2. *
* Introduction
* THE LUNGS
* USP Defention of aresol
* Dose Distributions in Animals and Humans
* Dose metrics
* Deposition
* Advantage and dis advantage of inhalation therapy
* Factor affect inhalation
* Pharmacokinetics of Inhaled Drugs
* L / T Ratio
* Pulmonary drug device
* Factors affect L / T ratio
* Effect of differing doses of inhaled budesonide
* Methacholine test
* Conclusion
* reference
3. *
*The inhaled route of administration is the preferred rout for
delivering preventer and reliever drugs to patients with
airflow obstructions.
*The inhaled route allows the delivery of relatively small doses
of drug directly to the airway achieving a high local
concentration, whilst at the same time minimizing systemic
adverse effects.
4. *
*But it would be a mistake to consider the lungs as
an administration site only suitable for the local
effect of drugs.
* Indeed, the respiratory tract may also be regarded
as a systemic administration route. (Peters and
Hulisz, 2015).
*The lungs have a large surface area available for
the systemic absorption of drugs: the alveolar-
capillary 33 barrier. This is a highly permeable and
highly irrigated membrane, less than 0.5 μm thick,
with a surface area of around 100 m2 (Dagar, 2007
5. *
*effective inhalation therapy, and especially
when a prolonged action of the drug is
desired, requires bypassing the lungs' clearance
mechanisms for the drug to be completely
absorbed
*The application of pharmacokinetics provides a
valuable tool for investigating lung deposition
and bioavailability and hence ways of
optimizing drug delivery .
6. * A.R.ClarkR.K.WolffM.A.EldonS.K.Dw
*Although the lungs are an internal organs, they
represent the largest surface (ca. 80 m 2) in the body
that is in direct contact with the external
environment .
*The pulmonary epithelium, where gas exchange takes
place, is thin (200–300nm) and permeable enough to
allow absorption of proteins, peptides and small
molecules.
* The lungs are also enzymatically less harsh than the
gut. Although lung fluid and tissues do contain
peptidases, proteases and cytochrome P450 enzymes,
they are at far lower levels than in the gut and 5–20
times lower than in the liver . As a result, the lack
9. *
*To be able to reach the lungs, through the
bronchial tree, a drug must be in aerosol form.
*Aerosols are relatively stable two-phase
systems.
An aerosol is a suspension of fine solid particles
or liquid droplets, in air or another gas.
aerosol usually refers to an aerosol spray that
delivers a consumer product from a can or
similar container.
10. *
*Aerosol deposition is an important parameter
in determining delivered dose.
*It is affected by particle characteristics,
respiratory tract anatomy, and breathing
patterns.
*It is also important to distinguish between total
respiratory tract deposition and regional
deposition
11. *
*Inhaled dose is the amount of material entering the
respiratory tract via the nose in most animal studies and via
the mouth in clinical studies.
*Alexander et al 41
*Respiratory minute volume = 0.608 x BW 0.852
Inhaled dose (mg) = Aerosol concentration (mg/L) x volume of air breathed (L)
= Aerosol concentration (mg/L) x minute volume (L/min) x
exposure time (min)
12. *
*
*Alexander D.J., Collins C.J., Coombs D.W., Gilkison I.S.,
Hardy C.J., Healey G., Karantabias G., Johnson N.,
Karlsson A., Kilgour J.D. and McDonald P., (2008).
Association of Inhalation Toxicologists (AIT) working party
recommendation for standard delivered dose calculation
and expression in non-clinical aerosol inhalation
toxicology studies with pharmaceuticals. Inhal. Tox., 20,
1179-1189
Deposited dose = Aerosol concentration (mg/L) x minute volume (l/min)
x exposure period (min) x deposition fraction
(tracheobronchial + pulmonary)
13. Deposition is difficult to quantify due to the three-dimensional
nature of the bronchial tract and commonly used 2D
technology. Gamma scintigraphy is the routinely used method
to determine particle deposition. The amounts of radio-
labelled material is low and image acquisition time is short (3
min) .Single photon emission computed tomography (SPECT)
imaging needs high radioactivity and acquisition of images
takes 15–30 min.
*Deposition
14. *
*The deposition of particles in the different
regions of the lungs depends on the particle
size of the formulation.
*Based on the particle size, three different
mechanisms of drug deposition are defined:
- namely impaction
-sedimentation
- diffusion
15. *
*the aerosol particles pass through the
oropharynx and upper respiratory passages at a
high velocity. Due to the centrifugal force, the
particles collide with the respiratory wall and
are deposited in the oropharynx regions
16. *
*Gravitational forces are predominantly
responsible for the sedimentation of particles.
Particles with sufficient mass and sizes
between one to 5 µm are deposited in the
smaller airways and bronchioles, where they
are deposited slowly, provided a sufficiently
long time span. Therefore, sedimentation is
also influenced by the breathing pattern. Slow
breathing provides a sufficient time span for
sedimentation
17. *
*Upon contact with the lung surfactant, the
dissolution of active pharmaceuticals
ingradiant in alveolar
*fluid is essential for diffusion. Additionally, the
concentration gradient also influences the
diffusion process.
20. *Brownian motion
.When a small particle is suspended in a fluid, it
subjected to the impact gas or liquid molecules. For
ultra fine particles (colloids), the instantaneous
momentum imparted to the particle varies random
which causes the particle to move on an erratic path
now known as Brownian motion. Figure 1 illustrates
the Brownian motion process.
21. *
*Rapid absorption
*Rapid onset of action
*the localization of drug activity in the lung
with minimal systemic toxicity (eg:
budesonide)
*large surface area available for the systemic
absorption of drugs
22. *
*Most addictive route of administration
*Difficulties in regulating exact amount of
dosage.
*In the upper airways, the ciliated epithelium
contributes to mucociliary sweeping, by which
the particles are drawn from the airways to the
mouth
* Already in the lungs, alveolar macrophages are
able to phagocyte particles shortly after their
deposition (Hickey, 2006).
23. *
*1- drug particle
*2- device and formulation
*3- drug molecule
*4- patient characteristic
*5- Droplet deposition
24.
25. *
*Particle size deposition
*Pulmonary drug dissolution
*Mucocilliary Clearance and Macrophage
Clearance
*Absorption to Lung Tissue
*Pulmonary Tissue Retention and Tissue
Metabolism
*Absorptive Drug Clearance to the Systemic
Perfusion
26. *Topical effect on upper and lower airways - respiratory drugs.
*Systemic effect via absorption and distribution in blood -
insulin, antivirals, etc.
*A certain amount of aerosolized drug will always impact in
the naso- or oropharynx and be swallowed.
*Efforts are made through improvement in delivery devices
and patient breathing technique to maximize the amount of
drug delivered to the lungs.
*yet due to its topical delivery it allows the administration of
a much smaller dose to achieve the desired effect.
27.
28. *
*Efficient delivery of inhaled medication is essential for
the success of COPD therapy. Global Initiative for Chronic Obstructive Lung Disease
(GOLD). Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. Available from:
http://www.goldcopd.org. 2013. Accessed August 26, 2013. Google Scholar
*The inhaler device may contribute to
optimal drug delivery Bateman ED: Improving inhaler use in COPD and the role of
patient preference. Eur Respir Rev. 2005;14:85–88. Crossref, Google Scholar
*A wide range of inhaler devices are available,
including pressurized metered dose inhalers
(pMDIs), dry powder inhalers (DPIs), nebulizers, and
soft mist inhalers (SMI).10 Each type of device has
its own advantages and disadvantages Newman SP: Inhaler treatment
options in COPD. Eur Respir Rev. 2005;14:102–108. Crossref, Google Scholar
29. *
*1. Pressurised Metered Dose Inhalers (pMDIs).
*Also known as pump inhalers, these are the
most commonly used inhaler devices.
* They are propellent-based and deliver a
specific, amount of medication to the lungs, in
the form of aerosol spray; which needs to be
inhaled.
*It releases reproducible doses every time on
actuation.
30. *
*2. Dry Powder Inhalers (DPIs)
*These types of inhalers deliver the medication in a dry
powder form.
*DPIs are breath-actuated devices, which depend on your
inhalation, to release the medication from the device.
*easier to use as they don’t need propellants and co-
ordination.
*Usually, DPIs are single dose devices, although multi-dose DPIs
are available as well
31. *
*3. Breath Actuated Inhalers (BAIs)
*An advanced version of the pMDI technology,
the breath-actuated inhaler combines the
advantages of a pMDI and DPI. The BAI senses
your inhalation through an actuator, and
releases the medication automatically.
*It can be used effectively by everyone –
children, adults and elderly.
32. *
*4. Nebulizers
*, nebulizers convert the liquid medication into
suitable aerosol droplets, which are best suited for
inhalation.
* Nebulizers do not require coordination and deliver
the medication quickly and effectively to the lungs
in the form of a mist.
*Nebulizers are preferred during asthma attacks, in
infants, children, elderly, critical, patients
unconscious patients, and those who cannot use a
pMDI or DPI effectively.
33. *
1. The dose should be reported as the calculated according to the formula:
* DD = C x RMV x D(min)/BW
* where:
- DD = delivered dose (mg/Kg);
- C = concentration of substance in air (mg/L); some time AC
- RMV =respiratory minute volume or the volume of air inhaled in one minute
(L/min);
- D = duration of exposure to the aresol(min);
- BW = bodyweight (Kg).
2. The RMV for mice, rats, dogs and cynomolgus monkeys should be calculated according to
the formula:
RMV(L/min) = 0.608 x BW(Kg)(0.852).
3. If deposited dose or the amount of material actually retained inthe respiratory tract is
presented as supplementary information,the way in which it is calculated should be clearly
stated.
4. Dose should always be presented in mg/Kg.
* Jatakanon A, Kharitonov S, Lim S, et al
* Effect of differing doses of inhaled budesonide on markers of airway inflammation in
patients with mild asthma
* Thorax 1999;54:108-114.
34. *
*Goal - To maximize lung deposition / minimize systemic
exposure and unwanted side effects
*High lung availability/Total systemic availability
*L / T Ratio
*Proportion of drug available from the lung, out of the total
systemically available drug
*Formula: (Lung dose)/(lung dose + GI dose)
*The higher the ratio the more efficient the aerosol drug
delivery to the respiratory tract
35. *
Notes:
A- first and fouth factor : increase delivery of drug to the lung while
aiming to reduce oropharyngeal deposition and swelling.
B- second factor : addresses the amount of drug that Is swallowed but
metabolized quickly
C- minimized amount of drug sawlloed
36. *
*To ensure that inflammation is suppressed whilst using the lowest
possible dose.
*Two double blind, placebo controlled studies.
*The first was a parallel group study involving three groups receiving
either 100 μg/day budesonide (n = 8), 400 μg/day budesonide The
budesonide dose of 100 μg had to be given as one puff daily while, in
those with mild to moderate stable asthma, the 400 μg dose ( could be
given as either once daily or two divided doses ) or a matched placebo
(n = 6).
*The second was a crossover study involving 10 subjects randomized to
receive 1600 μg budesonide The maximum recommended dose of
1600 μg daily ( was given as two divided doses in order to obtain the
maximum benefit with minimal side effects) or placebo. The groups
were matched with respect to age, PC20, baseline FEV1 (% predicted),
exhaled NO, and sputum eosinophilia.
37. *
*here were significant improvements in FEV1 following 400 μg
and 1600 μg budesonide (11.3% and 6.5%, respectively,
p<0.05).
*This was accompanied by significant reductions in eosinophil
numbers in induced sputum (0.7 and 0.9 fold, p<0.05).
*However, levels of exhaled NO were reduced following each
budesonide dose while PC20was improved only with 1600 μg
budesonide.
38. *
*FEV1 and FVC were measured with a dry
spirometer ( Vitalograph, Buckingham, UK).
*Morning and evening peak flow were measured
using a mini-Wright peak flow meter (Clement
Clarke International Ltd, Harlow, UK).
39. *
*Airway responsiveness was measured by
methacholine challenge with doubling
concentrations of methacholine (0.06–32 mg/ml)
delivered by dosimeter11 (Mefar, Bovezzo, Italy)
with an output of 10 μl per inhalation.
* The aerosols were inhaled at tidal breathing while
wearing a nose clip.
*A total of five inhalations of each concentration was
administered (inhalation time one second, breath
holding time six seconds). FEV1 was measured two
minutes after the last inhalation until there was a
fall in FEV1 of ⩾20%
40. *
* performed to evaluate how "reactive" or "responsive" your lungs are to things in the
environment.
* During the test, inhale doses of methacholine, a drug that can cause narrowing of
the airways, similar to those seen in asthma.
* A breathing test will be repeated after each dose of methacholine to measure the
degree of narrowing or constriction of the airways.
* The test starts with a very small dose of methacholine and, depending on your
response, the doses will be increased until either you experience 20 percent drop
in breathing ability, or you reach a maximum dose with no change in your lung
function.
41. *
*End exhaled NO was measured by a
chemiluminescence analyser (Model LR2000, Logan
Research, Rochester, UK) sensitive to NO from 1 to
5000 parts per billion (ppb, by volume) using a
previously described method.12
*In brief, subjects exhaled slowly at a flow rate of 5–
6 l/min from total lung capacity over 30–40 s
through a mouthpiece.
*NO was sampled at 250 ml/min from a side arm
attached to the mouthpiece. The measurement was
taken from the point corresponding to the plateau
of end exhaled CO2 (5–6% CO2) and represents the
lower respiratory tract sample. Results of the
analyses were computed and graphically displayed
on a plot of NO and CO2 concentration, pressure and
flow against time.
44. *
*Monitoring the number of eosinophils in
induced sputum may be the most accurate
guide to establish the minimum dose of inhaled
steroids needed to control inflammation. This,
however, requires further studies involving a
larger number of patients.