b10ph01 - dermatologic pharmacology

Block X | Pharmacology | Lesson 1Dermatologic PharmacologyMyrna L. Abello, MD, Ed.D.SGD 4CSeptember 18, 2015

DERMATOLOGIC PHARMACOLOGY

Drugs used in the treatment of the skin can be:1. Delivered Systemically

o Gets into the system2. Applied Topically

o Apply to site where the drug is wanted to act

3. Injected Directly to the Dermis4. Phototherapy-Ultraviolet Radiation

PHARMACOLOGICAL RESPONSE DETERMINED BY:

1. Regional variation in drug penetration Areas in the body are more permeable and may

require less drug for equivalent effect Examples: scrotum, face, axilla and scalp >

forearm (in terms of permeability)

2. Concentration Gradient An increase in concentration gradient increases

the mass of the drug transferred per unit time Example: Resistance to corticosteroids can

sometimes be overcome by use of higher concentrations of drug

3. Dosing schedule “Local Half-life” may be long enough to permit

once daily application with short systemic half-lives

Example: steroids (given once a day) is as effective as multiple applications in many conditions

4. Vehicles & Occlusion An appropriate vehicle maximizes the ability of

the drug to penetrate the outer layers of the skino Vehicles may themselves have important

therapeutic effects Occlusion (plastic wrap to hold drug and vehicle

to skin)

SGD 4C| GANZON, JUMAWAN, PINEDA, UDDIN of 10

SUMMARY/OUTLINEI. Dermatologic PharmacologyII. Pharmacological ResponseIII. AbsorptionIV. Choice of a VehicleV. Topical ApplicationVI. Glucocorticoids

a. Anti-Inflammatory Effects b. 7 Classesc. Principles in the use of Steroidsd. Adverse Effects

VII. Systemic GlucocorticoidsA. Adverse Effects

VIII. Tar CompoundsIX. Topical Antibacterial Agents

A. BACITRACINB. GRAMICIDINC. MUPIROCIND.RETAPAMULINE. POLYMYXIN B SULFATEF. NEOMYCING. GENTAMICIN

X. Topical Antibiotic in AcneA. CLINDAMYCINB. ERYTHROMYCINC. METRONIDAZOLED. TETRACYCLINE. SODIUM SULFACETAMIDE

XI. Acne PreparationsA. RETENOIC ACIDB. ISOTRETINOINC. ETRITINATE

XII. Anti-Pruritic AgentsA. DOXEPINB. PRAMOXINE

XIII. Anti-histaminesA. OLDER H1 RECEPTOR ANTAGONISTSB. NEWER H1 RECEPTOR ANTAGONISTSC. H2 RECEPTOR BLOCKERS

XIV. Agents Affecting PigmentationA. HYDROQUINONE & MONOBENZONEB. HYDROQUINONE C. MONOBENZONE D. GLUTATHIONEE. POLYPHENOLIC-GLUTATHION (GSH)

XV. SunscreensXVI. Keratolytic Agents

Block X |PHARMACOLOGY | Lesson 1Dermatologic Pharmacology

o Extremely effective in maximizing efficacy

5. State of the stratum corneum Topical absorption increased in dermatologic

disorders due to the presence of breaks/lesions in the skin

6. Presence of “Penetration Enhancers” Examples: Organic solvents such as dimethyl

sulfoxide (DMSO), urea, salicylic acido Added to the drug for better penetration

ABSORPTION CONTROLLED BY:

1. Concentration of drug in the vehicle Rate of diffusion is proportional to concentration The higher the concentration, the more effective

it is

2. The partition coefficient of drug between the stratum corneum and the vehicle Partition coefficient is the Drug’s ability to escape

from the vehicle Application of topical preparation is incorporated

into a vehicle and will take time for the drug to get out of vehicle and exert its effect

Increased lipid-solubility favors penetration through the skin in the relatively lipophilic stratum corneum

3. Diffusion coefficient of the drug in the stratum corneum Refers to the extent to which the matrix of the

barrier restricts the mobility of the drug An Increase in the molecular size of the drug will

decrease the diffusion coefficient. Drugs with greater molecular size, would cross

the membrane with difficulty while drugs with smaller molecular size will cross the membrane with ease

CHOICE OF A VEHICLE

A vehicle is any of various media acting usually as solvents, carriers, or binders for active ingredients.

A. Acute inflammation with oozing, vesiculation & crusting

Best treated with drying preparations (e.g. Tinctures, Wet dressings, lotions)

Lotions & Solutions are ideal for hairy & intertriginous areas

Choice of vehicle will depend on the type of lesion

B. Chronic Inflammation with xerosis, scaling & lichenification

Best treated with more lubricating preparations (e.g. Creams or Ointments)

Creamo Most acceptable and common

preparationo Safer to use if in doubt if lesion is wet or

dry o Emulsion of oil and water

Ointmento Most effective hydrating agentso Greasy & often undesirable (oleaginous

base e.g. petrolatum, mineral oil)

HOW MUCH TO APPLY?

“Fingertip Unit” (FTU)o Amount of ointment when squeezed out of a

tube to the palmar aspect of the index finger from the distal skin crease to the end of the finger

o Sort of an estimateo Approximate Value

- Males: 0.47g

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TRIVIA: 282 sq. cm. when spread on skin

approximately area covered by 2 hands2 FTU 4 hand areas

FACE & NECK 2.5 FTU (1.3g)

FRONT OF TRUNK 7 FTU (3.5g)

ONE ARM 3 FTU (1.5g)

ONE HAND (FRONT AND BACK)

1 FTU (0.5g)

ONE LEG 6 FTU (3.0g)


- Females: 0.42g- Generally rounded off to 0.50g or 1/2 g

TOPICAL GLUCOCORTICOIDS

Known as steroids in laymen’s term Therapeutic effectiveness based primarily on their

anti-inflammatory activity Antimitotic activity on human epidermis may account

for additional mechanism of action in psoriasisMechanism of Action:All natural and synthetic glucocorticoids act by:

ANTI-INFLAMMATORY EFFECTS OF GLUCOCORTICOIDS/STEROIDS

Decreased production of prostaglandins, cytokines & interleukins

o Inhibit synthesis of these substances which are called autacoids

Decreased proliferation & migration of lymphocytes & macrophageso By the inhibition of accumulation of neutrophils

and monocytes at the site of inflammation

7 CLASSES OF TOPICAL GLUCOCORTICOIDS

1. Betamethasone 0.05% Diproprionate (Diprolene®) in optimized vehicle (ointment, cream etc)

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Clobetasol Propionate (Temovate®) 0.05%- Highest efficacy, most potent

2. Amcinonide ointment 0.1% (Cyclocort®)Betamethasone Dipropionate ointment 0.05% (Diprosone®)

- High efficacy

3. Betamethasone Dipropionate Cream 0.05%Betamethasone Valerate Ointment 0.1% (Valisone®)

- Intermediate efficacy

4. Fluocinolone Acetonide Cream 0.025% (Synalar®) Triamcinolone Acetonide Ointment 0.9% (Kenalog®)

- Low efficacy

5. Betamethasone Dipropionate Lotion 0.05% (Diprosone®)

6. Aclomethasone Dipropionate Cream, Ointment 0.05% (Aclovate®)

- Low efficacy

7. Dexamethasone Sodium Phosphate Cream 0.1% (Decadron®)Hydrocortisone Cream, Ointment, Lotion 0.5% 1%, 2.5% (Hytone, Nutracort, Penicort)

- Lowest efficacy- Least potent

Class 1 – Most Potent Class 7 – Least Potent Important since there are instances when we

need a high or low efficacy drugs

PRINCIPLES IN THE USE OF STEROIDS

Steroid to be used chosen on basis of potency, site of involvement &severity

o Face is easy to penetrate so we use dose with lesser efficacy

Often a more potent steroid is used initially- Class 1 Twice-a-day application is sufficient; more frequent

application does not improve responseo There is such a thing as half-life and it will stay

there for a certain period of time

ADVERSE EFFECTS Usually, the adverse effects may be found topically but

our problem with adverse effects is those that are absorbed into the system. As much as possible, we would not want them to be absorbed in the system

All absorbable topical corticosteroids possess the potential to suppress the pituitary-adrenal axis

o “See-saw effect”o From local application, they can be absorbed

into the system

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Applying potent corticosteroid to extensive areas of the body for prolonged periods increases the likelihood of systemic effects

Children more susceptible & growth retardation is a concern

o Results to early closure of long boneso Be more careful when dealing with children

and steroids Adverse local effects:

o Usually occurs when applying topical steroids

o Atrophy- Present as depressed, shiny, often

wrinkled “Cigarette Paper”- appearing skin with prominent

telangiectasia- Occurs in the site of application

A tendency to develop purpura & ecchymosis (aka Steroid Rosacea)

o Persistent erythema, telangiectatic vessels, pustules, & papules in central facial distribution; Perioral dermatitis, steroid acne

Alterations of cutaneous infections, hypopigmentation, hypertrichosis, increased intraocular pressure, & allergic contact dermatitis

Intralesional glucocorticoids can cause cutaneous atrophy & hypopigmentation

o They are not very safe drugs

SYSTEMIC GLUCOCORTICOIDS Systemic: absorbed in the system

Reserve for acute treatment of transient illnesses or life-threatening dermatoses

Fewer side effects with every other day dosing & prednisone tapered to every other day ASAP

o e.g. Daily dose of 3x a day then reduce to 2x a day, then to once a day, to every other day

o Reason: reduced gradually for less adverse effects for withdrawal, and to prevent ADRENAL CRISIS

ADVERSE EFFECTS: SYSTEMIC GLUCOCORTICOIDS Short Term Oral

o Psychiatric problems, cataracts, myopathy, avascular necrosis, hypertension

Pulsed IVo Intravenous administration of steroidso Hypo or hypertension, hypo or hyperkalemia,

anaphylactic reaction, acute psychosis, seizures,& sudden death

“If we can avoid them, we avoid them.”

TAR COMPOUNDS Used mainly for the treatment of psoriasis, dermatitis

& lichen simplex chronicus Has Antipruritic properties (due to phenolic

constituents) Acute dermatitis may be irritated by even a weak

preparation (Contraindicated) Useful in sub-acute and chronic dermatitis and

psoriasisADVERSE EFFECTS: irritant folliculitis, photoirritation,

allergic contact dermatitis

TOPICAL ANTIBACTERIAL AGENTS Not recommended because of possibility of

sensitization Not given systemically due to many side effects Sensitization - main cause of the discontinuation of

certain drug practiceso e.g. use of sulaminamide, applying penicillin to

open wounds, discontinue of usage of antihistaminic drugs

BACITRACIN & GRAMICIDIN Gram (+) organisms, streptococcus, pneumococcus &

staphylococcus Not used systemically because they are toxic MOA: inhibits cell wall synthesis Sensitization low in therapeutic concentrations

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Most anaerobic cocci, Neisseriae, Tetanus bacilli, Diphtheria bacteria are sensitive

A. BACITRACIN Compounded in ointment base alone or with

neomycin, polymyxin B or both (aka BNP ointment) Microbial resistance may develop after prolonged use Side Effects: Contact urticaria, anaphylaxis, systemic

toxicity (rare), contact dermatitis (frequent) was isolated from a girl named Tracy very harmful antibiotics in a sense that they have side-

effects that’s why they’re only given locally and not systemically..

B.GRAMICIDIN Combined with neomycin, polymyxin, bacitracin,

nystatin Available only for topical use Neomycin is an aminoglycoside

o Side Effects: Nephrotoxic, Ototoxic, Neuromuscular defects

o Sensitization is low in therapeutic concentration

o Also used as antiseptic in surgery because aminoglycosides are not absorbed in GI tract and stay in GI canal to disinfect area

C.MUPIROCIN (Bactroban®) Relatively new drug Effective against most Gram (+) aerobic bacteria

including MRSA Effective in impetigo caused by S. Aureus & Group A

Beta Hemolytic Strepo Used to treat Impetigo contagiosa specificallyo Mercury was the former treatment but is now

known to be toxic and bannedo E.g. mercurechrome and merthiolate

Not appreciably absorbed systemically on intact skin Not absorbed systemically is preferred for topical

drugs

D. RETAPAMULIN New synthetic drug, newer than mupirocin Semisynthetic drug derived from pleuromutilin Effective in treatment of uncomplicated superficial

skin infection caused by Grp. A beta-hemolytic strep and S. aureus excluding MRSA for adult and pediatric patients 9 months and older

E. POLYMYXIN B SULFATE Mixed with drugs mentioned earlier Peptide antibody effective against Gram (-) organism

including P. Aeruginosa, E. Coli, Enterobacter & Klebsiella

Also effective with Proteus, Serratia, Gm (+) resistant species (Katzung: they are resistant)

MOA: Act on cell membrane. Toxic because the normal cell membrane will be affected

Not to exceed 200mg when applied to denuded skin o Causes neurotoxicity and nephrotoxicity

Hypersensitivity is uncommon because it is not usually used

F. NEOMYCIN Aminoglycoside Gm (-) including E. Coli, Proteus, Klebsiella &

Enterobacter MOA: inhibits CHON synthesis Available in topical formulation Rarely detectable in serum concentrations In presence of renal failure, it accumulates and results

in neurotoxicity, nephrotoxicity and ototoxicity, neuromuscular blockage

o Adverse effects of aminoglycosides in general Sensitization in eczematoid dermatitis Cross sensitivity to streptomycin, kanamycin,

paromomycin and gentamicin (other aminoglycosides)o Cross-sensitivity means that even if an individual

has not been exposed to these drugs, he may still develop allergies to other related drugs (same family and structure)

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o If the patient is allergic to one aminoglycoside, avoid administering other aminoglycosides

G. GENTAMICIN Aminoglycoside, narrow spectrum antibiotic for Gram

Negative Greater activity against pseudomonas More active against Staph & Group A Beta Hemolytic

Streptococci Used systemically, not topically Widespread topical use should be avoided

o Produces gentamicin resistant strain Serum concentration of 1-8 µg Accumulation in renal failure

o Results to Neurotoxicity, nephrotoxiciy and ototoxicity, neuromuscular blockage

Discouraged use for topical use to limit/prevent resistance since it is a potent broad-spectrum antibacterial drug

Avoid topical use as much as possible unlike in neomycin which can be used topically

TOPICAL ANTIBIOTIC IN ACNE Effectiveness of topical formulation is less than

systemic. For mild to moderate cases only. Systemic antibiotics to be used for severe cases Blast from the past: A plant called “earrings” (plant

with violet flowers) was said to be effective against acne. Not studied yet.

A. CLINDAMYCIN Very effective drug Approximately 10% absorbed. May cause rare cases

of bloody diarrhea & pseudomembranous colitis when absorbed systemically

Known commercially as (Dalacin C®) which is mixed in products such as Eskinol

Increased chance of systemic absorption and associated side effects with the use of Eskinol daily

Water based gel vehicle well-tolerated

“Not a good practice to use it left and right.”

B. ERYTHROMYCIN Used systemically; broad-spectrum antibiotic Avoid topical use as much as possible Inhibitory effect on P. Acnes Complication: Development of Resistant strains of

Stapho Correlated with the use of the topical formo If this occurs, topical form should be

discontinued and systemic therapy started Side Effects: Burning, drying, irritation Prescribed in patients allergic to penicillin. Reserved

for special cases

C. METRONIDAZOLE Topical Gel effective in acne rosacea Drug of choice (DOC) for Amoebiasis MOA: UNKNOWN but may relate to the inhibitory

effects on Demodex brevis (face mite) Oral form is carcinogenic in rats

o Main reason why we avoid giving topical use in pregnant women

Side Effect :Drying, Burning, Stinging Caution when applying near eye Not allowed for pregnant women

D. TETRACYCLINE Tetracyline HCl in a hydroalcoholic base containing N-

Decyl Methyl Sulfoxide Meclocycline sulfosalicylate in a cream base No demonstrable absorption when applied twice daily Inhibitory action on P. Acnes Side effect: Staining of teeth and bones No longer recommended today, just mentioned in the

discussion for history’s sake Used to be a popular drug for acne According to Katzung, it is no longer mentioned for

treating acne but other books say otherwise. Dr. Abello also states that it is still effective

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E. SODIUM SULFACETAMIDE Available as a 10% lotion (Klaron) & as 10% wash

(Ovace) combined with sulfur in the treatment of acne vulgaris & acne rosacea

MOA: Inhibition of P. Acnes by competitive inhibition of PABA utilization

Approximately 4% is absorbed percutaneously Contraindicated in patients sensitive to sulfonamides

ACNE PREPARATIONS Very popular nowadays

A. RETINOIC ACID Topically applied Remains in the epidermis with less than 10% systemic

absorption Action in acne is attributed to decreased cohesion

between epidermal cells and increased epidermal cell turnover

Results in expulsion of open comedones Efficacious

B. ISOTRETINOIN For severe cystic acne Recalcitrant to standard therapy MOA: inhibit sebaceous gland size & function Adverse effects: Similar to hypervitaminosis A

o Highly teratogenico Should not administer in pregnant womeno Stopped 6 months before pregnancy

C. ETRETINATE Still a Vitamin A/retinoid Treatment of psoriasis especially pustular forms Given orally 1-5mg/kg/day starting with 0.5mg Adverse effects: Similar to hypervitaminosis A

o Should not be taken by women of childbearing age

o More teratogenic than other vitamin A preparations

ANTIPRURITIC AGENTSFor itchiness, we administer anesthetics or

antihistaminicsAvoid antihistaminics locally because we expose the

individual to development of sensitization

A. DOXEPIN MOA: H1 & H2 antagonists property percutaneous

absorption Can cause drowsiness like other antihistamines Contraindications: Narrow angle glaucoma Tend to cause urinary retention because of

anticholinergic effects Drug must be discontinued 2 weeks prior to use

when patient uses Monoamine oxidase inhibitor (MAOi)o Doxepin enhances action of MAOi

B. PRAMOXINE Topical anesthetic available as 1% Cream, Lotion, Gel Applied 2-4x a day Adverse effect: transient burning and stinging

ANTIHISTAMINESA. OLDER H1 RECEPTOR ANTAGONISTS 1st generation antihistaminics Have some Anticholinergic activity Are sedating because they can cross the blood-brain

barrier. Advise patients taking antihistamines to avoid driving

or operating machineries as these drugs could cause sedation and drowsiness.

B. NEWER H1 RECEPTOR ANTAGONISTS Have lesser side-effects because they do not cross

the blood brain barrier Generally do not cause drowsiness/sedation Examples:

a.Terfenadineb.Astemizolec. Loratadine

C. H2 RECEPTOR BLOCKERS of 10

“THEY SAY THAT BEAUTY IS IN THE EYE OF THE BEHOLDER & I SAY THAT THE

MOST LIBERATING THING ABOUT IT IS REALIZING YOU ARE THE BEHOLDER. THIS

EMPOWERS YOU TO FIND BEAUTY IN PLACES WHERE OTHERS HAVE NOT

DARED TO LOOK, INCLUDING INSIDE OURSELVES.”

MYRNA L. ABELLO, M.D., ED.D.


Better used for patients with peptic ulcero Decreases gastric acid secretiono Examples

i. Cimetidine- enzyme inhibitor- Problem: inhibits cytochrome P450

which inhibits drug metabolizing enzyme causing increased effect sensitive to these enzymes

ii. Ranitidineiii. Famotidineiv. Nizatidine

AGENTS AFFECTING PIGMENTATIONA. HYDROQUINONE & MONOBENZONE

Appears to involve inhibition of the enzyme tyrosinase thus interfering with the synthesis of melanino E.g. Michael Jackson (MJ) who had irreversible

depigmentation leading to VITILIGO Do patch test prior to administration

o For local irritation/ allergic sensitizationHYDROQUINONE Causes temporary lightening Found in lightening agents

MONOBENZONE (Most likely what MJ used) Causes irreversible depigmentation TRIOXSALEN & METHOXSALEN

o Psoralens used for repigmentation of depigmented molecules of vitiligo

o Intercalate with DNA – inhibit DNA synthesiso Major Risks:

- Cataracts- Skin Cancer

B. GLUTATHIONE not among the whitening agents listed in

pharmacologic books, just included because of its increasing popularity

Principal intracellular non-protein thiol

Plays major role in maintenance of intracellular redox state

very important and useful

C. POLYPHENOLIC-GLUTATHIONE (GSH) Reduced glutathione Conjugates and their metabolites retain the

electrophilic and redox properties of the parent polyphenol

The reactivity of thioether metabolites exceed that of the parent polyphenol

Contribute to the Nephrotoxicity, Nephrocarcinogenicity& Neurotoxicity of a variety of polyphenols

Side effects:o

Allergic

reactionso Zinc deficiency after long periods of useo Skin whitening observed when taken in high

doses- Made possible as antioxidant that aids in

cell regeneration & counteracts free radicals

SUNSCREENS Topical agents useful in protecting against sunlight

A. PABA (Para-AminoBenzoic Acid) & its esters (Benzophenones, Dibenzoyl Methanes)

Absorb UV light in UV B wavelength 280 – 320 nm (range for erythema & tan)

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Take note: When drugs are applied topically, the person has more tendency

to develop hypersensitivity.

Hypersensitivity is more likely to develop with use of topical drugs.


B. SPF (Sun Protection Factor) For light skin: SPF 15 or more For dark skin: SPF 10-15

KERATOLYTIC AGENTS

A. SALICYCLIC ACID Solubilize cell-surface proteins that keep the

stratum corneum intact, resulting in desquamation of keratotic disorders

Keratolytic in concentrations of 3-6% Used in the treatment of warts Care should be practiced when used in patients

with diabetes “mantica de papel”

o Indication: warts removalo MOA: Contains salicylic acid which burns

warts

REFERENCES:

Katzung, BG, Masters, SB and AJ Trevor. 2012. Basic and Clinical Pharmacology. 12th Edition. USA:McGraw-Hill, Chapter 61, p 1061-1079.Excelsior. 2014. Dermatologic Pharmacology Handouts.Abello, ML. 2015. Dermatologic Pharmacology Lecture. September 18, 2015.

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b10ph01 - dermatologic pharmacology

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