Lecture 9 - ADME in the lung Flashcards
what is the pharmacokinetic model pathway following pulmonary drug inhalation?
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
what are factors impacting upon the PK/PD following inhalation?
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
what are corticosteroids ?what are the most effective corticosteroids and and what is their affect?
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
what are the limitations on the use of the chronic inhaled corticosteroids
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)
what is the factors of an ideal corticosteroid?
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
what are pharmacokinetic considerations for inhaled corticosteroids?
formulation
bioavailability
receptor binding affinity
on site activation
lung residence time
- lipophilicty, lipid conjugation
half-life
protein binding
clearance
describe pulmonary bioavailability
pulmonary bioavailability - all drug is deposited in lung is assumed to be systemically bioavailable
describe oral bioavailability
oral bioavailability - fraction of dose that it swallowed and absorbed through GI tract minus that inactivated by hepatic first pass metabolism
what is the systemic bioavailability made equal to ?
the pulmonary bioavailability plus oral bioavailability
what are corticosteroids such as BUD and FP inhaled as and what is the increased potential?
some corticosireids Cush as BUD and FP are inhaled in the active pharmacological form. there is increased potential for local oropharyngeal side effects
how are BDP and CIC corticosteroids inhaled as and what effect does this have?
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
what does prolonging the lung resistance time do and what effect does this have on the systemic side effects?
Prolonging LRT increases time the ICS interacts with the pulmonary glucocorticoid receptors
Enhances anti-inflammatory effects and neutral on systemic side effects
what is Mean absorption time? what is it a property of in terms of pharmacokinetics?
Difference in mean residence time between inhalation and IV administrations
mean absorption time is a property of lipophilicity - logP
how can we estimate lung resistance time ?
Can estimate LRT from determining mean absorption time (MAT)
describe the relationship between mean abortion time and LRT of the drug particle
The longer the MAT, the greater the lung residence of the drug