Lecture 4 & 6 Acne Vulgaris Miller & Klassen

Acne Vulgaris: common inflammation of

the pilosebaceous unit (sebaceous glands &

hair follicles)

Precipitating or risk factors for acne vulgaris

Hormones: androgens (puberty both genders), anabolic

steroids, oral contraceptives (levonorgestrel, progestin)

Family hx & environment (tropical climate, diet, exposure)

Habits: oil products, cosmetics, local friction, improper

cleansing of hair & skin

Drugs: phenytoin, phenobarbital, lithium, haloperidol,

bromides, iodides

Other: stress, premenstrual flares

Acne lesions

Closed comedone (1-2 mm): whiteheads

o First clinical sign, high tendency

to rupture

Open comedone (2-5 mm): blackheads

o Visible keratin plug, oxidized

melanin & oil = black, stable

Papules/pustules/nodules:

inflammatory lesions (bacteria)

Pathophysiology

1. Inflammatory cytokine release: promote PRISH

hyperkeratinisation and microcomedone (plug)

2. Hyperkeratosis: follicular epidermal hyperproliferation

clumping of keratinocytes plugging hair follicle

3. Excess sebum production secondary to androgens:

hormones cause oil glands to increase size & production

(hypersecretion) sebum becomes trapped solidifies

behind keratin plug

4. Bacterial growth & colonization: Propionibacterium acnes

proliferation metabolize oil to fats fatty acids

induce inflammation

Acne severity

Comedonal: closed & open comedones

Mild-moderate papulopustular:

superficial inflammatory lesions &

comedones

Severe: deep pustules/nodules (cysts)

that extend over large areas tissue

destruction (scars)

o May be painful

NOTE: <50 lesions = mild; >100 = severe

Goals of therapy

To prevent new lesions from forming,

heal existing lesions & minimize

permanent scarring

o Reduce keratinization, decrease

sebum production, reduce

microbial flora decrease

enzymes

Prevent psychological distress

Drugs in acne vulgaris

Pharmacotherapy for acne

Comedonal (mild) acne: re-assess at 2-3 mo

Topical retinoid (most effective) or benzoyl

peroxide (alone or in combo)

Add topical abx (clindamycin) to retinoid if

inflammatory lesions present

Last resort: add combined oral contraceptive

for females

Moderate acne: assess 2 mo for tolerability; 3 mo for

efficacy

Topical agents (BPO faster; all retinoids equally

effective)

Combinations: clinda + BPO or adapalene + BPO or

clinda + tretinoin

Oral abx for inflammatory lesions not responsive

to topical or if involves other areas (limit to 6 mo)

Severe acne: isotretinoin if other therapies have failed; hormonal therapy for women

Lecture 5 & 6 Acne Vulgaris Miller & Cairns

Dapsone 5% gel (bid)

General principles of topical txt

Cornerstone of acne treatment

Must treat ALL skin areas daily (not just current lesions)

Acne may worsen for first few wks

o Optimal effect delayed up to 12 weeks

o Maintenance essential to prevent recurrence

Initiate with lowest strengths in water-based products or

apply every second or third night for adaptation to occur

If using two different therapies, apply one in morning &

one in evening

General principles for abx therapy

Don’t use topical & oral abx together

Use in combo with benzoyl peroxide to

prevent bacterial resistance

Use judiciously for inflammatory acne

Restrict to < 6 mo

Benzoyl peroxide

MOA: antibacterial against P. acnes

Penetrates the stratum corneum

or follicular openings unchanged

Converts metabolically to benzoic

acid by cysteine within skin

o Liberates free oxygen radicals

that oxidize bacterial proteins

Skin peeling & comedolytic effects

5% absorbed from skin in 8 hrs

Uses:

Mild acne

(alone)

Adjunct for

all acne

(reduce abx

resistance)

ADRs

Dryness & irritation (redness) for first 1-2 weeks

Contact dermatitis (patch-test advised)

o Avoid contact w/ eyes & mucus membranes

Bleaches fabrics & hair

Oxidizes tretinoin (need to separate treatment)

MOA: anti-inflammatory &

antimicrobial

Inhibits bacterial dihydropterase

synthase in folic acid pathway

ADRs

Dryness

Rash, erythema, pruritis

Sunburn, burning

Aggravation of acne & peeling

* No evidence of drug-induced

hemolytic anemia in patients with

G6PD deficiency (compared to oral)

Uses

Sulfonamide-allergic patients

Patients exhibiting sensitivity or

intolerance to conventional anti-

acne agents

LOW REPSONSE RATE &

EXPENSIVE

Azelaic acid

MOA: not fully determined

Antimicrobial against P.

acnes

Inhibits conversion of

testosterone to

dihydrotestosterone

o DHT promotes

formation of acne

Uses

Acne vulgaris

Acne rosacea

Reduces inflammatory

lesions & erythema

ADR: mild irritation

with redness & dryness

of skin;

hypopigmentation

Exfoliants: phenol, resorcinol, sulfur,

salicylic acid, glycolic (alpha-hydroxy)

acid, azelaic acid

Limited evidence for safety & efficacy

Salicylic acid washes useful in young

pts with recent onset acne

Azelaic acid also antibacterial

o Hypopigmentation risk in

dark complexions

Lecture 5 & 6 Acne Vulgaris Miller & Cairns

Retinoic acid for acne

Uses

Topical: acne vulgaris & wrinkles (age/sun

damage)

Systemic: severe cystic acne

Effects of retinoids on skin

Stabilization of lysosomes (less

inflammation)

Increase RNAP activity

Decrease cohesion b/w epidermal cells

Increased epidermal cell turnover

Cause expulsion of open comedones

Transform closed comedones into open

Decrease sebaceous gland size & function

Decreases number of cell layers in stratum

corneum (from 14 5)

Prolonged use promotes dermal collagen

synthesis, new blood vessel formation &

thickening of epidermis decrease

appearance of wrinkles

Mechanism: steroid hormone receptors

Retinoic Acid Receptor

Natural ligands: trans retinoic acid, 9-cis-retinoic acid

After ligand activation, RAR forms heterodimer with RXR

Bind to retinoic acid response elements on DNA alter transcription of target genes

RAR-α Lipid elevation

Promoter of acute promyelocytic leukemia

RAR-β Modulates solid tumor development

RAR-γ Keratinocyte differentiation & irritation

Bone tenderness/abnormal bone growth

Teratogenicity

Retinoid X Receptor

Natural ligand: 9-cis-retinoic acid

Binds to retinoid X response elements of DNA

Modulation of cell growth, apoptosis, and differentiation

Vitamin A derivatives: non-selective

Retinoic acid (tretinoin, trans-retinoic acid)

Allitretinoin (9-cis retinoic acid)

Isotretinoin (13-cis-retinoic acid)

Selective retinoic receptor antagonists

more effective than tretinoin

Adapalene: derivative of naphtoic acid

o Selective for RAR-γ

o Also inhibits arachidonic acid

metabolism (less inflammation)

Tazarotene: pro-drug hydrolyzed to active

tazoratenic acid

o Selective for RAR-β/γ

o Anti-inflammatory and

antiproliferative actions

ADRs of topical retinoids

Burning/stinging sensation

Peeling, erythema, edema

Photosensitizing (less with adapalene)

Alopecia

Allergic dermatitis

Tazarotene absorbed = teratogenic

Isotretinoin: decreases sebum production by 70%;

decreased P. acnes & inflammation; normalizes

keratinization

Should follow two 8 week courses of different

antibiotics where there is less than 50%

improvement in acne

Dose: 0.5 mg/kg/day for 2-4 wks increase to 1

mg/kg/day with a 120-150 mg/kg cumulative dose

(over 5-6 mos)

ADRs of systemic retinoids

Similar to vitamin A-induced toxicity

Dry lips, dryness & desquamation of face

Headache

Corneal opacities

Decreased night vision

Increased intracranial pressure

Inflammatory bowel disease & anorexia

Muscle & joint pain (calcification)

Cholesterol & triglyceride elevation

Hepatotoxicity

Teratogenicity

Monitoring

CBC, LFT, lipids: baseline, 4 and 8 weeks

Pregnancy: 2 wk before & wk after

Lecture 5 & 6 Acne Vulgaris Miller & Cairns

Topical antibiotics for acne

MOA: eliminates P. acnes from follicle

decreased free fatty acid production and

subsequent inflammation

Concentrates medication in affected

area & reduces risk of systemic SEs

Uses: mild to moderate acnes

(inflammatory lesions)

Not as effective on trunk as face

Apply twice daily

P. acne resistance with prolonged

use

Choices

Topical erythromycin

o Safest in pregnancy, greatest resistance risk

o Combo products

Topical clindamycin

o Equal efficacy to topical erythromycin

o Rare cases of pseudomembranous colitis

o Disagreeable taste with topical use

Both have combo products with retinoic acid or BPO

Systemic antibiotics for acne

MOA: reduce P. acne from follicle

Use: moderate-severe inflammatory

acne

Disadvantages

GI upset

Vaginal candidiasis

Gram –ve folliculitis (proteus,

kleibsella)

Refractoriness due to resistant P.

acnes (esp. erythromycin)

Warning

If no response in 6 wk, switch to

different abx

Discontinue once acne has

improved

Always combine with BPO

Limit use to 6 months

Tetracycline: 1st choice (effective, low cost & less resistance)

Also inhibits chemotaxis, phagocytosis, complement

activation & cell-mediated immunity = anti-inflammatory

Contraindicated in pregnancy (2nd or 3rd trimester) & in

children <9 yo

SEs: photosensitivity reactions; NVD; vaginal candidiasis,

esophageal ulcerations, benign intracranial hypertension

(pseudotumor cerebri)

Starting dose: 250 mg qid or 500 mg bid empty stomach

for 2-3 weeks reduce to 250 or 500 mg od once new

lesions stopped forming

o Doxycycline (more lipid soluble): 50 – 100 mg od

Minocycline: equal efficacy

In patients unresponsive to tetracycline (expensive)

SEs: dizziness (vestibular irritation), drug-induced lupus

(reversible), hypersensitivity reactions

o Hypersensitivity: brown or blue-gray pigmentation

first occurs on mucus membranes of mouth, appears

after months-years (may not fade after DC)

Dose: 50 mg bid or 100 mg od (200 mg daily max)

Clindamycin: refractory acne

SEs: pseudomembranous colitis

(C. difficile) diarrhea

Dose: 150 mg od or bid

SMX/TMP: for severe refractory acne

Dose: 1 DS tab od (800/160 mg)

o TMP alone 300 mg bid

SE: skin rashes (Stevens Johnson)

Erythromycin

Used in females contemplating pregnancy

SEs: causes GI distress (cramps) – motilin-like effect

Drug interactions: P450 inhibition (anticoagulants,

digoxin, carbamazepine, statins, theophylline)

More P. acnes resistance (greatest risk)

Dose: 250 mg qid (or 500 mg bid) decrease with

response to 250-500 mg daily

Lecture 6 Acne Vulgaris Miller

Oral contraceptives for acne

OCs (estrogen) decrease amount of

circulating androgens and increase serum

binding hormone globulin

Approved OCs for acne

o Yasmin

o Tricyclen

o Alesse or Aviane

o Diane-35 or CyEstra-35

OCs equal efficacy in acne

Max effectiveness seen 4-6 mo

Spironolactone for acne

Androgen-receptor blockade

Dose: 50 mg daily or 100 mg bid (when

contraception is not required)

SEs: diuresis, hyperkalemia, irregular menstrual

periods

Avoid in pregnancy (feminization of male fetus)

Acne in pregnancy

Avoid

o Topical & oral retinoids

o Tetracyclines, SMX/TMP

o Anti-androgens (spironolactone)

o Hormones (oral contraceptives)

Select erythromycin (topical or oral) but not

estolate salt

Topical benzoyl peroxide is safe

Pediatric acne

Neonatal acne (birth-4 wk)

Self-limited

No comedones

Infantile acne (6 wk – 1 yr)

Self-limited

Comedones

Papules, pustules

Mid-childhood acne (1-7 yr)

Very uncommon

Gently txt with topical abx

Pre-adolescent| (7-12 yr or menarche in girls)

Txt similar to adults

Avoid tetracyclines <9 yo

Avoid OCs until 1 yr after menarche