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
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
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
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
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
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)
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)
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
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
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
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
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
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
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
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
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
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
18
Q
What is the current tx approach recommended for hyperhidrosis?
A
- > Topical antiperspirant therapy
- > Botulinum toxin
- > Anti-cholinergics
- > Sympathectomy
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
