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week 16 (Y2) > the medicine > Flashcards

the medicine Flashcards

1
Q

what is rational design

A

the strategy of creating new molecules with a certain functionality, based upon the ability to predict how the molecules structure will affect its behaviour

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2
Q

what are catecholamines

A

class of neurotransmitters and hormones that play crucial roles in the NS

3 main categories are:
dopamine
noradrenaline
epinephrine (adrenaline)

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3
Q

what do beta recpetors do

A

three types beta 1,2&3

control vasodilation

stimulate cardiac and smooth muscle

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4
Q

what do alpha receptors do

A

two types alpha 1 and alpha 2

intestinal relaxation
vasoconstriction
pupil dlation

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5
Q

what is Analytical characterisation

A

Evaluating the success of a combinatorial synthesis by determining the yield and the purity of the compounds.

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6
Q

how to seperate single conounds

A

purification by conventional techniques (e.g. chromatography)
determination of the yield by weighing the substances
confirmation of purity by elemental analysis or NMR spectroscopy

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7
Q

how to seperate compound mixtures

A

highly sensitive methods are required
mass spectroscopy coupled with H/uPLC or capillary electrophoresis (CE)

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8
Q

what are the two mehtods for Determining the most bioactive substance in a mixture, High Throughput Screening

A

On Bead screening
Deconvolution

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9
Q

What is On Bead screening

A

Compounds are covalently attached to the solid support
The solid-bound library is treated with a labelled biological target (receptor)
Selection of the labelled beads (highly automated methods) followed by structural characterisation
Requirement: Solid support/ linkers have to be water soluble

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10
Q

What is deconvolution

A

Preparation of sets of sub-libraries (each contains compounds, with one single known building block; the remaining positions contain all possible variations
Screening of the sub-libraries provides the mixture with the highest bioactivity.
Iterative deconvolution/ deconvolution by positional scanning

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11
Q

what % of compounds are abondended each year due to poor solubility?

A

40%

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12
Q

Describe lead selection of medicines

A

A lead chemical series for optimisation (application of rational design)
Probability of Success increased by identifying a back-up series
Probability of Candidate Selection is low
Probability of Success for a precedented mechanism is low and lower still for an unprecedented mechanism
Even after Candidate Selection still a long way from becoming a medicine

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13
Q

what is the BCS

A

Biopharmaceutical Classification System

a system used to classify drug substances based on their solubility and permeability characteristics. It is widely used in the pharmaceutical industry to guide the development of oral drug products.

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14
Q

what is class 1 of the BCS

A

high solubility
high permeability
rapid dissolution

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15
Q

what is class 2 of the BCS

A

low solubility
high permeability

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16
Q

what is class 3 of the BCS

A

high solubility
low permeability

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17
Q

what is class 4 of thr BCS

A

low solubility
low permeability

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18
Q

what is the BDDCS

A

Biopharmaceutical Drug Delivery Classification.

sha

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19
Q

what is class 1 of the BDDCS

A

minimal drug effects on the gut and liver

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20
Q

what is class 2 of the BDDCS

A

effects predominate in the gut by uptake, and efflux transporters can effect liver

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21
Q

what is class 3 of the BDDCS

A

absorptive transporter effects predominate (can be modulated by efflux transporters)

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22
Q

what is class 4 of the BDDCS

A

absorptive and efflux transporter effects could be important

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23
Q

what classes of the BDDCS have low permiability / metabolism

A

3 and 4

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24
Q

what classes of the BDDCS have high permiability / metabolism

A

1 and 2

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25
Q

what classes of the BDSCS have high solubility

A

1 and 3

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26
Q

what classes of the BDDCS have low solubility

A

2 and 4

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27
Q

describe relative difficulty in formulation design

A

most to least

poor permeability

high first pass metabolism

poor chemical stability

low solubility

instability in GI fluids

high dosage

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28
Q

describe Overview of Pharmaceutical Product Development

A

lead optimisation
preclinical evaluation
Safety/ tolerability Phase I, PoC in humans
Phase IIb/ Phase III studies
Post-marketing studies

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29
Q

what is efficacy

A

Efficacy refers to the ability of a drug or medical intervention to produce the desired therapeutic effect under ideal or controlled conditions. It is a measure of the extent to which a treatment is effective in achieving its intended purpose

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30
Q

what are 4 reasons for failure of clinical trials

A

efficacy
safety
commercial viability
other (formulation problems)

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31
Q

what is commercial viability

A

Commercial viability refers to the likelihood or feasibility of a product, service, or business endeavor being successful and profitable in the marketplace. It is an assessment of whether a particular business venture has the potential to generate sufficient revenue to cover its costs, achieve profitability, and sustain its operations over the long term.

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32
Q

benefits of an IV bolus dose

A

The correct dose will result in the correct
and optimal clinical outcome

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33
Q

what is an IV bolus dose

A

An IV bolus dose involves the direct injection of one
entire dose (i.e. the bolus) into the venous
circulation.
This results in the TOTAL dose being administered
and entering the systemic circulation.
The bioavailability is therefore 100 %

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34
Q

tell me about an IV bolus dose

A

As we inject a BOLUS dose into our patients, the starting concentration in the blood is the
highest and the drug will eventually distribution out to the circulation and be eliminanted.
Essentially we see a DECLINE in drug levels

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35
Q

what does T1/2 mean bolus dose

A

half life

it describes the time required for a quantity to reduce to half its initial value.

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36
Q

what does C0 mean bolus dose

A

initial conc, where the graph intercepts the y axis

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37
Q

what does kel mean bolus dose

A

elimination rate constant

linked to degredation

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38
Q

what does Cl mean bolus dose

A

clearance

tells you about elimination

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39
Q

what does Vd mean bolus dose

A

volume distribution

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40
Q

bolus dose

conc time graph

what can you calculate?

A

Once you calculate the gradient and intercept (basic
maths), you are then able to calculate other important
pharmacokinetics terms

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41
Q

what kinetics is bolus dose based on

A

1st order

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42
Q

define initial concentration

A

the concentration (e.g. mg/mL) or mg/L) in the body (blood)
following dosing of a drug (in mg) into the volume of the blood (in mL or L). This is
sometimes referred to as C0 (the concentration at time zero)

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43
Q

define volume distribution

A

the volume (mL or L) within which you dose (in mg) the drug

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44
Q

define elimination rate constant

A

a constant terms (like the degradation rate constant when
looking at zero or first order degradation). This is not useful on its own but it used to
convert into something which is more clinically useful. The term is referred to as kel

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45
Q

define clearence

A

this has been discussed previously. The term is referred to as Cl. This is a useful
indicator of the amount of drug removed from the body by the kidney or liver

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46
Q

define half life

A

the most important term clinically. It can be calculated from the both of the above
and is the time taken for a 50 % drop in drug levels in the body. The terms is referred to as
t1/2

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47
Q

whats ADME

A

ADME pharmacokinetics is an acronym that stands for Absorption, Distribution, Metabolism, and Excretion. It’s a set of processes that describe what happens to a drug within the body after administration

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48
Q

conc eq

A

mass(dose) / volume

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49
Q

Cl
clearance two equations

A

Cl = Kel X Vd
Cl = Dose / AUC (Area under curve)

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50
Q

describe half life relationships

A

0.693 X Vd / Cl

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51
Q

when does Vd increase in half life relationships

A

(E.g. pregnancy)
Drug distributes out of circulation to a
greater extent
Gets into more tissues
Takes longer to come back into circulation
And then back into liver
To be metabolism
Takes longer to be eliminated
Half-life increases

52
Q

when does clearance decrease in half life equation relationship

A

(E.g. hepatic impairment)
Takes longer for drug elimination
Due to less metabolism
Drug stays longer in body
Takes longer to be eliminated
Half-life increases

53
Q

when is the half life relationship not always valid

A

NOTE: This relationship is NOT always valid.
Renal failure with oedema, Vd will increase but Cl decreases so no net change in
half-life

54
Q

what is surgical prophylaxis

A

Surgical prophylaxis refers to the administration of antibiotics to prevent infections before and during surgery. The goal of surgical prophylaxis is to reduce the risk of surgical site infections (SSIs), which can occur when bacteria from the skin or surrounding tissues enter the surgical site during an operation.

55
Q

tell me about an IV bolus dose
gentamicin

A

Gentamicin is an aminoglycoside antibiotic commonly
used for the treatment of infections and surgical
prophylaxis.
It is not absorbed from the gut when administered
orally, and is therefore predominantly administered via
intramuscular or intravenous injection.
Gentamicin can cause serious dose-related side effects
including nephrotoxicity and irreversible hearing loss, so
it is important to ensure patients receive the correct
dose and are monitored regularly.

56
Q

if conc is changing what else is also diff / changing

A

volume

57
Q

what happens when there is a higher volume distribution

A

higher volume distribution
takes longer to come back into circulation
elimination time increases
increases half life

58
Q

what happens at a lower volume distribution

A

quicker to come back into circulation
elimination time decreases
faster half life / shorter hlaf life

59
Q

what is Vd vital to determining

A

the correct starting bolus dose

60
Q

what is the relationship between Kel and Cl

A

elimination rate constant is directly proportional to clearance

61
Q

what is AUC area under the curve related to

A

bioalailibility

if AUC is high
more exposure to the body

related to Cl

62
Q

what is the relationship between Cl and half life

A

indirectly proportional

low Cl - longer half life

63
Q

what can Cl be impacted by

A

aging
drug-drug interactions
disease induced

64
Q

how does Cl relate to having a good clinical outcome

A

Low Cl = good clinical outcome, less likely second dose required

dependant on theraputic window

65
Q

how can we use pharmacokietics to optimally create dosing regemins for sub groups of patients

A

PK helps us in working with inter individual variability.

66
Q

how will we use clinical pharmacokinetics in patient variability

A

pharmacokinetic models
identify the source of variability
use clinical/patient/demographic data

all for dosing regimin optimisation

67
Q

tell me about blood samples in clinical pharmacokinetics

A

Clinical pharmacy: collect blood samples which give us an informed
quantitative way to assess drug concentrations. The blood concentrations give
us pharmacokinetic data collected over time.
Clinicians will present this as concentration vs. time graphs
This helps us to relate a dose to a target concentration in our patients
where we expect to see an optimal clinical outcome.

68
Q

tell me about drug profiles on pharmacokinetics

A

tells you about absorption, distribution, metabolism, elimination

Clinical Pharmacokinetics
What do we do with pharmacokinetics?
Plasma concentration profiles are really important in
understating the impact of ADME on the clinical activity
* How long is absorption?
* Is distribution rapid?
* How effective is elimination?
* Do we see an effect (duration of
action)?
* Is it toxic (MTC)?
* How do I maintain the duration of
action?

69
Q

What is pharmacokinetics?

A

Pharmacokinetics can easily be defined as:
“..what the body does to a drug..”
It’s has its origins in two Greeks words:
Phamakon (meaning ‘drug’)
Kinetikos (meaning ‘movement’).
In a more precise context, it relates to the rate of change of a drug in a patient’s
body and can be surmised by four key processes given the acronym ADME
(Absorption-Distribution-Metabolism-Elimination).

70
Q

What can PK tell you from a drug therapy
perspective?

A

PK allows you to individualise dose
based on patients ADME

IV or oral dose?

Vd, Cl, t1/2
Dosing regimen

71
Q

give examples of inter individial variability

A

Age
Sex
Exercise
Infection
Diet
Occupational
exposure
Lactation

Renal function
Stress
Pyrexia
Alcohol
Smoking (multiple drugs)
Barometric pressure
GI function
Pregnancy
Infection

Liver function
Albumin concentration
Cardiovascular function
Circadian and seasonal variations
Immunisation

72
Q

PK absorption

A

When you see the phrase ‘drug absorption’ it is important to think about where
the drug is being absorbed to. Normally this is the systemic circulations

73
Q

give oral absorption examples

A

oral
topical
inhaled
subcutaneous
intra muscular

74
Q

give an example of drug delivery that avoids absorption

A

IV

75
Q

what can absorption delay

A

clinical effect via time

Absorption processes typically can delay the clinical effect of the drug, as a
result of the drug needing to go from the site of administration to the site of
action

76
Q

absorption dis

A

These steps are prerequisites to absorption and at each stage of this
process we can loose large amounts of our initially dosed drug.

77
Q

what is bioavailibility

A

Bioavailability refers to the proportion of a drug or other substance that enters the bloodstream and becomes available for systemic circulation after administration, typically compared to the same substance administered intravenously.

Bioavailability (F) means the extent to which the active moiety is
absorbed from a drug product and becomes available in the systemic
circulation

78
Q

How does a drug go from the
circulation into the cells of the
brain?

A

absorption via blood
blood travels to target (tissues)

Site of drug action typically intracellular. Absorption is a
pre-requisite for site-targeting and clinical effect
ALL TISSUES/ORGANS have a biological
membrane/barrier which drugs must be able to
transverse to reach their target sites and is highly
dependant upon the lipophilicity of the drug

79
Q

what is the most common route for drug entry into the body

A

Although there are many absorption routes for drug entry into the body, the most
frequently used route is the oral route. For this we have a number of factors to
consider if dosing using a solid dosage form

RATE: Absorption rate constant (ka)
EXTENT: Oral bioavailability (F)

80
Q

what is the absorption rate constant?

A

Ka

81
Q

what tells you how quickly a drug gets into the patient and how much

A

RATE: Absorption rate constant (ka)
EXTENT: Oral bioavailability (F)

82
Q

tell me about a conc / time graph for rate of absorption

A

lowe K = slower absorption/lower peak

peak on graph represents Cmax (conc max)

83
Q

what is Cmax

A

concentration max

84
Q

what is Tmax

A

time it takes to reach concentration maximum

85
Q

What is bioavailability a measure of ?

A

Measure of amount of drug entering the
systemic circulation.
We calculate F by looking at AUCs, and for an
orally dosed formulation we compare the AUC
given IV (F= 1) to that of the AUC for the oral
dose .

86
Q

bioavailibility is affected by:

A

Absorption
* Formulation
* Age (luminal changes)
* Food (chelation, gastric emptying)
* Vomiting/malabsorption (Crohn’s)
First pass metabolism
* metabolism before reaching systemic
circulation (gut lumen, gut wall, liver)

87
Q

Switching formulations
Palliative care example

A

Terminally ill cancer patients
Chronic pain
End-of-life care
Oral morphine tabs

88
Q

what does oral dose require in comparison to IV for the same drug

A

When giving a drug orally, we have to
account for drug loss on its pathway through
the stomach, small-intestine and liver.
The IV dose will deliver the drug directly into
the blood. The oral dose requires a higher
loading dose compared to the IV route to
accommodate the drug loss

89
Q

Pharmacokinetics: Distribution?

A

The process of drug movement from the
circulation, into the tissues and organs

90
Q

Warfarin
Small volume of distribution

A

5-8L

91
Q

Pharmacokinetics: Distribution
The volume of distribution

A

on’t forget that the human body is essentially one large fluid filled container.
Pharmacokinetics: Distribution
The volume of distribution
Actual Volume (L)

Blood 7
Plasma 4
Whole Body 42

Knowing the volume of distribution will give you
some concept of ‘where’ the drug is.

92
Q

define high plasma conc of drug

A

Vd less than 4

Drug is just
in plasma

93
Q

define low plasma conc of drug

A

Vd more than 42

Drug is
widely
distribution
into tissues

94
Q

what does Vd determine
distribution

A

Vd determines the initial concentration of a drug in patients
Can change depending on patient (under/overweight/malnutrition)

95
Q

what is the apparent volume?

A

In summary, the term “apparent” in the volume of distribution reflects the fact that it is a calculated parameter that provides insight into how a drug distributes throughout the body relative to its concentration in the plasma, rather than a direct measure of the physical volume occupied by the drug.

The volume of distribution is often called an ‘apparent’ volume as it doesn’t reflect a
real-life volume. This example of a beaker with charcoal and blue dye will illustrate
the point.

could have less ‘volume’ in the beaker

96
Q

plasma protein example in acidic environment

A

albumin

97
Q

plasma protein example in an acidic environment

A

AAG (α1-acidic glycoprotein)
[Basic drugs)

98
Q

Pharmacokinetics: Distribution
How plasma proteins govern drug distribution

A

drug bnding to plasma protein, sticks drug to it. forming a complex. this cant diffuse out the circulation, limiting availibility to tissues and organs.

unbound drug is good as it can exit circulation and enter tissues

to give a clinical response

Plasma proteins are too large to diffuse out of the circulation and into tissues

99
Q

what do a lot of antimalarials have

A

they have really high Vds they prefer to be in the tissues and organs therefore less is in circulation

distributed but stuck onto charcoal from example

conc in apparent vol is halved
apparent vol has doubled

close to 1 fu

100
Q

what is the term for plasma protein binding to drug

A

This binding is termed ‘protein binding’ and expressed
as the unbound fraction of drug in plasma (fuplasma).

101
Q

unbound fraction interpretation

A

100% means all of the drug is unbound

fu close to 1 = unbound

102
Q

tell me about phenytoin

A

90% protein bound
10% unbound

Drug which are bound onto plasma proteins are unable to diffuse due to the large
size of the drug-protein complex. For phenytoin, it has a high (relatively low) Vd (DESPITE
protein binding), because it is very lipophilic.

may have to give higher doses or a more potent drug

103
Q

what happens in phenytoin when a pateint has liver impairment/sepsis/pregnancy/burns)

A

Any changes in the concentration of plasma proteins (e.g. liver impairment,
pregnancy, sepsis, burn etc) can cause significant issues for highly protein bound
drugs, which now become more unbound and free in the circulation with a greater
potential for distribution. This can prolong the half-life of the drug also

more drug enters circulation a lot faster as there is less plasma protein present

103
Q

what factors reduce plasma protein conc

A

age higher
neonates
burns
liver impairment
pregnancy

104
Q

what is elimination a combination of

A

metabolism and excretion

105
Q

what is metabolism

A

the enzymatic conversion of a
drug to an alternative form

106
Q

what is excretion

A

the removal of the drug from the
body

107
Q

where does metabolism occur

A

liver and intestines SI

108
Q

where does excretion occur

A

kidney

109
Q

how many steps are involved in metabolism

A

2

These two steps of metabolism are interconnected and tightly regulated to maintain cellular homeostasis and meet the energy and biosynthetic needs of the organism. Catabolic pathways provide the energy and building blocks necessary for anabolic processes, while anabolic pathways utilize the energy generated by catabolism to drive biosynthesis and cellular growth. The balance between catabolism and anabolism is essential for the proper functioning and survival of cells and organisms.

110
Q

what are the two metabolism steps

A

phase 1:drug undegoes oxidation to expose a fucntional group. Phase 1 is the first process and is mediated by
a range of enzymes. The most commonest of
which are enzymes from the Cytochrome P450
family.

phase 2: large sugar molecule attaches to functional group. Makes polar and soluable. easy to eliminate in the kidney.

111
Q
A
112
Q

tell me a fact about CYP enzymes

A

CYP enzyme family metabolise >60 % of
drugs on market
Major hindrance to effective drug therapy
Common cause of drug interaction issues
Highly variable across population

53 CYP isozymes
The most prominent of which
is:
CYP3A4

113
Q

what are SNPs

A

SNPs, or Single Nucleotide Polymorphisms, are variations in a single nucleotide that occur at specific positions in the DNA sequence among individuals within a population. In simpler terms, they are differences in a single building block of DNA among people.

114
Q

what effect do snps have on drug metabolism

A

different rates of drug metbolism, from slow to ultra rapid due to CYP enzyme. slow metaboliser: give lower doses to have same clinical effect

115
Q

Pharmacokinetics: Elimination
Metabolism and the liver

liver impairment examples

A

Reduced liver
enzymes CYP
Reduce metabolism of
drugs

Plasma proteins
Alter unbound fraction
Change distribution
Changes metabolism?

Reduced blood flow
Reduce exposure of drugs
to liver

116
Q

Pharmacokinetics: Elimination
The kidneys

A

The kidneys are the primary organ for drug excretion from the body. Drugs can be
removed either intact (‘unchanged’) or following metabolic conversion from Phase 1
or 2 steps in the Liver. The nephron is the functional unit of the kidney and
processes blood through a filtration process a the glomerular capsules (Step 1).
* Kidney perfusion is around 650 mL/min
* Around 20 % of this is filtered
* Giving rise to the GFR of around 120 mL/min
* 180 L filtered each day but most if reabsorbed
* Around 2 L per day of urine is produced.

117
Q

excretion
The process involves the excretion of drug from the body through:

A

Urine (kidneys)
Faeces (liver-small-intestine)
Sweat
Tear fluid
Hair
Lungs

118
Q

When we talk about excretion, there are three important terms we need to think about
when we consider designing a dosage regiment

A

Half-life
Elimination rate
Clearance

119
Q

what is Cl relevent to

A

Clearance (CL)
This is one of the most important terms in pharmacokinetics. It governs how we design
our dosage regimen (OD, BD, TDS QDS) and is related to the elimination rate

120
Q

Cl definition

A

Definition: volume of blood or fluid from which drug is completely removed per unit time

121
Q

what does no Cl mean

A

toxicity / death

122
Q

what does good Cl mean

A

Liver and kidneys
SAFE = BALANCE

123
Q

what do you have to keep steady in a patient when giving a maintenence dose

A

plasma conc

124
Q
A

week 16 (Y2) (3 decks)

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