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MSK, Rheum, Derm > Friday Sweatman > Flashcards

Friday Sweatman Flashcards

1
Q

What are 2 factors that may have escalated the lice epidemic in recent years?

A
  • Rising tide of resistance to commonly used meds
  • SELFIES
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2
Q

What is the agent in lice infestation?

A
  • Wingless, 6-legged 2-4cm blood-sucking insects that live on human scalp
  • Infested children usually carry <20 mature lice
  • Feed on blood every 3-6 hours
  • Lay 5-6 eggs/day for 30d in a nit (shell) glued to base of hair
  • Can survive for up to 55 hrs off the human host
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3
Q

What are the symptoms of a lice infestation?

A
  • Infestations may be asymptomatic
    1. Itching arises from antigenic components in saliva injected during feeding
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4
Q

What is unique about lice treatment admin?

A
  • In order to achieve complete eradication, 2 or 3 courses of drug tx are usually necessary, spaced 1 week apart
  • Successful eradication requires both adult and egg stage -> topical application at intervals to kill recently emerged lice
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5
Q

What are the 2 tx categories for lice? Name some examples.

A
  • CHEMICAL: paralyze louse and cause fatal dehydration
    1. Malathion
    2. Permethrin
    3. Ivermectin
  • PHYSICAL: mechanically suffocate louse
    1. Benzoyl alcohol
    2. Cetaphil liquid cleanser
    3. Dimethicone
    4. Nit combing
    5. Bug busting
    6. Head shaving
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6
Q

Malathion

A
  • TOPICAL: apply enough to wet hair and scalp; air dry; allow to remain on scalp for 8-12 hrs, then shampoo thoroughly
  • AchE inhibition by metabolite
  • Hyperstimulation and paralysis of lice
  • NOT associated w/significant host toxicity
    1. Accidental oral/pulm exposure produces typical cholinergic toxicity -> diarrhea, cramping, rhinorrhea, chest tightening, wheezing, bradycardia, hypotension, confusion, convulsions
    2. Treatment w/atropine/2-PAM (pralidoxime)
  • Used widely in agriculture (pest control)
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7
Q

Permethrin

A
  • TOPICAL: apply to freshly washed damp hair; completely saturate hair and scalp; leave for 10 min, then rinse in water
  • Binds and INH louse voltage-gated Na channels -> paralysis
    1. No effect on host sodium channels
  • Minimal absorption: any absorbed drug rapidly inactivated by ester hydrolysis (keep away from eyes)
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8
Q

Ivermectin

A
  • TOPICAL: to dry hair, coating hair and scalp thoroughly; rinse w/water after 10 minutes
    1. No AEs when administered this way
  • Binds glutamate receptors gating chloride -> hyperpolarization of cell, leading to paralysis/death
    1. Also believed to act as GABA agonist, disrupting GABA-mediated CNS transmission
  • Orally: to treat infection w/Onchocerca volvulus, non-adult stage
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9
Q

What are some of the general concerns about the chemical lice drugs?

A
  • Exposures to neurotoxic pesticides have been linked to lowered IQ, diminished attention span, other neurodevo issues and childhood cancers
  • Insecticide resistance has also been found in head lice, particularly to Permethrin and Malathion
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10
Q

What are some of the mechs of resistance to insecticides?

A
  • Typical mechs common to o/drug classes
  • DEC concentration at target
  • INC rate of inactivation/removal
  • Pt mutations in target
  • Changes in CYP activity
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11
Q

Dimethicone

A
  • MECHANICAL method of elimination
  • Silicone-based polymer that works mechanically to lubricate hair to aid in removal of nits and lice, while physically occluding resp system of the louse
  • INH water excretion, causing prolonged immobilization or, in some cases, disruption internal organ failure
  • Applied to dry hair and left for 10 min, then shampood with warm water -> reduced counts of both lice and eggs
    1. Safe and highly effective: potentially less toxic and less resistance prone than pesticide-containing products
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12
Q

Air alle

A
  • Glorified hair dryer where application of heat causes dehydration and consequent death of both adult and egg infestation
  • One-hr treatment w/device moved gradually around scalp to ensure complete coverage
  • Far from completely effective: alternative txs still needed for lice
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13
Q

How is sweating controlled by ANS?

A
  • 3x106 eccrine sweat glands: soles of feet > forehead > palms > cheeks
    1. Secrete clear, odorless fluid for thermal regulation
  • 1x106 apocrine sweat glands: axilla (1:1 w/eccrine) and urogenital region
    1. Secrete thick, odorless fluid degraded by bacteria to produce odiferous products
  • Post-ganglionic SYM innervation
    1. Eccrine: Ach
    2. Apocrine: Catecholamines
  • Hypothalamic center regulates body temp via bloodflow to skin and eccrine sweat output
    1. Emo and physical activity modulate center via limbic system
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14
Q

How is the skin innervated?

A
  • Alpha-1, Alpha-2: constriction
  • Muscarinic 2, 3: no direct innervation of blood vessels -> nitric oxide-derived dilation in response to exogenous agents
  • Both sweat and bloodflow are controlled by the ANS to regulate body temperature
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15
Q

What is the classical pattern of symptoms found in a pt w/amplified cholinergic tone?

A
  • D: diarrhea
  • U: urination
  • M: myosis/muscle weakness
  • B: bronchoconstriction
  • B: bradycardia
  • E: emesis (vomiting)
  • L: lacrimation
  • S: salivation/sweating
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16
Q

What are the effects of the muscarinic antagonists?

A
  • Constipation
  • Urinary retention
  • Mydriasis/blurred vision
  • Large bronchiole dilation
  • Tachycardia
  • Antiemesis
  • DEC glandular secretions; hypo(an)hidrosis
  • Restlessness, confusion, delirium, hallucinations
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17
Q

How do cholinergic agonists increase secretions at a molecular level?

A
  • Ach binding INC IC Ca2+, activating K+, Cl- channels -> cell shrinkage via K+, Cl-, H2O efflux
  • Shrinkage activates basolateral Na+/K+/2Cl antiporter, leading to Na+, K+ and Cl- influx
    1. Na+, K+ fluxes recycled across basolateral mem, but Cl- flows unopposed into lumen, causing electrical gradient that drives Na+ out of the tissue and into the lumen paracellularly
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18
Q

What is the current tx approach recommended for hyperhidrosis?

A
  • > Topical antiperspirant therapy
  • > Botulinum toxin
  • > Anti-cholinergics
  • > Sympathectomy
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19
Q

Aluminum chloride

A
  • Short-term occlusion of eccrine and apocrine sweat gland ducts
    1. Combines w/keratin to produce fibrillar contraction of duct
  • Minimal systemic absorption; renal elimination
  • Avoid application to skin abrasion, inflamed, broken, wet, or recently shaved skin
    1. Infrequently may cause excessive irritation
20
Q

How does botulinum toxin work at the cholinergic nerve terminal?

A
  • Ach stored in vesicles -> elevated Ca2+ via voltage-dependent channels promotes fusion w/cell mem and exocytosis of Ach
  • Fusion process: VAMPs and SNAPs (SNAREs + syntaxin and synaptobrevin) interact -> exocytic release blocked by botulinum toxin cleaving SNAREs
21
Q

What is the mechanism of botulinum toxin?

A
  • Purified protein complex from Clostridium botulinum
  • Binding: heavy chain portion binds cell mem via unidentified high-affinity acceptor molecule
  • Internalizing: endocytosis
  • Blocking: light chain (active form of the toxin) cleaves protein (SNAP25) that enables fusion of Ach vesicles w/cell mem
    1. Also blocks release of “pain” neuropeptides: substance P, glutamate and calcitonin gene-related peptide (CGRP)
  • Sprouting: new nerve endings sprout and reconnect muscle, renewing neuro-effector coupling
22
Q

How is botulinum toxin applied? Risks? AEs?

A
  • Applied locally by injection
  • Capable of causing muscular paralysis
    1. Blocks BOTH muscarinic & nicotinic receptors
    2. Used for cosmetic smoothing of wrinkles
    3. Recently approved Rx for migraine headache
  • Systemic botulism is a rare, but reported event
    1. Respiratory arrest and death
    2. Otherwise, typical anti-cholinergic effects
  • Products contain albumin -> allergy issue
23
Q

What other drugs are used for hyperhidrosis?

A
  • Systemic anti-muscarinics: off-label -> passage across BBB could be problematic and limit dosage (e.g., atropine)
    1. Quaternary ammonium compounds don’t have this problem: Glycopyrrolate, Propantheline (nicotinic/muscarinic blocker)
    2. Oxybutynine: tertiary amine (passes BBB)
  • Propanolol/Clonidine DEC SYM CNS stimulation; emotional stability improved (reducing sweating)
  • Diltiazem blocks Ca2+ channels involved in secretion process -> part of the initial activation of the sweat gland secretory system
24
Q

Minoxidil

A
  • Topical agent: potent oral vasodilator (anti-HTN) is same drug
  • Unknown mech for hair re-growth -> may activate follicle directly or stimulate follicular microcirculation
    1. May also alter local androgen metabolism
  • Percutaneous absorption poor, so systemic effects unlikely, but theoretical if drug overused
    1. Skin abrasion, irritations, excoriations, psoriasis, or sunburn can cause systemic absorption
  • Drug tx must continue for effects to be maintained
25
Q

Finasteride

A
  • Oral: for hair loss or BPH
  • Testosterone analog: blocks 5-alpha reductase activity
  • DEC scalp and serum dihydrotestosterone (DHT) concentrations
    1. No effect on cortisol, estradiol, prolactin, TSH, thyroxine, cholesterol, or PTH-axis
    2. Loss of libido, sexual dysfunc, infertility, FEMINIZATION
  • Saw palmetto (serenoa repens; for BPH) has similar MOA, so exaggerated effects possible if pts use supplement (concurrent use NOT recommended)
26
Q

Eflornithine

A
  • Topical drug to reduce unwanted F facial hair
  • Mech related to DEC ornithine decarboxylase (mandatory step in polyamine production)
    1. DEC cell division and differentiation
    2. Trypanostatic action; used against sleeping sickness (not universally effective; NOT T. rhodesiense)
  • Limited percutaneous absorption; 6-8 wks to become noticeable
  • Not a depilatory agent -> continue hair removal techniques as needed
  • Facial and chin areas ONLY-> do NOT apply around eyes or to mucous membranes
  • Skin AEs occur rarely: most mild, and resolve w/o med tx or discontinuation
27
Q

Fluocinolone, Hydroquinone, Tretinoin

A
  • Temporary relief of facial skin darkening by hormonal changes, pregnancy, oral contraceptives, or hormone replacement therapy
  • Fluocinolone: anti-inflam corticosteroid
  • Hydroquinone: INH melanin formation, blocking melanocyte enzymatic oxidation of tyrosine to 3,4,-dihydroxyphenylalanine (DOPA)
  • Tretinoin: modulates skin growth and pigmentation
    1. INC keratinocyte shedding from retinoid-treated epidermis -> DEC epidermal melanin content
  • INC sensitivity to UV (PROTECTION NECESSARY)
28
Q

Mehtoxsalen

A
  • Oral/topical pigmenting agent: activated by exposure to UVA (320-400nm) -> peak photosens in 1-2 hrs, and can persist for days
  • Conjugation, cross-linking of DNA -> cell death
  • Delayed erythema, followed over several wks by INC epidermal melanization and thickening of stratum corneum
  • Vitiligo: melanocytes in hair follicle stimulated to move up the follicle and repopulate the epidermis
  • Symptomatic relief of psoriasis, tx of cutaneous T-cell lymphoma (mycosis fungoides): DNA photo damage and DEC cell proliferation
  • Alopecia areata, inflam dermatoses, eczema, lichen planus
  • Extent of topical absorption unknown
29
Q

Chemo-induced alopecia

A
  • Bulge is origin of future matrix cells, hair follicles -> usually NOT affected by chemo
  • Apoptotic cell death: DEC BCL-2, INC Bax & p53
  • Alopecia severity drug, dose, intensity, and route-dependent
  • Near complete hair loss well established: 2-3 mos
  • Psychological consequences for pt
30
Q

Scalp cooling

A
  • Banned by FDA in 1990: lack of firm evidence of benefit (about 50% efficacy in recent review)
  • Concerns:
    1. Viability of scalp micormetastases experiencing sub-lethal drug exposure
    2. How long should it take place? Pts w/diminished renal/hepatic clearance may still have significant serum drug levels when cooling process terminated
31
Q

What are some drugs that cause severe alopecia? Mild?

A
  • Severe: Anthracyclines (Doxorubicin), Taxanes, Cyclophosphamide, Etoposide, Vincas
  • Mild: Bleomycin, 5-FU, Hydroxyurea
  • Absolute incidence dependent on a # of factors
32
Q

What are the advantages/disadvantages of the various types of topical application?

A
  • Minimal systemic exposure
  • Cream (oil-in-water emulsions): generally less greasy, but LESS EFFECTIVE than ointments
    1. Lotion (diluted creams)
  • Gel (dilute crosslinked thixotropic system -> solid until agitated, then become liquid): can act as reservoirs in topical drug delivery
  • Ointment (best at drug delivery) provides barrier
  • Solutions (typically alcoholic liquids) don’t coat hair
  • Lacquer for finger/toenails and adjacent skin
  • Foam quickly dissolves with minimal residue
  • Powder easy to use, but generally LESS EFFECTIVE: prophylactic use
33
Q

Why are there oral and topical options for tx of fungal skin infections?

A
  • If infection is too widespread and too deeply seated, topical application may not provide high enough drug levels in the infecting organism to be cytotoxic
  • In these cases, infection elim can best be achieved with systemic delivery, recognizing that there is inherent INC risk of systemic AEs via this route
34
Q

What are the txs for widespread tinea infections?

A
  • ONLY ORAL
  • Terbinafine, Griseofulvin
  • Itraconazole, Flu, Keto
35
Q

What are the txs for localized tinea infection?

A
  • TOPICAL ONLY
  • Azoles
  • Terbinafine
  • Naftifine
  • Ciclopirox
36
Q

What are the txs for onychomycosis?

A
  • ORAL:
    1. Terbinafine
    2. Griseofulvin
    3. Itraconazole
    4. Fluconazole
  • TOPICAL:
    1. Ciclopirox
    2. Amorolfine
37
Q

Which anti-fungals work in the nucleus of the fungal cell?

A
  • Griseofulvin
  • Flucytosine
  • Ciclopirox
38
Q

Which anti-fungals target the fungal cell wall, compromising its integrity?

A
  • Azoles
  • Naftifine: blocks squalene 2,3-epoxidase, working in the same pathway as Terbinafine and the azoles
  • Terbinafine
  • There would be NO advantage to combined therapies with these agents
39
Q

Why is Ketoconazole a unique azole?

A
  • Unique in its ability, at doses higher than those required for anti-fungal activity, to INH synthesis of adrenal steroids -> leading to a reduction in ALDOSTERONE, CORTISOL, TESTOSTERONE
    1. Cholesterol side chain cleavage enzyme
    2. 17-alpha-hydroxylase
    3. 17,20-lyase
  • Sometimes employed clinically, e.g., in tx of hormone-sensitive prostate cancer
40
Q

What hormone-derived AEs can Ketoconazole produce?

A
  • Impotence (erectile dysfunction)
  • Menstrual irregularity
  • GYNECOMASTIA, male breast pain
  • Hot flushes or flashes
  • Serum testosterone concentrations return to baseline and symptoms abate when drug discontinued
41
Q

How are the Imidazoles substrates for/inhibitors of CYPs?

A
  • Most commonly substrates for CYP3A4: except Posaconazole
  • Note that Voriconazole is most CYP-involved, and Posaconazole is least
  • Remember: azoles INH ergosterol syn by blocking 14-alpha demethylase, a CYP enzyme needed to convert lanosterol to ergosterol
    1. Significant interpatient variability for Vori serum levels due to gene polymorphisms in CYP2C19
42
Q

What are the azole differences in regards to elim, preg category, conc in CSF, and QT prolongation?

A
  • NOTE: only Keto and Itra do NOT prolong QT
    1. QT prolongation may also arise from accumulation of concurrent drugs following diminished metabollism
  • Entry in CSF depends on molecular weight and affinity for P-gp
  • Vori: non-linear kinetics w/INC dose
  • Keto HEPATOTOXIC at high doses
  • ONLY Flu eliminated renally
  • ALL of them are preg category C or D
43
Q

Griseofulvin

A
  • Unable to penetrate skin, so topical app ineffective
  • Extensive hepatic metab -> renal/hepato/sweating elim
  • CYP3A4 inducer: DEC anticoag effect w/Coumarin and Warfarin (may manifest late; 12 wks)
    1. DEC contraceptive effect w/oral agents
    2. DEC Cyclosporine serum levels
    3. INC ethanol effects: tachycardia, flushing, diaphoresis
  • CONTRAINDICATIONS: pregnancy (teratogen), hepatotoxic, interferes w/porphyrin metab (porphyria: dark urine, mental disturbances, sensitivity to light)
  • Product of Penicillium: potential cross-sensitivity to pts w/penicillin/cephalosporin/carbapenem hypersensitivity
  • Photosensitizer: protective clothing, sunscreen
44
Q

Terbinafine

A
  • Generally well tolerated, esp for topical drug
  • INH production of ergosterol by INH conversion of squalene to its epoxide derivative
  • Hepatic metab/renal elim: long terminal half-life
    1. Rare hepatotoxicity reported
  • Transient lymphopenia and neutropenia w/oral drug -> AVOID IN IMMUNOSUPPRESSED pts (INC susceptibility to opportunistic infections)
    1. Routine CBCs
  • Category B drug: NO major concerns for risk in pregnancy
45
Q

Naftifine

A
  • Locally bactericidal: G+ and G-
  • Anti-inflam props via INH of inflam mediators, like PGs, LTs, and histamine -> VASOCONSTRICTION
  • Topical agent: hepatic metab/renal elim of fraction absorbed
    1. Avoid in hx of hypersensitivity to drug, co-formulated materials
    2. Cat B drug; limited data, where available
  • Do NOT combine w/topical azoles due to pharmacodynamic interference
    1. INH sterol production at earlier pt (potential for faster onset of action) than azoles, diminishing effectiveness -> INH squalene 2,3-epoxidase
  • No significant systemic drug interactions
46
Q

Ciclopirox

A
  • Topical ONLY; limited absorption
  • Hypersensitivity/allergy to drug or co-formulated materials possible
    1. May irritate if applied to skin abrasions
47
Q

Amorolfine

A
  • INH ergosterol syn
  • Topical only; limited absorption
  • Hypersensitivity/allergy to drug or co-formulated materials possible
    1. May irritate if applied to skin abrasions

MSK, Rheum, Derm (21 decks)

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