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Assignment Group 4
Assignment Group 4
GROUP 4
Definition
This is the period of time required for the concentration or amount of drug in the body to be
reduced by one-half.
We usually consider the half life of a drug in relation to the amount of the drug in
plasma.
A drug's plasma half-life depends on how quickly the drug is eliminated from the
plasma. A drug molecule that leaves plasma may have any of several fates.
It can be eliminated from the body, or it can be translocated to another body fluid
compartment such as the intracellular fluid or it can be destroyed in the blood.
Clearance is not an indicator of how much drug is being removed; it only represents
the theoretical volume of blood which is totally cleared of drug per unit time. Because
clearance is a first-order process, the amount of drug removed depends on the
concentration.
Clearance can be thought of as the proportionality constant that makes the average
steady-state drug level equal to the rate of drug administration. Clearance (rate out)
can be calculated from the dose (rate in) and average steady-state concentration:
2) Volume of distribution.
The distribution of the drug in the various body tissues is known as the volume of
distribution.
Half life of a drug is directly proportional to the volume of distribution.
When the drug is absorbed and reaches the plasma, it is distributed to the tissues.
Some drugs have high volume of distribution and are distributed to various
tissues, mostly adipose tissue. More time is required for their elimination, thus have
greater half life.
Both of these pharmacokinetic parameters are important in determining the half life of a
drug.
symbol to represent the half-life: t½
Half life = 0.693 x Vd/ total body clearance
Method of determination
Experimentally the half life can be determined by giving a single dose, usually intravenously,
and then the concentration of the drug in the plasma is measured at regular intervals.
The concentration of the drug will reach a peak value in the plasma and will then fall as the
drug is broken down and cleared from the blood.
The time taken for the plasma concentration to halve is the half life of that drug.
Examples
Some drugs like ibuprofen have very short half lives, others like warfarin and digoxin,
take much longer to eliminate from the plasma resulting in a long half life.
So drugs like ibuprofen that are cleared from the blood more rapidly than others need to be
given in regular doses to build up and maintain a high enough concentration in the blood to
be therapeutically effective.
As repeated doses of a drug are administered its plasma concentration builds up and reaches
what is known as a steady state.
Steady state
This is when the amount of drug in the plasma has built up to a concentration level that is
therapeutically effective and as long as regular doses are administered to balance the amount
of drug being cleared the drug will continue to be active.
The time taken to reach the steady state is about five times the half life of a drug.
Drugs like digoxin and warfarin with a long half life will take longer to reach a steady
state than drugs with a shorter half life.
MULTIPLE DOSING
During multiple dosage, elimination half life does have value in predicting the rate and relative
extent of drug accumulation, as well as the rate of washout after termination of treatment.
Clinicians should consider volume of distribution and clearance, in addition to elimination half,
when evaluating the pharmacokinetic properties of drugs.
ACHIEVING A STEADY STATE
The goal of any medication that will need to be taken on an ongoing basis, such as an
antidepressant, is to get it to a "steady state"—in other words, to the point at which the amount
that goes into the body is equal to the amount that's eliminated.
Interestingly, no matter what the half-life of a medication is, it takes about four times that
amount of time for the concentration of the drug to reach a steady state in the body. This means
that if you begin taking a medication with a half-life of 24 hours, after four days, or on the fifth
day, the rate of intake of the drug will approximately equal the rate of elimination. If the half-
life is 12 hours, you'll reach steady state at the beginning of the third day (after 48 hours).
APPLICATION IN ATHLETICS
Published half-life data is usually determined by measuring the decrease in parent drug in
serum or plasma. In the anti-doping world, the serum half-life is of limited value in
determining how long a substance stays in the body because it does not reflect the presence of
metabolites (break-down products from the parent drug). These metabolites are often what is
measured in anti-doping tests and the serum half-life does not necessarily reflect urine
concentrations which is the main sample of choice in anti-doping testing. Furthermore, the
half-life can vary greatly between individuals and is specific for each medication. It can be
dose-dependent and affected by other factors such as accumulation in adipose tissue. Marijuana
is an example of a drug that is excreted in the urine over a prolonged period that could take
weeks or months, depending on the route of administration, to clear completely from an
athletes’ body. Aspirin on the other hand, is an example of a rapidly excreted drug, and could
clear completely from an athletes’ body within hours.
Athletes are strictly responsible for what is found in their body at the time of a drug test.
Understanding clearance times of medications, which is the time it takes for the medication,
and its metabolites, to be completely eliminated from the body, becomes essential. This is
especially important if the athlete is prescribed a medication that is prohibited only in-
competition and they are going to be competing soon. If an athlete uses the medication out-of-
competition and it is still present in their body when tested at a competition, they may be held
responsible for an anti-doping rule violation. A physician or pharmacist should be able to assist
in predicting clearance times for medications. However, USADA cannot predict the clearance
time for any medication for any particular individual. If an athlete needs to use a substance
prohibited in-competition and they are close to competition time, they are strongly encouraged
to contact USADAs Drug Reference Department to learn if they need a Therapeutic Use
Exemption (TUE).
DRUG THERAPY CONSIDERTAION
The half life is an important concept for clinicians:
When treating infections, the antibiotic needs to be present long enough and at a high
enough dose to kill the infection
When taking a sleeping medication, you want it to work only so long that you wake
up refreshed, not groggy
When being treated for blood pressure problems (Hypertension) or cholesterol
problems (Hyperlipidemia) you'd like the medication to work all day.
Some medical conditions will either shorten or prolong the half life of a medication, which is
important for the clinician to consider, to avoid over or under dosing.
Kidney disease will reduce the excretion of medications that are primarily eliminated
through the kidney, allowing it to increase in the blood. This is predictable and should
be taken into consideration by the clinician
Certain medications interfere with the metabolism of other medications, either by
speeding up, or slowing down, the metabolism. The clinician has the information to
know what does what to what, to avoid this problem.
Certain foods can interfere with metabolism of medication. Grapefruit and grapefruit
juice can cause problems with this, and the clinician may tell one to avoid this food.
Drugs with a longer half-life take longer to work, but on the positive side, they take less
time to leave your bloodstream. On the flip side, those with a short half-life become
effective more quickly but are harder to come off of. In fact, drugs with very short half-
lives can lead to dependency if taken over a long period of time.
A drug's half-life is an important factor when it's time to stop taking it. Both the strength
and duration of the medication will be considered, as will its half-life. This is important
because you risk unpleasant withdrawal symptoms if you quit cold turkey.
Withdrawal symptoms are caused by quickly getting off of some types of medication.
When you are being weaned from this type of medication, the drug's half-life will be
considered so that those with a longer half-life will take longer to come off of.
Medication side effects occur usually when the blood level of the drug is not in its
steady state. That's why it's important to follow the dosage and duration
recommendations to the letter. Otherwise, the body will react and the effect of the drug
will be either toxic, as in more than intended, or not therapeutic, as in ineffective for
treatment.
One impact of half-life is found in the SSRI antidepressants. People taking SSRIs with
short half-lives are much more likely to experience SSRI discontinuation syndrome.
People taking an SSRI with a long half-life such as Prozac need to wait far longer
between stopping Prozac and starting a new antidepressant, such as an MAOI.
Masooma Naqvi (06331513034)
VOLUME OF DISTRIBUTION
INTRODUCTION
Definition :
It is defined as ;
"Fluid volume that would be required to contain the amount of drug present in the body at the
same concentration as in the plasma."
DESCRIPTION
According to its definition the volume of distribution (Vd) is not a physical space but a dilution
space which may also be called an apparent volume. The volume of distribution of a drug gives
the information about the distribution of that drug in the body.
The Vd is calculated as the ratio of the dose present in the body and its plasma
concentration , when the distribution of the drug between the tissues and the plasma is at
equilibrium. Accordingly, a drug that accumulates in tissues as e.g. fat tissue, will have a
relatively low plasma concentration with regard to the administered dose, and consequently,
the calculated Vd will be high.
Some drugs cannot enter cells because of their low lipid solubility. These drugs are
distributed throughout the body water in the extracellular compartment and have a relatively
small Vd (12-20 L).
Drugs that accumulate in organs either by active transport or by specific binding to tissue
molecules have a high volume of distribution, which can exceed several times the anatomical
body volume. Therefore, Vd should not be identified too closely with a particular anatomical
compartment. Lipid-soluble drugs are stored in fat. Bone is a reservoir for drugs such as
tetracycline and heavy metals.
Following are the values of Vd for different drugs
C= plasma concentration
All the volumes of distribution correspond to the ratio of an amount (A) of drug in the body
at a given time (At), and plasma (blood) concentration (C) at that time
Most importantly, the Vd is determined in conditions under which the drug distribution
between the plasma and the tissues is at equilibrium. By definition a Vd should only be
regarded as a proportionality constant (parameter) between a plasma concentration and the
corresponding amount of drug in the body. This proportionality constant having a volume for
dimension has been termed volume of distribution.
The bathtub model provides a physical model to explain how physical factors can influence
the volume of distribution. For example there is no loss of water from the bathtub. By putting
a known amount of drug (the dose) into the bathtub and measuring the concentration it is easy
to calculate the volume of distribution.
Molecules which can leave the vascular space but do not cross cell membranes easily (e.g.
highly ionised molecules) will mainly be in the extracellular compartment. Molecules which
can readily cross cell membranes may share the same physical volume as water
Plasma protein binding is another major reason why the apparent volume of distribution does
not correspond to a physical volume. But binding to plasma will lead to a smaller apparent
volume. Drugs bind to proteins like albumin and α1-acidglycoprotein. Because they bind to
plasma proteins they are extracted from plasma and included in drug concentration
measurements. This gives a misleading impression of the volume of distribution and this
phenomenon can be thought of as a ‘red herring’. When a sample of bathwater is removed it
also takes ‘red herrings’ with it. The concentration of drug will be higher in the sample than
in the rest of the bath water because of the higher concentration of drug bound to the ‘red
herrings’. The ‘red herring’ effect is caused by drug binding to plasma proteins. A higher
concentration in the sample leads to a lower apparent volume of distribution.
So, by this method, you measure the volume of initial dispersion of the drug. This volume is
usually called either Vinitial, or Vc, and it represents the behaviour of the drug during the first
rapid phase of distribution through the central compartment. It is generally determined by the
degree of protein binding. Drugs which are highly protein-bound will have a larger Vinitial if you
intend to measure free drug levels.
If you completely ignore the distribution of the drug into the tissues your volume of distribution
estimate is going to be inaccurate for the purpose of determining such things as loading doses.
The alternative approach is to ignore everything but the tissue distribution. This method takes
the slow late stages along the concentration/time curve (the terminal elimination phase) and
extrapolates a line of best fit from them.
Obviously this is going to be a massive overestimate for many drugs, particularly if they are
drugs which disperse extensively into the tissues. Your (time=0) concentration estimate will
potentially be a very low value, producing an unreasonably large Vd estimate. One could
potentially use the Vextrap value to identify drugs which have so much tissue distribution that
clearance by dialysis is near-impossible.
The Vinitial value and the Vextrap value both focus on the drug distributing into some
compartment volume (be it central or peripheral). Neither give a good estimate for the "ideal"
volume of distribution, one which you could reliably use to calculate your loading doses.
Varea is an attempt to get around the errors of focusing on just one compartment at a time. It uses
a non-compartmental pragmatic model, easily calculated from serial concentration
measurements.
where AUC is the area under the concentration-time curve and the "β" terminal elimination
time constant is the slow exponential rate of decline at the latter stages of a drug's tenure in the
body.
You take the whole concentration/time curve, integrate the area under it (AUC) and use
this to establish the "true" volume. This gives a better (smaller) Vd estimate than Vextrap but
is still frequently incorrect if there is significant distribution around compartments. The
Varea equation assumes that the rate of the concentration decline during the terminal
elimination phase is the average rate of clearance for the entire duration of the dose, and
that this rate remains constant. Practically, clearance is almost never constant and is
usually concentration-dependent ("first order") which means that using the "β" terminal
elimination time constant will always yield an underestimate of the "time=0" intercept and
therefore an overestimate of the Vd.
This problem also limits the utility of Varea in altered clearance states. For instance, for a
renally cleared drug Varea measured in a patient with renal failure will always be smaller
(because the slope of the β terminal elimination rate will be near-horisontal). But this will
not represent any sort of change in the drug's distribution.
The point of intersection hardly matters any more. Nobody needs to draw any intercept
lines.
Vss describes the volume of distribution during steady state conditions, i.e. when there is a
stable drug concentration. It is always going to be slightly lower than Varea because of the
effect of clearance on the β terminal elimination time constant.
Of all the volumes of distribution, Vss is probably the most useful for calculating the
loading dose. The loading dose, after all, is the dose you wish to give in order to achieve a
desired (steady state) drug concentration. With the simplicity of the steady state model, the
dose is calculated as (Vss × Css) where Css is the desired steady-state concentration.
Hafsa Shahid (06331513005)
Just after an i.v. drug administration, plasma concentration is maximal (C0). Before any drug
elimination or distribution, the amount of drug in the body is by definition equal to the
administered dose, and the plasma concentration is C0. Applying the definition of a Vd, the
initial volume of distribution (Vc) is
This equation assumes that C0 corresponds to an initial plasma concentration resulting from a
total drug mixing in blood before any drug elimination or distribution, which is generally an
unrealistic assumption. It is estimated by extrapolation to time zero of the drug disposition
curve . In the framework of a compartmental analysis, the initial volume of distribution is
termed volume of the central compartment and is obtained by mean of Eq
where Yi are intercepts of the different phases of the kinetic disposition obtained by fitting
the plasma drug concentration vs. time profile. Therefore, Vc can be viewed as the apparent
volume from which drug elimination occurs because kidney and liver, the two main clearing
organs, belong to the central compartment
The figure shows the correspondence between a tricompartmental model (right) vs. the
physiological and anatomical reality (left). The classical 2 or 3 compartmental mammillary
models are a simplistic representation of the body in 2 or 3 well-stirred compartments. The
mammillary topography is due to the anatomy of the cardiovascular system, which irrigates
different organs in a parallel pathway (rather than sequentially). The central compartment
corresponds to blood and all organs, which are in rapid equilibrium with blood (lungs, kidney
and liver). The kidney and liver being the two most important clearing organs, drug
elimination occurs from the central compartment (according to a first-order rate constant
noted K10), and the volume of the central compartment (Vc) can be viewed as the apparent
space from which drug elimination occurs. It is the reason why body clearance can be
estimated by the product of K10 and Vc. The peripheral compartment corresponds to organs
for which the rate of equilibrium with blood is slower, the number of required peripheral
compartments being indicated by the data itself .
(i) the dose which gains access to the systemic circulation should be accurately known and
(ii) the terminal phase during which Varea is computable should be a pure elimination phase.
When Varea is computed after extra-vascular drug administration and when the amount of
drug that gains access to the systemic circulation is unknown, what is actually estimated is
Varea/F, not Varea which can be calculated from the following equation ;
Where F is the bioavailability factor from 0 to 1. If F is unknown (no i.v. study), Varea/F is at
best of little value because Varea/F cannot be used to compute the actual amount of drug in the
body after an extra-vascular administration.
As Varea relies on total body clearance, Varea is not an appropriate Vd in those situations for
which clearance is null or apparently null. This is the case during i.v. infusion, once the steady-
state condition has been reached and the rate of drug input exactly compensates for the rate of
drug elimination. Under these con- ditions, the system behaves equivalently to a closed system
(no input and no output), i.e. as having a null clearance. In this circumstance, the use of Varea
overestimates the total amount of drug in the body and the appropriate Vd to be selected will
be the so-called Vss with following equation
Vss is a clearance independent volume of distribution that is used to calculate the drug
amount in the body under equilibrium conditions, i.e. during a drug i.v. infusion and also
during multiple drug administration once the steady-state conditions are achieved. Vss can be
derived using different approaches (compartmental, statistical moments, …). For a classical
mammillary compart- mental model, Vss is given by Equation
where K1j and Kj1 represent the distributional rate constants such as K12, K21, K13, K31,
etc. of the general mammillary model. Vss can also be derived using the statistical moments
approach described by Benet and Galeazzi.
where AUMC is the area under the first moment of the disposition curve, Cl the plasma
clearance, and MRT the mean residence time in the system.
Vss can also be computed during a multiple dosing regimen, but in this situation Eqn 15 will
overestimate the true Vss and corrections are required. When data are obtained in steady-state
conditions, Vss is given by following Equation;
Here are the dosing interval, the area under the first
moment curve within a dosing interval at steady-state, the area under the plasma
concentration time curve within a dosing interval at steady-state, and the area under the
plasma concentration curve from the last dose to infinity, respectively.
For all drugs, Varea is higher than Vss but generally, the difference remains small. The
difference between Varea and Vss can be very large, however, if a large fraction of the drug
is eliminated before reaching pseudo-equilibrium. This is the case for aminoglycosides when
considering the very late terminal phase .The difference between Varea and Vss derives from
the difference between pseudo-equilibrium and equilibrium conditions. In pseudo-
equilibrium conditions, plasma drug concentrations decrease because the drug is continually
removed from plasma at a rate proportional to plasma clearance.In contrast, in equilibrium
conditions, plasma concentration is constant because the rate of drug elimination is
compensated by the rate of drug input in the body (clearance is apparently null). Thus, all
things being equal (i.e. for the same total amount of drug in the body), plasma concentration
will be systematically lower in pseudo- equilibrium conditions than in equilibrium conditions.
Therefore, when establishing the correlation between the same amount of drug in the body
with plasma concentration, the proportionality constant should be higher in the pseudo-
equilibrium state (Varea) than in the equilibrium state (Vss), and Vss can be viewed as the
limit of Varea when the clearance tends towards zero. The impact of clearance on Varea
explains why Varea decreases when renal insufficiency exists. It would be errone- ous to
explain this decrease as an altered drug distribution. For instance, the pharmacokinetics of
gentamicin was inves- tigated in the horse before and after the occurrence of nephrotoxicity.
Varea was reduced by 36%, i.e. a reduction proportional to that of body clearance (40%)
whereas, as expected, the reduction of Vss was more limited.
Hafiz Hassan Butt (06331513023)
1) Timing of measurements
Depending on when the measurements are taken, the Vd will be different (i.e. it will correspond
to Vinitial if the measurements are taken too early, and Vextrap if they are taken during the
elimination phase).
2) Pharmacokinetic model
Vinitial, Vextrap, Varea and Vss are various ways to estimate the Vd of a drug from empirical
measurements. All of these methods will yield slightly different results or, occasionally
completely different results.
In highly protein bound drugs, the calculated volume of distribution for the "total" drug levels
will be totally different to the Vd calculated for the free drug. Total Vd will correspond to the
Vd of the binding protein rather than the drug itself.
1) Molecule size
The larger the molecule, the harder it will be for it to passively diffuse out of the central
compartment, and therefore the smaller the Vd.
2) Molecule charge
Highly ionised charged molecules will have higher water solubility, and may even be trapped
in the central compartment by electrostatic factors which keep them bound to proteins with
corresponding charge.
3) pKa
pKa determines the degree of ionisation and therefore influences lipid solubility.
4) Lipid solubility
Lipid solubility is one of the major determinants of Vd; highly lipid-soluble drugs will have
the highest Vd values because of the low fat content of the bloodstream.
5) Water solubility
Highly water-soluble drugs will have difficulty penetrating lipid bilayer membranes and
generally tent do have smaller volumes of distribution, essentially being limited to extracellular
water.
1) pH
pH interactes with the drug's pKa to influence the degree of lipid solubility. pH also influences
the degree of protein binding (a good exmaple of this is ionised calcium)
Dehydrated patients will have drug levels concentrated in the plasma just as all dissolved
substances are concentrated by loss of water.
3) Protein levels
For highly protein-bound drugs, lower serum protein levels will result in a higher free
(unbound) drug fraction. This may have little effect on the Vd as calculated from total drug
concentration, but if you are measuring free drug levels it will make the Vd appear smaller.
4) Displacement
Drugs may be displaced from their protein and tissue binding sites by the effects of pH or by
competition from other drugs/substances (eg. urea). Displaced drugs mayl redistribute into
plasma, decreasing the calculated Vd.
1) Age
As an old professor of mine had put it, babies are grapes and the elderly are raisins. As you
age, body water content decreases, shrinking the Vd of water-soluble drugs. Muscle mass also
decreases, and so tissue binding diminishes.
2) Gender
Female Vds tend to be higher than male Vds due to the generally higher body water content
3) Pregnancy
Both the body water and the body fat content increases, and therefore the Vd increases for most
drugs. Not to speak of the possible distribution into amniotic fluid and foetus.
4) Oedema
Oedema represents increased body water and this influences water-soluble substances; Vd
for these will increase
5) Ascites / effusions
Just as in oedema, large fluid collections may sequester water soluble drugs and act as
reservoirs.
Effects of apparatus
1) Adsorption on to apparatus
Dialysis filters and ECMO circuits tend to adsorb drugs in an unpredictable fashion, resulting
in an apparent increase in the volume of distribution.
2) Volume expansion
In the context of bypass circuits and other large extracorporeal machinery, there may be
2000-2500ml of additional extracorporeal fluid, which will change the volume of distribution
(particularly for drugs which are largely confined to the central compartment)
Cl = Vd / kel
3) Total amount of drug present in the body can be determined
Conclusion
1. Low molecular weight drugs have high Vd
2. Pharmakokinetics is the study of rates of absorbtion, distribution, metabolism and
excretion of drug.
3. We use different compartmental models to explain these parameters
4. Apparent volume of distribution is thus explained using Compartment models
5. It is the volume that would be required to contain all drug in the body if it was
distributed at concentration measured in the plasma.
REFERENCES
Essentials of Medical Pharmacology, 7th Ed. KDT
Textbook of Biopharmaceutics and Pharmacokinetics 1st Ed. Subramnayam
https://derangedphysiology.com/main/cicm-primary-exam/required-
reading/pharmacokinetics/Chapter%202.0.2/volume-distribution
https://synapse.koreamed.org/Synapse/Data/PDFData/1179TCP/tcp-24-74.pdf
https://www.nottingham.ac.uk/nmp/sonet/rlos/bioproc/halflife/index.html
https://www.news-medical.net/health/What-is-the-Half-Life-of-a-Drug.aspx
Applied biopharmaceutics and pharmacokinetics by shargel and Yu,s seven edition