DISTRIBUTION

PHARMACOKINETICPHARMACOKINETICSS

DISTRIBUTIONDISTRIBUTION

Definition:

“Process where by an absorbed chemical moves away from the site of absorption to other areas of the body”.

•Following absorption (skin, lung, or gastrointestinal tract) or systemic administration (IV, IP, IM) into the bloodstream, a drug distributes into interstitial and intracellular fluids.

•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.

•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 fat is slower.

Distribution • determines the transport ofdrugs to their site of action, to other sites, andto the organs of metabolism and excretion.

•Not uniform;

Difference in perfusion rates.

Penetrate - capillary endothelium.

Diffuse across the cell membrane.

DISTRIBUTION• Distribution is the dispersion of the drug among the various organs or

compartments within the body.

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

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

• Vd is the volume (Litre/kg) into which the drug appears to distribute and it is calculated from the dosage (kg) and the concentration 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

blood level 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

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 anyone’s 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 cross

biological 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 estimate the amount of antidote to be given.

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

Volume of Distribution

• Vd is helpful in the context of drug monitoring.• Predicts whether the practice of drug

measurement in blood will have any clinical value.

• Psychotropic drugs such as tranquilizers, antidepressants, antipsychotics, mood-altering agents, etc., create their effects by binding at sites within the central nervous system.

Volume of Distribution

• An abstract concept

• Gives information on HOW the drug is distributed in the body

• Used to calculate a loading dose

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.• VD is a theoretical Volume and determines the loading dose.• Clearance is a constant and determines the maintenance dose.• 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 CCombining the two, CLT C = kel C Vd and simplifying gives: CLT = kel Vd

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

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.

The factors determinining Distribution/ tissue permeability of a drug:

The physico-chemical properties of the drug, Binding to plasma and tissue proteins,

Blood flow

Special compartments and barriers,

Disease states, etc.

I. Physicochemical Properties of the Drug:

Drugs molecular weight (< 500 to 600 Da) easily cross 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

•Water-soluble molecules and ions of size below 50 daltons enter the cell through aqueous filled channels, whereas those of larger size are restricted 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 the intracellular fluids (pH 7.0) and concentrate there.

•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) of cattle 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.

Transportation of Drugs:

•Drugs are transported in the circulating blood in 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.

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).

•The plasma protein binding of drugs is usually reversible (weak chemical bonds); covalent binding of reactive drugs such as alkylating agents occurs occasionally.

•The binding of individual drugs ranges from very little (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.

•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

Protein- bounddrug

Protein- bounddrug

Free drugFree drug

TissuePlasma

The free drug concentration gradient drives transport across the membrane.

•A large variety of drugs ranging from weak acids, neutral compounds, and weak bases bind to 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.

Different drugs binding to different proteins

Binding sites for acidic agents AlbuminsBinding sites for acidic agents AlbuminsEx- Bilirubin, Bile acids, Fatty acids, Vitamin C, Salicylates, Sulfonamides, Barbiturates,Probenecid, Phenylbutazone ,Penicilins, Tetracyclines etc

Binding sites for basic drugs Binding sites for basic drugs Globulins GlobulinsEx- Adenosine, Quinacrine, Quinine, Streptomycin, Chloramphenicol, Digitoxin, Ouabain, Coumarin

• 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).

•The albumin can bind several compounds having varied structures, some substances even to 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)

II. Binding to b) Tissue Proteins:

•Many drugs accumulate in tissues at higher concentrations 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).

•Important in distribution from two viewpoints:

Firstly, it increases the apparent volume of distribution (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.

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).

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.

• 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 in displacement of warfarin from its binding site.

•Warfarin has high plasma protein binding of about 99% (free drug concentration -1%), shows a small volume of distribution (remains confined to 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.

Fat As a Reservoir:

•Many lipid-soluble drugs are stored by physical solution 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

Bone:

•The tetracycline antibiotics (and other divalent metal-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.

Blood Flow and Organ Size:

•The rate of blood flow to tissue capillaries varies 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 volume of the tissue).

•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: BLOOD BRAIN BARRIER and BLOOD CSF BARRIER

Central Nervous System and Cerebrospinal Fluid:

• The capillary endothelial cells in brain have 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).

•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 brain•More 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 to the brain•e.g: second-generation antihistamines, -loratidine, achieve far lower brain concentrations than do agents such as diphenhydramine and thus are non sedating.

•Another important factor in the functional blood-brain barrier involves membrane transporters that are efflux carriers present in the brain capillary endothelial cell and 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 to the tissue expressing.

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-carrier mediated 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

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.

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 polar antibiotics like penicillin-G, which do not normally cross it, gain access to the brain.

In hypoalbuminaemia, plasma protein binding of drugs may be reduced and high concentration of free drugs may be attained.

In congestive heart failure or shock the perfusion rate to the entire body decreases, which affect distribution of drugs.

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 drug that acts on the brain or cardiovascular system is administered rapidly by intravenous injection or by inhalation.

Example:

Use of the IV anesthetic thiopental, a highly lipid-soluble drug. Because blood flow to the brain is so high, the drug reaches its maximal concentration in brain within a minute of its intravenous injection.

After injection is concluded, the plasma concentration falls as thiopental diffuses into other tissues, such as muscle.

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