Exam 2 review Flashcards
Percutaneous absorption: trans follicular route
-dissolution of drug in vehicle
-diffusion to skin surface
-partitioning into sebum
-diffusion through lipids in sebaceous pore
-partitioning into viable epidermis
-diffusion through cellular mass of epidermis
-fibrous mass of upper dermis
-capillary uptake and systemic dilution
Percutaneous absorption: trans epidermal route
-dissolution of drug in vehicle
-diffusion to skin surface
-partitioning into STRATUM CORNEUM
-diffusion through PROTEIN LIPID MATRIX OF STRATUM CORNEUM
-partitioning into viable epidermis
-diffusion through cellular mass of epidermis
-fibrous mass of upper dermis
-capillary uptake and systemic dilution
paste
powder and ointment
absorption base
ointment and emulsifier
w/o ointment
ointment, emulsifiers, little water
w/o cream
-water, oitment, emulsifier in equalish amounts
o/w cream
-mostly water, oilment, emulsifier
o/w lotion
water, little oitment, emulsifier
soak
water
lotion(shake)
roughly half water and half powder
Layers of skin
-epidermis
-dermis
-subcutaneous layer
How thick is skin
0.5-6 mm
components of dermis
-connective tissue
-blood vessel
-nerves
-hair follicles
Sebum
-sticky oil that acts as a barrier against water loss
-antibacterial
-antifungal
Advantages of topical formulations
-high frug conc at application site
-low first pass effect
-low risk of systemic side effects
-easy to use
-self administration
-many OTCs
-non-invasive
Disadvantages of topical formulations
-poor adherence
-limited contact time
-messy
-small amount can be absorbed systemically
-skin irritation
-SENSITIZATION
-special packaging to measure dose
advantages of hydrocarbons
-emollient
-occlusive
-cheap
-non irritating
-insoluble in water
-not water washable
-anhydrous
disadvantages of hydrocarbons
-will not absorb water
-greasy
-insoluble in water
-not water washable
-anhydrous
examples of hydrocarbons
-white petrolatum
-white ointment
-vegetable shortening
-Vaseline
“heavy duty”
advantages of anhydrous bases
-absorb water
-emollient
-occlusive
-insoluble in water
-not water washable
-anhydrous
disadvantages of anhydrous bases
-greasy
-may be sensitizing
-compatibility problems
-insoluble in water
-not water washable
-anhydrous
examples of anhydrous bases
-lanolin
-aquaphor
-aquabase
-polysorb
-hydrophilic petrolatum
Advantages of w/o emulsion absorption
-absorb water: limited
-emollient
-occlusive
disadvantages of w/o emulsion absorption
-greasy
-sensitizing
-compatibility
-stability or microbial problems
examples of w/o emulsion absoption
-hydrous lanolin
-cold cream
-Eucerin
-hydrocream
-Rose water ointment
advantages of o/w emulsion (water removable)
-absorb water
-non greasy
-insoluble in water
-water washable
-contains water
disadvantages of o/w emulsion (water removable)
-less emollient
-non occlusive
-compatibility probs
-stability issues
-may dry out
-insoluble in water
-water washable
-contains water
examples of water removable bases (o/w emulsion)
-Vanishing Cream
-Dermabase®
-Velvachol®
-Unibase®
-Hydrophilic Ointment
USED FOR WEEPING LESIONS/OOZING WOUNDS
topical local delivery forms
-ointments
-creams
topical systemic delivery forms
-transdermal patch
true or false: drug absorption is slowed by stratum corneum
true
drug absorption through sweat pore
-low surface are
-slowed fir hydrophillic drugs
drug absorption through SC
-high surface area
-hydrophobic drugs slowed
drug absorption through hair follicle
-low surface area
-hydrophillic drugs are slowed
Stratum corneum (SC)
-major barrier for drug absorption
-layer of dead skin cells about 0.1 mm thick
-tightly packed, flat, dead skin cells
-no nucleus
Desquamation
-process by which epithelial “brick wall” is maintained at constant thickness
-turnover takes 21-28 days
What equation is used to calculte drug absorption across SC
Fick’s First law
Fick’s first law
dM/dt = (DK A* ΔC) / h
How do drugs cross the SC?
-intercellular route
-has to travel in the spaces between dead cells
Penetration enhancers for SC
-water
-helps separate hydrocarbon chains
-loosening=more permeable
true or false: Approximately 20% of water present in the body is accumulated in the skin, with 60–70% of this amount being accumulated in the dermis.
true
What factors affect drug absorption?
-O/W partition coefficient of drug
-size and charge
-contact time
-drug concentration
-surface area
-penetration enhancer
Pysiological factors that affect topical drug absorption
-anatomic site
-skin hydration: increase
-skin metabolism: decrease
-shedding: increase
-temperature: increase
-burn: increase
-eczema: increase
Neonates skin
-first 4 weeks of life
-thin skin
-pH 6.2-7.5
-susceptible to infection
pre term infants skin
-poor skin barrier function
-susceptible to infection
true or false: it is impossible to overdose on topical medications
False, drug absorption is just slow
Elderly skin
-thin
-dry
-increased pigmentation
-photo damage
-wrinkles
-Immunocompromised
transdermal drug delivery profile
-infusion like
-steady increase and platues
advantages of transdermal drug delivery
-bypass first pass effect
-reduce side effects
-reduce inter and intra patient variability
-increased patient complience
-self admin
-easy to apply
Disadvantages of transdermal
-lipophillic drugs with low MW
-potent drugs
-dhort half life
-irritation from adhesive
-Erythema: skin redness
-itching
-edema
-lag time to reach steady state
-skin damage: elderly
Components of a transdermal patch
-backing layer
-drug reservoir
-rate controlling membrane
-adhesive
Sometimes 2 and 3 combined
transdermal patch: couseling
-clean non hairy site
-site rotation
-apply firmly
-remove old patch
-excess drug in patched
-disposal methods
-avoid high heat
suggested sites for birth control patch
-abdomen
-butt
-shoulder
-upper arm
maximizing transdermal drug delivery: passive
-ALL METHODS TO MODIFY SC
-hydration
-chemical enhancers
-thermal passive
maximizing transdermal drug delivery: mechanical SC poration methods
-microstructure array
-SC removal
-high velocity particles/liquids
maximizing transdermal drug delivery: Electronically driven SC poration methods
-sonophoresis
-Ionophoresis
-Electroporation
-thermal poration
-radio frequency poration
Penetration enhancer for transdermal drugs
-Oleic acid
-increase spacing because of kinked cis structure
Iontophoresis
-drives drug across skin through hair follicles and sweat glands
-uses electric current
-charge repulsion, electro-osmosis
-local dermal anesthesia, corticosteroids, and GlucoWatch
-useful for PROTEIN/PEPTIDE DRUGS
routes of transdermal drug delivery
-diffusion
-iontophoresis
-electroporation
-microneedles
Advantages of vaginal drugs
-high conc at application site
-no first pass effect
-reduce side effects
-patient compliance
-non invasive
-easy to use
-self administration
-many OTCs
disadvantages of vaginal drugs
-only few drugs
-gender specific
-patient compliance
-irritation
-low residence time
-frequent application
-exposure to male sexual partner
-variability in drug absorption
common causes of vaginal infections
-fungi
-virus: HIV, HPV
-Protozoa
-Bacteria
rugae
fold, ridges and bumps in vagina
drug absorption in the vagina
-rich blood supply
-lymphatic vessels
-BP pushes fluid through intercellular gaps between epithelia cells(transudation)
Skin is vagina
-stratified squamous epithelium: 25 layers, regenerate 3-5 days
-thick lamina propria: collagen and elastin, nerve supply
-Fibrous layer adds strength and binds surrounding tissue
vaginal physiological considerations
-vaginal fluids: drug dissolution
-pH: drug ionization
-enzyme activity: drug stability
-transport routes: drug absorption
-mentural cycle
true or false: absorption can change depending on menstrual cycle
-true
-higher during diestrus
Cyclic changes in vaginal epithelium
-hydrophilic drugs: increased absorption during luteal phase
Vaginal formulation factors
-ease of administration
-drug release
-drug and excipient conc
-area of contact
-residence time
vaginal semi solids
-gels and creams
-inexpensive, prolonged resisdence
-messy, frequent use, hard to remove
Vaginal tabs
-ease of insertion
-more expensive, frequent applications, spreadability
vaginal suppositories
-easy to insert
-frequents, poor retention, spread ability
-can accommodate drugs in soln, emulsion, or susp.
controlled release forms: vaginal
-microspheres and rings
-expensive
-high tech
vaginal rings components
-made of silicon rubber and ethylene-vinyl acetate (EVA)
Benefits of vaginal ring
-30+ days
-increased pt compliance
-easy to use
-high and low dose
-requires dexterity to insert
vaginal dryness treatment
-estrogen replacement therapy
-oral tab and transdermal patch
Vaginal estrogen
-cream: daily for 2 weeks
-tab: daily for 2 weeks
-gel
-suppositories
-avoid first pass
vaginal dryness couseling
-bedtime
-delay intercourse
-avoid tampons
-oil based cream and suppositories weaken condoms and diaphragms
advantages of rectal delivery
-self admin
-unconscious or vomiting pts
-avoid 1st pass
-prevent and treat N/V
-useful if oral route is restricted
-localized drug delivery
-reduced systemic effects
Disadvantages of rectal route
-poor acceptance and compliance
-erratic absorption
-1st pass effect if placed too high in rectum
-may expel
-can leak
-not for immunocompromised
-mucosal irritation
rectum anatomy
-end of the large intestine that attaches the colon to the anus
-12-15 cm
-holds stool
-static environment
-no microvilla
-mucous volume= 1.2-3 ml
-pH=7
-highly vascularized
Hemorrhoids
-swollen blood vessels in and around anus and rectum
-treat with hydrocortisone acetate creams and ointments
-hydrocortisone acetate suppository
Constipation
-difficult bowel movements
-Glycerin suppository: promotes bowel movement, local irritation via dehydration, hyperosmotic
5-aminosalicylic acid (5-ASA)
-for ulcerative colitis
-extent of disease impacts formulation choice
Oral 5-aminosalicylic acid (5-ASA)
-release in the distal/terminal ileum or colon
-extensive disease
Liquid Enema: 5-aminosalicylic acid (5-ASA)
-may reach the splenic flexure
-do not frequently concentrate in the rectum
Suppositories: 5-aminosalicylic acid (5-ASA)
reach upper rectum
-15-20 cm beyond anal verge
Suppositories for drug delivery
-act as a protectant for local tissue
-carry drug for local OR systemic action
-avoid cutting
size and shape of rectal suppositories
-cylindrical or conical
-tapered
-2 grams
-1-1.5 inches long
-infant suppositories 1 g
Requirements of suppository bases
-nontoxic
-nonirritating
-inert
-compatible with med
-formed by compression or molding
-dissolve in presence of mucous or melt at 37 C
Suppository fatty bases
-melt base
-cocoa butter and synthetic substitutes
Suppository dissolvable bases
-water soluble/miscible base
-glycerinated gelatin
-PEG
PEG
-good substitute for fatty bases that melt in warm climates
-PEG supp. must be moistened to reduce hydroscopicity and local irritation
-hyperosmotic, dehydrates, and is used for constipation
fatty base drug release
-contains hydrophilic drugs: salt form releases faster
-melts
-spreads
dissolve base drug release
-hydrophobic and hydrophilic have same rate of release
-dissolves
-diffuses
Rectal drug absorption
-15 min-6 hour
-liquids absorb faster than suppositories
-prolong duration of effect
-peak blood levels vary
-bioavailability less than oral due to less surface area
-erratic absorption
Diazepam rectal vs nasal
-BIOAVAILABILITY OF
NASAL FORMULATIONS
RELATIVE TO RECTAL
DIAZEPAM WAS IN THE
RANGE OF 70–90%,
ALBEIT WITH HIGH
VARIABILITY.
true or false: rectal delivery is unsafe for newborns and children
False
-many rectal drug available for children
Bisacodyl suppository
-10 mg
-OTC laxative
-effective in 15-60 minutes
-pediatric
Artesunate suppository
-for children with severe malaria
-risk of premature expulsion
premature patients: caution for tissue tearing and infection
-lower psychological and social barriers in emergency
purpose of immunization
-protect against disease after exposure
immunization timing
-immunize before exposure
-childhood and adult schedules published annually
ideal vaccine
-induce immune response in all
-no adverse effects
-cheap to make
-not temp sensitive
passive immunization
-transfer of immunity from one person to another
-through IG or blood
-maternal antibodies: transfer accross placenta 3rd trimester
-temporary but immediate protection
maternal antibody transfer
-IgG transport last 2 months of pregnancy
-protect infant from infection during first months of life
Immunizations given in pregnancy
-tetanus
-influenza
-pertussis
-RSV
active immunity
-stimulate host to produce a protective response to a pathogen
-natural infection or immunization
-relies on immunologic memory
IgA
in secretions
IgE
-involved in allergy and anaphylaxis
-parasites
IgG
-large amounts in serum
-major antibody of secondary response
IgM
predominant early antibody
Secondary antibody response
-no maturation of IgM response
-antibodies respond quicker after secondary exposure: higher affinity, quick, longer, higher conc, mostly IgG
Phase 1
-follows IND
-small group tests in healthy volunteers
-goal is safety, tolerability and preliminary
immunogenicity involving different doses and different
immunization schedules
-8-12 months
Phase 2 studies
-larger number of volunteers(50-500)
-low risk and high risk
-goal: generate safety data, refine dose and immunization schedule, vaccine formulation, lot consistency
-18-24 months
Phase 3 study
-Blinded, randomized, controlled clinical trial
-Many participants(1000+)
-vaccine efficacy and safety
-leads to licensure application
How do we develop immunity?
1) virus enters body
2) virus enters cell
3)fuses with vesicles and RNA is released
4) virus assembly
5)virus release
6)Immune response
Live attenuated vaccine
-contain live organism
-limited replication in host
-immune response without causing disease
examples of live attenuated vaccines
-MMR
-varicella
-rotavirus
-nasal influenza
-oral polio
-typhoid
-yellow fever
Issues with live vaccines
-single dose to produce long lasting immunity
-timing
-contraindicated in pregnancy, immunosuppressed
whole, inactivated vaccines
-grown in culture
-exposed to heat/chemicals to inactivate
-sometimes purified to contain only portion needed to induce immunity
examples of whole, inactivated vaccines
-hepatitis
-polio
-rabies
issues with inactivated vaccines
-multiple doses needed to produce immunity
-booster doses
-minimal interference from circulating antibody
Fractional vaccines
-portion of pathogen that induces protective immunity
-reduces adverse effects associated with vaccine administration: soreness, redness, systemic reactions
examples of fractional vaccines
-polysaccharides vaccines
-recombinant DNA vaccines
-toxoids
-flu
-acellular pertussis
Polysaccharide vaccines
-long chains of sugar molecules fro bacterial capsule
-stimulate B cells without T helper cells
-ineffective in children <2
-no booster
-response is IgM
example of polysaccharide vaccine
pneumococcal)PPSV23)
conjugate vaccines
-polysaccharide linked to protein making it a more potent vaccine
-conjugation overcomes the disadvantages of polysaccharide vaccines: elicit memory response, disease in infants
examples of conjugate vaccines
Hib
PCV15, PCV20
meningococcal
recombinant DNA technology
-insert antigen gene into microorganism: yeast or bacteria
-Microorganism produces antigenic protein
-Antigenic protein harvested and purified for use as vaccine
recombinant DNA vaccines advantages
large amount of pure antigen
recombinant DNA vaccines disadvantages
expensive
examples of recombinant DNA vaccines
-Hep B
-HPV
-Influenza(Flublok)
-Recomb. Zoster
-Novavax COVID-19
-RSV
Toxoids
-inactivated bacterial toxins
-immune response to toxin produced by infecting bacteria
examples of toxoids
-tetanus
-diphtheria
nucleic acid vaccines
-immune response to the protein encoded by plasmid DNA or mRNA
-induces cell mediated and antibody responses
-gene for pathogen taken up by host cell
Nucleic acid vaccine characteristics
-Easy to manufacture
-cheap
-many trials: prophylaxis, therapeutic
-long lasting immunity
mRNA vaccines
-mRNA in lipid coat enters cell
-translated into viral protein
-immune system recognizes viral protein
-mounts immune response
-easy and cheap to make
-easy to modify
nucleic acid vaccine advantages
-cell mediated and antibody response
-pure
-no infectious risk
-easy and inexpensive to produce
nucleic acid vaccines candidates
Hep C
hepers simplex virus
-human immunodeficiency virus
-parasites
-cancer
-Sars-CoV-2
recombinant viral vector vaccines
-live vaccine engineered into carriers or vectors of antigens from other pathogens
-advantage of live vaccine
-may induce immune response to vector and target pathogen
True or false: pre existing immunity may limit effectiveness of nucleic acid vaccines
False
-limit effectiveness of recombinant viral vector vaccines
viral vector vaccine
-ebola
-parts of virus DNA are put in carrier
-like the spike protein
adjuvants
-Substance that enhances the immune response to the
antigen with which it is mixed
* Aluminum-containing materials primary adjuvant in
U.S.
* MF59 contains squalene (oil in water adjuvant)
[influenza vaccine] and AS01 contains saponin
adjuvants mechanism
-mechanism for improvement of immune response not completely determined: make antigen less soluble, enhance immune stimulatory signals, cause inflammatory response
Vaccine preparation
-vaccine prepared at time of administration: draw from vial, reconstitutes, needle on prefilled syringe
-pre filling is discouraged: use manufacturer prefilled syringes
IM admin
-deltoid: adults and children
-anterolateral aspect of the thigh for infants
-Needle size
* Adults 1 to 1 ½ inches; 22-25 gauge
* Infants and children 5/8 to 1 ¼ inch; 22-25 gauge
SubQ admin
-over tricepts: adults
-anterolateral aspect of thigh: infants
-pinch tissue
-45 degree angle
-5/5 inch, 23-25 G
Oral admin
-oral or mucosal pathogens
-live attenuated vaccines
-IgA production
Oral vaccine on a film
-attenuated virus on methylcellulose combined with sugar and surfactant
-easy to package and transport
-film dissolves in mouth
edible vaccines
-transgenic plants
-oral admin
-cheap
-rapid upscale of production
-minimize storage problems
mucosal admin
-antigen delivered to mucosal surface
-Nasal
-Oral
-Vagina or rectal
-IgA production
Nasal influenza vaccine
-live attenuated flu sprayed onto nasal mucosa
-immune response at site of pathogen entry
transdermal immunization
-needle free delivery
-patch application
Topical admin
-investigational delivery systems
Skin immune system
-barrier stratum corneum
-Langerhans celss
Intradermal vaccine admin
-Dermis and epidermis are rich in antigen presenting cells
* More efficient immune response with smaller amounts of
vaccine antigen
intradermal vaccine administration: advantages
-small volume
-often equivalent response as IM
intradermal vaccine administration: disadvantages
-single dose vial used as multidose
-off label use of vaccines
-may need vaccine reformulation
Intradermal vaccine possibilities
-mpox, rabies, flu
-yellow fever and inactivated polio
-
critical issue with vaccines
-exposure to temps outside recommended ranges can reduce potency
-errors cost $$$$
-loss of patient confidence
cold chain
The cold chain is
interconnected with refrigeration equipment that allows vaccines
to be stored at recommended temperatures to maintain their
potency
vaccine storage equipmant
-stand alone freezers and refrigerators
-refrigerator compartment can be used for vaccine storge
-water jugs
-keep vaccines away from freezer
-use only for biologics
refrigerator temperatures
-between 35-46 C
-2-8 C
-Average 40 F (5 C)
Freezer storage temps
-stand alone freezer
–frost free/automatic defrost cycle
- -58-5 F
- -50- -15 C
monitoring temperature
-twice daily recording
-digital thermometers
-alarms when closed
-notification sent to email or cell phone
Thermometers
-calibrated
-biosafe glycol encased probe
temperature excursions
-do NOT discard
-separate/ from other inventory
-call manufacture or health department for guidance
Clinical immunization program plans
-designated and individual and back up
-written plan for odering and deliveries
-emergency back up written plan
Global immunization issues
-vaccine integrity
-formulation tricks: dried nucleic acids in a sugar matrix, molecular ensilication
RTS,S vaccine for malaria
-targets circumsporozoite
protein on sporozoite surface
3 doses 1 month aparts
R21/Matrix M vaccine
-Targets plasmodium sporozoite
-3 doses with 4th dose one year later
vaccine cost consideration
-cost is only 1 component
-program start up costs: fridge, training
-administration costs: time to administer, outreach
RSV vaccines
-Pfizer bivalent RSVpreF (Abrysvo)
* GSK adjuvanted RSVpreF3 (Arexvy)
* Single dose
-give in pregnancy 32-36 weeks
RSV vaccine adverse effects
-injection site reactions
-arthralgia, myalgia, fatigue, headache
-Guillain Barre syndrome
Nirsevimab for infants
-long acting monoclonal antibody with efficacy to prevent RSV
-administer just prior to RSV season
What is a biofilm?
-phenotypic diversity
-aggregates
-various substrate utilization
-low metabolism
0low motility
-high attachment
0antibiotic resistant
-Biofilms
are sophisticated
communities of matrix-encased,
surface attached bacteria
hydrated structures
-contain water channels to allow nutrients and oxygen diffusion
Biofilm-Associated Infections
-65% of all bacterial infections are associated with biofilms
-Catheter, prostetic valve, pacemaker…
How do biofilms increase risk of infections?
- Bacteria that attach to a surface and grow as a biofilm are protected
from killing by innate host defenses and antimicrobial agents
-poor antibiotic penetration
-decreased cell replication
-efflux and inactivation
Small colony variants (SCVs)
-* Non-pigmented, non-haemolytic colonies
-COMMONLY found in biofilms
-slow growing: nutrient deficient bacteria=poor antibiotic activity
common organisms in biofilms
-Coagulasee-negative staphylococcus spp
-Staphylococcus aureus
-Gram negative bacilli: E coli
-CANDIDA ALBICANS
clinical implications of biofilms
-attachment and growth: persistant infections and metastatic spread
-involved in prostetic material and native tissue infections
-biofilms are less suseptible to antimicrobials
BAD BUGS NO DRUGS: No ESK(C)APE
-Enterococcus faecium
-Staph. aureus
-Klebsiella pneumoniae and Clostridiodes difficile
-Acinetobacter baumanii
-Pseudomonas aeruginosa
-Enterobacter spp and E.Coli
How do biofilms affect drug delivery?
-formulation
-pharmacokinetics
-polymers/coatings
-Stability
-Application
-Drug carriers
Surface properties that increase biofilm adhesion
-positive charge
-rough
-low topography
-stiff
Surface properties that decrease biofilm adhesion
-negative charge
-smooth
=soft
-high topography
Drug formulation for biofilms
-deliver antimicrobials to site of infection
-oral therapy
0IV therapy
-embedding/coating device with antimicrobials
-localized therapy: topical antiseptics, beads, spacers, cements
Central Venous Catheters and Infection Risk
-common
-Staphylococcus aureus and Staphylococcus
epidermidis
-
Short term CVC
-majority of all catheter related bloodstream infections
Peripherally inserted central catheter
-alternative to other catheters
-similiar infection risk to CVCs in ICU
Long term CVC
-surgically implanted
-prolonged chemotherapy
-home infusion
-hemodialysis
focus of preventative stratagies for catheter infections
-catheter hubs
-insertion site
True or false: removing catheters is a method recommended by CDC to prevent antibiotic resistance
True.
treatment approah of CRBSI
-prevention: infection control practices, topical antiseptics, antibiotic coated devices
-systemic and local therapy: IV therapy, antibiotic locks and washes
Combination therapy: killing biofilms
-improves killing of biofilms
-bacteriocidal regardless of biofilm formation
-Vanco+Rifammpin
-Vanco+Tigecycline
Antimicrobial properties for biofilm delivery
-penetration
-molecular size
0diffusion
-activity
-stability
-release from delivery mechanism
Guidelines to prevent catheter related infections
-sterile barrier
-2% chlorohexidine prep
-avoid routine replacement
-antiseptic impregnates CVCs
Guidelines to treat catheter related infections
-IV vanco for empiracal therapy
-avoid IV/PO linezolid for empiracal therapy
non-gram positive coverage
antibiotic locks
–catherter salvage
-if can’t be used, IV antibiotics
Formulation of antibiotic lock solutions
-ethanol: antiseptic
-anticoagulant: heparin, sodium citrate, EDTA
-antibiotic: dose several times higher than organism suppressibility]
Catheter Associated Urinary tract infections(CAUTI)
-WTF
-Why the foley?
Drug Delivery for CA-UTI Prophylaxis
-systemic antimicrobial NOT reccomended
-catheter irrigation NOT routinly used
-Antimicrobial coated catheters
Drug Delivery for CA-UTI Treatment
Systemic antimicrobials is recommended for most
symptomatic patients
host and antibiotic resistance
-host contributes to antibiotic resistance in PJI
-Daptomycin (DAP) resistance may occur in the absence of DAP
exposures
antibiotics in bone cement
-high doses increase rate and extent of release
-lasts 20 days
-high dose=unstable bone cement
Preventative Measures For
Device-Related Infections
-optimize bundles
-patient screening and decolonization
-Impregnated devices: silver, chlorohexidine, minocycline coating
-antibiotic beads, cements, spacers
-novel materials
Nebulizer
-air jet
-long inhalation times
-cleaning times
-frequent administration
pressurized metered dose
-propellant
-efficacy is less than 60%
dry powder inhaler
-dry powder
-small device
-high effort to be efficient
Alveoli
site of gas exchange
key features of airways
-Generations
-decrease with diameter and length
-geometrically increasing number
-dramatic increase in surface area
epithlia in bronchi
-mucus
-cillia
-ciliated columnar cells
goblet cell: secretes mucus
epithlia in bronchiole
-ciliated cuboidal cells
-shorter epithelim
-less mucus
lung mucus
-trap pathogens, irritants
-transport out of lungs
mucociliary escalatory
-cilia act like wave
-propel mucus and debris
-cough or sneeze out secretions
-hypozia, cigarette smoke, degydration slow dowsn
Type-I pneumocytes
-Broad, thin cells (0.1-0.5 µm dia)
-Cover ~ 95% of alveolar surface
-Short airway-to-blood path length
Type-II pneumocytes
-cuboidal cells that secrete
pulmonary surfactant
make type 1 cells to help repair epithelium
cell types in a respiratory unit
-Endothelial cells line capillaries
-Type 1 pneumocytes
-Type 2 Pneumocytes
Lung surfactants
-secreted by type 2
-decrease surface tension and maintains structure
-lipids, lipoproteins, cholesterol, and surfactant
-surfactant deficiency results in respiratory distress syndrome
obstructive diseases
-interfere with air flow in or out
-affect large or small airways
-COPD, CF, pneumonia
Restictive diseases
-interfere witht he expansion of the lungs or the chest wall
-reduced lung volume or lung capacity
-Pulmonary fibrosis, scoliosis, obesity, neuromuscular damage
pneumonia
Alveoli fill with a thick fluid,
making gas exchange difficult
Bronchitis
Airways are influenced due to
infection (acute) or due to a
prolonged irritant (chronic).
Coughing brings up mucus.
Asthma
Airways are inflamed due to
irritation, and bronchioles
constrict due to muscle spasms
Emphysema
Alveoli burst and fuse into
enlarged air spaces. Surface area
for gas exchange is reduced.
Cystic fibrosis
-autosomal recessive mutation in CFTR gene
-regulates transport of Na and Cl across epithelium
-produces thick, sticky mucus
-trap bacteria
-repeated infections
-lung damage and premature death
Factors affecting residence time in the airways
Mucus barrier
2. Mucociliary clearance
3. Alveolar clearance (Macrophages)
Factors affecting absorption & metabolism of drugs
- Surface area and blood supply
- Absorption barrier thickness
- Membrane permeability
- Metabolism and enzymatic activity
Mucus barrier
-dissolution: limited by viscosity
-diffusion: thickness, size of drug
factors affecting drug delivery: pharmaceutical
-particle diameter: 3-5 um for tracheobronchial region, <3 um for alveolar region
-particle characteristics
-aerosol stability
-aerosol velocity
Respirable fraction
% drug present in aerosol particles <5 μm in size
Aerodynamic diameter
diameter of spherical particle with unit
density that settles as same rate as particle in question
Mass median aerodynamic diameter (MMAD):
diameter at
which 50% of particles are larger and 50% are smaller
Geometric standard deviation (GSD)
ratio of diameters
corresponding to 84% and 50% on the cumulative frequency
curve
-
factors affecting drug delivery: physiological
-particle diameter
-characteristics
-gravity
-inertial impaction
-breathing pattern
Conventional nebulizers
aerosol generated at constant
rate whether patient inhaling or
exhaling
Breath-enhanced nebulizers
direct inhaled air within the
nebulizer à produce increased
volume of aerosol during the
inhalation phase.
Dosimetric nebulizers
release aerosol only during
inhalation phase.
improve poorly soluble drugs
-prodrug
improving peptides/proteins
-conjugation to polymers like polyethylene glycol to prevent protease digestion
excipients for inhalations
-Lactose, glucose, mannitol prevent aggregation
* Phospholipids increase dissolution
* Bile salts increase permeability (change mucus properties, open
tight junctions but can be toxic)
* Cyclodextrins – most promising to increase solubility, also non-toxic
