PK ADME Flashcards
What is pharmacokinetics?
study of what body does to drug
What type of relationship does pharmacokinetics deal with?
dose-concentration
how does pharmacokinetics link dose and concentration?
links how the dose delivered affects the concentration within the body
What is pharmacodynamics?
study of what drug does to body
What type of relationship does pharmacodynamics deal with?
concentration-effect relationship
How does pharmacodynamics link concentration and effect?
it determines how the effect varies with concentration achieved
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)
once drug absorbed in, what are the 2 forms of drug in body and are they permanently in these states/ can they change?
free drug
bound drug
eqm so can change
bound drug is sequestered (concealed) in blood, meaning…
cant leave, cant distribute to other compartments and sites to where It needs to act. And not free to do its job
plasma conc/ time curve: difference between IV and IR oral formn curves?
IR oral: drug conc 0% at start
IV: straight into bloodstream, so have some drug at 0min
What does the absorption of ADME describe?
how drug gets from dosage form -> site of action (normally blood)
usually for PK purposes what is the site of action?/ where is the drug measured?
blood
absorption is defined by a rate constant (Ka) and is linked to what?
rate at which drug is absorbed into the blood
what is the term given to the mass of drug that is administered?
dose
how much drug gets into the blood how quickly in an INTACT form?
BA (bioavailability
once drug crossed gut wall it travels across portal vein to what organ for metabolism before reaching the bloodstream?
liver
the apparent volume into which a drug is distributed depending on drug properties?
Vd
why are plasma protein and tissue bound drug molecules not included in the free concentration levels in the blood?
unable to act
drug in liver can be secreted into bile which is then secreted into small intestine, what does this mean for absorption?
reabsorbed
absorption form GI tract is X and Y
complex and dynamic
What does the distribution of ADME describe?
how the drug moves about the body, and how this movement may affect the concentration
What 2 pharmacokinetic parameters relate to distribution?
Vd
plasma/tissue binding
Drug in blood can -> (irreversible go to) to….
receptor binding -> effect
liver, bile + reabsorb/ metabolise
kidney + metabolise
-> excreted
Drug in blood can be <-> (in eqm) to….
drug in…
adipose tissue storage
peripheral tissues (stoage)
drug-plasma protein complex
What does the metabolism of ADME describe?
how the drug is altered once in the body
What occurs in phase 1 metabolism?
drug made more hydrophilic via oxidation, reduction or hydrolysis
What occurs in phase 2 metabolism?
drugs conjugated to allow for easy excretion
a chemical that is admin in non active form and is activated via a metabolic reaction such as codiene?
prodrug
What is first-pass metabolism?
extensive metabolism drugs passing through liver before reaching blood experience before reaching target site e.g. orally administered drugs
most common consequence of metabolism: metabolite may have….
no or reduced activity (compared to the parent compound)
what 2 things can also change if structure of durg changes?
function and efficacy
What does the elimination of ADME describe?
how the drug leaves the body
What are the two types of drug elimination?
- renal
- hepatic
What is renal elimination?
Elimination of polar drugs via the kidney
What is hepatic elimination?
excretion of drugs via liver
What is clearance (+units)?
volume of plasma/blood that is cleared of drug per unit time
(L/h)
are polar drugs likely to excreted renally or hepatically?
renally
What is half-life (+units)?
time taken for the concentration of the drug in the blood to fall to half its original value
(hrs)
absorption is all processes from…. to….
All processes from the site of administration to the site of measurement
What is disposition?
The processes that occur following absorption; e.g distribution and elimination
Distribution: The X transfer of drug to and from the site of measurement
reversible
Elimination: X loss of drug from the site of measurement. And how many processes can it occur by?
Irreversible
2: excretion and metabolism
What is excretion?
Irreversible loss of unchanged drug from the body
Metabolism: Conversion of the drug to an ….
alternative chemical species
formulations that show equivalent bioavailability profiles are…
bioequivalent
4 things necessary for drugs to be considered pharmaceutical equivalents?
- same active ingredient/s
- same dosage form
- same route of admin
- identical in strength/concentration
What is necessary for drugs to be considered pharmaceutical alternatives? 3
same therapeutic moiety but different:
- salts/complexes of that moiety
- dosage forms
- strengths
what method/ process used to show bioequivalence?
PK
why study PK? 2
- to understand dosages administered
- to calculate dosages in special populations eg children/preg/CKD
How is pharmacokinetic data presented?
conc in body/ time
What type of concentration plot do zero-order reactions show a straight line on?
normal
What type of concentration plot do first-order reactions show a straight line on?
logarithmic
What type of concentration plot do second-order reactions show a straight line on?
1/concn plot
whats the orders of reaction (dC/dt) for
zero
first
second
k
kC
kC^2
What order are 95% of therapeutic drugs eliminated by?
first order
When does zero-order elimination kinetics occur?
and whats this also called?
when the elimination process is saturated
- at higher concs elim rate no longer proportional to conc
AKA non linear kinetics
What is the relationship between ln and log?
Ln (x) = 2.303 Log (x)
PK ABSORPTION
The absorption phase of a drug is its movements between what two sites?
from site of administration -> systemic circulation
why is the no abssorption phase for IV or intra arterial RoA?
drug straight into circulation
What are the factors that affect the rate and extent of drug absorption? 4
- anatomical site
- disease state (physiological changes)
- drug properties
- formulation (can add solubility enhancers)
for drugs given via a RoA that has NO absorption phase, what does the plasma conc/ time curve only show?
eminimation process
no appearance of drug in circ, just looking at speed of elim from blood
what about a drug may affect the absorption?
- 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
What are examples of things present at the anatomical site that affect drug absorption rate and extent?
- mucus layer properties
- surface area (increased in SI due to villi)
- membrane thickness (thinner is better)
- vascularisation
- enzymatic activity
What are examples of physiological changes that can occur due to disease state that affect the rate and extent of drug absorption?
- inflammation e.g. IBS
- diarrhoea affects residence time (shorter for drug absorption)
What are the 3 categories of drug properties that affect drug Absorption rate and extent?
- physicochemical
- solid-state
- chemical stability
What are examples of physicochemical drug properties that affect drug absorption rate an extent?
- solubility/ dissolution rate
- pKa (ionisation state)
- lipophilicity
- complexation (e.g. cyclodextrins)
when it comes to drug lipophilicity, what type will be easier to cross membranes and therefore absorbed?
membranes very lipophilic. Easier for lipophilic drug to cross membrane compared to vwater soluble/ hydrophilic drug
when it comes to drug ionisation state, what will be easier to cross membranes and therefore absorbed?
and what impacts it?
unionised form will cross membrane
If have weak acid/ base drug, pH at site of administration impacts ionsiation state of drug thus absorption
Why does a drug’s solid state properties affect its rate and extent of absorption?
amorphous and crystalline forms can have differing solubilities
Why does a drug’s chemical stability affect its rate and extent of absorption?
if it’s degraded in e.g. stomach, won’t be absorbed as nothing left!
name a physiological change/ disease state that can affect rate and extent of residence time of a drug?
diarrhoea
how does MW affect rate of abs?
small molecules absorbed faster
how to make drug formulation more soluble?
use salt form or use stabilisers
to ensure enough of it in solution to be absorbed
molecule that helps adjust fluidity of membrane?
cholesterol
(same w liposomes, can adjust fluidity by changing cholesterol conc)
water soluble molecules/ proteins used for nutirent transfer DO/DO NOT cross memb easily
DO NOT
thus need carrier to help them enter cells
What are the two ways for which drugs can be absorbed across cells?
- passive diffusion: transcellularly, paracellularly
- carrier-mediated
What is the transcellular route? What type of drugs are likely to use this route?
directly through cells - lipophilic as do have to cross memb
What is the paracellular route? What type of drugs are likely to use this route?
in between the aqueous environment of cells - hydrophilic. small water soluble drugs
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?
add permeation enhancers to formulation, can open junctions and create more space between cells to allow drug to be absorbed through this route
Passive diffusion: doesn’t need energy, concentration gradient is instead driving diffusion of drug
how does drug move? to and from?
high -> low conc
= passive methods of diffusion obey Fick’s law and all those parameters impact how well drug is absorbed
Passive diffusion is not saturable, meaning what?
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
What factors affect the rate of passive diffusion across cell membranes?
- drug lipophilicity
- surface area available
- increased drug concentration
- thickness of epithelial layer
What is the main problem for drugs absorbed by carrier-mediated mechanisms?
can be transported out by efflux transporters affecting bioavailability
how does carrier mediated transport work?
carrier protein on either apical or basolateral side, helps drug cross the membrane
apical side close to blood or lumen?
lumen
basolateral close to blood or lumen?
blood
what type of drugs would benefit from carrier-mediated transport?
water soluble
What does the rate of drug absorption for carrier-mediated absorbed drugs depend on?
drug conc and affinity and transporter availability
Describe the components of the equation that describes the rate of drug transport for drugs absorbed by carrier-mediated transport
Jmax
C
Km
Jmax = rate of transport by receptors
C = conc of drug at site of absorption
Km = affinity of drug for transporter
What is the main difference between carrier-mediated and passive diffusion absorption of drugs?
carrier-mediated can become saturated
Under what conditions does carrier-mediated drug absorption follow first-order kinetics? Describe why.
- when not saturated bc rate will depend on drug conc
- high conc = initial fast release that decreases as drug conc decreases
Under what conditions does carrier-mediated drug absorption follow zero-order kinetics? Describe why.
- if saturated/rlly high drug conc
- no longer depends on drug conc
- depends on number of transporters/receptors available
true or false, there is competition between drugs using carrier mediated transport and the natural nutrient that is its substrate?
true
What are examples of drug effluxers?
- P-gp
- BCRP
- MRP2
Why do effluxers get rid of drugs?
- drug seen as toxin
- transporter uses ATP to rid of drug against concentration gradient
What are the 3 mechanisms through which the cell itself can uptake the drug?
Phagocytosis
Pinocytosis
Endocytosis
immune cells uptake nanomedicines by what process?
phagocytosis
extracellular fluid taken in by cell when it is drinking, process name?
pinocytosis
If drug binds to a receptor, will trigger what process where membrane will form mini vesicles and drug taken into intercellular space?
endocytosis
What are the 3 extravascular routes of administration?
- subcutaneous
- intradermal
- intramuscular
What steps must a drug administered subcutaneously undergo before absorption? What’s the clinical use of this route?
- distribution in interstitial fluid
- absorption through capillaries/local lymph nodes
- prolonged release
Where is a drug administered when intradermally?
between the dermis and epidermis
What are the clinical uses of the intradermal route?
vaccination/skin tests
What is the rate of intradermal drug absorption? Why?
- slow
- low fluid levels
What steps must a drug administered intramuscularly undergo before absorption?
- dissolution in interstitial fluid
- absorption to vessels in irrigating muscles
intramuscular admin drug absorption depends on what?
formulation and perfusion at site
Impact of MOLECULAR drug properties on absorption at different sites of administration
what main thing to consider for good drug?
Lipinski’s rule of 5:
MW < 500 Da
Log P <5
HBD < 5
(HBA < 10)
Impact of PHYSICO-CHEMICAL drug properties on absorption at different sites of administration
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
whatdrug classification system considers metabolism, not just solubility and permeability?
BDDCS
What is a BCS class I drug?
high solubility, high permeability
What is a BCS class II drug?
low solubility, high permeability
What is a BCS class III drug?
high solubility, low permeability
What is a BCS class IV drug?
low solubility, low permeability
What is a BDDCS class I drug?
high solubility, permeability metabolism
What is a BDDCS class II drug?
low solubility, high metabolism
What is a BDDCS class III drug?
high solubility, poor metabolism
What is a BDDCS class IV drug?
low solubility, poor metabolism
Absorption steps of oral drug formulation? what forms does it go through before absorbed?
dosage form
I
drug particles
I
dissolved drug
I
drug absorbed
All solids need to generate drug particles then dissolve to absorb. Taken longer than suspensions why?
as suspensions already in drug particle step
why do solutions have quickest absorption/ least steps?
alr in bioavailbale form, just need to cross emmbrane to be absorbed
non-enteral routes, parameters to consider for oro-mucosal route of admin?
rapid dissolution
muco-adhesive
increased residence times
non-enteral routes, parameters to consider for rectal route of admin?
rapid release
particle size
affinity for dosage form
non-enteral routes, parameters to consider for intranasal route of admin?
use of buffers
use of permeation enhancers
increase residence time
non-enteral routes, parameters to consider for pulmonary route of admin?
method of admin
drug loss
particle/droplet size
non-enteral routes, parameters to consider for transdermal route of admin?
affinity for dosage form
matrix vs reservoir
permeation enhancers
PK of drug absorption after a single dose…..
What are the features of zero-order absorption?
- constant rate
- independent of dose
carrier mediated transport (high drug concentration/saturated) and MR formulations are likely to follow what order?
zero
What are the features of first-order absorption?
- dependent on concentration
- applies to MOST drugs: rate is high initially and decreases over time as drug taken into systemic circ
stage 1 of abs kinetics for oral dosage forms?
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
why does elimination start automatically?
drug in blood circulation a
cmax and tmax is when absorption is in equilbrium with that process?
elimination
how does first order MR dosage form affect the pleateu on a kinetic curve?
extended/ longer
in stage 3 of absorption kinetics why is conc mostly determined by elimination rate?
abs ended, no more drug will appear in the blood
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.
single letter (a)
whats ka?
amount of drug in GIT -> to absorbed
whats ke?
amount of drug absorbed –>
EQUATIONS/ CALCS…….
shape of first order abs line plotted on semi log paper?
straight
what process is demonstrated by straight line on abs kinetic graph semi log paper? after initial curve up, then straight line down
elimination
How do you find elimination rate constant from a semi-log concentration time graph?
- work out gradient of 2 points on line
- then do m = -ke / 2.303
How do you find the theoretical initial concentration from a semi-log concentration time graph?
eqn p121 on iPad / extrapolate elim phase and read y-intercept
Describe the balance between absorption and elimination in stage 1 of concentration time graph.
- absorption predominates elimination (ka > ke)
- elimination still occurring but at slower rate than absorption
What is method of residuals?
- used to calculate absorption rate constant ka
- allows separation of absorption and elimination phases in early stage of absorption
assumptions that method of residuals relies on?
abs dominates over elimination,
both abs and elimination follow first order
pk follows one model compartment
How do you calculate method of residuals? (see slides)
- plot values on semi log scale
- create table with raw data from blood sampling and fill in conc
- fit the elimination data, draw straight line of linear regression and find out gradient for rate constant and extrapolate for A
- 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 - plot data for abs phase should be straight line
from the curve obtained from method of residuals, can now calculate the absorption rate constant ka, how?
from gradient of curve
m = -ka/2.303
how would you use method of residuals curve to find absorption half life t1/2?
from absorpiton curve or ka
ln2/ka
What are reasons for lag time?
- physiological: e.g. delayed gastric emptying
- formulation: site-specfic, dosage form, modified release
What is lag time?
time at which abs is said to start
How do you find the lag time from a semi-log concentration time graph?
revisit ! slide 43/p128
intersect of the abs and elimination curves = onset of abs
reason for lag time being negative?
not enough data so estimations are off therefore experimental error
PK: Bioavailability……..
What letter is used to denote bioavailability?
F
which route of admin has 100% bioavailability?
IV
active moiety is used to refer to what type of drug?
pro drug
3 factors that affect the rate and extent of abs and therefore BA?
drug degradation at site of admin
Pre-systemic elimination
Poor absorption
what affects drug degradation at the site of administration thus absorption?
- 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
what is meant by pre systemic elimination?
first pass effect
-Any metabolic activity that decreases amount of drug getting to systemic circulation
poor abs can be attributed to poor X and Y?
solubility and permeability
drug abs is referred to as the passage of drug across the epithelial membrane of what body structure?
small intestine
for a drug that is not as permeable, is lack of absorption and just elimination in the faeces more or less likely?
more
what is meant by Ff?
fraction of drug that has survived passage through the gut wall
once drugs are abs what circulation do they enter before going into thesystemic circ and liver?
portal vein
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?
systemic circulation
the final bioavailability of drug depends on what?
fraction that has made it through all these = product of all the fractions through all the different stages. Calculation.
Ff x Fg x Fh
What does the equation does Ff x Fg tell us?
bioavailability after drug enters portal vein and survives first pass effect
influx and efflux: another way drug can cross membrane
facilitated diffusion done using what transport?
carrier mediated
where would a drug be transported to and from if it enters an apical influx transporter?
from gut lumen into cell
where would a drug be transported to and from if it enters an efflux transporter on the basolateral side?
from cell to blood vessel
where would a drug be transported to and from if it enters an efflux transporter on the apical side?
from cell back to gut lumen
what transporter would be used to take a drug from a blood vessel and transport it back into the cell?
basolateral influx transporter
all of the efflux and influx transporters can ultimately affect BA as they affect..?
the frcation of drug making it through gut wall –> portal vein
Ideally have influx transporters on apical and effluc on basolateral.
IF: have opposite, fraction absorbed will be higher/lower?
lower
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?
efflux
ABCs require energy to work and work against a conc gradient, true or false?
true
give an example of an ABC
P-glycoprotein
ABC efflux transporters such as p glycoprotein can affect bioavailability. What is one adverse effect that they produce in cancer patients?
drug resistance
solute carrier transporters (SLC) are influx. if they are on the apical side why might this be a good thing?
help increase drug absorption
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?
protein dependent oligopeptide transporters POTs
other than POTs, name other solute carrier transporters SLCs
- Organic anion transporters (OATs)
- Organic cation transporters (OCTs)
- Nucleoside transporters (CNTs)
- Monocarboxylate transporters (MCTs)
pgp ( p glycoprotein) has many drug substrates, inducers and inhibitors. Name some areas where it is found outside the gut wall/ small intestine?
BBB, kidney, liver, lung, colon
P-glycoprotein (ABC1, Pgp) has huge potential for what?
drug interaction and for co-administration to affect drug bioavailiability
in the small intestine pgp is on the APICAL side on enterocytes. This means that the drug is transported from X back into Y?
from inside cell back to gut lumen
polymorphism is associated with pgp meaning expression can be different in different patients, true or false?
true
cyclosporine
verapamil
simvastatin
amiodarone
are examples of Pgp inhibitors/inducers/substrates?
inhibitors
rifampicin
paclitaxel
carbamazepine
are examples of Pgp inhibitors/inducers/substrates?
inducers
digoxin
vinblastine
are examples of Pgp inhibitors/inducers/substrates?
substrates
first pass metabolism is exclusive to oral admin and cannot happen with other sites of admin true or false?
false
first pass metabolism is exclusive to oral admin and cannot happen with other sites of admin true or false?
false
enterhepatic first pass effect means metabolism happens first in the X before the liver?
gut
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?
drug oxidation
CYP enz have high/low susceptibility to inducers and inhibitors
HIGH
Many CYP3A4 substrates are also substrates of the Pgp, therefore…
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
In gut wall, may have close contact with drug and CYP3A4, what does this mean for metabolism and BA?
metabolism still substantial and big impact on overall BA
what enzyme is involved in the metabolism of warfarin, pheytoin, losartan, diclofenac?
CYP2C9
what types of drugs are metabolised/ conjugated by UDP - glucaronosyltransferase enz ?
lipophilic drugs are conj with glucaronic acid
sulfotransferases are involved in the sulfation of hydrophilic or hydrophobic drug molecules?
hydrophobic
does detoxification (as done by UDP-g and sulfotransferases) make drugs more lipophilic or hydrophilic?
hydrophilic
in summary, what happens to drug when it is absorbed? in terms of BA?
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
The D in ADME: drug distribution & protein binding
Which fraction of drug can distribute: free or bound?
free
What does drug distribution depend on? 5
- drug properties
- tissue perfusion
- anatomical factors
- tissue composition
- physiological factors
What drug properties impact distribution?
- plasma protein binding
- tissue binding
What factors affect the RATE of distribution?
- tissue perfusion: higher = faster rate
- membrane permeability e.g. BBB difficult so slows down
name some examples of sites with well perfused tissue that therefore allow quick distribution
liver, kidney, lung
(fat = not well perfused = longer rate)
What factors affect the EXTENT of distribution?
- MW
- lipophilicity
- ionisation - pH and pKa
- protein binding
- intracellular binding
- patient factors
Do low or high MW drugs distribute more widely?
low
Do lipophilic or hydrophilic drugs distribute more widely?
lipophilic - able to cross membranes
How does ionisation affect the extent of distribution? Use the example of breast tissue.
- 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
if drug is unionised at pH in tissue, will it distribute easier or not?
easier
what sort of px factors affect extent of drug distribution?
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
for tissues with HIGH/LOW blood flow, equilibrium is reached quickly
HIGH blood flow (highly perfused)
In drugs with poor perfusion, what can determine drug accumulation?
drug physicochemical properties e.g. lipophilic can accumulate in fat
Why is exercise a considering factor with drug distribution?
- increases blood flow
- thus affects drug distribution and effect
What do we use apparent Vd for?
- to volume of a given body compartment
- we know that each body component has different volume, and chemicals distribute to these
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?
- ethanol
- penetrates total body water
What do we use to estimate the plasma compartment?
- dextrans (large polar polysaccharide)
- only permeates plasma
why may heparin be restricted to intravascular fluid?
high MW and polar drug
What is the typical region of a drug with a Vd value <10L?
intravascular fluid (blood incl plasma)
What are the drug properties of a drug with a Vd value <10L?
- high MW
- polar
- extensive plasma protein binding
What is the typical region of a drug with a Vd value 12-20L? Why?
- extracellular fluids
- small enough to leave circulation (transcellular) but not lipophilic enough to cross membranes
What are the drug properties of a drug with a Vd value 12-20L?
low lipid solubility, small
What is the typical region of a drug with a Vd value >20L?
- organs based on active transport and specific receptor binding
- hard to predict
What are the drug properties of a drug with a Vd value >20L?
- lipid soluble stored in fat
- heavy metals/tetracycline in bone
When drug lipophlic enough to cross memb and has affinity for tissue proteins/ components, Vd can be quite X and Y
wide and large
Is protein binding reversible or irreversible for most drugs?
reversible
but remember it can be saturated
What does albumin mostly bind to?
acidic drugs
What does alpha-1 glycoprotein mostly bind to?
basic drugs
What do lipoproteins mostly bind to?
neutral drugs
what fraction CANNOT diffuse into tissue/distribute, therefore where is this restricted to in body?
protein-bound
so high PPB will restrict Vd mostly to intravascular volume
What happens to the free fraction of drug and not the bound? 3
- can easily distribute
- can be eliminated
- can have pharmacological effect
Does protein-binding always limit distribution?
no
What factors affect protein binding and Vd? 3
- drug properties
- protein-related factors
- drug interactions
What drug properties affect protein binding and Vd?
molecular + physicochemical properties
- think lipophilicity and weak acid/ base
- ability to interact w negatively charged membranes
What protein-related factors affect protein binding and Vd? change in… 2
- protein concentration
- affinity for drugs
In what states can protein concentration be changed?
- liver disease
- pregnancy
- cystic fibrosis
- aging
- burns
- malnutrition
How do drug interactions affect protein binding and Vd?
protein-bound drug can be displaced by endogenous or exogenous compound binding to same protein
if 2 drugs given that bind to same protein, When is there a risk of interaction through protein displacement?
if
- drug is highly protein bound >90%
- small Vd
- interaction occurs in initial stage of co-treatment
What is an example of protein displacement?
- valproic acid displaces phenytoin from protein binding sites- inc fractiiion free drug
- also inhibits its metabolism
- can lead to phenytoin toxicity
Describe the equilibria that occurs between bound and free drug (image)
- 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
Describe the equilibria that occurs between free and distributed drug
- 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
what do all equilibria (free + bound, and bound + distributed) work together to maintain?
free drug conc
aDme: compartments and barriers…….
what are the general assumptions we make with pharmacokinetic models?
- drug absorbed instantaneously
- drug is eliminated uniformly
there’s one compartment model
- plasma conc. is true for the entire circulation
true/false: distribution is uniform for all drugs
false
what can happen to drug after IV bolus administration?
(Why might distribution not be uniform for some drugs?)
after IV admin, drug could distribute:
- quickly in well-perfused organs/tissue (rapid equilibrium)
- slowly to poor blood flow organs/tissues (slow equilibrium)
what are the compartments in two compartment model?
central compartment
peripheral compartment
what is the central compartment ?
systemic blood circulation
what are the compartments in one compartment model?
central compartment only
What pharmacokinetic process occurs only in the central compartment of a two-compartmental model? What rate constant is relevant?
- excretion
- elimination rate constant ke
what 3 organs linked to blood in central compartment?
brain
liver
kidneys
what is the alpha and beta phase in terms of compartment and distribution?
alpha: central -> peripheral
beta: distribution peripheral back -> central
why do we have 2 phases: alpha and beta with drug distribution in 2 compartment model?
as distribution is in equilibrium so can have drug leaving and entering peripheral
for PDC, conc in blood or systemic circ can fall as result of excretion but also due to what?
distribution to another compartment/ tissues and for nanomedicines: can also include tumour
what is the distribution phase in the two compartment model?
on plasma conc/time curve
where the drug is moving from central -> peripheral compartment
what is the elimination phase in the two compartment model?
predominant process during the second phase of the biphasic plot
on a plasma conc / time curve, for distribution then elim, for 2 compartment model describe what curve/line is seen?
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
classic example of drug distribution via 2 compartment data: Vancomycin
how long des distribution last?
1-2 hours
for an oral dose PK model curve, when will distribution show on curve?
if slow distribution = extra bit on line to show something else happening too not just absorption and elimination
What can remove drugs from the brain even after they’ve crossed the BBB?
efflux transporters
how do you try to pass the BBB?
using pro-drugs: exploit receptors/transporters
name 3 barriers to drug delivery
BBB
blood-cerebrospinal fluid barrier
placental barrier
what may cause disruptions in BBB integrity?
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
what is the blood-cerebrospinal fluid barrier?
barrier between the BBB and the CSF
how can we bypass the blood-cerebrospinal fluid barrier?
using intrathecal injections
purpose of placental barrier?
and when may this purpose be disrupted?
protect fetus from exposure to toxins/ drug
barrier not completely impenetrable: case of thalidomide: drugs may cross placental barrier if have right properties.
What structures from the placental barrier?
- trophoblast epithelia
- basement membrane
- foetal capillary endothelium
what characteristics will increase diffusion pass the placental barrier?
passive
MW <600Da
lipophilic drugs
unionised
Lower than blood pH compared to in adults
What are the possible modes of transport across the placental barrier? 4
endocytosis
active transport
facilitated transport
passive diffusion
why can drugs pass the placenta?
as the apical and basal membrane thickness decreases during pregnancy to allow nutrition to be exchanged, however, also allowing drugs to pass through
whats plasma?
the liquid phase of the blood, composed of water and proteins
what cells does the blood contain?
RBS (erythrocytes)
platelets (thrombocytes)
WBC (leucocytes)
binding to blood cells involves creation of an eqm between blood cells and plasma
how do you work out blood:plasma ratio?
Cwhole blood / Cplasma
how do you work out the drug blood partition coefficient?
Cblood ratio / Cplasma
PK usually based on PLASMA concentrations.
If blood-to-plasma concentration ratio is 1, what does this mean?
no issues as concentration in plasma reflects that in blood
PK usually based on PLASMA concentrations.
If blood-to-plasma concentration ratio is higher/lower than 1, what does this mean?
differences in PK parameters in blood vs plasma so needs adjustment
Why is it important to state whether samples are plasma or whole blood (example of cyclosporin)?
- 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
What’s considered the peripheral compartment in a two-compartmental model?
poorly perfused organs/tissue:
- muscle
- skin
- bone
- fat
What drugs can use paracellular diffusion to cross the BBB?
small hydrophilic molecules, H2O
What drugs can use transcellular diffusion to cross the BBB? Properties/chemistry
nonpolar, lipophilic molecules
- <400-500Da
- <8-10 H bonds
what may BBB paracellular transport be hindered by?
tight junctions presence
efflux transporters to contribute to decrease penetration of drug
What molecules can use carrier-mediated transport to cross the BBB?
- amino acids
- vitamins
- glucose
- ions
- nucleotides
- sugars
- fatty acids
- neurotransmitters
What molecules can use receptor-mediated transport to cross the BBB?
- transferrin
- insulin
- IgG
What molecules can use absorption-mediated transport to cross the BBB?
cationic proteins
What molecules can be effluxed out of the brain by ABC-type transporters?
- drugs
- metabolites
- fluorescent dyes
- neurotoxins
How does water cross the BBB?
aquaporins
how do ions cross BBB?
cotransporters and exchangers
What creates the barrier within the CSF of the spine?
choroid plexus epithelial responsible for CSF production
What excipient cannot be used in intrathecal injections?
antimicrobial preservatives
How does distribution change during pregnancy?
- plasma proteins change
- placental barrier thins increasing drug permeability
- metabolism can also occur at placental barrier
What can drugs do in the blood that affects its pharmacokinetics?
can bind to blood cells by:
- passively diffusing across the RBC membrane
- binding to intracellular components
An equilibrium is created between what due to drugs being able to bind to RBCs?
between blood cells and plasma
What properties of a drug can impact its distribution in brain?
- drug MW
- logP
- protein-binding
PK adMe: METABOLISM…..
what is metabolism?
Enzymatic modification of the chemical structure of a drug molecule to form one or more new chemical entities (metabolites)
What is drug metabolism AKA?
drug biotransformation
How does metabolism overlap with elimination?
elimination = irreversible loss of drug from site of measurement, occurring by metabolism and excretion
How does metabolism relate to absorption?
first pass metabolism impacts oral bioavailability
What is the importance of drug metabolism for PK?
- 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
What is an example of a metabolite that has equal pharmacological activity to its parent?
procainamide and metabolite n-acetyl procainamide – similar antiarrhythmic activity
What are examples of metabolites that have increased pharmacological activity to its parent?
prodrugs (activated by metabolism)
- enalapril vs enalaprilat
- prednisone vs prednisolone
What is an example of a metabolite that can cause toxic effects?
carbamazepine metabolised to carbamazepine epioxide responsible for drug toxicity
What are the organ sites of drug metabolism?
- Small intestine
- Skin
- Lungs
- Kidney
- Liver (majority)
How do drugs reach the liver from the systemic circulation?
high hepatic blood flow and lots of enz = lots of metabolism
HPV: from GIT following absorption
hepatic artery HA: directly from circulation
What are the 2 phases of metabolism?
phase I and phase II
What occurs in phase I metabolic reactions?
drugs made more hydrophilic
What occurs in phase II metabolic reactions?
drugs are conjugated w endogenous substance allowing for easy excretion
How do phase I metabolic reactions (AKA functionalisation reactions) occur in relation to phase II?
often before phase II but not always
How are drugs made more hydrophilic in phase I reactions?
polar functional groups unmasked/introduced to form metabolites more polar than parent drug
What are examples of polar functional groups introduced in phase I reactions?
hydroxy
amino
carboxyl
What are the most common types of phase I reactions?
- oxidation
- reduction
- hydrolysis
What occurs in phase I oxidation reactions? What enzymes carry this out?
addition of oxygen/removal of hydrogen – usually by cytochrome P450 enzymes
What occurs in phase I reduction reactions?
removal of oxygen/addition of hydrogen
What occurs in phase I hydrolysis reactions?
reaction of drug containing e.g. ester, amide w water -> cleavage of chemical bonds and more polar metabolites
What are cytochrome P450 (CYP450) enzymes?
superfamily of metabolising enzymes that metabolise 75% of total metabolism in human body
What cofactor do CYP450 enzymes contain?
haeme
What is the nomenclature of CYP enzymes?
- CYP +
- family: numbered 1, 2, 3…
- subfamily: A-Z
- individual enzyme within subfamily: numbered 1, 2, 3…
What CYP families metabolise most drugs in humans?
1-3
What is the most common subfamily in the liver? What proportion of drugs does it metabolise?
CYP3A, ~50%
What are examples of endogenous substances that drugs are conjugated w in phase II (AKA conjugation) reactions?
- glucuronic acid
- glutathione
- amino acids
At what sites of a drug does phase II conjugation occur?
- carboxyl
- hydroxyl
- amino
- sulfhydryl (SH)
What are examples of enzyme systems involved in phase I and II metabolic reactions?
eg
esterases - hydrolysis
amidases
MAO
alcohol dehrydrogenase
methyltransferase
N-acetyltransferase
What are examples of physiological factors affecting drug metabolism?
- age
- genetic factors
- pathology?
How does age affect drug metabolism?
- 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
how does hepatic and first pass metabolism change with age?
liver mass and blood flow decrease w age = decreasing hepatic (and 1st pass) metabolism in elderly
What is a genetic factor that can influence drug metabolism?
CYP450s can exhibit genetic polymorphism:
- different CYP metaboliser phenotypes
- differences in CYP expression between ethnic groups
What are the categories of CYP metaboliser phenotypes?
- poor
- intermediate
- extensive
- ultrarapid
and diff metabolites may be formed!
What is a clinical example of how different CYP metaboliser phenotypes affect drug metabolism?
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
What are examples of pathology that can affect drug metabolism
- hepatic or renal disease
- circulatory disorders eg HF
- infection/inflammation (chronic e.g. cancer, RA, coeliac disease)
How does hepatic/renal disease impact drug metabolism?
these organs are responsible for metabolism so their function is impaired
How do circulatory disorders impact drug metabolism?
- reduced perfusion of liver and kidneys
- these are sites of drug metabolism
How does infection and inflammation affect drug metabolism?
inflammatory cytokines may suppress CYP expression
How can drugs themselves influence drug metabolism?
DDIs
- drugs + substances can induce/inhibit enzymes that metabolite other drugs
- can auto-induce enzymes responsible for their metabolism
What are examples of non-drug substances that can induce/inhibit enzymes?
- alcohol
- cigarette smoke
- grapefruit juice
- St John’s Wort (2C9)
example od drug that us a CYP3A4 substrate AND inducer?
carbamazepine
What is the nature of drug metabolism kinetics at low/therapeutic drug concentrations? for most drugs
- 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)
What model describes the nature of drug metabolism kinetics when the metabolic pathways are saturable? (the exceptions to first order rule as before)
Michaelis-Menten enzyme kinetics (capacity-limited metabolism)
Michaelis-Menten equation
… Vmax[S]
V = —————-
Km + [s]
What is the V in the Michaelis-Menten equation?
enzymatic/metabolic reaction rate
What is the Vmax in the Michaelis-Menten equation?
maximum rate of enzyme reaction (when all enzymes’ reactive sites are saturated with substrate)
What is the Km in the Michaelis-Menten equation?
Michaelis-Menten constant (measure of affinity of substrate to enzyme) - substrate concentration at which V = ½Vmax
What is the [S] in the Michaelis-Menten equation?
substrate concentration
What is the significance of a drug having saturable metabolism? Michaelis-Menten enzyme kinetics
example drug
small change in dose can lead to a greater than proportional (or expected) increase in Css as saturable e.g. phenytoin
What is occurring at the zero-order region of a Michaelis-Menten graph?
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]
The E in ADME…
what is a one compartment model?
single IV bolus admin. = fast drug distrib. = rapid equilibrium established = proportional clearance of drug eliminated from blood
what is a one compartment model?
single IV bolus admin. = fast drug distrib. = rapid equilibrium established = proportional clearance of drug eliminated from blood
what does a one compartment model assume?
after admin, have instantaneous absorption of drug and v fast distribution to tissues in body
with one compartment model, followinf drug elim from blood you see a X, Y Z in drug conc in tissue
immediate, proportional decrease
what is the body considered to behave as?
in a 1 compartment model: 1 homogenous compartment
how do you work out the conc. of drug in a one compartment model?
Conc right after IV bolus injection
C0 = Dose/Vd
what is Ct = ?
Ct = D/Vd e^ket
what is ke?
elim rate constant
constant that defines rate of elim process
how the ke influences elim rate depends on what?
ORDER of elim process
most clinically used drugs, what is rate of drug elim proportional to/ dpeendent on?
conc of drug in blood
most drug elim follows what order kinetics?
first
how to convert lnx to log?
lnx = 2.303logx
how to determine C0?
extrapolate data to find y-intercept
how to determine ke form gradient of graph?
ke = -gradient x 2.303
how to find gradient form graph?
logy2 - logy1 / x2 - x1
what is the meaning of elim t1/2?
time taken for plasma conc/ amount of drug in body to be reduced by 50%
after 2 half lives, hm drug left in body? what %
25%
why is t1/2 used clinically?
it dictates frequency of dosing
t1/2 =
ln2/ke (0.693/ke)
will drugs with a larger ke have longer or shorter t1/2?
shorter t1/2
elim faster than drugs with smaller k and longer t1/2
what can be said about duration of effect of drugs following single dose admin?
rapidly eliminated
shorter duration of effect
drug conc quickly falls below MEC
PK dosing regimen…..
whats usually the goal of drug dosing regimen?
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)
Extravascular single dose concentration time graph
first drug conc inc at start then slope down (where elim takes over)
IV single dose concentration time graph
no increase at start/ absorption phase
fast distribution (dont see)
just elim- slope down
what 2 things to think abt with dosing regimen?
i.e. what 2 things can be changed to stay within therapeutic window?
size of DOSE
TIME interval between doses
Sketch a time concentration graph for multiple IV bolus administrations and label the Css max and Css min.
p 222
….
when may multiple admin of drug be given? wha type of condition
treating acute symptoms
at Css, drug conc stays the same T/F?
false, still have some fluctuations but all stay within range
Define steady state in terms of the relationship between input and output.
at steady state, input = output
i.e. the drug coming in is equivalent to that eliminated
whats Cav?
average conc at Css, but may not be the mathematical average
What does the input(av) depend on?
- dose
- bioavailability
- dosing interval
Input av = FD/t
What is input directly proportional to for extravascular administration?
bioavailability, dose
What is input directly proportional to for IV administration?
dose
What is input inversely proportional to? Explain how.
dosing interval: the shorter the interval, the greater the input
What is output dependent on?
steady state (Css) and clearance (CL)
Output av = CL * Css
If input = output, what is the equation for average steady state for extravascular administration?
Css = FD / Cltotal x t
t = tao = dosing interval
If input = output, what is the equation for average steady state for IV bolus administration?
Css = D/ Cltotal x t (tao)
no F as bioavailability of IV = 1
Css eqn doesnt tell you how quick Css was recahed (as not linked to dose) but what parameter does tell you about that?
only t1/2
On average, how many half-lives does it take to reach steady state?
5-6
will a drug with shorter/ longer t1/2 reach Css fastest?
drug w shortest t1/2 reaches Css fastest
How is the maximum Css calculated for IV bolus administration?
Css max = D / Vd (1-e^-ke tao)
How is the minimum Css calculated for IV bolus administration?
Css min = Css max - D/Vd
what parameter must you include before the D (dose) if admin is NOT IV?
F (bioavailability) as it wont be 1
what does Css max assume?
rapid absorption and distribution
what does Css min assume?
rapid distribution
How is Css concentration at any time calculated?
Ct ss = FD (e^-ket) / Vd (1-e^-ke tao)
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)
F = 0.75
Cl = 8.42
D = 250mg
tao = 8hrs
Css = FD/ taoCl
= 0.75250 / 8.42*8
= 2.78mg/mL
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?
Cl = 5
tao = 8
Css = 5ug/L
Css = D/ Cltao
5 = D/ 85
D = 200ug
why must you be careful when adjusting dose/ dosing in a narrow therapeutic range?
got more potential to go above or beyond it
toxic/ not working
What needs to be considered when building a dosing regimen?
- 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.
why look at CYP enzymes of px when considering for dosing regimen?
-> fast v slow metabolisers, will affect ADME
what about drug treatment will impact blood conc vs time curve (diff to prev dosing regimen factors to consider)
RoA
dosage form
unit dose
freq
LD
length of treatment
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.
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
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.
shorter dosing interval = higher conc than orig
(more often = reach higher conc)
longer dosing interval = lower conc than orig
Does the time taken to reach steady state change if the dosing interval is changed?
no as t1/2 still the same BUT reaching higher Cav
i.e. giving same dose more frequently = build up of conc
For immediate release dosage forms, what points need to be remembered regarding the Css?
Css max and min need to be within the therapeutic window
For immediate release dosage forms, what points need to be remembered regarding the DOSING INTERVAL?
- 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
what to remember for dosing interval and dose selection for MR?
check recommended interval
To summarise, average steady state concentration changes with… 2
- the frequency of administration
- the size of the dose administered
Plasma concentration-time graph for transdermal dose showing steady state being reached
- how will it differ to oral dose
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
What type of dosage forms give us steady state with a plateau?
- transdermal or anything w a reservoir system as this will have zero-order kinetics release
- infusions
Conc-time curve for steady state- what are the 3 phases?
wash in
steady state
wash out
the wash in phase looks like absorption but we know…
exact rate at which drug enters body
What does the rate of infusion depend on?
- elimination rate constant
- concentration of drug
(balance of input and output)
for steady state, when does elimstart?
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
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
first order
dependent on conc
Describe how the rate of elimination changes according to its order of kinetics.
- initially slow as it depends on concentration
- as concentration increases, elimination increases
- by the time infusion stops, only elimination occurring
EQUATIONS p235
time to reach Css depends on what?
t1/2
What is the aim of a loading dose?
to reach steady state concentrations quickly
in what 2 circumstances may we need to consider how long it takes to get to Css, therefore consider a LD?
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
for drugs with HIGH X, you should consider aloading dose
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
What is the loading dose equation for infusions/parenteral administration?
LD= Vd * Css
give an example of drug where LD used with infusion?
antibiotics in hospital
What equation summarises the concentration at any time point of an infusion including the loading dose?
slide 35.
Apart from a loading dose, how else can we quickly achieve steady state concentrations in an infusion?
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)
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?
VD = 0.2L * 80kg = 16L
LD = Vd * Css
= 16 * 4
= 64mg
What data do you use to obtain the half-life, clearance and rate elimination constant from an IV infusion graph?
the wash-out data - this is the elimination data which when plotted on a semi-log will give straight line
what parameter is determined from the elim phase?
t1/2
what is calculated from t1/2?
ke
when can Vd be calculated from data?
if Css reached
How do you calculate clearance is steady state has not yet been reached?
Cl = dose/AUC
- use trapezoidal method to calculate AUC
admE part 2 …….
what is drug elimination?
irreversible loss of drug from site of measurement occurring by metabolism and excretion
how (2) is a drug eliminated from body?
by being chemically changed into something else (metab)
or physically removed from body (excreted)
where is majority of drugs eliminated/cleared?
mainly in the kidney or liver
less importantly - excretion via lung/saliva/sweat
lung = major organ for excretion of what substances?
gaseous and volatile
how can pulmonary drug excretion be used?
alcohol breathalysers tests - quantify excretion of ethanol
drug excretion into saliva depends on what 2 things?
pH partition
protein binding
saliva drug conc. could be used to indicate what?
drug plasma conc.
major function of kidney?
regulate fluid vol and composition within body
how does the kidneys maintain salt and water balance?
excrete excess electrolytes, water, waste
conserves necessary solutes
what is an issue with swallowed saliva in terms of excretion?
saliva bound to drug depending on pH partition and protein binding = drug reabsorption
how do the kidneys eliminate drug substances? 2 ways
- metabolism (sometimes)
- excretion in the urine
what 3 processes handle renal excretion/ elim?
glomerular filtration
tubular secretion
tubular reabsorption - active/passive
what molecules are excreted in glomerular filtration?
free drug - unbound drug
small, water soluble drugs
depends on size - fit thru pores
what molecules are excreted in tubular secretion?
secreted molecules
specialised active transport systems
what molecules are excreted in tubular reabsorption?
active or passive reabsorption from renal tubules -> blood
lipophilic and unionised drug crosses
Hydrophilic and ionised drugs cannot cross
influenced by drug lipophilicity
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
hydrophilic ionised
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
hydrophilic ionised
what is GFR?
Rate of blood filtering in the glomeruli = glomerular
filtration rate
what is the GFR in a normal adult male?
125 mL/min
what sort of drugs can be filtered freely (renal) and which cannot?
small, water soluble CAN
large proteins eg albumin and protein bound drug CANNOT
what can lower GFR?
impaired kidney functions
what drugs are excreted via tubular secretion?
weak acids
penicillins
tubular secretion is an active transport process requiring what?
against conc grad
needs carrier energy supply
tubular secretion - drug goes from to where?
from blood pasma to PT lumen
excreted in urine
active transport systems eg tubular secretion can be used by more than 1 drug species meaning prone to…
competition (secretion of drugs w lower affinity may be inhibited)
higher affinity for AT system will be secreted
approx hm water/fluid in glomerular filtrate is also reabsorbed ?
99%
what type of drugs/ compounds more prone to tubular reabsorpiton- limited renal elim?
lipophilic, unionised
(also ionisable drugs but present in tubules in unionised form)
name examples of substrates for carrier mediated/ active tubular reabsorption
endogenous substances: vitamins, AAs, potentially glucose
how can we alter renal eliminiation?
change urine pH
what happens when reduce urine pH?
acidic urine
1. weakly acidic drugs = unionised + reabsorbed = reduced elimination
2. weakly basic drugs = ionised = increased elimination
how can you get acidic urine?
eg protein rich diet, ascorbic acid co-administration
when reduce urine pH, weakly basic drugs will be ionised and inc elim eg in cases of what?
toxicity, OD eg amphetamine (basic drug)
what happens when increase urine pH?
basic urine
1. weakly basic drugs = unionised + reabsorbed = reduced elimination
2. weakly acidic drugs = ionised = increased elimination
how can you get basic urine?
co-administer bicarbonates
example of weakly acidic drugs that will be ionised and inc elim when you increase urine pH?
barbiturate
trapped in tubule lumen, excreted w urine
how can you promote elim of weakly basic drugs eg amphetamine?
reduce urine pH
how can you promote elim of weakly acidic drugs eg barbiturates?
increase urine pH
how do you calculate the renal excretion?
= glomerular filtration + tubular secretion - tubular reabsorption
what is maximum rate of renal elim = to?
GFR
how is the rate of renal elimination (GFR) calculated?
determining the renal clearance of inulin, creatinine
what is creatinine? and its use
calculates rate of renal elimination
endogenous compound
eliminated by the kidney only - tests kidney function
formula for renal clearaance?
CL renal = urine flow x urine conc / plasma conc
T/F creatinine is filtered in glomeruli, NOT secreted / reabsorbed in renal tubules
True
how are drugs excreted in the liver?
via biliary system or closely linked to drug metabolism
what drug metabolism reactions undergo in the liver?
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
for a drug to be elim form liver, it must enter what?
the hepatocytes
then metab and or ecreted back into blood/bile
what is enterohepatic circulation?
when bile delivered into SI form there material may be reabsorbed into blood/ excreted within faeces
name of system used for recycling bile salts and endogenous substances also take advantage?
enterohepatic circulation
allows prolonged exposure of drug to body
what drugs enter enterohepatic circulation?
bile salts but also
NSAIDs
opioids
digoxin
warfarin
…
describe the 3 steps of enterohepatic circulation in case of drugs
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
drugs with what MW are excreted almost exclusively into urine?
small
<300
drugs with what MW are excreted exclusively in both urine and bile?
middle
300-500
drugs with what MW are excreted almost exclusively into bile?
big
> 500
whats the most important factor for determining drug concs within body?
Clearance
what is drug clearance influenced by?
dose
blood flow
intrinsic function of liver/ kidneys
what may -> false interpretation of drug Cl?
PPB
what is clearance of a drug? not eqn
vol of plasma/ blood from which drug is cleared per unit time
drug Cl equation.
CL = ke x Vd
what does Cl NOT indicate regarding drug conc?
rate of decline in drug conc
R of E =
CL x Ct
Ct: conc of drug in blood at time t
whats R of E directly proportional to?
drug conc
R of E of most drugs follows what order process?
first
only free (non-bound) drugs may be cleared.
what type of drugs bind to albumin?
acidic drugs
what reduces albumin binding? thus -> more free drug
disease state (cancer)
competition (presence of second acidci drug)
more or less drug will be eliminated in the disease state as much more is available/free?
more
100% of albumin present in healthy state, how mcuh may be reduced to is disease state eg cancer?
50%
= more free drug
Rof E eqn- prop to drug conc
total drug conc will dec if have dec binding to protein BUT free drug conc will remain same or not?
remain same
E in ADME part 3….
what is the total body clearance
overall cl of a drug by eliminating organs
describe the organ body clearance?
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
how do you calculate total body clearance?
renal Cl+ hepatic Cl+ other organs Cl
elimination = X+Y
excretion + metabolism
most drug elim by both
how to calc combined elim?
CL = renal Cl (CLr) + metabolic Cl (CLm)
when drug elim follows first order kinetics (common), each elim pathway has rate constant dependent on X and Y
elim pathway Cl
drug Vd
how do you work out the renal elimination rate constant?
renal CL/ Vd
how do you work out the metabolic elimination rate constant?
metabolic CL/Vd
elim rate constant for overall elim process =
sum of rate constants for the 2 processes
ke = kR + kM
drug in body = X + Y
drug in urine + metabolite
what is Fe?
fraction of the (bioavailable) drug dose that is unchanged in urine
how do you work out Fe?
CLr/CLt
ratio of CL
OR
kR/ke
overall/ total body Cl =
ke x Vd
how to find CLr is fe and CLt known?
CLr/CLt
… so CLr = fe x CLt
how to find CLm?
CLm = CL - CLr
how to find Km from ke and kr?
kM = ke - kr
what is hepatic extraction?
rate at which liver extracts drug from the blood – by metabolism and removal into bile
what does the hepatic extraction rate depend on? 2
hepatic blood flow (HBF)
intrinsic ability of the liver to handle (e.g. metabolise) the drug
how do you workout the maximum hepatic extraction rate?
equal to Cl of whole drug
drug conc (Cin) x HBF (hepatic blood flow)
what is the extraction ratio (E)?
Fraction of drug amount presented to the organ which is eliminated during a single pass through the organ
what do the extraction ratios (E) mean?
0 and 1?
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
action ratio E = measure of an organs…
relative efficiency in drug elimination
action ratio E = measure of an organs…
relative efficiency in drug elimination
how do you workout the extraction rate (E)?
(conc in - conc out)/ conc in
what is the hepatic blood flow value?
1.5L/min
CL organ =
QE
total blood flow x E
what does hepatic blood flow vary with?
diet
food intake
physical activity (1-2L/min)
what are low extraction drugs?
drugs w HER < 0.3
diazepam, warfarin, salicylic acid, phenytoin, and procainamide
what are high extraction drugs?
drugs w HER > 0.7
lidocaine, propranolol, morphine, verapamil
what does it mean if the hepatic extraction ratio <0.3?
low extraction ratio drugs
what does it mean if the hepatic extraction ratio >0.7?
high extraction ratio drugs
what does it mean if the hepatic extraction ratio 0.3-0.7?
intermediate extraction ratio drugs
what are low extraction ratio drugs affected by?
unchanged by changes in blood flow
what are high extraction ratio drugs affected by?
greatly affected by changes in blood flow
hepatic blood flow increase = during meal digestion
hepatic blood flow decrease = exercise/ cirrhosis/ heart failure/ old age
hepatic extraction may be limited by 2?
intrinsically low ability of liver to extract drug (low ER)
blood flow to liver
when does hepatic blood flow increase?
during meal digestion
when does hepatic blood flow decrease?
exercise/ cirrhosis/ heart failure/ old age
benefits of urine samples for pk analysis
less invasive, easier to collect than plasma/ blood
in a simple case where drug NOT significantly metabolised,
drug in body (Db) -> drug in urine (Du)
via what parameter/ constant?
kr
rate of renal elim (as elim in urine)
graph p 668
what is the total amount of drug that can be recovered through urinary excretion equal to?
D = Du ∞
at any time point, what 2 D = D = Du∞?
drug in body Db + drug in urine Du
amount of drug appearing in urine may be calc from what?
loss of drug in body
kr x Db
T/F rate is a +ve value as drug appearing in urine (not being lost)
true
drug in body Db = ?
Du ∞ - Du
when can you assume cumulative total = Du∞ which is equal to dose admin, D?
once no more drug being collected
what will intercept be equal to for D graph?
Du∞ (=D)
what will gradient equal on D graph?
rate constant, kr
