enrolled in
  initial trials of the drug and also in clinical
  practice were experiencing unexpected weight
  loss, the effects of the drug on weight began to
  be studied.
• Mechanism for weight loss is still poorly
  understood

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2. Leptin

• Naturally occurring hormone that plays a role in
  satiety and weight maintenance.
• Produced in adipocytes
• Its role in weight regulation is related to its
  effects on the hypothalamus, where it leads to
• satiety
• decreased food intake
• increased energy expenditure in the periphery
• Weight loss was relatively modest.

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Other drugs withdrawn from the market

• Phentermine, fenfluramnie dexfenfluramine
• Were formerly prescribed appetite suppressants
• Stimulate NE release
• They cause cardiac valve disease and pulmonary
  hypertension