lecture 6

Question 1

i’m vivo pharmacology uses

Answer 1

animal models

Question 2

what research is in vivo pharmacology

Answer 2

ADME research

activity
adsorption
metabolism
excretion

Question 3

list the 10 in vivo pharmacology toxicology tests

Answer 3

• acute toxicity
• synchronic toxicity
• chronic toxicity
• reproductive toxicity
• immunotoxicity
• pharmacokinetics
• in vitro permeation studies
• in vivo adsorption studies
• pharmacology
• irritation + sensitisation

Question 4

what is pharmacokinetics

Answer 4

where u determine concentration profiles + the drugs fate in the body

Question 5

what is pharmacodynamics

Answer 5

examining the effect of the drug on the body

Question 6

what must be done in order to accelerate the drug discovery program

Answer 6

u must identify the most appropriate in vivo pharmacology solution

Question 7

the reason ppl study the in vivo PK-PD relationship is to:

Answer 7

-make quantitative analysis of the dose response relationship
- describe + predict the time course effects resulting from drug doses
- observe how much the target must be modulated in order to observe statistically significant efficacy
- identify a efficacious dosing regime with an acceptable therapeutic index

Question 8

in vivo PK studies are extremely

Answer 8

interdisciplinary

Question 9

interdisciplinary meaning

Answer 9

the info from PK studies are related to a bunch of different branches

Question 10

properly executed PK-PD studies require a team of experts in what fields

Answer 10

• establishing the most appropriate animal model
• animal dosing and handling
• measuring efficacy in different models
• identifying the most appropriate PD readout for the drug + model tested
• design quantitative PD assays
• measure drug conc in different tissue matrices.
• evaluate and analyse and the PK data

Question 11

PD is the

Answer 11

drugs affect on the body

Question 12

PK is the

Answer 12

fate of the drug in the body
+ conc profiles

Question 13

PD memory

Answer 13

D == what the drug is doing to the body + it’s effects

Question 14

PK memory

Answer 14

Killed = it’s fate

the fate of the drug in the body

Question 15

what percentage of the animal models are rats or rodents

Answer 15

90%

Question 16

why are rodents used as majority of the animal models

Answer 16

• short lifecycle and lifespan
• low cost + time saving + reproduce faster
• small size so smaller dose
• genesfor diseases with human origin have counterparts in rodents

Question 17

why are rodents sometimes not used

Answer 17

• larger animals are used for longitudinal studies as they live longer
• more similar in size to humans allowing us to address issues relating to scaling up to human therapy.

Question 18

what larger animals are usually used in animal models

Answer 18

dogs

Question 19

what influences the selection of certain species+ what effect does this have

Answer 19

their maintenance
harder to maintain = less likely to be used

this limits the accuracy of results (hard to scale up to human therapy when small animals are used)

Question 20

animal models must have what in relation to the human disease

Answer 20

they must recapitulate all aspects of it
must have the genes and the genotype
- they must be able to replicate the human symptoms

Question 21

what is the new animal model

Answer 21

zebra fish

Question 22

why are zebra fish being used as new animal modes

Answer 22

• see through bodies; we can follow the drug
• similar metabolic characteristics to humans
• make many embryos allowing us to have optical clarity over the developing embryo
• used for genetic mutant + therapeutic screening
• CRISPR : using zebra fish is accelerating our understanding of the molecular mechanisms of human genetic diseases

Question 23

is the body an in vivo or in vitro system

Answer 23

in vivo

Question 24

the body in vivo system consists of what

Answer 24

inflow (absorption)
outflow (clearance)
of drugs

Question 25

what do prospective drugs require

Answer 25

a minimal set of physiochemical properties

Question 26

do we know the conc of a drug in in vitro

Answer 26

yesss bc the drug is confined to a known volume

Question 27

when are measurements taken in in vitro

Answer 27

after a steady state / equilibrium has been attained amount plotted against time ( rises then plateaus)

Question 28

is in vitro an open or closed system

Answer 28

closed

Question 29

why is in vitro conc measurement critical

Answer 29

bc we know the conc of the drug critical bc all measurements of drug activity is based on its concentration when an effect is observed ( potency, efficacy + affinity)

Question 30

is in vivo a closed or open system

Answer 30

open

Question 31

i’m in vivo: days describing potency is associated with what

Answer 31

it’s associated with time as we do not know the amount of drug in a certain volume, we dk it’s concentration

Question 32

graph for in vivo

Answer 32

amount against time rises, reaches a peak then falls once again.

Question 33

what is the C max

Answer 33

max peak concentration of a drug in the bloodstream after a dosing regime

Question 34

C min

Answer 34

the min concentration of a drug observed in the central compartment during repeated doses

Question 35

what is the extraction ratio

Answer 35

ratio of the drug quantity entering the body and the drug quantity flowing into a removal organ (liver)

Question 36

MRSD

Answer 36

maximum recomm need starting dose at the beginning of clinical trials

Question 37

NOAEL

Answer 37

no observed adverse effect level for a drug

Question 38

NOEL

Answer 38

no observed effect level for a drug

Question 39

T

Answer 39

dosage interval period between doses on a repeating doses study

Question 40

volume of distribution meaning

Answer 40

movementof drug from intravascular compartment (blood plasma) to extravascular (intercellular + extracellular) compartments in the body

Question 41

what can the volume of distribution be used to see

Answer 41

detects small portions of the drug in different areas of the body

Question 42

what is the central compartment

Answer 42

the blood stream

Question 43

is the body an equilibrium or a non equilibrium system

Answer 43

non equilibrium

Question 44

how is the body a non equilibrium system

Answer 44

there is no time for an equilibrium to occur drugs enter and are removed at a certain rate

Question 45

what is meant by drug clearance

Answer 45

the removal of a drug from the body

Question 46

what organs can clear drugs from a body

Answer 46

liver kidney brain sweat glands lungs 🔺🔺

Question 47

the organs that can clear drugs from the body, excluding the lungs are seen as

Answer 47

processes connected in parallel

Question 48

drugs administered orally undergo ebay metabolism

Answer 48

FIRST PASS METABOLISM

Question 49

what is first pass metabolism

Answer 49

process that happens to orally administered drugs - absorption from the gastrointestinal tract + then being moved to the liver via the portal vein

Question 50

first pass metabolism memory

Answer 50

1st = mouth bc most preferred absorption gastrointestinal tract , portal vein, liver

Question 51

why are drugs being administered orally a problem for pharmacokinetics

Answer 51

- the drugs fate bc they bioavailability is not 100

Question 52

what is bioavailability

Answer 52

the % of the administered drug that reaches the systemic circulation

Question 53

what bioavailability score is the best

Answer 53

100!! high values are better means they’re more available more drug available to reach the target

Question 54

what administration leads to a bioavailability of 100

Answer 54

INTRA VENOUSLY administered drugs these are not oral

Question 55

why do orally administered drugs have a lower bioavailability compared to intra venously administered drugs

Answer 55

- intestinal epithelium absorption - first pass metabolism: wich reduces the conc of the active drug before it gets to the target or the systemic circulation.

Question 56

what organ is the main site of the first pass effect

Answer 56

the liver it can still occur in the lungs or any other metabolically active tissue

Question 57

what is the bioavailability value and how is it reported

Answer 57

its an avergage value it varies between the human polulation its reported using a range of deviations +-

Question 58

what is F

Answer 58

oral bioavailability total fraction of a drug that enters the central compartment when administered orally

Question 59

whats is Fabs

Answer 59

the fraction of the drug thats absorbed

Question 60

what is Fesc

Answer 60

fraction of drug that escapes// isnt metabolised by the passage in the liver

Question 61

equation to find F

Answer 61

F = Fabs x Fesc total % entering the central compartment after being taken orally = % absorbed x % that escaped metabolism

Question 62

high F value eg

Answer 62

50% or more

Question 63

medium F value

Answer 63

25 - 50

Question 64

low F value

Answer 64

25%

Question 65

how else can we determine F

Answer 65

assessing area under the conc-time curve for intravenous drugs vs oral drugs F = AUC oral / AUC iv

Question 66

where does first pass metabolism occur

Answer 66

gut wall or liver prevents oral drugs from reaching the systemic circulation along with incomplete absorption

Question 67

which drugs usually have very low oral availability

Answer 67

common drugs like insulin which would be broken down by gastric acid.

Question 68

what happens when a common drug has very low oral abailability

Answer 68

it must be administered using other routes

Question 69

how are drugs that arent administered orally cleared??

Answer 69

cleared by the heptatic or renal system

Question 70

which organ clears non polar drugs

Answer 70

liver

Question 71

the efficiency of the liver being a removal organ can be expressed using what ratio

Answer 71

the EH ratio extraction ratio

Question 72

what is the EH ratio

Answer 72

way of expressing how good the liver is at clearing

Question 73

EH ratio

Answer 73

extraction ratio EH = 1- [out] / [in] answer = amount of drug metabolised by the liver

Question 74

what is clearence

Answer 74

the rate of complete cleansing of a given volume of body water per unit time time it takes to clean xxx units of water