Lecture 9 - ADME in the lung

Question 1

what is the pharmacokinetic model pathway following pulmonary drug inhalation?

Answer 1

the patients uses the inhalers and the particles are deposited into the lungs and absorbed.

or

swallowed fraction absorbed from gut into the liver. Some excreted through liver through inactivation of first pass metabolism and active drug entering systemic circulation

Question 2

what are factors impacting upon the PK/PD following inhalation?

Answer 2

formulation and device characteristics
- Lung deposition (amount and distribution) mainly related to Fine powder fraction
- how long drug particles stay in pulmonary

Individual drug molecule properties e.g.
- Receptor binding affinity
- LogP, solubility, pKa
- PK ‘profile’ (e.g. metabolic features, protein binding, Vd, CL)

Patient use of the inhalation device

Question 3

what are corticosteroids ?what are the most effective corticosteroids and and what is their affect?

Answer 3

corticosteroids as effective anti-inflammatory medications

inhaled corticosteroids are the most effective treatment available for asthma

effects of corticosteroids are modulated at the glucocorticoid receptor and the pharmacokinetic properties can impact on benefits and adverse effects of ICS

Question 4

what are the limitations on the use of the chronic inhaled corticosteroids

Answer 4

Systemic effects
HPA (hypothalamic-pituitary-adrenal) axis effects
Growth suppression
Corticosteroid-induced osteoporosis (↓ osteocalcin)
Skin thinning & bruising

Local effects
Oral candidiasis
Pharyngitis/laryngitis (husky/hoarse voice)

Question 5

what is the factors of an ideal corticosteroid?

Answer 5

Efficacy:
- Potency
High receptor binding
- Prolonged effect in lung
Lipophilicity
Lipid conjugation

High lung deposition

Safety
Low oral bioavailability
High systemic clearance
High plasma protein binding
- Negligible oropharyngeal effects
Low deposition
On-site activation

Question 6

what are pharmacokinetic considerations for inhaled corticosteroids?

Answer 6

formulation

bioavailability

receptor binding affinity

on site activation

lung residence time
- lipophilicty, lipid conjugation

half-life

protein binding

clearance

Question 7

describe pulmonary bioavailability

Answer 7

pulmonary bioavailability - all drug is deposited in lung is assumed to be systemically bioavailable

Question 8

describe oral bioavailability

Answer 8

oral bioavailability - fraction of dose that it swallowed and absorbed through GI tract minus that inactivated by hepatic first pass metabolism

Question 9

what is the systemic bioavailability made equal to ?

Answer 9

the pulmonary bioavailability plus oral bioavailability

Question 10

what are corticosteroids such as BUD and FP inhaled as and what is the increased potential?

Answer 10

some corticosireids Cush as BUD and FP are inhaled in the active pharmacological form. there is increased potential for local oropharyngeal side effects

Question 11

how are BDP and CIC corticosteroids inhaled as and what effect does this have?

Answer 11

Some corticosteroids (such as BDP and CIC) are actually pro-drugs and converted in lungs to their active forms by esterases

Reduces potential for off-target side effects

Incidence of oral candidiasis (Ciclesonide, 2.5%) vs (Fluticasone, 22%) was reported in one study

Question 12

what does prolonging the lung resistance time do and what effect does this have on the systemic side effects?

Answer 12

Prolonging LRT increases time the ICS interacts with the pulmonary glucocorticoid receptors

Enhances anti-inflammatory effects and neutral on systemic side effects

Question 13

what is Mean absorption time? what is it a property of in terms of pharmacokinetics?

Answer 13

Difference in mean residence time between inhalation and IV administrations

mean absorption time is a property of lipophilicity - logP

Question 14

how can we estimate lung resistance time ?

Answer 14

Can estimate LRT from determining mean absorption time (MAT)

Question 15

describe the relationship between mean abortion time and LRT of the drug particle

Answer 15

The longer the MAT, the greater the lung residence of the drug

Question 16

describe the process of desire to maximise local anti-inflammatory activity

Answer 16

1. release of the drug form aerosol particle is made up of different processes which is influences by the amount of composition of the locally available lining fluid and by intrinsic properties of the drug and the carrier particle.
2. absorption of the drug across the pulmonary epithelium: this process is amino controlled by its physicochemical properties
3. clearance of the undissolved particle

Question 17

what is increased logP associated with?

Answer 17

increased LogP associated with anger pulmonary residence time, associated with lipophilic side chains

Question 18

should inhaled corticosteroids have long or short half-if - what is desirable?

Answer 18

An ICS with a long half-life but low systemic concentration may be safer than an ICS with a shorter half-life but present in higher concentrations

Question 19

what does high protein binding result in?

Answer 19

high protein binding results in low systemic unbound drug concentration - only the unbound drug is pharmacologically active

Question 20

what is organ is used for clearance for corticosteroids ?

Answer 20

the liver is the most important organ for Clearence for corticosteroids - hepatic blood flow is 90L/hr

rapid clearance should minimise systemic side effects