Pharmacology for Various Dermatological Diseases Flashcards
Basal Cell Carcinoma treatments
o First line: topical fluorouracil with imiquimod
o Metastatic: No set regimen; cisplatin recognized as best single agent
o New therapy: Vismodegib
Squamous Cell Carcinoma treatments
o First line: Surgery with radiation
o Metastatic: No set regimen; cisplatin recognized as best single agent
Malignant Melanoma treatments
- Immunotherapy: aldesleukin, interferon-a-2B, ipilimumab, nivolumab, pembrolizumab
- Signal transduction inhibition: dabrafenib, sorafenib, trametinib, vemurafenib
- Classic chemotherapy: several agents, often with short-lived responses
Actinic Keratosis treatments
- Topical fluorouracil with imiquimod
- Diclofenac – an NSAID that acts as a chemical peel and decreases inflammation
- Trichloroacetic acid – acts as a chemical peel
Imiquimod
• Used for treatment of basal cell carcinoma, actinic ketatosis, and HPV infection
• Topical
• Immunostimulant that…
o Activates TLR7/TLR8 as a ligand (stimulates TH1CD4 cells to ramp up immune response)
o Blocks adenosine receptors
o Represses Hedgehog signaling as a ligand for oncogenic glioma-associated oncogene
• Adverse effects
o Photosensitivity (patients should avoid sunlight)
o Rash at application site
o Compromise condom/diaphragm contraceptives in HPV treatment
Vismodegib
• Used in treatment of basal cell carcinoma
• Oral
• Works by blocking smoothened (SMO) downstream signaling of Hedgehog pathway
• Adverse effects
o Intraurterine fetal death – you must confirm you are not pregnant, be on effective birth control, and continue that birth control for 7 months post treatment
o Male mediated teratogenicity – it can get in sperm and fertilization will yield a severely affected baby
o Alopecia – not uncommon for cancer treatments, but not fun
Aldesleukin
• Used to treat malignant melanoma
• Exogenous IL-2 agonist – results in proliferation/differentiation of B/T-cells, monocytes, macrophages, CTLs, and NK cells)
• IV or SC infection (inpatient only)
• Adverse effects
o Can cause damage to ANY organ system
o CNS/cardiac/pulmonary toxicities are all BBW
o Capillary leak syndrome is a major concern
• Stimulation of CD122hi-NK cells and direct IL-2-CD25 endothelium cause release of pro-inflammatory cytokines and vasoactive mediatory production
• These result in increased vascular permeability, hypotension, pulmonary edema, liver cell damage, and renal failure
o Can stimulate T-reg cells that dampen robustness of immune response
• Necessary testing
o Thallium stress testing for to establish normal cardiac/pulmonary function
o PFTs to establish normal pulmonary function
o Baseline and daily on-treatment CXRs
Interferon-a 2b
• Used to treat malignant melanoma • Exogenous interferon – stimulates CD8 T-cells/NK cells to kill tumor cells (perforin, granzyme, and FAS-ligand mediated cell death) • Adverse effects o Increased risk of autoimmune disease o Increased risk of cardiac disease o Depression and suicidal ideation o Damage to blood, lungs, and liver • Necessary testing o ECG monitoring for cardiac function o Routine CBCs to manage blood o Regular CXRs for lungs o LFTs/enzyme screenings for liver
Ipilimumab
• Used to treat malignant melanoma
• CTLA4 antagonist – binds and blocks interactions by CTLA4 to promote T-cell activation
• Side effects
o Toxic epidermal necrolysis
o Endocrineopathies, diarrhea, peripheral neuropathy
o Avoid using in pregnancy
o Often CTLA4 blockers have a higher risk of serious side effects (more activation of the immune reponse, rather than difficulty turning it off)
Nivolumab
• Used to treat malignant melanoma
• PD1 antagonist – blocks PD1 so once T-cells are turned on, it won’t dampen the immune response
• Side effects
o Toxic epidermal necrolysis
o Endocrineopathies, diarrhea, peripheral neuropathy
o Avoid using in pregnancy
Pembolizumab
• Used to treat malignant melanoma
• PD1 antagonist – blocks PD1 so once T-cells are turned on, it won’t dampen the immune response
• Side effects
o Toxic epidermal necrolysis
o Endocrineopathies, diarrhea, peripheral neuropathy
o Avoid using in pregnancy
Dabrafenib
BRAF V600E/V600K/V600D and wild-type BRAF
• Used for malignant melanoma
• Oral
• Have VERY widespread adverse effects throughout the body
o Skin = new primary tumor development (BCC/SCC) and Steven-Johnson syndrome
o Eye = retinal detachment
o Avoid during pregnancy
Sorafenib
multiple intracellular/cell surface kinases
• Used for malignant melanoma
• Oral
• Have VERY widespread adverse effects throughout the body
o Skin = new primary tumor development (BCC/SCC) and Steven-Johnson syndrome
o Eye = retinal detachment
o Avoid during pregnancy
Trametinib
MEK1/MEK2
• Used for malignant melanoma
• Oral
• Have VERY widespread adverse effects throughout the body
o Skin = new primary tumor development (BCC/SCC) and Steven-Johnson syndrome
o Eye = retinal detachment
o Avoid during pregnancy
Vemurafenib
BRAF V600E
• Used for malignant melanoma
• Oral
• Have VERY widespread adverse effects throughout the body
o Skin = new primary tumor development (BCC/SCC) and Steven-Johnson syndrome
o Eye = retinal detachment
o Avoid during pregnancy
Ketoconazole (“-azole”)
• Used for local or widespread tinea and potentially for hormone-sensitive prostate cancer
• Topical for local and oral for widepsread
• At normal doses: inhibits fungal cytochrome P450, blocking 14-alpha-sterol demethylase to block ergosterol synthesis to stop formation of the fungal cell membrane (fungistatic)
• At high doses: inhibits adrenal steroid synthesis (decreased aldosterone, cortisol, testosterone)
o May be used to treat hormone-sensitive prostate cancer
• Side effects
o CYP3A4 substrate (competes with other drugs)
o Hepatotoxicity (from metabolism)
o Classic hormone-derived adverse effects
• Erectile dysfunction, gynecomastia, male breast pain (from testosterone decrease)
• Menstrual irregularity, hot flashes (aldosterone decrease)
Griseofluvin
• Used to treat widespread tinea and onychomycosis
• Oral (poor skin penetration)
• Inhibits the mitotic spindle in the nucleus (no replication for the fungus)
• Side effects
o CYP3A4 inducer
• Decreased anticoagulant effects of Coumadin/Warfarin
• Decreased contraceptive ability of oral birth control
• Decreased cyclosporine serum levels
• Increased ethanol effects
o Porphyria – enzyme disorder porphyrin metabolism caused by this drug
• Results in porphyrin accumulation
• Vomiting, muscle weakness, seizure, and skin manifestations typically occur
o Teratogen so don’t take while pregnant
o B-lactam allergy cross reactivity because its derived from Penicillium
o Photosensitivity often occurs
Terbinafine
• Used to treat tinea and onychomycosis
• Topical or oral
• Inhibit squalene epoxidase to block ergosterol synthesis and cause toxic squalene accumulation (fungicidal)
• Side effects
o Lympho/neutropenia – routine CBCs are recommended; increased risk for opportunistic infection; don’t use in immunosuppressed patients
• OK to use in pregnancy!
Naftifine
• Used for tinea and cutaneous bacterial infections
• Topical
• Mechanisms include:
o Fungicidal: Selective inhibition of squalene epoxidase to block ergosterol synthesis and cause toxic squalene accumulation
o Anti-inflammatory/vasoconstriction: inhibition of prostraglandins/leukotrienes/ histamine
o Anti-bacterial: can kill off gram+ and gram- infections locally
• Side effects
o Don’t use with “-azole” drugs, they work on the same pathway
o Avoid if patient is allergic
Cicloprirox
- Used for local tinea/onychomycoses
- Topical
- Poorly understood mechanism of action
- Some worry of hypersensitivity
Amorolfine
- Used for local tinea/onychomycoses
- Topical
- Poorly understood mechanism of action
- Some worry of hypersensitivity
Malathion
• Topical shampoo – apply, air dry without rinse, leave on for 8-12 hours, then rinse
• Organophospate insecticide – inhibits acetylcholinesterase so acetylcholine levels are increased in the louse, resulting in excessive stimulation and paralysis
• Proper use yields no side effects
• Incorrect use will yield systemic symptoms of cholinergic toxicity
o Diarrhea, cramping, wheezing, hypotension, etc.
o Can be reversed with atropine or pralidoxime
Permethrin
- Topical shampoo – wash hair, then apply for 10 minutes, then rinse
- Voltage gated Na+ channel blocker – results in paralysis
- Toxic to aquatic life and cats
- No major toxicities in humans
Ivermectin
• Two formulations
o Topical shampoo – apply to dry hair, then rinse
o Oral – can be used in several parasitic infestations
• Two mechianisms
o Chloride glutamate receptor agonist – allows for Cl- influx into the cell, causing hyperpolarization, thus paralysis
o GABA disruptor – disrupts neural transmission through inhibition of GABA receptors
• No major adverse effects
Dimethicone
- Silicone based polymer – apply to dry hair, leave for 10 minutes, then use a lice comb to remove lice. Then clean with regular shampoo
- Suffocates the lice, allowing for easy removal
- Fairly effective over a 3 week course (1 treatment per week)
- No side effects
Air Alle
• Fancy air dryer that dehydrates both lice and eggs
Aluminum Chloride
Hyperhidrosis drug
- Anti-persperant – combines with keratin to produce fibrillar contraction o the duct, thus occlusion and a halt to sweating
- Can cause skin inflammation locally if barrier is disrupted (wet, recent shave, cut, etc.)
Botulinum toxin
Hyperhidrosis drug
• Inhibits release of Acetylcholine through inhibition of intra-neuronal vesicle fusion
o Toxin is endocytosed by the neuron
o After entering the neuron cytoplasm, the toxin cleaves SNAP-25 and SNARE proteins needed for vesicle fusion to allow for neurotransmitter release
o Halts the release of neurotransmitter, resulting in muscle paralysis/inhibition of eccrine sweat gland activity
• Side effects
o Typical anticholinergic effects
o Albumin allergy (used in the formulation of the injectable agent)
o Systemic botulism CAN occur although it’s extremely rare
Glycopyrrolate/ Propantheline
Hyperhidrosis drug
- Off-label use
- Anti-muscarinic that can stop the M2, M3 stimulation of eccrine sweat glands
- Both quaternary ammonium compounds, so won’t cross BBB
Oxybutynin
Hyperhidrosis drug
- Off-label use
- Anti-muscarinic that can stop the M2, M3 stimulation of eccrine sweat glands
- Crosses BBB causing sedation
Minoxidil
- Used to promote hair growth (Trichogenic)
- Oral
- Mechanism is not known! Though to possibly promote bloodflow to hair follicles
- Initially marketed as an oral anti-hypertensive, but hair growth was noted as a side effect
Finasteride
• Used to promote hair growth (Trichogenic)
• Oral
• Blocks 5-a-reductase activity – results in decreased dihydrotestosterone levels (no effects on other hormone levels)
• Saw palmetto organic supplements work in a similar manner; should not be taken together
• Side Effects
o Sexual dysfunction/infertility/feminization because of decreased dihydrotestosterone
Eflornithine
• Used to decrease hair growth (Anti-trichogenic)
• Oral
• Inhibits ornithine decarboxylase – reduces cell division/differentiation which includes the hair follicle (6-8 weeks of use needed)
o Only to be used on facial cheeks/chin
• May help treat African sleeping sickness, but potentially not adequate alone
*Tri-Luma (Flourcinolone/Hydroquinone/Tretinoin)
• Used to decrease hyperpigmentation of the skin
• Oral multi-drug
o Flourcinolone – corticosteroid for anti-inflammation
o Hydroquinone – stops melanin formation by blocking the melanocyte from oxidizing [tyrosine → 3,4-dihydroxyphenylalanine (DOPA)]
o Tretinoin – increases keratinocyte turnover
• Side effects
o Increase sensitivity to UV radiation
Methoxsalen
• Used in many skin conditions to:
o Resolve hypopigmentation: vitiligo
o Induce cell death/turnover: psoriasis, mycosis fungoides, eczema, lichen planus
o Promote hair growth: alopecia areata
• Topical or oral
• Works through application/dosing then exposure to UVA (320-400nm)
o Thought to cause crosslinking of DNA and cell death
o Allows for replacement of non-functional cells or malignant cells with new, normal cells
Chemotherapy Induced Allopecia
- Induced via 1decreased Bcl-2 or 2increased Bax/p53
- Often psychologically devastating for cancer patients
- Will resolve from buldge stem cells which are not affected by the chemo
- Scalp cooling = not approved method to keep hair; may stop drug action at scalp micrometastases
Uncomplicated, Non-MRSA infections Treatments
- Dicoxacillin/Nafcillin/Oxacillin – B-lactamase resistant penicillins (PBP binding)
- Cephalexin/Cefazolin – cephalosporins (PBP binding)
- Clindamycin/ Vancomycin – for those with B-lactam allergies
CA-MRSA Treatments
- Can be treated with incision/drainage alone
- Trimethoprim-Sulfamethoxizole – folate synthesis antagonist
- Minocycline/Doxycycline/Clindamycin/Linezolid – ribosome inhibitors (different subunits)
Serious MRSA Treatments
- Vancomycin (IV) – typical inpatient empiric therapy
- Linezolid – effective and stops exotoxin production
- Daptomycin – may be effective (in vitro studies) but can’t be used in lung (surfactant inactivation)
Polymicrobial Infections Treatments
- MRSA drug + broad spectrum anti-biotic
- Piperacillin +tazobactam
- Imipenem-cilastin + meropenem
- Ceftraroline fosamil – new cephalosporin on the block
Pox virus family treatments
Smallpox, molluscum contagiosum
o Cidofovir
• Varicella Zoster
chickenpox, cold sores
o Acyclovir/Valacyclovir/Famciclovir
HHV-6
Roseola
o Cidofovir, Foscarnet, Ganciclovir/Vanganciclovir
HHV-7
Roseola
o Cidofovir
HHV-8
Kaposi sarcoma
o Cidofovir, Famciclovir, Ganciclovir/Vanganciclovir, Valacyclovir
Adalimumab
• Used to treat psoriasis
• SC injection
• TNF-a monoclonal antibody – binds TNF-a to stop it from interacting with p55/p75 cell surface receptors. Allows for decrease in inflammation/produce immunosuppression
• Side effects
o Increased susceptibility to opportunistic infections
• Don’t start with active infection
• Report any signs of chronic infection re-activation
• Don’t receive vaccines with this drug
o Increased chance for new malignancy development
o Cardiotoxic – worry of CHF, hypotension, angina, arrhythmia
o Lupus- like syndrome – fever, arthralgia, rashes
o Irritation at injection site – consider injection site rotation
Alefacept
• Used to treat psoriasis
• IM injection
• [LFA3-IgG1] fusion protein (human) – binds CD2 on T-cells to prevent activation, thus inflammation/produce immunosuppression. Also induces apoptosis
• Side effects
o Increased susceptibility to opportunistic infections
• Don’t start with active infection
• Report any signs of chronic infection re-activation
• Don’t receive vaccines with this drug
o Increased chance for new malignancy development
o Irritation at injection site – consider injection site rotation
Apremilast
• Used to treat psoriasis
• Oral
• Phosphodiesterase-4 (PDE4) inhibitor – increases cellular cAMP to decrease inflammation. Not well understood, but decreases inflammation/produce immunosuppression
• Side effects
o Increased susceptibility to opportunistic infections
• Don’t start with active infection
• Report any signs of chronic infection re-activation
• Don’t receive vaccines with this drug
o Increased chance for new malignancy development
Etacercept
• Used to treat psoriasis
• SC injection
• [p75 TNF receptor-FcIgG1 segment] fusion protein – false receptor that binds to/inactivates TNF but doesn’t affect production to decrease inflammation/produce immunosuppression
• Side effects
o Increased susceptibility to opportunistic infections
• Don’t start with active infection
• Report any signs of chronic infection re-activation
• Don’t receive vaccines with this drug
o Increased chance for new malignancy development
o Lupus- like syndrome – fever, arthralgia, rashes
o Irritation at injection site – consider injection site rotation
Infliximab
• Used to treat psoriasis
• IV administration
• IgG1k monoclonal antibody for TNF-a – binds soluble/trans-membrane TNF-a to inactivate it and decrease inflammation/produce immunosuppression
• Side effects
o Increased susceptibility to opportunistic infections
• Don’t start with active infection
• Report any signs of chronic infection re-activation
• Don’t receive vaccines with this drug
o Increased chance for new malignancy development
o Cardiotoxic – worry of CHF, hypotension, angina, arrhythmia
• Contraindicated with history of heart failure
o Lupus- like syndrome – fever, arthralgia, rashes
o Hepatotoxic – regular LFTs are recommended
Uztekinamab
• Used to treat psoriasis
• IV administration
• IgG1k monocloncal antibody for IL – binds p40 subunits of IL12/IL23 to decrease inflammation/produce immunosuppression
• Side effects
o Increased susceptibility to opportunistic infections
• Don’t start with active infection
• Report any signs of chronic infection re-activation
• Don’t receive vaccines with this drug
o Increased chance for new malignancy development
Calcipotriene
• Used to treat psoriasis
• Topical
• Vit. D receptor agonist – after binding the drug-VitD complex associated with RXR-a to influence DNA expression via Vitamin D response elements
• Side effects
o Irritation at the application site – often reduced through formulation with corticosteroids
o Photosensitivity at application site
o Hypercalcemia/hypercalciuria with large doses
• With maximum dose over more than 4 weeks, this occurs due to Vit D influecnce
Calcitriol
- Used to treat psoriasis
- Topical
- Hormonally active Vit.D3 – works to promote DNA expression via Vitamin D response elements
- Typically better tolerated so recommended for use on sensitive skin areas
5 other RAR drugs that weren’t really discussed
- Acitretin
- Tazarotene
- Adapalene
- Isotretinoin
- Tretinoin
Hydrocortisone
• Used to treat ance
• Topical
• Mild corticosteroid – best used on face/sensitive areas
• Side effects
o Cushingoid syndrome if applied in large quantities/used extensively
Betamethsone valerate
• Used to treat ance
• Topical
• Moderate corticosteroid – fluorinated for increased efficacy
• Side effects
o Cushingoid syndrome if applied in large quantities/used extensively
o Rosacea-like rash – should never be used on the face due to fluorination
Fluocinonide
• Used to treat ance
• Topical
• Potent corticosteroid – fluorinated for increased efficacy
• Side effects
o Cushingoid syndrome if applied in large quantities/used extensively
o Rosacea-like rash – should never be used on the face due to fluorination
Clobetasol proprionate
• Used to treat ance
• Topical or Intralesional Injection
• Very potent corticosteroid – best used on areas of thick skin (hyperkeratotic, lichenfield dermatoses, palms, sole of feet)
• Side effects
o Cushingoid syndrome if applied in large quantities/used extensively
Benzoyl Peroxide
• Used to treat acne and decubitus ulcers
• Topical
• Pro-drug that is converted to benzoid acid which:
o Liberates free radicals to kill P. acnes
o Keratolytic to produce drying/desquamative actions
• Often will be formulated with antimicrobials
• Side effects
o Drying, peeling, and irritation of skin at application site
o Bleaching hair/colored fabrics (strong oxidant)
o Damage to eyes and mucous membranes if contact
Salicyclic acid
• Used to treat acne/hyperkeratotic disorders
• Topical
• Causes desquamation of the horny layer of skin
• Side effects
o Prolonged/application over large areas can cause salicylism
o Neonatal toxicity via breast milk or contact if applicated to the mother’s chest
Treatment for Tuberculoid Leprosy
o Tuberculoid: Dapsone + Rifampicin (12 months)
Treatment for Lepromatous Leprosy
o Lepromatous: Dapsone + Rifampin + Clofazimine (24 months)
Dapsone
• Used to treat all forms of leprosy (Hansen’s disease)
• Mechanisms
o Inhibits dihydropteroate synthetase conversion of [PABA → dihydropteroatic acid], ultimately inhibiting formation of tetrahydrofolate production in the mycobacterium (stops thymidine synthesis, halting nucleic acid synthesis)
o Inhibits neutrophil chemotaxis by an unknown mechanism
• Side effects
o Metabolized into Hydroxylamine
• Causes hemolysis
• Causes methemoglobinemia (oxidation of iron in heme, resulting in impaired oxygen binding/transport) often resulting in blue nailbeds and blue lips
o Contraindicated in patients with G6PD deficiency
o Can cause sulfone syndrome
• Dermatitis often of the forehead
• Lymphadenopathy of the cervical lymph nodes
• Liver enzyme abnormalities are seen in used long-term
o Steven-johnson syndrome may occur
o Impaired renal function can cause toxic accumulation of the drug
Rifampin
• Mechanism
o Inhibits RNA synthesis by binding B-subunit of RNA polymerase; halting protein synthesis
• Low affinity for mammalian polymerase
• Bactericidal for intra/extracellular TB or leprosy
• Resistance
o Alteration of B-subunit of RNA polymerase (quite common, never use this drug alone)
• Pharmacology
o Absorption is good orally
• Food/para-aminosalicyclic acid can decrease absorbtion
o Distribution into all tissues and fluids
• Penetrates CSF
• Largely protein bound
o Metabolized in the liver via deactylation
• Liver dysfunction will change metabolic dynamics of the drug
• Increased deacetylation will be noted in the first two weeks of treatment
o Excreted in bile in the GI tract; will be reabsorbed via enterohepatic circulation if unchanged
• Adverse Effects
o Hepatotoxicity – jaundice will occur in people with liver disease/alcoholics/elderly/slow acetylators
o Body fluid discoloration is not really bad, but kinda weird
• Patients are advised to wear glasses because tears will stain contacts
• Drug interactions
o CYP inducer, worry of drug-drug interactions
Clofazimine
• Used to treat leprosy (Hansen’s Disease)
• Mechanism
o Binds guanine/cytosine of mycobacterial DNA (these bases happen to appear more frequently in the bacterium than human host cells)
• Adverse effects
o Immune mediated inflammatory reactions, often of skin and peripheral nerves
o Staining of body
• Tanning/bronzing of the skin
• Sweat, tears, urine, poop, and breast milk stained brown-black (can be misinterpreted as GI bleeding!)
• May cause depressions/suicide
o Allergy may warrant use of several anti-microbials in combination therapy
Thalidomide
• Mechanism
o Inhibits NfKB up-regulation of TNF-a production
o Blocks leukocyte migration involved in disease process
• Adverse effects
o Major teratogen causing phochomelia (severe birth defect with muted limb growth)
o May increase HIV viral load due to leukocyte effect
Clarithromycin
- alternative treatment for leprosy used in place for clofazimine
- look in annotated FA for info!
Minocycline
- alternative treatment for leprosy used in place for clofazimine
- look in annotated FA for info!
Ofloxacin
- alternative treatment for leprosy used in place for clofazimine
- look in annotated FA for info!
Monitoring/other facts for skin anti-virals
- All given orally; viral infections come from within, so no topicals dammit!
- They all block viral DNA polymerase
- Creatinine monitoring (for kidney function) is vital; these drugs are renally eliminated
Anti-virals and phosphorylation
- Remember! Many of these drugs need phosphorylation in order to be activated!
- Cidofovir and foscarnet both do not require this step
- Viruses can stop encoding for the kinases needed to activate anti-virals, so these two drugs are of select advantage when you’re facing a resistant virus
Anti-virals and cross-hypersensitivity
- While we have a handful of drugs, an adverse reaction can result in removing several anti-virals from consideration for treatment.
- As listed we have 5 for viral skin infections that can cross react all ending in “-clovir”
Toxicities for anti-virals (5)
- Acyclovir/Valacyclovir → seizure induction
- Cidofovir → nephrotoxicity; use with probenecid to prevent this
- Famciclovir → NO ISSUES (“good for the whole family”)
- Foscarnet → electrolyte imbalances; chelates Ca2+
- Ganciclovir/Valganciclovir → anemia, leukopenia, neutropenia, thrombocytopenia, teratogen!
