Phendimetrazine - A Pharmacologic Remedy for Simple Obesity

Overview

Phendimetrazine, also known as Phendimetrazine tartrate, is an anorectic (suppresses appetite) agent used to manage exogenous or simple obesity. It is an orally administered sympathomimetic medication and is used as an adjunct for a short period of time in weight loss regimens involving reduced calorie intake and lifestyle modifications. Phendimetrazine was one of the first anti-obesity medications to receive the earliest FDA (the United States Food and Drug Administration) marketing approval in 1961.

Drug Group

Phendimetrazine belongs to the class of anorexigenic (causes loss of appetite) drugs. In addition, it stimulates the central nervous system (CNS) and elevates blood pressure. Chemically, it is considered a prototype of amphetamines. Since stimulant or amphetamine-related drugs possess a potential risk of developing dependency (drug abuse), Phendimetrazine is categorized as a controlled substance schedule III by the DEA (Drug Enforcement Administration).

Available Strengths and Dosage Forms

Phendimetrazine is orally administered and is available in both tablet as well as capsule forms. Its dosage forms include -

• Phendimetrazine tablet contains 37.5 mg (milligram) of Phendimetrazine tartrate. It is a circular, biconvex-shaped, and yellow-colored tablet.

• Phendimetrazine capsules are extended-release dosages available in brown or clear-colored capsules containing 105 mg of Phendimetrazine tartrate.

For Patients

What Is Simple Obesity?

Obesity is a global health concern and a persistent pandemic resulting in unwanted clinical complications that are commonly preventable. It is considered an avoidable healthcare burden. In recent years, its prevalence has increased by more than 50 percent, even in countries like the United States, which has top-rated healthcare systems. Predictive statistical models forecast that one in every two adults will be overweight or obese by 2030. The World Health Organization (WHO) defines overweight as a body mass index (BMI) between 25 to 29.9 kilogram per square meter (kg/m2), and obesity when BMI is greater than or equal to 30 kg/m2.

Simple or exogenous obesity widely refers to obesity resulting from disproportionate or imbalanced meal consumption. It is often triggered when food consumption exceeds the energy requirement of the body, where the extra calories are converted into fats. On the other hand, endogenous obesity occurs due to metabolic dysfunction, such as endocrine disorders. Some of the causes of simple obesity are as follows -

• Overeating.

• Inadequate physical activity.

• Sedentary lifestyle.

• Alcohol consumption.

• Regular intake of sweetened and high-calorie beverages.

• Consumption of foods with high calorie and increased fat content.

How Does Phendimetrazine Work?

Although diet control, regular physical activity, and lifestyle adaptations are considered gold standard methods for obesity management, pharmacotherapy for obesity and overweight has also significantly evolved over the recent decades. These anti-obesity medications (AOMs) are used for long-term obesity management and are also approved by the FDA. AOMs combined with lifestyle modifications are recommended for treating obesity and overweight.

Phendimetrazine belongs to the anti-obesity medication (AOM) and is considered a weight-loss medicine that primarily reduces food appetite (desire to eat). This considerably reduces food intake, thereby reducing the accumulation of calories in the body. Phendimetrazine is a sympathomimetic agent that increases sympathetic stimulation (for example, increasing heart rate, elevating blood pressure, etc.). This physiologically stimulating effect makes the body physically active and energetic.

How Is Phendimetrazine Administered?

Phendimetrazine is only advised for adults and older children above 17 years of age. It is not recommended for pediatric use. Also, it is prescribed only as monotherapy and not as a combination medication. The recommended dosage for Phendimetrazine is as follows -

• The usual prescribed dosage for adults is one tablet (35 mg) of Phendimetrazine to be taken two or three times a day, preferably one hour prior to taking meals.

• The dose is often customized to an individual’s BMI for achieving an optimal response in weight reduction with the minimal effective Phendimetrazine dose.

• Sometimes, half a tablet (17.5 mg Phendimetrazine) is also recommended. The overall dosage must not go beyond two tablets thrice daily.

• Phendimetrazine is only prescribed for a short duration as an adjunct to a weight reduction regimen, which includes diet restriction and appropriate physical activity.

• The individuals' body mass index (BMI) before starting Phendimetrazine must be equal to or higher than 30 kg/m2 and also unresponsive to exclusive measures of weight reduction (exercise and diet).

• Extended-Release Phendimetrazine Capsules - Only one capsule of 105 mg Phendimetrazine is recommended, preferably 30 to 60 minutes prior to meals in the morning.

What Are the Side Effects of Phendimetrazine?

Overdosage or interactions with other medications could result in adverse reactions while using Phendimetrazine. Some of the clinical side effects are as follows -

• Dizziness.

• Dryness in the mouth.

• Difficulty sleeping.

• Irritability.

• Nausea.

• Vomiting.

• Diarrhea.

• Constipation.

• Trouble in speaking.

• Seizures.

• Weakness.

• Vision disturbances like blurred vision.

• Uncontrolled anger.

• Hallucinations.

• Nervousness.

• Problems related to the heart valve.

• Uncontrolled muscular movements.

• Irregular or pounding heartbeats.

• Abnormal mood changes.

What Are the Precautions to Be Followed While Taking Phendimetrazine?

Important precautionary measures should be strictly followed during Phendimetrazine therapy to avoid unwanted side effects, overdosage, and drug dependency. It also ensures effective weight reduction without added complications. Some of the notable precautions are as follows -

• Drug Dependency and Abuse - Phendimetrazine is categorized as a controlled substance of Schedule III by DEA. Since it is related to amphetamines, excessive use could result in severe psychological dependence along with intense social dysfunction. Hence, the dosage prescribed by the physician should be strictly followed.

• At the same time, abrupt Phendimetrazine cessation after prolonged treatment would cause extreme weakness, fatigue, and depression. While stopping the medication, doses should be gradually lowered.

• Clinical parameters such as heart rate, blood pressure, and renal function tests should be periodically checked to prevent adverse complications.

• Dietary Considerations - It is advised to take Phendimetrazine medication one hour before mealtime since the presence of food interferes with abdominal absorption of Phendimetrazine. Also, dietary guidelines mentioned for weight reduction must be followed without discontinuation.

• Missed Dose - When a dose is missed, skip the missed dose if the next dose is scheduled shortly. Do not add the doses, as it would result in an overdose. In case of doubts, get it clarified from the physician or healthcare provider.

• Overdose - Avoid overdosing or doubling doses. In case of consuming more than the prescribed dose, immediately contact emergency healthcare services or poison control centers for supportive management.

• Storage - The tablets and capsules of Phendimetrazine must be stored in a cool, dry place away from direct sunlight, heat, or moisture. It should be kept in the original container away from children’s reach. It is stored at room temperature between 20 degrees Celsius and 25 degrees Celsius.

For Doctors

What Are the Indications of Phendimetrazine?

Both tablets and capsules of Phendimetrazine are indicated for managing exogenous or simple obesity and overweight in adults and adolescents above 17 years of age. Phendimetrazine is indicated in the following conditions -

• Prescribed for a few weeks as a short-term adjunct in the weight reduction regimen where the individuals remain obese or unresponsive to regular exercise and diet schedule alone.

• The individual’s BMI should be more than or equal to 30 kg/m2 before starting Phendimetrazine therapy.

• Phendimetrazine is also indicated in regimens following caloric restriction for weight loss management.

• Extended-release capsules of Phendimetrazine tartrate are indicated for individuals with BMI equal to or higher than 27 kg/m2 and also having comorbid risk conditions such as diabetes, controlled hypertension, and hyperlipidemia.

• Generally, Phendimetrazine is indicated for obese individuals who are seen not responding to the usual weight loss protocol of diet restriction and exercises alone.

What Are the Contraindications of Phendimetrazine?

Phendimetrazine is a CNS-stimulating agent and is contraindicated in certain clinical conditions, which include extreme excitability and other associated clinical conditions. Some of its contraindications include -

• Known case of hypersensitivity to Phendimetrazine, its components, or any other medication.

• Hyperthyroidism.

• Moderate and severe forms of hypertension.

• Arteriosclerosis (advanced stage).

• Symptomatic cardiovascular disorders.

• Glaucoma.

• Idiosyncrasy (unexplained drug allergy) reactions to agents containing sympathomimetic amines.

• Phendimetrazine is contraindicated in individuals who are extremely nervous, agitated, and have a drug abuse history.

• It is not recommended in individuals who are under CNS stimulant medications.

What Are the Pharmacological Aspects of Phendimetrazine?

Phendimetrazine is an anti-obesity medication and an anorectic agent. Understanding its pharmacological action and clinical aspects helps in the optimal and effective management of overweight or obesity, preventing undesired complications.

1. Pharmacodynamics

Phendimetrazine is a phenylalkylamine derivative that belongs to the prototype drug class of amphetamines. It is a sympathomimetic amine used for treating obesity. Its pharmacological effects include stimulating the central nervous system (CNS), elevating blood pressure, and increasing the cardiac force of contraction.

2. Mechanism of Action

Phendimetrazine is an anorexigenic drug that suppresses appetite by stimulating CNS. However, this mode of action is not fully established and is still under research. Some of the proven mechanisms are as follows -

• Phendimetrazine stimulates adrenergic receptors and activates the release of neurotransmitters (norepinephrine and dopamine) from the terminal end of the nerves.

• It also inhibits the reuptake of these released neurotransmitters (norepinephrine and dopamine) in the nerve endings, thereby increasing their extracellular levels.

• Studies show that certain types of adrenoceptors and dopamine receptors exhibit effects on food intake.

• Through complex neurochemical pathways, these neurotransmitters stimulate the CNS to reduce appetite and suppress the intake of food.

• Thus, Phendimetrazine significantly reduces calorie intake and thereby favors weight loss in the management of obesity.

3. Pharmacokinetics

• Absorption - Following oral administration, 30 percent of Phendimetrazine is significantly converted into Phenmetrazine, where both compounds induce a similar anorectic response.

• Phendimetrazine is absorbed readily from the gastrointestinal tract. It reaches its peak level in plasma within one to three hours of administration, and its total absorption is completed in four to six hours.

• Distribution - It is evenly distributed, achieving a half-life of 1.9 hours for Phendimetrazine tablets and 9.8 hours for extended-release Phendimetrazine capsules.

• Metabolism - The drug undergoes hepatic metabolism (in the liver) and is converted into two metabolites (Phendimetrazine-N-oxide and Phenmetrazine). Phendimetrazine resists monoamine oxidase (a key enzyme in removing norepinephrine and dopamine) metabolism.

• Excretion - Phendimetrazine is excreted through the kidneys as urine. Proper renal functioning is essential for complete clearance of the drug.

Chemical Taxonomy

Chemically, Phendimetrazine belongs to phenyl morpholine and is an aromatic compound with morpholine and benzene rings linked by carbon or nitrogen bonding.

• Kingdom - Organic compounds.

• Super Class - Organo heterocyclic compounds.

• Class - Oxazinanes.

• Sub Class - Morpholines.

• Direct Parent Compound - Phenylmorpholines.

• Alternative Parent Compound - Alkylamines, trialkyl amines, acyclic compounds, azabicyclic compounds, hydrocarbon derivatives, etc.

• Substituents - Amine, aromatic heterocyclic compound, arylalkylamine, benzenoid, organic nitrogen compound, etc.

• Molecular Framework - Aromatic heterocyclic compounds.

• External Descriptor - Morpholines.

• DEA Classification - Schedule III and Schedule IV.

Toxicity

Phendimetrazine is a CNS stimulant and has the potential risk of being misused or abused. Also, due to its sympathomimetic effect, overdosage could lead to cardiovascular or CNS complications. Some of the toxic side effects of Phendimetrazine are as follows -

• Unusual restlessness.

• Confusion.

• Belligerence.

• Hallucinations.

• Panic or agitated state.

• Fatigue.

• Depression.

• Suicidal tendency.

• Arrhythmias.

• Hypertension.

• Hypotension.

• Dehydration.

• Tourette syndrome.

• Circulatory or cardiac collapse.

• Gastrointestinal disturbances like nausea, diarrhea, abdominal cramps, and vomiting.

• Convulsions.

• Rhabdomyolysis.

• Renal ischemia.

• Coma.

Clinical Studies

Clinical studies have proved that adult obese or overweight subjects when treated with Phendimetrazine and dietary management along with appropriate exercise, lost more weight when compared to those individuals administered with placebo during clinical trials. The rate of weight loss in Phendimetrazine-treated individuals when compared to placebo-treated individuals were found to increase by a fraction in terms of pounds per week. The weight loss rate was higher in the initial treatment weeks, with successive decreases in the following weeks showing a tachyphylaxis effect.

Warnings and Precautions

Phendimetrazine is an anti-obesity drug that therapeutically reduces appetite and food intake. However, while prescribing Phendimetrazine, warnings and precautions should be considered since the drug carries the potential risk of developing serious side effects along with drug dependence and abuse. Some of the associated warnings are as follows -

• Phendimetrazine has a potential risk of CNS overstimulation, resulting in agitation, nervousness, and behavior changes.

• It increases the risk of pulmonary hypertension, causing edema in the lower extremity edema, exertional dyspnea, and unexplained chest pain.

• Valvular heart disease is associated with excessive use of certain anorectic agents; hence, Phendimetrazine should not be prescribed with other anti-obesity drugs.

• Phendimetrazine gets absorbed rapidly by the exposure route. Inhalation of Phendimetrazine results in abuse of the drug.

• Phendimetrazine poisoning results in convulsions, fatal complications like coma, and even death.

What Are the Drug Interactions of Phendimetrazine?

Phendimetrazine interacts with other medications when used concomitantly. Some of its notable drug interactions are as follows -

• Concurrent use with any other CNS stimulant increases sympathomimetic activity, resulting in CNS excitability such as hyperactivity, dyskinesia, and muscle fasciculation.

• Administering Phendimetrazine with monoamine oxidase inhibitors (MAOIs) results in a hypertensive crisis. It should be given after 14 days of administering monoamine oxidase inhibitors.

• Phendimetrazine interacts with Guanethidine when used in combination and decreases its hypotensive effects.

• The dosage of Insulin and oral hypoglycemic agents must be altered when administered with Phendimetrazine in diabetic patients.

Specific Considerations

• Pregnancy - No published evidence is available indicating the effects of Phendimetrazine in pregnant women. However, considering weight loss would cause adverse effects on the fetus and maternal health, the use of Phendimetrazine is contraindicated during pregnancy.

• Breastfeeding and Nursing Safety - To date, no clinical studies have documented the presence of Phendimetrazine in human milk. Phendimetrazine is not recommended for nursing mothers if the risks outweigh the benefits.

• Pediatric Use - The safety and clinical efficacy of Phendimetrazine are not well established in the pediatric age group (below 17 years of age).

• Geriatric Use - Dose selection should be cautiously in elderly individuals, evaluating the renal, cardiac, and hepatic functioning, other clinical conditions, and associated medications.