Pharmacokinetics Drug Distribution

PHARMACOKINETICS
DR.MUHAMMAD USMAN KHALID
DPT,MS-NMPT

DEFINITION
• The study of “kinetics” or movement of a drug in the body

DISTRIBUTION OF DRUGS
The movement of a
drug from the blood
stream to various
tissues of the body

DISTRIBUTION OF DRUGS
•A drug reversibly leaves
the blood stream and
enters the interstitium
(ECF) and/or the cells of
the body

Distribution of drug
in the absence of elimination

Distribution of drug
when elimination is present

Log scale of drug
distribution

THE DISTRIBUTION OF DRUG DEPENDS
ON
• Differences in regional blood flow,
determine the rate of uptake of drug
• Capillary permeability & Special
Barriers ---- BBB, placental barrier
• Drug structure - lipid solubility,
ionization
• Binding of drugs to
macromolecules

BLOOD FLOW AND DRUG DISTRIBUTION
• The initial rate of distribution of a drug depends heavily on blood flow to
various organs
• Brain, liver, kidney > muscle, skin > fat, bone
• At equilibrium, or steady state, the amount of drug in an organ is related to
mass of the organ and its properties, as well as to the properties of the
specific drug

BLOOD FLOW AND DRUG DISTRIBUTION
• Size of the organ – and concentration gradient
• Skeletal muscle –blood tissue gradient remains high even after a relatively
large amount of the drug has been transferred
• Brain – blood tissue gradient reduced to zero on distribution of a smaller
amount of drug, preventing further uptake of drug.

DRUG REDISTRIBUTION
• The relative distribution of a drug in the body changes with time
• This is seen with highly lipophilic drugs such as thiopental
• I/v thiopental produce short duration of hypnosis
• GA in 10-20seconds, effect stops 5-15 minutes due to redistribution
• – initial high concentration achieved in brain (blood flow + lipid solubility of
drug)--- then slow distribution to skeletal muscle and adipose tissue
(redistribution)

Permeability and Special Barriers to drug distribution
BBB, placental barrier
Drug structure --- lipid solubility, ionization

BBB
• BBB may not be fully developed at birth
• Inflammation, such as that result
from meningitis, may increase the
ability of ionized, poorly soluble
drugs to cross the BBB

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RedistributionRedistribution
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BLOODBLOOD

PLACENTAL BARRIER
• Lipid soluble drugs cross the placental barrier more easily than polar drugs;
drugs with a molecular weight of less than 600 pass the placental better
than larger molecule
• The possibility that drug administered to the mother may cross the placenta
and reach the fetus is an important consideration in therapy
• Drug transporter e.g., P-glycoprotein transporter transfer drugs out of the
fetus

CAPILLARY PERMEABILITY --LIVER &
SPLEEN
• large, discontinuous capillaries
through which large plasma
proteins can pass
• Drugs exchange freely between
blood and interstitium in the liver

BINDING OF DRUGS
TO PROTEINS
INERT BINDING
(DRUG +
NONREGULATORY
MOLECULES --- NO
EFFECT)

THE DRUGS EXISTS IN PLASMA IN THE FREE
FORM OR BOUND TO PLASMA PROTEINS
D + S DS
Free binding complex
drug site
• Extent of binding is highly variable --- 0% to 99
• The free drug is maintained as a constant fraction
of the total drug
• When the free drug levels fall, the bound drug is
releases

• Only the free drug diffuses through the capillary
walls
• Drug bound to proteins is a nondiffusible form–
it serves as a store (reservoir) & the drug is
released when the free drug levels fall
• Only free drug is available for pharmacological
action, metabolism, and excretion
• It is the free drug in the interstitial fluid that
exerts a pharmacological effect

• The amount of a drug that is bound to
protein depends upon
• The concentration of free drug
• Its affinity for binding site
• The concentration of protein
• Saturable binding sometimes leads to non-
linear relation between dose and free
(active) drug concentration

• Plasma albumin is most important; β globulin and acid glycoprotein also
bind some drugs
• Plasma albumin binds mainly acidic drugs
• 2 molecules per albumin molecule.
• Warfarin, NSAIDS, Sufonamides
• Basic drugs may be bound by β globulin & acid glycoprotein-- Quinine

CLINICAL SIGNIFICANCE OF PLASMA
PROTEIN BINDING
• Extensive protein binding
• Prolongs duration of action of the drug
• Slows drug elimination(metabolism and / or elimination)
• CRF and CLD results in hypoalbuminemia with ↓ binding of
drugs
• Drug interaction
• Many drugs may compete the same binding sites.
• Thus one drug may displace another from the binding
sites resulting in toxicity
• indomethacin displaces warfarin from protein binding
sites leading to increase warfarin levels
• Tolubutamide (95% bound) displaced by a sulphonamide
• Chloroquine strongly bounds to extravascular tissue protein

DISTRIBUTION -- WHERE THE DRUG
GOES?
• The drug is distributed to
various fluid compartments of
the body
-Volumes of distribution
-Apparent spaces

Total body fluid (42 liters)
in a 70 Kg adult

Hydrophobic small molecule --- ethanol

Hydrophilic
low molecular weight
---Aminoglycoside
---Gentamicin

Hydrophilic
low molecular weight
---Aminoglycoside
---Gentamicin
Protein bound molecules
Very large molecules --- heparin

EXTRACELLULAR FLUID
Drugs that have a low molecular weight
but are hydrophilic --- Example
Atracuronium 11 L (8-15)

Plasma compartment
Very high molecular weight drugs, or
drugs that bind to plasma proteins
excessively
Example: heparin 4L (3-5)

Fat (0.2-0.35 L/Kg) ---
highly lipid soluble molecules --- DDT
Bone (0.07 L/Kg)
certain ions --- lead, fluoride

Vd equal to or higher than total body water
Diffusion to intracelullar fluid .
Vd equal to total body water.
Ethanol 38 L (34-41)
Drug that binds strongly to tissues.
Vd higher than total body water.
Fentanyl: 280 L
Propofol: 560 L
Digoxin : 385 L

APPARENT VOLUME
OF DISTRIBUTION
(VD)
IT IS THE VOLUME OF TOTAL BODY FLUID INTO WHICH A
DRUG “APPEARS” TO DISTRIBUTE

Vd = amount of drug in the body(dose)
plasma concentration
Vd is expressed as in units of volume

APPARENT VOLUME OF DISTRIBUTION
(VD)
• Most drugs distribute unevenly in several compartments
• Apparent volume of distribution assumes that the drug distributes uniformly
in a single compartment
• In most cases , the “initial” plasma concentration, C0, is determined by extrapolation
from the elimination phase

FEATURES OF VD
• The higher the Vd, the lower the
plasma concentration and vice
versa.
• A very low Vd value may indicate
extensive plasma protein binding
of the drug.

FEATURES OF VD
• A very high Vd value may indicate
that the drug is extensively bound to
the tissue sites
• An exceptional large Vd indicate
considerable sequestration of the
drug in some organ or the
compartment

SIGNIFICANCE OF VD
• To calculate the loading dose of a drug
• Drug displacement, Vd & drug
interaction
• Vd and half life of a drug
• Vd can be used to calculate the amount
of drug needed to achieve a desired

VD AND DRUG DOSAGE
• To calculate the loading dose of a drug -------Drugs with large Vd need a
loading dose to achieve the desired plasma concentration
• Vd can be used to calculate the amount of drug needed to achieve a desired
• (Vd ) (C1) = amount of drug initially in the body
• (Vd ) (C2) = amount of drug needed to achieve the desired plasma drug
concentration
• Additional dose needed = Vd (C2 – C1)

DRUG DISPLACEMENT, VD &
DRUG INTERACTION
• A very low Vd value indicate extensive plasma protein binding of the drug.
• Displacement of drug from albumin --- ↑in the “free” drug
• If the therapeutic index of the drug is small. An ↑ in free drug concentration
may lead to
• ↑ therapeutic effects
• ↑ toxic effects
• Tolubutamide (95% bound) displaced by a sulphonamide

EFFECT OF A LARGE VD ON HALF LIFE OF
A DRUG
• A very large Vd indicate that most
of the drug is in the extraplasmic
space and is unavailable to
excretory organs. --- the longer is
half life and the duration of
action of the drug

• Vd may be influenced by age, sex, weight, and disease processes – edema,
ascities
• The Vd is altered by diseases
• For drugs that are normally bound to plasma protein
• Liver disease – through reduce protein synthesis
• Kidney disease – through urinary protein loss
• An exceptional large Vd
• For drugs that avidly bound in peripheral tissues, the drug’s concentration in plasma may drop
to very low values even though the total amount in the body is very large
• Vd is 50,000 liters for quinacrine

DRUG DISTRIBUTION
• Blood flow
• Capillary permeability
• Binding of drugs to plasma proteins and tissues
• Binding to plasma proteins
• Binding to tisssue proteins
• Hydrophobicity
• Volume of distribution

Pharmacokinetics Drug Distribution

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