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
