DISTRIBUTIONDISTRIBUTION OF DRUGOF DRUGDr. Muslim SuardiDr. Muslim Suardi

Faculty of Pharmacy Faculty of Pharmacy University of Andalas University of Andalas

20092009

DistributionDistribution of Drug of Drug

After absorption

or

Injected intravenously

Heart

Bloodstream

IntroductionIntroduction

Once a drug has gained excess to the blood stream, it is subjected to a number of processes called as Disposition Processes that tend to lower the Cp.

1.Distribution: Reversible transfer of a drug between compartments.

2.Elimination: Irreversible loss of drug from the body. It comprises of biotrans- formation & excretion.

DistributionDistribution of Drug of Drug

Involves reversible transfer of a drug between compartments.

Drug molecules are distributed is throughout the body by systemic circulation

Drug Distribution Drug Distribution

“Reversible transfer of drug from one site to another within the body”

Drug Distribution Drug Distribution

Reversible Transfer of a Drug between:

Blood

Extra Vascular Fluids

Tissues of the body

(Fat, muscle, & brain tissue)

Distribution ProcessDistribution Process

• Distribution is a Passive Process

• Driving force is the concentration gradient between the blood &

extravascular tissues

Drug in Drug in Systemic CirculationSystemic Circulation

Unbound

Bound

Diffusion of Diffusion of DDrugrug

Diffusion of unbound drug until equilibrium is established.

Distribution of DrugDistribution of Drug

By blood to:

1. Receptor

2. Non receptor, caused side effects

3. Eliminating organs: liver & kidneys

4. Tissues: brain, skin & muscle

5. Placenta, breast milk

6. Bound to proteins in the plasma & tissues

7. Fat

Distribution in TissueDistribution in Tissue

Distribution of a drug is not uniform throughout the body because different

tissues receive the drug from plasma at different rates & to different extents.

Factors Factors AAffecting ffecting DDrug rug DDistributionistribution

Rate of distribution• Membrane permeability • Blood perfusion

Extent of Distribution• Lipid Solubility • pH - pKa • Plasma protein binding • Intracellular binding

Circulatory SystemCirculatory System

• Artery: which carry blood to tissues

• Veins: which return blood back to the heart

• BW 70 kg, 5L of blood, 3 L plasma

• 50% of the blood is in large veins or venous sinuses

• Mixing of drug in the blood occurs rapidly

Circulatory SystemCirculatory System

• Drug molecules rapidly diffuse through fine capillaries to the tissues filled with interstitial fluid

• Interstitial fluid + plasma water is termed the extracellular water

Drug Drug MMolecules olecules AAcross cross CCell ell MMembraneembrane

Depend upon:

• Physicochemical nature of both the drug & the cell membrane

• Cell membrane: Protein & bi-layer of phospholipid

• Lipid-soluble drug more easily

• Drug-protein complex: too large

Drugs Transverse ProcessDrugs Transverse Process

Passive diffusion (mainly)

Hydrostatic pressure

Passive Passive DDiffusioniffusion

Drug molecules move from high to low

Fick’s Law of Diffusion

Distribution is a Passive Process

Driving force is the conc. gradient between the blood & extravascular tissues

DiffusionDiffusion

Diffusion of unbound drug until equilibrium is established.

Fick’s Law of Diffusion Fick’s Law of Diffusion

Rate of drug diffusion

dQ/dt = -DKA/h (Cp-Ct)

• D = the diffusion constant

• K = the lipid-water partition coefficient

• A = the surface area of the membrane

• h = the thickness of the membrane

Hydrostatic pressureHydrostatic pressure

Figure !

Role of DistributionRole of DistributionPharmacological action of a drug depends upon its concentration at the site of action

So that,

Distribution plays a significant role in the:

Onset,

Intensity, &

Duration of action.

UniformUniformity of Dity of Drugrug DistributionDistribution

Distribution of a drug is not Uniform throughout the body because different

tissues receive the drug from plasma at different rates & to different extents.

PPatternsatterns of Drug D of Drug Distributionistribution

1.The drug may remain largely within the vascular system.

Ex: Plasma substitutes such as dextran & drugs which are strongly bound to plasma protein

PPatternsatterns of Drug D of Drug Distributionistribution

2.Some are uniformly distributed throughout the body water.

Ex: low MW water soluble compounds (EtOH) & a few sulfonamides

PPatternsatterns of Drug D of Drug Distributionistribution

3.A few drugs are concentrated specifically in one or more tissues that may or may not be the site of action.

Ex: Iodine (in the thyroid gland), chloroquine (in the liver even at conc 1000 times those present in plasma), tetracycline (irreversibly bound to bone & developing teeth) & highly lipid soluble compounds (distribute into fat tissue)

PPatternsatterns of Drug D of Drug Distributionistribution

4.Most drugs exhibit a non-uniform distribution in the body (largely determined by the ability to pass through membranes & their lipid/water solubility). The highest concentrations are often present in the kidneys, liver, & intestine.

VVolume of Distributionolume of Distribution

Apparent Vd: to quantify the distribution of a drug between plasma & the rest of the body after oral or parenteral dosing.

Called as Apparent Volume because all parts of the body equilibrated with the drug do not have equal conc.

The drug would be uniformly distributed to produce the observed blood conc.

Factors Related with the Factors Related with the Differences Differences ofof Drug Distribution Drug Distribution

1. Tissue Permeability of the Druga. Physiochemical Properties of the drug

eg. MW, pKa & o/w Partition coefficient.

b. Physiological Barriers to Diffusion of

Drugs.

2. Organ/Tissue Size & Perfusion Rate

Factors Related with the Factors Related with the Differences Differences ofof Drug Distribution Drug Distribution

3. Binding of Drugs to Tissue Component

(Blood components & Extravascular

Tissue Proteins)

4. Miscellaneous Factors Age, Pregnancy, Obesity, Diet, Disease

states, & DI.

Tissue Permeability of the Tissue Permeability of the DrugsDrugs

Depends Upon: 1. Rate of Tissue Permeability

2. Rate of Blood Perfusion.

The Rate of The Rate of TTissue issue PPermeabilityermeability

Depends upon:

1. Physicochemical nature of the drug

2. Physiological barriers that restrict the

diffusion of drug into tissues.

Physiochemical Properties that Physiochemical Properties that IInfluence nfluence DDrug rug DDistributionistribution

MW

pKa

o/w Partition coefficient.

Diffusion of Drug MoleculeDiffusion of Drug Molecule

• Drugs having MW <400D easily cross the capillary membrane to diffuse into the extracellular interstitial fluids.

• Penetration of drug from the Extracellular Fluid (ECF) is a function of MW & ionization

Diffusion Related with MW & Diffusion Related with MW & IonizationIonization

* Molecular Size:

Small ions of size <50D enter the cell through aqueous filled channels where as larger size ions are restricted unless a specialized transport system exists for them.

* Ionisation

A drug that remains unionized at pH values of blood & ECF can permeate the cells more rapidly.

Blood & ECF pH normally remains constant at 7.4, unless altered in conditions like systemic alkalosis/acidosis

LipophilicityLipophilicity

Only unionized drugs that are lipophilic rapidly crosses the cell membrane

e.g. Thiopental, a lipophilic drug, largely unionized at blood & ECF pH readily diffuses the brain where as Penicillins which are polar & ionized at plasma pH do not cross BBB.

PENETRATION OF DRUGS PENETRATION OF DRUGS THROUGH BTHROUGH BBBBB

• A stealth of endothelial cells lining the capillaries.• It has tight junctions & lack large intra cellular pores.• Further, neural tissue covers the capillaries.• Together, they constitute the BBB• Astrocytes: Special cells/elements of supporting tissue

are found at the base of endothelial membrane.• The BBB is a separation of circulating blood & CSF

maintained by the choroid plexus in the CNS.

BBBBBB

• BBB is a lipoidal barrier

• It allows only the drugs having high o/w partition coefficient to diffuse passively where as moderately lipid soluble & partially ionized molecules penetrate at a slow rate.

BBBBBB

• Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria ) & large or hydrophillic molecules into the CSF, while allowing the diffusion of small hydrophobic molecules (O2, CO2,

hormones).Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins.

Various Various AApproaches to pproaches to PPromote romote CCrossing BBBrossing BBB

• Use of permeation enhancers: DMSO.

• Osmotic disruption of the BBB by infusing internal carotid artery with mannitol.

• Use of Dihydropyridine Redox system as drug carriers to the brain (the lipid soluble dihydropyridine is linked as a carrier to the polar drug to form a prodrug that rapidly crosses the BBB )

PENETRATION OF DRUGS THROUGHPENETRATION OF DRUGS THROUGH PLACENTAL BARRIER PLACENTAL BARRIER

• Placenta is the membrane separating fetal blood from the maternal blood.

• It is made up of fetal trophoblast basement membrane the endothelium.

• Mean thickness in early pregnancy is (25 µm) which reduces to (2µm) at full term.

RedistributionRedistribution

Highly lipid soluble drugs when given by i.v. or by inhalation initially get distributed to organs with high blood flow, e.g. brain, heart, kidney etc.

Later, less vascular but more bulky tissues (muscles, fat) take up the drug & Cp falls & drug is withdrawn from these sites.

RedistributionRedistribution

If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of the drug action

Greater the lipid solubility of the drug, faster is its redistribution.

RedistributionRedistribution

If the site of action of the drug was in one of the highly perfused organs, redistribution results in termination of the drug action.

Greater the lipid solubility of the drug, faster is its redistribution.

Drug Distribution & tDrug Distribution & t1/2el1/2el

• Drug elimination is mainly governed by renal & other metabolic processes

• Extensive drug distribution has the effect of diluting in a large volume, harder for the kidney to filter by GF

• t1/2 el is prolonged if Cl is constant & Vd is increased

• t1/2 el = 0.693 Vd/Cl

Clinical ExamplesClinical Examples

Large Vd & long t1/2el

• Dirithromycin is extensively distributed in the tissues resulting in a large SS Vd of ± 800L. t1/2el in human ± 44h, large total body Cl 226-1040 mL/min, & given s.i.d. Small Cl generally leads to a longer t1/2el. In this case, Cl is large but t1/2el is longer because of the large Vd.

Clinical ExamplesClinical Examples

Small Vd & a long t1/2el

• Tenoxicam, is a NSAID • 99% bound to plasma protein, t1/2el of 67h• Low lipophilicity & highly ionized• Very polar, drug penetrates membranes slowly• Synofial fluid peak level only 1/3 plasma, occurs

20h later than plasma• Drug poorly distributed to body tissues, Vd 9.6L• In this case: t1/2el is long because the plasma

tenoxicam cl is so small that dominates

Drug AccumulationDrug Accumulation

Depend upon:

Blood flow

Affinity of the drug for the tissue

Processes of Drug AccumulationProcesses of Drug Accumulation

• Affinity of the drug for the tissue

• Concentrated drug in the adipose tissue

• Binding of drug to proteins or other macromolecules in tissue

• Drug is irreversible bound into a particular tissue

Affinity of Affinity of TThe he DDrug for rug for TThe he TTissue issue

• Uptake of the drug into the tissue is generally controlled by the difussional barrier of the capillary membrane & other cell membrane

• Brain is well perfused with blood, but many drugs with good aqueous solubility have high kidney, liver, & lung concentration, & yet little brain drug concentration.

Concentrated Concentrated DDrug in rug in TThe he AAdipose dipose TTissueissue

• Drug uptake into a tissue is generally reversible

• Drugs with a high lipid/water partition coefficient are very fat soluble & tend to accumulate in adipose tissue.

• Because of the extraction of drug out of the tissue is so slow.

• Drug may remain for days

Concentrated Concentrated DDrug in rug in TThe he AAdipose dipose TTissue issue

• Adipose tissue is poorly perfused with blood, accumulation is slow

• Once the drug is concentrated in fat tissue, removal from fat may also be slow

• DDT is highly lipid soluble & remains in fat tissue for years!

Binding of Binding of DDrug to rug to PProteins or roteins or OOther ther MMacromoleculesacromolecules

• Digoxin is highly bound to proteins in cardiac tissues, large Vd 440L & long t1/2el 40h

• Some drugs may complex with melanin in the skin & eye (long term phenotiazine)

• Tetra forms an insoluble chelate with Ca

• Amphetamine is actively transported into adrenergic tissue

Drug is Drug is IIrreversible rreversible BBound ound IInto a nto a PParticular articular TTissueissue

• Drug/reactive intermediate metabolite become covalently bound to a macromolecule within the cell

• Many purine & pyrimidine used in cancer therapy are incorporated into nucleic acids, causing destruction of the cell

DDistribution & Pharmacodynamicistribution & Pharmacodynamic

• Onset of drug action depends upon the rate of unbound drug that reaches the receptor at a MEC to produce a PD response

• Onset time is often dependent upon the rate of drug uptake & distribution to the receptor site

• The intensity of a drug action depends upon the total drug concentration of the receptor site & the number of receptor occupied by drug

Effect of Binding on Effect of Binding on VVdd

• Extend of protein binding in plasma or tissue will affect Vd

• Drugs highly bound to plasma proteins will have a low fraction of free drug in plasma water, harder to diffuse, & less extensively distributed to tissues

• Drugs with low plasma protein binding have greater unbound fraction, easier diffusion & greater Vd

Protein Binding Protein Binding

Protein BindingProtein Binding

Many drugs interact with:

• Plasma Proteins

• Tissue Proteins

• Macromolecules: melanin, DNA

To form a macromolecule complex

Drug-Protein BindingDrug-Protein Binding

Process:

Reversible

Irreversible

ReversibleReversible

Weaker chemical bonds:

Hydrogen bond

van der Waals forces

IrreversibleIrreversible

Strongly by covalent chemical bonding

• Toxicity for a long time period (chemical carcinogenic) or

• Short time period (reactive chemical intermediates)

• Ex: PCT, reactive metabolite intermediate interact with liver proteins

Plasma Proteins Plasma Proteins

Albumin

Acid glycoprotein

Lipoproteins

Studying Protein BindingStudying Protein Binding

• Equilibrium dialysis • Dynamic dialysis • Diafiltration • Ultrafiltration• Gel chromatography • Spectrophotometry • Electrophoresis • Optical rotary dispersion & circulatory dichroism

Important Factors in Binding Important Factors in Binding

1. The drug

2. The protein

3. The affinity between drug & protein

4. Drug interaction

5. The pathophysiologic condition of the

patient

1. The drug1. The drug

• Physicochemical properties of the drug

• Total concentration of the drug in the body

2. The protein2. The protein

1. Quantity of protein available for drug-protein binding

2. Quality of physicochemical nature of the protein synthesized

3. Affinity 3. Affinity BBetween etween DDrug & rug & PProteinrotein

Includes the magnitude of the association constant

4. Drug 4. Drug IInteractionnteraction

• Competition for the drug by other substances at a protein-binding site

• Alteration of the protein by a substance that modifies the affinity of the drug for the protein.

• Ex: aspirin acetylates lysine residues of albumin

5. Pathophysiologic Condition5. Pathophysiologic Condition

Example:

Drug-protein binding may be reduced in uremic patients & in patients with hepatic

disease

REFERENCESREFERENCES

• Shargel, Wu-Pong & Yu, 2004.

• Rani & Hiremath, 2000.

• Brahmankar & Jaiswal, 2008.

• Gibaldi, 1982.