Dermatotherapeutics - Systemic.pptx

Prof. Satyendra Kumar Singh
Department of Dermatology and Venereology
Institute of Medical Sciences,
B.H.U., Varanasi
Dermatotherapeutics -
Systemic
Digital LectureSeries

Contents
• Introduction
• Sulfones
• Antihistamines
• Systemic Steroids
• Antibacterial Agents
• JAK inhibitors and PDE inhibitors
• Antifungal Drugs
• Antiviral Drugs
• Antiparasitic Agents
• Retinoids
• Cytotoxic Agents
• Antimalarials
• Drugs Used During Pregnancy &
Lactation
• MCQs
• Photo Quiz

Introduction
• A better understanding of diseases has resulted in the evolution of
drugs that act more specifically with minimal risk to the patient
• Today dermatologists are well equipped with an array of new
therapeutic tools in his/her armamentarium for the successful
management of various dermatoses
• Drug interactions, resistance and side effects, however, pose
challenge to the treating physician
• Commonly used systemic agents in dermatological disorders will be
discussed

Sulfone : Dapsone
• Dapsone is 4,4-diaminodiphenylsulfone derivative of sulfones
• Metabolized in liver and excreted by the kidneys
• It can cross blood brain brain barrier and placenta & is detectable in breast milk
• Doses : 50 to 300 mg/day
• Mechanism of action
• Antimicrobial agent interfere with folate biosynthetic pathway by inhibiting
dihydrofolic acid via inhibiting dihydropteroate synthatase
• Antinflammatory action by inhibiting migration of neutrophil & inhibiting
neutrophil chemotaxis
• Also Inhibits release of inflammatory mediators
• Drug interaction : with rifampicin, probenecid and trimethoprim

Sulfone : Dapsone
• Dapsone resistance : In leprosy (changes in DNA sequences in fol P gene)
• Indications
− Antiinfective drug- Hansen disease, malaria, leshmaniasis, pneumocystis
− Antiinflammatory drug-
• Consistently responsive : Dermatitis herpetiformis, erythema elevatum diutinum,
linear IgA dermatosis etc
• Adjunctive combination treatment :
− Autoimmune blistering diseases: pemphigus, bullous pemphigoid, mucous
membrane pemphigoid
− Neutrophilic dermatosis: subcorneal pustular dermatosis, pyoderma
gangrenosum, Sweet syndrome
− Autoimmune diseases & others like Behcet’s disease, hidradenitis suppurativa

Dapsone : Adverse Effects
• Hematological : hemolytic anemia and methemoglobinemia
• Liver: hepatitis, cholestatic jaundice, hypoalbuminemia
• Muco-cutaneous : morbilliform exanthem, erythema multiformae,
exfoliative dermatitis, SJS/TEN, photosensitivity
• Others : Gastric irritation, nausea, anorexia, headache, fatigue,
psychosis, peripheral neuropathy, motor neuropathy
• Life- threatening side effects: Dapsone hypersensitivity syndrome,
hemolysis, methemoglobinemia, agranulocytosis, aplastic anemia,
hemophagocytic syndrome, SJS/TEN

Laboratory Monitoring with Dapsone
• Before initiation of therapy
− CBC
− Reticulocyte count
− Hepatic function test
− Renal function test
− glucose -6- phosphate
dehydrogenase( if needed)
• During therapy
− CBC weekly for first month
and twice a month for next 2
months, periodically
thereafter
− Reticulocyte count weekly for
first month and twice a month
for next 2 months;
periodically thereafter

Antihistamines
• Histamine receptors are heptahelical transmembrane molecules.
• They are wildly expressed on body and are of four types:-
− H1 receptors & H2 receptors : found on neuron, smooth muscle, epithelium,
endothelium and multiple immune cells.
− H2 receptors : also found on gastric mucosal parietal cells
− H3 receptors : located on histaminergic neuron, & responsible for histamine
production & release.
− H4 receptors : expressed in bone marrow and on pheripheral hematopoietic
cells
• Antihistamine classification:-
− First generation H1 Antihistamines
− Second generation H1 Antihistamines
− Tricyclic antihistamine
− Mast cell degranulation inhibitor

• H1 antihistamine are lipophilic and cross blood brain barrier reaches
CNS causes sedation
• Metabolized in liver and excreted in urine caution to be taken with
liver disease and likelihood of interaction with drugs
Firstgeneration antihistamines Doses
Chlorpheniramine maleate 25-50mg, 6-8 hourly
Diphenylhydramine HCl 25-50mg, 6-8 hourly
Promethazine 12.5-25mg, 6-8 hourly
Hydroxyzine HCl 12.5-25mg, 6-8 hourly
Cyproheptadine HCl 4-8mg, 8-12 hourly
First Generation Antihistamines

Second Generation Antihistamines
• Second generation antihistamines act as inverse agonist on histamine
receptors
• They have minimal sedative, anticholinergic effects and once a day
dosing
Drug dose
cetrizine 5-10mg
desloratidine 2.5-5mg
ebastine 10-20mg
fexofenadine 120-180 mg
levocetrizine 5-10 mg
loratidine 5-10 mg

Mechanism of Action
• Act by competitive inhibition of the actions of histamine by receptor
blockade thereby reducing histamine mediated pruritus.
• These drugs also prevent vasodilation, transduction and formation of
typical wheals on the vascular endothelial surface.
• Key points
− Desloratadine and mizolastine are safe in renal disease patients
− Cetrizine, fexofenadine and desloratadine are safe in hepatic patients
− Loratidine is currently approved as a safe drug to use in pregnancy &
lactation
− Chlorpheniramine and diphenhydramine are also considered safe in
pregnancy

H1 Antihistamines (H1 AH)
• Indication
− Acute urticaria
− Chronic idiopathic urticaria and
dermatographism
− Pruritus associated with histamine
release
− Mastocytosis
• Adverse effect
− CNS disturbance-sedation, blurred
vision, tremor etc.
− GI complaints- nausea, vomiting
anorexia etc
− Anticholinergic effects-dry mouth,
postural hypotention
− Cardiac arrhythmias
• Contraindication
− Narrow angle glaucoma
− Concomitant use of mono amine
oxidase inhibitor
• Risk benefit assessment
− History of cardiac arrhythmias
− First trimester of pregnancy
− Prostatic hypertrophy

Systemic Steroids
• Systemic steroids are used for their anti-inflammatory &
immunosuppressive effects in various dermatoses
• Mostly low doses are used over the shortest possible time period
• High doses of steroids are used in emergencies & in periods of stress
and trauma

Mechanism of Action
• At the Cellular Level
− Steroids passively diffuse through the cell membrane
− Bind to intra-cytoplasmic soluble protein receptors to form a
complex
− This complex enters the nucleus
− Regulates the transcription of a limited number of genes
− Decreased synthesis of pro-inflammatory molecules (ILs, cytokines,
& proteases)

Mechanism of Action
• Synthesis of lipocortin increases
• Reduces phospholipase A2 activity
• Reduces the concentration of PGs, & LTs
• Steroids reduce the no. of monocytes, lymphocytes & eosinophils and
increase the no. of neutrophils
• Modify cellular activation, proliferation & differentiation

Indications
• Long Term Systemic Steroids – Pemphigus, bullous pemphigoid, SLE,
dermatomyositis, eosinophilic fasciitis, vasculitis, neutrophilic
dermatoses & lepra reaction
• Short Term Schedule – Atopic dermatitis, acute/disseminated eczema
of varying etiology
• Also used in toxic epidermal necrolysis, erythema nodosum, erythema
multiforme, exfoliative dermatitis, lichen planus and discoid lupus
erythematosus

FDA- Approved Indications of Systemic Steroids
• Pemphigus vulgaris, pemphigus foliaceus
• Bullous pemphigoid
• Stevens Johnson Syndrome and TEN
• Systemic lupus erythematosus
• Dermatomyositis
• Erythema multiforme minor
• Severe urticaria

Equivalent Doses of Corticosteroids
Prednisolone/Prednisone 5 mg
Methylprednisolone 4 mg
Triamcinolone 4 mg
Deflazacort 6 mg
Betamethasone/Dexamethasone 0.75 mg
Hydrocortisone 20 mg

Side Effects
• Adverse effects vary & depend on the type of steroid used, the dosage
& duration and patient factors
• Low dose administration over a longer duration is more likely to
precipitate side effects than a high dose over a short period
• Immunosuppression, precipitation of infection & suppression of the
HPAaxis
• Calcium and Vitamin D supplementation is essential in
postmenopausal women & elderly patient

Side Effects
• Following lists the side effects in head-to-toe order :-
raised ICT
, psychosis, glaucoma, premature cataract, Cushingoid
features, activation of pulmonary TB, hypertension, gastritis,
perforation, pancreatitis, worsening of diabetes, osteoporosis,
premature closure of epiphysis, avascular necrosis of the femur

Antibacterial Agents
• Penicillins
− Still the drug of choice for infections caused by gram-positive cocci
− Antistaphylococcal penicillins include oxacillin, dicloxacillin,
flucloxacillin and naficillin orally for mild infections or systematically
− Acute side effects:- Life-threatening angioedema and hypersensitivity
reactions such as urticaria, morbifilliform rashes, exfoliatve
dermatitis, drug fever, serum sickness or Stevens Johnson syndrome
− Injectable form are always preferred over oral forms for their proven
efficacy

Other Penicillins
• Aminopenicillins (ampicillin, amoxicillin)
• Carboxypenicillins (Carbenicillin, Ticarcillin)
• Ureidopenicillin (Mezlocillin, Azlocillin, Piperacillin)
• ß-lactam group of Monobactams (Aztreonam) & Carbapenems
(Imipenem, Meropenem)
• ß-lactamase inhibitors – Clavulanic acid, Sulbactam, Tazobactam
• NOTE : In combination formulations these restore the antibiotic
activity of Amoxicillin (Clavulanic acid), ampicillin (Sulbactam) &
Piperacillin (Tazobactam) against a spectrum of both gram positive &
negative organisms

Other Penicillins
• Benzathine penicillin G in syphilis-
− Primary, secondary or early latent syphilis- 2.4 million units IM
single dose
− Late latent, latent with unknown duration, or tertiary syphilis
(with normal cerebrospinal fluid examination)- 2.4 million units
IM weekly for 3 weeks
• Aqueous penicillin G in syphilis-
− Neurosyphilis (including ocular)- 3-4 million unit IV every4
hours for 10-14 days

Cephalosporines
Generation Drug details with adultdosing
Firstgeneration
(Gram Positive)
Cefadroxil (0.5-1gm BD orally),
Cephalexin (0.5-1gm QID orally)
Second generation
(Gram Positive)
Cefuroxime (1.5gm 6-8 hourly, I.V.)
Cefaclor (0.5-1gm TDS,orally)
Third generation
(Nosocomial Gram negativeincluding
Enterobactericeae & Ps.aeruginosa)
Ceftriaxone (2gm, 12hourly, I.V.)
Cefpodoxime (200mg, BD orally)
Cefixime (0.4gm BD orally)
Fourth Generation
(Nosocomial Gram Negativeincluding
Enterobactericeae & Ps.Aeruginosa)
Cefipime ( 1-2gm, 8-12hourly,I.V.)
Fifth Generation
(Gram Positive, Gram Negative,lactamase
stability)
Ceftarolin (600mg, 12 hourly,i.v.)

Aminoglycoside
• Action spectrum of aminoglycosides is mainly against gram-negative
bacteria, and they act synergistically with penicillins against
staphylococci
• Should not be used alone in skin infections to avoid drug resistance
among gram-negative bacteria and Ps. aeruginosa
• Systemic : Tobramycin, Netilmicin and Amikacin
• Topical : Neomycin
• Both Topical & Systemic : Gentamicin
• Side effects include Ototoxicity & Nephrotoxicity

Tetracyclines
• Based on their half-lives these are classified as follows:-
• Short acting- Oxytetracycline and tetracycline
• Intermediate acting- Demeclocycline and methacycline
• Long acting- Doxycycline, Minocycline, Tigecycline
• Dosage Schedule
− Tetracycline – 250-500mg QID daily
− Doxycycline - 200mg loading dose, f/b 100mg /day
− Minocycline -200mg loading dose, f/b 100mg BD
− Side effects - photosensitivity & gastrointestinal disturbances
− Minocycline - Vertigo ( in females around day 2-4 of starting the drug)

Indication of Doxycycline
Disease Dose
Acne 100mg/d
Rosacea 40mg/d
Hidradenitis suppuratia 100mg/d
Bullouspemphigoid 200-300mg/d
Perioral dermatitis 50-100mg/d
Neutrophilicdermatoses 200mg/d
Sarcoidosis 200mg/d
Bacillaryangiomatosis 200mg/d
Kaposi sarcoma 200mg/d
Prurigo pigmentosa 200mg/d
Coldurticaria 200mg/d
Acquired perforatingdermatosis 100-200mg/d

Precautions
• Avoid in pregnancy, lactation and <8 yr of age, as it causes teeth
anomalies and skeletal growth depression in foetus
• Tetracyclines should not be administered with food, antacids, milk or
iron containing compound

Macrolides & Lincosamides
• Macrolides - Erythromycin, Roxithromycin, Azithromycin,
Clarithromycin
• Lincosamides - Lincomycin, Clindamycin
• Cross-resistance amongst macrolides and lincosamides is the rule
• Their main Spectrum of action is against Gram-positive cocci
• Clarithromycin is effective against MRSA, Mycobacterium leprae
• Telithromycin is a newer semisynthetic macrolide that acts against
Gram-positive bacteria

Dosage Schedule
• Erythromycin - 250-500mg, orally, 6 hourly
• Clarithromycin - 250-500mg, orally, 12 hourly
• Azithromycin - 500 mg, orally before food, 24 hourly
• Lincomycin - 500 mg, IV/orally, 8 hourly
• Clindamycin - 300-600mg, IV/orally, 8-12 hourly
• Side effects
− Erythromycin may cause gastritis
− Lincosamides may cause diarrhoea
− 10% of patients may suffer from pseudomembranous colitis

Quinolones
• Quinolones (norfloxacin, ciprofloxacin, ofloxacin, moxifloxacin,
pefloxacin, enoxacin) have a wide range of action & good tolerability
• Their use in dermatology is limited to P
.aeruginosa infections, UTI
and Leprosy
• Side effects:-
− GI disturbances are more frequent than CNS &phototoxic
adversities

Vancomycin and Lipoglycopeptides
• Vancomycin
−A glycopeptide, effective against gram positive bacteria
− Dose: 1 gm, 12 hourly,i.v.
−Side effects: Nephrotoxicity, Ototoxicity, Red man syndrome,
Phlebitis
• Lipoglycopeptides
− Dalbavancin, Oritavancin andTelavancin
−Semisynthetic derivative of vancomycin

Oxazolidinones and Daptomycin
• Oxazolidinones
− Linezolid: 600mg twice daily, Tedizolid: 200mg once daily
− Inhibit protein synthesis by binding to the 23S and 50S ribosomal subunit
− Active against gram positive organism (including anaerobes) and
nontuberculous mycobacteria such as M. chelonae and M. fortuitum
− Side effects: thrombocytopenia and leukopenia
• Daptomycin
− A lipopeptide antibiotic
− Approved for the complicated skin and soft tissue infection caused by S.
aureus (including MRSA), penicillin resistant S. pneumoniae and vancomycin
resistant enterococcus
− Dose: 4mg/kg i.v. every 24 hours for 7-14 days
− Side effect: myopathy

JAK Inhibitors
• The Janus Kinase and signal transducer and activator of transcription
(JAK-STAT) is an intracellular signaling pathway upon which many
different pro-inflammatory signaling pathways converge
• First generation JAK inhibitors
Drug Inhibits FDAapproved
indications
Dose
Tofacitinib JAK1/3>2 Rheumatoidarthritis 5mg twicedaily
Ruxolitinib JAK1/2 Myelofibrosis
Polycythemiavera
5-25mg twicedaily
Baricitinib JAK1/2 none none
Oclacitinib JAK1 Canine atopicdermatitis n/a

Indications in Dermatology:
Alopeciaareata Erythemamultiforme
Atopicdermatitis Graft-versus-hostdisease
Chronic actinicdermatitis Hypereosinophilicsyndrome
Chronic mucocutaneouscandidiasis Lupuserythematosus
Cutaneous T-celllymphoma Mastocytosis
Dermatomyositis Palmoplantar pustulosis

Side Effects:
• Infection – urinary tract infection, varicella zoster virus reactivation
• Increase in total cholesterol, LDL and HDL
• Cytopenias

Phosphodiesterase Inhibitors
• Types:
− PDE-3 inhibitors: cilostazole, dipyridamol, milrinone
− PDE-4 inhibitors: apremilast, crisaborole, roflumilast
− PDE-5 inhibitors: sildenafil, tadalafil, vardenafil and avanafil
− Non-specific PDE inhibitors: theophylline, ibudilast

FDA-approved Uses:
• Psoriasis and Psoriatic arthritis: Apremilast ( day1- 10mg OD, day2-
10mg BD, day3- 10mg morning and 20mg evening, day4- 20mg BD,
day5- 20mg morning and 30mg evening, day6- 30mg BD)
• Pulmonary arterial hypertension (PAH): Sidenafil (20mg TDS), tadalafil
(40mg/d)
• Erectile dysfunction (ED): Sildenafil (25-100mg/d), tadalafil (5-
20mg/d), vardenafil (5-20mg/d), avanafil (50-200mg/d)
• Peripheral arterial disease: Cilostazol (100mg BD), pentoxifylline
(400mg TDS)

• Sildenafil, vardenafil and tadalafil have been associated with hearing
loss
• Often the hearing loss is unilateral and may occur during the initial 24
hours
• It is temporary in one third of cases
• Blue tinted visual disturbances- temporary and reversible
• Periapism- erection lasting more than 4 hours

Antifungal Drugs
• Systemic antifungal drugs play an important role in the management
of superficial, deep and systemic fungal infections
• Fungal cell wall is made up of chitin and their cell membrane is made
up of ergosterol

Classification of Antifungals Based on
Mechanism of Action
1. Nucleic acid synthesis inhibitor- Flucytosine
2. Disruption of microtubules- Griseofulvin
3. Cell wall synthesis inhibitor- Echinocandins
4. Cell membrane
−Azoles-
• Triazoles- Itraconazole, voriconazole, fluconazole,
posaconazole
• Imidazoles- Ketoconazole
− Allylamines-Terbinafine
−Polyenes- Amphotericin-B

Indications for Systemic Antifungals
• Failure of topical therapy
• Poor compliance regarding topical application
• Extensive superficial fungal infections
• Deep mycoses/systemic fungal infection
• Recurrent attacks presence
• Involvement of hair & nails
• Presence of associated immunocompromised states

Systemic Antifungal : AZOLES
• Triazoles- Itraconazole, Fluconazole, Voriconazole, Posaconazole
• Imidazoles - Ketoconazole
• Mechanism of action: by inhibiting 14-α demethylase affecting
ergosterol synthesis in the cell membrane
• Drug interactions are more with these groups because of the
involvement of cytochrome P-450 system

Azoles Common Indications Comments
Itraconazole Candidiasis (100-200mg/day)
Pityriasis versicolor (200mg/day)
Dermatophytosis (200mg/day)
Pulse therapy in onychomycosis(400
mg/day for 1 week every month for 2 or 3 months
for finger & toenails,respectively)
Deep fungal: Eumycetoma,chromomycosis,
histoplasmosis, blastomycosis,aspergillosis
Increased riskof
hepatotoxicity,
congestive heart
failure, prolong
QT-interval and
druginteractions
Fluconazole Candidiasis (100-200mg/day)
Pityriasis versicolor (300 mg/week for 2 weeks)
Dermatophytosis (300 mg/week for 6weeks)
Cryptococcal meningitis
Coadministration
with statins
(increased
myopathy),safe
in infants

Azoles Common Indications Comments
Ketoconazole Candidiasis (200-400mg/day)
Pityriasis versicolor (400 mg single dose
or 200 mg/day for 5 days)
Dermatophytosis (200-400 mg/dayfor
4- 8 weeks)
Eumycetoma, sporotrichosisand
chromomycosis.
Hepatotoxicity,
gynecomastia,adrenal
insufficiency, strong
inhibitor ofCYP-3A4
Voriconazole Candidemia, invasiveaspergillosis,
Fluconazole resistant oralcandidiasis
For >40 kg weight- 400mg BD for first 24
hour then 200mg BDthereafter
Photophobia,
abnormalvision,
hallucination

Systemic Antifungal : ALLYLAMINES
• Terbinafine
− Mechanism of action- inhibiting squalene epoxidase, results in the
accumulation of squalene and subsequent deficiency of ergosterol
− Drug resistance in dermatophytes is attributed to single nucleotide
polymorphisms (SNPs) in squalene epoxidase (SE) gene
− Indications:-
• Tinea cruris/corporis- 7.5mg/kg once a day for 4- 6 weeks
• Onychomycosis- 6 weeks for fingernails, 12 weeks for toenails
− Side effects:-
• Headache, GI symptoms, altered taste, loss of smell
• Acute generalized exanthematous pustulosis (AGEP)

Polyenes
• Derived from Streptomyces species
• Include Amphotericin B, Nystatin and Natamycin
• Binds on to the cell membrane and cause cell leakage
• Amphotericin-B
− Oral absorption is very poor
− Indications:- Mucormycoses (Black fungus), aspergillosis,
candidiasis, cryptococcal meningitis in HIV, visceral leishmaniasis,
febrile neutropenia and deep mycosis

Amphotericin-B
• Available in four parenteral forms:
• Amphotericin B deoxycholate/Conventional (0.5-1 mg/kg/day)
• Liposomal amphotericin B (AmBisome) (3 mg/kg/day)
• Amphotericin B lipid complex (ABLC)
• Amphotericin B colloid dispersion (ABCD)
• Side effects : infusion related (fever, chills, thrombophlebitis),
Nephrotoxicity- which is countered to a certain extent by tagging
liposomes to the drug, anemia

Griseofulvin
• Derived from Penicillium griseofulvum
• Sweat potentiates the entry of the drug in the stratum corneum
• Mechanism of Action
− Inhibition of intracellular microtubules and so inhibits the
formation of mitotic spindles
− Defective fungal filaments dehydrate and curl; hence griseofulvin
was also called – curling factor
− Also known to inhibit leucocyte movement and has an anti-
inflammatory action

Griseofulvin
• Indications
− Effective only against dermatophytes and used in Tinea capitis, T
.
cruris, corporis, pedis and unguim
− Oral dose is 6-8 mg/kg/day in two divided doses for 4 – 8 weeks
• Side effects
− Nausea, gastritis, intolerable headache
− Disulfiram like reaction
− Photosensitivity, pancytopenia

Systemic Antifungals in Special Situations
• Elderly :- Terbinafine is the antifungal of choice for dermatophytosis &
onychomycosis because of clinically insignificant drug interaction and
Less hepatotoxic than azoles
• Hepatic failure :- Fluconazole may be used with caution, Voriconazole
can be used (halve the dose) in mild to moderate hepatic cirrhosis
• Renal failure :- Oral itraconazole and voriconazole – No dose adjustment,
• Terbinafine and Fluconazole are excreted primarily through kidney

Systemic Antifungals in Special Situations
• Cardiac disease :- Terbinafine
• Pregnancy :-
− Category B- Terbinafine,Amphotericin-B
− Category C- Itraconazole, Fluconazole, Ketoconazole
− Category D- Voriconazole
• Lactation :- Fluconazole is compatible with breastfeeding

Antiviral Drugs
• Early use of antivirals is advisable to reduce viraemia and fulminant
infection and to minimize nerve damage
• In herpes simplex, varicella and herpes zoster, antiviral drugs should
be used within 24, 48 and 72 hours of skin eruption respectively
HerpesZoster

Acyclovir
• Synthetic purine analogue used orally, intravenously, and topically
• It is converted by viral thymidine kinase to acyclovir triphosphate
which subsequently inhibits viral DNA polymerase
• Resistance due to alteration or deficiency of viral thymidine kinase
• Half life is 2 to 3.5 hours and excretion is almost entirely renal
• Commonly used orally to treat herpes simplex and varicella zoster
virus infection

Acyclovir
• Intravenous acyclovir is used in fulminant infections, the occurrence
of CNS complications and in immunocompromised patients
• Neonatal HSV infection:- 20 mg/kg every 8 hour, IV for 14 – 21 days
• Side effects:-
− Renal tubular crystallization with rapid IV administration
− Interstitial nephritis
− Thrombophlebitis

Dosage Schedule of Antivirals
Acyclovir Valacyclovir Famciclovir
Herpes simplex
Primary
200mg, 5 timesa
day for 7-10days
1g, twice a dayfor
7-10 days
250mg, 3 timesa
day for 7-10days
Recurrence
400mg, 3 timesa
day for 5days
500mg, twice aday
for 3 days
125mg, twice aday
for 5 days
Suppressive 400mg, twice aday 1g, once aday 250mg, twice aday
Herpes zoster
800mg, 5timesa
day for 7days
1g, 3 times a day
for 7 days
500mg, 3 timesa
day for 7days

Foscarnet
• Pyrophosphate-containing antiviral drug
• Noncompetitively inhibits viral DNA polymerases
• Does not require phosphorylation therefore active against many strains of
virus that are resistant to acyclovir, famciclovir, or ganciclovir
• Indications:-
− CMV retinitis
− Acyclovir-resistant HSV infections (40mg/kg every 8 hour for 14-21
days)
• Side effects:-
− Nephrotoxicity (typically occurs during 2nd week)
− Diarrhoea

Interferons
• Interferon α, β and γ belong to the cytokine network and are
implicated in host defense
• They have antiviral, anti-proliferative and immunomodulatory
properties
• α-interferon is frequently used in dermatology in mycosis fungoides,
viral warts, Behçet disease, Kaposi sarcoma, nonmelanoma skin
cancer
• Dosing : 1 to 3 million units I.M. 1 to 3 times/week (CTCL)
• Side effect: flu-like symptoms, fatigue and neutropenia
• Caution: cardiac disease and psychiatric illness

Antiparasitic Drugs
• Ivermectin:
• Semisynthetic anthelminthic derived from fermented products of
Streptomyces avermitilis
• Indications: strongyloidisasis and onchocerciasis, scabies and pediculosis
capitis
• Dose of 200 µg/kg is advocated on an empty stomach, half life 18 hours
• Mechanism of action
− It blocks glutamate-gated chloride ion channels, causing
neuromuscular paralysis in the parasite
• Adverse effects:
− Less common: pruritus, fever, lymphadenopathy
− Rare SJS/TEN, tachycardia, encephalopathy

Thiabendazole
• Acts by inhibition of the enzyme fumarate reductase
• Metabolized in liver excretion by urine
• Indication: cutaneous larva migrans and currens
• Dosage: 1.5g/day for 2 days
• Adverse effects : anorexia, abdominal discomfort, hepatotoxicity

Retinoids
• It include all synthetic and natural compounds that have activity
similar to vitamin-A
• Classification :-
− First generation (non-aromatic) - isotretinoin and tretinoin (all-
trans retinoic acid)
− Second generation (mono-aromatic) - etretinate and acitretin
− Third generation (poly-aromatic) – bexarotene

Retinoids : Mechanism of Action
• At the cellular level, the cytosolic retinoid binding protein ⟹
transfers it to the nucleus
• Retinoids activate the nuclear receptors and regulate gene
transcription
• They induce cellular differentiation, have anti-inflammatory and
antiproliferative action
• In skin they have an anti-keratinising effect, and in sebaceous glands,
they reduce sebum production and decrease maturation of sebocytes

Retinoids : Indications
• FDA-Approved :
− Severe acne (isotretinoin)
− Severe plaque psoriasis (acitretin)
− Cutaneous T-cell lymphoma (bexarotene)
• Off label uses: rosacea (papulopustular, granulomatous), hidradenitis
suppurativa, pityriasis rubra pilaris, Darier’s disease, ichthyosis and
keratodermas

Retinoids : Dosing and Onset of Action
Retinoid
Dermatologic
al
condition
Dose Onset ofaction
Isotretinoin Nodulocystic acne 0.5-1 mg/kg/day 3-4 weeks
Acitretin
Severeplaque
psoriasis
0.5-1 mg/kg/day 4-6 weeks
Bexarotene
Cutaneous Tcell
lymphoma
300 mg/m²/day 3-6 months

Retinoids :Dosage Schedule
• Acitretin (25-75mg/day) is the chosen retinoid for psoriasis, although
uses is limited to pustular and palmoplantar psoriasis
• Acitretin with PUVA is termed Re-PUVA
• Side effects:-
− Cheilitis (earliest and most common)
− Paronychia, pyogenic granuloma
− Hypertriglyceridemia, deranged LFT
− Diffuse idiopathic hyperostosis (DISH)

Treatment with Oral Isotretinoin
Pre Post

Methotrexate
• Dosage Schedule
− Can be taken orally, I.V., S.C. or I.M.
− Oral dose commonly used is 2.5-15 mg/week in single dose
− ‘Winstein-Frost’ schedule recommends usage in 3 divided doses, given
at an interval of 12 hours, on a weekly basis
• Side effects
− Side effects infrequent when used as per standard therapeutic
guidelines
− Hepatotoxicity, pneumonitis, diffuse interstitial fibrosis,
pancytopenia, gastritis
− MTx is a potential teratogen and abortifacient(category X)

Methotrexatetoxicity
Plaque Psoriasis

Methotrexate
• Monitoring guidelines
− Includes complete haemogram, LFT and USG scan of the liver
− Tests are best done at 0,1,2,4,8, & 12 weeks, and later regularly
every third month in long term therapy
− Baseline liver biopsy is indicated at a cumulative dose of 1.5 g of
total methotrexate usage in high-risk patients while in others at 4g
− Patients with grade I and II disease- can continue therapy
− Grade IIIA- can continue with repeat biopsy after 6 months
− Grade IIIB and IV- Discontinuation of therapy

Methotrexate
• Indications in psoriasis
− Erythrodermic psoriasis, psoriatic arthritis, pustular, extensive severe
plaque not responding to conventional treatment, lack of response to
PUVA/UVB or systemic retinoids
• Contraindications
− Pregnancy, severe renal and liver compromise, chronic alcoholism,
active infection, immunosuppresion
• Risk factors for mtx induced hepatotoxicity
− Extensive alcohol consumption, persistent abnormal LFT
, coexisting
hep B & hep C infection, diabetes, obesity, hyperlipidaemia,
hepatotoxic drugs, lack of folate supplementation

Azathioprine
• Derived from 6-mercaptopurine, and considered a safer
immunosuppressant because of infrequent toxicity
• Indications
− Used for its both immunosuppressive
and anti-inflammatory effects
− Commonest indication is pemphigus
vulgaris
− Other indications:- vasculitis, neutrophilic
dermatoses, CTD and recalcitrant
photodermatoses
Pemphigusvulgaris

Azathioprine
• Bioavailability 88%, protein binding 30%
• Elimination half-life is 5 hours
• Enzymes for the 3 metabolic pathway includes Thiopurine
methyltransferase (TPMT), Xanthine oxidase (XO) and Hypoxanthine
guanine phospho-ribosyltransferase (HGPRT)
• Drug interaction
− ACE inhibitors such as captopril may increase the risk of
leukopenia
− Sulphasalazine inhibits TPMT enzyme activity, thus causes toxicity

Azathioprine
• Absolute contraindications include pregnancy, TPMT (thiopurine
methyltransferase) levels of <5 U and the presence of fulminant
infections
• Pregnancy category D
• Dosage Schedule
− 0.5-2.5mg/kg/day, while the commonly used dosage 50-100
mg/day
• Side effects
− Pancytopenia, precipitation of infections and drug hypersensitivity
syndromes, teratogenicity, hepatic transaminase elevations
− TPMT assay prior to starting treatment is always advisable

Cyclophosphamide
• Derivative of nitrogen mustard acts by damaging the DNA molecule
through its active metabolites
• It is cell cycle nonspecific and depresses B cell functions more than T
cells
• Acrolein, an inactive metabolite, is the responsible for bladder toxicity.
Hence proper hydration and good urinary output is needed
• Indications
− Used in severe pemphigus alone or as a constituent of
Dexamethasone-Cyclophosphamide pulse therapy
− Advanced mycosis fungoides, lupus erythematosus and Wegener’s
granulomatosis

Cyclophosphamide
• Dosage Schedule
− Orally in a dose of 1-5 mg/kg/day in equal divided doses or as a
single dose of 50-200 mg/day
− Parental dose of 5-9 mg/kg/day in lupus nephropathy and serious
lupus vasculitis
− Pregnancy category D drug
• Side effects
− Haemorrhagic cystitis, bladder carcinoma, leucopenia, anagen
effluvium are common toxicities. Risk of bladder cancer is 8-10-
fold higher in these patients

Hydroxyurea
• Affects DNA synthesis & repair and gene regulation through inhibition
of ribonucleotide reductase
• Withdrawal of drug results in a rapid reversal of its effect
• Oral tab are used in a dose of 1-1.5 g/day in divided doses
• Used infrequently in recalcitrant psoriasis, erythromelalgia and Sweet
syndrome
• Side effects
− Marrow suppression, elevated transaminases, altered renal
function and poikiloderma

Cyclosporine-A
• Acts by decreasing T-cell & keratinocyte proliferation
• Also reduces levels of ILs & TNF
• Used in widespread erythrodermic or pustular psoriasis
• It’s a rapid ‘cooldown’ of the inflammatory component of a florid
psoriasis
• Also used in atopic dermatitis, recalcitrant urticaria & pyoderma
gangrenosum
• Dose : 2.5-5 mg/kg/day
• Side effects
− Renal dysfunction, hypertension, tremors & gingival hyperplasia
− Pregnancy category C drug

Mycophenolate Mofetil
• MPA was used widely in psoriasis in previous years and mycophenolate
mofetil, an esterified form with greater bioavailability is now used in
atopic dermatitis, lupus erythematosus, psoriasis, refractory P
.G. and
bullous diseases
• MMF gets cleaved to MPA after absorption. It acts by inhibiting de novo
purine synthesis
• It affects T & B- cells predominantly
• Side effects
− Include nausea, diarrohea, strangury and an increased incidence of
viral & bacterial infections

Antimalarials : Hydroxy Chloroquine (HCQ)
• Immunologic and anti-inflammatory effects: decrease in T cell release
of IL-1, IL-6, TNF and interferon gama
• Usual dose : 400 mg/day
• Photoprotective effects: high concentration in epidermis because of
their affinity for pigment
• Metabolized in liver but only 15 to 25 % of total clearance is through
kidney
• Half life is 40-50 days, excretion 20% unchanged in urine, also biliary
excretion

Antimalarials : Hydroxy Chloroquine (HCQ)
• Dermatologic indications
• Lupus erythematosus, porphria cutanea tarda, solar urticaria,
dermatomyositis, generalized granuloma annulare, polymorphous
light eruption (PMLE)
• Contraindication
• Severe blood dyscresis, hepatic dysfuntion and retinal or visual
field changes
• Pregnancy category C drug

• FDA pregnancy safety category of common topical/systemic
medications used in dermatology
Drugs Used During Pregnancy and Lactation

• Antihistamines
• Safe- diphenhydramine, chlorpheniramine, cyproheptadine and
loratidine
• Avoid- hydroxyzine, fexofenadine
• Antihistamines may suppress lactation and create infantile irritability
• Chlorpheniramine, is regarded as first-line antihistamine treatment
for pregnant patients
• Loratadine is recommended as a treatment for dermatoses of
pregnancy, such as mild pemphigoid gestationis, after the first
trimester or for polymorphic eruption of pregnancy

• Systemic corticosteroids
• Avoid in the first trimester because of a risk of multiple-organ anomalies
• Short-term therapy is best advocated in the second and third trimesters
• High-dose oral corticosteroid therapy during pregnancy is associated with
intrauterine growth retardation, low birth weight infants, and inhibition
of endogenous corticosteroid production, and orofacial clefts
• Although listed in category C, the literature indicates that topical
steroids are first-line therapy in inflammatory diseases during pregnancy

• Antibacterial Agents
• Safe : macrolides, penicillins and cephalosporins
• Avoid : quinolones, tetracycline. Silver sulphadiazine is not advised in
the third trimester because of risk of foetal haemorrhage
• Antiviral Drugs
• Systemic antivirals are safe in all trimesters
• Acyclovir is indicated as a topical treatment for herpes simplex or as
a systemic treatment for herpes zoster, genital herpes, or varicella

• Antiparasitic Drugs
• Treatment of choice indicated for pregnant patients suffering from
scabies is topical permethrin, which is category B and safe during
pregnancy
• Sodium stibogluconate is indicated as a treatment for leishmaniasis.
Studies have included pregnant patients treated with the drug, but
data are insufficient to determine its safety

• Retinoids
• Systemic retinoids are totally contraindicated during pregnancy and
lactation
• Topical retinoids, tretinoin and adapalene, both are category C and
should not be used during pregnancy

• Acitretin :
• Category X
• Risk of fetal anomalies is 25 times higher than for the general population
• May cause microtia/anotia, micrognathia, cleft palate, congenital heart defects
and aortic-arch abnormalities, thymic defects, retinal or optic-nerve
abnormalities, and central nervous system malformations
• Total elimination of acitretin and its metabolites from the body takes up to 2
months
• With alcohol consumption during treatment, acitretin is metabolized to
etretinate, which has a half life of up to 168 days, and the teratogenic effect may
hold up to 3 years
• Female patients should be advised not to drink alcohol during and at least 2
months after discontinuation of acitretin therapy and to use at least two kinds of
contraception for 3 years after discontinuation of the drug

• Isotretinoin :
• Category X
• During the first trimester, it may cause fetal loss, and later use
may cause malformations, such as microtia, stenosis of the
external ear canal, cleft palate, hydrocephalus, and cardiac
outflow tract defects
• Female patients of child-bearing age who are sexually active
should use two methods of birth control during and for 1 month
after treatment

Effect of Drug With Respect to the Trimesters
of Pregnancy & Lactation
• Before Conception (contraception Failure)
• Use of Azathioprine, Methotrexate, NSAIDs, Griseofulvin,
Itraconazole, Tetracycline and Rifampicin may result in contraceptive
failure either directly or through hepatic enzyme induction
• First Trimester
• Differentiating cells, when affected, result in defective organogenesis
and congenital anomalies
• Hence, FDA pregnancy Category X and D drugs are totally avoided;
they include Retinoids, Finasteride, Methotrexate, Thalidomide,
Colchicine, Spironolactone, Griseofulvin and Cyclophosphamide

Effect of Drug With Respect to the Trimesters
of Pregnancy & Lactation
• Second Trimester
• Metabolism of drugs may be at a slower pace in the foetus compared to the
mother
• Drug excretion into the amniotic fluid results in a prolonged contact of the foetal
skin with the drug
• Third Trimester
• Non-teratogenic conditions occur; for example, sulphonamide-induced
kernicterus, rifampicin-related foetal haemorrhage and immunosuppression ,
NSAIDs causing oligo hydroamnios
• Lactation
• Teratogenic drugs are best avoided. This include anti-neoplastics which may
induce immunosuppression or a possible carcinogenesis

MCQs
1) Methotrexate falls under the categoryof?
A. Folate antagonist metabolite
B. Folate reductase agonist
C. Folate antagonist antimetabolite
D. Folate synthetaseagonist
Q.2) Which of the following is incorrect about retinoids?
A. First generation-isotretinoin
B. Second generation-acitretin
C. Third generation-trifarotene
D. Fourth generation-etretinate

3) Fexofenadine pregnancy category is?
A. A
B. B
C. C
D. X
Q.4) The dosage of intravevous methylene blue in the treatment of dapsone-
induced methaemoglobinemia?
A. 50-60mg/kg
B. 0.1-0.2mg/kg
C. 5mg/kg
D. 1-2mg/kg
MCQs

MCQs
Q.5) Central hypothyroidism is an adverse effect of:
A. Acitretin
B. Isotretinoin
C. Oral Tretinoin
D. Bexarotene
Q.6) Which of the following doesn’t affect microtubules:
A. Gresiofulvin
B. Vemurafenib
C. Colchicine
D. Paclitaxel

MCQs
Q.7) Which of the following is not an adverse effect of
Hydroxychloroquine?
A. Cardiomyopathy
B. Hematologic toxicity
C. Retinal toxicity
D. Phototoxicity
Q.8) Which of the following is Not an Antistaphylococcal penicillin:
A. Oxacillin
B. Dicloxacillin
C. Flucloxacillin
D. Benzathine penicillin

MCQs
Q.9. Which of the following is the more commonly associated with
photosensitivity?
A. AKT
B. Sulfonamides
C. Doxycycline
D. Minocycline
Q.10. Oxsoralen plus UVA results in the following except:
A. Forms monofunctional adducts
B. Binds to purine bases
C. Can form DNA crosslink
D. Suppresses DNA synthesis

MCQs
Q.11. Which of the following is the most appropriate treatment for
intrahepatic cholestasis-
A. Methotrexate
B. Mycophenolate mofetil
C. Ursodeoxycholic acid
D. Topical steroid

A 60 yr old male,farmer by occupation, presented with facialand hand lesions
since 10 months. Identify the lesions and best treatment :
A. Psoriasis vulgaris, topicalsteroid
B. Atopic dermatitis, topicalsteroid
C. ChronicActinic Dermatitis,Azathioprine
D. Lichen planus pigmentosus, topicalsteroid
Photo Quiz

A 23 yr old male presented with eruption of grouped vesicles on an
erythematous base 20 days before. The patient now complains of pain inthe
same area.The most appropriate treatment for the pain is:
A. Oral Steroids
B. OralAcyclovir
C. Methylcobalamine withpregabalin
D. Calaminelotion
Photo Quiz

A 12-month-old male brought by mother with history of fever and ruptured
bullae and erosions with honey crust around mouth for 3 days. Identify the
condition and its treatment:
A. Herpes labialis, oralacyclovir
B. Bullous impetigo,
oralantistaphylococcal
C. Scabies, topicalpermethrin
D. Psoriasis, topicalsteroid
Photo Quiz

Q. Identify the condition and best treatment for patient:
A. Tinea corporis, oralantifungal
B. Lupus vulgaris, oralsteroid
C. Psoriatic arthritis, Oralmethotrexate
D. Psoriasis vulgaris, oralsteroids
Photo Quiz

Photo Quiz
Q.28 weeks amenorrheic lady with skin lesions on abdomen since 10
days.
Diagnosis and treatment?
A. Pemphigoid gestationis, oral steroids
B. PUPPP
, oral steroids
C. Tinea corporis, oral fluconazole
D. Psoriasis vulgaris of pregnancy, emollient

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