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Semester 1 - ICPP > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

what are drugs?

A

exogenous

signalling molecules

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2
Q

what are the 4 main processes in drug therapy?

A

Absorption
Distribution
Metabolism
Elimination

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3
Q

what is the mnemonic for the 4 processes in drug therapy?

A

ADME

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4
Q

of the 4 main processes of drug therapy, which two are involved in ‘drug in’?

A

Absorption

Distribution

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5
Q

of the 4 main processes of drug therapy, which two are involved in ‘drug out’?

A

Metabolism

Elimination

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6
Q

what are the 2 types of drug administration

A

enteral

parenteral

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7
Q

what does enteral mean?

A

Delivery into internal environment of body - GI Tract

  • Oral
  • Sublingual
  • Rectal
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8
Q

what does parenteral mean?

A

Delivery via all other routes that are not the GI - includes

  • Intravenous
  • Subcutaneous
  • Intramuscular
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9
Q

What is a useful mnemonic to memorise the types of drug administration?

A 
Oi ! It is Sir! 
Oral 
Intravenous 
Intramuscular
Transdermal
Intranasal
Subcutaneous 
Sublingual
Inhalation
Rectal
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10
Q

describe the oral route of drug administration

A
  • Oral route - majority of formulations most convenient
  • Normally little absorption in stomach
  • Drug mixes with chyme enters small intestine
  • Constant GI movement - mixing - presenting drug molecules to GI epithelia
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11
Q

what is the typical transit time for the drug through the small intestines?

A

3-5 hours

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12
Q

what is the pH of small intestines?

A

weakly acidic 6/7

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13
Q

how can drug be absorped?

A

 Passive Diffusion
 Facilitated Diffusion
 Primary / Secondary Active Transport
 Pinocytosis

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14
Q

describe passive diffusion of drugs

A
  • Common mechanism for lipophilic drugs weak acids/ bases
  • Lipophilic drugs e.g. steroids diffuse directly down concentration gradient into GI capillaries. when drug enters the blood, it is immediately removed due to blood flow
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15
Q

describe passive diffusion of weak acids and bases

A

weak acids become protonated so become neutral so can pass through the membrane.
weak bases become deprotonated and become neutrak so can pass through the membrane

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16
Q

describe the absorption of valproate

A

Valproate : Anti -Epileptic Drug weak acid pKa = 5
• In gut at pH 6 - 10 % Valproate protonated - Lipophilic
• Lipophilic species crosses GI epithelia

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17
Q

describe facilitated diffusion in drug absorption

A 
Solute Carrier (SLC) Transport
• Molecules (or Solutes) with nett ionic + or - charge within GI pH range can be carried across GI epithelia
• Passive process based on electrochemical gradient for that (solute) molecule
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18
Q

what are solute carrier transporters?

A

SLCs are either Organic Anion Transporters and Organic cation Transporters
• Large family – expressed in all body tissues
• Pharmacokinetically important for drug absorption and elimination
• Highly expressed in GI, Hepatic and Renal Epithelia

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19
Q

describe secondary active transport in drug absorption

A

• SLCs can also enable drug transport in GI by Secondary Active Transport
• Not utilise ATP -Transport driven by pre-existing electrochemical gradient
across GI epithelial membrane e.g. Renal OATs and OCTs

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20
Q

give 2 examples of drugs that are absorbed using secondary active transport

A
  • Fluoxetine/Prozac - SSRI antidepressant co-transported with Na+ ion
  • Penicillins - co-transported with H+
    ion
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21
Q

what are the Physicochemical Factors that affect drug absorption?

A
  • GI length /SA
  • Drug lipophilicity / pKa
  • Density of SLC expression in GI
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22
Q

what are the GI Physiology factors that affect drug absorption?

A
  • Blood Flow: Increase post meal – drastically reduce shock/anxiety exercise
  • GI Motility: Slow post meal - rapid with severe diarrhoea
  • Food /pH: Food can reduce/increase uptake. Low pH destroy some drugs
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23
Q

how does first pass metabolism affect drug absorption?

A

‘First Pass’ metabolism: Reduces availability of drug reaching systemic circulation - therefore affects therapeutic potential

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24
Q

describe first pass metabolism in gut lumen and gut wall/liver

A

• Gut Lumen: Gut/Bacterial Enzymes - can denature some drugs
• Gut Wall/Liver: Some drugs metabolised by two major enzyme groups
Cytochrome P450s - Phase I Enzymes
Conjugating - Phase II Enzymes
• Much larger expression of Phase I &II Enzymes in Liver

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25
Q

define bioavailability

A

Fraction of a defined dose which reaches its way into a specific body compartment

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26
Q

describe bioavailability reference

A

• CVS (Circulation) is most common reference compartment
• For CVS/Circulatory Compartment
Bioavailability Reference - IV bolus = 100%
- No physical/metabolic barriers to overcome

• For other routes - compare amount reaching CVS by other route referenced
to intravenous bioavailability
• Most common comparison oral or (O)/(IV)

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27
Q

how do you work out oral bioavailability

(F)?

A

Measure:
• Total Area Under Curve for IV route
• Total Area Under Curve for Oral route

F = Amount reaching Systemic Circulation/ Total drug Given IV

F(Oral) = AUC(Oral)/AUC(IV)
• F lies between 0 and 1
• Informs choice of administration route

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28
Q

what is drug distribution?

A

How drugs journey through body
• To reach and interact with therapeutic and non-therapeutic target
• Interaction with other molecules - affect on pharmacodynamics

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29
Q

what is the first stage of drug distribution?

A
  • Bulk flow - Large distance via arteries to capillaries
  • Diffusion - Capillaries to interstitial fluid to cell membranes to targets
  • Barriers to Diffusion - Interactions /local permeability/non- target binding
30
Q

At the level of the capillary, how is the diffusion process affected by the ‘microleakiness’ of the capillaries?

A

• Differing levels of capillary permeability
• In certain capillary beds the capillary endothelial cells
can be fenestrated or sinusoidal meaning there are larger gaps for the drugs to diffuse through. For many drug molecules, these ‘leak’ points facilitate access into the interstitial fluid and from there onto the drug targets.
• Variation in entry by charged drugs into tissue interstitial fluid/target site
• Capillary membrane also express endogenous Transporter & OATs/OCTs

31
Q

what are the 3 types of capillaries?

A

continuous
fenestrated
sinusoids

32
Q

how are the structure in the body described?

A

• In reality body highly heterogenous set of
structures and tissues
• This heterogeneity and the differing proportion of major cellular and molecular types within a tissue, can significantly affect the concentration of drug
achieved throughout the different tissues
• Multiple mini ‘compartments’

33
Q

what are the Major factors affecting drug distribution?

A

Drug Molecule Lipophilicity/Hydrophilicity
Degree of drug binding to plasma and/or tissue proteins
The mass or volume of tissue and density of binding sites
within that tissue

34
Q

how does Drug Molecule Lipophilicity/Hydrophilicity affect drug distribution?

A

• If drug is largely lipophilic can freely move across membrane barriers
• If drug is largely hydrophilic journey across membrane barriers dependent
on factors described for Absorption
 Capillary permeability ( very ‘tight’ to very leaky )
 Drug pKa & Local pH
 Presence of OATs/OCTs (in capillary and target tissue membranes

35
Q

how does Degree of drug binding to plasma and/or tissue proteins affect drug distribution?

A

In circulation many drugs bind to proteins e.g.
 Albumin - Globulins
 Lipoproteins - Acid glycoproteins

• Only free drug molecule can bind to
target site(s)
• Binding in plasma/tissue decreases
free drug available for binding
• Plasma/Tissue protein bound drug
acts as ‘dynamic reservoir’
36
Q

describe the equilibrium between bound and unbound protein

A 
• Binding forces not strong
– bound/unbound in equilibrium
• Binding for given drug can
• be up to  100% (Aspirin  50% )
• Varying number of binding site
for given drug
• Competition for binding site
affects free plasma conc and
Pharmacodynamics
37
Q

how do we make it simpler to think of how drug moves throughout whole body?

A

Drug Molecules are Solutes in Body Fluid Compartments:
Body Fluid Compartments: A Simple Model for Drug
Distribution in the Human Body
• Simplify body fluid compartments in to model with three main compartments -
- Plasma Water = Plasma Water
- Extracellular Water = Plasma Water + Interstitial Water
- Total Body Water = Plasma Water + Interstitial Water + Intracellular Water

38
Q

what does Increasing Penetration by Drug into Interstitial and Intracellular Fluid Compartments Lead to?

A

 Decreasing Plasma Drug Concentration

 Increasing Vd

39
Q

what is the‘Apparent’ Volume of Distribution (Vd)?

A

it is a ratio used to estimkate the distribution of a drug within the body relative to the total amount of fluid in the body.
Models grouping of main fluid compartments as though ‘All One Compartment’
• Hence ‘Apparent’ : it’s a very useful ‘Pretend’ Concept
• Provides summary measure of drug molecule behaviour in distribution
• Referenced to Plasma concentration – easiest to measure
• Summarises movement out of Plasma –> Interstitial
–> Intracellular Compartment
• Vd value dependent on push/pull factors described

40
Q

what is the equation for the ‘Apparent’ Volume of Distribution (Vd)?

A

Volume of Distribution (Vd) = Drug Dose/[Plasma Drug]t=0

41
Q

what does smaller values of Vd mean?

A

Smaller Vd values - less penetration of Interstitial/Intracellular Fluid Compartment

42
Q

what does larger values of Vd mean?

A

Larger Vd

values - greater penetration of Interstitial/Intracellular Fluid Compartment

43
Q

what are the Vd units?

A

Litres (assume ‘standard’ 70 kg body wt. )

Litres/kg (more referenced to individual patient body wt. )

44
Q

what is drug elimination?

A

Elimination
• Term used to cover both Metabolic and Excretory Processes
• Both ‘flow’ processes closely integrated to optimise drug removal

45
Q

what 2 functions does drug elimination have?

A

• Protective and Homeostatic function

46
Q

what is the evolutionary advantage of drug elimination?

A

• Evolutionary advantage in recognising xenobiotics – potential toxins

47
Q

what type of molecules does elimination remove?

A

• Elimination removes both exogenous and endogenous molecular species

48
Q

what is drug metabolism?

A

drug metabolism refers to the conversion of a drug from its active form to an inactive form(can be broken down).
Once metabolised - drugs usually inactivated but not always

49
Q

where does drug metabolism largely take place and via which enzymes?

A

Drug Metabolism largely takes place in Liver via Phase 1 and II enzymes

50
Q

how many phases are there in hepatic metabolism?

A

Phase 1 and II

51
Q

where are phase I and phase II enzymes normally found?

A

found all over the body however the major abundance of these enzymes would be in the liver - Very large hepatic reserve – also ‘first port of call’ after GI absorption

52
Q

what is the function of phase 1 and phase 2 enzymes in drug metabolism?

A

Metabolise drugs - increase ionic charge in order to enhance renal elimination.
an example of lipophilic drugs, without being acted on by these enzymes, they’d diffuse out of the renal tubes and back into plasma meaning they won’t be excreted.

53
Q

which molecule carries out phase 1 metabolism?

A

Phase 1 Metabolism is carried out by Cytochrome P450 Enzymes

54
Q

what are Cytochrome P450 Enzymes(CYP450s)?

A

they are large group of isozymes that you can find on the external side of the ER. They;re versatile generalists which means that they can metabolise a wide range of molecules. However, they carry this process out slowly.

55
Q

what is the function of Cytochrome P450 Enzymes?

A

their job is to increase the ionic charge in drugs, they do this through catalysing redox, dealkylation and hydroxylation reactions

56
Q

what happens to the drugs after they are metabolised by phase 1 enzymes?

A

they will either be eliminated immediately or will go to phase 2

57
Q

what are pro-drugs?

A

they are inactive drugs which become active after being metabolised by phase 1 enzymes.

58
Q

give an example of a pro drug

A

an example is codeine which is activated to morphine. codeine is metabolised by the CTYP2D6 enzyme, this enzyme shows genetic polymorphism

59
Q

which molecules carry out phase 2 metabolism?

A

Phase 1I Metabolism is carried out by Hepatic Enzymes

60
Q

what is the difference between hepatic enzymes and CTYP2D6 enzymes?

A
  • Phase I1 enzymes - mainly cytosolic enzymes - not membrane bound like CTYP2D6 enzymes
  • Phase II still generalists but exhibit more rapid kinetics than CYP450s
61
Q

describe phase 2 drug metabolism

A
  • Enhance hydrophilicity by further increasing ionic charge - add to Phase I
  • Catalyse: Sulphation - Glucorinadation - Glutathione conjugation - .Methylation and N-acetylation
  • Phase II metabolised drugs have further increased ionic charge
  • Phase II metabolism enhances renal elimination
62
Q

describe the Cytochrome P450 Enzymes and give the 5 main isozymes

A

Cytochrome P450 enzymes include three superfamilies
• Three superfamilies CYP 1, 2 and 3
• Isozyme members in each family coded by suffix: e.g. CYP3A4
• Six isozymes metabolise around 90% prescription drugs. 5 of these are:CYP 1A2, CYP 2C19, CYP 2D6, CYP 2C8/9, CYP 3A4/5
• Other isozymes exhibit very variable hepatic expression
• Each isozyme optimally metabolise specific drugs but do show overlap

63
Q

what are the factors that affect drug metabolism?

A

Many Factors of Direct Clinical Relevance
• Age (Variable patterns in paediatric groups reduced in elderly)
• Sex (gender differences drugs e.g. alcohol metabolism slower in women)
• General Health/Dietary/Disease - you need to consider the health of the liver, kidneys and the CVS(HRH)
- negative effects of this causes a Decreased Functional Reserve

CYP450s:
• Other drugs (Rx/OTC) can induce or inhibit CYP450s
• Genetic variability/polymorphism/ non-expression affects CYP450s

64
Q

what are the Major Categories for Factors

affecting Drug Elimination: The Royal Acronym HRH?

A
  • Heart (CVS)
  • Renal
  • Hepatic

–>Decreased Functional Reserve

65
Q

describe CYP450 induction and the therapeutic consequences of this

A

• Concurrent administration of certain drugs (including just the one drug) can
induce specific CYP450 isozymes
• Induction mechanism via: increased transcription ; increased translation ; slower degradation
• If another drug in body metabolised by induced CYP450 isozyme then its
rate of elimination will be increased
• Plasma levels of drug will then fall
• For patient can have serious therapeutic consequences if levels drop significantly
• Induction process typically occurs over 1-2 weeks

66
Q

give an Example of a drug that is affect by CYP450 Induction?

A

Carbamezepine (CBZ)
• CBZ is an anti-epileptic metabolised by CYP3A4
• CBZ induces CYP 3A4 – lowering its own levels affecting control of epilepsy
• CBZ needs careful monitoring in first few month post prescription

67
Q

describe CYP450 Inhibition

A

• Concurrent administration of certain drugs (including just the one drug) can
inhibit specific CYP450 isozymes
• Inhibition mechanism via: competitive/non-competitive inhibition
• If another drug in body metabolised by inhibited CYP450 isozyme then its
rate of elimination will be slowed down
• Plasma levels of drug will then increase
• For patient can have serious side effects consequences if levels rise significantly
• Inhibition process occurs within 1 to a few day

68
Q

give an example of CYP450 Inhibition

A

Grapefruit Juice
• Grapefruit Juice inhibits CYP 3A4
• CYP 3A4 metabolises Verapimil used to treat high blood pressure (BP)
• Consequence can be much reduced BP and fainting

69
Q

describe how genetic factors can affect phase 1 drug metabolism and what needs to be considered in relation to this

A

when it comes to certain CYP450 isozymes, there is genetic variation present that affects who is more likely and unlikely to present it.
for example:
• CYP2C9: Not expressed in: 1% Caucasians; 1% Africans
• Metabolises NSAIDs, Tolbutamide, Phenytoin,
• CYP2C19: Not expressed in: 5% Caucasians; 30% Asians
• Metabolises Omeprazole, Valium, Phenytoin

• Need to consider safety/efficacy if not metabolised /rapidly metabolised

70
Q

what is Genetic Polymorphism?

A

the term relates to existence of multiple forms of a gene

71
Q

describe how genetic polymorphism affects phase 1 drug metabolism

A

‘Pro-drugs’ activated by Phase I metabolism to active species
Earlier example: Codeine to Morphine
• CYP2D6 gene highly polymorphic
• CYP2D6 variants categorized into: poor; normal/high; ultrarapid metabolisers
Poor - codeine to morphine - may not experience pain relief
Ultrarapid - codeine to morphine - lead to morphine intoxication/ADRs

Semester 1 - ICPP (7 decks)

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