Dermatopharmacology Flashcards
MOA: H1 and H2 antihistamines
Inverse agonists (downregulate constitutively activated state of receptor) or antagonists at histamine receptors
T/F: Histamine levels are elevated in the skin of chronic urticaria
True
H1 antihistamines with Pregnancy category A
None
Adverse effects: 1st gen H1 antihistamines
Sedation Impaired cognitive function Anticholinergic effects (dry mouth, constipation, dysuria, and blurred vision)
T/F: 1st gen H1 antihistamines are not metabolized by cytochrome P-450 system
False
Pregnancy category B 1st gen H1 antihistamines
Diphenhydramine
Chlorpheniramine
Pregnancy category B 2nd gen H1 antihistamines
Loratadine
Cetirizine
Carboxylic acid metabolite of hydroxyzine, mainly excreted unchanged; >10% get drowsiness (most sedating of second-generation antihistamines
Cetirizine
Tricyclic antidepressant with H1 and H2 antihistamine activity; effective in urticaria and depressed patients with neurotic excoriations; available orally and topically
Doxepin
Black box warning: Doxepin
Suicidality
Three interconvertible forms of vitamin A
Retinol (alcohol)
Retinal (aldehyde)
Retinoic acid (acid)
Precursors of vitamin A
Carotenoids
Storage form of Vitamin A
Retinol (in the liver)
MOA: Retinoids
Binds cytosolic retinoid binding protein → transported to the nucleus → binds intracellular nuclear receptors
Vitamin A and related natural and synthetic compounds are known as
Retinoids
Major retinoid receptors in keratinocytes
RXR-α and RAR-γ (most abundant in skin)
Effect of photoaging on retinoid receptors
Decreased RXR-α and RAR-γ
Effects of binding to RAR/RXR
Inhibits AP1 and NF-IL6 - important in proliferation and inflammatory responses
Inhibits TLR2 - important in inflammation
Decrease tumorigenesis and induces apoptosis
Antikeratinization (downregulates K6 and K16)
Inhibits ornithine decarboxylase
Increase TH1 cytokines and Decrease TH2 cytokines (helpful in CTCL)
Earliest and most common SE of systemic retinoids
Cheilitis
Seen in 75%–90% of isotretinoin patients as a result of dryness of the nasal mucosa
Staphylococcus aureus colonization
SE of retinoid used in conjunction w/ tetracyclines
Pseudotumor cerebri
Bone toxicity in retinoids more common in acitretin
Diffuse idiopathic skeletal hyperostosis (DISH)
Most common laboratory abnormality, highest risk w/ bexarotene
Hyperlipidemia/hypertriglyceridemia
T/F: Discontinue retinoid if fasting TGs >800 mg/dL because of a pancreatitis risk
True
T/F: If LFT elevations are greater than 3× the upper limit of normal, should discontinue retinoid
True
Occurs in 80% on bexarotene
Central hypothyroidism
Decreased TSH and T4
Leukopenia (neutropenia) and agranulocytosis are most common with which retinoid
Bexarotene
Most common adverse results in pregnant patients exposed to isotretinoin
Spontaneous abortion (20%) Retinoid embryopathy (18-28%)
Specific features of Retinoid embryopathy - Craniofacial:
Microtia Cleft palate Microphthalmia Hypertelorism Dysmorphic facies Ear abnormalities
Specific features of Retinoid embryopathy - CNS
Microcephaly
Hydrocephalus
CN7 palsy
Cortical and cerebellar defects
Specific features of Retinoid embryopathy - CV
Cardiac septal defects
Tetralogy of Fallot
Transposition of great vessels
Aortic arch hypoplasia
Specific features of Retinoid embryopathy - Thymus
Thymic aplasia/ectopia
Interaction: Bexarotene + Gemfibrozil
Bexarotene is metabolized by cytochrome P450 3A4; avoid with gemfibrozil as it inhibits 3A4 → Increased plasma levels of bexarotene → severe hypertriglyceridemia
Basic structure of corticosteroids
3 hexane rings and 1 pentane ring
Exogenous Corticosteroids absorbed in
Upper jejunum
Short-acting Corticosteroids
Hydrocortisone and cortisone: ↓glucocorticoid, ↑mineralocorticoid activity
Half life: 8–12 hours
Intermediate-acting Corticosteroids
Prednisone, prednisolone, methylprednisolone, and triamcinolone: ↑glucocorticoid and ↓mineralocorticoid activity
Half life: 24–36 hours
Long-acting Corticosteroids
Dexamethasone and betamethasone: ↑↑glucocorticoid, no mineralocorticoid activity
Half life: 36–54 hours
T/F Glucocorticoid receptor (GCR) binds to CS in the cytoplasm then translocates to nucleus
True
Increased Cortisol-binding globulin
Estrogen therapy
Pregnancy
Hyperthyroidism
Decreased Cortisol-binding globulin
Hypothyroidism
Liver disease
Renal disease
Obesity
Converts steroids to active forms in the liver
11β-hydroxysteroid dehydrogenase
Major downregulator of cell-mediated immunity
IL-10
Physiologic CS therapy dose
5 to 7.5 mg/day day of Prednisone
Risk factors for HPA Axis Suppression
Abrupt cessation of CS (always taper if CS course is >4 weeks) Major stressor (surgery, trauma, or illness) Divided dosing (BID or TID) Daily dose given at any time other than the morning
T/F Alternate day dosing lowers risk of cataracts or osteoporosis
False
Two clinical presentations of exogenous adrenal insufficiency
- Steroid withdrawal syndrome (SWS): most common presentation; presents with (p/w) arthralgias, myalgias, mood changes, headache, fatigue, and anorexia/nausea/vomiting; no change in serum cortisol level, but rather ↓available intracellular CS
- Adrenal (Addisonian) crisis: extremely uncommon; life-threatening; p/w symptoms of SWS + hypotension, ↓↓↓cortisol levels
Glucocorticoid effects: CS
Hyperglycemia
Increased appetite/weight gain
Mineralocorticoid effects: CS
HTN
CHF
Weight gain
Hypokalemia
Lipid effects: CS
Hypertriglyceridemia (may result in acute pancreatitis)
Cushingoid changes
Menstrual irregularity
Lipodystrophy (moon face, buffalo hump, and central obesity)
Cutaneous effects: CS
Decrease wound healing Striae Atrophy Telangiectasias Steroid acne Purpura Infections (staphylococcal, herpes virus) Telogen effluvium Hirsutism Pustular psoriasis flare (upon drug withdrawal) Perioral dermatitis Contact dermatitis Hypopigmentation
Unique adverse effects of Intramuscular CS
Cold abscesses Subcutaneous fat atrophy Crystal deposition Menstrual irregularities Purpura
Most commonly used provocative test for adrenal function
ACTH stimulation
More accurate test for basal adrenal function (advantage); main disadvantage is patient compliance
24 hour urine free cortisol
Primary screening tool to evaluate adrenal insufficiency
AM cortisol
First generation (nonaromatic) topical retinoid 1-2% skin absorption in normal skin Improvement in 8-12 weeks Pregnancy Category C All RAR Nuclear receptors For acne and photoaging SE include irritation, erythema, peeling, pruritus, photosensitivity, and temporary worsening of acne Inactivated by UV (apply at night) Oxidized by benzoyl peroxide
Tretinoin (all-trans-RA)
First generation topical retinoid Improvement in 4-8 weeks Pregnancy Category D All RAR and RXR Nuclear receptors Used for Kaposi sarcoma SE include irritation, erythema, and pruritus
Alitretinoin
Third generation topical retinoid Improvement in 8-12 weeks Pregnancy Category C RAR-β/γ > α Nuclear receptors For acne SE include irritation, erythema, peeling, and pruritus Light stable
Adapalene
Third generation topical retinoid <5% systemic absorption in normal skin Improvement in 8-12 weeks Pregnancy Category X RAR-β/γ > α Nuclear receptors For acne and plaque psoriasis SE include irritation, erythema, peeling, and pruritus
Tazarotene
Third generation topical retinoid Improvement in 20 weeks Pregnancy Category X All RXR Nuclear receptors For CTCL SE include irritation, and erythema
Bexarotene
First generation (nonaromatic) systemic retinoid Half life of 1 hour Metabolism: Hepatic Excretion: Bile, urine Pregnancy Category X All RAR Nuclear receptors For Acute promyelocytic leukemia
Tretinoin (ATRA or all-trans-Retinoic Acid)
First generation systemic retinoid
Half life of 20 hours
Metabolism: Hepatic
Excretion: Bile, urine
Pregnancy Category X (women must have 2 negative pregnancy tests prior to initiating; requires contraception for 1 month before, during, and 1 month after cessation of therapy)
For Severe acne and other follicular disorders
Isotretinoin (13-cis-Retinoic Acid)
Isotretioin dose for acne
Usual daily dose: 0.5–1 mg/kg per day
Goal cumulative dose: 120–150 mg/kg for severe acne
Only retinoid to affect sebum production so P. acnes unable to thrive
Isotretinoin
Second generation (monoaromatic) systemic retinoid
Half life of 120 days
Metabolism: Hepatic (to acitretin)
Excretion: Bile, urine
50 times more lipophilic than acitretin → persists very long
No longer available
Etretinate
Second generation systemic retinoid
Half life of 2 days
Metabolism: Hepatic
Excretion: Bile, urine
Pregnancy Category X (requires contraception for 1 month before, during, and 3 years after cessation of therapy)
For Psoriasis (pustular, erythrodermic, severe and recalcitrant plaque)
Acitretin
Why should concurrent alcohol use avoided in Acitretin intake?
Because alcohol → acitretin conversion to etretinate → significantly prolonged effects
Dose of Acitretin
Usual dose: 25–50 mg/day
Can be combined with PUVA (Re-PUVA); acitretin is given 10-14 days prior to starting PUVA, which accelerates the response
Third generation (polyaromatic) systemic retinoid
Half life of 7–9 hours
Metabolism: Hepatic
Excretion: Hepato-biliary
Pregnancy Category X (requires contraception for 1 month before, during, and 1 month after cessation of therapy)
All RXR Nuclear receptors
For CTCL resistant to at least one systemic therapy
Bexarotene
Dose of Bexarotene
Usual starting dose is 75 mg/day up to 300 mg/day
Response to treatment takes up to 6 months
Why should Gemfibrozil be avoided with use of Bexarotene?
Worsens the hypertriglyceridemia
Phosphodiesterase-4 (PDE-4) inhibitor used for psoriasis and psoriatic arthritis
Apremilast
MC SE of Apremilast
Diarrhea and nausea which resolve on their own within 4 weeks usually
JAK 1 and 3 inhibitor FDA approved for moderate to severe rheumatoid arthritis (RA) patients who have failed MTX
Topical and oral have been tested in psoriasis; reports of oral used in alopecia areata
Tofacitinib
JAK 1 and 2 inhibitor FDA approved for treatment of intermediate- or high-risk myelofibrosis
Topical version tested in psoriasis; reports of oral used in alopecia areata
Ruxolitinib
MOA: Azathioprine
Azathioprine’s active metabolite, 6-TG (thioguanine), is produced by the hypoxanthine guanine phosphoribosyltransferase (HGPRT) pathway and shares similarities with endogenous purines → therefore, it gets incorporated into DNA and RNA → inhibits purine metabolism and cell division (particularly in fast-growing cells that do not have a salvage pathway, like lymphocytes)
Convert azathioprine into inactive metabolites
Xanthine oxidase Thiopurine methyltransferase (TPMT)
Diminishes T-cell function and antibody production by B-cells
Azathioprine
Concomitant use with Azathioprine increases risk of myelosuppression
ACE inhibitors
Sulfasalazine
Folate antagonists
Decreases activity of xanthine oxidase which may lead to myelosuppressino with use of Azathioprine
Allopurinol or Febuxostat
FDA approved indications of Azathioprine
Organ transplantation and severe RA
Monitoring: Azathioprine
Baseline pregnancy test
Tuberculin skin test
Annual complete physical examination with particular attention to possible lymphoma and squamous cell carcinoma
CBC with differential and liver function tests every 2 weeks for the first 2 months and every 2 to 3 months thereafter
Increased risk of hepatosplenic T-cell lymphoma with Azathioprine use
TNF-α inhibitor
MOA: Cyclosporine
Forms a complex with cyclophilin, which inhibits calcineurin – an intracellular enzyme – which in turn reduces the activity of NFAT-1 (transcribes various cytokines, such as IL-2)
↓IL-2 production leads to decreased numbers of CD4 and CD8 cells.
Dermatologic dose of Cyclosporine
5 mg/kg daily and can be used continuously for up to 1 year according to the FDA (2 years for worldwide consensus data)
Cyclosporine lipid nanoparticles formulation maximum dermatolyte dose = 4 mg/kg
Obese patients - ideal body weight should be used
FDA approved dermatologic indications of Cyclosporine
Psoriasis
Two most notable SEs of Cyclosporine, which are dose- and duration-dependent
Nephrotoxicity (Irreversible kidney damage is avoided if patients receive dermatologic doses (2.5–5 mg/kg daily), have dose adjusted when creatinine increases by 30% from baseline, and use cyclosporine for no longer than 1 year)
Hypertension (occurs in 27% of psoriasis patients and is thought to be secondary to renal vasoconstriction; Prescription of choice = CCBs, because they do not alter cyclosporine serum levels)
T/F: There is risk of NMSC in psoriasis patients taking Cyclosporine treated for >2 years
True
Other SE of Cyclosporine
Hypertrichosis Gingival hyperplasia Myalgia, paresthesia, tremors Malaise Hyperuricemia (can precipitate gout), hypomagnesemia, and hyperkalemia
Monitoring of Creatinine in Cyclosporine
Recheck creatinine level if ↑ by >30% from baseline → if remains elevated above 30%, ↓dose by at least 1 mg/kg for 4 weeks, then:
- If the creatinine level drops back down to <30% above baseline, can continue therapy
- If it does not drop, then discontinue therapy; if it returns to within 10% of baseline, cyclosporine can be resumed at lower dose
If at any time creatinine increases by ≥50% above baseline, discontinue therapy until level returns to baseline
Monitoring: Cyclosporine
Two baseline blood pressures at least 1 day apart and two baseline creatinine values at least 1 day apart
Baseline BUN, CBC, LFTs, fasting lipid profile, magnesium, potassium, and uric acid
Reevaluation of labs and blood pressure every 2 weeks for the first 1 to 2 months, then every 4 to 6 weeks with blood pressure checked at every visit
MOA: Methotrexate
Binds dihydrofolate reductase with greater affinity than folic acid → prevents conversion of dihydrofolate to tetrahydrofolate (a necessary cofactor of purine synthesis) → inhibition of cell division
The inhibition of dihydrofolate reductase may be bypassed by
Leucovorin (folinic acid) or Thymidine
An active, naturally occurring version of folate (vitamin B9); most commonly used medication for rescue of high-dose MTX adverse effects/overdose
Leucovorin (folinic acid)
↓MTX-induced adverse effects
↓GI adverse effects by 26% (nausea, vomiting, and abdominal pain)
↓risk of LFT abnormalities by 76%
↓risk of pancytopenia
↑ability to tolerate MTX (↓MTX discontinuation rate for any reason)
FDA approved dermatologic indications of Methotrexate
For extensive, severe, debilitating, or recalcitrant psoriasis and Sezary syndrome
Absolute contraindications to Methotrexate use
Pregnancy (category X)
Lactation
Testing indicated for high cumulative doses (≥ 1.5–4 g) of Methotrexate
Liver biopsy (gold standard)
Monitoring: Methotrexate
CBC w/ differential, LFTs, creatinine, BUN, and viral hepatitis panel at baseline, then repeat weekly for first month (excluding the viral hepatitis panel), and gradually decrease frequency to every 3 to 4 months (e.g., every 2 weeks × 2 months, every month × 2 months, every 3 months thereafter)
Causes UV and radiation recall (toxic cutaneous reactions reappear on previously irradiated skin)
Methotrexate
MOA: Mycophenolate mofetil
Binds and inhibits inosine monophosphate dehydrogenase - a key enzyme for the de novo synthesis of purines, which is essential in activated lymphocytes
Dermatologic doses of Mycophenolate mofetil
From 2 to 3 g divided in twice daily doses
Antacids and proton pump inhibitors decreases its serum levels
Mycophenolate mofetil
Requires gastric acidity for cleavage into its active state
Most common SEs of Mycophenolate mofetil
Diarrhea, abdominal pain, nausea, and vomiting
Mycophenolate mofetil is associated with a form of neutrophil dysplasia which is characterized by nuclear hypolobulation with a left shift (may predict the development of neutropenia) called
Pseudo-Pelger-Huet anomaly
MOA: Hydroxyurea
Impairs DNA synthesis through inhibition of ribonucleotide diphosphate reductase; hypomethylates DNA resulting in altered gene expression
Most common adverse effect of Hydroxyurea
Megaloblastic anemia (myelosuppression)
Can cause dermatomyositis-like eruption, lichenoid drug eruption resembling graft-versus-host disease, leg ulcers, alopecia, photosensitivity, radiation recall, and hyperpigmentation of the skin and nails
Hydroxyurea
MOA: Cyclophosphamide
An alkylating agent (exerts its effect by directly damaging DNA via cross-linking)
Metabolite of Cyclophosphamide which is cleaved intracellularly into acrolein and enhances cellular damage by depleting glutathione store
Aldophosphamide
Occurs in 5% to 41% as a result of acrolein (prevented by adequate hydration as well as mesna, which binds acrolein in the bladder and reduces irritation) associated with increased risk of transitional cell carcinoma of the bladder
Hemorrhagic cystitis
Cutaneous SE of Cyclophosphamide
Permanent pigmented band on the teeth
Anagen effluvium
Hyperpigmentation of skin and nails
MOA: Chlorambucil
Alkylating agent that directly damages DNA via cross-linking
MOA: Antimalarial agents
Inhibit ultraviolet-induced cutaneous reactions by binding to DNA and inhibiting superoxide production
Raise intracytoplasmic pH and stabilize the microsomal membrane → ↓ability of macrophages to express MHC complex antigens on cell surface
Reduce lysosomal size and impair chemotaxis
Inhibit platelet aggregation and adhesion
Steady-state concentration of antimalarial agents is attained at
3 to 4 months, which explains the long treatment duration required to achieve clinical benefit
FDA approved dermatologic indications of antimalarial agents
SLE
Malaria
RA
Contraindicated in patients who have myasthenia gravis
Chloroquine
T/F: Continued use of CQ and HCQ is contraindicated in patients who develop retinopathy
True
Mucocutaneous drug reactions of antimalarial agents
Yellow pigmentation of the skin (quinacrine)
Drug-induced LP
Morbilliform hypersensitivity eruption; may also present as erythroderma or SJS - Risk is much greater in dermatomyositis (31%) than lupus (3%)
Psoriasis exacerbation (CQ in particular)
Bluish-gray to black hyperpigmentation in 10-30% of patients treated for ≥4 months typically affecting the shins (clinically indistinguishable from type II minocycline hyperpigmentation), face, and palate
Nail hyperpigmentation
Ophthalmologic toxicity with CQ and HCQ
Corneal deposits (keratopathy) Neuromuscular eye toxicity (ciliary body dysfunction) Retinopathy (maculopathy) - Irreversible
Eye monitoring recommendations with CQ and HCQ
Baseline examination including visual field testing
Dilated examination and visual acuity testing within first year of starting therapy
Dilated examination and visual acuity testing yearly after 5 years of treatment
MOA: Dapsone
Inhibits myeloperoxidase → ↓oxidative damage to normal tissue in various neutrophilic dermatoses (affects eosinophils and monocytes to a lesser extent)
Decreases hydrogen peroxide and hydroxyl radical levels
Inhibits chemotaxis of neutrophils, although this has not been demonstrated in therapeutic doses
Dapsone undergoes significant enterohepatic recirculation, thus remaining in the circulation for how many days
30 days
FDA approved indications for Dapsone
Dermatitis herpetiformis
Leprosy
Dose-related AE and occurs in ALL individuals to some degree (related to oxidative stress from N-hydroxy metabolites of Dapsone)
Hemolytic anemia
Methemoglobinemia
Most serious idiosyncratic reaction to dapsone, usually occurs at 7 weeks (3–12 weeks) and may manifest as fever, pharyngitis, and occasionally sepsis
Agranulocytosis
Most recover quickly after cessation of dapsone; may consider giving G-CSF
Peripheral neuropathy with Dapsone is seen predominantly in
Distal motor
Decreases risk of methemoglobinemia without affecting dapsone’s plasma level
Cimetidine
Vitamin E - may also provide small amount of protection
Monitoring: Dapsone
Baseline G6PD level, CBC w/ differential, LFTs, renal function tests, and UA
Monitor CBC very closely during “high-risk window” for agranulocytosis: CBC weekly for 4 weeks, then every 2 weeks until 3 months into treatment (agranulocytosis is most common in first 12 weeks of treatment)
After 3 months, continue checking renal function, LFTs, and UA every 3 to 4 months
Methemoglobin levels - needed if there is clinical suspicion of decreased oxygen circulation or anemia
T/F: Most patients treated with dapsone for dermatitis herpetiformis rapidly respond within 24 to 36 hours
True
Fully human dimeric fusion protein (TNF-receptor linked to Fc portion of IgG) that binds both TNF-α (soluble and membrane-bound) and TNF-β
Given subcutaneously
Etanercept
Chimeric monoclonal IgG antibody binding TNF-α only (targets soluble and transmembrane TNF-receptor)
Given intravenously
Infliximab
Fully human monoclonal IgG antibody against transmembrane TNF-receptor
Given subcutaneously
Adalimumab
FDA approved indications for TNF-α inhibitors
Plaque psoriasis
Psoriatic arthritis
Fully human monoclonal IgG1 antibody directed against the common p40 subunit of IL-12 and IL-23; FDA approved for adults with psoriasis and psoriatic arthritis; some evidence for efficacy in hidradenitis suppurativa
Ustekinumab
Possible association with reversible Posterior leukoencephalopathy syndrome
Ustekinumab
Chimeric IgG monoclonal antibody targeting the B-cell surface antigen (CD20) used in pemphigus vulgaris and severe bullous pemphigoid
Rituximab
IL-1 inhibitors
Canakinumab
Anakinra
Rilonacept
Gevokizumab
Most commonly reported SE of IL-17 inhibitors
Nasopharyngitis
MOA: neutralizes IL-17A
Secukinumab
Ixekizumab
MOA: antagonizes the IL-17 receptor
Brodalumab
Monoclonal anti-IgE antibody → ↓IgE levels and ↓IgE receptors on mast cells and basophils; FDA approved for allergic asthma and chronic idiopathic urticaria
Odalimumab
MOA: Vismodegib
Targets sonic hedgehog pathway by inhibiting smoothened receptor → GLI1/2 transcription factors stay inactive → inhibition of transcription of target genes
SE of Vismodegib
Muscle spasms (MC) Alopecia Dysgeusia Fatigue Nausea, anorexia, and diarrhea
Used for metastatic and locally advanced basal cell carcinoma, as well as those unamenable to surgery/radiation; may be used in patients with nevoid basal cell carcinoma syndrome
Vismodegib
MOA: Vemurafenib and Dabrafenib
Inhibition of BRAF
BRAF: serine/threonine signal transduction kinase important to the MAPK pathway, which regulates cell division
MOA: Imatinib mesylate
Tyrosine kinase inhibitor
Binds to the kinase domain of various tyrosine kinases (e.g., Bcr-Abl, c-Kit receptor [CD117], and platelet-derived growth factor receptor [PDGFR])
Used in melanoma, myeloproliferative hypereosinophilic syndrome, and dermatofibrosarcoma protuberans
Imatinib mesylate
Most common cutaneous reaction with Imatinib mesylate
Superficial edema (periorbital edema mainly)
A nitrogen mustard alkylating agent, is used for patch/plaque MF; contact dermatitis is the most common SE, but anaphylaxis and SCC development are the most concerning
Mechlorethamine hydrochloride
MOA: 5-Fluorouracil
Antimetabolite/pyrimidine analog which binds to thymidylate synthase (normally converts deoxyuridine → thymidine), and results in ↓DNA synthesis
MOA: Imiquimod
Activator of Toll-like receptors 7 and 8 → activation of NF-κB transcription factor → Increase cytokines/chemokines (e.g., TNF α and IFN γ) → innate/acquired immune pathway stimulation → antitumor and antiviral activity
Also antiangiogenic, proapoptotic, and increased lymphatic transport of immune cells/factors → tumor destruction
Bactericidal agent made by Bacillus subtilis with activity against Neisseria and gram positives (GP)
Bacitracin
MOA: Bacitracin
Binds to C55-prenol pyrophosphatase → disruption of bacterial cell wall peptidoglycan synthesis
Antibacterial agents commonly causing allergic contact dermatitis (especially common in patients with stasis dermatitis/ulcers)
Bacitracin
Neomycin
Bactericidal agent made by Bacillus polymyxa and B. subtilis with activity against GN (e.g., Pseudomonas)
Pregnancy category B
Polymixin B
MOA: Polymixin B
↑cell membrane permeability via detergent-like phospholipid interaction
Aminoglycoside made by Streptomyces fradiae with activity against GP and GN; possibility of ototoxicity/nephrotoxicity but very rare
Pregnancy category D
Neomycin
MOA: Neomycin
Binds 30s subunit of bacterial ribosomal RNA → ↓protein synthesis
Made by Pseudomonas fluorescens with activity against MRSA (can ↓nasal carriage) and S. pyogenes but resistance has been reported; not effective against Pseudomonas (made by Pseudomonas)
Pregnancy category B
Mupirocin
MOA: Mupirocin
Binds to bacterial isoleucyl tRNA synthetase → ↓RNA/protein synthesis
Pleuromutilin made by Clitopilus scyhpoides with activity against MRSA, S. pyogenes, and anaerobes; FDA approved for impetigo to MSSA and S. pyogenes
Retapamulin
MOA: Retapamulin
Binds to L3 protein on 50s subunit of bacterial ribosome → ↓protein synthesis
Aminoglycoside made by M. purpurea with activity against GP and GN (e.g., Pseudomonas)
Gentamicin
MOA: Gentamicin
Binds to bacterial 30s ribosomal subunit →↓protein synthesis
MOA: Silver Sulfadiazine
Binds bacterial DNA → ↓DNA synthesis; also disrupts cell walls and membranes
Sulfa drug Activity against GP and GN, including MRSA and P. aeruginosa which may cross-react with sulfonamides; Used extensively for burn wounds
Pregnancy category B
Silver Sulfadiazine
SE: Silver Sulfadiazine
Hemolysis (in G6PD patients) Methemoglobinemia Renal insufficiency Argyria Leukopenia Unmasking porphyria
Quinolone-derivative with high iodine concentration with activity against GP and GN and dermatophytes/yeasts
Iodoquinol
Broad-spectrum antibacterial agent that functions via strong oxidizing properties (good vs P. acnes) – no bacterial resistance reported to date; Used for acne and has keratolytic properties
Benzoyl peroxide
Nitroimidazole that disrupts DNA synthesis with activity against protozoa and anaerobes; not active against P. acnes, staphylococcus, streptococcus, fungi, or Demodex
Pregnancy category B
Metronidazole
Dicarboxylic acid that activity against P. acnes thus used in acne and rosacea (including perioral dermatitis); also competitively inhibits tyrosinase → ↓pigmentation so used in hyperpigmentation disorders
Azelaic acid
MOA: Azelaic acid
Disrupts mitochondrial respiration, ↓DNA synthesis (especially in abnormal melanocytes), and ↓ROS production by PMNs
MOA: Sodium sulfacetamide
Inhibits bacterial dihydropteroate synthetase (prevents conversion of PABA → folic acid) → ↓nucleic acid/protein
MOA: Penicillins
β-Lactam ring binds to bacterial enzyme DD-transpeptidase → inhibits formation of peptidoglycan cross-links in the bacterial cell wall → cell wall breakdown
Peniciliins which are good for GP cocci, like MSSA
First generation:
Dicloxacillin
Oxacillin
Ampicillin + mononucleosis/allopurinol/lymphocytic leukemia
Generalized morbilliform itchy eruption starting 1 week after antibiotic initiation
Peniciliins with antipseudomonal activity
Third and Fourth generation:
Carboxypenicillins (carbenicillin)
Ureidopenicillins (piperacillin)
Treatment of choice for animal or human bites
Amoxicillin-clavulanate
Prolongs renal excretion → ↑penicillin levels (also can ↑cephalosporin levels)
Probenicid
How many % of cephalosporin-allergic patients are penicillin-allergic
2%
Structure of cephalosporins
β-lactam ring + 6-membered dihydrothiazine ring
Cephalosporins that are best for GP cocci, but not good for MRSA or penicillin-resistant S. pneumonia
First generation:
Cefadroxil
Cephalexin
Cephalosporins that have more GN activity and less GP activity; good for H. influenzae, M. catarrhalis, N. meningitides, and N. gonorrhoeae
Second generation:
Cefaclor
Cefuroxime
Cephalosporins with good GN activity, but not GP activity; some good for P. aeruginosa (i.e., ceftazidime); good for soft tissue abscesses and diabetic foot ulcers
Third generation: Cefixime Cefdinir Cefotaxime Ceftazidime Cefpodoxime Ceftriaxone
Cephalosporins with broad coverage – MSSA, nonenterococcal streptococci, and GNs (including P. aeruginosa)
Fourth generation:
Cefepime
How many of of penicillin-allergic patients have cross reactivity with cephalosporins?
5-10%
Why should cephalosporins not be given aminoglycosides?
↑risk of nephrotoxicity
MOA: Vancomycin
Tricyclic glycopeptide that inhibits bacterial cell wall synthesis
Most common cause of drug-induced Linear IgA Bullous Disease as a result of IgA antibodies to LAD285 and IgA/IgG to BP180
Vancomycin
Only works for GP organisms – most important use in dermatology is against MRSA skin and soft tissue infections
Vancomycin
MOA: Macrolides
Bind to 50s subunit of bacterial ribosome → ↓protein synthesis; also has antiinflammatory properties
Not used as commonly these days because of ↑resistance (particularly S. aureus) and GI SEs; Used for Lyme disease, erythrasma/pitted keratolysis, anthrax, erysipeloid, chancroid, and LGV; may be used for acne, rosacea, and pityriasis rosea; potent CYP3A4 inhibitor (e.g., monitor use of warfarin, mexiletine, theophylline, and statins [↑ rhabdomyolysis])
Erythromycin
Better than erythromycin for GPs; often used as second line prophylactic antibiotic in dermatology surgery for PCN/CSN-allergic patients; has some GN activity (E. coli, N. gonorrhoeae, H. ducreyi, and C. trachomatis)
Azithromycin
Erythromycin estolate in pregnancy
Hepatotoxicity (intrahepatic cholestasis) in mother
Possible association of cardiovascular malformation and pyloric stenosis if fetus exposed in utero
Better than erythromycin for GPs; CYP3A4 inhibitor (less potent than erythromycin); Has activity against some GNs, atypical mycobacteria (good activity against M. leprae), T. pallidum, B. burgdorferi, and T. gondii
Clarithromycin
MOA: Fluoroquinolones
Inhibits DNA gyrase (bacterial topoisomerase II) +/− topoisomerase IV → DNA fragmentation
DNA gyrase - target in GN
topoisomerase IV - target in GP
Target of 1st and 2nd generation Fluoroquinolones
(ciprofloxacin, ofloxacin, and nalidixic acid)
only target DNA gyrase (topoisomerase II) → only effective against GN
Target of 3rd and 4th generation Fluoroquinolones
(levofloxacin, moxifloxacin, sparfloxacin, and gatifloxacin): target both topoisomerase forms (IV > II) → ↑GP coverage and ↓bacterial resistance; slightly ↓efficacy against GN
Treatment of choice for cutaneous anthrax (B. anthrax)
Ciprofloxacin
Has good activity for GNs, like P. aeruginosa
Ciprofloxacin
Fluoroquinolone NOT associated with photosensitivity
Levofloxacin
SE: Quinolones
GI symptoms (#1) CNS SEs (headache, dizziness, seizures, psychosis, and depression) Tendinitis/tendon rupture Hypersensitivity Photosensitivity/photo-onycholysis
T/F: Quinolones are CYP1A2 inhibitors
True
Decreases absorption of Quinolones
Administration with divalent cations (calcium, magnesium, aluminum, and zinc)
MOA: Tetracyclines
binds 30s subunit of bacterial ribosome → ↓protein synthesis; antiinflammatory properties (e.g., inhibits multiple matrix metalloproteinases, neutrophil migration, and ↓innate cytokines)
Treatment of choice in LGV
Doxycycline
Treatment of choice for rickettsial and rickettsial-like infections
Doxycycline
Treatment of choice in early stage of Lyme disease
Doxycycline
Minocycline hyperpigmentation types
Type 1: Blue-gray in sites of facial scarring – stains for iron and melanin
Type 2: Blue-gray on shins and/or forearms – stains for iron and melanin
Type 3: Diffuse muddy brown on sun-exposed skin – stains melanin only; represents a low-grade phototoxic eruption with PIH
SE: Tetracyclines
GI symptoms Acute vestibular SEs Benign intracranial hypertension/pseudotumor cerebri (↑risk if given w/ isotretinoin) Photosensitivity/photo-onycholysis Vaginal candidiasis GN acne/folliculitis
SE: Minocycline
Hyperpigmentation of skin/nail beds/teeth/ mucous membranes/bone
Serum sickness-like reactions
Drug-induced Sweet’s syndrome
Autoimmune hepatitis
DRESS/DHS
Llupus-like syndrome (usually ANA+ and antihistone AB+ )
Cutaneous PAN/vasculitis (pANCA+)
Produces tooth discoloration in patients below 8 years old
Tetracyclines
Tetracyclines are excreted except for this which can be used in renal disease
Doxycycline (mainly GI)
MOA: Rifampin
binds β-subunit of bacterial DNA-dependent RNA polymerase → ↓RNA/protein synthesis
Major CYP450 inducer
Rifampin
↑drug clearance/↓efficacy (e.g., OCPs, warfarin, azoles, CCBs, statins, and cyclosporine)
Should NOT be given as monotherapy, because of rapid development of resistance
Rifampin
SE: Rifampin
Orange-red discoloration of body fluid CNS (headache and drowsiness) GI symptoms Development of rifampin-dependent antibodies (can → anaphylaxis, flu-like symptoms, renal failure, and hemolytic anemia) Hepatotoxicity (especially w/ isoniazid) DVTs Pulmonary fibrosis Ocular SEs Worsening of porphyria (induces δ-ALA synthetase), Possible hemorrhagic disease of the newborn and mother in pregnancy
MOA: Trimethoprim-sulfamethoxazole (or cotrimoxazole)
Dihydrofolate reductase inhibitor (trimethoprim) + dihydropteroate synthetase inhibitor (sulfamethoxazole) → ↓tetrahydrofolic acid → ↓bacterial nucleic acid/protein synthesis
This can:
↑dapsone levels
↑hematologic toxicity in patients taking MTX (both ↓THF)
↑renal toxicity in patients taking cyclosporine
↑K+ in patients on ACEIs/ARBs
Trimethoprim-sulfamethoxazole (or cotrimoxazole)
Accounts for 30% of SJS/TEN cases
Trimethoprim-sulfamethoxazole (or cotrimoxazole)
MOA: Clindamycin
Lincosamide that binds to 50S subunit of bacterial ribosomal RNA → ↓ribosomal translocation/protein synthesis
Helps determine whether inducible resistance is present in an erythromycin-resistant, clindamycin-sensitive organism (bacteria with erm gene)
“D zone” test
May produce an antibiotic-associated colitis
Clindamycin
MOA: Linezolid
Binds 23S portion of 50S ribosomal subunit of bacteria
SEs: Linezolid
Myelosuppression in 2%
Serotonin syndrome (if given with serotonergic drugs)
Optic/peripheral neuropathy
MOA: Quinupristin and dalfopristin
Diffuses through bacterial cell wall and binds 50s ribosomal subunit sites → ↓protein synthesis
MOA: Daptomycin
Depolarizes bacterial cell membrane → cell death
Guanosine analog that requires phosphorylation
Acyclovir
Initial phosphorylation of Acyclovir by:
Acyclovir monophosphate
Subsequent phosphorylation of Acyclovir by:
Acyclovir triphosphate
MOA: Acyclovir
After phosphorylation, competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase → incorporates into viral DNA → chain terminates and ↓viral duplication
Dermatologic indications of Acyclovir
Herpes simplex infections
Varicella zoster
Recurrent EM 2° to HSV (>6 outbreaks per year)
Prodrug of acyclovir with great bioavailability; with oral and topical forms and has the same uses as acyclovir with excellent SE profile (Rarely can cause TTP/HUS in HIV patients)
Valacyclovir
More effective at ↓VZV pain than acyclovir
Famciclovir and valacyclovir
Indication of Penciclovir (topical only)
Herpes labialise
Nucleoside phosphate analog of deoxycytidine monophosphate effective in HPV, HSV, CMV retinitis, orf, and molluscum; does not require viral thymidine kinase
Cidofovir
MOA: Cidofovir
Acts as a competitive inhibitor and alternate substrate for viral DNA polymerases → incorporates into DNA strand → blockage/termination of DNA synthesis
MOA: Foscarnet
An intravenous pyrophosphate analog that binds to pyrophosphate-binding site on viral DNA polymerase → inhibition of pyrophosphate cleavage from deoxyadenosine triphosphate → disruption of DNA elongation
Treatment of choice for acyclovir-resistant HSV
Foscarnet
SE: Foscarnet
Penile erosions Thrombophlebitis Nephrotoxicity Seizures Electrolyte disturbances
MOA: Bleomycin
Binds DNA → single strand breaks → ↓protein synthesis → ↑apoptosis/necrosis of keratinocytes
Chemotherapeutic agent that can be used intralesionally for warts
Bleomycin
SE: Bleomycin
Injection pain
Raynaud’s phenomenon
Loss of nail plate/nail dystrophy
Flagellate hyperpigmentation
MOA: Podophyllin
Antimitotic agent that binds tubulin → cell cycle arrest in metaphase
Blistering agent (comes from blister beetle/Spanish fly, Lytta vesicatoria) which is applied in office under occlusion for warts/molluscum then washed off at home 4 hours later
Cantharidin
MOA: Cantharidin
Disrupts desmosomes → intraepidermal acantholysis → bullae
Green tea (Camellia sinensis)–derived polyphenol epigallocatechin gallate → apoptosis, inhibition of telomerase, and an antioxidant effect on cells; approved for genital/perianal warts
Sinecatechins
MOA: Azoles
inhibit 14α demethylase (catalyzes conversion of lanosterol to ergosterol) → ↓ergosterol → ↓cell membrane synthesis, ↑ membrane rigidity/permeability, growth inhibition, and cell death
Metabolized mainly in liver (CYP3A4); absorption enhanced in an acidic environment; FDA approved for dermatophyte onychomycosis, oropharyngeal/esophageal candidiasis, blastomycosis, histoplasmosis, and aspergillosis refractory to amphotericin B
Itraconazole
Itraconazole dosage for Onychomycosis
200 mg/day for 12 weeks course for toenails
Contraindications: Itraconazole
Ventricular dysfunction and CHF
Active liver disease or h/o liver toxicity with other drugs
Concurrent use of certain drugs metabolized via CYP3A4 as it is a CYP3A4 inhibitor
Concurrent use with levomethadyl, dofetilide, statins, midazolam, triazolam, nisoldipine, and ergot alkaloids
FDA approved for vaginal/oropharyngeal/esophageal candidiasis and cryptococcal meningitis
Fluconazole
Contraindications: Fluconazole
Potent CYP2C9 inhibitor – Do NOT administer with pimozide, quinidine, cisapride, erythromycin, terfenadine, astemizole, voriconazole, or statins
Systemic form not commonly used today because of the associated high rate of hepatic toxicity; If used, typically <10 days; FDA approved for tinea corporis/cruris/pedis/capitis, chronic mucocutaneous candidiasis, vaginal and cutaneous candidiasis, chromoblastomycosis, blastomycosis, histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis
Ketoconazole
New generation of azoles used primarily for serious, invasive fungal infections in immunosuppressed hosts (invasive aspergillosis, Candida infections, and Fusarium infections)
Voriconazole
SE: Voriconazole
Severe phototoxicity (including pseudoporphyria, and xeroderma pigmentosum-like changes)
↑risk SCC
↑risk visual disturbances
MOA: Allylamines
Inhibit squalene epoxidase (catalyzes conversion of squalene to lanosterol) → ↓cell membrane synthesis
FDA approved for dermatophyte onychomycosis and tinea capitis (granule formulation)
Terbinafine
Terbinafine dosage for Onychomycosis
6 weeks 250 mg/day for fingernail onychomycosis
12 weeks 250 mg/day for toenail onychomycosis
Highly effective against endothrix organisms (most commonly T. tonsurans)
Terbinafine
Rare SE: Terbinafine
Taste/smell disturbance Severe skin reactions (e.g., SJS/TEN) Sisual disturbance Hepatobiliary dysfunction/hepatitis/liver failure (idiosyncratic) Hematologic abnormalities Rhabdomyolysis Depression Exacerbation of SLE Drug-induced SCLE
FDA approved for dermatophyte onychomycosis and tinea corporis/cruris/pedis/capitis; more effective in tinea capitis caused by Microsporum (e.g., M. canis) than terbinafine
Griseofulvin
MOA: Griseofulvin
Interferes with tubulin → inhibition of mitosis; binds to keratin in keratin precursor cells → resistance to fungal infections
MOA: Ciclopirox olamine
Disrupts fungal cell membrane transport of important molecules, ↓cell membrane integrity, inhibits cellular respiratory enzymes, and blocks important enzymatic cofactors
MOA: Polyenes
Binds Candida cell membrane sterols → ↑permeability → cell death
MOA: Echinocandins
Inhibit β-(1,3)-D-glucan synthase → ↓ glucan production → disrupt cell wall synthesis
MOA: Ivermectin
Binds glutamate-gated chloride ion channels of parasite nerve/muscle cells → ↑membrane permeability → hyper-polarization → death
SE of Ivermectin that occurs in patients with onchocerciasis, presents with rash/systemic symptoms/ocular reactions
Mazzotti reactions
MOA: Albendazole
Stops tubulin polymerization → immobilization and death of parasite
MOA: Thiobendazole
Inhibits fumarate reductase
FDA approved for neurocysticercosis and hydatid disease
Albendazole
FDA approved for strongyloides, cutaneous larva migrans, and visceral larva migrans
Thiobendazole
MOA: Permethrin
Disables sodium transport channels on cell membranes of arthropods → paralysis
Related to pyrethrins, which come from flowers of genus Compositae
Dosage of Permethrin for Scabies
Scabies (5% cream is the treatment of choice; neck down application – 2 overnight applications separated by 1 week
MOA: Malathion
Organophosphate that inhibits acetylcholinesterase in arthropods → neuromuscular paralysis
MOA: Lindane
Organochlorine → ↓neurotransmission → arthropod respiratory/muscular paralysis
MOA: Spinosad
Instigates arthropod motor neurons → paralysis
Topical anti parasite that may cause seizures if ingested or multiple applications
Lindane
Ultraviolet A spectrum
320–400 nm
Ultraviolet B spectrum
280–320 nm
MOA: Psoralen + UVA
Photoactivated psoralen molecules form 3,4 or 4’,5’ cyclobutane monofunctional adducts to pyrimidines in DNA → interstrand DNA cross-link → ↓DNA synthesis/cell cycle arrest
UVA-1
340–400nm
MOA: UVB
↓DNA synthesis (i.e., in psoriatic epidermis) and ↑p53 → cell cycle arrest/keratinocyte apoptosis; ↓proinflammatory cytokines, ↓Langerhans cells in skin
Narrowband UVB
311–313nm
Broadband UVB
280–320
Excimer laser
308 nm
Treatment of choice for Vitiligo
NB-UVB
Pheresis via venous catheter in arm vein → blood cells separated into leukocyte-rich buffy coat and RBCs (returned back to patient) → 8-methoxypsoralen added to leukocytes → UVA radiation → reinfusion
Extracorporeal photochemotherapy
Contraindication: ECP
Severe cardiac disease - because of difficulty in handling added fluid volume
Activated by blue light (Blu-U device); no need for occlusion
Aminolevulinic acid (ALA)
Activated by red light (Aktilite) and is more lipophilic; occlusion recommended
Methyl aminolevulinate (MAL)
MOA: Photodynamic therapy
Photosensitizers are ultimately converted to protoporphyrin IX within cells → activated to a higher energy state (along with production of reactive oxygen species, including singlet O2) primarily with light ≈ 410 nm (Soret band, blue), but also has other peaks (e.g., 635 nm, red) → localize by mitochondria → necrosis/apoptosis of malignant cells
T/F: Neoplastic cells accumulate more porphyrins than normal cells
True
Aromatic compounds that absorb radiation and convert it into longer, lower-energy wavelengths
Chemical sunscreen
Chemically inert compounds that reflect/scatter radiation
Physical sunscreen
Zinc oxide and titanium dioxide
MOA: Hydroquinone
Competes with tyrosine as substrate for tyrosinase; production of ROS → melanocyte damage
MOA: Pimecrolimus and tacrolimus
bind to FK506-binding protein forming a complex → complex binds to enzyme calcineurin → prevention of calcineurin from dephosphorylating transcription factor NFAT-1 → ↓transcription of cytokine IL-2 → ↓T-cell activation/proliferation
MOA: Pimecrolimus and tacrolimus
Bind to FK506-binding protein forming a complex → complex binds to enzyme calcineurin → prevention of calcineurin from dephosphorylating transcription factor NFAT-1 → ↓transcription of cytokine IL-2 → ↓T-cell activation/proliferation
MOA: Vitamin D analogs
Product binds to vitamin D receptors → drug-receptor complex + RXR-α binds to DNA at vitamin D response elements → ↓keratinocyte proliferation/epidermal differentiation, ↓IL-2/IL-6/IFN-γ/GM-CSF, ↓NK-cell and cytotoxic T-cell activity, ↑involucrin/transglutaminase → enhanced cornified envelope formation
MOA: Thalidomide
Inhibits TNF-α and IFN-γ, ↓IL-12 production, ↓helper T-cells, ↑suppressor T-cells, ↑IL-4/5 production, ↓PML chemotaxis, and ↓histamine/acetylcholine/prostaglandins
Anticholinergic agent used orally or topically for hyperhidrosis which blocks acetylcholine’s effects on sweat glands
Glycopyrrolate
Antichlolinergic agent which is approved for overactive bladder but can be used for hyperhidrosis
Oxybutinin
Phosphodiesterase inhibitor that: ↑erythrocyte/leukocyte deformability ↓platelet aggregation ↓TNF-α ↓neutrophil adhesion
Pentoxifylline
Used for erythema nodosum leprosum (FDA approved), HIV-related disorders, lupus erythematosus, GVHD, prurigo nodularis, and neutrophilic dermatoses (e.g., Behcet’s disease)
Thalidomide
MOA: Nicotinamide
Inhibits PARP-1 →↓NFκB transcription → ↓leukocyte chemotaxis; ↓lysosomal enzyme release; stabilizes leukocytes by inhibiting PDE → immunomodulation; ↓lymphocytic transformation/antibody production; ↓mast cell degranulation
MOA: Colchicine
Binds tubulin dimers in leukocytes → mitotic arrest in metaphase and ↓chemotaxis
Riminophenazine dye used for antibiotic (i.e., antimycobacterial, especially multibacillary leprosy and erythema nodosum leprosum) and antiinflammatory (e.g., SLE, pyoderma gangrenosum, erythema dyschromicum perstans, and discoid LE) purposes
Clofazimine
Has the SE of reversible orange-brown skin and body fluid discoloration
Clofazimine
CYP1A2 substrates
theophylline/caffeine, warfarin, and pimozide
CYP1A2 inhibitors
fluoroquinolones, macrolides (e.g., erythromycin), and ketoconazole
CYP1A2inducers
phenytoin, barbiturates, rifampin, and cigarette smoke
CYP2C9 substrates
phenytoin, sulfonamides, warfarin, fluvastatin, and losartan
CYP2C9 inhibitors
fluconazole and TMP-SMX
CYP2C9 inducers
carbamazepine and rifampin
CYP2D6 substrates
tricyclic antidepressants (e.g., doxepin and amitriptyline), metoprolol/propranolol, antidysrhythmics (e.g., encainide and propafenone), antipsychotics (e.g., clozapine and pimozide)
CYP2D6 inhibitors
SSRIs (e.g., fluoxetine and sertraline), pimozide, and terbinafine
CYP2D6 inducers
carbamazepine, phenytoin, and rifampin
CYP3A4 substrates
warfarin, carbamazepine, doxepin, sertraline, antidysrhythmics (e.g., amiodarone, digoxin, and quinidine), CCBs (e.g., diltiazem and nifedipine), chemotherapy (e.g., doxorubicin, vinblastine, and cyclophosphamide), H1 antihistamines, HMG CoA reductase inhibitors (lovastatin and simvastatin), oral contraceptives/estrogens, cyclosporine, tacrolimus, corticosteroids, dapsone, pimozide, benzodiazepines, protease inhibitors, and colchicine
CYP3A4 inhibitors
azole antifungals (e.g., ketoconazole and itraconazole), clarithromycin/erythromycin, metronidazole, protease inhibitors, SSRIs (e.g., sertraline), grapefruit juice, cimetidine, and CCBs
CYP3A4 inducers
rifampin, griseofulvin, anticonvulsants (e.g., phenytoin and carbamazepine), dexamethasone, and St. John’s wort
