Isotretinoin (Accutane) Analysis

Wednesday, April 30, 2008

accutane3d

Overview

Isotretinoin, also known as Accutane, is a medication mainly used to treat harsh acne. Isotretinoin can also be used as a chemotherapy medication to treat skin cancer. A form of skin disease it can treat is keratosis diffusa fetalis, which is present at birth and is distinguished by a thickening layer of the keratin in fetal human skin. Since isotretinoin comes from Vitamin A and is located naturally in the human body, it is classified as a retinoid. The oral version of isotretinoin is marketed under numerous trade names, the most common one being Accutane.

The IUPAC name of isotretinoin is (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8-tetraenoic acid. It can be identified using a CAS number (4759-48-2), ATC code (D10AD04), PubChem code (5282379), and DrugBank code (APRD00140). The chemical formula for isotretinoin is C20H28O2. It weights 300.44 g/mol. Some pharmacokinetic data includes; the drug’s variable bioavailability, a 99.9% protein binding, hepatic metabolism, half life of 10-20 hours, and renal and fecal excretion (RxList).  A structural diagram of isotretinoin is displayed below (RxList):

accutane1

Usually, four to five months of Accutane use will result in cleared acne. The medication is potent and is effective with all types of breakouts. Accutane should only be used for severe or long lasting acne that does not respond to use of creams or antibiotics. Isotretinoin can be safer than long term antibiotic use even though the drug has numerous side effects. Over two million people have used Accutane, therefore its safety and effectiveness is well documented (A.O.C.D.).

History and Background

Before isotretinoin was developed, the main treatment for ruthless acne was antibiotics such as erythromycin or tetracyclines. While these drugs have been useful, their effectiveness is limited to only fighting against the Propionibacterium acnes bacteria. Eventually, strains of the bacteria became more resistant to the antibiotics, causing the antibiotics to be less effective. 

High doses of the fat-soluable Vitamin A were an early and efficient way of treating acne. While large doses of Vitamin A have the same effects as Accutane, it is harmful because of tissue build up. Vitamin A already present in the bloodstream forms Accutane naturally in the body. This is why large amounts of Vitamin A can cause the same birth defects as Accutane. Luckily, the body is able to quickly remove Accutane from the body because it is naturally present (A.O.C.D.).

High doses of isotretinoin result in high toxicity, similar to Vitamin A toxicity; the higher the dose, the more severe the side effects. The most Vitamin A that should be taken at one time is 3 milligrams. At this dose, there are no side effects for Vitamin A. Isotretinoin is available in 2.5mg capsules (also 5mg, 10mg, 20mg, and 40mg). Although, isotretinoin causes birth defects more than Vitamin A does at similar doses (Accutane Online).

The development of isotretinoin was released in 1982 by Hoffmann-La Roche. This was a significant step forward in the treatment of acne. The synthetic compound resulted in few side effects as well as a superior therapeutic benefit than Vitamin A. A study funded by Roche in 1984 caused high doses of the drug to become main stream in treatment. Independent research indicated that lower dosages were effective in treatment, but Roche's dosage recommendations continued to be used (“History”). Roche’s patents for isotretinoin expired in early 2002, which led to the development of cheaper generic versions of the drug by numerous companies (Brennan).

Currently, isotretinoin is only used after other acne products have failed to produce positive results. Usually, acne treatment starts with medications like adapelene. The next stage is oral antibiotics, and lastly isotretinoin therapy. Other treatments are less effective, but related to less severe side effects at lower costs. The higher costs are due to a higher dosage. Using any substance that has a toxic level requires medical regulation. Another factor is the cost of the medicine (e.g. taking 10mg daily is less expensive than taking 80mg daily).

Disfiguring birth defects or malformation potential were related to the drug ever since its creation, so taking the drug while pregnant is strongly discouraged. When a person who was pregnant took the drug, it was found to have approximately 30% rates of congenital malformation, versus a 3-5% baseline risk (Bérard). Prescriptions of the drug became under analysis starting in 1998, as less than half of the prescribers were being tested for pregnancy, typically relying on less sensitive urine tests (Holmes). The Federal Drug Administration (FDA) instituted restrictions on prescribing and dispersing the drug with the “System to Manage Accutane Related Teratogenicity” (SMART) in 2000 and the iPLEDGE program in 2006, which prevents the use of a drug containing isotretinoin during pregnancy due to resulting birth defects. These laws were based on the grounds that women who took the drug while pregnant were underreported by Roche between 1982 and 2000, and that once generic manufacturers entered the market, risk management was no longer centralized (Woodcock). A study found that pregnancy rates were high during this period, finding that one in every 30 women were pregnant per year, but 84% of pregnancies were ended by induced abortion (Bérard).

Pharmacodynamics

Isotretinoin clearly shrinks the sebaceous glands (located in the skin of mammals) and reduces the production of sebum (made of lipids and debris of dead fat-producing cells). It stabilizes keratinization and prevents the formation of blackhead pimples. Isotretinoin works by altering the synthesis of RNA under the direction of DNA (DNA transcription), similar to other retinoids (DrugBank). This reduces the output and size of the sebaceous gland, making the cells that are molted off into the sebaceous glands less sticky, and in turn decreasing the ability to form blackheads.

Approximately 50% of people that take Accutane are cured so that they no longer require treatment for acne. Although, in the first couple weeks of treatment, about one in five patients get worse, where as one in 500 patients get extremely worse. However, it is the most effective drug when treating severe acne. Normally, a patient only need to use Accutane for four to six months, but the patients who need to be retreated receive up to 12 months of total treatment.

Blood fat levels may be increased due to the use of Accutane; some times to risky levels. However, when use of the drug is stopped, the fat levels revert back to normal. Sometimes, it may even affect the liver. This is why regular blood tests are necessary during Accutane treatment. Risk of damage is extremely low if these precautions are honored (A.O.C.D.).

Pharmacokinetics

When isotretinoin is taken orally, it is best absorbed with a high fat meal because of the chemical compound’s high level of ability to dissolve fats, lipids, oils, and non-polar solvents (also known as lipophilicity). A crossover study found that the peak plasma concentration more than doubled when taken after a high fat meal compared to on an empty stomach. Isotretinoin is mainly attached to plasma proteins, namely albumin. In human plasma, after orally taking isotretinoin, at least three metabolites have been detected (retinoic acid, 4-oxo-retinoic acid, 4-oxo-isotretinoin). In addition, isotretinoin irreversibly oxidizes to 4-oxo-isotretinoin. The metabolites of isotretinoin are excreted through urine and feces. The average biological half-life is 21 hours, with a standard deviation of 8.2 hours (W.A. Colburn).

A greater chance of a cure is present when a patient takes increasingly more Accutane. Sadly, adverse effects depend on the dosage level. Almost no side effects occur at a low level, whereas high doses result in more unpleasant side effects related to the drying effects on the oil glands. A balance between effectiveness and side effects results from an adjusted dose (A.O.C.D.).

The following table is the Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74:

accutane2

Adverse Effects

Over the past 20 years, Accutane has caused a vast number of dangerous, sometimes life threatening side effects. Since the active ingredient in Accutane is Vitamin A, effects of the drug are similar to that of large amounts of Vitamin A. When taken in excessive amounts, Vitamin A can cause damage to the body. Therefore, side effects of Accutane are similar to that of a Vitamin A overdose (Rossi).

There are different levels of reaction to the drug. Some of these reactions, as well as the percentage of people who experience the negative side effects, include: Chapped lips (90%), countered by a using Vaseline or Aquaphor as a lip moisturizer; Dry skin and itching (80%) helped by frequent moisturizer creams; Dryness of nose, mild nosebleed (80%), helped by "AYR nasal gel"; Irritation of the eyelids and eyes (40%), joint and muscle pains (15%), temporary hair thinning (10%), rash (7%), intestinal symptoms (5%), urinary symptoms (5%), headache (5%), increased sensitivity to sun (5%), decreased night vision (<1%), depression, and thoughts of suicide (<1%) (A.O.C.D.).

Some have advocated that Vitamin E supplements can reduce high-dose retinoid’s toxicity without decreasing drug effectiveness. However, tests have been done that prove this to be false (Kus). Also, patients who are being treated by isotretinoin are not allowed to donate blood for at least one month after therapy has stopped. This is due to reports of birth defects to unborn children.

Birth Defects

Isotretinoin is a teratogen, and causes the most damaging side effect if taken while pregnant; birth deficiency. It is vital that women do not take Accutane or any drug containing isotretinoin while pregnant. Common birth defects that result from use of the drug during pregnancy are missing earlobes, visual and hearing impairment, mental retardation, and facial deformity. Isotretinoin is classified as ADEC Category X and FDA Pregnancy Category X, as use is contraindicated in pregnancy (Klasco).

The manufacturer recommends that pregnancy not be present in female subjects two weeks before using isotretinoin. Also, effective contraception should be used during treatment, as well as for at least one month pre and post-therapy (Roche). Between 1982 and 2003, more than 2,000 women became pregnant while using the drug; most resulting in miscarriage or abortion. Approximately 160 of these babies were born with birth defects. Therefore, on August 12, 2005, the FDA introduced the iPLEDGE program in an effort to make sure females don’t become pregnant while using isotretinoin (iPLEDGE).

Depression

A possible link to clinical depression through isotretinoin has been suggested by numerous studies (O’Donnell/Bremner). However, there is no factual evidence. Some lawsuits have been won because of the argument that isotretinoin causes suicide and depression and is in part responsible for the strict control of the drug in America. Reports of depression, thoughts of suicide, and attempted suicide in isotretinoin treated patients have been reported by the FDA Adverse Events Reporting System. Of the 431 cases reported between 1982 and May 2001, 37 patients had committed suicide (Wysowski). No underlying relationship been established and further studies are necessary, while analyses have suggested a connection between isotretinoin therapy and depression (Schweitzer/Hull). 

Studies have displayed that people who are eligible for isotretinoin treatment because of acne have an increased risk of clinical depression compared to the general population (Gupta/Niemeier). Chee Hong claims that anxiety can produce acne and depression, which in turn creates more anxiety. He describes depression due to isotretinoin use as “an idiosyncratic side-effect (Chee Hong).” Also, it has been shown that isotretinoin treatment for severe acne reduces depression and anxiety, for tests have shown acne to be a major depressant in most tested subject’s lives (Rubinow/Chia). A study using positron emission tomography (PET) displayed changes in brain imaging of patients who used the drug, but the relevance of this discovery is unknown (Bremner).

Personal Experience and Conclusion

While growing up, I experienced severe acne. I consulted a dermatologist my freshman year in high school and he recommended Accutane. My family and I were made well aware of the dangers of Accutane, as we had to read a plethora of material and sign numerous forms. I was young and largely following my parents advice. While creams and moisturizers were failing, insecurity was resulting from my acne problem; so I was desperate to try anything that would clear up my skin.

I did not experience many severe side effects at the time. All that occurred was my skin became extremely dry and my lips were frequently chapped. Also, I avoided sunlight because of warning from my doctor. Besides these generally common side effects, I had no problems with the drug. I was extremely happy with the results, as my face and skin cleared up within six months of commencing treatment.

I would not recommend Accutane or other forms of isotretinoin treatment to others who qualify, as it is apparent that it is dangerous to those who may have depression problems, and now that I'm grown up, I don't believe in taking man-made chemicals for reasons like acne. My parents could have helped me work through self-conscious parts of my being instead of turning to a drug for a solution. What also concerns me is that a study showed altered brain images in patients after use of isotretinoin, which may indicate long term side effects. However, with the current technology and advancements in medicine in the U.S., it's possible there may be a time where I would comfortable with the use of isotretinoin as a treatment for severe acne. But it doesn't seem that the benefits of the drug outweigh the negatives.

 

References

"Accutane." American Osteopathic College of Dermatology. A.O.C.D.. 30 Apr 2008 

"About iPLEDGE." iPLEDGE: Committed to Pregnancy Prevention. iPLEDGE. 30 Apr 2008 

"Accutane (Isotretinoin)." RxList: The Internet Drug Index. 2008. Warner-Lambert Company LLC. 30 Apr 2008 

"Accutane: What is it?." Accutane Online. 02 APR 2008. 30 Apr 2008

Bérard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D (2007). "Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective". British journal of clinical pharmacology 63 (2): 196-205.

Bremner JD. Does isotretinoin cause depression and suicide? Psychopharmacol Bull 2003;37(1):64-78.

Bremner JD, Fani N, Ashraf A, Votaw JR, Brummer ME, Cummins T, et al. Functional brain imaging alterations in acne patients treated with isotretinoin. Am J Psychiatry 2005;162(5):983-91.

Brennan, Lisa. "N.J. Jury Assesses $2.62M Against Roche in Accutane Trial." New Jersey Law Journal 07 JUN 2007

Chee Hong Ng, Isaac Schweitzer (2003)The association between depression and isotretinoin use in acne Australian and New Zealand Journal of Psychiatry 37 (1), 78–84.

Chia CY, Lane W, Chibnall J, Allen A, Siegfried E. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study. Arch Dermatol 2005;141(5):557-60.

DrugBank database - Isotretinoin (APRD00140), 12 November 2006, University of Alberta.

Gideon K., Avner M., and Shear N.. "Generic isotretinoin: a new risk for unborn children." Canadian Medical Association 170(2004): 1567-1568.

Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol. 1998;139(5):846-50.

"History." Accutane Side Effects. Parker Waichman Alonso LLP. 30 Apr 2008 

Holmes SC, Bankowska U, Mackie RM (1998). "The prescription of isotretinoin to women: is every precaution taken?". Br. J. Dermatol. 138 (3): 450-5.

Hull PR, D'Arcy C. Isotretinoin use and subsequent depression and suicide: presenting the evidence. Am J Clin Dermatol 2003;4(7):493-505.

Klasco RK, editor. Drugdex system, vol. 128. Greenwood Village (CO): Thomson Micromedex; 2006.

Kus S, Gün D, Demirçay Z, Sur H. Vitamin E does not reduce the side-effects of isotretinoin in the treatment of acne vulgaris. Int J Dermatol 2005;44(3):248-51.

Ng CH, Schweitzer I. The association between depression and isotretinoin use in acne. Aust N Z J Psychiatry 2003;37(1):78-84.

Niemeier V, Kupfer J, Demmelbauer-Ebner M, Stangier U, Effendy I, Gieler U. Coping with acne vulgaris. Evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology 1998;196(1):108-15.

O'Donnell J. Overview of existing research and information linking isotretinoin (accutane), depression, psychosis, and suicide. Am J Ther 2003;10(2):148-59.

Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.

Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.

Rubinow DR, Peck GL, Squillace KM, Gantt GG. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987;17(1):25-32.

W.A. Colburn, F.M. Vane, and H.J. Shorter. "Pharmacokinetics of isotretinoin and its major blood metabolite following a single oral dose to man." European Journal of Clinical Pharmacology 24.512 DEC 2004 689-694.

Webster, Guy F. "Acne Vulgaris." Clinical Review 325(2002): 475-479.

Woodcock, Janet. U.S. Food and Drug Administration. 11 DEC 2002. FDA/Office of Legislation. 30 Apr 2008

Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001;45(4):515-9.

Wednesday, April 30, 2008
menu icon
exit-icon right arrow icon
Link copied!