Lecture 9: ADME in the lungs Flashcards
What do many of the drugs used for the primary maintenance of the respiratory conditions have the potential to cause?
Iatrogenic diseases if not appropriately used
What are the factors impacting upon drug PK/PD following inhalation?
- Formulation and device charateristics
- Individual drug molecule properties
- Patient use of the inhalation device
What are the formulation and device characteristics that impact upon drug PK/PD following inhalation?
- Lung deposition (amount and distribution)
- Pulmonary residence time of drug particle
What are the indivdual drug molecule properties that impact upon drug PK/PD following inhalation?
- Receptor binding affinity
- LogP, solubility, pKa
- PK ‘profile’ (eg metabolic features, protein binding, Vd, CL)
What kind of steroid is budesonide?
A synthetic pregnane steroid and non-halogenated cyclic ketal corticosteroid.
What are the chemical names of steroid molecules?
- Cholesterol
- Budesonide
- Ciclesonide
- Mometasonefuroate
- Fluticasone propionate
- Beclometasone dipropprionate
What are effective anti-inflamattory medications?
corticosteroids
What are the most effective treatment options avaialable for asthma?
Inhaled corticosteroids
What modulates the effects of corticosteroids?
The glucocorticoid receptor
What can impact on realistation of benifit and adverse effects of ICS?
Pharmacokinetic properties
What are the systemic effects of chronic ICS?
- HPA (hypothalamic-pituitary adrenal) axis effects
- Growth suppresion
- Corticosteroid-induced osteoporosis
- Skin thinning and bruising
What are the local effects of chronic ICS?
- Oral candidiasis
- Pharyngitis/ laryngitis (husky/ hoarse voice)
What has an abnormally flattened circadian cortisol cycle been linked with?
Chronic fatigue syndrome, insomnia and burnout
What does the HPA axis regulate?
- metabolic system
- cardiovascular system
- immune system
- Reprodcutive system
- Central nervous system
What is an ideal corticosteroid?
- High receptor binding
- Prolonged effect in lung; lipophilicity, lipid conjugation
- High lung deposition
- Low oral bioavailability
- High systemic clearance
- High plasma protein biniding
- Low oropharyngeal deposition
- Onsite oropharyngeal activation
What are the pharmacokinetic considerations for ICS?
- Formulation
- Bioavailability
- Receptor binding affinity
- On-site activation
- Lung residence time
- Lipophilicity
- Lipid conjugation
- Half-life
- Protein binding
- Clearance
Wha is the fine-particle fraction?
The fine particle dose divided by the total emitted dose.
What is the mass median aerodynamic diamter?
The MMAD divides the aerosol size distribution in half. It is the diameter at which 50% of the particles of an aerosol by mass are larger and 50% are smaller.
What is the total emitted dose or delivered?
The mass of drug emitted per actuation that is actually available for inhalation at the mouth
What is the fine particle dose?
The mass of particles <5 μm in size within the total emitted dose.
What is pulmonary bioavailability?
All drug that is deposited in lung is assumed to be systemically bioavailable
What is oral bioavailability?
Fraction of dose that is swallowed and absorbed through GI tract minus that inactivated by hepatic first pass metabolism
What is systemic bioavailability?
Pulmonary bioavailability + Oral Bioavailability
What is Beclometasone dipropionate (BDP) metabolised by?
Cyp P450
Describe the metabolism of Beclometasone dipropionate (BDP)
- Metabolised by P450 to form M4, M5
- Metabolised by esterases to form M1, M2, M3
What metabolite of beclomethasone dipropionate has appreciable corticosteroid activity?
Only metabolite M1
How is the magnitude of receptor binding affinity expressed?
Expressed as relative receptor affinity (compared to decamethasone which is assigned a value of 1)
What corticosteroids are inhaled in the active pharmacological form?
- Budensonide
- Fluticasone propionate (FP)
What are drugs that are inhaled in the active pharmacological from at risk of?
increased potential for local oropharyngeal side effects
What corticosteroids are pro drugs?
- Beclometasone dipropionate (BDP)
- Ciclesonide
How are corticosteroids pro drugs converted to thier active form?
Converted by esterases in the lungs
What is the active metabolite of Beclometasone dipropionate (BDP)?
Beclometasone 17-monopropionate
What are the formulation parameters critical for pulmonary deposition?
- inhaled particel size; fine particle fraction and mass median aerodynamic diamter
- Inhaler device
- Patient inhalation technique
What does prolonging lung residence time result in?
Increases time the ICS interacts with the pulmonary glucocorticoid receptors
How can you estimate lung residence time?
From determining mean absorption time
What is the mean absoprtion time?
Difference in mean residence time between inhalation and IV administrations
What does a long mean absorption time mean?
The greater the lung residence of the API
What does a long mean absorption time mean?
The greater the lung residence of the API
What is an increase in logP assosicated with?
Longer pulmonary respiratory residence time - this is associated with lipophilic side chains
What does a negative logP value mean?
The compound has a high affinity for the aqueous phase - more hydrophillic
What does a logP of 0 mean
The compound is equally partitioned between the lipid and aqueous phases
What does a postive logP mean?
higherconcentration in the lipid phase (i.e., the compound is more lipophilic).
What minimises the potential for systemic side effects?
A short half life
What does a high protein binding result in?
Low systemic unbound drug concentrations
Is bound drug pharmacoligically active?
No
What is the most important organ of clearance for corticosteroids?
Liver - cytochrome p450 3A
What is the hepatic blood flow?
~90Lhr
What is the hepatic blood flow?
~90Lhr
