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BM213: Introduction to Pharmacology > Block E Lecture 2: Volume of Distribution > Flashcards

Block E Lecture 2: Volume of Distribution Flashcards

1
Q

What is the permeability of a drug across a membrane related to?

A

The chemistry of the drug of interest
(Part 1, Slide 3)

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2
Q

What are 3 cellular barriers which a drug may need to cross?

A

Gastrointestinal mucosa (for orally administrated drugs)
Blood brain barrier (BBB)
Placenta
(Part 1, Slide 4)

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3
Q

What do mediated transporters at cellular barriers mediate?

A

Transport of certain drugs around the body
(Part 1, Slide 4)

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4
Q

How does the volume of liquid affect the concentration of a drug?

A

Same dose in a higher volume results in less concentration
(Part 1, Slide 5)

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5
Q

How do we calculate the theoretical concentration of a “compartment” of the body?

A

Concentration = Dose / Volume (of said compartment)
(Part 1, Slide 6)

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6
Q

Why do large molecules have a very small volume of distirbution?

A

As they stay mainly in the plasma
(Part 1, Slide 7)

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7
Q

Why do hydrophilic small molecule drugs (such as penicillins) have a relatively small volume of distribution?

A

As they distribute into the extracellular fluid (ECF)
(Part 1, Slide 7)

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8
Q

What is the extracellular fluid?

A

Interstitial fluid + the Plasma
(Part 1, Slide 7)

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9
Q

What is interstitial fluid?

A

The fluid found in the spaces around cells in tissue, it surrounds cells providing a medium (instrument) for exchange of nutrients, gases, waste materials between blood vessels and cells
(Part 1, Slide 7)

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10
Q

Why do highly lipid soluble drugs (such as tricyclic antidepressants) have a large volume of distribution?

A

As they distribute far more widely into tissues
(Part 1, Slide 7)

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11
Q

What does a drug having a volume of distribution of 0.04L/kg in the plasma or less mean?

A

That it is thought to be confined to the plasma
(Part 1, Slide 7)

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12
Q

What does a drug having a volume of distribution value in the plasma larger than 0.6 L/kg thought to mean?

A

That the drug is thought to be distributed to all tissues in the body, especially the fatty tissue
(Part 1, Slide 7)

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13
Q

What does a drug having a volume of distribution value greater than 10,000 L mean?

A

That most of the drug is in the tissue and very little is circulating in the plasma
(Part 1, Slide 7)

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14
Q

What are 4 factors affecting distribution?

A

Answers include:
Molecular size
Lipid solubility
Ionisation
Binding to plasma proteins
Rate of blood flow
Special barriers
(Part 1, Slide 8)

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15
Q

What is the one-compartment model of volume of distribution?

A

The body is considered one single compartment, and a drug is assumed to spread itself uniformly throughout the body
(Part 1, Slide 12)

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16
Q

What is the two-compartment model of volume of distribution?

A

The body is considered to be 2 compartments, a central and a peripheral compartment and a drug is assumed to spread rapidly to the central compartment while spreading more slowly into the peripheral compartment
(Part 1, Slide 12)

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17
Q

Why are the one and two-compartment models of volume of distribution inaccurate?

A

As they are simplifications of a more complicated process, and some drugs can accumulate in specific compartments
(Part 1, Slide 14)

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18
Q

How can tetracycline cause tooth discoloration?

A

It accumulates in bones and tooth due to having a high affinity for calcium
(Part 1, Slide 14)

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19
Q

Where can amiodarone accumulate and what can this cause?

A

It accumulates in the liver and lungs and this can cause hepatitis and interstitial pulmonary fibrosis
(Part 1, Slide 14)

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20
Q

How can chloroquine lead to ocular toxicity?

A

It accumulates in the retina as it has ahigh affinity for melanin
(Part 1, Slide 14)

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21
Q

Why is partition (distribution) of drugs into fat a relatively small issue for most drugs?

A

As blood circulation to fat is low (<2% of cardiac output) resulting in a small amount of blood (and therefore drug in the blood) reaching fat
(Part 1, Slide 15)

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22
Q

Why is partition (distribution) of drugs into fat a problem for some drugs?

A

As they can accumulate in fat
(Part 1, Slide 15)

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23
Q

What is 1 way that drug accumulation into fat be resolved?

A

By adjusting certain drug dosages to account for obesity
(Part 1, Slide 15)

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24
Q

What are 3 types of drugs which commonly require dosage adjustment in obese patients?

A

Answers include:
Low-molecular-weight heparins
Aminoglycoside
Antibiotics
Certain anaesthetics
Monoclonal antibodies
Chemotherapeutics
(Part 1, Slide 15)

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25
Q

How are drugs transported in the bloodstream?

A

Partly in solution as free (unbound) drug and partly reversibly bound to blood components
(Part 1, Slide 16)

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26
Q

What do acidic and basic drugs bind more extensively to?

A

Acidic drugs bind more extensively to albumin whereas basic drugs usually bind more extensively to alpha-1 acid glycoprotein, lipoproteins or both
(Part 1, Slide 16)

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27
Q

How does the extent of a drug binding to a plasma protein and binding to tissues effect the extent of drug distribution?

A

As only unbound drug molecules are avalible for passive diffusion to extravascular or tissue sites where the pharmacologic effects of the drug occur
(Part 1, Slide 16)

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28
Q

What does the unbound drug concentration in systemic circulation typically determine?

A

Drug concentration at the active site and therefore efficacy
(Part 1, Slide 16)

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29
Q

How does the body act as a reservoir for a drug?

A

As it slowly delivers it to the organs of elimination (the liver and kidneys)
(Part 1, Slide 17)

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30
Q

What is drug elimenation?

A

The loss of a drug from the body
(Part 2, Slide 3)

31
Q

What is metabolism?

A

Conversion of a chemical entity
(Part 2, Slide 3)

32
Q

What is excretion?

A

Elimination of a substance from the body
(Part 2, Slide 3)

33
Q

What are the 2 main routes of drug excretion?

A

The liver and kidney
(Part 2, Slide 4)

34
Q

Other than the kidneys and liver, what are 4 other routes of drug excretion?

A

The intestines (through faeces)
The lungs (through breathing out)
The breasts (through breast milk)
Through the skin (via sweat)
Tears
(Part 2, Slide 4)

35
Q

What needs to be considered when a drug is excreted through breast milk?

A

Transfer to a baby / infant
(Part 2, Slide 4)

36
Q

What is a human mass balance study?

A

A key study in the clinical pharmacology package of new drug applications, with the goal being to understand how drugs are absorbed, metabolised and excreted after dosing
(Part 2, Slide 5)

37
Q

What are the 3 key objectives of a human mass balance clinical study?

A

To determine the mass balance of drug-related material following dose administration
To determine the ratio of parent drug to metabolite(s) in circulation
To determine the primary route of excretion of drug-related material
(Part 2, Slide 5)

38
Q

What 2 things are collected in a human mass balance clinical study to help understand the metabolites found?

A

Urine and faeces
(Part 2, Slide 5)

39
Q

Where does metabolism most commonly occur?

A

In the liver
(Part 2, Slide 6)

40
Q

What do phase 1 reactions of metabolism do?

A

Introduce a reactive group into the molecule
(Part 2, Slide 6)

41
Q

What are 3 examples of reactions that could occur in phase 1 of metabolism?

A

Oxidation
Hydroxylation
Dealkylation
Deamination
Hydrolysis
Reduction
(Part 2, Slide 6)

42
Q

What do phase 2 metabolism reactions allow?

A

Conjugation to the molecule
(Part 2, Slide 6)

43
Q

What does phase 2 metabolism reactions allowing conjugation to the molecule achieve?

A

It makes the molecule hydrophilic, thus making it suitable for elimination via the kidney
(Part 2, Slide 6)

44
Q

What are some compounds delivered as, and what do they need to rely to become an active agent?

A

Some compounds are delivered as a pro-drug and therefore rely on metabolism to transform them into an active agent
(Part 2, Slide 7)

45
Q

What are CYP450 enzymes?

A

They are a super family of enzymes which are typically involved in oxidation, reduction and hydrolysis phase 1 metabolism reactions within the liver
(Part 2, Slide 8)

46
Q

What can drug-drug interactions result in, involving CYP450 enzymes?

A

Drug-drug interactions can result in the induction (increase in) or inhibition of CYP450 enzymes which may result in undesirable clinical effects
(Part 2, Slide 8)

47
Q

What enzyme activity is reduced by liver disease?

A

CYP450 enzymes
(Part 2, Slide 8)

48
Q

Approximately what percentage of drugs in clinical use are CYP450 enzymes responsible for metabolising?

A

70-80%
(Part 2, Slide 8)

49
Q

Why is CYP3A4 often considered the most important drug-metabolising enzyme?

A

Due to its relatively high expression in the liver and intestine, though it’s hepatic expression does vary between individuals
(Part 2, Slide 9)

50
Q

Why can CYP3A4 be subject to drug-drug interactions?

A

Due to its major role
(Part 2, Slide 9)

51
Q

State 2 common drug-drug interaction involving CYP3A4.

A

Clarithromycin/erythromycin + simvastatin resulting in myopathy or rhabdomyolysis

Diltiazem / verapamil + prednisone resulting in immunosuppression due to increase prednisolone levels
(Part 2, Slide 9)

52
Q

What does myopathy refer to?

A

Any disease which affects the muscles which control voluntary movement in the body
(Part 2, Slide 9)

53
Q

What fruit is a potent inhibitor of intestinal CYP3A4?

A

Grapefruit
(Part 2, Slide 9)

54
Q

Most drugs are conjugated in phase 2 metabolism in the liver to enable excretion via the kidney, why do some drugs not have to go though this?

A

Some drugs are sufficiently water soluble to allow immediate excretion via the kidney
(Part 2, Slide 11)

55
Q

Where does a drug go when it’s taken orally?

A

It enters the intestinal bloodstream which goes via the liver before reaching the general circulation
(Part 2, Slide 12)

56
Q

What can the first pass through the liver when a drug is taken orally result in?

A

Extensive metabolism before a drug reaches the site of action
(Part 2, Slide 12)

57
Q

What are 3 examples of drugs which undergo extensive first pass metabolism?

A

Answers Include:
Aspirin
Isosorbide dinitrate
Levodopa
Lidocaine
Morphine
Propranolol
(Part 2, Slide 12)

58
Q

What is bioavalibility?

A

The proportion of a drug which enters the circulation when introduced to the body (and therefore is able to have an active effect)
(Part 2, Slide 13)

59
Q

What is hepatic extraction ratio?

A

The fraction of the drug entering the liver in the blood which is irreversible removed during one pass of the blood through the liver
(Part 2, Slide 13)

60
Q

How is hepatic extraction ratio calculated?

A

Amount in - amount out / amount in
(Part 2, Slide 13)

61
Q

What percentage of CYP450 enzymes does the intestine wall contain?

A

<1%
(Part 2, Slide 14)

62
Q

Name 1 example of a drug which the intestine wall significantly contributes to metabolising despite containing less than 1% of CYP450 enzymes.

A

Cyclosporine
Midazolam
Verapamil
(Part 2, Slide 14)

63
Q

What percentage of plasma reaching the glomerulus is filtered through pores in the glomerular endothelium?

A

20%
(Part 2, Slide 16)

64
Q

What 2 things are passively and actively reabsorbed from the renal tubules back into the circulation?

A

Water and electrolytes
(Part 2, Slide 16)

65
Q

What do large polar compounds, which make up most drug metabolites need to diffuse from the renal tubules back into the circulation?

A

A specific transport mechanism needs to exist for their reabsorption
(Part 2, Slide 16)

66
Q

Water soluble molecules are able to be excreted with urine. What happens to lipid soluble molecules?

A

They are able to cross the renal tubular membrane and be reabsorbed
(Part 2, Slide 17)

67
Q

How can transporters be used therapeutically?

A

They can provide competition for active secretion resulting in higher concentrations for a longer time
(Part 2, Slide 18)

68
Q

What is drug clearance?

A

The volume of plasma cleared of a drug over a specified time period
(Part 2, Slide 19)

69
Q

What is the unit of measurement for drug clearance?

A

Volume / time
(Part 2, Slide 19)

70
Q

How is drug clearance calculated?

A

Rate that the drug is removed from the plasma / concentration of the drug in plasma
(Part 2, Slide 19)

71
Q

What is the total rate of elimination?

A

A composite (sum) of the rate of all sites of metabolism and excretion
(Part 2, Slide 20)

72
Q

What does the rate of elimination vary with?

A

The drug plasma concentration (with higher concentrations resulting in a faster elimination rate)
(Part 2, Slide 20)

73
Q

How is the rate of elimination calculated?

A

The amount of drug elimination (mg)/ Time passed (h)
(Part 2, Slide 20)

74
Q

Why does rate of elimination matter?

A

As a high rate of elimination results in sharp peaks and troughs with limited accumulation when dosing is repeated whereas a low rate of elimination results in accumulations of the drug overtime with repeated doses
(Part 2, Slide 21)

BM213: Introduction to Pharmacology (15 decks)

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