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Lab 3 > PK ADME > Flashcards

PK ADME Flashcards

1
Q

What is pharmacokinetics?

A

study of what body does to drug

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2
Q

What type of relationship does pharmacokinetics deal with?

A

dose-concentration

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3
Q

how does pharmacokinetics link dose and concentration?

A

links how the dose delivered affects the concentration within the body

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4
Q

What is pharmacodynamics?

A

study of what drug does to body

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5
Q

What type of relationship does pharmacodynamics deal with?

A

concentration-effect relationship

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6
Q

How does pharmacodynamics link concentration and effect?

A

it determines how the effect varies with concentration achieved

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7
Q

Draw a plasma concentration graph typical of an immediate-release oral dosage form. Label the axes, Cmax, AUC, elimination, therapeutic window, absorption, distribution, elimination, toxic, effect/potency, and no effect

(look at image p 32)

A
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8
Q

once drug absorbed in, what are the 2 forms of drug in body and are they permanently in these states/ can they change?

A

free drug
bound drug

eqm so can change

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9
Q

bound drug is sequestered (concealed) in blood, meaning…

A

cant leave, cant distribute to other compartments and sites to where It needs to act. And not free to do its job

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10
Q

plasma conc/ time curve: difference between IV and IR oral formn curves?

A

IR oral: drug conc 0% at start
IV: straight into bloodstream, so have some drug at 0min

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11
Q

What does the absorption of ADME describe?

A

how drug gets from dosage form -> site of action (normally blood)

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12
Q

usually for PK purposes what is the site of action?/ where is the drug measured?

A

blood

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13
Q

absorption is defined by a rate constant (Ka) and is linked to what?

A

rate at which drug is absorbed into the blood

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14
Q

what is the term given to the mass of drug that is administered?

A

dose

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15
Q

how much drug gets into the blood how quickly in an INTACT form?

A

BA (bioavailability

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16
Q

once drug crossed gut wall it travels across portal vein to what organ for metabolism before reaching the bloodstream?

A

liver

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17
Q

the apparent volume into which a drug is distributed depending on drug properties?

A

Vd

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18
Q

why are plasma protein and tissue bound drug molecules not included in the free concentration levels in the blood?

A

unable to act

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19
Q

drug in liver can be secreted into bile which is then secreted into small intestine, what does this mean for absorption?

A

reabsorbed

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20
Q

absorption form GI tract is X and Y

A

complex and dynamic

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21
Q

What does the distribution of ADME describe?

A

how the drug moves about the body, and how this movement may affect the concentration

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22
Q

What 2 pharmacokinetic parameters relate to distribution?

A

Vd
plasma/tissue binding

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23
Q

Drug in blood can -> (irreversible go to) to….

A

receptor binding -> effect

liver, bile + reabsorb/ metabolise
kidney + metabolise
-> excreted

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24
Q

Drug in blood can be <-> (in eqm) to….

A

drug in…
adipose tissue storage
peripheral tissues (stoage)

drug-plasma protein complex

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25
Q

What does the metabolism of ADME describe?

A

how the drug is altered once in the body

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26
Q

What occurs in phase 1 metabolism?

A

drug made more hydrophilic via oxidation, reduction or hydrolysis

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27
Q

What occurs in phase 2 metabolism?

A

drugs conjugated to allow for easy excretion

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28
Q

a chemical that is admin in non active form and is activated via a metabolic reaction such as codiene?

A

prodrug

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29
Q

What is first-pass metabolism?

A

extensive metabolism drugs passing through liver before reaching blood experience before reaching target site e.g. orally administered drugs

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30
Q

most common consequence of metabolism: metabolite may have….

A

no or reduced activity (compared to the parent compound)

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31
Q

what 2 things can also change if structure of durg changes?

A

function and efficacy

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32
Q

What does the elimination of ADME describe?

A

how the drug leaves the body

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33
Q

What are the two types of drug elimination?

A
  • renal
  • hepatic
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34
Q

What is renal elimination?

A

Elimination of polar drugs via the kidney

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35
Q

What is hepatic elimination?

A

excretion of drugs via liver

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36
Q

What is clearance (+units)?

A

volume of plasma/blood that is cleared of drug per unit time
(L/h)

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37
Q

are polar drugs likely to excreted renally or hepatically?

A

renally

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38
Q

What is half-life (+units)?

A

time taken for the concentration of the drug in the blood to fall to half its original value
(hrs)

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39
Q

absorption is all processes from…. to….

A

All processes from the site of administration to the site of measurement

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40
Q

What is disposition?

A

The processes that occur following absorption; e.g distribution and elimination

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41
Q

Distribution: The X transfer of drug to and from the site of measurement

A

reversible

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42
Q

Elimination: X loss of drug from the site of measurement. And how many processes can it occur by?

A

Irreversible
2: excretion and metabolism

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43
Q

What is excretion?

A

Irreversible loss of unchanged drug from the body

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44
Q

Metabolism: Conversion of the drug to an ….

A

alternative chemical species

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45
Q

formulations that show equivalent bioavailability profiles are…

A

bioequivalent

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46
Q

4 things necessary for drugs to be considered pharmaceutical equivalents?

A
  • same active ingredient/s
  • same dosage form
  • same route of admin
  • identical in strength/concentration
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47
Q

What is necessary for drugs to be considered pharmaceutical alternatives? 3

A

same therapeutic moiety but different:
- salts/complexes of that moiety
- dosage forms
- strengths

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48
Q

what method/ process used to show bioequivalence?

A

PK

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49
Q

why study PK? 2

A
  • to understand dosages administered
  • to calculate dosages in special populations eg children/preg/CKD
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50
Q

How is pharmacokinetic data presented?

A

conc in body/ time

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51
Q

What type of concentration plot do zero-order reactions show a straight line on?

A

normal

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52
Q

What type of concentration plot do first-order reactions show a straight line on?

A

logarithmic

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53
Q

What type of concentration plot do second-order reactions show a straight line on?

A

1/concn plot

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54
Q

whats the orders of reaction (dC/dt) for
zero
first
second

A

k
kC
kC^2

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55
Q

What order are 95% of therapeutic drugs eliminated by?

A

first order

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56
Q

When does zero-order elimination kinetics occur?
and whats this also called?

A

when the elimination process is saturated
- at higher concs elim rate no longer proportional to conc
AKA non linear kinetics

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57
Q

What is the relationship between ln and log?

A

Ln (x) = 2.303 Log (x)

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58
Q

PK ABSORPTION

The absorption phase of a drug is its movements between what two sites?

A

from site of administration -> systemic circulation

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59
Q

why is the no abssorption phase for IV or intra arterial RoA?

A

drug straight into circulation

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60
Q

What are the factors that affect the rate and extent of drug absorption? 4

A
  • anatomical site
  • disease state (physiological changes)
  • drug properties
  • formulation (can add solubility enhancers)
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61
Q

for drugs given via a RoA that has NO absorption phase, what does the plasma conc/ time curve only show?

A

eminimation process

no appearance of drug in circ, just looking at speed of elim from blood

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62
Q

what about a drug may affect the absorption?

A
  • Size of molecules
  • Viscosity
  • Anatomical characterists of site of admin/ injection: vascularity and amount of fatty tissue
  • Lipid solubility of drug, formn, ROA
  • Primary site of admin: SI. First pass effect higher absorption
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63
Q

What are examples of things present at the anatomical site that affect drug absorption rate and extent?

A
  • mucus layer properties
  • surface area (increased in SI due to villi)
  • membrane thickness (thinner is better)
  • vascularisation
  • enzymatic activity
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64
Q

What are examples of physiological changes that can occur due to disease state that affect the rate and extent of drug absorption?

A
  • inflammation e.g. IBS
  • diarrhoea affects residence time (shorter for drug absorption)
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65
Q

What are the 3 categories of drug properties that affect drug Absorption rate and extent?

A
  • physicochemical
  • solid-state
  • chemical stability
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66
Q

What are examples of physicochemical drug properties that affect drug absorption rate an extent?

A
  • solubility/ dissolution rate
  • pKa (ionisation state)
  • lipophilicity
  • complexation (e.g. cyclodextrins)
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67
Q

when it comes to drug lipophilicity, what type will be easier to cross membranes and therefore absorbed?

A

membranes very lipophilic. Easier for lipophilic drug to cross membrane compared to vwater soluble/ hydrophilic drug

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68
Q

when it comes to drug ionisation state, what will be easier to cross membranes and therefore absorbed?
and what impacts it?

A

unionised form will cross membrane
If have weak acid/ base drug, pH at site of administration impacts ionsiation state of drug thus absorption

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69
Q

Why does a drug’s solid state properties affect its rate and extent of absorption?

A

amorphous and crystalline forms can have differing solubilities

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70
Q

Why does a drug’s chemical stability affect its rate and extent of absorption?

A

if it’s degraded in e.g. stomach, won’t be absorbed as nothing left!

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71
Q

name a physiological change/ disease state that can affect rate and extent of residence time of a drug?

A

diarrhoea

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72
Q

how does MW affect rate of abs?

A

small molecules absorbed faster

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73
Q

how to make drug formulation more soluble?

A

use salt form or use stabilisers
to ensure enough of it in solution to be absorbed

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74
Q

molecule that helps adjust fluidity of membrane?

A

cholesterol

(same w liposomes, can adjust fluidity by changing cholesterol conc)

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75
Q

water soluble molecules/ proteins used for nutirent transfer DO/DO NOT cross memb easily

A

DO NOT
thus need carrier to help them enter cells

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76
Q

What are the two ways for which drugs can be absorbed across cells?

A
  • passive diffusion: transcellularly, paracellularly
  • carrier-mediated
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77
Q

What is the transcellular route? What type of drugs are likely to use this route?

A

directly through cells - lipophilic as do have to cross memb

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78
Q

What is the paracellular route? What type of drugs are likely to use this route?

A

in between the aqueous environment of cells - hydrophilic. small water soluble drugs

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79
Q

If drug mols too big, not enough space between cells for them to undergo paracellular transport, however what can be done to make this likely?

A

add permeation enhancers to formulation, can open junctions and create more space between cells to allow drug to be absorbed through this route

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80
Q

Passive diffusion: doesn’t need energy, concentration gradient is instead driving diffusion of drug
how does drug move? to and from?

A

high -> low conc
= passive methods of diffusion obey Fick’s law and all those parameters impact how well drug is absorbed

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81
Q

Passive diffusion is not saturable, meaning what?

A

Drug absorbed as long as conc gradient maintained. If drug given orally for example, have high conc in gut lumen and ocnc that’s absorbed will be removed quick = maintain good conc gradient, and have absorption of drug

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82
Q

What factors affect the rate of passive diffusion across cell membranes?

A
  • drug lipophilicity
  • surface area available
  • increased drug concentration
  • thickness of epithelial layer
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83
Q

What is the main problem for drugs absorbed by carrier-mediated mechanisms?

A

can be transported out by efflux transporters affecting bioavailability

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84
Q

how does carrier mediated transport work?

A

carrier protein on either apical or basolateral side, helps drug cross the membrane

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85
Q

apical side close to blood or lumen?

A

lumen

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86
Q

basolateral close to blood or lumen?

A

blood

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87
Q

what type of drugs would benefit from carrier-mediated transport?

A

water soluble

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88
Q

What does the rate of drug absorption for carrier-mediated absorbed drugs depend on?

A

drug conc and affinity and transporter availability

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89
Q

Describe the components of the equation that describes the rate of drug transport for drugs absorbed by carrier-mediated transport
Jmax
C
Km

A

Jmax = rate of transport by receptors

C = conc of drug at site of absorption

Km = affinity of drug for transporter

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90
Q

What is the main difference between carrier-mediated and passive diffusion absorption of drugs?

A

carrier-mediated can become saturated

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91
Q

Under what conditions does carrier-mediated drug absorption follow first-order kinetics? Describe why.

A
  • when not saturated bc rate will depend on drug conc
  • high conc = initial fast release that decreases as drug conc decreases
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92
Q

Under what conditions does carrier-mediated drug absorption follow zero-order kinetics? Describe why.

A
  • if saturated/rlly high drug conc
  • no longer depends on drug conc
  • depends on number of transporters/receptors available
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93
Q

true or false, there is competition between drugs using carrier mediated transport and the natural nutrient that is its substrate?

A

true

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94
Q

What are examples of drug effluxers?

A
  • P-gp
  • BCRP
  • MRP2
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95
Q

Why do effluxers get rid of drugs?

A
  • drug seen as toxin
  • transporter uses ATP to rid of drug against concentration gradient
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96
Q

What are the 3 mechanisms through which the cell itself can uptake the drug?

A

Phagocytosis
Pinocytosis
Endocytosis

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97
Q

immune cells uptake nanomedicines by what process?

A

phagocytosis

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98
Q

extracellular fluid taken in by cell when it is drinking, process name?

A

pinocytosis

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99
Q

If drug binds to a receptor, will trigger what process where membrane will form mini vesicles and drug taken into intercellular space?

A

endocytosis

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100
Q

What are the 3 extravascular routes of administration?

A
  • subcutaneous
  • intradermal
  • intramuscular
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101
Q

What steps must a drug administered subcutaneously undergo before absorption? What’s the clinical use of this route?

A
  • distribution in interstitial fluid
  • absorption through capillaries/local lymph nodes
  • prolonged release
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102
Q

Where is a drug administered when intradermally?

A

between the dermis and epidermis

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103
Q

What are the clinical uses of the intradermal route?

A

vaccination/skin tests

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104
Q

What is the rate of intradermal drug absorption? Why?

A
  • slow
  • low fluid levels
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105
Q

What steps must a drug administered intramuscularly undergo before absorption?

A
  • dissolution in interstitial fluid
  • absorption to vessels in irrigating muscles
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106
Q

intramuscular admin drug absorption depends on what?

A

formulation and perfusion at site

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107
Q

Impact of MOLECULAR drug properties on absorption at different sites of administration
what main thing to consider for good drug?

A

Lipinski’s rule of 5:
MW < 500 Da
Log P <5
HBD < 5
(HBA < 10)

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108
Q

Impact of PHYSICO-CHEMICAL drug properties on absorption at different sites of administration

A

pKa and ionisation state
- pH of microenvironment

Saturation solubility
- Drug properties
- pH (for ionisable drugs)
- Salt formation (for ionisable drugs)

Drug crystal form
- Crystalline vs amorphous
- Polymorphism

Complexation
- e.g. cyclodextrins

Drug stability

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109
Q

whatdrug classification system considers metabolism, not just solubility and permeability?

A

BDDCS

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110
Q

What is a BCS class I drug?

A

high solubility, high permeability

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111
Q

What is a BCS class II drug?

A

low solubility, high permeability

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112
Q

What is a BCS class III drug?

A

high solubility, low permeability

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113
Q

What is a BCS class IV drug?

A

low solubility, low permeability

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114
Q

What is a BDDCS class I drug?

A

high solubility, permeability metabolism

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115
Q

What is a BDDCS class II drug?

A

low solubility, high metabolism

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116
Q

What is a BDDCS class III drug?

A

high solubility, poor metabolism

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117
Q

What is a BDDCS class IV drug?

A

low solubility, poor metabolism

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118
Q

Absorption steps of oral drug formulation? what forms does it go through before absorbed?

A

dosage form
I
drug particles
I
dissolved drug
I
drug absorbed

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119
Q

All solids need to generate drug particles then dissolve to absorb. Taken longer than suspensions why?

A

as suspensions already in drug particle step

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120
Q

why do solutions have quickest absorption/ least steps?

A

alr in bioavailbale form, just need to cross emmbrane to be absorbed

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121
Q

non-enteral routes, parameters to consider for oro-mucosal route of admin?

A

rapid dissolution
muco-adhesive
increased residence times

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122
Q

non-enteral routes, parameters to consider for rectal route of admin?

A

rapid release
particle size
affinity for dosage form

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123
Q

non-enteral routes, parameters to consider for intranasal route of admin?

A

use of buffers
use of permeation enhancers
increase residence time

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124
Q

non-enteral routes, parameters to consider for pulmonary route of admin?

A

method of admin
drug loss
particle/droplet size

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125
Q

non-enteral routes, parameters to consider for transdermal route of admin?

A

affinity for dosage form
matrix vs reservoir
permeation enhancers

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126
Q

PK of drug absorption after a single dose…..

What are the features of zero-order absorption?

A
  • constant rate
  • independent of dose
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127
Q

carrier mediated transport (high drug concentration/saturated) and MR formulations are likely to follow what order?

A

zero

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128
Q

What are the features of first-order absorption?

A
  • dependent on concentration
  • applies to MOST drugs: rate is high initially and decreases over time as drug taken into systemic circ
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129
Q

stage 1 of abs kinetics for oral dosage forms?

A

lots of drug in gut,
rate constant fast,
first order process,
little bit of elimination,
low conc so low rate

2 processes exist in parallel

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130
Q

why does elimination start automatically?

A

drug in blood circulation a

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131
Q

cmax and tmax is when absorption is in equilbrium with that process?

A

elimination

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132
Q

how does first order MR dosage form affect the pleateu on a kinetic curve?

A

extended/ longer

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133
Q

in stage 3 of absorption kinetics why is conc mostly determined by elimination rate?

A

abs ended, no more drug will appear in the blood

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134
Q

As dose constant, rate constant also constant so can just define all this as what? instead of all parameters, so simplify calculations for rest of pKa.

A

single letter (a)

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135
Q

whats ka?

A

amount of drug in GIT -> to absorbed

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136
Q

whats ke?

A

amount of drug absorbed –>

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137
Q

EQUATIONS/ CALCS…….
shape of first order abs line plotted on semi log paper?

A

straight

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138
Q

what process is demonstrated by straight line on abs kinetic graph semi log paper? after initial curve up, then straight line down

A

elimination

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139
Q

How do you find elimination rate constant from a semi-log concentration time graph?

A
  1. work out gradient of 2 points on line
  2. then do m = -ke / 2.303
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140
Q

How do you find the theoretical initial concentration from a semi-log concentration time graph?

A

eqn p121 on iPad / extrapolate elim phase and read y-intercept

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141
Q

Describe the balance between absorption and elimination in stage 1 of concentration time graph.

A
  • absorption predominates elimination (ka > ke)
  • elimination still occurring but at slower rate than absorption
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142
Q

What is method of residuals?

A
  • used to calculate absorption rate constant ka
  • allows separation of absorption and elimination phases in early stage of absorption
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143
Q

assumptions that method of residuals relies on?

A

abs dominates over elimination,
both abs and elimination follow first order
pk follows one model compartment

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144
Q

How do you calculate method of residuals? (see slides)

A
  1. plot values on semi log scale
  2. create table with raw data from blood sampling and fill in conc
  3. fit the elimination data, draw straight line of linear regression and find out gradient for rate constant and extrapolate for A
  4. read conc off elimination line, extrapolate time points of what blood conc should have been if there was no abs
    5/6. Fill table, just reading from graph, column 4 by subtracting column 3 from 2
  5. plot data for abs phase should be straight line
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145
Q

from the curve obtained from method of residuals, can now calculate the absorption rate constant ka, how?

A

from gradient of curve

m = -ka/2.303

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146
Q

how would you use method of residuals curve to find absorption half life t1/2?

A

from absorpiton curve or ka

ln2/ka

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147
Q

What are reasons for lag time?

A
  • physiological: e.g. delayed gastric emptying
  • formulation: site-specfic, dosage form, modified release
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148
Q

What is lag time?

A

time at which abs is said to start

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149
Q

How do you find the lag time from a semi-log concentration time graph?
revisit ! slide 43/p128

A

intersect of the abs and elimination curves = onset of abs

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150
Q

reason for lag time being negative?

A

not enough data so estimations are off therefore experimental error

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151
Q

PK: Bioavailability……..

What letter is used to denote bioavailability?

A

F

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152
Q

which route of admin has 100% bioavailability?

A

IV

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153
Q

active moiety is used to refer to what type of drug?

A

pro drug

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154
Q

3 factors that affect the rate and extent of abs and therefore BA?

A

drug degradation at site of admin
Pre-systemic elimination
Poor absorption

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155
Q

what affects drug degradation at the site of administration thus absorption?

A
  • Physiology of site of absorption… lots of enzymatic activity? Properties of epithelia, mucus layer? Etc.
  • properties of drug. May just not be stable in acidic stomach
  • dosage form
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156
Q

what is meant by pre systemic elimination?

A

first pass effect
-Any metabolic activity that decreases amount of drug getting to systemic circulation

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157
Q

poor abs can be attributed to poor X and Y?

A

solubility and permeability

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158
Q

drug abs is referred to as the passage of drug across the epithelial membrane of what body structure?

A

small intestine

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159
Q

for a drug that is not as permeable, is lack of absorption and just elimination in the faeces more or less likely?

A

more

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160
Q

what is meant by Ff?

A

fraction of drug that has survived passage through the gut wall

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161
Q

once drugs are abs what circulation do they enter before going into thesystemic circ and liver?

A

portal vein

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162
Q

does the equation: Ff x Fg x Fh refer to the bioavailability once the drug is:

-in solution
-absorbed via gut wall
-passed portal vein and first pass effect
-in systemic circulation?

A

systemic circulation

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163
Q

the final bioavailability of drug depends on what?

A

fraction that has made it through all these = product of all the fractions through all the different stages. Calculation.

Ff x Fg x Fh

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164
Q

What does the equation does Ff x Fg tell us?

A

bioavailability after drug enters portal vein and survives first pass effect

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165
Q

influx and efflux: another way drug can cross membrane
facilitated diffusion done using what transport?

A

carrier mediated

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166
Q

where would a drug be transported to and from if it enters an apical influx transporter?

A

from gut lumen into cell

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167
Q

where would a drug be transported to and from if it enters an efflux transporter on the basolateral side?

A

from cell to blood vessel

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168
Q

where would a drug be transported to and from if it enters an efflux transporter on the apical side?

A

from cell back to gut lumen

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169
Q

what transporter would be used to take a drug from a blood vessel and transport it back into the cell?

A

basolateral influx transporter

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170
Q

all of the efflux and influx transporters can ultimately affect BA as they affect..?

A

the frcation of drug making it through gut wall –> portal vein

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171
Q

Ideally have influx transporters on apical and effluc on basolateral.
IF: have opposite, fraction absorbed will be higher/lower?

A

lower

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172
Q

drug transport in GIT: ATP binding casette proteins (ABC) tend to participate more in active processes, do they tend to be more influx or efflux?

A

efflux

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173
Q

ABCs require energy to work and work against a conc gradient, true or false?

A

true

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174
Q

give an example of an ABC

A

P-glycoprotein

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175
Q

ABC efflux transporters such as p glycoprotein can affect bioavailability. What is one adverse effect that they produce in cancer patients?

A

drug resistance

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176
Q

solute carrier transporters (SLC) are influx. if they are on the apical side why might this be a good thing?

A

help increase drug absorption

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177
Q

name one influx transporter that can be exploited for prodrugs such as valacylovir and acyclovir, that can bind to the transporter and increase abs as the active moiety is not absorbed as well w/out them?

A

protein dependent oligopeptide transporters POTs

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178
Q

other than POTs, name other solute carrier transporters SLCs

A
  • Organic anion transporters (OATs)
  • Organic cation transporters (OCTs)
  • Nucleoside transporters (CNTs)
  • Monocarboxylate transporters (MCTs)
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179
Q

pgp ( p glycoprotein) has many drug substrates, inducers and inhibitors. Name some areas where it is found outside the gut wall/ small intestine?

A

BBB, kidney, liver, lung, colon

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180
Q

P-glycoprotein (ABC1, Pgp) has huge potential for what?

A

drug interaction and for co-administration to affect drug bioavailiability

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181
Q

in the small intestine pgp is on the APICAL side on enterocytes. This means that the drug is transported from X back into Y?

A

from inside cell back to gut lumen

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182
Q

polymorphism is associated with pgp meaning expression can be different in different patients, true or false?

A

true

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183
Q

cyclosporine
verapamil
simvastatin
amiodarone

are examples of Pgp inhibitors/inducers/substrates?

A

inhibitors

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184
Q

rifampicin
paclitaxel
carbamazepine

are examples of Pgp inhibitors/inducers/substrates?

A

inducers

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185
Q

digoxin
vinblastine

are examples of Pgp inhibitors/inducers/substrates?

A

substrates

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186
Q

first pass metabolism is exclusive to oral admin and cannot happen with other sites of admin true or false?

A

false

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187
Q

first pass metabolism is exclusive to oral admin and cannot happen with other sites of admin true or false?

A

false

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188
Q

enterhepatic first pass effect means metabolism happens first in the X before the liver?

A

gut

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189
Q

in the gut wall metabolism is catalysed by CYP3A4, meaning that there can be significant drug metabolism in this area. What is the main method of detoxification that this enzyme catalyses?

A

drug oxidation

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190
Q

CYP enz have high/low susceptibility to inducers and inhibitors

A

HIGH

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191
Q

Many CYP3A4 substrates are also substrates of the Pgp, therefore…

A

can have drug that’s effluxed, brought back to gut lumen. Drug may be absorbed by diffusion doesn’t have to be carrier mediated. Comes into cell then pgp takes back to gut lumen. Can try again to come into cell and if it does, may be metbaolsied by CYP3Af. Combiniation and affected bioav

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192
Q

In gut wall, may have close contact with drug and CYP3A4, what does this mean for metabolism and BA?

A

metabolism still substantial and big impact on overall BA

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193
Q

what enzyme is involved in the metabolism of warfarin, pheytoin, losartan, diclofenac?

A

CYP2C9

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194
Q

what types of drugs are metabolised/ conjugated by UDP - glucaronosyltransferase enz ?

A

lipophilic drugs are conj with glucaronic acid

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195
Q

sulfotransferases are involved in the sulfation of hydrophilic or hydrophobic drug molecules?

A

hydrophobic

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196
Q

does detoxification (as done by UDP-g and sulfotransferases) make drugs more lipophilic or hydrophilic?

A

hydrophilic

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197
Q

in summary, what happens to drug when it is absorbed? in terms of BA?

A

Drug goes to gut wall and can interact with efflux transporters, CYP enz then -> liver where can meet same efflux transporter and CYP enz. Fraction that makes it to blood circulation can become lower and lower with each step

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198
Q

The D in ADME: drug distribution & protein binding

Which fraction of drug can distribute: free or bound?

A

free

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199
Q

What does drug distribution depend on? 5

A
  • drug properties
  • tissue perfusion
  • anatomical factors
  • tissue composition
  • physiological factors
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200
Q

What drug properties impact distribution?

A
  • plasma protein binding
  • tissue binding
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201
Q

What factors affect the RATE of distribution?

A
  • tissue perfusion: higher = faster rate
  • membrane permeability e.g. BBB difficult so slows down
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202
Q

name some examples of sites with well perfused tissue that therefore allow quick distribution

A

liver, kidney, lung

(fat = not well perfused = longer rate)

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203
Q

What factors affect the EXTENT of distribution?

A
  • MW
  • lipophilicity
  • ionisation - pH and pKa
  • protein binding
  • intracellular binding
  • patient factors
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204
Q

Do low or high MW drugs distribute more widely?

A

low

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205
Q

Do lipophilic or hydrophilic drugs distribute more widely?

A

lipophilic - able to cross membranes

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206
Q

How does ionisation affect the extent of distribution? Use the example of breast tissue.

A
  • unionised crosses membranes
  • if drug unionised in blood, can accumulate in breast tissue
  • breast tissue is slightly acidic
  • if drug weak base, it becomes ionised and unable to cross back
  • therefore can be excreted in breast milk
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207
Q

if drug is unionised at pH in tissue, will it distribute easier or not?

A

easier

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208
Q

what sort of px factors affect extent of drug distribution?

A

total body weight/composition, age, disease state

depending on drug properties and affinity for particular tissues.
Can change with age and disease state. Distribution is different in infants and adults and in diseased px that can change body composition

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209
Q

for tissues with HIGH/LOW blood flow, equilibrium is reached quickly

A

HIGH blood flow (highly perfused)

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210
Q

In drugs with poor perfusion, what can determine drug accumulation?

A

drug physicochemical properties e.g. lipophilic can accumulate in fat

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211
Q

Why is exercise a considering factor with drug distribution?

A
  • increases blood flow
  • thus affects drug distribution and effect
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212
Q

What do we use apparent Vd for?

A
  • to volume of a given body compartment
  • we know that each body component has different volume, and chemicals distribute to these
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213
Q

we can use specific test compounds to estimate the volume of a given body compartment

What do we use to estimate total body water and why?

A
  • ethanol
  • penetrates total body water
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214
Q

What do we use to estimate the plasma compartment?

A
  • dextrans (large polar polysaccharide)
  • only permeates plasma
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215
Q

why may heparin be restricted to intravascular fluid?

A

high MW and polar drug

216
Q

What is the typical region of a drug with a Vd value <10L?

A

intravascular fluid (blood incl plasma)

217
Q

What are the drug properties of a drug with a Vd value <10L?

A
  • high MW
  • polar
  • extensive plasma protein binding
218
Q

What is the typical region of a drug with a Vd value 12-20L? Why?

A
  • extracellular fluids
  • small enough to leave circulation (transcellular) but not lipophilic enough to cross membranes
219
Q

What are the drug properties of a drug with a Vd value 12-20L?

A

low lipid solubility, small

220
Q

What is the typical region of a drug with a Vd value >20L?

A
  • organs based on active transport and specific receptor binding
  • hard to predict
221
Q

What are the drug properties of a drug with a Vd value >20L?

A
  • lipid soluble stored in fat
  • heavy metals/tetracycline in bone
222
Q

When drug lipophlic enough to cross memb and has affinity for tissue proteins/ components, Vd can be quite X and Y

A

wide and large

223
Q

Is protein binding reversible or irreversible for most drugs?

A

reversible
but remember it can be saturated

224
Q

What does albumin mostly bind to?

A

acidic drugs

225
Q

What does alpha-1 glycoprotein mostly bind to?

A

basic drugs

226
Q

What do lipoproteins mostly bind to?

A

neutral drugs

227
Q

what fraction CANNOT diffuse into tissue/distribute, therefore where is this restricted to in body?

A

protein-bound
so high PPB will restrict Vd mostly to intravascular volume

228
Q

What happens to the free fraction of drug and not the bound? 3

A
  • can easily distribute
  • can be eliminated
  • can have pharmacological effect
229
Q

Does protein-binding always limit distribution?

A

no

230
Q

What factors affect protein binding and Vd? 3

A
  • drug properties
  • protein-related factors
  • drug interactions
231
Q

What drug properties affect protein binding and Vd?

A

molecular + physicochemical properties
- think lipophilicity and weak acid/ base
- ability to interact w negatively charged membranes

232
Q

What protein-related factors affect protein binding and Vd? change in… 2

A
  • protein concentration
  • affinity for drugs
233
Q

In what states can protein concentration be changed?

A
  • liver disease
  • pregnancy
  • cystic fibrosis
  • aging
  • burns
  • malnutrition
234
Q

How do drug interactions affect protein binding and Vd?

A

protein-bound drug can be displaced by endogenous or exogenous compound binding to same protein

235
Q

if 2 drugs given that bind to same protein, When is there a risk of interaction through protein displacement?

A

if
- drug is highly protein bound >90%
- small Vd
- interaction occurs in initial stage of co-treatment

236
Q

What is an example of protein displacement?

A
  • valproic acid displaces phenytoin from protein binding sites- inc fractiiion free drug
  • also inhibits its metabolism
  • can lead to phenytoin toxicity
237
Q

Describe the equilibria that occurs between bound and free drug (image)

A
  • free drug injected into circulation
  • binds to plasma protein
  • equilibrium established where if some of free drug is eliminated, drug released from protein to keep free and bound fractions constant
238
Q

Describe the equilibria that occurs between free and distributed drug

A
  • free drug distributes (if right properties) to tissue
  • in tissue drug can further bind to components + proteins
  • tissue binding changes, drug distributing from blood does too
239
Q

what do all equilibria (free + bound, and bound + distributed) work together to maintain?

A

free drug conc

240
Q

aDme: compartments and barriers…….

what are the general assumptions we make with pharmacokinetic models?

A
  • drug absorbed instantaneously
  • drug is eliminated uniformly

there’s one compartment model
- plasma conc. is true for the entire circulation

241
Q

true/false: distribution is uniform for all drugs

A

false

242
Q

what can happen to drug after IV bolus administration?
(Why might distribution not be uniform for some drugs?)

A

after IV admin, drug could distribute:

  • quickly in well-perfused organs/tissue (rapid equilibrium)
  • slowly to poor blood flow organs/tissues (slow equilibrium)
243
Q

what are the compartments in two compartment model?

A

central compartment
peripheral compartment

244
Q

what is the central compartment ?

A

systemic blood circulation

245
Q

what are the compartments in one compartment model?

A

central compartment only

246
Q

What pharmacokinetic process occurs only in the central compartment of a two-compartmental model? What rate constant is relevant?

A
  • excretion
  • elimination rate constant ke
247
Q

what 3 organs linked to blood in central compartment?

A

brain
liver
kidneys

248
Q

what is the alpha and beta phase in terms of compartment and distribution?

A

alpha: central -> peripheral
beta: distribution peripheral back -> central

249
Q

why do we have 2 phases: alpha and beta with drug distribution in 2 compartment model?

A

as distribution is in equilibrium so can have drug leaving and entering peripheral

250
Q

for PDC, conc in blood or systemic circ can fall as result of excretion but also due to what?

A

distribution to another compartment/ tissues and for nanomedicines: can also include tumour

251
Q

what is the distribution phase in the two compartment model?
on plasma conc/time curve

A

where the drug is moving from central -> peripheral compartment

252
Q

what is the elimination phase in the two compartment model?

A

predominant process during the second phase of the biphasic plot

253
Q

on a plasma conc / time curve, for distribution then elim, for 2 compartment model describe what curve/line is seen?

A

Initial drop in central compartment (drug distribution) then elimination
Peripheral: drug coming in so looks more like an absorption curve
See increase in conc of durg in tissue, reach eqn then elimination fomr peripheral compartment

254
Q

classic example of drug distribution via 2 compartment data: Vancomycin
how long des distribution last?

A

1-2 hours

255
Q

for an oral dose PK model curve, when will distribution show on curve?

A

if slow distribution = extra bit on line to show something else happening too not just absorption and elimination

256
Q

What can remove drugs from the brain even after they’ve crossed the BBB?

A

efflux transporters

257
Q

how do you try to pass the BBB?

A

using pro-drugs: exploit receptors/transporters

258
Q

name 3 barriers to drug delivery

A

BBB
blood-cerebrospinal fluid barrier
placental barrier

259
Q

what may cause disruptions in BBB integrity?

A

tumour e.g. glioma, at tumour margin have changes

  • angiogenesis means tumours are nutrient hungry and blood vessels develop rapidly and improperly
  • vessels are more permeable, bigger gaps allowing immune, red blood cells and nanomedicines in
260
Q

what is the blood-cerebrospinal fluid barrier?

A

barrier between the BBB and the CSF

261
Q

how can we bypass the blood-cerebrospinal fluid barrier?

A

using intrathecal injections

262
Q

purpose of placental barrier?
and when may this purpose be disrupted?

A

protect fetus from exposure to toxins/ drug
barrier not completely impenetrable: case of thalidomide: drugs may cross placental barrier if have right properties.

263
Q

What structures from the placental barrier?

A
  • trophoblast epithelia
  • basement membrane
  • foetal capillary endothelium
264
Q

what characteristics will increase diffusion pass the placental barrier?
passive

A

MW <600Da
lipophilic drugs
unionised
Lower than blood pH compared to in adults

265
Q

What are the possible modes of transport across the placental barrier? 4

A

endocytosis
active transport
facilitated transport
passive diffusion

266
Q

why can drugs pass the placenta?

A

as the apical and basal membrane thickness decreases during pregnancy to allow nutrition to be exchanged, however, also allowing drugs to pass through

267
Q

whats plasma?

A

the liquid phase of the blood, composed of water and proteins

268
Q

what cells does the blood contain?

A

RBS (erythrocytes)
platelets (thrombocytes)
WBC (leucocytes)

269
Q

binding to blood cells involves creation of an eqm between blood cells and plasma

how do you work out blood:plasma ratio?

A

Cwhole blood / Cplasma

270
Q

how do you work out the drug blood partition coefficient?

A

Cblood ratio / Cplasma

271
Q

PK usually based on PLASMA concentrations.
If blood-to-plasma concentration ratio is 1, what does this mean?

A

no issues as concentration in plasma reflects that in blood

272
Q

PK usually based on PLASMA concentrations.
If blood-to-plasma concentration ratio is higher/lower than 1, what does this mean?

A

differences in PK parameters in blood vs plasma so needs adjustment

273
Q

Why is it important to state whether samples are plasma or whole blood (example of cyclosporin)?

A
  • impacts dose adjustment and therapeutic range considerations
  • ciclosporin conc in plasma is 20-50% of that in whole blood
  • desired therapeutic range of 100-400ng/mL in blood vs 50-150ng/mL in plasma

Remember when thinking therapeutic range and assessing if in window for px

274
Q

What’s considered the peripheral compartment in a two-compartmental model?

A

poorly perfused organs/tissue:

  • muscle
  • skin
  • bone
  • fat
275
Q

What drugs can use paracellular diffusion to cross the BBB?

A

small hydrophilic molecules, H2O

276
Q

What drugs can use transcellular diffusion to cross the BBB? Properties/chemistry

A

nonpolar, lipophilic molecules

  • <400-500Da
  • <8-10 H bonds
277
Q

what may BBB paracellular transport be hindered by?

A

tight junctions presence
efflux transporters to contribute to decrease penetration of drug

278
Q

What molecules can use carrier-mediated transport to cross the BBB?

A
  • amino acids
  • vitamins
  • glucose
  • ions
  • nucleotides
  • sugars
  • fatty acids
  • neurotransmitters
279
Q

What molecules can use receptor-mediated transport to cross the BBB?

A
  • transferrin
  • insulin
  • IgG
280
Q

What molecules can use absorption-mediated transport to cross the BBB?

A

cationic proteins

281
Q

What molecules can be effluxed out of the brain by ABC-type transporters?

A
  • drugs
  • metabolites
  • fluorescent dyes
  • neurotoxins
282
Q

How does water cross the BBB?

A

aquaporins

283
Q

how do ions cross BBB?

A

cotransporters and exchangers

284
Q

What creates the barrier within the CSF of the spine?

A

choroid plexus epithelial responsible for CSF production

285
Q

What excipient cannot be used in intrathecal injections?

A

antimicrobial preservatives

286
Q

How does distribution change during pregnancy?

A
  • plasma proteins change
  • placental barrier thins increasing drug permeability
  • metabolism can also occur at placental barrier
287
Q

What can drugs do in the blood that affects its pharmacokinetics?

A

can bind to blood cells by:

  • passively diffusing across the RBC membrane
  • binding to intracellular components
288
Q

An equilibrium is created between what due to drugs being able to bind to RBCs?

A

between blood cells and plasma

289
Q

What properties of a drug can impact its distribution in brain?

A
  • drug MW
  • logP
  • protein-binding
290
Q

PK adMe: METABOLISM…..

what is metabolism?

A

Enzymatic modification of the chemical structure of a drug molecule to form one or more new chemical entities (metabolites)

291
Q

What is drug metabolism AKA?

A

drug biotransformation

292
Q

How does metabolism overlap with elimination?

A

elimination = irreversible loss of drug from site of measurement, occurring by metabolism and excretion

293
Q

How does metabolism relate to absorption?

A

first pass metabolism impacts oral bioavailability

294
Q

What is the importance of drug metabolism for PK?

A
  • drug metabolite can have no/reduced/equal/increased/toxic activity compared to parent compound
  • can play a role in drug interactions
  • genetic/environmental/disease factors can impact drug-metabolising enzymes
295
Q

What is an example of a metabolite that has equal pharmacological activity to its parent?

A

procainamide and metabolite n-acetyl procainamide – similar antiarrhythmic activity

296
Q

What are examples of metabolites that have increased pharmacological activity to its parent?

A

prodrugs (activated by metabolism)

  • enalapril vs enalaprilat
  • prednisone vs prednisolone
297
Q

What is an example of a metabolite that can cause toxic effects?

A

carbamazepine metabolised to carbamazepine epioxide responsible for drug toxicity

298
Q

What are the organ sites of drug metabolism?

A
  • Small intestine
  • Skin
  • Lungs
  • Kidney
  • Liver (majority)
299
Q

How do drugs reach the liver from the systemic circulation?

A

high hepatic blood flow and lots of enz = lots of metabolism

HPV: from GIT following absorption
hepatic artery HA: directly from circulation

300
Q

What are the 2 phases of metabolism?

A

phase I and phase II

301
Q

What occurs in phase I metabolic reactions?

A

drugs made more hydrophilic

302
Q

What occurs in phase II metabolic reactions?

A

drugs are conjugated w endogenous substance allowing for easy excretion

303
Q

How do phase I metabolic reactions (AKA functionalisation reactions) occur in relation to phase II?

A

often before phase II but not always

304
Q

How are drugs made more hydrophilic in phase I reactions?

A

polar functional groups unmasked/introduced to form metabolites more polar than parent drug

305
Q

What are examples of polar functional groups introduced in phase I reactions?

A

hydroxy
amino
carboxyl

306
Q

What are the most common types of phase I reactions?

A
  • oxidation
  • reduction
  • hydrolysis
307
Q

What occurs in phase I oxidation reactions? What enzymes carry this out?

A

addition of oxygen/removal of hydrogen – usually by cytochrome P450 enzymes

308
Q

What occurs in phase I reduction reactions?

A

removal of oxygen/addition of hydrogen

309
Q

What occurs in phase I hydrolysis reactions?

A

reaction of drug containing e.g. ester, amide w water -> cleavage of chemical bonds and more polar metabolites

310
Q

What are cytochrome P450 (CYP450) enzymes?

A

superfamily of metabolising enzymes that metabolise 75% of total metabolism in human body

311
Q

What cofactor do CYP450 enzymes contain?

A

haeme

312
Q

What is the nomenclature of CYP enzymes?

A
  • CYP +
  • family: numbered 1, 2, 3…
  • subfamily: A-Z
  • individual enzyme within subfamily: numbered 1, 2, 3…
313
Q

What CYP families metabolise most drugs in humans?

A

1-3

314
Q

What is the most common subfamily in the liver? What proportion of drugs does it metabolise?

A

CYP3A, ~50%

315
Q

What are examples of endogenous substances that drugs are conjugated w in phase II (AKA conjugation) reactions?

A
  • glucuronic acid
  • glutathione
  • amino acids
316
Q

At what sites of a drug does phase II conjugation occur?

A
  • carboxyl
  • hydroxyl
  • amino
  • sulfhydryl (SH)
317
Q

What are examples of enzyme systems involved in phase I and II metabolic reactions?

A

eg
esterases - hydrolysis
amidases
MAO
alcohol dehrydrogenase
methyltransferase
N-acetyltransferase

318
Q

What are examples of physiological factors affecting drug metabolism?

A
  • age
  • genetic factors
  • pathology?
319
Q

How does age affect drug metabolism?

A
  • metabolic pathways mature at different rates: infants metabolise drugs to different rate/extents and form diff metabolites
  • liver mass + blood flow decrease w age = dec hepatic (and 1st pass) metabolism in elderly
320
Q

how does hepatic and first pass metabolism change with age?

A

liver mass and blood flow decrease w age = decreasing hepatic (and 1st pass) metabolism in elderly

321
Q

What is a genetic factor that can influence drug metabolism?

A

CYP450s can exhibit genetic polymorphism:

  • different CYP metaboliser phenotypes
  • differences in CYP expression between ethnic groups
322
Q

What are the categories of CYP metaboliser phenotypes?

A
  • poor
  • intermediate
  • extensive
  • ultrarapid

and diff metabolites may be formed!

323
Q

What is a clinical example of how different CYP metaboliser phenotypes affect drug metabolism?

A

codeine: prodrug metabolised by CYP2D6 -> morphine

poor metabolisers have little/no morphine conversion and experience nausea due to codeine accumulation

ultrarapid metabolisers convert too much morphine quickly -> dangerously high conc of morphine in blood, could -> respiratory/CNS depression

324
Q

What are examples of pathology that can affect drug metabolism

A
  • hepatic or renal disease
  • circulatory disorders eg HF
  • infection/inflammation (chronic e.g. cancer, RA, coeliac disease)
325
Q

How does hepatic/renal disease impact drug metabolism?

A

these organs are responsible for metabolism so their function is impaired

326
Q

How do circulatory disorders impact drug metabolism?

A
  • reduced perfusion of liver and kidneys
  • these are sites of drug metabolism
327
Q

How does infection and inflammation affect drug metabolism?

A

inflammatory cytokines may suppress CYP expression

328
Q

How can drugs themselves influence drug metabolism?

A

DDIs
- drugs + substances can induce/inhibit enzymes that metabolite other drugs
- can auto-induce enzymes responsible for their metabolism

329
Q

What are examples of non-drug substances that can induce/inhibit enzymes?

A
  • alcohol
  • cigarette smoke
  • grapefruit juice
  • St John’s Wort (2C9)
330
Q

example od drug that us a CYP3A4 substrate AND inducer?

A

carbamazepine

331
Q

What is the nature of drug metabolism kinetics at low/therapeutic drug concentrations? for most drugs

A
  • only a fraction of metabolising enzyme sites are occupied
  • therefore rate of metabolism depends on drug concentration remaining in body
  • first-order (increases w drug conc)
332
Q

What model describes the nature of drug metabolism kinetics when the metabolic pathways are saturable? (the exceptions to first order rule as before)

A

Michaelis-Menten enzyme kinetics (capacity-limited metabolism)

333
Q

Michaelis-Menten equation

A

… Vmax[S]
V = —————-
Km + [s]

334
Q

What is the V in the Michaelis-Menten equation?

A

enzymatic/metabolic reaction rate

335
Q

What is the Vmax in the Michaelis-Menten equation?

A

maximum rate of enzyme reaction (when all enzymes’ reactive sites are saturated with substrate)

336
Q

What is the Km in the Michaelis-Menten equation?

A

Michaelis-Menten constant (measure of affinity of substrate to enzyme) - substrate concentration at which V = ½Vmax

337
Q

What is the [S] in the Michaelis-Menten equation?

A

substrate concentration

338
Q

What is the significance of a drug having saturable metabolism? Michaelis-Menten enzyme kinetics
example drug

A

small change in dose can lead to a greater than proportional (or expected) increase in Css as saturable e.g. phenytoin

339
Q

What is occurring at the zero-order region of a Michaelis-Menten graph?

A

rate of metabolism slows and plateaus as the enzyme active sites are all saturated meaning there’s no effect in the further increase of [S]

340
Q

The E in ADME…

what is a one compartment model?

A

single IV bolus admin. = fast drug distrib. = rapid equilibrium established = proportional clearance of drug eliminated from blood

341
Q

what is a one compartment model?

A

single IV bolus admin. = fast drug distrib. = rapid equilibrium established = proportional clearance of drug eliminated from blood

342
Q

what does a one compartment model assume?

A

after admin, have instantaneous absorption of drug and v fast distribution to tissues in body

343
Q

with one compartment model, followinf drug elim from blood you see a X, Y Z in drug conc in tissue

A

immediate, proportional decrease

344
Q

what is the body considered to behave as?

A

in a 1 compartment model: 1 homogenous compartment

345
Q

how do you work out the conc. of drug in a one compartment model?
Conc right after IV bolus injection

A

C0 = Dose/Vd

346
Q

what is Ct = ?

A

Ct = D/Vd e^ket

347
Q

what is ke?

A

elim rate constant
constant that defines rate of elim process

348
Q

how the ke influences elim rate depends on what?

A

ORDER of elim process

349
Q

most clinically used drugs, what is rate of drug elim proportional to/ dpeendent on?

A

conc of drug in blood

350
Q

most drug elim follows what order kinetics?

A

first

351
Q

how to convert lnx to log?

A

lnx = 2.303logx

352
Q

how to determine C0?

A

extrapolate data to find y-intercept

353
Q

how to determine ke form gradient of graph?

A

ke = -gradient x 2.303

354
Q

how to find gradient form graph?

A

logy2 - logy1 / x2 - x1

355
Q

what is the meaning of elim t1/2?

A

time taken for plasma conc/ amount of drug in body to be reduced by 50%

356
Q

after 2 half lives, hm drug left in body? what %

A

25%

357
Q

why is t1/2 used clinically?

A

it dictates frequency of dosing

358
Q

t1/2 =

A

ln2/ke (0.693/ke)

359
Q

will drugs with a larger ke have longer or shorter t1/2?

A

shorter t1/2
elim faster than drugs with smaller k and longer t1/2

360
Q

what can be said about duration of effect of drugs following single dose admin?

A

rapidly eliminated
shorter duration of effect

drug conc quickly falls below MEC

361
Q

PK dosing regimen…..

whats usually the goal of drug dosing regimen?

A

trying to treat chronic condition + want blood concs of drug to stay in therapeutic window - want drug effective not toxic.
between MEC and MSC

(to maintain steady plasma concentration over a period of time)

362
Q

Extravascular single dose concentration time graph

A

first drug conc inc at start then slope down (where elim takes over)

363
Q

IV single dose concentration time graph

A

no increase at start/ absorption phase
fast distribution (dont see)
just elim- slope down

364
Q

what 2 things to think abt with dosing regimen?
i.e. what 2 things can be changed to stay within therapeutic window?

A

size of DOSE
TIME interval between doses

365
Q

Sketch a time concentration graph for multiple IV bolus administrations and label the Css max and Css min.
p 222

A

….

366
Q

when may multiple admin of drug be given? wha type of condition

A

treating acute symptoms

367
Q

at Css, drug conc stays the same T/F?

A

false, still have some fluctuations but all stay within range

368
Q

Define steady state in terms of the relationship between input and output.

A

at steady state, input = output

i.e. the drug coming in is equivalent to that eliminated

369
Q

whats Cav?

A

average conc at Css, but may not be the mathematical average

370
Q

What does the input(av) depend on?

A
  • dose
  • bioavailability
  • dosing interval

Input av = FD/t

371
Q

What is input directly proportional to for extravascular administration?

A

bioavailability, dose

372
Q

What is input directly proportional to for IV administration?

A

dose

373
Q

What is input inversely proportional to? Explain how.

A

dosing interval: the shorter the interval, the greater the input

374
Q

What is output dependent on?

A

steady state (Css) and clearance (CL)

Output av = CL * Css

375
Q

If input = output, what is the equation for average steady state for extravascular administration?

A

Css = FD / Cltotal x t

t = tao = dosing interval

376
Q

If input = output, what is the equation for average steady state for IV bolus administration?

A

Css = D/ Cltotal x t (tao)

no F as bioavailability of IV = 1

377
Q

Css eqn doesnt tell you how quick Css was recahed (as not linked to dose) but what parameter does tell you about that?

A

only t1/2

378
Q

On average, how many half-lives does it take to reach steady state?

A

5-6

379
Q

will a drug with shorter/ longer t1/2 reach Css fastest?

A

drug w shortest t1/2 reaches Css fastest

380
Q

How is the maximum Css calculated for IV bolus administration?

A

Css max = D / Vd (1-e^-ke tao)

381
Q

How is the minimum Css calculated for IV bolus administration?

A

Css min = Css max - D/Vd

382
Q

what parameter must you include before the D (dose) if admin is NOT IV?

A

F (bioavailability) as it wont be 1

383
Q

what does Css max assume?

A

rapid absorption and distribution

384
Q

what does Css min assume?

A

rapid distribution

385
Q

How is Css concentration at any time calculated?

A

Ct ss = FD (e^-ket) / Vd (1-e^-ke tao)

386
Q

Practice q 1:
An adult male is administered 250mg of an antibiotic every 8 hours for 7 days. Literature values state that this antibiotic is about 75 % available and has a clearance of 8.42 L/h.
Calculate average plasma concentration of this patient (at Css)

A

F = 0.75
Cl = 8.42
D = 250mg
tao = 8hrs

Css = FD/ taoCl
= 0.75250 / 8.42*8
= 2.78mg/mL

387
Q

Practice q 2:
A paediatric patient requires maintenance dosing with gentamicin which has a clearance of 5 L/h. What maintenance iv dose of gentamicin should you give every 8 hours to maintain an average steady state plasma level of 5 µg/L?

A

Cl = 5
tao = 8
Css = 5ug/L

Css = D/ Cltao
5 = D/ 85
D = 200ug

388
Q

why must you be careful when adjusting dose/ dosing in a narrow therapeutic range?

A

got more potential to go above or beyond it
toxic/ not working

389
Q

What needs to be considered when building a dosing regimen?

A
  • therapeutic window: narrow/ wide
  • onset of action: loading dose necessary?
  • dosage form: IR/MR
  • disease progression/response to treatment: kidney/liver impairment? titration?
  • patient-related PK parameters: age, weight, kidney/liver function, genetic factors (fast/slow metabolisers), etc.
390
Q

why look at CYP enzymes of px when considering for dosing regimen?

A

-> fast v slow metabolisers, will affect ADME

391
Q

what about drug treatment will impact blood conc vs time curve (diff to prev dosing regimen factors to consider)

A

RoA
dosage form
unit dose
freq
LD
length of treatment

392
Q

What happens to the plasma-time concentration graph if the DOSE is increased and why? Sketch the original curve in blue and increased curve in pink.

A

still get up/down fluctuations but will be taller and graph moved up

Css is higher as need higher conc to reach Css with new dose

393
Q

What happens to the plasma-time concentration graph if the DOSING INTERVAL is changed? Sketch the original curve in blue, the decreased (shorter) in red and the increased (longer) in pink.

A

shorter dosing interval = higher conc than orig
(more often = reach higher conc)

longer dosing interval = lower conc than orig

394
Q

Does the time taken to reach steady state change if the dosing interval is changed?

A

no as t1/2 still the same BUT reaching higher Cav
i.e. giving same dose more frequently = build up of conc

395
Q

For immediate release dosage forms, what points need to be remembered regarding the Css?

A

Css max and min need to be within the therapeutic window

396
Q

For immediate release dosage forms, what points need to be remembered regarding the DOSING INTERVAL?

A
  • determine target Css max and min
  • dosing interval will be estimated based on time it takes to go from Css max to min
  • round to clinically convenient interval e.g. 18.56 is not convenient
397
Q

what to remember for dosing interval and dose selection for MR?

A

check recommended interval

398
Q

To summarise, average steady state concentration changes with… 2

A
  • the frequency of administration
  • the size of the dose administered
399
Q

Plasma concentration-time graph for transdermal dose showing steady state being reached

  • how will it differ to oral dose
A

oral dose: fluctuations
transdermal: single dose and gets up to Css (absorption phase) then remains there straight line
patch removed, get elim phase i.e. decrease conc

400
Q

What type of dosage forms give us steady state with a plateau?

A
  • transdermal or anything w a reservoir system as this will have zero-order kinetics release
  • infusions
401
Q

Conc-time curve for steady state- what are the 3 phases?

A

wash in
steady state
wash out

402
Q

the wash in phase looks like absorption but we know…

A

exact rate at which drug enters body

403
Q

What does the rate of infusion depend on?

A
  • elimination rate constant
  • concentration of drug

(balance of input and output)

404
Q

for steady state, when does elimstart?

A

as soon as drug enters systemic circulation
processes exist in parallel BUT initially rate of entry much higher than rate of elim, see inc conc but stop input and just see elim

405
Q

what rate of order in steady state?
hint: at start elim rate not fast as not much drug in blood, then when remove input eg patch, elim takes over

A

first order
dependent on conc

406
Q

Describe how the rate of elimination changes according to its order of kinetics.

A
  • initially slow as it depends on concentration
  • as concentration increases, elimination increases
  • by the time infusion stops, only elimination occurring
407
Q

EQUATIONS p235

A
408
Q

time to reach Css depends on what?

A

t1/2

409
Q

What is the aim of a loading dose?

A

to reach steady state concentrations quickly

410
Q

in what 2 circumstances may we need to consider how long it takes to get to Css, therefore consider a LD?

A

when px changed from infusion ->extravasc (oral) eg in hospital

also IR -> MR, may be asked to adjust last day on IR/ overlap treatments so get Css in enough time

411
Q

for drugs with HIGH X, you should consider aloading dose

A

t1/2

as the higher t1/2 is, longer it takes ot get to Css, meaning youre below MEC for longer. need therapeutic effect so give LD to get in therap window

412
Q

What is the loading dose equation for infusions/parenteral administration?

A

LD= Vd * Css

413
Q

give an example of drug where LD used with infusion?

A

antibiotics in hospital

414
Q

What equation summarises the concentration at any time point of an infusion including the loading dose?

slide 35.

A
415
Q

Apart from a loading dose, how else can we quickly achieve steady state concentrations in an infusion?

A

Wagner’s method:

  • initial high infusion rate for t = half-life
  • then when t = half-life, slow down infusion rate

(inc input so conc inc. plasma conc depends on what cmoes from bolus injection & infusion)

416
Q

If the Vd for gentamicin is equal to a patient’s extracellular fluid volume (0.2L/kg) and patient weighs 80kg, what loading dose would you give to achieve a therapeutic plasma concentration of 4mg/L?

A

VD = 0.2L * 80kg = 16L

LD = Vd * Css
= 16 * 4
= 64mg

417
Q

What data do you use to obtain the half-life, clearance and rate elimination constant from an IV infusion graph?

A

the wash-out data - this is the elimination data which when plotted on a semi-log will give straight line

418
Q

what parameter is determined from the elim phase?

A

t1/2

419
Q

what is calculated from t1/2?

A

ke

420
Q

when can Vd be calculated from data?

A

if Css reached

421
Q

How do you calculate clearance is steady state has not yet been reached?

A

Cl = dose/AUC

  • use trapezoidal method to calculate AUC
422
Q

admE part 2 …….

what is drug elimination?

A

irreversible loss of drug from site of measurement occurring by metabolism and excretion

423
Q

how (2) is a drug eliminated from body?

A

by being chemically changed into something else (metab)

or physically removed from body (excreted)

424
Q

where is majority of drugs eliminated/cleared?

A

mainly in the kidney or liver

less importantly - excretion via lung/saliva/sweat

425
Q

lung = major organ for excretion of what substances?

A

gaseous and volatile

426
Q

how can pulmonary drug excretion be used?

A

alcohol breathalysers tests - quantify excretion of ethanol

427
Q

drug excretion into saliva depends on what 2 things?

A

pH partition
protein binding

428
Q

saliva drug conc. could be used to indicate what?

A

drug plasma conc.

429
Q

major function of kidney?

A

regulate fluid vol and composition within body

430
Q

how does the kidneys maintain salt and water balance?

A

excrete excess electrolytes, water, waste

conserves necessary solutes

431
Q

what is an issue with swallowed saliva in terms of excretion?

A

saliva bound to drug depending on pH partition and protein binding = drug reabsorption

432
Q

how do the kidneys eliminate drug substances? 2 ways

A
  1. metabolism (sometimes)
  2. excretion in the urine
433
Q

what 3 processes handle renal excretion/ elim?

A

glomerular filtration
tubular secretion
tubular reabsorption - active/passive

434
Q

what molecules are excreted in glomerular filtration?

A

free drug - unbound drug
small, water soluble drugs
depends on size - fit thru pores

435
Q

what molecules are excreted in tubular secretion?

A

secreted molecules
specialised active transport systems

436
Q

what molecules are excreted in tubular reabsorption?

A

active or passive reabsorption from renal tubules -> blood

lipophilic and unionised drug crosses
Hydrophilic and ionised drugs cannot cross
influenced by drug lipophilicity

437
Q

will lipophilic/unionised OR hydrophilic, ionised drugs not be able to cross membrane in tubular reabsorption thus stay trapped in renaltubule lumen and get excreted w urine

A

hydrophilic ionised

438
Q

will lipophilic/unionised OR hydrophilic, ionised drugs not be able to cross membrane in tubular reabsorption thus stay trapped in renal tubule lumen and get excreted w urine

A

hydrophilic ionised

439
Q

what is GFR?

A

Rate of blood filtering in the glomeruli = glomerular
filtration rate

440
Q

what is the GFR in a normal adult male?

A

125 mL/min

441
Q

what sort of drugs can be filtered freely (renal) and which cannot?

A

small, water soluble CAN

large proteins eg albumin and protein bound drug CANNOT

442
Q

what can lower GFR?

A

impaired kidney functions

443
Q

what drugs are excreted via tubular secretion?

A

weak acids
penicillins

444
Q

tubular secretion is an active transport process requiring what?

A

against conc grad
needs carrier energy supply

445
Q

tubular secretion - drug goes from to where?

A

from blood pasma to PT lumen
excreted in urine

446
Q

active transport systems eg tubular secretion can be used by more than 1 drug species meaning prone to…

A

competition (secretion of drugs w lower affinity may be inhibited)
higher affinity for AT system will be secreted

447
Q

approx hm water/fluid in glomerular filtrate is also reabsorbed ?

A

99%

448
Q

what type of drugs/ compounds more prone to tubular reabsorpiton- limited renal elim?

A

lipophilic, unionised
(also ionisable drugs but present in tubules in unionised form)

449
Q

name examples of substrates for carrier mediated/ active tubular reabsorption

A

endogenous substances: vitamins, AAs, potentially glucose

450
Q

how can we alter renal eliminiation?

A

change urine pH

451
Q

what happens when reduce urine pH?

A

acidic urine
1. weakly acidic drugs = unionised + reabsorbed = reduced elimination
2. weakly basic drugs = ionised = increased elimination

452
Q

how can you get acidic urine?

A

eg protein rich diet, ascorbic acid co-administration

453
Q

when reduce urine pH, weakly basic drugs will be ionised and inc elim eg in cases of what?

A

toxicity, OD eg amphetamine (basic drug)

454
Q

what happens when increase urine pH?

A

basic urine
1. weakly basic drugs = unionised + reabsorbed = reduced elimination
2. weakly acidic drugs = ionised = increased elimination

455
Q

how can you get basic urine?

A

co-administer bicarbonates

456
Q

example of weakly acidic drugs that will be ionised and inc elim when you increase urine pH?

A

barbiturate
trapped in tubule lumen, excreted w urine

457
Q

how can you promote elim of weakly basic drugs eg amphetamine?

A

reduce urine pH

458
Q

how can you promote elim of weakly acidic drugs eg barbiturates?

A

increase urine pH

459
Q

how do you calculate the renal excretion?

A

= glomerular filtration + tubular secretion - tubular reabsorption

460
Q

what is maximum rate of renal elim = to?

A

GFR

461
Q

how is the rate of renal elimination (GFR) calculated?

A

determining the renal clearance of inulin, creatinine

462
Q

what is creatinine? and its use

A

calculates rate of renal elimination
endogenous compound
eliminated by the kidney only - tests kidney function

463
Q

formula for renal clearaance?

A

CL renal = urine flow x urine conc / plasma conc

464
Q

T/F creatinine is filtered in glomeruli, NOT secreted / reabsorbed in renal tubules

A

True

465
Q

how are drugs excreted in the liver?

A

via biliary system or closely linked to drug metabolism

466
Q

what drug metabolism reactions undergo in the liver?

A

phase 1: oxidised/ reduced/ hydrolysed uncovering polar groups polar mols easily excreted via kidneys

phase 2: metabolite coupled to endogenous mol- conjugated mols inactive + highly water soluble thus excreted

467
Q

for a drug to be elim form liver, it must enter what?

A

the hepatocytes

then metab and or ecreted back into blood/bile

468
Q

what is enterohepatic circulation?

A

when bile delivered into SI form there material may be reabsorbed into blood/ excreted within faeces

469
Q

name of system used for recycling bile salts and endogenous substances also take advantage?

A

enterohepatic circulation
allows prolonged exposure of drug to body

470
Q

what drugs enter enterohepatic circulation?

A

bile salts but also
NSAIDs
opioids
digoxin
warfarin
…

471
Q

describe the 3 steps of enterohepatic circulation in case of drugs

A

drug/ metabolite in liver is secreted into bile (stored in gall bladder)

bile + drug released into SI

drug the reabsorbed back into blood + to liver returned

472
Q

drugs with what MW are excreted almost exclusively into urine?

A

small

<300

473
Q

drugs with what MW are excreted exclusively in both urine and bile?

A

middle

300-500

474
Q

drugs with what MW are excreted almost exclusively into bile?

A

big

> 500

475
Q

whats the most important factor for determining drug concs within body?

A

Clearance

476
Q

what is drug clearance influenced by?

A

dose
blood flow
intrinsic function of liver/ kidneys

477
Q

what may -> false interpretation of drug Cl?

A

PPB

478
Q

what is clearance of a drug? not eqn

A

vol of plasma/ blood from which drug is cleared per unit time

479
Q

drug Cl equation.

A

CL = ke x Vd

480
Q

what does Cl NOT indicate regarding drug conc?

A

rate of decline in drug conc

481
Q

R of E =

A

CL x Ct

Ct: conc of drug in blood at time t

482
Q

whats R of E directly proportional to?

A

drug conc

483
Q

R of E of most drugs follows what order process?

A

first

484
Q

only free (non-bound) drugs may be cleared.
what type of drugs bind to albumin?

A

acidic drugs

485
Q

what reduces albumin binding? thus -> more free drug

A

disease state (cancer)
competition (presence of second acidci drug)

486
Q

more or less drug will be eliminated in the disease state as much more is available/free?

A

more

487
Q

100% of albumin present in healthy state, how mcuh may be reduced to is disease state eg cancer?

A

50%

= more free drug
Rof E eqn- prop to drug conc

488
Q

total drug conc will dec if have dec binding to protein BUT free drug conc will remain same or not?

A

remain same

489
Q

E in ADME part 3….

what is the total body clearance

A

overall cl of a drug by eliminating organs

490
Q

describe the organ body clearance?

A

Cl of a drug by a specific organ e.g. renal clearance = volume of plasma/blood cleared of drug per unit time by the kidney

491
Q

how do you calculate total body clearance?

A

renal Cl+ hepatic Cl+ other organs Cl

492
Q

elimination = X+Y

A

excretion + metabolism

most drug elim by both

493
Q

how to calc combined elim?

A

CL = renal Cl (CLr) + metabolic Cl (CLm)

494
Q

when drug elim follows first order kinetics (common), each elim pathway has rate constant dependent on X and Y

A

elim pathway Cl
drug Vd

495
Q

how do you work out the renal elimination rate constant?

A

renal CL/ Vd

496
Q

how do you work out the metabolic elimination rate constant?

A

metabolic CL/Vd

497
Q

elim rate constant for overall elim process =

A

sum of rate constants for the 2 processes

ke = kR + kM

498
Q

drug in body = X + Y

A

drug in urine + metabolite

499
Q

what is Fe?

A

fraction of the (bioavailable) drug dose that is unchanged in urine

500
Q

how do you work out Fe?

A

CLr/CLt
ratio of CL

OR
kR/ke

501
Q

overall/ total body Cl =

A

ke x Vd

502
Q

how to find CLr is fe and CLt known?

A

CLr/CLt

… so CLr = fe x CLt

503
Q

how to find CLm?

A

CLm = CL - CLr

504
Q

how to find Km from ke and kr?

A

kM = ke - kr

505
Q

what is hepatic extraction?

A

rate at which liver extracts drug from the blood – by metabolism and removal into bile

506
Q

what does the hepatic extraction rate depend on? 2

A

hepatic blood flow (HBF)

intrinsic ability of the liver to handle (e.g. metabolise) the drug

507
Q

how do you workout the maximum hepatic extraction rate?

A

equal to Cl of whole drug

drug conc (Cin) x HBF (hepatic blood flow)

508
Q

what is the extraction ratio (E)?

A

Fraction of drug amount presented to the organ which is eliminated during a single pass through the organ

509
Q

what do the extraction ratios (E) mean?
0 and 1?

A

0 - most of the drug escapes elimination during a single pass through the organ

1 - most of the drug is eliminatED during a single pass through the organ

510
Q

action ratio E = measure of an organs…

A

relative efficiency in drug elimination

511
Q

action ratio E = measure of an organs…

A

relative efficiency in drug elimination

512
Q

how do you workout the extraction rate (E)?

A

(conc in - conc out)/ conc in

513
Q

what is the hepatic blood flow value?

A

1.5L/min

514
Q

CL organ =

A

QE
total blood flow x E

515
Q

what does hepatic blood flow vary with?

A

diet
food intake
physical activity (1-2L/min)

516
Q

what are low extraction drugs?

A

drugs w HER < 0.3

diazepam, warfarin, salicylic acid, phenytoin, and procainamide

517
Q

what are high extraction drugs?

A

drugs w HER > 0.7

lidocaine, propranolol, morphine, verapamil

518
Q

what does it mean if the hepatic extraction ratio <0.3?

A

low extraction ratio drugs

519
Q

what does it mean if the hepatic extraction ratio >0.7?

A

high extraction ratio drugs

520
Q

what does it mean if the hepatic extraction ratio 0.3-0.7?

A

intermediate extraction ratio drugs

521
Q

what are low extraction ratio drugs affected by?

A

unchanged by changes in blood flow

522
Q

what are high extraction ratio drugs affected by?

A

greatly affected by changes in blood flow

hepatic blood flow increase = during meal digestion

hepatic blood flow decrease = exercise/ cirrhosis/ heart failure/ old age

523
Q

hepatic extraction may be limited by 2?

A

intrinsically low ability of liver to extract drug (low ER)

blood flow to liver

524
Q

when does hepatic blood flow increase?

A

during meal digestion

525
Q

when does hepatic blood flow decrease?

A

exercise/ cirrhosis/ heart failure/ old age

526
Q

benefits of urine samples for pk analysis

A

less invasive, easier to collect than plasma/ blood

527
Q

in a simple case where drug NOT significantly metabolised,

drug in body (Db) -> drug in urine (Du)

via what parameter/ constant?

A

kr
rate of renal elim (as elim in urine)

528
Q

graph p 668

A
529
Q

what is the total amount of drug that can be recovered through urinary excretion equal to?

A

D = Du ∞

530
Q

at any time point, what 2 D = D = Du∞?

A

drug in body Db + drug in urine Du

531
Q

amount of drug appearing in urine may be calc from what?

A

loss of drug in body

kr x Db

532
Q

T/F rate is a +ve value as drug appearing in urine (not being lost)

A

true

533
Q

drug in body Db = ?

A

Du ∞ - Du

534
Q

when can you assume cumulative total = Du∞ which is equal to dose admin, D?

A

once no more drug being collected

535
Q

what will intercept be equal to for D graph?

A

Du∞ (=D)

536
Q

what will gradient equal on D graph?

A

rate constant, kr

Lab 3 (21 decks)

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