Flow physics of Human Respiratory system (Part: Physiology)

Author: Vivekkumar P
Mentor: Prof.Manaswita Bose, Energy science & Engg, IITB.

1 Methods of administration route:

• Oral tract (Drugs pass through the gastrointestinal tract)
In this method when the drug passes through the gastrointestinal path the ab-
sorption of drug mainly depends it’s own dissolvability and dissolve kinetics of
gastrointestinal fluid. After the dissolution of drug the metabolism transports the
drug into the veins.

• Intravenous tract (Drugs injected directly into the veins)

In IV administration the drug molecules directly into the blood streams. Here the
gastrointestinal tract is bypassed. In this method the target organ (eg., Diseased
lung) is not located so the drug needs to be distributed across entire body. Before
implementing IV, the barriers between the blood vessels and lung tissue should be
well known.

• Pulmonary tract (Drugs utilizes the lung airway paths)

The inhaled drug particles directly delivered into the target organ (Lung tissue).
Also the high pulmonary concentration can be achieved via this approach. Com-
paratively the required dosage level is low than the Oral and IV administration to
treat Chronic Obstructive Pulmonary Disease (COPD) patients. After inhalation
the particles undergoes various stages. They are,
1. Drug particle or droplet deposition.
2. Drug dissolution in the lung fluids.
3. Mucociliary clearance in the conducting airways and macrophage clearance in
the alveolar space.
4. Absorption (of dissolved drug) to the lung tissue.
5. Pulmonary tissue retention and potential pulmonary metabolism.
6. Absorptive drug clearance (drug transport) from the lung tissue to the systemic
perfusion.

1.1 Drug particle or droplet deposition:

During inhalation of drug, a fraction of dose gets deposited inside the inhaler itself
and remaining particles reach respiratory system. When the particle travel through the
complex airway, deposition occurs at Mouth/throat region, the conducting airways and
alveolar site. Generally the total deposition of drugs in the lung system is known as Lung
dose. Pulmonary deposition occurs at Central region (large airways) and/or Peripheral
region (smaller airways + alveolar space).

Lung dosage and pulmonary deposition depends on aerodynamic particle diame-

ter, inhalation flow, inhaler device characteristics and disease oriented factors.
Mainly aerodynamic particle diameter determines whether the particle deposit in mouth-
throat region or in the airways. Particles with a diameter of 0.5-5.0µm have the high
success rate of deposition in the lung. particles with above 5.0µm deposit in mouth-throat
region which reduces the lung dosage.

Figure 1: Simulations were performed using Multiple-Path Particle Dosimetry software.

Each simulated particle size represents one simulation.The inhalation characteristics used
for the simulation were an inhaled volume of 2 L, an inhalation flow rate of 60 L/min,
and a breath-holding time of 8 seconds.

1.2 Drug dissolution in the lung fluids:

After deposition the drugs needs to be dissolved by fluids of the epithelial lining and
alveolar lining fluid. The dissolution characteristics of drug determines the location of
absorption.

1.3 Mucociliary Clearance and Macrophage Clearance:

In lung airways, the drug particles mainly removed by mucociliary clearance, which
is an evolutionary pulmonary protection mechanism against bacteria and dust particles.
Here, the upward movement of mucus towards the pharynx removes the particles from
the airways. The mucociliary clearance process achieves faster rate with a wider airways
diameter. Automatically the particles which are deposited at the central airways removed
quickly. In alveoli region the particles are removed with the help of alveolar macrophages.
The removed particles are transported to lung-draining lymph nodes. Compared to Mu-
cociliary Clearance, the Macrophage Clearance process is far slower.

1.4 Absorption to Lung Tissue:

After achieving the successful clearance of Mucociliary clearance and Macrophage clear-
ance now the dissolved drug is absorbed by the lung tissue. The absorption rate mainly
depends on patient airway characteristics and drug characteristics. The absorption rate
at alveolar space is much higher than the central airways due to very high perfusion
(Blood passage).
Figure 2: Pulmonary absorption kinetics based on local physiologic characteristics of
respiratory tract regions.

1.5 Pulmonary Tissue Retention and Tissue Metabolism:

High pulmonary tissue retention time is required for most drugs to increase the duration
of efficiency. Now the pulmonary tissue redistribute the absorbed drug to the other part
of airways through systemic blood circulation.

1.6 Absorptive Drug Clearance to the Systemic Perfusion:

The local perfusion vary with respect to various parts of airways. At alveolar region
due to high perfusion and large absorption area the absorptive clearance occurs rapidly.
But in central airways the absorption rate is low due to low perfusion.
 Figure 3: Inhaled drug particle deposition in healthy versus diseased lungs.

1.7 Reference:
Borghardt, J.M., Kloft, C. and Sharma, A., 2018. Inhaled therapy in respiratory dis-
ease: the complex interplay of pulmonary kinetic processes. Canadian respiratory journal,
2018.