The drug may remain largely within the blood, within fatty tissue, or at a multitude of other possible locations. Vd = volume of distribution D = dose Cp = plasma level k = kg body weight
Drugs with high Vd are not present in the blood to any extent and it follows, therefore, that tests on blood specimens may give an inaccurate picture of total body burden of the drug. In other words, one must measure blood content of drug because it is impractical to measure organ content, but the drug produces symptoms depending on the organ content. In actuality, the key feature of drug monitoring from the perspective of correlation between concentration and symptoms is that an equilibrium exists between the drug at the receptor and the drug’s concentration in the blood. This equilibrium, furthermore, is more likely to exist for a drug with low Vd; drugs with this property, therefore, are good candidates for drug monitoring by measurement of blood concentration. Because the CNS is quite remote from the blood, such psychotropic agents are frequently not suitable subjects for therapeutic drug monitoring.
a list of drugs that have been recommended for therapeutic drug monitoring because studies show that the concentrations of these drugs correlate with overdose-induced symptoms. Knowing the concentration of the drug in plasma is clinically useful. Column 1 of the table shows a list of drugs for which the opposite is true. Column 1 drugs should not be monitored because the drug level is frequently unrelated to symptoms of overdose, degree of toxicity, prognosis, etc.
DISTRIBUTIONDefinition:“Process where by an absorbed chemical movesaway from the site of absorption to other areasof the body”.•Following absorption (skin, lung, orgastrointestinal tract) or systemicadministration (IV, IP, IM) into the bloodstream,a drug distributes into interstitial andintracellular 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 ofdrug distributed into tissues depends on;• Cardiac output, Regional blood flow, Capillarypermeability and tissue volume.•Well-perfused organs (liver, kidney, brain)initially receive most of the drug•Lesser perfused pnes: delivery to muscle, mostviscera, 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 flowSpecial 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 sizebelow 50 daltons enter the cell through aqueousfilled channels, whereas those of larger size arerestricted unless a specialized transport systemexists for them. •According to the pH-partition hypothesis,basic drugs present in blood (pH 7.4) readilyenter into acidic tissues and fluids, including theintracellular fluids (pH 7.0) and concentratethere.
•Conversely, acidic drugs attain highconcentrations in the relatively more alkalinebody fluids.•Example:Weak organic bases administeredparanterally diffuse passively from blood (pH7.4) into rumen fluid (pH 5.5 -6.5) of cattle andsheep, where they become trapped byionization.Similarly, weak bases tend to be accumulatein milk since the pH of milk is slightly acidic (pH6.5 to 6.8) to the blood.
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 inplasma and is pharmacologically active,diffusible, and available for metabolism andexcretion.
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 cellmembranes because of their larger size).
•The plasma protein binding of drugs is usuallyreversible (weak chemical bonds); covalentbinding 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 ratiobetween the bound and free fractions of thedrug.
•When the concentration of the free drug fallsdue to redistribution, metabolism or excretion,the free: bound ratio is maintained bydissociation of the bound form of the drug.•Thus plasma protein binding mainly serve as areservoir, which supplies free drug wheneverrequired. Free drug Protein bound drug
Plasma Tissue Protein- bound Protein- bound drug drug Free drug Free drugThe free drug concentration gradient drives transport across the membrane.
•A large variety of drugs ranging from weakacids, neutral compounds, and weak bases bindto plasma proteins.•Acidic drugs generally bind to plasma albuminand basic drugs to alfa1 acid glycoproteins;binding to other plasma proteins(e.g., lipoproteins and globulins) occurs to amuch smaller extent.
Different drugs binding to different proteins Binding 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 GlobulinsEx- Adenosine, Quinacrine, Quinine, Streptomycin,Chloramphenicol, Digitoxin, Ouabain, Coumarin
• For the majority of drugs, binding to plasmaalbumin (Mol. Wt. 65,000), which comprises>50% of the total proteins, is quantitativelymore important. •The binding of drugs to albumin may showlow capacity (one drug molecule per albuminmolecule) or high capacity (two or more drugmolecules per albumin molecule).
•The albumin can bind several compoundshaving varied structures, some substances evento a single site. Groups of drugs that bind to thesame site compete with each other for binding.•Some drugs may bind to blood componentsother than plasma proteins (e.g., phenytoin andpentobarbitone bind to haemoglobin)
II. Binding to b) Tissue Proteins:•Many drugs accumulate in tissues at higherconcentrations than those in the extracellularfluids and blood called localization.•Tissue binding of drugs (cellular constituents);Proteins, phospholipids, or nuclear proteinsand generally is reversible or some caseirreversible (covalent chemical bonding).
•Important in distribution from two viewpoints:Firstly, it increases the apparent volume ofdistribution (in contrast to plasma protein bindingwhich decreases it)Secondly it results in localisation of a drug at aspecific site in the body produce local toxicity.Examples: Aminoglycoside antibiotic gentamicin Nephroand vestibular toxicity.
Paracetamol and chloroform metabolitesbind hepatotoxicity.Tetracyclines, fluoride (infants or children)during odontogenesis results in permanentbrown-yellow discoloration of teeth.Chlorpromazine, chloroquine leadsretinopathy (Hounds breeds).
Drug displacement interactions:•Drug displacement interactions occurbetween two or more drugs that bind to sameplasma protein site.•If one drug is binding to such a site, thenadministration of second drug having higheraffinity for the same site results in- Displacement of first drug from its bindingsite.
• Generally, In many cases, the impact ofinteractions is minimal•In some instances a slight displacement of adrug will result in marked increase in itsbiological activity.Ex: Administration of phenylbutazone to apatient on warfarin therapy results indisplacement of warfarin from its binding site.
•Warfarin has high plasma protein binding ofabout 99% (free drug concentration -1%), showsa small volume of distribution (remains confinedto blood compartments) and has a narrowtherapeutic index.• If just 1% of warfarin is displaced by thephenylbutazone, the concentration of freewarfarin will be doubled (2%).•The enhanced concentration of free warfarinmay cause severe haemorrhagic episodes,which may result in lethality.
Fat As a Reservoir:•Many lipid-soluble drugs are stored by physicalsolution in the neutral fat.•In obese persons, the fat content of the bodymay be as high as 50%, and even in leanindividuals it constitutes 10% of body weight;hence fat may serve as a reservoir for lipid-solubledrugs.Ex: The highly lipid-soluble barbiturate thiopental
Bone:•The tetracycline antibiotics (and other divalentmetal-ion chelating agents) and heavy metals(Cadmium, Fluoride, lead or radium) mayaccumulate in bone and become a reservoir byadsorption onto the bone crystal surface andeventual incorporation into the crystal latticecauses toxicity.•Adsorption process for some drugs showstherapeutic advantages for the treatment ofosteoporosis.
Blood Flow and Organ Size:•The rate of blood flow to tissue capillariesvaries widely as a result of unequal distributionof cardiac output to various organs.•The drug distribution to a particular organ ortissue depends on the size of the tissue (tissuevolume) and tissue perfusion rate (volume ofblood that flows per unit time per unit volumeof the tissue).
•Highly perfuse tissues such as lungs, kidneys,liver, heart, adrenals, and brain are rapidlyequilibrated with lipid soluble drugs.•Muscle and skin are moderately perfuse, so theyequilibrate slowly with the drug present in blood.•Adipose tissues, bones and teeth being poorlyperfuse, take longer time to get distributed withthe 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 ispresent except that it is epithelial cells that are joined bytight junctions rather than endothelial cells.•The lipid solubility of the nonionized and unboundspecies of a drug -an important determinant of itsuptake by the brain•More lipophilic a drug is, the more likely it is to crossthe 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 agentssuch as diphenhydramine and thus are non sedating.
•Another important factor in the functional blood-brainbarrier involves membrane transporters that are effluxcarriers present in the brain capillary endothelial celland capable of removing a large number of chemicallydiverse drugs from the cell.Example:P-glycoprotein (P-gp, encoded by the MDR1 gene) andthe organic anion-transporting polypeptide (OATP) areexporters are to dramatically limit access of the drug tothe tissue expressing.
Placental barrier:•The maternal and foetal blood vessels are separated by a layerof trophoblastic cells that together constitute the placentalbarrier.•The characteristics generally the same as BBB.• However, restricted amounts of lipid insoluble drugs, especiallywhen present in high concentration or for long periods inmaternal blood gain access to the foetus by non-carriermediated processes.• Thus, the placental barrier is not as effective as the blood-brainbarrier and impermeability of the placental barrier to polarcompounds is relative rather than absolute.•So care must be taken while administration of all types of drugsduring pregnancy because of the uncertainty of their harmfuleffects 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 arealtered in disease states.Examples:In meningitis and encephalitis, the blood-brain barrier becomes more permeable and thepolar antibiotics like penicillin-G, which do notnormally 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 adrug usually is by metabolism and excretion•But also may result from redistribution of thedrug from its site of action into other tissues orsites.•Redistribution is a factor in terminating drugeffect primarily when a highly lipid-soluble drugthat acts on the brain or cardiovascular system isadministered rapidly by intravenous injection orby inhalation.
Example:Use of the IV anesthetic thiopental, a highlylipid-soluble drug. Because blood flow to thebrain is so high, the drug reaches its maximalconcentration in brain within a minute of itsintravenous injection.After injection is concluded, the plasmaconcentration falls as thiopental diffuses intoother tissues, such as muscle.