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3.24 > Lecture 9: ADME in the lungs > Flashcards

Lecture 9: ADME in the lungs Flashcards

1
Q

What do many of the drugs used for the primary maintenance of the respiratory conditions have the potential to cause?

A

Iatrogenic diseases if not appropriately used

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2
Q

What are the factors impacting upon drug PK/PD following inhalation?

A
  • Formulation and device charateristics
  • Individual drug molecule properties
  • Patient use of the inhalation device
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3
Q

What are the formulation and device characteristics that impact upon drug PK/PD following inhalation?

A
  • Lung deposition (amount and distribution)
  • Pulmonary residence time of drug particle
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4
Q

What are the indivdual drug molecule properties that impact upon drug PK/PD following inhalation?

A
  • Receptor binding affinity
  • LogP, solubility, pKa
  • PK ‘profile’ (eg metabolic features, protein binding, Vd, CL)
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5
Q

What kind of steroid is budesonide?

A

A synthetic pregnane steroid and non-halogenated cyclic ketal corticosteroid.

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6
Q

What are the chemical names of steroid molecules?

A
  • Cholesterol
  • Budesonide
  • Ciclesonide
  • Mometasonefuroate
  • Fluticasone propionate
  • Beclometasone dipropprionate
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7
Q

What are effective anti-inflamattory medications?

A

corticosteroids

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8
Q

What are the most effective treatment options avaialable for asthma?

A

Inhaled corticosteroids

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9
Q

What modulates the effects of corticosteroids?

A

The glucocorticoid receptor

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10
Q

What can impact on realistation of benifit and adverse effects of ICS?

A

Pharmacokinetic properties

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11
Q

What are the systemic effects of chronic ICS?

A
  • HPA (hypothalamic-pituitary adrenal) axis effects
  • Growth suppresion
  • Corticosteroid-induced osteoporosis
  • Skin thinning and bruising
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12
Q

What are the local effects of chronic ICS?

A
  • Oral candidiasis
  • Pharyngitis/ laryngitis (husky/ hoarse voice)
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13
Q

What has an abnormally flattened circadian cortisol cycle been linked with?

A

Chronic fatigue syndrome, insomnia and burnout

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14
Q

What does the HPA axis regulate?

A
  • metabolic system
  • cardiovascular system
  • immune system
  • Reprodcutive system
  • Central nervous system
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15
Q

What is an ideal corticosteroid?

A
  • 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
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16
Q

What are the pharmacokinetic considerations for ICS?

A
  • Formulation
  • Bioavailability
  • Receptor binding affinity
  • On-site activation
  • Lung residence time
  • Lipophilicity
  • Lipid conjugation
  • Half-life
  • Protein binding
  • Clearance
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17
Q

Wha is the fine-particle fraction?

A

The fine particle dose divided by the total emitted dose.

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18
Q

What is the mass median aerodynamic diamter?

A

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.

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19
Q

What is the total emitted dose or delivered?

A

The mass of drug emitted per actuation that is actually available for inhalation at the mouth

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20
Q

What is the fine particle dose?

A

The mass of particles <5 μm in size within the total emitted dose.

21
Q

What is pulmonary bioavailability?

A

All drug that is deposited in lung is assumed to be systemically bioavailable

22
Q

What is oral bioavailability?

A

Fraction of dose that is swallowed and absorbed through GI tract minus that inactivated by hepatic first pass metabolism

23
Q

What is systemic bioavailability?

A

Pulmonary bioavailability + Oral Bioavailability

24
Q

What is Beclometasone dipropionate (BDP) metabolised by?

A

Cyp P450

25
Q

Describe the metabolism of Beclometasone dipropionate (BDP)

A
  • Metabolised by P450 to form M4, M5
  • Metabolised by esterases to form M1, M2, M3
26
Q

What metabolite of beclomethasone dipropionate has appreciable corticosteroid activity?

A

Only metabolite M1

27
Q

How is the magnitude of receptor binding affinity expressed?

A

Expressed as relative receptor affinity (compared to decamethasone which is assigned a value of 1)

28
Q

What corticosteroids are inhaled in the active pharmacological form?

A
  • Budensonide
  • Fluticasone propionate (FP)
29
Q

What are drugs that are inhaled in the active pharmacological from at risk of?

A

increased potential for local oropharyngeal side effects

30
Q

What corticosteroids are pro drugs?

A
  • Beclometasone dipropionate (BDP)
  • Ciclesonide
31
Q

How are corticosteroids pro drugs converted to thier active form?

A

Converted by esterases in the lungs

32
Q

What is the active metabolite of Beclometasone dipropionate (BDP)?

A

Beclometasone 17-monopropionate

33
Q

What are the formulation parameters critical for pulmonary deposition?

A
  • inhaled particel size; fine particle fraction and mass median aerodynamic diamter
  • Inhaler device
  • Patient inhalation technique
34
Q

What does prolonging lung residence time result in?

A

Increases time the ICS interacts with the pulmonary glucocorticoid receptors

35
Q

How can you estimate lung residence time?

A

From determining mean absorption time

36
Q

What is the mean absoprtion time?

A

Difference in mean residence time between inhalation and IV administrations

37
Q

What does a long mean absorption time mean?

A

The greater the lung residence of the API

37
Q

What does a long mean absorption time mean?

A

The greater the lung residence of the API

38
Q

What is an increase in logP assosicated with?

A

Longer pulmonary respiratory residence time - this is associated with lipophilic side chains

39
Q

What does a negative logP value mean?

A

The compound has a high affinity for the aqueous phase - more hydrophillic

40
Q

What does a logP of 0 mean

A

The compound is equally partitioned between the lipid and aqueous phases

41
Q

What does a postive logP mean?

A

higherconcentration in the lipid phase (i.e., the compound is more lipophilic).

42
Q

What minimises the potential for systemic side effects?

A

A short half life

43
Q

What does a high protein binding result in?

A

Low systemic unbound drug concentrations

44
Q

Is bound drug pharmacoligically active?

A

No

45
Q

What is the most important organ of clearance for corticosteroids?

A

Liver - cytochrome p450 3A

46
Q

What is the hepatic blood flow?

A

~90Lhr

46
Q

What is the hepatic blood flow?

A

~90Lhr

3.24 (28 decks)

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