Medicine for acne: Oral contraceptives

Oral contraceptives.
Ovarian hypersecretion of androgens can be suppressed with oral contraceptives. Most oral contraceptives contain combinations of estrogens and progestational agents. Oral contraceptives with estrogen (ethynyl estradiol or mestranol) and progestins of low androgenic activity are the most useful. Higher dose estrogen pills are more effective but not as safe.
Most synthetic progesterones have some degree of androgenic activity, which is undesirable in patients who already have signs of androgen excess. Oral contraceptives that appear to be useful in androgenic disorders and acne include Demulen, Ovcon 35, Modicon, Brevicon, and Ortho-Novum 7/7/7. The progesterone ethynodiol diacetate in Demulen is a relatively low androgenic progesterone. Norethindrone is more androgenic, but the low doses contained in Ovcon-35, Modicon, and Brevicon make these pills relatively nonandrogenic. Triphasil, containing levonorgestrel, and Diane (available outside the United States), containing cyproterone acetate, produced a 72% reduction in acne.
The estrogenic and androgenic activity of various oral contraceptives are listed in the Formulary. In many instances acne flares after the use of oral contraceptives is discontinued. Selection of an appropriate agent may provide the benefit of effective acne therapy for women who have chosen an oral contraceptive for birth control. Women in their thirties and forties without risk factors such as smoking or a family history of premature cardiovascular disease can safely use low-dose oral contraceptives to reduce ovarian androgen secretion.
Drugs that may reduce the effectiveness of oral contraceptives
Antibiotics
ampicillin, amoxicillin, isoniazid, metronidazole, penicillin, rifampin, tetracycline
Anticonvulsant drugs
barbiturates, carbamazepine, ethosuximide, phenytoin, primidone
Sedatives and hypnotics
barbiturates, benzodiazepines, chloral hydrate
Others
antacids, antimigraine preparations, clofibrate

Medicine for acne: Antiandrogen therapy

The majority of patients with acne do not have serum androgen abnormalities. The profound sebum suppression produced by isotretinoin has to a large extent eliminated the need for antiandrogenic therapy. Antiandrogenic therapy is reserved for patients with acne who have clinical signs of androgen excess and for those in whom other treatments have failed.
Patient population.
There is a group of women with treatment-resistant, late-onset, or persistent acne. Some of these women have signs suggesting hyperandrogenism, such as hirsutism, irregular menses, or menstrual dysfunction, but others are normal. Serum androgens may or may not be elevated.
Ovulation abnormalities.
Ovulation disturbances have been found in 58.3% of women acne patients, with a prevalence of anovulation in juvenile acne and of luteal insufficiency in late-onset/persistent acne. Women affected by late-onset or persistent acne have a high incidence of polycystic ovary disease. Polycystic ovaries are not necessarily associated with menstrual disorders, obesity, or hirsutism. The presence of polycystic ovaries in acne patients does not correlate with acne severity, infertility, menstrual disturbance, hirsutes, or biochemical endocrinologic abnormalities.
Androgens.
A combination of the effects of circulating androgens and the effects of their metabolism at the hair follicle modulates sebum production and acne severity. Androgens (free testosterone [fT], dehydroepiandrosterone sulfate [DHEAS]) are the most important hormones in the pathogenesis of acne. Plasma-free testosterone is the active fraction of testosterone and determines plasma androgenicity.
Diagnosis--serum androgen levels.
fT and DHEAS are the most practical ways of evaluating hormonal influences in the female. DHEAS is the best index of adrenal androgen activity.
Treatment
Three options.
There are three options for treating acne systemically with hormone manipulation. Estrogen suppresses ovarian androgen, glucocorticoids suppress adrenal androgen, and antiandrogens (spironolactone) act at the peripheral level (hair follicle, sebaceous gland).

Medicine for acne: Isotretinoin Side effects

Isotretinoin Side effects
Side effects occur frequently, are dose-dependent, and are reversible shortly after discontinuing treatment. Patients with side effects can be managed at a lower dosage for a period long enough to reach the 120 mg/kg cumulative dose level. Explain to patients that the long-term benefit is related to the cumulative dosage, not to the duration of therapy.
The incidence of side effects was documented in a large study. Patients in that study stopped isotretinoin for the following reasons: mucous/skin effects (2.5), elevated triglyceride levels (2.0), musculoskeletal effects (1.3), headaches (1.1), elevated liver enzyme levels (0.6), amenorrhea (0.4), and other (0.5).
Teratogenicity--pregnancy prevention program.
Isotretinoin is a potent teratogen primarily involving craniofacial, cardiac, thymic, and central nervous system structures. A number of physicians inadvertently prescribed isotretinoin to pregnant women, which resulted in birth defects. For this reason the FDA considered withdrawing isotretinoin in 1988. Roche Laboratories designed the pregnancy prevention program; as a result, isotretinoin is still available.
The pregnancy prevention program is available from Roche Laboratories in a box containing a qualification checklist for patients, information about treatment, contraception counseling and serum pregnancy testing information, an optional referral form for expert counseling on contraception and patient self-evaluation, consent forms, and a follow-up survey.
Women should be educated about the risks to the fetus and the need for adequate contraception. Sexually active women should have a pregnancy test and postpone therapy until their next normal menstrual period. Some physicians will not prescribe isotretinoin to women of child-bearing age unless they are taking oral contraceptives. Others withhold isotretinoin if abortion is not an option. Isotretinoin is not mutagenic, nor is it stored in tissue. It is recommended that contraception be continued for 1 month after stopping isotretinoin. Patients can be reassured that conception is safe after this 1-month period. One study showed that from the fourth month of treatment onward, a statistically significant increase in the mean sperm density, sperm morphology, and motility were not affected. One year after treatment there was no evidence of any negative influence of 6 months of treatment with isotretinoin on spermatogenesis.
Plasma lipid abnormalities.
Accutane therapy induces an elevation of plasma triglycerides. In one study of patients (ages 14 to 40 years) treated for 20 weeks with 1 mg/kg/day, the maximum mean triglyceride levels rose 46.3 mg/dl in men and 52.3 mg/dl in women. In that study, 2 of 53 patients had a triglyceride elevation over 500 mg/dl, and 8 had elevations of 200 to 500 mg/dl. Triglyceride levels rise after 6 weeks of therapy and continue to rise while therapy continues. Age, sex, and weighted dose do not appear to be risk factors for triglyceride elevations. Overweight subjects are 6 times more likely to develop significant elevations in serum triglyceride, and subjects with elevated baseline triglyceride levels are 4.3 times more likely to develop significant elevations. Plasma lipid and lipoprotein levels return to baseline by 8 weeks after treatment. Liver and lipid abnormalities rarely necessitate dosage reduction and the need for repeat laboratory tests after initial normal values has been questioned.
Hyperostoses.
Asymptomatic hyperostoses (spurs) of the spine and extremities can be documented radiographically in some patients but do not seem to be of concern with a standard course of isotretinoin therapy.
Cheilitis.
Cheilitis is the most common side effect, occurring in virtually all patients. Application of emollients should be started with the initiation of therapy to minimize drying.
Approximately 40% of patients develop an elevated sedimentation rate during treatment. Isotretinoin does not specifically affect skeletal or myocardial muscles, 28% of patients complain of musculoskeletal symptoms. Accutane contains the preservative parabens; those patients with a proven allergy to parabens cannot receive Accutane. Exuberant granulation tissue may occur at the sites of healing acne lesions and is more likely to develop in patients who have preexisting crusted, draining, or ulcerated lesions. Granulation tissue can be controlled with intralesional steroid injections or silver nitrate sticks. Severe dry skin or eczema commonly occurs on the backs of the hands. Routine use of moisturizers and infrequent washing is recommended.

Medicine for acne: Isotretinoin Therapy (2)

Isotretinoin therapy.
Patients are seen frequently during the course of therapy (e.g., every 4 weeks). Isotretinoin is given in two divided doses daily, preferably with meals. Many patients experience a moderate to severe flare of acne during the initial weeks of treatment. This adverse reaction can be minimized by starting at 10 to 20 mg twice each day and gradually increasing the dosage during the first 4 to 6 weeks. Treatment is discontinued at the end of 16 to 20 weeks, and the patient is observed for 2 to 5 months. Those with persistently severe acne may receive a second course of treatment after the posttreatment observation period.
Response to therapy.
At dosages of 1 mg/kg/day, sebum production decreases to approximately 10% of pretreatment values and the sebaceous glands decrease in size. Maximum inhibition is reached by the third or fourth week. Within a week, patients normally notice drying and chapping of facial skin and skin oiliness disappears quickly. These effects persist for an indefinite period when therapy is discontinued.
During the first month, there is usually a reduction in superficial lesions such as papules and pustules. New cysts evolve and disappear quickly. A significant reduction in the number of cysts normally takes at least 8 weeks. Facial lesions respond faster than trunk lesions.
Resistant patients.
Younger patients (14 to 19 years of age) and those who have severe acne relapse more often. [acne relapses more often than facial acne. A return of the reduced sebum excretion rate to within 10% of the pretreatment level is a poor prognostic factor. with microcystic acne (whiteheads) and women with gyneco-endocrinologic problems are resistant to treatment. Women who do not clear after a total cumulative dose of 150 mg/kg need laboratory and clinical evaluation of their endocrinologic status. They may benefit from antiandrogen therapy.
Psychosocial implications.
Patients successfully treated with isotretinoin have significant posttreatment gains in social assertiveness and self-esteem. There is also a significant reduction in anxiety and depression.
Patients with minimal facial acne but with symptoms of dysmorphophobia (inappropriate depression and/or anxiety response to mild acne) are often treated with long-term antibiotic therapy with no perceived improvement. These patients respond to isotretinoin in that they are satisfied with the cosmetic results achieved. The incidence of relapse is greater than that of other acne patients and often requires additional therapy in the form of antibiotics or further isotretinoin.
Laboratory studies.
Pregnancy tests, triglyceride tests, complete blood counts, and liver function tests are performed on patients taking isotretinoin.

Medicine for acne: Isotretinoin Therapy (1)

Dosage.
The severity of the side effects of isotretinoin is proportional to the daily dose. Start with lower dosages and progressively increase the dosage in accordance with the tolerance.
The cumulative dose may be more important than the duration of therapy. A cumulative dose of greater than 120 mg/kg is associated with significantly better long-term remission. This dosage level can be achieved by either 1 mg/kg/day for 4 months or a smaller dosage for a longer period. The therapeutic benefit from a total cumulative dose of more than 150 mg/kg is virtually nonexistent. Analysis of 9 years of experience demonstrated that 1 mg/kg/day of isotretinoin for 4 months resulted in the longest remissions. Relapse rates in patients receiving 0.5 mg/kg/day were approximately 40% and those receiving 1.0 mg/kg/day were approximately 20%. Younger patients, males, and patients with truncal acne derive maximum benefit from the higher dosages. In these patients, dosages less than 0.5 mg/kg/day for a standard 4-month course are associated with a high relapse rate. Treat older patients with facial acne with a dosage of 0.5 mg/kg/day. Double the dosage if there is no response at the end of 2 months. Side effects depend on the dosage and can be controlled through reduction.
Duration of therapy.
A standard course of isotretinoin therapy is 16 to 20 weeks. Approximately 85% of patients are clear at the end of 16 weeks; 15% require longer treatment. Side effects are related to the dosage. Treat for a longer duration at a lower dosage if mucocutaneous side effects become troublesome. Patients with large, closed comedones may respond slowly and relapse early with inflammatory papules. Another ill-defined group responds slowly and requires up to 9 months until the condition begins to clear.
Relapse and repeat courses of isotretinoin.
Approximately 39% of patients relapse and require oral antibiotics (23%) or additional isotretinoin (16%). Relapse usually occurs within the first 3 years after isotretinoin is stopped; most often during the first 18 months after therapy. Some patients require multiple courses of therapy. The response to repeat therapy is consistently successful, and side effects are similar to those of previous courses. Repeat courses of isotretinoin seem to be safe.

Medicine for acne: Isotretinoin (Accutane)

Isotretinoin (Accutane 10-, 20-, 40-mg capsules)
Isotretinoin (13-cis retinoic acid), an oral retinoid related to vitamin A, is a very effective agent for control of acne and in the induction of long-term remissions, but it is not suitable for all types of acne. Isotretinoin affects all major etiologic factors implicated in acne. It dramatically reduces sebum excretion, follicular keratinization, and ductal and surface Propionibacterium acnes counts. These effects are maintained during treatment and persist at variable levels after therapy. A number of side effects occur during treatment. Isotretinoin is a potent teratogen; pregnancy must be avoided during treatment. Isotretinoin is not mutagenic; female patients should be assured that they may safely get pregnant but should wait for at least 1 month after stopping isotretinoin. Age is not a limiting factor in patient selection.
Indications
Severe, recalcitrant cystic or nodular and inflammatory acne.
A few patients with severe disease respond to oral antibiotics and vigorous drying therapy with a combination of agents such as benzoyl peroxide and sulfacetamide/sulfur lotion. Those who do not respond after a short trial of this conventional therapy should be treated with isotretinoin to minimize scarring.
Moderate acne unresponsive to conventional therapy.
Moderate acne usually responds to antibiotics (e.g., tetracycline or erythromycin 500 mg twice daily) plus topical agents. Change to a different antibiotic (e.g., minocycline 100 mg twice daily) if response is poor after 3 months. Change to a third antibiotic (e.g., ampicillin, a cephalosporin, or trimethoprim/sulfamethoxazole) if response is poor after 3 months on the second antibiotic. Change to isotretinoin if response is unsatisfactory after three consecutive 3-month courses of antibiotics. Patients who have a relapse during or after three courses of antibiotics are also candidates for isotretinoin.
Patients who scar.
Any patient who scars should be considered for isotretinoin therapy. Acne scars leave a permanent mark on the skin and psyche.
Excessive oiliness.
Excessive oiliness is disturbing and can last for years. Antibiotics and topical therapy may provide some relief, but isotretinoin's effect is dramatic. Relief may last for months or years; some patients require a second or third course of treatment.
Severely depressed or dysmorphophobic patients.
Some patients, even with minor acne, are depressed. Those who do not respond to conventional therapy are candidates for isotretinoin. They respond well to isotretinoin, although some may relapse quickly and require repeat courses.

Medicine for acne: Spironolactone

Spironolactone (SPL) has antiandrogenic properties and is used to treat acne. Men do not tolerate the high incidence of endocrine side effects, therefore it is only used in women. SPL decreases steroid production in adrenal and gonadal tissue. In women, total serum testosterone decreases and dehydroepiandrosterone sulfate is either decreased or remains unchanged. Free testosterone levels are unchanged or decreased. SPL acts as an antiandrogen peripherally by competitively blocking cytosol receptors for dihydrotestosterone in the sebaceous glands.
Indications.
Spironolactone can be used with antibiotics or oral contraceptives or as a single drug therapy. Therefore it can be used when the source of androgen is either adrenal or ovarian or when screening for serum androgens is normal. Cyproterone acetate has similar effects (available outside the United States). A formulation of cyproterone acetate, in combination with 50 or 35 mug of estradiol, is available outside the United States. These drugs (Diane and Dianette) serve as an oral contraceptive and as an inhibitor of androgen receptors.
Usage in Acne:
Spironolactone causes a significant reduction in sebum secretion and a decrease in the lesion counts of patients. Studies show that SPL at a dosage of 200 mg/day suppresses sebum production by 75% and can reduce lesion counts by up to 75% over a 4-month period.
Adverse reactions.
Side effects are dose related. The incidence is high, but the severity is generally mild and most women tolerate treatment. Menstrual irregularities (80%) such as amenorrhea, increased or decreased flow, midcycle bleeding, and shortened length of cycle occur. Oral contraceptives reduce the incidence and severity of menstrual irregularities. Breast tenderness or enlargement and decreased libido are infrequent. Other effects include mild hyperkalemia, headache, dizziness, drowsiness, confusion, nausea, vomiting, anorexia, and diarrhea. There are no documented cases of spironolactone-related tumors in human beings. The safety of spironolactone use during pregnancy is unknown.