Chapter 90: Drugs for Disorders of the Skin

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You know, usually when we think of a barrier, we picture something like a brick wall, right?

Yeah, completely solid.

Exactly, it's solid, it's impenetrable, and it's basically just there to keep the outside world out.

And for a long time, that's exactly how people thought about the human skin.

You know, you put a cream on it, it sits on the surface, and end of story.

Right, but then you actually studied dermatologic pharmacology, and suddenly, well, that brick wall looks a lot more like a highly active, highly permeable two -way street.

Yeah, it really does.

I mean, it is the absolute definition of a systemic gateway.

The skin is our largest organ, and treating it requires, you know, a profound respect for pharmacokinetics.

Literally everything applied to that surface has the potential to alter systemic physiology.

And that is exactly our mission for this Deep Dive, so welcome.

Today, we are stepping into the role of your personal one -on -one tutors to help you master chapter 90 of Len's Pharmacotherapeutics for advanced practice nurses and physician assistants.

We really are.

We're gonna look at the skin not as a static wall, but as an interactive ecosystem.

We'll explore how we manipulate that ecosystem,

starting from, you know, gently tweaking the surface, all the way to rewiring the immune system from the inside out.

Yeah, and we are zeroing in on the exact agents that non -specialists need to know.

We'll connect the underlying path of physiology directly to your therapeutic goals, and then tie that drug selection to safe clinical outcomes.

That includes black box warnings and monitoring parameters you're definitely going to face in clinical practice.

Okay, so let's unpack this.

Before we even talk about which active drug to prescribe, we have to talk about how it actually gets past that barrier in the first place.

Which is so crucial.

Right, so think of the active drug as the cargo and the formulation like the cream, the ointment, the gel as the delivery vehicle.

If you put perfectly good cargo in the wrong vehicle, it is just never going to reach its destination safely.

No, it won't.

It might just sit on the surface, or worse, you know, it might cause a massive pileup.

That's a great analogy.

The vehicle actively dictates the drug's absorption.

So let's break down the primary vehicles to understand why.

Ointments, for example, have an oil or petroleum jelly base with very little water.

So they're super thick.

Super thick, yeah.

And because they are thick and occlusive, they basically trap moisture against the skin.

This hydrates the stratum corneum, which is that outermost layer causing the cells to swell.

Oh, wow.

And that swelling literally loosens the lipid matrix between the cells, creating wider channels for the drug to slip through.

So that is why ointments provide the absolute highest medication absorption.

Okay, so they are fantastic for dry, thickened skin, right?

Like the, like, shenification you see from chronic scratching.

Because, yeah.

But, and this is a big, but you do not want to put an occlusive ointment on oozing or weeping skin.

You'll just trap that exudate, create this perfect breeding ground for bacteria, and cause maceration.

Right, yeah, you definitely want to avoid that.

So for inflamed or sensitive skin, we pivot to creams.

These are emulsions of oil and water, so they're lighter, and allow the skin to actually breathe.

Makes sense.

And then you have lotions, which are water -based and non -greasy, because they spread so easily and evaporate quickly without leaving a residue behind.

Lotions are your go -to for really large surface areas or hairy regions.

Right.

Finally, gels.

They are transparent, usually water or alcohol -based, and they liquefy on contact.

They provide this nice cooling effect as the alcohol evaporates, making them ideal for oily skin, especially on the face.

So matching the vehicle to the lesion is step one.

Step two is choosing the actual active ingredient.

And in dermatology, topical glucocorticoids are basically the cornerstone, right?

Absolutely.

Table 90 .1 in the text lays out the relative potency, and we aren't just talking about a mild anti -itch cream across the board here.

The potency ranges dramatically.

It really does.

You've got super high potency agents like clobotasol propionate at 0 .05%, all the way down to the least potent over -the -counter mainstays like hydrocortisone at 1%.

Yeah, and we use these to relieve inflammation and itching by inhibiting the synthesis of chemical mediators, things like prostaglandins and leukotrienes.

But absorption isn't just about the drug's inherent strength.

Right.

It depends heavily on the surface area you're treating, the duration of use, and crucially, whether the area is occluded.

And here's where it gets really interesting for you as a prescriber.

A patient might be prescribed a medium potency steroid.

Right.

But if they apply it and then wrap the area in an occlusive dressing, that occlusion can boost percutaneous absorption by up to tenfold.

Tenfold.

It's crazy.

Yeah.

You've essentially just turned a moderate treatment into a massive systemic dose.

Which leads directly to our safety alerts for this chapter.

Locally, that massive dose over time inhibits collagen synthesis.

So that causes atrophy of the dermis and epidermis literally sitting out the skin.

Wow.

Yeah, you'll see striae, purpura, and telangiectasias.

But systemically, if a patient is absorbing high amounts,

it enters the bloodstream and triggers a negative feedback lip in the brain.

Yeah, that leads to systemic adrenal suppression.

And in children, this can cause really profound growth delay.

So patient education here is just paramount.

We have to instruct them to apply a really thin film, rub it in gently, and never use occlusive dressings unless explicitly prescribed.

Right, never.

And for pediatric populations, think about this.

A tight -fitting plastic diaper acts as a highly effective occlusive dressing.

You simply cannot put a high -potency steroid under a tight diaper.

No, absolutely not.

So now let's transition from general inflammation to conditions where the skin is overgrowing or shedding abnormally.

Okay.

We use keratolytic agents to, the shedding of that horny layer, the stratum corneum.

Salicylic acid and sulfur are the big names here, right?

Yeah, they are.

So salicylic acid works by dissolving the intracellular cement that basically binds those dead scales to the stratum corneum.

But, and you have to watch out for this, if you use high concentrations over really large areas, it doesn't just stay in the skin.

Right, the systemic absorption.

Exactly.

The systemic absorption can actually lead to salicylism, which is salicylate toxicity.

Patients will present with tinnitus, hypopnea, and even psychological disturbances.

It's a huge safety priority.

And then sulfur promotes peeling and drying, and it's often combined with salicylic acid for an additive effect.

So by peeling away that top layer and unclogging pores, we naturally arrive at the most common dermatologic disease clinicians face, which is acne.

Yes, acne.

And I wanna push back on a huge misconception here.

Patients, and honestly, their parents will swear up and down that eating greasy food or chocolate is causing their breakouts.

We've all had time.

They think it's just about teenagers needing to wash their faces better, you know?

Right, but the research clearly demonstrates that dietary changes provide virtually no benefit.

I mean, gentle cleansing helps reduce surface oiliness, sure, but vigorous scrubbing actually exacerbates the condition because it irritates the follicles.

That makes a lot of sense.

The true pathophysiology of acne is this four -part cascade.

It begins with an increase in androgens during puberty, which massively upregulates sebum production.

Simultaneously, the turnover of follicular epithelial cells increases, which plugs up the pores.

And that plugged pore, which is just full of sebum, is an absolute buffet for propionobacterium acne, or P acne.

The total buffet.

Right, this is a microbe that normally just hangs out harmlessly on the skin, but trapped in that sebum, it rapidly multiplies and basically converts the sebum into irritant fatty acids, triggering a massive painful inflammatory response.

Exactly, and the treatment algorithm from the American Academy of Dermatology attacks those specific mechanisms.

Okay, let's walk through it.

So for mild acne, we start with topical therapy.

Benzoyl peroxide is a first -line drug.

It works primarily by releasing active oxygen, which physically oxidizes bacterial proteins, suppressing the P acnes.

You know what fascinates me about that?

Unlike standard topical antimicrobials, benzoyl peroxide does not promote bacterial resistance.

Right, which is huge.

Yeah, because it's essentially a sheer chemical oxidation, the bacteria can't mutate around it.

But there is a crucial safety alert from Health Canada that we need to mention.

Oh, the hypersensitivity one.

Yeah.

They found a risk for potentially serious, sometimes life -threatening hypersensitivity reactions, especially in patients with asthma.

So you have to monitor for severe allergic reactions, not just the expected local drying and peeling.

That's a really good point.

Now, alongside benzoyl peroxide, the algorithm recommends topical retinoids, like tretinoin.

These are vitamin A derivatives that bind to specific nuclear receptors to normalize the hyperproliferation of epithelial cells.

Right.

Tretinoin thins the stratum corneum, which unplugs existing comedones, and crucially, helps other topical drugs penetrate the follicle better.

But when a patient progresses to moderate or severe acne, we have to escalate to oral therapies, right?

Yeah.

We introduce oral antibiotics, typically doxycycline or minocycline, to systemically suppress the bacteria and reduce inflammation.

Yeah, but you have to manage expectations here.

Totally.

The benefits develop very slowly, often taking like three to six months to see maximal effects.

We also consider hormonal agents for female patients, like combination oral contraceptives to decrease androgen activity or spironal lactone.

Let's talk about spironal lactone for a second.

It blocks androgen receptors on the sebaceous glands, reducing sebum.

But because it also acts as a diuretic that competes with aldosterone in the kidneys, you absolutely must diligently monitor the patient's labs for hyperkalemia.

Yes, monitoring potassium is non -negotiable there.

And then we reach the heavy hitter.

Here's where it gets really interesting.

For severe nodulocystic acne that hasn't responded to anything else, we use isotretinoin, which is often known by its classic brand name, Accutane.

The big one.

Think of isotretinoin not just as a treatment, but as a controlled demolition of the sebaceous glands.

You are fundamentally altering gene expression to shrink those glands and shut off sebum production.

By removing the oil, you literally starve the P.

acnes bacteria by just boarding up their food source.

It is incredibly effective because it targets almost all the pathophysiologic factors of acne.

But the side effect profile requires extreme clinical vigilance.

I mean, we were dealing with black box warnings here.

Serious ones.

Yeah, there is a documented risk for severe depression and suicidal ideation, as well as significantly elevated triglycerides.

You also have severe drug interactions.

If a patient takes isotretinoin with a tetracycline antibiotic or vitamin A supplements, they risk developing pseudo tumor cerebre.

Which is wild.

Right.

It's a dangerous pressure building accumulation of cerebrospinal fluid in the brain.

But the absolute most critical safety priority is its teratogenicity.

Isotretinoin causes severe structural and cognitive defects in a developing fetus.

It's devastating.

Because of this, prescribing it requires enrollment in the IPL age program, which is a strictly non -negotiable risk management system.

If a patient is capable of becoming pregnant, they need two negative pregnancy tests before the initial prescription.

Two of them.

Two.

They must commit to using two reliable forms of birth control starting one full month before treatment and continuing one month after.

And the clinician has to verify a negative pregnancy test every single month before authorizing a refill.

It is highly regulated for a reason.

So far, we've discussed manipulating the surface and clearing out localized clogged pores.

Let's shift our focus to a condition where the entire epidermal ecosystem is in overdrive due to an internal immune misfire.

Psoriasis.

Right.

So in psoriasis, inflammatory T lymphocytes play the central role.

They basically mistakenly attack healthy tissue, releasing cytokines that drive an incredibly accelerated maturation of epidermal cells, the keratinocytes.

Yeah, the timeline completely shifts.

Normally, a skin cell takes about 30 days to mature and reach the surface, but in psoriasis, it happens in just four days.

So the dead cells pile up, creating those characteristic thick silvery clacks.

And treatment is stepped based on severity.

For mild to moderate cases, we use topicals.

We already covered glucocorticoids, but we also utilize vitamin D3 analogs, like calcipotri.

These bind to vitamin D receptors in the skin to suppress keratinocyte proliferation.

But since it's a vitamin D derivative, applying too much over a large area can lead to systemic absorption and moderate hypercalcemia.

Got it.

We also use tazartine, which is another topical vitamin A derivative.

What's amazing about tazartine is that it is highly lipophilic.

Oh, right.

Yeah, it actually stores itself in the fat cells of the skin, meaning it slowly leaches out and provides therapeutic benefits for months after the patient actually stops applying it.

That's amazing.

And older treatments include anthraline, which literally intercalates between DNA strands to inhibit DNA synthesis in those fast -growing cells,

and coltars, which suppress DNA synthesis, but come with an unpleasant odor and easily stain the skin and hair.

Yeah, tars are definitely messy.

When dealing with moderate to severe psoriasis, we bring in systemic conventional agents, which are outlined in table 90 .5.

Okay, let's go through the table.

Methotrexate is a classic folic acid antagonist.

It's cytotoxic, targeting tissues with a high growth fraction.

But because it doesn't distinguish between hyperactive skin cells and other rapidly dividing cells in the body, you face a high risk of GI ulceration, bone marrow suppression, and severe hepatotoxicity.

Another conventional agent is acetretin, and honestly, this is where pharmacokinetics gets just completely wild.

Oh, definitely.

Acetretin is a retinoid with a half -life of about 49 hours.

But if a patient consumes alcohol, the alcohol undergoes a chemical reaction with the drug right in the liver.

It acts like a biological time machine, basically converting the acetretin back into an older, highly toxic drug called the tretinate.

Yes.

And suddenly, instead of a 49 -hour half -life, you have a highly teragenic drug trapped in the fat tissues with a half -life of 120 days.

That metabolic quirk massively prolongs the danger window.

Female patients capable of reproduction must participate in the Do Your PART Pregnancy Prevention Program.

They must commit to strech birth control, not just during treatment, but for three full years post -treatment, while completely avoiding alcohol during therapy and for two months after.

Three years of pregnancy prevention for a skin pill.

I mean, that highlights exactly why we need to understand the cellular mechanisms, not just memorize a dosing chart.

Exactly.

We also have apremilast, which is a PDE4 inhibitor that reduces inflammation but causes significant weight loss and GI effects.

And cyclosporine, a really powerful systemic immunosuppressant that carries a major risk for nephrotoxicity.

And because of the massive liver and kidney toxicities of those conventional drugs, we frequently turn to biologic agents for severe psoriasis.

Ah, the biologics.

Yeah, these are administered by injection and target, very specific inflammatory cytokines in the immune cascade.

We use TNF antagonists like adalumumab and interleukin antagonists like ustekinimab, which specifically blocks IL -12 and IL -23.

These biologics are essentially sniper rifles compared to the shotgun approach of methotrexate.

But you know, whenever I see an immunosuppressant, my immediate thought is, what are we leaving the back door open for?

Well, by taking out those specific cytokines, we're blinding the immune system to certain invaders.

So these biologic agents pose a significant risk for serious opportunistic infections and cancer.

That's a big deal.

It is.

You must always run a test for latent tuberculosis before starting a patient on a biologic,

as suppressing TNF or interleukins can allow dormant TB to just instantly reactivate and disseminate.

Wow.

We also have phototherapy options for psoriasis like coltar combined with UVB light, or PUVA, which is a photosensitizing oral sorolin drug, combined with deep penetrating UVA light.

Right.

So let's pivot now from these systemic autoimmune disorders to localized battles.

Some are internal misfires like eczema, and some are external invaders like viruses and parasites.

Let's start with atopic dermatitis, or eczema.

It's also driven by abnormal T lymphocyte activity, creating severe chronic itching and inflammation.

The first line of defense is foundational barrier repair, heavy moisturizers, and topical glucocorticoids.

But when those aren't enough, or the lesions are on delicate areas like the face, we use second line agents, topical calcineurin inhibitors, namely tacrolimus and pymacrolimus.

Tacrolimus works wonderfully to reduce inflammation without causing the skin thinning we see with long -term steroid use.

So why is it strictly a second line agent?

It comes entirely down to safety.

Calcineurin inhibitors locally suppress the T cells in the skin.

But if absorbed systemically over time, that loss of local immune surveillance carries a potential risk for skin cancer and lymphoma.

Ah, I see.

Yeah, so the FDA requires they be reserved only for patients who have failed first line therapy.

We also have a newer topical PDE4 inhibitor, chrysoborole, which reduces inflammation with a much safer systemic profile.

Okay, moving on to viral invaders.

Phenereal warts, which are caused by HPV.

The textbook explicitly divides treatments into provider applied versus patient applied therapies because the mechanisms and risks are vastly different here.

They really are.

For provider applied, we have podophyllin.

This is a highly caustic resin that arrests cell mitosis, causing the wart tissue to literally necrosis and fall off.

And because it is so caustic, it must be washed off within a few hours of application by the provider.

If it's left on, the intense systemic absorption can lead to central and peripheral neuropathy, blood disgraceas, and really profound kidney damage.

That is intense.

It operates completely differently from patient applied therapies like amikimod.

Yeah, amikimod is fascinating.

It doesn't directly kill the HPV virus or the wart tissue at all.

No, it doesn't.

Instead, it binds to toll -like receptor seven on the skin's immune cells, basically stimulating the patient's own body to produce interferon and tumor necrosis factor to mount a localized immune attack against the virus.

There's also cunicatins, a patient applied ointment that is actually a refined green tea extract.

Next, we address the physical invaders ectoparasites, specifically infestations of lysinscabies.

How do we choose between the different lysinscabies treatments?

Well, table 90 .9 is your clinical guide here.

Permithrin is the gold standard first -line treatment.

It works by disrupting the sodium channels of the parasite's nerve cells, basically paralyzing and killing them.

It is highly effective and safe for humans.

What about spinosad?

Spinosad is a newer topical agent that is also highly effective, and wonderfully, it doesn't require the tedious combing for nits, though it is quite expensive.

And then there is lindane.

This drug needs a flashing neon warning sign in clinical practice.

It kills mites by attacking their nervous system.

But how does a topical bug killer end up carrying a black box warning for fatal seizures in the human patient?

Because lindane is highly lipid -soluble.

It doesn't just penetrate the chitin shell of the mite.

It easily penetrates intact human skin, enters the bloodstream, and crosses the blood -brain barrier.

Oh, wow.

Yeah, and once in the central nervous system, it can trigger severe convulsions.

The FDA explicitly warns that lindane must never be used in infants, children, patients under 110 pounds, pregnant women, or really anyone with a history of seizures or broken, irritated skin.

It sounds incredibly dangerous.

It is strictly a treatment of absolute last resort when all other safer options have failed.

Well, if a topical approach isn't working, we do have a systemic option, ivermectin.

It's the only oral medication approved for these ectoparasites.

It paralyzes adult parasites by binding to specific chloride channels in their nerve and muscle cells.

But there's a catch.

It doesn't kill the ova, the eggs.

So if you're treating lice, you have to give a second oral dose about a week later to kill the newly hatched nymphs before they can lay more eggs.

Finally, we wrap up chapter 90 with a pharmacology of daily defense and cosmetic therapies.

For sunscreens, the goal is protection from both UVA rays, which penetrate deeply to cause photoaging and skin cancer, and UVB rays, which cause immediate sunburns.

You know, patients are always asking for waterproof or sweat -proof sunscreen, but the FDA actually cracked down on that terminology because it's medically inaccurate.

Right, it's misleading.

Sunscreens can only claim to be water -resistant for either 40 or 80 minutes of swimming or sweating.

After that, the barrier is compromised and reappletation is mandatory.

In the cosmetic realm, we heavily utilize onybotulinum toxin A, which is commonly known as Botox.

It is injected into specific facial muscles, where it essentially cleaves a transport protein called SNA25.

Okay.

Without SNA25, acetylcholine vesicles cannot fuse with a nerve membrane, completely blocking acetylcholine release and causing localized flaccid muscle paralysis.

It's incredibly precise, but it still carries a black box warning regarding the toxin spreading beyond the injection site.

If it migrates systemically, it can cause profound respiratory or swallowing difficulties, though this is exceedingly rare with the tiny micro doses used for facial cosmetics.

Now for the treatment of hair loss, we have topical minoxidil.

Originally developed as an oral blood pressure medication, it's a really potent vasodilator.

Right.

When applied topically, it increases cutaneous blood flow and opens potassium channels to prolong the active growth phase of the hair follicle.

But patients must be educated that this is a lifelong commitment.

Why is that?

Because if they stop applying it, any newly gained hair simply falls out in three to four months.

Oh, that's frustrating.

Now for systemic hormone driven hair loss in men, we use oral finasteride.

It's a five alpha reductase inhibitor, meaning it blocks the enzyme that converts testosterone into dihydrotestosterone or DHT, which is the hormone responsible for shrinking hair follicles.

But there is a massive safety priority here.

Right, regarding pregnant women.

Because it blocks DHT, finasteride is highly teratogenic to male fetuses, preventing normal genital development.

Pregnant women must not even handle crushed or broken finasteride pills.

Not at all.

The transdermal absorption alone is enough to cause severe genitourinary abnormalities in the fetus.

We also have a fluoronathine cream, which works in the opposite way.

It slows unwanted facial hair growth in women by inhibiting polyamine synthesis, which is an enzyme crucial for rapid cell division in the hair follicle.

Well, that covers the vast pharmacologic landscape of chapter 90.

And it brings us right back to our starting point.

We began by picturing the skin as a simple brick wall.

But looking at everything we just covered, it is just stunning how absorptive, communicative, and metabolically active it truly is.

It really is a dynamic organ.

I mean, a simple topical keratolytic can cause systemic salicylism.

An oral pill for acne requires the striptease pregnancy monitoring program in modi medicine.

A shampoo for lice can cross the blood -brain barrier and cause fatal seizures.

Treating the skin really requires treating the whole patient.

It means constantly anticipating percutaneous absorption, understanding drug half -lives, and respecting the underlying pathophysiology.

Exactly.

For the advanced practice nursing and PA students listening, mastering this logical flow from the cellular disease mechanism to the drug's exact mechanism of action, right down to the specific monitoring and patient education is what separates rote memorization from true clinical mastery.

It's how you ace your exams, but more importantly, it's how you ensure safe, patient -centered care.

We've spent all this time talking about how to suppress the immune system, peel the stratum corneum, or chemically eradicate bacteria with active oxygen.

But you know, it makes you wonder as we learn more about the complexities of the skin microbiome, will the next era of dermatology stop focusing on wiping out bacteria with things like benzoyl peroxide?

Oh, that's a fascinating thought.

Right, like maybe instead we'll focus on prescribing live topical probiotics to actually farm a healthier, more resilient skin barrier.

It's definitely something to think about the next time you reach for that sterile tube of cream.

Thank you so much for joining us for this deep dive.

Keep asking questions, keep looking past the surface, and we'll catch you next time.

Signing off from the last minute lecture team.