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Alopecia areata is a disease which is characterized by losing of hair from some or all areas of the body of the human especially from the human scalp. Hair loss tends to be rather rapid and usually involves one side of the head more than the other side. Alopecia areata affects both males and females. These type of hair loss differs from males to females and also different than male pattern baldness which is an inherited condition. Sometimes it is called spit baldness as it causes spots which are bald on the scalp which usually appears in the first stages of the disease. 3% of the infected cases the condition may spread to the epidermis which is called Alopecia universalis or may spread to the entire scalp which is called Alopecia totalis. These conditions may appear in other species.
What are the causes for Alopecia areata?
Scientists and researchers suggested that Alopecia areata is mainly caused by an abnormality in function of the immune system. These abnormality leads to autoimmunity where the antibodies attack certain cells in the human causing destruction to these cells. Till now there is no evidence about Alopecia areata but scientists and researchers suggested that there is an autoimmune disease which cause damage to the hair follicle and undergo some changes in the cells leading to falling of the hair from the scalp but the real reason is unknown till now. Alopecia areata is usually associated with some autoimmune diseases like cancer, ulcerative colitis, lupus, vitiligo and rheumatoid arthritis. Sometimes Alopecia areata occurs within family members suggesting that it may be caused due to gene or heredity.
The most common type of Alopecia areata is tha one that causes loss in one or more round spots on the scalp in one side more than the other side.
Diffuse Alopecia areata: When hair lost more diffusely over the whole scalp.
Alopecia areata multilocularis: shows multiple areas of hair loss.
Alopecia monolocularis: when hair loss is only in one spot which may be in anywhere of the scalp of the head.
Alopecia areata barbae: when the disease is only limited only in the beard.
Alopecia areata totalis: When patient loss all his hair.
Alopecia areata universalis: When hair is lost from all the body including the public hair.
N.B: Alopecia areata totalis and Alopecia areata universalis are very rare.
Signs and symptoms:
First symptoms are soft, small bald patches which take many different shapes but mainly are rounded shaped. It mostly affects the beard and the scalp but mostly the scalp but also may occur on any hair bearing part of the body. There may be different areas of the skin where hair loss occurs. It may be permanently or for a period of time. The area of lost hair may be slightly painful or may tingle.
The hair tends to fall out fastly over a short period of time and always involves one side from the scalp.
Another presentation in case of Alopecia that there may be a case of exclamation point hairs where hairs become narrower along the length of the strand closer to the basement cells which produce a certain character called "exclamation point" like shape.
In case of healthy person with healthy hair if you tried to pull some hair out none of the hair would fall out but in case of Alopecia areata if you tried to pull some hair they will easily be removed from your scalp because the follicles are already been attacked by the antibodies in your bodies due to the autoimmune disease.
People with Alopecia areata can sometimes complain with hair loss, hypogonadism and ciceromegaly which are characterized by short stature.
Treatment of alopecia:
Spironolactone is considered an aldosterone antagonist known in clinical practice as a potassium-sparing diuretic used to treat high blood pressure. Potassium-sparing diuretics are usually used to help decrease the amount of water in the body by stimulating the kidneys to increase the flow of urine, This helps to lower blood pressure. Unlike some other diuretics, these medicines do not cause the body to lose potassium, an important electrolyte required by the human body. Spironolactone therapy might reduce shedding of hair in those persons without hyperandrogenism and may promote some hair growth in those with hyperandrogenism (an excessive production of male hormones).. Spironolactone is a steroid with a basic steroid nucleus consisting of four rings. Spironolactone is 98% protein bound while its primary metabolite, Canrenone, is at least 90% protein bound. Canrenone is the active antagonist of the aldosterone, and it is the primary metabolite contributing to the diuretic action of spironolactone.
Absorption and metabolism of spironolactone:
Spironolactone is quickly absorbed, with maximum plasma levels reached in about 30 to 60 minutes. Food helps spironolactone absorption. The percentage of drug that is detected in the systemic circulation after oral administration exceeds 90%.
Spironolactone is quickly metabolized by the liver. Canrenone could be interconverted enzymatically to its hydrolytic product, canrenoate. No unmetabolized drug is passed out via the urine. The major metabolites are canrenone and potassium canrenoate that are excreted through bile and urine.
Mechanism of spironolactone action in treatment of androgenetic alopecia:
Spironolactone is a powerful antiandrogen. The term antiandrogen, means prevention of expression of androgen activity at target sites and does not include other mechanisms of decreasing androgen action, such as a reduction in production of androgens, intervention with androgen metabolism, or change in androgen plasma protein binding.
However, the action of Spironolactone is directed at both reducing the production and blocking the effect of androgens at the cellular level. It is evident that Spironolactone reduces testosterone production in the adrenal gland by the depletion of microsomal cytochrome P450 and by affecting the cytochrome P450 dependent enzymes 17a-hydroxylase and desmolase. The destruction of microsomal cytochrome P450 by spironolactone may be restricted to those tissues in which microsomal 17a-hydroxylase activity is elevated. The binding of spironolactone to 17- hydroxylase-cytochrome P450 may convert spironolactone to a metabolite that destructs the heme portion of the cytochrome P450, thereby reducing steroid 17-hydroxylation.
Spironolactone is also a competitive inhibitor of DHT-receptor binding and interferes with the translocation of that complex into the nucleus. Spironolactone, a strong competitor for the androgen receptor, is a powerful agonist, whereas canrenone, a weak competitor, is a potent antagonist. The exact antagonists of endogenous or exogenous androgens are the weak agonists, which depend only on a incessant supply of the compound to attain full inhibition. The antiandrogen effect of spironolactone could be produced by the parent compound on the adrenal gland and the metabolite on the receptor site.
The protestation activity of spironolactone is inconsistent but influences the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) by reducing the response of LH to gonadotropin-releasing hormone (GnRH), and so reducing the androgen production.
Dosage of spironolactone:
Spironolactone as a drug is available only in 25-mg or 50-mg tablets. The dosage of spironolactone used in clinical practice may vary from 50 to 300 mg per day and can be given as a single dose or divided doses. The minimum threshold for effective treatment of pattern hair loss however has been found to be about 100 mg daily, similar to that seen in hirsutism. At doses of 100mg per day, nominal changes in circulating androgens are observed. With a higher dose of 300mg or more per day, plasma testosterone reduces considerably, but this elevated dose has almost no clinical advantages and only increases the side effects.
Clinical reports of use of spironolactone in patterned hair loss:
There are very small number of documented reports in the literature concerning the use of spironolactone in pattern hair loss. Small open trials have discovered some clinical effect in androgenetic alopecia, but regrowth takes a long time to develop.
All studies so far have been carried out on women only.
* In one study, 12 women with "androgen-dependent alopecia," were observed for 12 months. 6 were using spironolactone therapy of 75 to 100 mg daily and 6 were untreated controls. Both groups showed a mean decrease in target area nonvellus hairs, but the decrease in the control group was statistically significant. Enhanced non-vellus growth was witnessed in two patients who had their spironolactone dose doubled after 12 months from the 75 or 100 g per day used during the first year.
* In a second study, there was an improvement in six of seven female patients with androgenic alopecia being treated with 200 mg spironolactone per day.
Side effects of spironolactone:
One of the potential side effects of spironolactone in both men and women is the acute intoxication of potassium, a condition called hyperkalemia (elevated potassium levels). Decreased libido, impotence, and worse still, gynecomastia (excessive development of the male breasts) are among symptoms that occur in men treated with spironolactone, thus confining the systemic use to women. In women, breast tenderness, irregular menses, and mood swings are common side effects. Women of childbearing age who are treated with spironolactone shall use effective contraception, preferably a concomitant oral contraceptive pill. If pregnancy occurs while treatment with spironolactone, there is a probable risk of feminization of the male fetus.
Non steroidal antiandrogens:
E.g : Flutamide
Flutamide is a non-steroidal antiandrogen that is devoid of any other hormonal activity. It most probably acts after converting to 2-hydroxyflutamide, which is a strong competitive inhibitor of dihydrotestosterone (DHT) binding to the androgen receptor.
Flutamide's antiandrogen activity and its affinity for the androgen receptor in various androgen-sensitive tissues make it significant to investigate its role in androgen-mediated responses like androgenetic alopecia. As Flutamide is potent enough to have a feminizing effect in men, its use is restricted to treating female pattern hair loss. Anti-androgen therapy might prevent the degeneration of further follicles into vellus-hair production, but is improbable to restore terminal hair production in previously effected follicles.
Metabolism of flutamide
Flutamide is rapidly absorbed, reaching maximum plasma levels after about 4 to 6 hours. The drug is quickly metabolized to at least 10 plasma metabolites. One of these, the 2-hydroxy-flutamide is responsible for its biologic activity. Flutamide and its metabolites are excreted primarily in the urine. At least 16 percent systemic absorption was seen with the application of 5 mg of a topical preparation of Flutamide in 50 percent propylene glycol and 50 percent ethano1. The rate of metabolism is slower with the use of topical Flutamide. However, the same metabolites are present in urine and plasma after both, oral and topical doses.
Mechanism of action for flutamide
Flutamide shows potent antiandrogenic effects. It exerts its antiandrogenic action through inhibiting androgen uptake and/or by inhibiting the nuclear binding of androgen in target tissues or both. In mature rat studies, Flutamide was shown to cause regression of the targeted androgen tissues such as the prostate and seminal vesicles by blocking the inhibitory feedback of testosterone on luteinizing hormone (LH) production, which thereby resulted in increasing their plasma concentrations.
Adult men treated with 750 mg per day Flutamide had similar effects. The predominant pituitary effect appears to be improvement of the frequency of pulses of LH secretion. The drug might be effective in vitro as an antiandrogen, however, in vivo the rise in plasma testosterone levels may limit its antiandrogenic effects.
Flutamide, or most likely 2-hydroxy-flutamide, inhibits tissue uptake and retention of testosterone and also inhibits formation of the nuclear steroid-androgen receptor complex. Antiandrogens without a steroidal structure might inhibit the negative feedback of the gonadal steroids so that more gonadotropins are released by the pituitary and more of testosterone and estradiol are produced by the gonads. These nonsteroidal antiandrogens require a associated antigonadotropin to prevent an increase in the androgen load, which could neutralize their inherent antiandrogen effect. Flutamide inhibits negative feedback of gonadal steroids at the hypothalamic-pituitary leve1. It decreases the cytochrome P450 content in the testicular microsomal fraction in male rats and inhibits testicular microsomal 17 to 20-hydroxylase and 17 to 20 lyase activity- this might be the mechanism of androgen biosynthesis suppression.
Dosage of flutamide
Flutamide is available with a prescription under the brand name Eulexin. Other brand or generic formulations could be available as well. Doses of Flutamide for metastatic prostatic carcinoma are 250 mg three times every day, but in case of treatment of hirsutism, doses of 125 mg twice a day have been found to be effective. Topical Flutamide are used in androgenetic alopecia.
Side Effects of flutamide
Side effects of oral Flutamide are mainly gastrointestinal, like diarrhea. A high occurrence of dry skin has also been reported. A Serioust side effect to be cautious about in oral administration is hepatotoxicity, including progressive liver failure, which limits the usefulness of the drug in treatment of androgenetic alopecia. Evidence of hepatic injury includes increased serum transaminase (liver enzyme) levels, jaundice, hepatic encephalopathy, and death due to acute hepatic failure. Serum transaminase levels shall be measured before starting treatment with Flutamide. Liver function tests should be also obtained at the first signs and symptoms suggestive of liver dysfunction, as nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms or jaundice.
Flutamide must not be given to pregnant women or women desiring to become pregnant.As if the drug crosses the placental barrier, it would be expected to produce male pseudohermaphroditism, similar to cyproterone acetate. Thereby Flutamide should be combined with an oral contraceptive in women of child-bearing potential to decrease the risk of pregnancy.
Corticosteroids are probably the most popular form of treatment for alopecia areata. There is supporting evidence to prove the theory that alopecia areata is a T-cell mediated response, and corticosteroids are known to exert a potent inhibitory effect on the activation of T lymphocytes. Corticosteroids reduce inflammation and pain as well, and could be administered in four different ways; topically as a cream or lotion, intralesional as a local injection into the bald patches, and systemically either as injections into a muscle or oral administration. Each of these methods of administration varies in potency, and also bears variable rates of success and side effects. Currently, topical creams are available with several commercial trade names and with different concentrations of steroids. They are only applied to the regions of hair loss and they are the mildest form of the steroid treatment. Generally dermatologists will try a milder form of treatment before attempting to use stronger forms with their greater potential for side effects.
Precautions and side effects of topical corticosteroid treatment
When using a topical steroid, it is important that the steroid is sufficiently potent to control the skin condition in order to avoid significant local and systemic side effects. The minimum effective strength or class of topical steroid in alopecia areata has not yet been determined, although it would appear that 1% hydrocortisone is too weak. The maximum effective strength remains to be determined. Topical steroids have established an important accomplishment in dermatological therapeutics; but widespread misuse has led to considerable side effects.
For this very reason, efficacy, risks and benefits of the treatment option must be taken in consideration before implementing any treatment regimen. The risk of systemic absorption and the potential associated side effects with the use of corticosteroids should be evaluated during long-term treatment. If topical applications are to be applied in the periocular area, a baseline eye exam and regular follow-up examinations are strongly recommended to check for glaucoma and/or cataracts. Children with extensive alopecia areata applying more than 45 g per month of class I or II topical steroids need to be monitored carefully for significant systemic absorption and side effects. Side effects of topical steroid therapy in children and adults include:
â€¢ Folliculitis (inflammation of the hair follicle).
â€¢ Hypertrichosis (Growth of hair in excess of the normal).
â€¢ Acneiform eruption.
â€¢ The potential for developing local atrophy (wasting) and telangiectasias (chronic dilation of groups of capillaries causing elevated dark red blotches on the skin).
It is important to note that there are major problems in defining and comparing the success rate of topical corticosteroids with other treatment routines for alopecia areata. Many reports on trials involve a small number of patients without any control group for comparison. This leads to the inability to compare trials using different kinds of treatments. Absence of age matched groups with alopecia areata of similar extent and duration coupled with the different parameters individual clinicians use to define satisfactory hair re-growth, make comparison between different treatment types almost impossible.
Like the other topical corticosteroids, fluocinolone has anti-inflammatory, antipruritic and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is not clear. However, corticosteroids are thought to act by induction of phospholipase A2 inhibitory proteins, together called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as the prostaglandins and leukotrienes by inhibition of the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.
The amount of percutaneous absorption of topical corticosteroids is determined by various factors including the vehicle and the integrity of the epidermal barrier. Occlusive dressings with hydrocortisone for up to 24 hours have not been demonstrated to increase penetration; however, occlusion of hydrocortisone for 96 hours noticeably enhances penetration. Topical corticosteroids could be absorbed from normal intact skin while inflammation and/or other disease process in the skin increase the percutaneous absorption.
Minoxidil was introduced in the early 1970s as a treatment for the hypertension. Minoxidil is in the class of treatments called "Potassium Channel Openers" that are used mainly for treating persons with high blood pressure. Although various potassium-channel openers have been used in research for many years, Minoxidil is the only approved drug in this category of drugs for the use in humans. Hypertrichosis or undesirable hair growth was seen as a side effect of the medication. This directly led to the development of a topical formulation of Minoxidil for the treatment of androgenetic alopecia in men and consequently in women. Now Minoxidil is available in two forms to treat different conditions. The Oral Minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness (alopecia). 2% topical Minoxidil was first marketed for hair re-growth in men in 1986 in the United States and then the 5% product became available in 1993.
Mechanism of Action:
Minoxidil does not show any anti-androgen effect. In animal studies, the drug does not stimulate testosterone secretion or adrenal androgen secretion. In humans, serum testosterone levels do not change as well, after topical application of Minoxidil.
Clinical trials of topical Minoxidil in male and female hair loss all show a noticeably rapid increase in hair growth, measured by either hair counts or hair weight. This increase is apparent within about 6-8 weeks of starting treatment which generally peaks by 12-16 weeks. Reversal of follicular miniaturization can hardly be a reasonable explanation for this rapid hair growth. It seems more likely that Minoxidil triggers the follicles in the latent part of telogen into anagen.
Since it was originally a blood-pressure drug it was believed that Minoxidil worked by increasing the amount of blood to the hair follicles. However, other vasodilators do not stimulate the similar response, so it is apparent that local vasodilatation (dilation of blood vessels) does not appear to play a primary role in hair growth associated with Minoxidil. Minoxidil sulfate appears to be the active metabolite accountable for hair growth stimulation. Orally administered Minoxidil lowers blood pressure by relaxing vascular smooth muscle through the action of its sulphated metabolite, Minoxidil sulphate, as an opener of sarcolemmal KATP channels. The series of experiments by researchers on cultured vibrissae follicles and on the stumptail macaque showed some evidence that the stimulatory effect of Minoxidil on hair growth is also due to the opening of potassium channels by Minodixil sulphate. However this idea has been hard to prove and to date there has been no clear demonstration that KATP channels are expressed in the hair follicle.
Minoxidil has a well-known effect on the prolongation of keratinocyte (the keratinocyte is the building block of the epidermis) growth and on increasing the proportion of hairs in anagen in monkeys and humans with androgenetic alopecia. Experiments show that Minoxidil also appears to prolong the survival time of keratinocytes in vitro.
Whatever the mechanism that Minoxidil modulates hair growth, there is a primary effect on cell function. The hair follicle is a composite complex structure comprising epithelial, dermal, pigment and immune cells, and a perifollicular vasculature and neural network. Interactions between these cells are involved in regulating epithelial growth and differentiation and the hair cycle. Several of these cell types have been used in isolation to study Minoxidil action, but trails to localize Minoxidil or a Minoxidil metabolite binding to a specific cell population within the hair follicle have been unsuccessful.
â€¢ CNS: Fatigue, headache
â€¢ CV: Tachycardia (unless given with beta-adrenergic blocker or other sympatholytic drug), pericardial effusion and tamponade; changes in direction and magnitude of T-waves; cardiac necrotic lesions (reported in patients with known ischemic heart disease, but risk of minoxidil-associated cardiac damage cannot be excluded)
â€¢ Dermatologic: Temporary edema, hypertrichosis (elongation, thickening, and enhanced pigmentation of fine body hair occurring within 3-6 wk of starting therapy; usually first noticed on temples, between eyebrows and extending to other parts of face, back, arms, legs, scalp); rashes including bullous eruptions; Stevens-Johnson syndrome; darkening of the skin
â€¢ GI: Nausea, vomiting
â€¢ Hematologic: Initial decrease in Hct, Hgb, RBC count
â€¢ Local: Irritant dermatitis, allergic contact dermatitis, eczema, pruritus, dry skin/scalp, flaking, alopecia (topical use)
â€¢ Respiratory: Bronchitis, upper respiratory infection, sinusitis (topical use)
â€¢ Risk of intense orthostatic hypotension if given with guanethidine. Stop guanethidine; if not possible, hospitalize patient.
Finasteride is a competitive and specific inhibitor of Type II 5Î±-reductase intracellular enzyme, which converts the androgen testosterone into DHT. Two distinct isozymes are found in mice, rats, monkeys, and humans: Type I and II. Each of these isozymes is differentially expressed in tissues and developmental stages. In humans, Type I 5Î±-reductase is predominant in the sebaceous glands of most regions of the skin, including scalp, and liver. Type I 5Î±-reductase is responsible for about one-third of circulating DHT. The Type II 5Î±-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles as well as the liver, and it is responsible for two-thirds of circulating DHT. In humans, the mechanism of action of finasteride is based on the inhibition of the Type II isozyme. Using native tissues (scalp and prostate), in vitro binding studies examining the potential of finasteride to inhibit either isozyme revealed a 100-fold selectivity for the human Type II 5Î±-reductase over Type I isozyme (IC50=500 and 4.2 nM for Type I and II, respectively). For both isozymes, the inhibition by finasteride is accompanied by reduction of the inhibitor to dihydrofinasteride and adduct formation with NADP+. The turnover for the enzyme complex is slow (t1/2 approximately 30 days for the Type II enzyme complex and 14 days for the Type I complex). Finasteride has no affinity for androgen receptor and doesn`t have androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects. Inhibition of Type II 5Î±-reductase blocks the peripheral conversion of testosterone to DHT, resulting in significant reduction in serum and tissue DHT concentrations.
Side effects in Men
Some common side effects of Finasteride treatment in men are decreased libido, reduced semen volume, and erectile dysfunction, with each occurring in fewer than 2 percent of men younger than 41 years and to some extent more often in older men. Contrarily, a recent study by Overstreet et al showed that Finasteride 1mg daily for 48 weeks does not have effect on spermatogenesis or semen production in men aged 19 to 41 years.
Many recipients of this drug are elderly men taking 5 mg per day. There is no effect of long-term use on bone mineral density. Reversible painful gynaecomastia (abnormal enlargement of the male mammary glands) has been reported and the incidence is thought to be around 0.001 percent. Many of these adverse effects in men on Finasteride resolved while they remained on drug itself, and any remaining adverse effects were cleared up once the drug was stopped. With regards long-term safety, Finasteride for men has now been in medical use for over 10 years.
Side effects in women
Finasteride is a teratogen, as it can cause malformation of the fetus. In animal studies, male rats exposed to Finasteride in utero developed hypospadias (a developmental anomaly of the urethra) with cleft prepuce, decreased anogenital distance, reduced prostate weight and altered nipple formation.
Officially, women of potential childbearing age should not administer Finasteride or even handle crushed or broken tablets. The risk of teratogenicity in humans has not been evaluated but Finasteride may cause hypospadias in the developing male fetus. Exposure to semen of men who are taking Finasteride does not pose a real risk to the pregnant woman's male fetus. Finasteride tablets are coated to prevent contact with the active ingredients during manipulation.
In studies conducted with women premenopause, the finasteride was always provded to the women along with birth control pills. The use of birth control to ensure pregnancy did not occur while using finasteride was a must given the potential effects finasteride can have on male embryos.