Pharmacology – ACNE TREATMENT (MADE EASY)
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Pharmacology – ACNE TREATMENT (MADE EASY)


In this lecture we’re gonna cover the pharmacology
of drugs used for acne treatment. So let’s get right into it by first discussing
the pathophysiology of acne. Acne is a multifactorial inflammatory disease
that affects the skin’s oil glands and hair follicles. The oil-producing glands present in our skin,
known as sebaceous glands, are usually attached to hair follicles and release a fatty substance
called sebum that helps protect and lubricate the skin and hair. Acne occurs when sebum and dead skin cells
become trapped in a hair follicle, thus forming a small plug known as microcomedo. Overtime as sebum and dead skin cells accumulate
in the blocked pore, microcomedo may enlarge to form an open comedo knows as blackhead
or closed comedo knows as whitehead. Now, there are three major factors thought
to be important in the pathogenesis of acne. The first one is overproduction of sebum. The second one is follicular hyperkeratinization. And the third one is presence of acne-causing
bacteria that includes various strains of Propionibacterium acnes, abbreviated as P.
acnes. Now let’s discuss these a bit more… So, overproduction of sebum is generally the
result of excessive growth and activity of the sebaceous glands, which leads to clogged
pores that trigger spots of inflammation. The most common causes affecting activity
of sebaceous glands include (1) Genetics. Our genes influence the size and activity
of the sebaceous glands. So the larger and more active the glands are,
the greater the chance of developing acne. (2) Hormonal changes: for example, at puberty,
the body begins producing more androgen-type hormones, which cause the sebaceous glands
to enlarge and produce more sebum. Now, let’s move onto to the second major
cause of acne that is follicular hyperkeratinization. So hyperkeratinization occurs when the cells
of the follicle become cohesive and do not shed normally onto the skin’s surface. As a result dead cells tend to clump together,
blocking pores and causing a backup of sebum in the follicle. Moving on to our third major cause of acne
that is prevalence of acne-causing bacteria, specifically P. acnes that thrives in the
oily depths of our pores. The airless environment that results from
the formation of plug in the hair follicle causes the bacterium to proliferate and turn
sebum into fatty acids that in turn activate inflammation in nearby skin cells. Now, let’s move on to discussing the mechanism
of action of drugs used in treatment of acne. The available pharmacotherapeutic options
can be divided into three main groups; (1) Retinoids, (2) Antimicrobials, and (3) Hormonal
Therapy. So let’s discuss these one by one starting
with Retinoids. Retinoids are a class of compounds derived
from vitamin A or having structural or functional similarities with vitamin A. Their main targets
are epidermal cells known as suprabasal keratinocytes. Upon entry into cells, if needed, retinoid
first gets converted into its biologically active form that is retinoic acid. Retinoic acid is then shuttled by cellular
retinoic acid binding protein (CRABP) into the nucleus where it binds to either the retinoic
acid receptors (RARs) or the retinoid X receptors (RXRs). These retinoic acid bound receptors then bind
to, so called, retinoic acid response elements on target genes causing activation of transcription
factors. These, in turn, activate the synthesis of
heparin-binding epidermal growth factor (HB-EGF) and amphiregulin (AR), which through the interaction
with epidermal growth factor-receptor (EGF-R), cause proliferation of basal keratinocytes,
thereby inducing thickened epidermis. Through this action, retinoids promote shedding
of keratinized mature and dead skin cells at the surface, which leads to expulsion of
mature comedones and suppression of microcomedo formation. The examples of topical retinoids are Tretinoin,
Adapalene, and Tazarotene. Now, in general all retinoids share the same
mechanism of action, however, unlike the topical agents, oral retinoid called Isotretinoin
has additional unique inhibitory activity on the sebaceous glands. That is, it inhibits the proliferation and
differentiation of sebum-producing cells, thereby shrinking the sebaceous glands and
decreasing sebum production. In addition to that, oral Isotretinoin also
reduces colonization with P. acnes and the number of leukocytes that aggregate at the
inflamed site thereby reducing the number of infected and inflamed comedones. Now, when it comes to side effects topical
agents are known to cause skin dryness, irritation, redness, swelling, blistering, and sensitivity
to sunlight. Oral Isotretinoin, on the other hand, is much
more potent medication than topical retinoids and thus is associated with more severe side
effects that include mood changes, muscle or bone pain, and gastrointestinal disorders
among many others. Furthermore, isotretinoin is known to cause
birth defects and thus should be absolutely avoided in pregnancy. Now let’s move on to our second group of
drugs used in treatment of acne that is antimicrobials. So drugs that belong to this group target
P. acnes, a gram-positive bacterium that is involved in the pathogenesis of acne. As you may already know the drugs of choice
for this, are antibiotics. The most commonly used antibiotics for acne
include Sulfamethoxazole and Trimethoprim, which block two consecutive steps in the biosynthesis
of tetrahydrofolate that is needed by bacterial cells for eventual production of DNA, RNA,
and amino acids. Other antibiotics include Clindamycin, Doxycycline,
Minocycline, Erythromycin and Azithromycin, which disrupt bacterial ribosome to inhibit
protein synthesis. Ultimately all of these antibiotics inhibit
the growth of susceptible P. acnes as well as reduce inflammation, which helps to clear
acne. For more detailed explanation of these and
many other antibiotics check out my video dedicated to pharmacology of antibiotics. Now, when it comes to side effects, if antibiotic
is taken orally, most common complaints include nausea, vomiting and diarrhea. On the other hand if antibiotic is applied
externally to skin, the common adverse reactions may include dryness, redness, and itching. Now, unfortunately overuse of antibiotics
can promote the growth of resistant bacteria, which can make treating acne more challenging. To limit the resistance, topical agent called
Benzoyl Peroxide is often prescribed either alone or in addition to antibiotics. So Benzoyl Peroxide reduces the likelihood
of developing antibiotic resistance due to its unique mechanism of action, which involves
release of free oxygen radicals into the pores. Since P. acnes bacteria cannot survive in
an oxygen-rich environment, it gets killed by direct toxicity. In addition to its antimicrobial properties,
Benzoyl Peroxide appears to have an anti-inflammatory action, as well the ability to speed up the
turnover rate of epithelial cells, thereby promoting resolution of comedones. When it comes to side effects, because Benzoyl
Peroxide is applied directly to skin, common complaints are similar to other topical acne
treatments and include dryness, redness, itching, and burning. Now let’s move on to our last group of drugs
used in treatment of acne that is hormonal therapy. As we have learned so far, sebaceous glands
and sebum production play a central role in acne formation. They also happen to be regulated by androgen
hormones. Majority of the circulating androgens are
produced by gonads and the adrenal gland, however they are also produced locally by
sebocytes, which are the major cell type in sebaceous glands that secrete sebum. Now, sebum production is mainly regulated
by dehydroepiandrosterone-sulfate abbreviated DHEA-S. Although DHEA-S is considered a weak androgen,
the sebocytes have required enzymes to convert it into stronger androgens, starting with
androstenedione, then testosterone, and finally the strongest one, dihydrotestosterone. Despite their formation within the sebocytes,
these androgens can also be absorbed from the outside. Once inside the cell, testosterone and dihydrotestosterone
bind to the cytoplasmic receptor to form complex which then enters the nucleus and binds to
specific gene, thus initiating cellular responses that lead to sebocyte proliferation and enhanced
sebum excretion. Now the problem arises when the level of androgen
hormones, such as testosterone, increases, for example during the puberty period. This can lead to overstimulation of androgen
receptors, which in turn can result in excessive sebum production, subsequent clogging of the
pores and formation of favorable environment for the growth of P. acnes bacteria. Now, to mitigate this problem, agent called
Spironolactone is used due to its ability to block the androgen receptors within sebocytes
and thus inhibit androgen-induced sebocyte proliferation. Now, just like increase in hormones during
puberty can trigger acne, hormonal changes in females, such as those relating to menstrual
cycle, can also affect breakouts. The main culprit in this case appears to be
the low or changing levels of estrogen, which leads to increased testosterone to estrogen
ratios during specific segments of the menstrual cycle. Estrogen is thought to suppress sebum production
by directly opposing the effect of testosterone as well as inhibiting testosterone secretion. In addition to that, estrogen increases production
of sex hormone-binding globulin, abbreviated SHBG which is a protein that regulates certain
hormones including testosterone and dihydrotestosterone, by binding them and making them unavailable
for cells to use. So another option for treating hormonal acne
is to alter the natural female reproductive cycle with the use of oral contraceptives
that work by few different mechanisms. Firstly, the estrogen component of hormonal
contraceptives works to boosts levels of sex hormone-binding globulin thereby decreasing
levels of free testosterone. Secondly, oral contraceptives suppress luteinizing
hormone production by the pituitary gland, which in turn decreases androgen synthesis
by the ovaries. And lastly, oral contraceptives inhibit 5α-reductase,
which is the enzyme responsible for the conversion of testosterone to the most potent and active
androgen, dihydrotestosterone. Now the most commonly used oral contraceptives
have low doses of synthetic estrogen, Ethinyl Estradiol, combined with differing progestin
components. Because synthetic progestins have androgenic
activity that may exacerbate or trigger acne, it’s prudent to select oral contraceptive
that contains a progestin with low androgenic properties such as Norgestimate or Desogestrel. Now, when it comes to side effects, Spironolactone
can cause increased urination, irregular periods, and breast tenderness. On the other hand, side effects of oral contraceptives
can include nausea, headache, breast tenderness, breakthrough bleeding, weight gain and increased
risk of blood clots. And with that I wanted to thank you for watching
I hope you enjoyed this video, and as always, stay tuned for more.

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