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Pharmacokinetics
What happens when you take a drug? Where does it go and how does it get there?
It is possible that a large portion of a drug is not necessarily used for its intended function as
it may be transported to the wrong part of the body or metabolised and excreted before
use/activation
...

To calculate total drug exposure:
Plot drug concentration against time, the area under the curve gives total drug exposure
...
The concentration then
decreases over time due to distribution, metabolism and excretion
...


-

From the plot we can calculate the maximum concentration
...
This is done by
changing the formulation of the drug
...


This information allows for the calculation of the ideal amount of drug to be taken by a
person which causes effect without being toxic
...

How do we design a drug to be fit for purpose?
1
...
Consider a potential lead compound and make several molecules
3
...
Analyse how active a compound is and which part of the body it will target
5
...
Clinical candidate – checking that the compound works in humans
7
...
Drug market (also includes phase 4, which is when those on the drug are monitored
for side effects against different medications)
There are pressures to develop drugs
...


-

Larger companies buy products from small companies who have conducted the
original tests
...
(last approx
...


-

The active ingredient within supermarket drugs is the same as the branded ones
...


The driving forces for developing a new drug:
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A disease that needs treating

-

When existing therapies become ineffective

-

Individualisation of treatments (screening a person’s genome to make personalised
medication – a very expensive approach)

-

Cost vs income – depends how many people are affected by the disease and how
much money can be made compared to the cost of making them
...


-

Neurological diseases have been difficult to treat and proved unsuccessful so far
...
This is an in-silico experiment
...
(May be aware of a certain 3D structure which is the
target, such as a protein pocket within a molecule, this can allow for the
identification of the pocket and design of a molecule to fit inside it)

-

Different algorithms may allow for this

-

Can either do a structure-based design which is a direct approach where the
structure is known, and the 3D space of the active site is understood
...


-

Indirect approach, is when we don’t know what the pocket looks like, but we have a
good understanding of the molecule which fits inside it
...
Can do a high throughput screen with a library of
these molecules all with differing functionalities
...


Examples of this approach:
-

Carbonic anhydrase inhibitor (Dorzolamide) is designed to be an anti-glaucoma
agent (an eye disease related to a build-up of pressure) and acts by decreasing the
production of aqueous humour
...


-

Enalapril is an angiotensin-converting-enzyme responsible for converting angiotensin
1 into angiotensin 2, which causes vasoconstriction, in turn increasing blood
pressure
...
It is administered as a pro-drug which
is processed (metabolised) within the liver allowing it to reach the target tissue
...


Bioassays and screening
Carried out via an in-vitro test which is done by isolating a target
...

- Would be expensive in terms of keeping the cells alive
...
Must also consider how long to grow the cells for, how
long to expose to dose and what sort of dosages should be applied
...


From these tests we can consider in-vivo testing on small and large animals
There are also other analytical methods such as NMR, spectroscopy and SPR
...
Also, would
reduce costs
...

They will be healthy and will not have other diseases which does not show the effect
of this
...

This phase is only to test if the drug is toxic
...

-

Any deaths will prevent the drug from being moved forward
...

May have a regimented diet
...

All occurs at one site
...


Phase 3: Large group (1500-3000) of ill patients over different sites
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Tested against a placebo or other therapy via a double-blind test
...

The subgroups may all be given different dosages or formulations
...


Phase 4: drug put on the market and allow for more side effects to be identified
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-

It is essential that lab documents are kept as these must all be proofed before a drug
can be marketed
...


Results obtained from the patients after clinical trials:
Ideally allow for the understanding of:
-

the pharmacokinetics and pharmacodynamics of the drug

-

how the drug is distributed around the body

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how the drug works (could be different to the models i
...
what was expected)

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drug interactions and contradictions (such as how other diseases effect the
treatment)

-

receptor sensitivity of the patient, as a drug may show less effect after a period of
time

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the social environment of a patient (for example different types of water may affect
the drug interaction)

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Clinical state of the patient

Marketing of the drug
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Packaging and formulation must be right (otherwise the drug may not be bought)

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Clear clinical case (how the drug will be used) is critical and must be given

-

Problems and interactions must be reported

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Trends in prescribing must be reviewed
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It is difficult to design a drug for everybody as people have different BMI’s, lifestyles, ages,
weights, metabolisms and genetic make-up
...


ADME
Absorption is the movement of drugs into the body
...

-

Drugs administered orally, intramuscularly and subcutaneously need to undergo
absorption
...


Pathways of drug absorption:
Lipinski’s rule of 5
- Molecular weight of less than 500
- LogP of less than 5
- Less than 5 hydrogen bond donors
- Less than 10 hydrogen bond acceptors
Oral drug delivery: A major route which involves release into the GI tract
...

Effect on absorption
Considering the chemical nature of the drugs being absorbed
...

It is important to understand the compartmental aspects (where in the body) of the drug
...

Types of administration
Can have different types of injections: (all have slow release)
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Subcutaneous – does not penetrate a blood vessel, just injects into the tissue
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(TB vaccine, Hep B) Less hazardous as the needle is longer, more painful
...
Bolus – one administration,
infusion is on drip so is administered over time
...
Must be sterile and some medical skill is needed to get into a vein
...
Allows for you to be up and about quicker than with general anaesthetic
...
Requires specialised administration with a higher possibility of
infection
...
Often referred to as topical
...

Administration by inhalation
Some administered by breathing in or pressing the inhaler down
...

Enables the oral delivery of large molecules
...
The compression of
tissue causes the drug to be released
...
Using cell lines, which involves growing cells
...
The bottom of it is permeable to small
molecules
...

Can analyse how much drug has remained within the cell or the model for the blood
...
These cells would not have as tight gap junctions
...
Cannot use humans, use anaesthetised rat
...


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In-vitro
...
In silico can be done, but only when some
information is known
...

(Relate to models)

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Distribution
Must consider the type of drug being taken, including how it is presented, it’s formulation
and the active ingredient’s action within the body
...

-

The drug must enter the blood plasma to have effect
...

(Albumin is a small protein found in high abundance within the blood plasma, one of
its main functions is to attach to drugs or hormones and help transport them)

-

Once attached to a protein molecule the drug is now bigger in size and harder to
excrete
...
A different drug can be present for
different amounts of time within different organs and tissues within the body
...


If a molecule enters and leaves quickly then the concentration of the drug at maximum is
likely to be toxic
...
Formulation helps to
alter this
...
This is a
process of dissolving which involves making a molecule more ionisable
...
The
drug then gets transported to the liver (where it can be metabolised) before entering the
veins which carry the blood to the heart
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The blood can now be
pumped through the arteries around the body
...
Put drug into
the vein to allow for metabolism and as the walls of veins are thinner than artery
walls
...
Sequestering (by a
protein) of drug: bound to unbound
...

Volume distribution = total concentration of drug in the body (dosage)/concentration of
drug in plasma
Dose = Volume distribution X plasma concentration
Distribution is majorly affected by blood flow as this moves the drug around the body
...

Albumin also typically binds to drugs, sequestering it so preventing movement into
tissues
...

This must always be an equilibrium
...


It is difficult to get drugs into the brain due to the presence of a blood brain barrier
...


Drug distribution patterns – all depends on Lipinski’s rules
-

A drug may remain largely within the vascular system
Molecules with low molecular weight that are water soluble may be uniformly
distributed throughout body water
Few drugs are concentrated specifically in one or more tissues that may/may not be
the site of action
Most drugs are non-un-informally distributed throughout the body
...
Xenobiotics are foreign biotics (could be a drug or a living thing
that shouldn’t be there)
...

-

Some drugs are metabolised into an active function (pro-drugs – drugs that are not
active until metabolised by the liver), whereas are destroyed by this action
...
Anywhere with
enzymes
...


-

Must consider where the metabolism is happening and how long it takes to occur
...
Mainly done within the liver and produces metabolites which can be transported
around the body or excreted
...
(methylation would increase lipophilicity)
Enzymes
- Are selective biological catalysts
- Catalyse central metabolic pathways
- Enhance rates of reaction
- Accelerate the rate at which equilibrium is reached
- May exhibit stereospecificity (can target drugs to them to increase or inhibit action)
- May require co-factors (ions or organic molecules)
Classification
- Phase 1: cytochrome P450’s (CYP) – family of isozymes, responsible for
biotransformation, function via oxidation
...

- Alcohol dehydrogenase – catalyse alcohol oxidation to an aldehyde and then to an
acid
...
When metabolised, can be excreted easier
...

Excretion – this is when the drug enters the kidneys and starts to be filtered out of the
blood and removed from the body
...
Most small molecules and released through the urine after being
filtered by the kidneys
...


-

Different methods of analysis are chosen based on the patient as well as the data
that will be able to be obtained
...
Gives
an idea of a drug profile
...
How
drugs work individually and together effects how the drug is absorbed and distributed
...

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Different drugs have different targets and can enter different parts of the cell
...
A tissue has the ability to form specialised functions
...
Acts as a barrier
against foreign particles
...

These cells are highly connected and separate different fluid compartments
...

-

Interactions between cells include tight junctions, adherens, desmosomes and gap
junctions
...


-

To deliver a drug through an epithelial membrane must go through a transcellular
route (membrane is made of a lipid bilayer and therefore small hydrophobic drugs
can pass through) or a leaky junction
...


-

A paracellular route is between the cells and is dependent on how leaky the
junctions are
...
(Acetone makes junctions leakier) The
paracellular transport of drugs is important in terms of absorption in the GI tract
...
Paracellular has a lower bioavailability in terms of its
pathway
...
Having a preference for transporting
positive molecules
...


Epithelial cells are found in all major cavities of the body
...


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Line most organs, including the stomach
...


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Can specialise to act as sensory receptors
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Female reproductive organs are lined with ciliated epithelial cells
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Epithilia – not found in all epithelial cells
...
Act is a sensory aspect as well as for transport and
absorption
...

Connective tissue – supports and binds other tissues together
...

Often also produce chemicals and blood cells that help to support the proliferation
of other cell types
...
Contains numerous microfilaments
composed of actin and myosin
...


-

Skeletal tissue allows for movement of bones and other structures

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Smooth muscle forms organs and changes shape to facilitate bodily functions
...
Delivering drugs
to different organs can be difficult
...

To get into the brain, drugs must surpass the blood brain barrier)

Mechanisms by which drugs can cross membranes:
-

Passive diffusion – most common, uses enzymes to use things through
...
Almost all drugs are water soluble,
which allows them to undergo passive diffusion
...

Drugs must also be lipophilic enough to pass through a cell membrane
...
Non-specific diffusion
...

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Add functional groups to a molecule to help it to interact with the cell
...


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Facilitated diffusion

This is the process of spontaneous passive transport of molecules or ions across a
membrane via transmembrane integral proteins
...
This can go against a concentration gradient
...

A lipid membrane is a hydrophobic bilayer, so a hydrophilic drug will not pass through
...

-

Shows that other components are found within the layer
...


Diagram:

Membrane proteins
-

These are the different types of proteins found within a cell
...
These allow the membrane to understand what is being taken in or given
out
...


-

Blood from the heart goes to lungs and then to all other organs
...


The main component of blood is water, followed by ions, amino acids, proteins and cells
(red blood cells etc)
...
Blood plasma is what suspends
white blood cells
...

Blood vessels

-

Both veins and arteries have 3 layers: an inner epithelial layer, a smooth muscle
layer and an outside layer
...
Meaning they are stronger and stiffer
meaning they are more able to push the blood around the body
...


-

It is known that veins hold more blood than arteries
...
Therefore, by injecting
into the veins the drug is diluted
...


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Changes in pressure allow for this blood flow

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There are many valves in the blood stream to help the movement of blood

Lymphatic system:
Collects all of the liquid which seeps out of the blood
...

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Cells need liquid around them to deliver nutrients and taking away toxins as well as
needing an aqueous environment in general
...


-

It distributes liquid around the extracellular environment and also acts as a filtration
system, it can be used for diagnosis as molecules that should not be found within
cells normally may also be found within this system
...
Things that shouldn’t be
within this liquid are collected here
...

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Alveoli allow for interaction between the blood and the air within the lungs
...


-

When a drug is taken into the lungs it must go from the bigger areas to the smaller
areas
...


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There is a small degree of metabolism within the lungs
...
The liver is divided into 4 main sections, each area with its
own function
...
This is the best filtering system within the
body
...

-

Testing for proteins in the urine shows dysfunction of the kidney as these should not
be able to enter the urine
...

Controls the water which is passed into the urine
...


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Bowman’s capsule provides ultra-filtration
...
Water is taken from the loop, so the salts
become more concentrated, the salts can the re-enter the blood
...
Controls the dilution of urine

GI tract:
Drugs travel from mouth to the oesophagus to stomach to the small and large intestine
...

Small intestine - Includes the duodenum, jejunum and ileum

-

Site for chemical and mechanical digestion
...

(The membranes within the small intestine are more permeable than the stomach
membranes)

-

The epithelial cells have microvilli which further increase the surface area and allow
for unionised drugs to be absorbed
...

Villi are highly vascular, have thin-walled blood vessels and facilitate absorption of
dietary compounds
...


-

Function of the small intestine is the digestion of food and the absorption of
nutrients
...


-

Transit time of food or a drug is 2-6 hours
...
Increased by constipation, gut surgery and
autonomic neuropathy
...
(Calcium
should not be taken with tetracyclines as it competes for uptake carriers)

-

Food can affect the time a drug is within the stomach, absorption can be delayed by
solution, absorption, binding or competition for uptake carriers
...


Large intestine
-

This is where the last useful parts of the drug are abstracted, due to the high surface
area
...


The stomach:
This has different functions and regions
...
One role of the
stomach is to hold food or pharmaceuticals within the stomach until they are fully broken
down
...
Drugs can go through but must be
designed specifically
...


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To cross the blood brain barrier the molecules must have lipophilicity, be of less than
700 in molecular weight or use a specific transporter
...
This can now allow things that shouldn’t enter to
enter as well as the drug
...
Pinocytosis is the popping off of small
parts of cells
...
When things are on the outside of the membrane, they
can also be taken into the cell in this way
...

The In-vivo one involves giving an animal a bolus injection and then monitoring the
concentration within the brain
...
Expensive and has a low through-put
...


First-pass effect
-

Where the drug is fully or partially metabolised before it becomes bioavailable
...


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If a drug is given orally it may be extensively metabolised by the liver before reaching
circulation
...


Calculations of drug ionisation
- Drugs can be characterised as weak acids or weak bases, which is if the drug is
ionised or un-ionised
...

pKa of a drug is the dissociation or ionisation constant
...
The protonated form of a week acid is nonionised
...
g
...

Weak bases – best absorbed in the intestine
...

e
...
Morphine needs to be in a basic solution so does not uptake a proton to become
ionised
To calculate need to know if a weak base or acid
...
2/1 = HB+/B
So, for every 3
...
Cell membrane are impermeable to polar
molecules
...
By keeping within the blood, a drug is less likely to be detected in a urine sample
...
Alkaline using allows for a greater fraction of the drug to be
protonated and therefore neutral, allowing them to pass through membranes
...
Allowing it to
be neutral and lipid soluble
...

(For excretion of this drug want to make ionised, by basifying the urine)

When pKa = pH the solution is in neutral form
...

-

By changing the nature of the drug, it allows for it to be moved from different
compartments within the body
...


Formulations of drugs

-

If a drug goes above therapeutic level this shows that it will have an effect
...
It can be seen
that C is less absorbed so has a lower bioavailability
...


-

If the dose is the same, the area under the curve is the same
...
So,
the bioavailability can be different in different people
...
This is important for treating children
...
Adding an
ester group can make a drug more lipophilic but may cause cleavage that is not wanted
...
This can also make the drug and prodrug and could lead to a decrease in bioavailability
...
Either by acting on cell receptors or
changing the way the drug is presented (pro-drug)
...


-

When a drug is taken orally it goes to the stomach, then to the intestine, where is it
absorbed and goes to the liver where it is broken down
...
Can
add a capsule or change the formulation
...
Waxy coatings can allow for slower release which gives a better
therapeutic value for longer
...

- Immobilised artificial membrane (IAM): monolayers of phospholipid analogues that
are covalently bonded to the surface of silica particles
...


-

Similar to the caco-2-layer
...


Pig skin is representative of human skin
...

Although all types of skin from different parts of the body are different
...
Human skin can
be taken from dead bodies, fat reduction and sex changes
...

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To see how good a model is, it must be compared to another model
...

So hairless skin is needed to show how the drug moves through the epithelial cells
...
As lipophilic drugs will prefer to reside in the fatty tissue
...

Skin cannot be damaged to be able to be used
...

Animal lives within a well-controlled cage allowing for controlled dosage
...


-

Use ADME to determine the absolute bioavailability
...
Need more than one animal model to be
representative
...


-

Perfusion is typically fast, blood carries the drug around fast
...
Occurs when the barrier is thin
...
Drug has a low MW and a near optimal LogP
...


K >1 – Drug prefers to be within the tissue so is lipophilic
K<1 – Drug prefers to be in the plasma, so is highly polar

Since plasma and tissue reach equilibrium quickly Cv = Cp (concentration coming out of
vessel is equal to the concentration within the plasma)
So Cv = Ct/Kt
-

Transport of the drug in and out of the tissue is equal to the difference between the
rate of delivery and removal
...

Rt = Q(Ca-Ct/Kt)
When transporting to the tissue Rt is positive, when being taken away, Rt is negative
...

Permeation problem – drug doesn’t permeate well into the tissue
...
Equilibrium between the plasma and the tissue is
very slow
...
Limited by permeability and surface area of the
lumen
...
This is a good
model for the blood brain barrier

Bioavailability (F)
-

Displays how much of a drug actually gets into contact with the tissue
...


-

Reduced by: slow dissolution, low lipophilicity, large molecular weight, diarrhoea,
gut contents, efflux and 1st pass metabolism
...


-

Can stop the liver from breaking down a drug by adding in an enzyme inhibitor
...


Quantification

This assumes that IV is 100% as the dose is given straight into the vein
...

Full equation gives the absolute bio-availability of the drug
...

-

Effect of 1st pass metabolism is expressed at ER (the extraction ratio)
F = 1 – ER
f = extent of absorption

Absolute bioavailability:
F = f x (1-ER)
-

Calculate the area under the curve for this to be able to be done
...
Assumes rapid mixing and
immediate homogenisation
...

Kel = rate constant of elimination
Drug goes into one compartment and it just diffuses around this one-part model and then is
excreted from this same compartment
...

-

Put a drug into 1 model this is then excreted into the next compartment
...


Model 2:
Has 2 compartments which must maintain equilibrium between each part
...
Assumes that the
central (body) compartment is uniformly mixed shortly after administration and that the
peripheral compartment equilibrates with the body
...
There will be a steady state reached in
each tissue, but the drug will not be uniformly dispersed around the body
...


If taking data points, using an animal for example, must take readings at different time
points
...

- If a mathematical model can be fitted it prevents needing to analyse all data points
...

Also considers equilibrium over time
...


-

equilibrium causes the rate of change to slow
...

Steady-state – no net change in concentration
...

Bolus dose – instantaneous input into the compartment One injection into the body
...
Rate of change as the drug starts
to move
...

Rate = K x Co
First-order process is when the rate is proportional to the concentration of one of the
chemicals
...

Rate = K x C1 x C2
Saturable process is when the interaction of two chemicals
...
This is
when the limit is reached and the graph plateaus
...
These are all limited by a factor (band width)
...

Mass-balance equation shows the change in concentration over time
...
Shows how long it is
therapeutically useful for
...


-

Limited by the amount of enzyme when forming an enzyme substrate complex,
when have excess of substrate
...


Steady-state assumption
...
This is done by plotting 1/v against 1/[s] and gives information for Km and Vmax
...


Drug clearance/excretion
...
Air also contributes to the
distribution of a drug through the lungs
...

Drug from the plasma enters the Nephron where from this it is excreted within the urine
...


How to calculate Kel experimentally
-

Plot a graph of ln[plasma] vs time
Slope gives -Kel

This is not that easy as drugs do not only exist in the plasma, they are also metabolised
there due to enzymes
...

Enzyme limited kinetics
- t/12 is no longer equal which shows a zero-order reaction
...

Clearance: the volume cleared per unit time
...
Shape also depends on these
factors
...
Clearance is a descriptive term used to evaluate
efficiency of drug removal from the body
...

Cl = rate of elimination/cp
Or
Cl = dose/AUC
Total systemic clearance
Injecting in the first compartment allows for equilibration to occur
...
Time delay is because the drug has to be
eliminated from both compartments
...

-

All related to bioavailability

Can also look at renal clearance vs the total body clearance
...
Some drugs get re-absorbed due to their characteristics
...
Ability to filter the drug through the membrane is the
glomerular filtration rate
...

Clren = GFR x fu
Clren = urine flow x fu
(As GFR = Clren)
Clren = urine flow x [drug]urine/[drug]plasma
Glomerular filtration is a passive filtration process
...
For people that have renal
dysfunction, GFR is determined from creatine (a breakdown product from muscle)
clearance
...




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