other types of delivery- lungs and parenteral and rectal/vaginal Flashcards
two types of drug inhalation applications
local delivery and systemic delivery
example of local delivery
bronchodilators, antibiotics
example of systemic delivery
insulin, other peptides/proteins, opioids, antimigraine drugs
advantages of local action
direct access to site of disease, rapid action, avoids GI tract and first pass hepatic metabolism, lower dose, less side effects
advantages of systemic action
avoids GI tract and first pass hepatic metabolism, non invasive, no needles, high bioavailability, rapid absorption, rapid action
3 types of inhalers
nebuliser, pressurised metered dose inhalers (pMDI), dry powder inhaler (DPI)
what is an aerosol
dispersion of solid particles or liquid droplets in a gas
describe the anatomy of the lungs
upper airways and lower airways/alveoli, air velocity and diameter decreases going down, surface area increases going down
function of upper airways
conducting zone, filter and condition inspired air
function of lower airways and alveoli
respiratory zone, gas exchange
2 blood circulation systems
bronchial and pulmonary circulation
describe the bronchial circulation
part of systemic circulation, supplies conducting zone, high pressure system, 1% cardiac output
describe pulmonary circulation
derives from pulmonary artery, part of respiratory zone, low pressure system, 100% cardiac output, capillaries in close contact with alveolar epithelium
name 3 types of epithelia and examples
pseudostratified- basal, non/ciliated, goblet cells
cuboidal- ciliated and clara cells
squamous- type 1/2 pneumocytes
what protects the alveolar epithelium
alveolar macrophages
describe the alveolar epithelium
more than 95% of total lung surface area, protected by alveolar macrophages, very thin, contains type 1 and 2 pneumocytes
what are pneumocytes
alveolar cells found on surface of alveoli in lungs
describe type 1 pneumocytes
extended and thin cytoplasm with protuberant nucleus (bulging out/on surface) , 95% of alveolar surface area, provides short diffusing pathway to bloodstream
describe type 2 pneumocytes
cuboidal cells, 5% of alveolar surface area, synthesizes lung surfactant
describe the lung lining fluid system
airway to viscoelastic mucus layer
alveoli to aqueous fluid coated by lung surfactant
what is the airway to viscoelastic mucus layer composed of
water and glycoproteins
describe the two phases of lung liniging fluid
upper- viscous gel layer
lower- less viscous, in contact with epithelium
what is the the function of airway to viscoelastic mucus layer
protects epithelium from dehydration, inhaled particles, microbiological infection
describe the alveoli to aqueous fluid coated by lung surfactant layer
isotonic, pH 6.8, contains most of plasma proteins in low conc, contains macrophages
what is lung surfactant synthesised by
type 2 pneumocytes
describe lung surfactant
one molecule thick layer, 90% phospholipids and 10% proteins
main function of lung surfactant
decrease surface tension of alveoli, enhance recognition of foreign particles by macrophages
what does particle deposition in lungs depend on
particle properties (shape, charge, size, density), respiratory tract morphology, inhalation technique
3 main mechanisms of particle deposition
inertial impaction, sedimentation, diffusion
what is inertial impaction and what causes it
particles unable to remain in the streamline when air changes direction due to inertia, particles stick no airway walls, caused by particles with high mass and velocity
where does inertial impaction occur
oropharynx and upper airways
where does sedimentation occur
lower airways and alveoli
what is sedimentation caused by and what does it depend on
particles deposit in respiratory tract due to gravity, depends on residence time in lungs and settling velocity
where does diffusion occur
alveoli
what is diffusion favoured by
long residence time
what is diffusion in lungs
particles <1um are propelled in random directions by collision with gas molecules until they hit a surface
how are patients recommended to inhale and why
slow, quiet, deep breath then hold their breath for a few seconds
increases deposition
why does the recommended inhalation technique increase deposition
decreases inertial impactions, increases residence time, more time for sedimentation/diffusion/particle growth
why is the efficiency of inhalers poor and explain for each type of inhaler
max 20% emitted dose deposit in lungs, due to high impaction in oropharynx
nebuliser- droplets too large
pMDI- particles emitted at high velocity
DPI- high inspiration flow rate needed to aerolize and disaggregate powder
2 ways particles are eliminated
mucociliary clearance in tracheo-bronchial tree
alveolar macrophages in alveoli
how does mucociliary clearance in tracheo-bronchial tree eliminate particles
particles trapped in mucus are propelled to pharynx by action of cilia and swallowed, rapid mechanism
how does alveolar macrophages in alveoli eliminate particles
particles engulfed by macrophages and transported to ciliated region, particle recognition enhanced by lung surfactant, slow mechanism
desrcibe the metabolic activity in lungs
all metabolic enzymes found in the liver are present in lungs but in lower amounts, protease in lining fluid, low metabolic activity
what enzyme is present in lining fluid
protease, activity balanced by antiproteases
why high and rapid absorption from alveolar region into systemic circulation
large SA, thin barrier, high blood flow, no mucus/mucociliary clearance
how does age affect lung deposition
lowers lung deposition in children, high impaction in oropharynx, low sedimentation and diffusion, high inspiratory flow if crying
how does lung disease affect lung deposition
lowers lung deposition in asthma, copd, emphysema, cystic fibrosis
how does smoking influence the lungs
cilia destroyed, impaired mucociliary clearance, decreased uptake by alveolar macrophages, leaky respiratory epithelium, higher drug absorption
what does parenteral delivery mean
not via gut, usually injections, directly to bloodstream, avoids 1st pass hepatic metabolism
routes of parenteral delivery
intravenous, intramuscular, subcutaneous, minor routes (intraarterial, intracardiac…)
why is parenteral delivery good
.rapid- IV enters plasma immediately and drug dispersed into tissue rapidly
.local/targeted effects
.improved bioavailability- drug wont be absorbed or degraded
.can control drug level
(dose/response relationship)
.can be used for unconscious/uncooperative patients
problems/precautions with parenteral delivery
air embolism- injection of air bubbles
bleeding- haemophilia (no blood clots)
cost- training and specialised formula
fever- from pyrogens
infiltration/extravasation- local tissue damage
overdose due to rapid onset
particulates- pulmonary embolism
phlebitis- vein irritation
sepsis- sterile practise
thrombosis/blood clot
what are pyrogens
chemical substance that causes fever
what is extravasation
leakage of drugs outside of veins and into surrounding tissue
considerations to take when using parenteral delivery
dosing volume
patient comfort- isotonicity (solution will sting if hyper/hypotonic, may cause phlebitis if enters vein)
drug stability and formulation
convenience for practitioner/patient
drug release and absorption
what is phlebitis
inflammation of vein near surface of skin
why are parenterals not convenient
require training for delivery and techniques for safety, labour intensive and costly
name 2 improved parenteral forms that can be used by patients themselves at home
prefilled syringes, infusion pumps
formulation requirements of parenterals
sterility bc they bypass infection barriers, isotonic, pH 7.4, most routes only tolerate small volumes so large volumes for IV must be isotonic and isoosmotic, intravenous formulations must be particle free and water miscible
name and describe the two forms of parenterals
solution dosage forms- drug immediately available for absorption, action determined by site of administration and devices used
dispersed dosage form- onset slower, drug must dissolve into aqueous phase
formulation requirements for intravenous formulations
particle free and water miscible
large volume parenterals for IV must be…
isotonic and isoosmotic
types of injectables
injection- liquid preparations of drug substances/solution
for injection- dry solid in a vehicle
injectable emulsion- liquid preparation of a drug substance dissolved/dispersed in a emulsion medium
injectable suspension- liquid preparation of solid suspended in a suitable liquid medium
for injectable suspension- dry solid that disperses when a vehicle is added idk
advantages and disadvantages of intravenous delivery
advantage- guaranteed delivery and distribution, immediate effect
disadvantage- requires clinical training, must be sterile, complications, availability of sites (loss of sites in long term treatment), cannot be removed
biopharmaceutics of IV route
drug injected into vein, passes to heart, passes through pulmonary circulation, heart pumps it around tissues, drug returns to heart through liver, metabolised
administration of small volumes in parenteral delivery
can be injected directly, slow injection if concentrated, often mixed with LVP
how can large volumes be administerd parenterally
central venous catheter emptying into subclavian vein, continuous infusion via drip feed or metering pump
example of continuous infusion via drip feed/metering pump
analgesia, chemotherapy
name the pumps that give continuous treatment outside hospital environments or for patient controlled analgesia
ambulatory and implantable pumps
formulation requirements for small volume parenterals
sterile, particle free, pH 3-9 as long as injection is slow/rapidly diluted, cosolvents preservatives are allowed, surfactants can be used to aid solubility
formulation requirements for large volume parenterals
used for electrolyte balance/parenteral nutrition/plasma replacement, volume >100ml, usually isotonic, preservatives not permitted, cant tolerate large differences for physiological conditions
formulation problems in intravenous administration
drugs that are hydrophobic enough to cross lipid membranes are poorly water soluble so it must be solubilised for intravenous use, drugs precipitate into small crystals or bind to plasma proteins, causes irritation/phlebitis/embolisms
solution to the formulation problems in intravenous administration
salts, cosolvents, surfactants, pH control/ionisation, use more sophisticated formulation (eg. emulsions, liposomes, polymer drug conjugates)
what happens to particles when injected? (biopharmaceutics of IV particles)
particle injected by IV, passes into heart then round pulmonary circulation, particles larger than 5um lodge in pulmonary capillaries, may cause embolisms, smaller particles pass around tissue before reaching liver and spleen, taken up by Kupffer cells in liver and metabolised
what cells take up IV particles and where are they
Kupffer cells in liver
what happens to large IV particles
lodge in pulmonary capillaries, causes embolisms
what happens to smaller IV particles
pass around tissues before reaching liver and spleen
what is subcutaneous delivery
injections into fatty/connective tussue beneath the skin
disadvantages of subcutaneous delivery
slower absorption (less well perfused than IM route), slower release, not suitable for irritating formulations
what is subcutaneous delivery used for
vaccines, some vitamins, most commonly insulin
what is intramuscular delivery and some general points
injection into muscle tissue
muscle has good blood supply so rapid absorption, can inject solutions/suspensions/depot implants, injection doesnt need to be water miscible, small volume route
advantages and disadvantages of intramuscular delivery
advantages- rapid absorption into bloodstream, can formulate sustained depots, removable implanted devices
disadvantages- local muscle damage, cant use in cardiac failure, must avoid blood vessel
why does intramuscular delivery have rapid absorption
muscle has good blood supply
why cant intramuscular delivery be used in cardiac failure
no muscle perfusion (no blood flow)
what is rectal drug delivery
dosage forms administered via anus into the rectum/lower colon
where is rectal drug delivery administered
rectum or lower colon
why use rectal drug delivery
local and systemic effect
types of rectal dosage forms
suppositories- solid bullet shape, insert with finger
enemas- liquid in squeeze bag with long insertion tube, 100-150ml
microenemas- liquid/paste in tube similar to superglue, 5-10ml
foams/cream/gel/ointment- rectal admin, use applicator or apply by hand
why use rectal route
local conditions in rectum/nearby, oral route is unavailable and this is safer than injections, GI surgery/damaged, vomiting episodes, sleeping/unconscious patient, very old/young/mentally disturbed, drugs with extensive first pass metabolism (rectal blood supply doesnt go through liver), convenient night time therapy
problems with rectal drug delivery
not popular, inconvenient, leakage, proctitis (rectal inflammation) if prolonged administration, bowel movements, unpredictable drug absorption
local therapy uses of rectal drug delivery
laxative for chronic constipation, bowel evacuation to clear constipation before surgery/endoscopy/radiology, enemas, chronic bowl diseases, inflammation, haemorrhoids
what is proctitis
rectal inflammation
systemic therapy uses of rectal drug delivery
pain relief, nausea after chemo, arthritis, seizures, infections
what happens to drugs administered high in the rectum
drained by superior rectal veins, carried direct to liver, subject to metabolism
what happens to drugs administered low in rectum
delivered systemically by inferior rectal vein before passing through liver, not subject to metabolism
process of rectal delivery
- rectal area (high and low rectum stuff)
- rectal absorption of drugs
- retention time of dose form
rectal processing of drugs
absorption across mucosal epithelium, no villi, lymphatic absorption takes place, rectal veins bypass liver but lower colon veins dont, 50% dose bypass liver on 1st pass
rectal absorption of drugs
can be slow and incomplete, influenced by position of dosage form, reduced by faecal matter, depend in disease state and retention time
what reduces rectal absorption of drugs
faecal matter
retention time of rectal drugs
disease state can alter toilet frequency, diarrhoea- shorter and constipation longer, drugs can affect muscles, irritant drugs can stimulate evacuation like in laxatives
requirements for formulation design of rectal route drugs
must release drug, spread across epithelium, non irritant, neutral pH 7 secretions of mucin, rectal environment has little buffering capacity to help drugs ionise
different type of formulation designs of rectal drugs
liquids- immediately available but leak
pastes/suspensions- retained better
foams- rapid knock down and spreading
tablets- bad, little water for disintegration
suppositories- melt at body temp, can give prolonged action if melt slowly, viscous and retained
common bases for suppositories in rectal drug delivery
hydrophobic wax fats, witepsols, hydrophilic waxes, macrogols, gelatin, glycerogelatin
problems with drug release in rectal delivery
drug cant retain in base, drugs can reduce melting point/viscosity, surfactants can irritate, different charges on gelatin, ionic binding of oppositely charged drugs, hydrophobic bases release ionised drugs but hydrophilic bases release hydrophobic drugs
why use drug delivery to vagina
local condition treatment like infections/dryness/irritation/contraception/labour
rarely used
methods of administrating into vagina
pessaries- wax based suppositories/compressed tablets, inserted high up with stick
gel/foam/cream- administered with syringe applicator
topical creams/ointments- external/internal around vulva
douches- liquid for washing out
sponges/rings- specialised purposes
physiology of vaginal mucosa
not ciliated, epidermal thickness dependent on cycle of circulating oestrogen and progesterone in menstrual cycle, up to 24 cell layers thick in early cycle, good blood supply, epidermis supported on layer of elastic fibres and underlying muscle
physiology of vaginal secretions
normal 3-4g per hour, main source is cervix, blood vessels in vaginal walls and glands at vaginal entrance, viscosity changes with hormonal cycle, vagina has its on microorganisms that maintain healthy environment
effects of age on vaginal physiology and consequences
prepuberty- thin mucosal epithelium, pH ~5
post menopause/after hysterectomy- oestrogen deficient, thin epidermis (4 layers instead of 24), reduced elasticity and vascularisation, reduced secretions and glycogen
consequences- prone to dryness/irritation/infection
formulation design of vaginal delivered drugs
non irritating, non drying, high patient acceptability (no vaginal leakage, no stains on underwear, discreet, comfortable), compatible with environment as changing pH/microflora can cause pathogens to grow, restoring acidic pH can fix infections, must not interfere with sexual activity
formulation designs for vaginal drug delivery for treating dryness
hormone replacement therapy eg. oral oestrogen replacement
formulation designs for vaginal drug delivery for contraception
sponge soaked in spermicide
what can vaginal therapy be used for
infections, STDs, induction of labour and abortion, spermicide, vaginal dryness
