Principles of Drug Distribution

7/28/2019 Principles of Drug Distribution

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DRUGDISTRIBUTION


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DISTRIBUTION

Definition:

Process where by an absorbed chemical movesaway from the site of absorption to other areas

of the body.

Following absorption (skin, lung, orgastrointestinal tract) or systemic

administration (IV, IP, IM) into the bloodstream,a drug distributes into interstitial andintracellular fluids.


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Interstitial fluid represents about 15% of the

total body weight.

Intracellular fluid(fluid inside cells) - 40%of

the total body weight.

Blood plasma - 8%of the body weight.


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The rate of delivery and potential amount of

drug distributed into tissues depends on;

Cardiac output, Regional blood flow, Capillary

permeability and tissue volume.

Well-perfused organs (liver, kidney, brain)

initially receive most of the drug

Lesser perfused pnes: delivery to muscle, most

viscera, skin, and fatis slower.


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Distribution

determines the transport of

drugs to their site of action, to other sites, and

to the organs of metabolism and excretion.

Not uniform;

Difference in perfusion rates.

Penetrate - capillary endothelium.

Diffuse across the cell membrane.


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DISTRIBUTION

Distribution is the dispersion of the drug among the various organs orcompartments within the body.

The apparent volume of distribution (Vd), has been devised to describe thedistribution of the drug.

Apparent volume of distribution is the theoretical volume that would haveto be available for drug to disperse in if the concentration everywhere inthe body were the same as that in the plasma or serum, the place wheredrug concentration sampling generally occurs.

Vd is the volume (Litre/kg) into which the drug appears todistribute and it is calculated from the dosage (kg) and theconcentration of drug in the blood (kg/L) and body weight(kgs)

Vd = D/(Cp x k)

Example: Assume that 100 g of alcohol are ingested by a man who weighs 70 kg and the bloodlevel is found to equal 2.38 g/L. Vd = D/(Cp x k)

Vd = 0.100 kg/(0.00238 kg/L x 70 kg)

Vd = 0.60 L/kg or 42 L for this man


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Volume of Distribution (Vd )

values range from about 5% of body volume to as high as 400 L.

The latter figure is much higher than anyones total volume, so Vd

is an

artificial concept.

Importance - it will predict whether the drug will reside in the blood or in the

tissue.

Water soluble drugs will reside in the blood, and fat soluble drugs will reside

in cell membranes, adipose tissue and other fat-rich areas. Volume of Distribution also relates to whether a drug is Free / protein bound

Drugs that are charged tend to bind to serum proteins.

Protein bound drugs form macromolecular complexes that cannot crossbiological membranes and remain confined to the bloodstream.

Pathological states may also change Vd. Because Vd mathematically relates blood concentration to dosage it may be

employed in interpretation of laboratory results.

Useful for providing an estimate of dosage, it follows that it can help estimatethe amount of antidote to be given.

Indicate whether there is any value in trying to enhance elimination as, forexample, by dialysis.


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Volume of Distribution

Vd is helpful in the context of drug monitoring.

Predicts whether the practice of drugmeasurement in blood will have any clinicalvalue.

Psychotropic drugs such as tranquilizers,

antidepressants, antipsychotics, mood-altering agents, etc.,create their effects by binding at sites withinthe central nervous system.


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V

Volume 100 L

Clearance

10 L/hr

Volume of Distribution, Clearance and

Elimination Rate Constant


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Important Concepts

VD is a theoretical Volume and determines

the loading dose.

Clearance is a constant and determines

the maintenance dose.

CL = kVD.

CL and VD are independent variables. k is a dependent variable.


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Volume of Distribution

An abstract concept

Gives information on HOW the drug isdistributed in the body

Used to calculate a loading dose


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Loading Dose

Dose = Cp(Target) x Vd


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Clearance (CL)

Ability of organs of elimination (e.g. kidney,liver) to clear drug from the bloodstream.

Volume of fluid which is completely cleared of

drug per unit time. Units are in L/hr or L/hr/kg

Pharmacokinetic term used in determination

of maintenance doses.


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Clearance

Volume of blood in a defined region of the

body that is cleared of a drug in a unit time.

Clearance is a more useful concept in reality

than t 1/2 or kel since it takes into account

blood flow rate.

Clearance varies with body weight.

Also varies with degree of protein binding.


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Clearance

Rate of elimination = kel D,

Remembering that C = D/Vd And therefore D= C Vd

Rate of elimination = kel C Vd Rate of elimination for whole body = CLT C

Combining the two,

CLT C = kel C Vd and simplifying gives:CLT = kel Vd


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Drug Half-Life


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The factors determinining

tissue permeability of a drug:

The physico-chemical properties of the drug,

Bindingto plasma and tissue proteins,

Blood flow

Special compartments and barriers,

Disease states, etc.


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I. Physicochemical Properties of the Drug:

Drugs molecular weight (< 500 to 600 Da) easilycross the capillary membrane to penetrate into

the extracellular fluids (except in CNS) because

junctions between the capillary endothelial cells

are not tight.

Passage of drugs from the ECF into the cells;

molecular size

degree of ionization and

lipophilicity


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Water-soluble molecules and ions of size

below 50 daltons enter the cell through aqueous

filled channels, whereas those of larger size arerestricted unless a specialized transport system

exists for them.

According to the pH-partition hypothesis,

basic drugs present in blood (pH 7.4) readily

enter into acidic tissues and fluids, including theintracellular fluids (pH 7.0) and concentrate

there.


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Conversely, acidic drugs attain high

concentrations in the relatively more alkaline

body fluids.Example:

Weak organic bases administered

paranterally diffuse passively from blood (pH

7.4) into rumen fluid (pH 5.5 -6.5) ofcattle and

sheep, where they become trapped by

ionization.

Similarly, weak bases tend to be accumulate

in milk since the pH of milk is slightly acidic (pH

6.5 to 6.8) to the blood.


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Transportation of Drugs:

Drugs are transported in the circulating bloodin two forms: free form and bound form

(plasma proteins).

Free form of drugs is usually dissolved in

plasma and is pharmacologically active,

diffusible, and available for metabolism and

excretion.


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II. Binding to a) Plasma Proteins:

Significance of plasma-protein binding;

Affects distribution,

Pharmacologically inactive,

Non-diffusible,

Not available for metabolism or excretion

(As they cannot pass through capillaries and cell

membranes because of their larger size).


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The plasma protein binding of drugs is usually

reversible (weak chemical bonds); covalent

binding of reactive drugs such as alkylatingagents occurs occasionally.

The binding of individual drugs ranges from verylittle (e.g., Theophylline) to very high (e.g.,

warfarin).

In circulating blood, there is a constant ratio

between the bound and free fractions of the

drug.


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When the concentration of the free drug falls

due to redistribution, metabolism or excretion,the free: bound ratio is maintained by

dissociation of the bound form of the drug.

Thus plasma protein binding mainly serve as a

reservoir, which supplies free drug whenever

required.

Free drug Protein bound drug


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Protein- bound

drug

Protein- bound

drug

Free drugFree drug

TissuePlasma

The free drug concentration gradient drives transport across the membrane.


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A large variety of drugs ranging from weak

acids, neutral compounds, and weak bases bindto plasma proteins.

Acidic drugs generally bind to plasma albumin

and basic drugs to alfa1 acid glycoproteins;

binding to other plasma proteins

(e.g., lipoproteins and globulins) occurs to a

much smaller extent.


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Different drugs binding to different proteins

Binding sites for acidic agents Albumins

Ex- Bilirubin, Bile acids, Fatty acids, Vitamin C,

Salicylates, Sulfonamides, Barbiturates,Probenecid,

Phenylbutazone ,Penicilins, Tetracyclines etc

Binding sites for basic drugs Globulins

Ex- Adenosine, Quinacrine, Quinine, Streptomycin,Chloramphenicol, Digitoxin, Ouabain, Coumarin


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For the majority of drugs, binding to plasma

albumin (Mol. Wt. 65,000), which comprises>50% of the total proteins, is quantitatively

more important.

The binding of drugs to albumin may show

low capacity (one drug molecule per albumin

molecule) or high capacity (two or more drug

molecules per albumin molecule).


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The albumin can bind several compounds

having varied structures, some substances evento a single site. Groups of drugs that bind to the

same site compete with each other for binding.

Some drugs may bind to blood components

other than plasma proteins (e.g., phenytoin and

pentobarbitone bind to haemoglobin)


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II. Binding to b) Tissue Proteins:

Many drugs accumulate in tissues at higherconcentrations than those in the extracellular

fluids and blood called localization.

Tissue binding of drugs (cellular constituents);

Proteins, phospholipids, or nuclear proteins

and generally is reversible or some case

irreversible (covalent chemical bonding).


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Important in distribution from two viewpoints:

Firstly, it increases the apparent volume ofdistribution (in contrast to plasma protein binding

which decreases it)

Secondly it results in localisation of a drug at a

specific site in the body produce local toxicity.

Examples:Aminoglycoside antibiotic gentamicin Nephro

and vestibular toxicity.


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Paracetamol and chloroform metabolites

bind hepatotoxicity.

Tetracyclines, fluoride (infants or children)

during odontogenesis results in permanent

brown-yellow discoloration of teeth.

Chlorpromazine, chloroquine leads

retinopathy (Hounds breeds).


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Drug displacement interactions:

Drug displacement interactions occur

between two or more drugs that bind to same

plasma protein site.

If one drug is binding to such a site, then

administration of second drug having higher

affinity for the same site results in- Displacement of first drug from its binding

site.


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Generally, In many cases, the impact of

interactions is minimal

In some instances a slight displacement of a

drug will result in marked increase in its

biological activity.

Ex: Administration of phenylbutazone to a

patient on warfarin therapy results indisplacement of warfarin from its binding site.


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Warfarin has high plasma protein binding of

about 99% (free drug concentration -1%), shows

a small volume of distribution (remains confinedto blood compartments) and has a narrow

therapeutic index.

If just 1% of warfarin is displaced by the

phenylbutazone, the concentration of free

warfarin will be doubled (2%).

The enhanced concentration of free warfarin

may cause severe haemorrhagic episodes,

which may result in lethality.


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Fat As a Reservoir:

Many lipid-soluble drugs are stored by physicalsolution in the neutral fat.

In obese persons, the fat content of the body may

be as high as 50%, and even in lean individuals it

constitutes 10% of body weight; hence fat may

serve as a reservoir for lipid-soluble drugs.

Ex: The highly lipid-soluble barbiturate thiopental


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Bone:

The tetracycline antibiotics (and other divalentmetal-ion chelating agents) and heavy metals

(Cadmium, Fluoride, lead or radium) may

accumulate in bone and become a reservoir by

adsorption onto the bone crystal surface and

eventual incorporation into the crystal lattice

causes toxicity.

Adsorption process for some drugs shows

therapeutic advantages for the treatment of

osteoporosis.


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Blood Flow and Organ Size:

The rate of blood flow to tissue capillariesvaries widely as a result of unequal distribution

of cardiac output to various organs.

The drug distribution to a particular organ or

tissue depends on the size of the tissue (tissue

volume) and tissue perfusion rate (volume of

blood that flows per unit time per unit volumeof the tissue).


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Highly perfuse tissues such as lungs, kidneys,

liver, heart, adrenals, and brain are rapidly

equilibrated with lipid soluble drugs.

Muscle and skin are moderately perfuse, so they

equilibrate slowly with the drug present in blood.

Adipose tissues, bones and teeth being poorly

perfuse, take longer time to get distributed with

the same drug.

IV. Specialized Compartment and Barriers:


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BLOOD BRAIN BARRIER and BLOOD CSF BARRIER

Central Nervous System and

Cerebrospinal Fluid:

The capillary endothelial cells in brainhave tight junctions and lack pores or

gaps.

Surrounding the tight and overlapping

endothelial layer is a continuous

basement membrane.

These basement membranes in turn

are enveloped by perivascular foot

processes formed by astrocyte cells

that encircle about 85% of the surface

areas of brain capillaries. Together these layers add up to a

formidable non-polar barrier called

the blood-brain barrier (BBB).


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At the choroid plexus, a similar blood-CSF barrier is

present except that it is epithelial cells that are joined by

tight junctions rather than endothelial cells.

The lipid solubility of the nonionized and unbound

species of a drug -an important determinant of its

uptake by the brainMore lipophilic a drug is, the more likely it is to cross

the blood-brain barrier.

Often is used in drug design to alter drug distribution tothe brain

e.g: second-generation antihistamines, -loratidine,

achieve far lower brain concentrations than do agents

such as diphenhydramine and thus are non sedating.


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Another important factor in the functional blood-brain

barrier involves membrane transporters that are efflux

carriers present in the brain capillary endothelial celland capable of removing a large number of chemically

diverse drugs from the cell.

Example:

P-glycoprotein (P-gp, encoded by the MDR1 gene) and

the organic anion-transporting polypeptide (OATP) are

exporters are to dramatically limit access of the drug tothe tissue expressing.


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Placental barrier:The maternal and foetal blood vessels are separated by a layer

of trophoblastic cells that together constitute the placental

barrier.

The characteristics generally the same as BBB.

However, restricted amounts of lipid insoluble drugs, especially

when present in high concentration or for long periods in

maternal blood gain access to the foetus by non-carriermediated processes.

Thus, the placental barrier is not as effective as the blood-brain

barrier and impermeability of the placental barrier to polar

compounds is relative rather than absolute.So care must be taken while administration of all types of drugs

during pregnancy because of the uncertainty of their harmful

effects on developing foetus.

Risk Category of Drugs Classification

Oth b i


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Other barriers:

The prostrate, testicles, and globe of eyes

contain barriers that prevent drug penetration

to tissues.

Lipid soluble drugs can penetrate and reach

these structures freely, whereas water-soluble

drugs entry is restricted.


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V.Disease States:

Distribution characteristics of several drugs are

altered in disease states.

Examples:

In meningitis and encephalitis, the blood-brain

barrier becomes more permeable and the polarantibiotics like penicillin-G, which do not

normally cross it, gain access to the brain.


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In hypoalbuminaemia, plasma protein binding of

drugs may be reduced and high concentration offree drugs may be attained.

In congestive heart failure or shock the perfusionrate to the entire body decreases, which affect

distribution of drugs.


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Redistribution:


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Redistribution:

Termination of drug effect after withdrawal of a

drug usually is by metabolism and excretion

But also may result from redistribution of the

drug from its site of action into other tissues or

sites.

Redistribution is a factor in terminating drug

effect primarily when a highly lipid-soluble drugthat acts on the brain or cardiovascular system is

administered rapidly by intravenous injection or

by inhalation.


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Example:

Use of the IV anesthetic thiopental, a highlylipid-soluble drug. Because blood flow to the

brain is so high, the drug reaches its maximal

concentration in brain within a minute of itsintravenous injection.

After injection is concluded, the plasma

concentration falls as thiopental diffuses into

other tissues, such as muscle.


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Principles of Drug Distribution