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What is Phentermine?

About Phentermine

Phentermine has long been the mainstay drug therapy for obesity.   Phentermine was developed in the 1950's as a weight loss drug.  Until that time, the only drugs which had been used for weight loss were classic amphetamines.  Phentermine was developed in response to severe side effects of classic amphetamines including overstimulation of the central nervous system and the substantive addictive nature of these drugs (2,4,9).   Because of the chemical differences between phentermine and the classic amphetamines, phentermine does not accumulate in the brain like amphetamines, but instead is distributed uniformly throughout the body. (4)

The Phentermine drug has the favorable weight loss therapeutic effect of appetite suppressants.   It is thought that a portion of the brain, the hypothalamus exerts direct control over feeding behavior.   In that area of the brain, there is a “feeding center”, which you to eat, and a “satiety center”, which tells you when you are full.   In the human brain, the feeding and satiety centers are regulated by chemicals known as neurotransmitters.   Increased levels of the neurotransmitters norepinephrine and dopamine suppress the feeding center.  While increased levels of serotonin in the satiety center suppress the appetite (9,12).   It has been shown in animal studies that stress can increase the number of places a neurotransmitter has to bind to on the target cell (receptor sites) in order to produce an effect. For instance, if an animal is under stress, it can take more serotonin than usual to stimulate the satiety center.  Stress can also increase the release of norepinephrine, which can overstimulate the feeding center and cause overeating (19).  

The stomach and intestines, which are collectively known as the gut, have the ability to respond to chemicals that circulate in the bloodstream.  Increased levels of norepinephrine in the bloodstream can decrease blood flow to the gut. Those chemicals can cause the blood vessels in the gut to decrease in size.  Decreasing the flow of blood to the gut will cause gut function to slow down.  It will also slow down the absorption of whatever is in the gut, since absorption of food is dependent on blood flow (4,7).

The autonomic nervous system (ANS) controls the function of the cardiovascular system, the heart and lungs, and the digestive system, the gut.  The ANS regulates the body’s core temperature within a range from 97.6 to 99.6 degrees Fahrenheit.  The ANS regulates core temperature by raising and lowering the body’s metabolism, and by stimulating sweating and shivering.  Increasing each cell’s energy use increases the amount of heat produced by that cell, and the sum total of the heat produced by all the body’s cells will result in an increase in the body’s core temperature.  Under conditions of decreased caloric intake, the ANS will lower metabolism as a self-preservation mechanism, resulting in a slightly lower core temperature.  Carbohydrate and fat intake stimulate ANS activity even if the total caloric intake is not increased.  Increased activity of the ANS is manifested by increased levels of norepinephrine in the bloodstream. (3)

Phentermine works in the brain by increasing dopamine levels in the feeding center.  This increase suppresses the appetite (9).   Phentermine also increases norepinephrine levels in the feeding center, which also decreases appetite (2).   The increased norepinephrine levels do not seem to affect the satiety center however. Phentermine also decreases blood flow to the gut by increasing levels of norepinephrine in the blood stream. The drug also affects blood flow in the gut directly by decreasing the size of the blood vessels there (4).  Phentermine increases ANS activity by increasing norepinephrine levels in the bloodstream. This has a small effect on metabolism. That effect is similar to that of the amphetamine drugs such as dexedrine and benzphetamine, but the effect is not nearly as pronounced (3).

To a great extent the problem with the use of phentermine as a diet drug is the development of tolerance in patients treated with the drug.   Tolerance is the decreased effectiveness of the drug, in terms of appetite control, that occurs after a patient uses the drug for a certain length of time.  This length of time varies from individual to individual.  Some patients never develop tolerance even after prolonged use.  Others develop tolerance after a few days and a few never achieve any appreciable appetite control with the drug.  Some researchers have stated that the cessation of weight loss while using phentermine, or any other diet drug, defines tolerance. Weight loss though, is governed not only by food intake, but also by total daily energy expenditure.   Phentermine does not substantially affect energy expenditure or metabolism (12).

Some researchers theorize that tolerance is due to the fact that there is a limited amount of norepinephrine in the human system, and that those limited stores are depleted by repeated administration of phentermine (13).  Others postulate that the cells that respond to phentermine or norepinephrine become fatigued after repeated stimulation.  Another theory is that the body is able to metabolize and excrete phentermine more and more efficiently as time passes.  Eventually, the drug is metabolized so rapidly that effective blood levels are not maintained long enough for the drug to exert the desired therapeutic effect (1,16).  

Studies have shown that some individuals can have blood levels of phentermine that are up to four times higher than others who are given the same dose of the drug.  This large variance does not appear to be related to age, sex, body weight, diet, time of dosing, or any other identifiable patient characteristic (5).  It is possible that the wide variances in blood levels between individuals can explain the different responses described above that individuals manifest after being given the same dose of phentermine.  These wide blood level variances also point to the different tolerance range between individuals.

It has been shown that drinking carbonated beverages (sodas) or drinking orange, cranberry, or grapefruit juice, will result in faster excretion of Phentermine from the body through the kidneys (8).   Excessive water intake, or the use of diuretics such as caffeine or “fluid pills”, such as hydrochlorothiazide (HCTZ) or furosemide (Lasix), can increase urine output, and thus increase the excretion rate of phentermine, and so decrease its effectiveness. A neutral or alkaline urine, or a low urine output, will result in slower excretion of the drug.  It has not been conclusively shown in clinical studies that slower excretion will result in a prolonged or an increased therapeutic Phentermine effect. It has been noted that patients have evidenced a lesser tendency to develop tolerance when they drink lemon water, and they tend to develop tolerance more rapidly when they drink large amounts of plain water or when they use large amounts of carbonated beverages, caffeine or other diuretics.  This association has not been proven by clinical studies.

Phentermine is available in several dosages and forms.  The form produced and distributed by Medeva Pharmaceuticals is a 30 milligram capsule known as Ionamin.  The active drug is bound to a resin complex that releases the drug over time.  Fastin is a form of phentermine produced by SmithKline Beecham Pharmaceuticals.  It is supplied as a 30 milligram capsule.  The form of the drug produced and distributed by Gate Pharmaceuticals is a 37.5 milligram pill known as Adipex-P.  Neither Fastin or Adipex-P has timed-release characteristics.  Adipex-P reaches a higher level in the bloodstream than any other form, but it is cleared from the bloodstream faster than the timed-release form (7).

There are generic forms of Fastin and Adipex-P, but there is not a generic form of Ionamin available.  There is also a generic Phentermine Hydrochloride (the form of the drug used in Fastin and Adipex-P) that is available in a 15 milligram dose.  One of the most frequently asked questions at the clinic by patients is whether they should use the brand name or the generic form of the drug.  Most patients believe that brand name and generic drugs are identical.  In reality, generic drugs can be compared to generic foods or other generic products, in that there are appreciable and measurable differences between brand name and generic products.  A brand name product has to be within a five percent tolerance of the ideal, with the ideal being defined as 100% bioavailability of the drug. Bioavailability is defined as the percentage of the drug dose ingested that actually enters the system and reaches its target organ or action site.  Generic brands can meet the lower standard of being within 25% of the ideal, and still be marketed under the name of the parent compound.  Because of the wide variation in patient response to Phentermine, there is no hard and fast rule that can be adhered to in regard to the brand versus generic issue.  Each patient must try all forms and brands of the drug to ascertain which is the most effective and well-tolerated form for their particular circumstances.

In our experience, the main reason to prescribe Fastin rather than Adipex-P is in those patients who experience side effects such as insomnia, jitteriness, irritability, or palpitations, with the higher dose of phentermine that is present in Adipex-P.  Ionamin would also be an appropriate drug in those circumstances, since the resinated (timed-release) form of Phentermine is associated with lower peak blood levels of the drug.  Higher peak blood levels of phentermine are associated with more undesirable side effects in some individuals.  Thus, most patients prefer Adipex-P, as it is the higher dose with the potential for greater appetite control (15).

The usual starting dosage of Adipex-P is one pill a day.  Patients who have never taken Phentermine before or who have not taken the drug in a long time may even begin with half a pill, pursuant to their doctor's prescription.  This may help alleviate side effects such as insomnia or jitteriness.  The usual starting dosage of Fastin or Ionamin is one capsule a day.  Some patients develop tolerance after varying lengths of time.  

Phentermine will only control one's appetite for ten to twelve hours.  Thus when taking Phentermine at eight a.m. you will likely not have similar appetite control at bedtime.  Some doctors advise their patients to take Phentermine between ten a.m. and noon or ten to twelve hours before bedtime for those who go to bed at odd hours.  Because an acidic urine can speed up excretion of Phentermine, some doctor's advise not to drink carbonated beverages, or grapefruit, orange, or cranberry juice, while taking Phentermine.

Patients should not use the drugs phenylephrine, pseudoephedrine, or phenylpropanolamine while they are on Phentermine. These medicines are found in most cold, cough, and decongestant medicines, such as Actifed, Sudafed, and Tylenol sinus.  The interaction of phentermine with those drugs can cause shakiness, tremor or insomnia. The interaction can rarely cause a significant increase in blood pressure.

The most common side effect associated with the use of Phentermine is dry mouth followed by insomnia (sleeplessness), shakiness or “jitteriness”, dizziness, irritability, headaches, nausea, constipation, or palpitations (elevated or irregular heart rate).  Less commonly, patients can experience an elevation in their blood pressure. For this reason, the drug must be used cautiously in patients who are on medication for high blood pressure. These patients are generally advised to monitor their blood pressure at least every other day for the first two weeks of therapy. If their pressure is elevated on two or more occasions, they should notify their physician immediately.  Some men can experience impotence and delayed ejaculation.  Those side effects can be especially troublesome during the first few days of therapy, and usually resolve with continuing use.  Rarely, some male patients can have difficulty urinating because of swelling in the prostate which can be made worse by the medication (11). If a patient has been taking phentermine for two consecutive months or longer, and is planning to have surgery under general anesthesia, they must be sure to make their surgeon aware of their use of the drug. There have been reports of hypotension (low blood pressure) in such patients when they are placed under anesthesia. The most significant consequence of this occurrence is that it can lead to brain damage.  These patients should stop taking their phentermine for at least two weeks prior to their surgery.

Phentermine cannot be used in patients who have a coronary artery blockage, because it can reduce the size of small blood vessels, and can cause a critical decrease in the amount of oxygen delivered to the heart muscle.  Patients with significant coronary artery blockage can also have blockages in other blood vessels like those to the lungs and kidneys. Phentermine would be dangerous to use in those patients for the same reason.  Phentermine cannot be used in patients with glaucoma.  The drug can cause a sudden increase in the pressure inside the eye, which can lead to permanent blindness.  The drug should not be used in patients with an overactive thyroid, until their condition is definitively treated.  Use of phentermine in those patients can result in an increase in their symptoms of shakiness, tremors, insomnia, and increased heart rate.  It is not safe to use phentermine in pregnant or breast-feeding women.  The safe use of the drug in patients under the age of sixteen has not been established in clinical studies (11).  Phentermine can place patients with a history of kidney stones at a higher risk to form another stone.  Those patients are advised to avoid caffeine, alcohol, and dehydration, and they are advised to keep their urine acidic by drinking cranberry or grapefruit juice.

Phentermine is not approved by the FDA for continuous use in patients for longer than a three month period. This is because no studies supporting the safety and effectiveness of prolonged use of phentermine were submitted to the FDA at the time of the drug’s approval, and also because of the issue of the development of tolerance.  Because the patent on phentermine has expired, there is at present no financial incentive for any of the major drug companies to underwrite research to assess the safety and efficacy of the long-term use of the drug. When the drug was approved by the FDA in the 50's, the atmosphere surrounding the use of such drugs was quite restrictive. The medical community had a very negative experience with the use of the amphetamines for weight loss in the 20's and 30's, because of the addictive properties of those drugs. Since Phentermine was chemically related to those drugs, there was a universal assumption that relatively long-term phentermine use could lead to the same type of addictive problems.

Fastin, Adipex-P, Ionamin, and Tenuate rated schedule IV conrolled diet drugs are not associated with physical dependence, which is a characteristic of the opiate drugs such as hydrocodone, oxycodone, and codeine, diazepam or Valium and the classic amphetamines.  Physical dependence means that the patient becomes physically ill, sometimes very seriously, when the drug they are on is suddenly withdrawn.

In most states, patients who wish to obtain medication for use in a diet program are only allowed to obtain the drug from their personal physician, or from a physician with which they have established a “previous doctor-patient relationship”, and they are usually required to have a complete blood work-up and an extensive physical examination on their initial visit.  

When discontinuing Phentermine medication, patients need to taper their dose of Phentermine over one to two weeks, if they have been on the medication continuously for two months or more. If they have been taking phentermine for two months or longer and then stop taking it suddenly, they can experience profound fatigue (tiredness) for as long as a week after their last dose.  Some doctors direct their patients to take one-half a pill for three or four days, and then take one-fourth a pill for three or four more days. If they are taking capsules, patients can open the capsules and divide the dose by hand to achieve lower doses.  They can then use their maintenance medication on an as-needed basis for vacations, or if there is an unusual amount of stress.  

Phentermine maintenance patients must engage in a strenuous aerobic exercise program at least twice a week.  Maintenance patients who are male are also advised to consume an average of no more than 1,800-2,200 calories a day, and female patients are advised to consume an average of no more than 1,200 to 1,800 calories a day.

(1) Mori, MA, Kobayashi M, et. al., Metabolism of mephentermine and its derivatives by the microsomal fraction from male Wistar rat livers, Xenobiotica, 1993; 23(1): 11-18
(2) Samanin R, Garattini S, Neurochemical mechanism of action of anorectic drugs, Pharmacology and Toxicology, 1993; 73(2): 63-68 Aug.
(3) Landsberg L, Young JB, Sympathoadrenal activity and obesity: physiological rationale for the use of adrenergic thermogenic drugs, International Journal of Obesity and Related Metabolic Disorders, 1993; 17 Suppl 1: S29-34 Feb.
(4) Morselli, PL, Maggini C, et. al., An integrated approach to the clinical pharmacology of anorectic drugs, Central Mechanisms of Anorectic Drugs, Raven Press, New York, c. 1978, pp 243-265
(5) Groenewoud G, Schall R, et. al., Steady-state pharmacokinetics of phentermine extended-release capsules, International Journal of Clinical Pharmacology, Therapy and Toxicology, 1993; 31(8): 368-372
(6) Beckett AH, Brookes LG, Administration of two or more related drugs to investigate the effect of molecular modification and formulation on drug absorption, metabolism, and excretion, Journal of Pharmaceutical Pharmacology, 1971; 23: 837-41
(7) Hinsvark ON, Truant AP, et. al., The oral bioavailability and pharmacokinetics of soluble and resin-bound forms of amphetamine and phentermine in man, Journal of Pharmacokinetics and Biopharmaceutics, 1973; 1(4): 319-328
(8) Beckett AH, Brookes LG, The metabolism and urinary excretion in man of phentermine, and the influence of N-methly and p-chloro-substitution, Journal of Pharmaceutical Pharmacology, 1971; 23: 288-94
(9) Sprague JE, Culbertson JL, Weight loss: An overview of anorexic agents, Pharmacy Times, 1997; 65-74
(10) Von Moltke, LL, Greenblatt DJ, Appetite suppressant drugs as inhibitors of human cytochromes P450: In vitro inhibition of P450-2D6 by d- and l-fenfluramine, but not phentermine, Journal of Clinical Psychopharmacology, 1998; 18(4): 338-341
(11) Physician’s Desk Reference, c. 1999, Medical Economics Company, Montvale, NJ, pp. 2488-89
(12) Sullivan, AC, Gruen RK, Mechanisms of appetite modulation by drugs, Federation Proceedings, 1985; 44(1 Pt.1): 139-44, Jan.
(13) Goodman & Gilman’s The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill Health Professions Division, c.1996, p. 220
(14) Case reports of relatively long-term use (greater than 3 months) of phentermine at the Wayne Clinic, unpublished
(15) Wayne Clinic data, patients who had taken phentermine alone, weight loss (or gain) per visit, and percent of patients satisfied with the control of their appetite provided by the medication, unpublished
(16) Goodman & Gilman, p. 444
(17) McCann UD, Yuan J, Ricuarte GA, Neurotoxic effects of (racemic) fenfluramine and phentermine, alone and in combination, on monomaine neurons in the mouse brain, Synapse, 1998; 30: 239-246
(18) Lew R, Weisenberg B, et. al., Combined phentermine/fenfluramine administration enhances depletion of serotonin from central terminal fields, Synapse, 1997; 26: 36-45
(19) Stanford SC, Stress: A major variable in the psychopharmcologic process, The Pharmacology and Biochemistry of Behavior, 1996; 54(1): 211-217


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Our top diet product award goes to Phenhermine™. Phenhermine™ demonstrates best of class effective weight loss results at a reasonable cost.  And most importantly without common unfavorable side effects associated with other diet products.

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