Anti-Obesity Drugs

ANTI-OBESITY DRUGS


ANTI-OBESITY DRUGS

Basics of Obesity:

  • Definition: Obesity is a complex metabolic disorder due to abnormality between energy intake & energy expenditure.
  • Associated with insulin resistance, dyslipidemia & cardiovascular disease.

Control center:

  • Arcuate nucleus in mediobasal hypothalamus – Main integrating center for feeding & regulation of body weight.

Substances stimulating food intake & influencing obesity:

  • Orexin & Ghrelin
  • Neuropeptide Y (NP-Y)
  • Agouti-related peptide (AgRP)
  • Melanocyte-stimulating hormone (MSH)
  • CART (cocaine and amphetamine-related transcript)
  • 5-HT2C (serotonin receptors)
  • Insulin
  • Leptin
  • Endocannabinoids

THERAPIES FOR OBESITY MANAGEMENT:

  • Basis: Mainly targets the above-discussed substances or mechanisms.

I) DIET:

  • Four recommended diet types for weight loss.
    • Atkins – Very low carbohydrate
    • Traditional – Lifestyle, exercise, attitudes, relationships, nutrition [LEARN]
    • Ornish – Very high carbohydrate
    • Zone – Low carbohydrates.

II) PHARMACOLOGICAL THERAPIES:

  • Criteria for Anti-obesity drug therapy initiation:
    • BMI > 30 kg/m2 or BMI > 27 with obesity-related risk-factors.

DRUGS INVOLVED:

1. Drugs targeting 5-HT2 receptor:

  • 5-HT2 activation causes weight loss.
  • MOA: 
    • Increases serotonin level (reuptake inhibitors).
  • Drugs: 
    • Lorcaserin 
    • Selective 5HT2c agonist decreases appetite.
  • Adverse effect
    • Headache (Most common).
    • Increased valvular heart disease & psychiatric effects.

2. Gastrointestinal lipases inhibitors:  

  • Orlistat
  • MOA: 
    • Gastrointestinal lipases necessary for fat absorption from diet.
    • inhibiting lipases, decreases upto 30% fat absorption –> weight loss.
  • Adverse effects: 
    • Loose stools, increased defecation & oily discharge.
  • Management: 
    • Simultaneous natural fiber use. 

3. Appetite suppressant:

  • Sibutramine
  • MOA – 
    • Blocks pre-synaptic uptake of both nor-epinephrine & serotonin –-> Potentiation of anorexic effects of both these neurotransmitters in CNS.
  • Side effects – 
    • Mild BP elevation, headache, insomnia, dry mouth & constipation.

4. Cannabinoid receptor antagonist:

  • Rimonabant – 
    • Acts on Cannabinoid (CB1) receptor → Increased serotonin & dopamine levels.
  • MOA – 
    • Blocks orexigenic action of ghrelin → Causes appetite reduction.
    • Also causes lipolysis & increases BMR.
  • Adverse effects –
    • Decrease BP
    • Nausea
    • Vomiting
    • Depression (leading to suicidal tendencies)
    • Anxiety.

5. Combination drugs:

  • Phentermine + Topiramate.
  • Side effects – 
    • (Common) Mood changes, fatigue, insomnia & tachycardia.
    • Teratogenic & contra-indicated in pregnancy.

6. Newer drugs:

  • Naltrexone + bupropion:
    • Recently approved for chronic weight management.
  • Adverse effects –
    • Potentially cause suicidal thoughts.
    • Neuropsychiatric reactions.
    • Tolerance development to anorexic effect, on long duration.

7. Newer targets:

  • NPY & AgRP antagonists – 
    • Neuropeptide Y (NP-Y) & Agouti-related peptide (AgRP) antagonists.
  • MSH & CART agonists – 
    • Melanocyte stimulating hormone (MSH) & CART (cocaine and amphetamine related transcript) agonists.

SHORT FLOWCHART ON PHYSIOLOGICAL & PHARMACOLOGICAL FOOD INTAKE REGULATION

III) SURGICAL APPROACH:

  • Bariatric surgery:
  • Indication: 
    • BMI > 40kg/m2 or BMI > 35 with obesity related co-morbidities.

IV) OBSOLETE THERAPIES:

  • Amphetamines, fenfluramine & dexfenfluramine – Used previously for obesity treatment.
  • Fenfluramine & dexfenfluramine – Banned due to cardiotoxicity risk.

Exam Important

ANTI-OBESITY DRUGS

  • Arcuate nucleus in mediobasal hypothalamus is the main integrating center for feeding & regulation of body weight.
  • 5-HT2 activation causes weight loss.
  • Drugs targeting 5-HT2 receptor includes mainly Lorcaserin, which is a selective 5HT2c agonist which decreases appetite.
  • Orlistat is used as an anti-obesity drug, which mainly acts by inhibiting gastrointestinal lipases.
  • Sibutramine is an appetite suppressant, acts by blocking pre-synaptic uptake of both nor-epinephrine & serotonin.
  • Rimonabant is used as an anti-obesity drug, which mainly acts by antagonizing cannabinoid (CB1receptor.
  • Rimonabant mainly blocks orexigenic action of ghrelin, increases serotonin & dopamine levels, ultimately resulting in appetite reduction.
  • Rimonabant is an anti-obesity drug, which decreases BP.
  • Combination of Phentermine + Topiramate is used for anti-obesity regime.
  • Phentermine + Topiramate are teratogenic & contraindicated in pregnancy.
  • Naltrexone + bupropion combination is recently approved for chronic weight management.
  • Recently anti-obesity regime involves Neuropeptide Y (NP-Y) & Agouti-related peptide (AgRP) antagonists, and Melanocyte-stimulating hormone (MSH) & CART (cocaine and amphetamine-related transcript) agonists.
  • Fenfluramine & dexfenfluramine were used as an anti-obesity drug but, banned due to cardiotoxicity risk.

 

Don’t Forget to Solve all the previous Year Question asked on ANTI-OBESITY DRUGS

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