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Wednesday, August 20, 2025

Anorexiants


Introduction

Anorexiants are drugs that suppress appetite, reduce food intake, or alter satiety signaling, leading to weight loss. They are primarily prescribed as part of a comprehensive weight management program that includes dietary modification, exercise, and behavioral therapy.

Obesity is a major global health problem, strongly linked to diabetes mellitus type 2, cardiovascular disease, dyslipidemia, non-alcoholic fatty liver disease, sleep apnea, and certain cancers. In patients with BMI ≥30 kg/m², or BMI ≥27 kg/m² with comorbidities, pharmacological intervention may be appropriate if lifestyle modification alone fails.

Anorexiants belong to diverse pharmacological classes, with mechanisms ranging from central nervous system (CNS) stimulation to neurotransmitter modulation and gut–brain axis signaling.

Mechanism of Action

Anorexiants act through several pathways that regulate appetite and satiety:

  1. Sympathomimetic agents (stimulant-like):

    • Increase norepinephrine and dopamine release in hypothalamus.

    • Suppress appetite by stimulating satiety centers.

    • Examples: Phentermine, Diethylpropion, Benzphetamine, Phendimetrazine.

  2. Serotonin pathway modulators:

    • Enhance serotonin signaling in hypothalamic feeding centers, promoting satiety.

    • Example: Lorcaserin (withdrawn in 2020 due to cancer risk).

  3. Combination therapy:

    • Phentermine + Topiramate (Qsymia®): combines appetite suppression and enhanced satiety.

    • Bupropion + Naltrexone (Contrave®): targets reward and craving pathways.

  4. GLP-1 receptor agonists (anti-obesity but not classic anorexiants):

    • Mimic incretin hormone GLP-1, delaying gastric emptying and enhancing satiety.

    • Examples: Liraglutide (Saxenda®), Semaglutide (Wegovy®).

    • Though technically “anti-diabetic/anti-obesity agents,” they have strong anorexiant effects and are often included in discussions of modern anorexiants.

Major Anorexiant Drugs and Doses

1. Phentermine

  • Class: Sympathomimetic amine (similar to amphetamine).

  • Indication: Short-term management of obesity (up to 12 weeks).

  • Dose:

    • 15–37.5 mg orally once daily (before breakfast or 1–2 hours after).

  • Adverse effects: Insomnia, tachycardia, elevated BP, anxiety, dry mouth, constipation.

  • Contraindications: Cardiovascular disease, uncontrolled hypertension, hyperthyroidism, history of drug abuse, pregnancy.

2. Diethylpropion

  • Class: Sympathomimetic amine.

  • Indication: Short-term obesity management.

  • Dose:

    • Immediate release: 25 mg three times daily before meals.

    • Extended release: 75 mg once daily mid-morning.

  • Adverse effects: Nervousness, insomnia, hypertension, palpitations.

  • Contraindications: Pulmonary hypertension, severe atherosclerosis, glaucoma, hyperthyroidism.

3. Benzphetamine

  • Class: Sympathomimetic amine.

  • Indication: Short-term obesity management.

  • Dose: 25–50 mg orally once or twice daily (max 150 mg/day).

  • Adverse effects: Restlessness, increased blood pressure, arrhythmias.

  • Contraindications: Coronary artery disease, uncontrolled hypertension, history of drug abuse.

4. Phendimetrazine

  • Class: Sympathomimetic amine (prodrug, converted to phenmetrazine).

  • Indication: Short-term obesity management.

  • Dose:

    • Immediate release: 35 mg orally 2–3 times daily, 1 hour before meals.

    • Extended release: 105 mg once daily in the morning.

  • Adverse effects: Irritability, insomnia, tachycardia, risk of dependence.

5. Phentermine + Topiramate (Qsymia®)

  • Class: Combination anorexiant (sympathomimetic + antiepileptic).

  • Indication: Chronic weight management.

  • Dose:

    • Start with 3.75 mg/23 mg once daily for 14 days, then increase to 7.5 mg/46 mg once daily.

    • Maximum dose: 15 mg/92 mg daily.

  • Adverse effects: Paresthesia, dizziness, insomnia, dry mouth, constipation, cognitive impairment, teratogenic risk (cleft lip/palate).

  • Contraindications: Pregnancy, glaucoma, hyperthyroidism, recent MAOI use.

6. Bupropion + Naltrexone (Contrave®)

  • Class: Dopamine/norepinephrine reuptake inhibitor + opioid receptor antagonist.

  • Indication: Chronic weight management.

  • Dose:

    • Week 1: 1 tablet (8 mg naltrexone/90 mg bupropion) daily.

    • Titrated up to 2 tablets twice daily by Week 4.

  • Adverse effects: Nausea, constipation, headache, insomnia, increased BP, seizure risk (bupropion).

  • Contraindications: Uncontrolled hypertension, seizure disorders, opioid use, eating disorders, pregnancy.

7. GLP-1 Receptor Agonists (off-label classed as anorexiants due to satiety effect)

a. Liraglutide (Saxenda®)

  • Dose: 3 mg subcutaneous daily (titrated from 0.6 mg).

  • Adverse effects: Nausea, vomiting, diarrhea, pancreatitis risk, gallbladder disease.

b. Semaglutide (Wegovy®)

  • Dose: 2.4 mg subcutaneous once weekly (titrated up from 0.25 mg).

  • Adverse effects: GI intolerance, increased risk of thyroid C-cell tumors (in animals), pancreatitis.

Clinical Uses

  • Primary indication: Adjunct to diet and exercise in weight management.

  • Obesity-related comorbidities: Can improve glycemic control, reduce BP, improve lipid profile, and decrease risk factors for type 2 diabetes.

  • Secondary benefit: Some agents (bupropion/naltrexone) reduce food cravings and emotional eating, while GLP-1 analogues reduce cardiometabolic risk.

Contraindications

  • Absolute:

    • Pregnancy and breastfeeding

    • Cardiovascular disease (sympathomimetics)

    • Uncontrolled hypertension

    • Glaucoma

    • History of drug abuse (stimulants)

    • Seizure disorder (bupropion)

    • Chronic opioid use (naltrexone/bupropion)

    • Personal/family history of medullary thyroid carcinoma or MEN2 (GLP-1 agents)

  • Relative:

    • Mild hypertension

    • Controlled cardiac disease

    • Psychiatric illness (risk of mood disturbances)

Adverse Effects

Sympathomimetics (phentermine, diethylpropion, etc.):

  • Insomnia, restlessness

  • Palpitations, tachycardia, hypertension

  • Dry mouth, constipation

  • Abuse potential and psychological dependence

Phentermine/Topiramate:

  • Cognitive slowing, mood changes

  • Teratogenicity (fetal oral clefts)

  • Paraesthesia and dizziness

Bupropion/Naltrexone:

  • Nausea, vomiting, constipation

  • Hypertension

  • Seizure risk (bupropion)

GLP-1 Receptor Agonists:

  • Gastrointestinal intolerance (nausea, vomiting, diarrhea)

  • Rare pancreatitis

  • Possible thyroid tumors (animal studies)

Precautions

  • Duration of use: Sympathomimetic anorexiants generally recommended for short-term use (≤12 weeks). Phentermine/topiramate, bupropion/naltrexone, and GLP-1 agonists are approved for long-term use.

  • Monitoring: Regularly monitor weight, blood pressure, heart rate, and metabolic parameters.

  • Pregnancy testing: Required before and during therapy with phentermine/topiramate due to teratogenic risk.

  • Discontinuation: Should be tapered (especially phentermine/topiramate, GLP-1 agents) to avoid withdrawal or rebound effects.

Drug Interactions

  • MAO inhibitors: Contraindicated with sympathomimetic anorexiants → risk of hypertensive crisis.

  • SSRIs/SNRIs: Risk of serotonin syndrome with bupropion/naltrexone.

  • Opioids: Naltrexone blocks opioid effects, precipitating withdrawal in opioid-dependent patients.

  • Antihypertensives: Reduced effectiveness with stimulants due to sympathomimetic effects.

  • Alcohol: Increases seizure risk with bupropion.

  • Antidiabetics: GLP-1 agonists combined with insulin or sulfonylureas increase risk of hypoglycemia.

Role in Therapy

  • First-line: Lifestyle interventions remain the cornerstone.

  • Second-line: Pharmacotherapy with anorexiants is considered in patients with BMI ≥30 or ≥27 with comorbidities who fail lifestyle interventions.

  • Third-line: Bariatric surgery is considered if pharmacological therapy fails or in cases of morbid obesity.

Future Perspectives

  • New agents: Tirzepatide (dual GLP-1/GIP agonist) shows promise for superior weight loss.

  • Personalized medicine: Genetic and metabolic profiling may help tailor anorexiant therapy to maximize efficacy and minimize side effects.

  • Combination therapy: Exploring synergistic drug pairings for durable weight loss.

  • Focus on safety: Addressing long-term cardiovascular and oncologic safety in ongoing trials.

Summary of Key Anorexiants and Doses

  • Phentermine: 15–37.5 mg PO daily (short-term).

  • Diethylpropion: 25 mg TID or 75 mg ER daily.

  • Benzphetamine: 25–50 mg 1–2 times daily (max 150 mg).

  • Phendimetrazine: 35 mg TID or 105 mg ER daily.

  • Phentermine + Topiramate: 7.5/46 mg daily (max 15/92 mg).

  • Bupropion + Naltrexone: Up to 2 tabs BID (each 8/90 mg).

  • Liraglutide (Saxenda): 3 mg SC daily.

  • Semaglutide (Wegovy): 2.4 mg SC weekly.



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