DISTRIBUTION OF DRUG Dr. Muslim Suardi Faculty of Pharmacy University of Andalas 2009

Distribution of Drug After absorption or Injected intravenously Heart Bloodstream

Introduction 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 C p. 1.Distribution: Reversible transfer of a drug between compartments. 2.Elimination: Irreversible loss of drug from the body. It comprises of biotrans- formation & excretion.

Distribution of Drug Involves reversible transfer of a drug between compartments. Drug molecules are distributed is throughout the body by systemic circulation

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

Drug Distribution Reversible Transfer of a Drug between: Blood Extra Vascular Fluids Tissues of the body (Fat, muscle, & brain tissue)

Distribution Process Distribution is a Passive Process Driving force is the concentration gradient between the blood & extravascular tissues

Drug in Systemic Circulation Unbound Bound

Diffusion of Drug Diffusion of unbound drug until equilibrium is established.

Distribution 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 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 Affecting Drug Distribution Rate of distribution Membrane permeability Blood perfusion Extent of Distribution Lipid Solubility pH - pKa Plasma protein binding Intracellular binding

Circulatory 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 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 Molecules Across Cell Membrane 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 Process Passive diffusion (mainly) Hydrostatic pressure

Passive Diffusion 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

Diffusion Diffusion of unbound drug until equilibrium is established.

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 pressure Figure !

Role of Distribution Pharmacological 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.

Uniformity of Drug Distribution Distribution of a drug is not Uniform throughout the body because different tissues receive the drug from plasma at different rates & to different extents.

Patterns of Drug Distribution 1.The drug may remain largely within the vascular system. Ex: Plasma substitutes such as dextran & drugs which are strongly bound to plasma protein

Patterns of Drug Distribution 2.Some are uniformly distributed throughout the body water. Ex: low MW water soluble compounds (EtOH) & a few sulfonamides

Patterns of Drug Distribution 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)

Patterns of Drug Distribution 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.

Volume 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 Differences of Drug Distribution 1. Tissue Permeability of the Drug a. 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 Differences of 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 Drugs Depends Upon: 1.Rate of Tissue Permeability 2.Rate of Blood Perfusion.

The Rate of Tissue Permeability Depends upon: 1. Physicochemical nature of the drug 2. Physiological barriers that restrict the diffusion of drug into tissues.

Physiochemical Properties that Influence Drug Distribution Physiochemical Properties that Influence Drug Distribution MW pKa o/w Partition coefficient.

Diffusion 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 & Ionization * 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

Lipophilicity 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 THROUGH BBB 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.

BBB 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.

BBB 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 (O 2, CO 2, hormones). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins.

Various Approaches to Promote Crossing 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 THROUGH 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.

Redistribution 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.

Redistribution 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.

Redistribution 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 & t 1/2el 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 t 1/2 el is prolonged if Cl is constant & V d is increased t 1/2 el = V d /C l

Clinical Examples Large V d & long t 1/2el Dirithromycin is extensively distributed in the tissues resulting in a large SS Vd of ± 800L. t 1/2el in human ± 44h, large total body C l mL/min, & given s.i.d. Small C l generally leads to a longer t 1/2el. In this case, C l is large but t 1/2el is longer because of the large Vd.

Clinical Examples Small V d & a long t 1/2el Tenoxicam, is a NSAID 99% bound to plasma protein, t 1/2el 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: t 1/2el is long because the plasma tenoxicam cl is so small that dominates

Drug Accumulation Depend upon: Blood flow Affinity of the drug for the tissue

Processes 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 The Drug for The Tissue 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 Drug in The Adipose Tissue 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 Drug in The Adipose Tissue 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 Drug to Proteins or Other Macromolecules Digoxin is highly bound to proteins in cardiac tissues, large V d 440L & long t 1/2el 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 Irreversible Bound Into a Particular Tissue 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

Distribution & 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 V d Extend of protein binding in plasma or tissue will affect V d 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 V d

Protein Binding

Many drugs interact with: Plasma Proteins Tissue Proteins Macromolecules: melanin, DNA To form a macromolecule complex

Drug-Protein Binding Process: Reversible Irreversible

Reversible Weaker chemical bonds: Hydrogen bond van der Waals forces

Irreversible 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 Albumin Acid glycoprotein Lipoproteins

Studying Protein Binding Equilibrium dialysis Dynamic dialysis Diafiltration Ultrafiltration Gel chromatography Spectrophotometry Electrophoresis Optical rotary dispersion & circulatory dichroism

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 drug Physicochemical properties of the drug Total concentration of the drug in the body

2. The protein 1.Quantity of protein available for drug- protein binding 2.Quality of physicochemical nature of the protein synthesized

3. Affinity Between Drug & Protein Includes the magnitude of the association constant

4. Drug Interaction 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 Condition Example: Drug-protein binding may be reduced in uremic patients & in patients with hepatic disease

REFERENCES Shargel, Wu-Pong & Yu, Rani & Hiremath, Brahmankar & Jaiswal, Gibaldi, 1982.