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ICPP > Session 7: Pharmoacokinetics > Flashcards

Session 7: Pharmoacokinetics Flashcards

1
Q

What are the main 4 factors affecting rates of drug in-drug out?

A

Absorption
Distribution
Metabolism
Elimination

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2
Q

What are the main routes of drug administration?

A 
Oral 
Transdermal 
Topic 
Subcutaneous
Intravenous
Intrathecal
Intramuscular 
Rectal
Inhalation
Sublingual
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3
Q

Relating to drug administration, what is the difference between enteral and parenteral?

A

Enteral is delivered into the internal environment of the body
Parenteral is delivery to all the other routes that are not the GI

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4
Q

If a drug is given in tablet or capsule form, the stomach is largely where what occurs?

A

Disintegration and disaggregation of the tablet

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5
Q

Does much absorption take place in the stomach for most drugs? Why is this?

A

No, little absorption takes place here because of the thick mucous layer that protects it from self digestion limits the absorption

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6
Q

How do the majority of enteral drugs enter the circulation?

A

They mix with gastric fluid and chyme and enter the weakly acidic environment of the small intestine, where the majority of drug absorption takes place

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7
Q

What are the plicae circulares?

A

The small circular folds of the small intestine

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8
Q

What is the role of the plicae circulares?

A

To increase the overall surface area of the small intestine

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9
Q

Apart from the plicae circulares, what other features of the small intestine help in increase the surface area?

A

Villi

Microvilli

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10
Q

What is the typical transit time through the small intestine?

A

3-5 hours

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11
Q

Apart from the physical dimensions of the small intestine, what other feature is a key factor in its role in drug absorption? Why is this important?

A

pH: weakly acidic (between 6-7)

It is important in determining the ratio of drug molecule that exists in ionised and unionised state

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12
Q

What are the 4 major mechanisms of drug absorption?

A

Passive diffusion
Facilitated diffusion
Active transport
Pinocytosis

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13
Q

What is the most common way that drugs can pass across lipid membranes?

A

By being of small molecular weight and not strongly ionic (lipophillic)

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14
Q

How do lipophilic molecules pass through the lipid membrane?

A

Passive diffusion

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15
Q

What kind of molecules are lipophilic?

A

Steroids

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16
Q

How is the concentration gradient of the drug maintained when the drug diffuses across the lipid membrane?

A

The drug is constantly carried away from the gut by the capillary supply of the small intestine

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17
Q

At physiological pH, if a drug is acidic, what does this mean?

A

It will release a proton (H+) to go from HA to H+ and A-?

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18
Q

At physiological pH, if a drug is basic, what does this mean?

A

It will gain a proton (H+) to go from B to BH+

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19
Q

Does the ionised form of a drug diffuse readily across the lipid bilayer?

A

No, it cannot diffuse directly through

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20
Q

How does the ionised form of a drug pass through the lipid bilayer?

A

Facillitated diffusion

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21
Q

The rate of uptake of weak acids or bases depends on what?

A

pKa or pKb

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22
Q

What is the pKa or pKb?

A

The pH value at which the weak acid or base exists in the 50% ionised and 50% unionised form

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23
Q

What determines the rate of diffusion across from the gut lumen into the epithelial cells?

A

The proportion of the drug that exists in the unionised/ionised state

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24
Q

What equation do we use to work out how well a drug will diffuse passively out of the lumen of the small intestine?

A

Henderson-Hasselbach

pKa= pH + log10 [AH]/[A-]

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25
Q

If we know that the proportion of [HA]/[A-] is 0.1, what does this tell us about the drugs ability to pass through the lipid membrane?

A

Irrespective of drug concentration, 10% is unionised at that point and therefore 10% of the drug will be able to diffuse across the membrane

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26
Q

When the drug moves out of the gut lumen as an AH (unionised) species, how is the equilibrium, as defined by Henderson-Hassebach equation, kept?

A

More A- ions will combine with free protons to become AH and move across the membrane by passive diffusion

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27
Q

Give examples of molecules that have low lipid solubility with a nett residual ionic charge

A

Glucose
Amino acids
Neurotransmitters

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28
Q

How do molecules such as glucose, amino acids and neurotransmitters pass through the lipid membrane, despite their low lipid solubility and ionic charge?

A

Facilitated diffusion

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29
Q

Is facilitated diffusion an active or a passive process?

A

Passive

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30
Q

How does facilitated diffusion work?

A

Using the electrochemical concentration gradient across the cell membrane

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31
Q

What are OCTs?

A

Organic Cation Transporters

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32
Q

What are OATs?

A

Organic Anion Transporters

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33
Q

What are the solute carrier proteins?

A

OCTs and OATs

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34
Q

Where are OCTs and OATs expressed in the body?

A

Throughout all body tissues

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35
Q

What are the two types of active transport and how do they differ?

A

Primary- The direct use of ATP to transport molecules across a lipid membrane
Secondary- The indirect use of ATP to transport molecules across a lipid membrane (to set up the electrochemical gradient)

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36
Q

OCTs and OATs can use which type of active transport to move ionised molecules across the lipid bilayer?

A

Secondary active transport

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37
Q

What process is important for the transport of large molecules across the blood brain barrier?

A

Endocytosis

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38
Q

When would exocytosis be used during drug absorption?

A

Delivery of hormones more locally for neurotransmitters into the synaptic cleft

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39
Q

What anatomical/physiological factors of the gut could affect drug absorption?

A

The structure of the stomach and gut lumen:
e.g. total surface area available, gut lumen pH, density of active and passive transport mechanisms, blood flow
Drug metabolism in the gut:
e.g. First pass metabolism

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40
Q

What is a xenobiotic?

A

A compound that is foreign to the body that is not normally produced or found in the body

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41
Q

Virtually all molecules that are absorbed by the gut will travel via what to where?

A

The hepatic portal vein

Liver

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42
Q

What happens to the drug during passage through the liver?

A

It will enter liver cells and be metabolised by Phase I and phase II enzymes

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43
Q

What is bioavailability?

A

The relative amount of a drug that reaches the greater systemic circulation (once the drug has gone through their first passage of hepatic circulation)

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44
Q

What does the fraction of bioavailability tell us about the drug?

A

It reflects all the physiochemical and biological barriers to its absorption and post hepatic systemic distribution

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45
Q

How do you work out the bioavailability of a drug?

A

Amount of drug reaching systemic circulation / total amount of drug administered

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46
Q

Which route of administration will usually involve more barriers to systemic uptake than intramuscular or subcutaneous routes?

A

Oral (Enteral)

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47
Q

What is the bioavailability of drugs administered by the IV route?

A

1

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48
Q

How do we work out oral bioavailability (F)?

A

Amount of drug getting in by oral route/ amount of drug administered from the IV route

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49
Q

What can oral bioavailability fraction tell us about a drug?

A

Tells us the optimal route a drug needs to be given to reach its therapeutic concentration and therefore determines the amount of drug the oral formulation needs to be given

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50
Q

What is AUC?

What does this tell us?

A

Area under curve

It is the total drug exposure overtime

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51
Q

What happens to AUC as you decrease oral bioavailability?

A

AUC decreases

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52
Q

What is the drug distribution defined as?

A

How the drug molecule reaches and interacts with its cellular targets

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53
Q

Once a drug gets into the cardiovascular system proper, how it is rapidly distributed around the body over large distances?

A

Bulk flow through the arterial system

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54
Q

Following bulk flow via arteries, drugs will transverse over much shorter distances via what method of transport?
From where to where?

A

Diffusion

Capillaries to surrounding interstitial fluid and tissues

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55
Q

The overall rate of delivery to a given tissue bed is dependent on what?

A

The density of the capillary supply

The ‘micro-leakiness’ of the capillaries

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56
Q

The drug will reach well __________ organs such as ______, ________, _________ more rapidly than skin, bone or adipose tissue

A

vascularised
kidneys
heart
lungs

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57
Q

True or false: There are varying degrees of “leakiness” depending on the tissues supplied by capillaries

A

True

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58
Q

Which tissues have more “leaky” capillary beds?

How is this achieved?

A 
Intestinal
Endocrine
Pancreatic
Kidney
Achieved through cells being fenestrated by pores
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59
Q

In tissues of the liver, bone marrow, lymph and spleen, endothelial cells are separated by what?
What does this allow?

A

Slit junctions or large intercellular gaps

Allows large movements of molecular material

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60
Q

How do lipophilic drugs enter the brain?

A

Diffusion

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61
Q

How do endogenous compounds and drugs with a residual electrical charge cross the blood brain barrier?

A

Vesicles, depends on the drug

62
Q

What are the major factors affecting distribution of a drug throughout the body?

A

Lipophilicity
Degree of binding to plasma protein
Degree of binding to tissue protein
Mass or volume of tissue and density of binding sites

63
Q

How does lipophilicity relate the to movement of drug out of plasma and into tissues?

A

The more lipophillic a molecule is, the greater it will be able to move from plasma and into surrounding tissues, especially those with high lipid content

64
Q

What factors relate to further penetration of tissues once they have entered from the plasma?

A

pH of the tissue interstitial fluid
pKa of the drug
presence of OAT/OCT carriers

65
Q

What is the main plasma protein?

A

Albumin

66
Q

How do drug molecules bind to albumin?

A

Relatively weak electrical polar bonding but enough for them to act as a reservoir

67
Q

What does the fact that drugs can bind to plasma proteins mean in terms of the drugs affects?

A

It means that it contributes to the concentration of “free” unbound drug that is available to exert a pharmacological and hence therapeutic effect

68
Q

In plasma, there is an __________ between the protein bound and unbound form. What does this mean in terms of the proportion of drug that is bound and the concentration of the drug?

A

equilibrium

That the proportion of the drug that is bound to proteins remains the same despite the concentration of the drug

69
Q

The body fluid compartments in order of drug movement can be modelled as:

A

Plasma water = plasma water
Extracellular water = plasma water + interstitial water
Total body water = plasma water + interstitial water + intracellular water

70
Q

What is the order of drug passing through either “body fluid compartment”

A

Plasma –> Interstitial fluid –> Intracellular fluid

71
Q

Plasma water is about ____L or about _____% of our total body weight

A

3L

4.5%

72
Q

Interstitial fluid is about ____L or about _____% of our total body weight

A

11L

15.5%

73
Q

Intracellular water is about _____L or about _____% of our total body weight

A

28L

40%

74
Q

Total body water is about 42L or about ____% of our total body weight

A

42L

60%

75
Q

What is a drugs ‘Apparent’ Volume of Distribution (Vd)?

A

A value that tells us how the drug will behave in the whole body and generally partition into tissues

76
Q

What is a very important aspect of calculating the Vd?

A

That concentrations are references to the real plasma concentrations of the specific drug of interest

77
Q

What is the equation used for Vd?

A

Total amount of drug in body / plasma concentration of drug ( at time= zero)

78
Q

If drug can diffuse out of the plasma compartment and pass into other real fluid compartments, because it is more lipid soluble or less highly bound, will it have a higher or a lower plasma concentration?

A

Lower

79
Q

What happens to the concentration of drug with increasing water volume?

A

Concentration of drug decreases with increasing water volume

80
Q

What happens to the drug concentration in plasma as the volume of distribution is increased?

A

The drug concentration in plasma is lowered as the volume of distribution increases

81
Q

On a graph of Time against the log scale of Volume of Distribution, how do we work out the “Apparent Volume of Distribution”?
What do you have to ignore for this back extrapolation?

A

By back extrapolating along the log drug concentration curve until it reaches the y-axis i.e. time=zero.
You have to ignore the early distribution phase

82
Q

What units can be used to express Vd?

A

Litres OR Litres/Kg (where the average theoretical body weight is 70kg)

83
Q

Why might the L/Kg value of Vd be preferred in the clinical setting rather than just as L?

A

Because body weight varies in individuals and patient groups and the dosing schedule of the drugs will be different in each in order to reach therapeutic concentrations

84
Q

Vd can be considerably affected by what?

A

Changes in protein binding throughout both fluid and tissue compartments
Other drugs: binding sites may be taken up by these drugs

85
Q

Why is the volume of distribution an ‘apparent’ volume of distribution?

A

The model treats each distinct tissue compartment as comparable when the drug will actually move into different tissue compartments (lung,skin,brain,heart,adipose) differently. They are not ‘real’ volumes

86
Q

The tissue compartments apparent ‘volume’ for any given drug is really dependent o what?

A

How much binding capacity they have for a given drug

87
Q

Why are drugs eliminated from the body?

A

Prevent them from remaining in the body and accumulating and disrupting homeostatic regulation

88
Q

Generally, how are drugs eliminated from the body?

A

By changing the structure of the drug in two major ways: Oxidation/reduction or hydrolysis

89
Q

What happens during Phase I reactions of drug elimination?

A

Introduction or unmasking of more polar groups on the molecule (such as -OH or -NH2)

90
Q

What happens during Phase II metabolic reactions of drug elimination?

A

Addition of a number of available molecules that conjugate with the drug molecule

91
Q

What are some important conjugating molecules that are used during Phase II elimination?

A

Glycine
Glutathione (Glutamate, Cysteine, Glycine)
Glucoronate (Very similar in structure to glucose)

92
Q

What molecules can be added to drugs to enhance their polarity?

A

Methyl groups
Acetyl groups
Sulphate groups

93
Q

Where do Phase I and Phase II reactions usually take place?

A

Liver

94
Q

Enzymes for Phase I and Phase II can also be found where, besides the liver?

A

Throughout most tissue types in varying degrees

95
Q

First pass metabolism at the _____ can also contribute to drug metabolism

A

Gut

96
Q

Why are drugs metabolised during Phase I and Phase II reactions?

A

To enhance their ionic charge and make them easier to eliminate/excrete at the kidneys

97
Q

Why is it essential that lipophilic compounds in particular are metabolised?

A

Otherwise, they will diffuse back down their concentration gradients through the renal cell membranes and back into the plasma

98
Q

Phase I metabolism is carried out by what?

A

Cytochrome P450s (CYP450s)

99
Q

Where are CYP450s located?

A

The external face of the ER in hepatocytes

100
Q

True or false: Drugs can be eliminated only following Phase I and Phase II reactions?

A

False, they can be eliminated directly after phase I, after both phase I and II, or can enter directly into phase II and be eliminated following that

101
Q

Why might some drugs bypass phase I metabolism?

A

If they already possess -OH, -NH2 or COOH groups

102
Q

How many isoenzymes metabolise 90% of prescription drugs?

A

6

103
Q

True or false: There is a wide range of variability between individuals and types of CYP450 expression

A

True

104
Q

The CYP family of enzymes are said to be what in terms of the molecules that they can metabolise?

A

Generalists

They are not designed to metabolise specific molecules but deal with a wide range of molecules

105
Q

What aspect of CYP family of enzymes can explain the great variation in elimination half-lives seen in drugs?

A

The versatility of the enzymes in the molecules that they metabolise, rather than being highly specific

106
Q

Metabolic elimination takes place how soon after the drug enters the liver?

A

As soon as it does, no waiting

107
Q

What are some factors that may affect metabolic elimination?

A 
Sex
Age
Genetic status
Cardiac output 
Disease state
108
Q

True or false: Some drugs can inhibit or induce CYP450 enzymes

A

True

109
Q

What three way can induction of CYO450 family members take place?

A

Transcription
Translation
Slower degradation

110
Q

Induction will lead to more rapid _______ of the therapeutic substrate

A

Elimination

111
Q

True or false: Some drugs can induce their own metabolism

A

True

112
Q

Some drugs can inhibit P450 enzymes which can result in what ?

A

Elevation of plasma levels

Rick of toxic side effects

113
Q

Inhibition of CYP450s can occur in which two ways, explain them both?

A

Competitively- two drugs being metabolised at the same site

Non-competitively- inhibitor being at a separate site

114
Q

How long does induction of CYP450 by drugs typically take?

A

1-2 weeks

115
Q

How long does inhibition of CYP450 by drugs typically take?

A

1-3 days

116
Q

In some cases metabolism is required for an inactive _______ to become active

A

pro-drug

117
Q

The vast majority of excretion is carried out where?

A

At the kidney

118
Q

Apart from the kidney, some drugs can also be excreted via what?

A

The intestinal route, the lungs, sweat or other bodily fluids

119
Q

Renal excretion is recognised as being divided into what three parts?

A

Glomerular filtration
Proximal tubular secretion
Distal tubular reabsorption

120
Q

Metabolism involves increasing the what of drugs by biotransformation?

A

Ionic nature

121
Q

Why does the liver need to metabolise the drugs that pass through it to help the kidney to secrete them?

A

By making the drugs more ionic, they will be excreted out of the plasma more easily as they can diffuse across the tubule with the help of OATs and OCTs and they are less likely to diffuse back into plasma

122
Q

About how much of the renal blood supply serves the glomerulus?

A

20%

123
Q

How does the unbound free fraction of the drug and its metabolites get into the Bowman’s capsule?
What is this process limited by?

A

Diffuses through capillary slits

Overall glomerular filtration

124
Q

If 20% of renal blood supply serves the glomerulus, where does the remaining 80% of renal blood go?

A

Through the peritubular capillaries of the proximal tubule

125
Q

How are suitably charged drug molecules and their ionic metabolites transported into the tubular lumen?

A

By secondary active transport by OATs and OCTs

126
Q

The general OATs transport what kind of molecules?

A

Deprotonated weak acids

127
Q

The general OCTs transport what kind of molecules?

A

Protonated weak bases

128
Q

Why is the process of proximal tubular secretion more effective than the passive process that occurs in glomerular filtration?

A

Because it is served by 80% of the renal blood supply

129
Q

What happens to drug metabolite concentration during distal tubular reabsorption?

A

As water is reabsorbed along the length of the tubule the drug metabolite concentration increases

130
Q

What happens during distal tubular reabsorption if the drug metabolite is in a lipophilic form?

A

It will passively diffuse down it’s concentration gradient back into the bloodstream, resulting in a lower rate of effective elimination

131
Q

What is drug clearance?

A

The overall rate of elimination of a drug from the body

132
Q

The total body clearance of a drug includes all the contributions made by what processes?

A

Biotransformation

Excretion

133
Q

For the majority of drugs, the major routes of elimination are what?

A

Hepatic and renal

134
Q

Total body clearance=

A

Hepatic Clearance + Renal Clearance

135
Q

Using a model to represent a real compartment i.e. plasma, how could we define the clearance of a drug from that compartment?

A

The volume of plasma that is completely cleared of the drug per unit time

136
Q

Why is understanding the rate of clearance important?

A

Because the rate of clearance affects how long the drug stays in the body and along with Vd, what dosing levels are required to reach a therapeutic range
It also affects how toxic levels of the drug are reached

137
Q

The balance between the rate of ______ and ______ will determine the level of drug in the plasma. Which in turn determines the balance between therapeutic benefit and the risk of what?

A

Drug in
Drug out

Side effects

138
Q

Factors that affect elimination will also affect clearance, they are?

A

Heart
Renal
Hepatic

139
Q

What is the definition of drug half life (t1/2)?

A

The amount of time over which the concentration of a drug in plasma decreases to one half of that concentration from when it was first measured

140
Q

Why is Drug Half- Life clinically important?

A

It tells us how long the drug will stay in the body and what the repeat dosing regime is going to be like to achieve therapeutic concentration

141
Q

At time zero, the amount of drug in the body is what?

A

100%

142
Q

To calculate the proportion of drug in the body at 6 half lives what do we do?

A

1/2 x 1/2 x 1/2 x 1/2 x 1/2 x 1/2 = 1.5%

143
Q

What are the units for clearance?

A

ml/min

144
Q

What is first order/linear kinetics?

A

When metabolism or excretion is proportional to the concentration of drug

145
Q

What is zero order/non-linear kinetic?

A

When the CYPs/enzymes/transporters are saturated as they cannot work any faster and therefore the rate of clearance is reduced

146
Q

Most drugs taken alone at therapeutic level have what order kinetics? Why?

A

First-order (Linear)

Because the CYPs/enzymes/transporters can deal with them

147
Q

At higher concentrations, elimination of drugs will at some point become what?

A

Non-linear (saturated)

148
Q

Under what circumstances can saturation happen, besides high concentration of drug?

A

When the volume of distribution factors (circulation, renal and hepatic) all act to reduce affect half-life and clearance. For example: In the very ill, In the elderly

149
Q

In zero order kinetics relatively small dose changes can do what?

A

Produce large increments in plasma drug concentration

Lead to serious toxicity

150
Q

During zero order kinetics, is the 1/2 life calculable?

A

No, it is hard to predict the dosage regimes

151
Q

Give some examples of drugs that exhibit zero order kinetics

A

Prozac
Alcohol
MDMA
Paracetamol

152
Q

The possibility of non-linear clearance kinetics increases with what?

A

Polypharmacy

ICPP (8 decks)

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