Distribution of drug

Prof. Dr. Shah Murad

shahmurad74@yahoo.com

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 Determinants of distribution

Distribution of drugs to the tissues depends upon:

Size of the organ

Blood flow
Solubility
Binding

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>>>>Once a drug has gained access to the

blood stream,it gets distributed to the other

tissues that initially had no

drug>>>>>concentration gradient in the

direction of plasma to tissues.

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
 The
The extent
extent of
of distribution
distribution of
of aa drug
drug depends
depends
on
on

1.
1. its
its lipid
lipid solubility
solubility
2.
2. Ionization
Ionization at at physiological
physiological pH
pH
3.
3. Plasma/tissue
Plasma/tissue proteins
proteins binding
binding
4.
4. Differences
Differences in in regional
regional blood
blood flow
flow

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 Drug distributes until…………
 Movement of drug proceeds until an equilibrium
is established between unbound drug in plasma
and tissue fluids.

 Subsequently there is a parallel decline in both

due to elimination.

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 Fate of drug
 If a drug is required to act throughout the body

OR
>>>>>>>>to reach an organ inaccessible to
topical administration>>>>>>>>>>>>>>>>>>>
It must be got into the blood and into other body
compartments. 6
 Most drugs distribute widely>>in part
dissolved in body water>>in part bound
to plasma proteins>>in part to tissues.

 Distribution is often uneven,for drugs may

bind selectively >>to plasma or tissue
proteins OR >> be localised within
particular organs.

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 The site of localisation of a drug is likely to
influence its action,eg. Whether it >>crosses
the blood brain barrier to enter the
brain>>amount and strength of protein or
tissue binding(stored drug) <><><><><>will
affect the time it spends in the body
and<><><><><> thereby its duration of
action.
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Selective distribution within the body occurs
because of special affinity between particular drugs
and particular body constituents.
 Many drugs bind to proteins in the plasma,LIKE
phenothiazines and chloroquine bind to melanin-
containing tissues,including the retina>>>>which
may explain the occurrence of retinopathy.
 Drugs may also concentrate selectively in a particular
tissue because of specialised transport
mechanisms,eg. IODINE in the thyroid.

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 Size of organ determines the concentration
gradient between blood and the organ;eg:
skeletal muscle can take up a large amount of
drug

WHY THE LARGE AMOUNT OF DRUG IS TAKEN

BY SKELETAL MUSCLE

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Answer is SIMPLE

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 Because skeletal muscle is very large organ

 So concentration in the muscle tissue remains

low<><><><><>and the blood-tissue
gradient is high,even after relatively large
amounts of drug have been administered

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 Incontrast , BRAIN is smaller ,
distribution of a smaller amount of
drug into it will raise the tissue
concentration…..and>>>>>reduce
to>>>>>ZERO,the blood-tissue
concentration
gradient…….PREVENTING
>>>>>further uptake of drug.

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 BLOOD FLOW OF the tissue
 Blood flow to the tissue is an important factor
of determination of the rate of uptake of
drug<><><><><><>as a result>>>>well-
perfused tissues like brain,heart,kidneys,will
often achieve higher tissue concentrations…
sooner than poorly perfused tissues,like fat and
bone

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If the drug is >>>>rapidly
eliminated,>>>>the
concentration in poorly
perfused
tissues<><><><><><><>
may never rise significantly

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 SOLUBILITY
 The solubility of a drug in tissue influences
the concentration of the drug in the
extracellular fluid surrounding the blood
vessels.

 If the drug is very soluble in the cells,the

concentration in the perivascular
extracellular space will be lower and
diffusion from the vessel into the
extravascular tissue space will be
facilitated. 16
 Some organs including brain, have a high lipid
content and thus dissolve a high concentration
of lipid-soluble agents.>>>>>>>as a
result>>>>>a very lipid-soluble anesthetic will
transfer out of the blood,and into the brain
tissue more rapidly and to a greater extent
than a drug with low lipid solubility.

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 Plasma protein/tissue binding of
the drug
 Many natural substances circulate
around the body partly free in plasma
water and partly bound to plasma
proteins….these include
cortisol,thyroxine,iron,copper and in
hepatic or renal failure,byproducts of
physiological intermediary
metabolism. 18
 Drugs,too,circulate in the protein bound and
free states,and the importance is that the free
fraction is pharmacologically active whereas the
protein-bound part is a reservoir of drug that is
inactive because of this binding.

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 Free and bound fractions are in
equilibrium and free drug removed
from the plasma by metabolism,
dialysis or excretion is replaced by
drug released from the bound
fraction.

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 Albumin is the main binding protein for
many natural substances and drugs. Its
complex structure has a net negative charge at
blood pH and a high capacity but low(weak)
affinity for many basic drugs,i.e. A lot is bound
but it is readily released.
 Two particular sites on the albumin molecule
bind acidic drugs with high affinity(strongly) but
these sites have low capacity.
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Saturation of binding sites on plasma proteins in general is
unlikely in the doses in which most drugs are used.

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 Other binding proteins in the blood include lipoprotein
and alfa-1 acid glycoprotein,both of which carry basic
drugs such as quinidine,chlorpromazine,and
imipramine.

 Such binding may have implications for therapeutic

drug monitoring according to plasma concentration.

 Thyroxine and sex hormones are bound in the plasma

to >>>>>>>specific GLOBULINS
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 CHARACTERISTIC OF PP &
DRUG

Protein binding is largely determined by the

hydrophobicity of the drug molecule

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Drug % unbound(free)
Warfarin 1
Diazepam 2
Frusemide 2
Tolbutamide 2
Phenytoin 9
Trimethoprim 30
Morphine 65
Amoxicillin 82
ethosuximide 100

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 Diseases & PP binding
 Diseasemay modify protein binding of drugs
to an extent that is clinically relevant.

 Inchronic renal failure , hypoalbuminemia

and retention of products of metabolism that
compete for binding sites on protein are
both responsible for the decrease in protein
binding of drugs.
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 Most affected are acidic drugs that are
highly protein
bound,eg.PHENYTOIN>>specific care is
needed when initiating and modifying the
dose of such drugs for pts with renal
failure.

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 Chronic liver disease also leads to
hypoalbunemia and increase of endogenous
substances such as bilirubin that may compete
for binding sites on protein.

 Drugs that are normally extensively protein

bound must be used with special care>>>>b/c
increased free concentration of
diazepam,tolbutamide and phenytoin may be
toxic in these conditions. 28
Drug Free (unbound form)

Diazepam 2(6% in liver Disease)

Frusemide 2(6% e nephrotic S)
Clofibrate 4(11% e nephrotic S )
Phenytoin 9(19% e renal disease)
Triamterene 19(40% e renal dis
Theophylline 35(71% e liver disease)
Digoxin 75(82% in renal disease)

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 Interaction during distribution
 Displacement from plasma protein binding sites
may contribute to adverse reaction.

 A drug that is extensively protein bound can be

displaced from its binding site by a competing
drug,so raising the free(& pharmacologically
active)concentration of the first drug>>>>>
CLASS I DRUGS
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 Unbound(free)drug is now available
for distribution away from the plasma
and for metabolism and
excretion>>>>commonly the result
is that the free concentration of the
displaced drug quickly returns close
to its original value and any extra
effect is transient.
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 For a displacement interaction to become
clinically important ,a second mechanism
usually operates>>>>sodium valproate can
cause phenytoin toxicity because it both
displaces phenytoin from its binding site on
plasma albumin and inhibits its metabolism.

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 Similarly ASPIRIN and PROBENECID(and other
NSAIDs) displace the folic acid antagonist
METHOTREXATE from its protein binding site
and reduce its rate of active secretion by the
renal tubules>>>resulting in serious
methotrexate toxicity.

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 Bilirubin is displaced from its binding protein
by sulphonamides,vitamin K,X-ray contrast
media,or indomethacin >> in the neonate
this may cause a significant risk of
KERNICTERUS,for its capacity to metabolise
bilirubin in immature.

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 Directinteraction between drugs may
also take place in the
plasma,eg;protamine with
heparin.desferrioxamine with iron.
Dimercaprol with arsenic >>>> all are
usefull effects

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 Tissue binding
 Some drugs distribute readily to regions of the body
other than plasma…like ……..many lipid soluble drugs
which may enter fat stores ……eg: most
bezodiazipine,verapamil and lignocaine.
 Less is known about plasma protein binding because
>>solid tissue samples can be obtained only by
invasive biopsy,but extensive binding to
tissues>>delays elimination from the body
and>>accounts for the>>>>>>long half life of
chloroquine and amiodarone.
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 Displacementfrom tissue binding sites
may be a mechanism for Pharmacokinetic
interaction>>>>>and may cause
unwanted effects.

 CLASS I & CLASS II DRUGS

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 When quinidine is given to pts who are
receiving digoxin,the plasma concentration of
free digoxin may double because quinidine
displaces digoxin from binding sites in tissue ,
as well as plasma proteins.

 NOTE THAT QUINIDINE ALSO IMPAIRS RENAL

EXCRETION OF DIGOXIN leading to îî s.effects

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Very interesting term used in
Pharmacotherapeutics

Vd
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 APPARENT VOLUME OF
DISTRIBUTION (Vd)
 Presume that the body behaves as a
single homogeneous compartment with
volume V , into which drug gets
immediately and uniformly distributed>>>
V= dose administered I.V
plasma concentration

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Since the drug does not actually distribute into
20 litres of body water,with the exclusion of the
rest of it,,this is only an apparent volume of
distribution which can be defined as
“the volume that would accommodate all the in
the body,if the concentration throughout was
the same as in plasma”.

 Thus , it describes the amount of drug present

in the body as a multiple of that contained in a
unit volume of plasma.
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 Such information is clinically useful

 Consider drug overdose.

 Removing a drug by haemodialysis is likely to

be a beneficial exercise only if a major
proportion of the total body load is in the
plasma,eg. with salicylate which has a small
distribution volume; but haemodialysis is an
inappropriate treatment for overdose with
dothiepin which has a large distribution volume.
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 The pattern of distribution from plasma to
other body fluids and tissues is a characteristic
of each drug that enters the circulation and it
varies between drugs.

 Precise information on the concentration of

drug attained in various tissues and fluids
requires biopsy samples and for
understandable reasons this is usually not
available for humans.

 What can be done then ??? 43

 What can be sampled readily in humans is
blood plasma,the drug concentration ,in which ,
taking account of the dose,is a measure of
whether a drug tends to remain in the
circulation or to distribute from the plasma in to
the tissues.

 If a drug remains mostly in the plasma,its

distribution volume will be small;if it is

present mainly in other tissues the distribution
volume will be LARGE 44
 How to calculate Vd
 The principle for establishing the distribution
volume is essentially that of using a dye to find
the volume of a container filled with liquid.
 The weight of DYE that is added divided by the
concentration of dye once mixing is complete
gives the distribution volume of the dye,WHICH
IS VOLUME OF CONTAINER.
 Similarly,the distribution volume of a drug in
the body may be determined after a single IV
bolus dose by dividing the dose given by the
concentration achieved in plasma. 45
 The result of this calculation,the distribution
volume,in fact only rarely corresponds with a
physiological body space such as extracellular
water or total body water,for it is a measure of
the volume a drug would apparently occupy
knowing the dose given and the plasma
concentration achieved and assuming the entire
volume is at that concentration(APPARENT Vd)
 Indeed,for some drugs that bind extensively to
extravascular tissues,the Vd, which is based on
the resulting low plasma concentration,is many
times total body volume
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 Lipid insoluble drugs do not enter cells- vd
approximates extracellular fluid volume,eg;
streptomycin,gentamicin 0.25 L/kg

 Distribution is not only a matter of dilution but

also binding and sequestration.DRUGS
extensively bound to PPs are largely restricted
to the vascular compartment and have low
values,eg. Phenylbutazone & warfarin(99%
bound) V=0.1 L/kg 47
 Drugs sequestered in other tissues may have Vd much

more than total body water or even body mass,eg.

DIGOXIN 6L/kg,PROPRANOLOL 4L/kg,MORPHINE 3.5

L/kg because most of the drug is present in other

tissues,and plasma concentration is low.

 THEREFORE in case of POISONING,drugs with large Vd

are not easily removed by haemodialysis

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 DISEASES & Vd

 Pathological states, like CCF,uraemia,cirrhosis

of liver,etc can alter the Vd of many drugs by
altering distribution of body water,permeability
of membranes,binding proteins or by
accumulation of metabolites that displace the
drug from binding sites.
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 INTERESTING TERM
 REDISTRIBUTION: highly lipid soluble
drugs given I.v or by inhalation initially get
distributed to organs with high blood flow,eg.
Brain,heart,kidney,etc. Later less vascular but
more bulky tissues(muscle,fat) take up the
drug-plasma concentration falls and the drug is
withdrawn from these sites.if the site of action
of the drug was in one of the highly perfused
organs,redistribution results in termination of
drug action. 50
 RULING CHARACTERISTIC in
Redistribution

 GREATER THE LIPID SOLUBILITY OF THE

DRUG , FASTER IS its REDISTRIBUTION

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 ClassicaL ExamplE of
RedistributioN
 Anaesthetic action of thiopentone is terminated
in few minutes due to REDISTRIBUTION.
 However,when the same drug is given
repeatedly or continuously over long
periods,the low perfusion high capacity sites
get progressively filled up and the drug
becomes longer acting.

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THANK YOU
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