Pharmacokinetics Flashcards
What does pharmacodynamics describe
the interaction of drugs and their receptors (including affinity and efficacy) and the tissue distribution of the receptor
What does pharmacokinetics describe
the factors that determine the concentration of the drug at the target receptor
What does relationship between administered dose and concentration at the target site depend upon
absorption,
distribution,
metabolism
excretion
How does plasma concentration of a drug vary over time for:
a) a single iv bolus dose
b) oral dose
a) initially high then decreases
b) initially increases to a peak as drug is absorbed, before decreasing as metabolism and excretion increase
What is the range the plasma conc of a drug must be within
therapeutic window - higher than minimum effective conc. but lower than the minimum toxic conc
Do you want the therapeutic window to be wide
yes this is ideal
How is the therapeutic window reflected in dosing strategies
An effective dosing strategy will maintain the plasma concentration within
the therapeutic window for as long as necessary
What kind of chemicals are local anaesthetics
Where do they act? What does this mean?
weak bases
intracellular side of the Nav channels
They must cross the plasma membrane to access the intracellular compartment.
How do local anaesthetics cross into the intracellular compartment
in their un-ionised form (D)
Why does the chemistry of inflammation affect the transport of local anaesthetics
Local inflammation decreases tissue pH (higher H+
concentration).
This shifts the equilibrium to favour DH+
Local anaesthesia is delayed or even prevented
Which form of a weak base/acid is more likely to cross the PM
un-ionised form is usually more lipid soluble so diffuses readily, whereas
the ionised form cannot cross the membrane
Name 2 subgroups in the SLC superfamily
organic anion transporters (OATs)
organic cation transporters (OCTs).
Name a SRC that is a drug target itself
SERT (transports serotonin)
Name members of the SRC superfamily that are a) highly selective and b) less selective
a) SERT
b) OCT, OAT - can transport a wide range of structurally diverse molecules
Describe the ABC superfamily
Give an example
ATP-binding cassette superfamily use ATP to drive drug efflux from cells.
MDR1 (P-glycoprotein, P-gp) is a particular example. They may be important drug resistance.
What are SLC and ABC superfamilies particularly important for in pharmacokinetics
absorption from the small intestine, excretion into the bile or urine, and transport across
the blood-brain barrier
What is the only time a drug does not have to cross a barrier to reach the plasma
iv
What is the fastest and most certain route of drug administration
When would this be useful
iv
if the drug has a small therapeutic window
Why might you use a slow iv administration of a drug over a fast administration
A rapid bolus injection can produce a very high plasma
concentration, initially in the right side of the heart and pulmonary circulation. Slow i.v.
infusion avoids this high peak plasma concentration while still avoiding uncertainly inherent
in absorption from other sites
Disadvantages of iv drug administration (3)
injection or infusion requires a
skilled practitioner, and inconvenience to the patient. There is also risk of infection
What are disadvantages of subcut. or intramuscular injections
rate of absorption can be unpredictable and inconsistent. These
injections can also be painful.
What is the rate of absorption dependant on for subcutaneous/ intramuscular injections
diffusion through the tissue and removal by local
blood flow, as long as the drug can cross the capillary endothelium
How does absorption differ between intramuscular and subcit injections
Blood flow to
the muscle is higher than to the skin, so absorption from intramuscular is often more rapid
than for subcutaneous. Exercise increases muscle blood flow, increasing absorption.
Why is oral administration the most common route for drug administration
cheap and easy to administer (self administering)
How are oral drugs absorbed
via gut epithelium
lipophilic molecules will diffuse passively
What does rate of diffusion of oral drug across gut epithelium depend upon (4)
rate of diffusion is highest for highly lipophilic drugs, whereas
charged or highly polar drugs diffuse poorly. The rate of diffusion also depends on the
concentration gradient and the surface area of membrane.
Where does most oral drug absorption occur in the gut
small intestine (large SA)
Are drugs absorbed in the stomach
e stomach has a relatively low surface area and a thick mucosa, so little drug absorption
occurs. An exception are the tetracyclines, which are soluble at acid pH but insoluble at
neutral pH.
Why are tetracyclines absorbed in the stomach
what if they are not absorbed in the stomach
soluble at acid pH but insoluble at
neutral pH.
Any tetracycline that enters the intestines precipitates and is lost in the faeces
What happens to the equilibria of weak bases in the stomach
what does this mean for absorption
shifted to DH+
poor absorption, may become trapped
What happens to weak acids in the stomach
shifts equilibrium towards DH so absorption is favoured
Does the small intestine favour absorption of weak acids or bases
upper small intestine favours absorption of weak bases over weak acids. Despite these
effects, the extremely large surface area of the small intestine means that most oral drugs
are absorbed in the small intestine
Name a drug that is absorbed by a gut transporter
which transporter
what does it treat
levadopa
phenylalanine transporter
Parkinson’s
Name 2 things that affects general drug absorption in the gut
splanchnic bloodflow
gastric motility
How does gastric motility affect drug absorption
The rate of
absorption of drugs that are mainly absorbed in the intestines will be increased if gastric
emptying is accelerated and decreased if gastric emptying is slowed
How does vomiting or diarrhoea affect drug absorption
reduces absorption
How does splanchnic blood flow affect drug absorption
Increased splanchnic blood
flow after a meal may increase the rate of absorption, whereas decreased splanchnic blood
flow in heart failure may reduce the rate of drug absorption.
How can you stop stomach acid degrading oral drugs
enteric coating
describe enteric coating
usually stable at acidic pH but break down at higher pH.
Digestion of peptides and proteins prevents their use as orally-active drugs (e.g. insulin)
What is the first pass effect
To reach the systemic plasma, the drug must be absorbed through gut epithelium and then
travel through via the portal circulation and the liver. Many drugs are metabolised by
enzymes in the small intestinal wall or the liver
What is bioavailability
The fraction of the delivered dose that reaches the systemic circulation
Name some factors that can cause low bioavailability (5)
inability to cross the gut epithelium,
transport back into the gut lumen,
metabolism of the drug in the intestinal
wall or liver (or by bacteria),
patient-specific factors such as interactions with other drugs
or food,
altered motility (e.g. vomiting).
Which drug administration routes can be taken to avoid stomach or the first pass effect (2)
rectal or sublingual
What is the series of the aqueous compartments in the body considered in pharmacokinetics
plasma |(endothelium) | interstitial fluid | (PM) | intracellular | (specialised barrier eg BBB) | transcellular
Describe the vascular endothelium
a single layer of cells that lines blood vessels and separates the
plasma compartment from the interstitial compartment. The nature of the endothelial
barrier varies between tissues.
What and how can some molecules pass through the vascular endothelium
endothelial cells of peripheral capillaries have small gaps between the cells that allow free passage to polar small molecules less than approximately 500-600 daltons. Small, lipophilic molecules can also diffuse through the endothelial cell plasma membrane
Give an example of a larger molecule that is restricted to the plasma unless specifically transported
Why is it restricted to the plasma
the anti-coagulant, heparin
Unfractionated
heparin is a carbohydrate polymer of variable chain length, with a molecular weight of 3-30
kDa. It cannot permeate the gaps between endothelial cells, and is not specifically
transported
Describe the capillary walls supplying the brain
have very tight junctions between endothelial cells and are further surrounded by astrocytes
which molecules can pass the BBB
if they are sufficiently lipophilic or if taken up by transporters/ via transcytosis
What can disrupt the BBB
Give an example
inflammation
In bacterial meningitis, for example, allowing increased access to hydrophilic
antibiotics such as aminoglycoside antibiotics and β-lactam antibiotics (e.g. penicillin).
Name an important BBB transporter
Pglycoprotein (P-gp; MDR1)
What is ivermectin toxicity associated with
a frameshift mutation and
premature stop codon in the mdr1a gene in collie dogs
Why can human MDR1 polymorphisms be associated with drug toxicity
What is it also associated with
. P-gp reduces the
therapeutic effects of some drugs in the CNS, but also reduces the CNS toxicity of some
drugs
even clinical efficiency of antidepressants, but
this is less well established.
How does fetal pH relate to maternal pH
What can this lead to
Fetal pH is usually slightly lower
than maternal pH, which can lead to ion trapping
Name an example which shows the placenta is not a perfect barrier to drugs
What is an ongoing scandal showing it is still a problem
thalidomide
The recent sodium valproate scandal
What is Vd and what does it describe
volume of distribution (Vd)
often used to describe the distribution of drugs in the body.
the volume that would contain the total amount of drug in the body at a
concentration equal to the plasma concentration.
What is the equation to Vd
𝑉𝑑 =
𝑡𝑜𝑡𝑎𝑙 𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑜𝑑𝑦
————————-
𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 (𝐶)
where C=C(free) + C (bound)
What is the Vd of heparin similar to
plasma volume (restricted to this compartment)
What kind of drug is gentamicin
Why is it useful when considering Vd
aminoglycoside antibiotic
it is small enough to cross the endothelium between the cells. It
distributes in the plasma and interstitial compartments -
represent the total extracellular fluid
What is the Vd of ethanol
similar to total body water water (42-45 litres) as it has a broad distribution throughout the body compartments
How does tissue binding/ partitioning into fat affect Vd
Why
increases Vd
it is the free (unbound) drug that exchanges between
compartments. As more drug binds to tissues in the interstitial, intracellular or fat
compartments, the concentration of free drug there falls. More drug will leave
the plasma and the plasma concentration falls. Therefore, tissue binding or partitioning
means that a greater amount of drug is accommodated with a lower plasma concentration.
Where can tissue binding occur
Where does it mostly happen for lipophilic drugs
to membranes, extracellular proteins or receptors
more likely to partition into fat
Which tissues can heavy metals adsorb to
bone
Why is the Vd very high for highly lipophilic drugs or heavy metals
Heavy metals
can become adsorbed to bone, lipophilic drugs are more likely to partition into fat so more tissue binding has occurred
What is the Vd of morphine
250 litres!!
What must be remembered when considering the Vd of thiopental
it is a very lipophilic GA so partitioning in fat is particularly important
What can decrease Vd
binding to plasma proteins
Why will Vd increase as more drug binds to plasma proteins
total concentration in plasma will be higher so
total drug in body/ plasma conc
will be smaller as denominator is bigger
What does binding to plasma proteins allow in PK
allows the plasma to carry more drug
Is it free or bound drug that exchanges with other body compartments
free
It is the free (unbound) drug that exchanges with other body compartments, and it is the free drug that is cleared by metabolism or renal excretion.
What is the major binding protein in plasma
What is the plasma [albumin]
How does this concentration compare with therapeutic concentration of most drugs
albumin
0.6mM
much higher than therapeutic conc
True or false
Albumin has many binding sites
true
including two sites for acidic drugs (e.g. warfarin,
salicylic acid, phenytoin) and other sites for neutral and basic drugs
Can warfarin bind to albumin
yes warfarin is acidc and albumin has two sites for acidic drugs (e.g. warfarin,
salicylic acid, phenytoin).
Give 4 instances when albumin levels can fall
liver disease,
old age,
nephrotic disease
major burns
What must you consider when using data about oral administration from one species to another (4)
What does this lead to
Taste and feeding behaviours (e.g. neophilia vs. neophobia) can affect how best to administer a drug to different species.
Differences in digestive tract physiology (e.g. in ruminants) can affect the rate and extent of drug absorption.
Grooming behaviour can lead to (often unintended) oral administration of topically-applied drugs.
Species-specific differences in drug metabolism are also extensive.
This can lead to poor correlations of bioavailability in humans other animals.
Which drugs can bind to α1-glycoprotein
Where is it expressed
basic (partitcularly beta blockers and antidepressants)
Although normally expressed at a low level in plasma,
it is an acute phase reactant that is increased during inflammation or stress.
True or false
plasma protein binding is saturable
What does this mean for C(free) and C(bound)
Which drugs is tshi knowledge important for
true
When a low percentage of binding sites are occupied,
an increase in dose gives a proportional increase in Cfree and Cbound. As the binding sites become saturated, an increase in dose will disproportionately increase in Cfree
drugs that almost saturate albumin in their therapeutic range (e.g.
phenytoin).
Give an example of competition for albumin binding
bilirubin which is normally eliminated by conjugation by neonates but competes against sulphonamides for binding
Why can it be dangerous to give sulphonamides to neonates
bilirubin normally
eliminated by conjugation, which is slow in neonates. If it is displaced from plasma proteins
by e.g. sulphonamides, Cfree will increase. This can lead to increased bilirubin in the brain and neurological damage.
Is a drug evenly distributed once it reaches the plasma
Once a drug has been absorbed into the plasma it will be rapidly and evenly distributed
through the blood. However, blood supply to different tissues is not evenly distributed
Which organs are not well perfused
skin, skeletal muscle and
fat
What is a consequence of some drugs being rapidly distributed through well perfused tissues but distribute through poorly-perfused tissues more slowly
that the apparent volume of distribution immediately after an i.v. bolus injection may be
much lower than the apparent volume of distribution much later, or when a steady state is
reached during infusions.
What are drugs metabolised by
the same enzyme systems that defend us from xenobiotics
What are phytoalexins
toxins against predation
What are important sources of xenobiotics
plants
environmental pollution, cosmetic products, food additives, agrochemicals, foods processing, as well as pharmaceutical drugs.
Why do hydrophilic xenobiotics not have to be metabolised
Membranes are a barrier to absorption of hydrophilic
xenobiotics, so can be readily excluded. Hydrophilic xenobiotics that are absorbed can also be readily excreted.
What would happen to lipophilic xenobiotics if they were not metabolised
not readily excreted , so they would accumulate in fats and phospholipid bilayers
What is the general strategy for metabolism of of lipophilic molecules
to convert a
lipophilic molecule into a more hydrophilic molecule that can be readily excreted.
What is the main site of xenobiotic metabolism
Name 6 other sites
liver
small intestine, nasal mucosa lungs skin kidneys blood
What is the first site for first pass metabolism
small intestine
How can the process of hepatic drug metabolism be divided
into phase 1 (functionalisation) and phase 2 (conjugation)
What are the purposes of phases 1 and 2 of hepatic drug metabolism
phase 1: makes a more reactive metabolite
phase 2: Makes a less reactive metabolite that is
(usually) more hydrophilic and higher molecular weight
What happens in phase 1 of hepatic drug metabolism
introduces/ unmasks a functional group to alter biological properties of drug
may activate or inactivate the drug
Give an example of a pro-drug
codeine - turned on by hepatic drug metabolism
What does phase 2 of hepatic drug metabolism do
how does it affect drug activity
uses the reactive functional group to add another molecule. This usually increases
the water solubility of the drug.
Phase 2 can also inactive a drug, though even some
conjugated drugs can have activity
name a drug that already has an appropriate functional group so does not require phase 1
paracetamol
Which superfamily is very important in phase 1 of drug metabolism
cytochrome P450
What does the CYP superfamily comprise
Is it well conserved?
18 CYP families with 57 genes (and 58 pseudogenes) have been identified in the human genome.
no: huge diversity between species, in terms of number of genes,
expression of orthologues, tissue distribution patterns, substrate specificities and activities,
and sensitivity to inhibitors.
How many drugs does CYP2D6 metabolised
involved in metabolism of up to 25% of current drugs.
How does the presence of CYP2D6 vary between individuals
What does this mean for drug research
Humans carry only one CYP2D6 gene, which is missing or nonfunctional in 7-8% of Caucasian Americans. Mice have nine different, functional Cyp2d genes and rats have six
This makes it difficult to extrapolate drug metabolism studies from animals to humans
Which are the most important CYP families
CYP1, 2, 3
Which CYP is responsible for metabolism of half of clinical drugs
CYP3A4 is responsible for metabolism of approximately 50% of clinical drugs
How can you tell a CYP that deals with metabolism of endogenous products from those which metabolise xenobiotics
CYPs involved
in metabolism of endogenous substrates (such as cholesterol) have very strict substrate
specificity. Xenobiotic metabolising CYPs cannot afford this selectivity. They must accommodate large structural diversity of substrates with a large and fluid substrate binding
site
What does the broad scope of xenobiotic metabolising CYP sacrifice
rate - slower than other CYP
How does the wide structural diversity of of potential substrates affect drug-drug interactions
makes drugdrug interactions more likely
Where are CYPs located
ER membrane
Where is a site of lipophilic drug accumulation in the cell
ER membrane where CYPs are located
Which molecules do CYPs use to metabolise drugs
O2 and haem.
Haem binds O2 into CYP active site.
CYPs also use H+
from NADPH, supplied by NADPH-cytochrome P450 oxidoreductase
What is a potentially harmful outcome of CYP activity
How is this mitigated
Often, more O2 is
consumed than needed, so superoxide is produced.
Superoxide dismutase converts this safely into water
How can you inhibit CYPs
Since many drugs can be metabolised by the same CYP isoform, drugs may compete
What is Prozac a substrate for
Fluoxetine (Prozac) is a substrate of CYP2D6, CYP2C19 and CYP3A4, and can also inhibit these isoforms (particularly CYP2D6).
Do drugs react the same way with each isoform of the CYP
Some drugs are metabolised by one CYP isoform but act as competitive inhibitors of other
isoforms. (Quinidine, for example, is a competitive inhibitor of CYP2D6 but not a substrate.)
How does ketoconazole react with CYP3A4
forms a complex with the Fe3+ form of haem in CYP3A4
