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    General Rules1. Get a mental picture of what's going on "inside".(Think about anatomy and histology in terms of "how things work.")2. Drugs MUST have some ability to dissolve in WATER to move around (be absorbed, reach sites of action). In almost all cases

    drugs must also have a certain degree of lipid solubility to move around (leave and enter capillaries, enter and leave cells).Solubility is a preference not an absolute. "Water Soluble", "Lipid Soluble"

    3. Perspective limits what you can appreciate and leads to what may seem like strange statements:o We can only sample from the blood stream. (just a fact)o What we describe is about the entire MASS of drug administered. We generally talk about a "fraction" of the drug

    dose that does X (e.g., 60% is eliminated in urine) Individual molecules are "on their own."o Drug is not "in the body" until it is in the blood stream.A molecule of drug that has just reached portal circulation from

    the gi tract may or may not have been absorbed yet. A molecule of drug that reaches the portal circulation via the

    systemic circulation HAS been absorbed.4. Pharmacokinetics needs to be understood as a WHOLE. You should expect that SOME parts don't make sense until you've

    seen ALL the parts.5. Understand Equillibrium:

    o Drug effects are USUALLY proportional (though not always linear) to drug concentration at the site of action.o Drug concentrations in the blood stream (measured in either serum or plasma) are USUALLY proportional (and

    usually linear) to drug concentrations at the site of action.o Drug concentration in the blood stream is ALMOST ALWAYS an excellent predictor of drug action (either efficacy or

    toxicity) even though they may not be identical to the concentration in the target tissue.6. Pharmacokinetics are the consequence of physiologic processes (that may or may not be altered by disease).7. "Species differences in pharmacokinetics are the PRIMARY difference between Veterinary pharmacology and Human

    pharmacology". Disease-induced differences are the PRIMARY difference between basic and clinical pharmacology.Do you understand proportional? linear? equillibrium?

    Administration Routes

    General Principles

    Drugs dissolve in body fluid (water).Drugs enter the circulatory system by moving from one fluid "place" to another (often with the fluid, sometimes not).Drugs must enter the circulatory system before they can be distributed to sites of action.(Drugs for enteric effects and topical effects are an obvious exception.)Therefore, drugs are not IN the body until they are IN the bloodstream.

    Oral Administration

    Advantages

    Convenient, cheap, no need for sterilization, variety of dose forms

    (fast release tablets, capsules, enteric coated, layered tablets, slow release, suspensions, mixtures)

    You can get the dose back if you move fast enough.

    DisadvantagesVariability due to physiology, feeding, disease, etc.Intractable patientsFirst-pass effectEfficiently metabolized drugs eliminatedby the liver before they reach the systemic circulation.

    Table 1. Location of processes involved in the absorption of oral drugs.

    Process Primary Location Secondary Location(s)

    Tablets disintegrate (a suspension forms) Stomach Duodenum for enteric coated forms

    Drug dissolves from suspension Stomach DuodenumDrug in lipid suspension may be picked up by lacteals (absorption) Duodenum, jejunum, ileum

    Drug in solution crosses mucosa (absorption) Duodenum, jejunum Stomach, Ileum, colon

    Patient and Pharmaceutical Factors

    Pill compression, coatings, suspending agents, etc.GI transit time (too slow or too fast), inflammation, malabsorption syndromesRegional differences

    Stomach - most species (Abomasum - ruminants, C3- camelids)mechanical preparation"flat" absorptive surfacepH extremeRumenoreticulum (C1& C2- camelids)

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    stratified squamous epitheliumpH varies with dietmetabolism by bacterial florasignificant volume of fluid compared to body waterSmall Intestine (all species)large absorptive surfacespecialized absorptive functionsrelatively neutral pHColon/Rectum (all species)accessiblelarge absorptive surface

    Intramuscular Administration

    AdvantagesMORE CONSISTENT absorption vs oral or sub-cutaneousCertainty of administrationDepot or sustained effect possible (procaine penicillin G, methylprednisolone acetate, desoxycorticosterone pivalate)IM is a viable route for unconscious, vomiting or fractious patients; last resort for dehydrated patients.MOST of the time, IM = IV for efficacy / potencyDisadvantagesMore difficult for owners (small patients)PainMuscle DamageDose cannot be recovered.Injectable dose forms

    Drug Vehicle Dose Form

    Water Sol Water Sol Aqueous Solution

    Water Sol Lipid Sol Suspension

    Lipid Sol Water Sol Suspension

    Lipid Sol Lipid Sol Lipid Solution

    Process

    1. Drug in suspension or lipid solution dissolves in tissue fluid (takes time, may slow absorption)2. Drug in aqueous solution only has to MIX with the tissue fluid (immediately available for absorption).3. Drug in tissue fluid solution diffuses into capillaries4. Drug (in solution) in capillaries is carried to circulatory system.

    ANY of these processes can be "rate limiting" for absorption. (Rate limiting - if multiple steps must occur, the SLOWEST process

    controls the overall rate).

    Bolus injection roughly sphericalaqueous solution mixes with tissue fluid for rapid absorption. The drug is already dissolved in "water", so dissolution in tissue fluid is notrate-limiting. Entry of drug into circulatory system limited (only) by rate of blood flow to the tissue.

    blood flow varies by body region/muscle group, so exercise may affect absorption rate

    lipid soluble vehicle The bolus remains relatively spherical. Lipid vehicle must "degrade" or dissolve very slowly. Mixing and dissolutionin tissue fluid occurs from surface of bolus, so entry of drug into circulatory system limited by rate of drug "dissolution". (Movement fromthe "bolus" to the tissue fluid).

    Occasionally, vehicle may be absorbed more rapidly than drug. Then the drug "falls" out of solution in the tissue and dissolves very

    slowly.

    Produces tissue residuesReduces effectPatient and Pharmaceutical FactorsDrug and vehicle solubility

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    pH extremesRegional blood flow variability

    Subcutaneous Administration

    Advantages

    Can be given by the owner (small patients)Vasoconstrictor can be added to prolong effect at site of interestDisadvantagesVariability

    ProcessMuch like intramuscular (though the architecture of the tissue is much different)Patient and Pharmaceutical FactorsMore autonomic control over blood flow (than muscle)dehydration, cold, stress, DECREASE blood flow heat INCREASES blood flow< /p>

    Topical

    Advantages

    IF FOR systemic therapy - easy painless application (e.g., mass medication of cattle)IF FOR skin therapy - reduced systemic effects / enhanced skin effectsDisadvantagesPatients groom themselves (topically applied, orally absorbed)Toxic skin reactions

    Variable blood flow to skinCOMPLEX relationship between drug, vehicle, skin physiology. IF FOR systemic effect DO NOT assume absorption will happen.Studies indicate everything from "pretty good" to "zero" with the same preparation.ProcessDiffusion through stratified epithelium"Passage" through adnexal structuresPatient and Pharmaceutical FactorsLipid solubility and molecule sizeSkin hydration and abrasion

    Area of applicationAmbient and patient temperatureBe suspicious of topical formulations from compounding pharmacies.Some work, some don't. SEE:Hoffman SB, Yoder AR,Trepanier LA. Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats. J Vet Pharmacol Ther.2002 Jun;25(3):189-93.Vehicle effects"like" vehicles retain drug on skin surface

    (e.g., aqueous drug in aqueous vehicle, lipid drug in lipid vehicle)

    drugs in "unlike" vehicles leave the vehicle to move to skin

    (e.g, aqueous drug in lipid suspension, lipid drug in aqueous suspension)

    Intraperitoneal

    Advantages

    Larger absorptive surface area than IM / SubcutaneousDisadvantagesDrugs or vehicles may cause peritonitisDamage to organs by needlesInjection into organsProcessSimilar to subcutaneousGreater blood flowLess flow regulationPatient and Pharmaceutical FactorsGenerally restricted to laboratory animals

    Intrathecal

    Advantages

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    Direct delivery to site of actionDisadvantagesDifficult dose calculation

    CSF volume is not proportional to body weight

    Toxicity likely, and toxicity may be unusualIntroduce infection into a VERY bad location.Process

    Absorption is usually by diffusion and very slow

    Intra-articular

    Advantages

    Direct delivery to site of action. High concentrations can be produced in the joint.DisadvantagesIt may be difficult to hit the joint space depending on the species (size of joint space).Difficult dose calculation

    Joint space volume depends on disease

    Recommended doses tend to be larger than necessary.

    Irritation of joint surfaces/capsule (chemical effects, biochemical/physiologic effects.)Introduce infection. (PSGAG - Adequan - injections now generally get "antimicrobial chaser".)Joint "flushes" don't count.Process

    Absorption from the site to systemic circulation is variable but often quite fast. Systemic concentrations of the drug may be produced.Effects in joint may not persist. (Drug and dose form dependent)

    "Regional" (Intra-arterial, Interosseous, Intravenous with tournequet)

    Advantages

    High concentrations of drug delivered to tissues increases desired effect (e.g., antibacterial action) for similar systemic exposure(compared to traditional administration modalities). These techniques appear to produce extremely high concentrations "pointed at"(this is not really targeting) the tissue of interest. Used primarily for anti-tumor therapy and infectious disease therapy when bloodsupply is questionable. Evidence documenting clinical outcomes is scarce.DisadvantagesDose calculation is best guess. Dosing is still really systemic. Approach to tourniquet use varies.

    Arteries are logical injection sites, difficult to canulate. Intra-arterial lines difficult to insert/maintain. Veins are flowing the wrong way,tournequets required. Injection into bone medullary cavities?Limited number of efficacy studies (especially in animals)ProcessProduce AND SUSTAIN high blood-to-tissue gradient to increase tissue concentrations of drug. Requires sustained infusion orapplication of tourniquet following bolus dosing.Varies FROM: systemic dose given by regional vein after tournequet appl ication. Retain tournequet for extended time period (1/2 hour?more?) TO: intraarterial injection of supplemental dose calculated on the size of the region served by the artery TO: supplemental doseor full systemic dose in bone marrow cavityPatient and Pharmaceutical FactorsRather expensive procedure; GO GET TRAINING from somebody who uses this routinely.

    Per rectum

    Advantages

    Access to GI abosption in unconscious or vomiting patientsDrug can be recovered before absorption is completeDisadvantages

    Animals may not willingly retain the drugProcess

    As for oral without mechanical preparation by stomach

    Physical and Physiologic "spaces"(Figure)

    Vascular space = plasma / plasma water + RBCs (lots) +WBCs (a few)

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    Don't forget the intracellular space inside the vascular space...

    Size~ 7% of body weightEquilibriabetween water and various plasma / serum proteinsbetween ionized and unionized drugbetween plasma and cellsDistribution in 10 to 30 minutes (mixing)Tissue space (intracellular fluid / cells)

    SizeThe rest (excepting structural protein, bone matrix)Equilibriabetween water and various tissue proteinsbetween ionized and unionized drugbetween water and cellsDistribution in minutes to hours/daysExtracellular Space - exists in both vascular and tissue spacesSize~ 15 - 20% of body weightincludes extracellular fluid in bloodstream (plasma)Equilibriabetween water and proteinsbetween ionized and unionized drugDistribution in 30 minutes to 1.5 hours

    Intracellular space - exists in both vascular and tissue spacesSize~ 35 - 45% of body weightEquilibriabetween ionized and unionized drugintracellular pH different (lower) than extracellularDistribution in 30 minutes to 12+ hoursReserved spacesSpecial barriers between plasma and tissue fluidCSFaqueous humorprostatic fluidDistribution in minutes to neverMost dosing situations -> irrelevantImportant if the disease is in the reserved space.

    Movement between spaces

    Vascular space (extracellular) to tissue (extracellular) spaceTranscytoticEndothelial junctions with inflammationDiffusion through endothelial cell membranesCarried in cells or on proteins in very special circumstancesExtracellular space (of tissue) to intracellular space (of tissue)Diffusion through lipid bilayer of cells

    Active uptake by cells (few drugs, few cell types)Vascular extracellular space to vascular intracellular space (drugs can move into RBCs and WBCs)Diffusion through lipid bilayer of cellsWBCs may actively acquire certain drugs

    Dif fus ion l imited dist r ibut ion

    Diffusion is usually slow (relative to mixing and distribution within vascular system)Tissue distribution of the drug controlled by the ability of the drug to diffuse into the tissue

    Blood f low l imited dist r ibut ion

    Diffusion can be VERY rapidTissue distribution of the drug controlled by the rate of drug delivery to the tissue (total mg/minute) which is controlled by blood flow /gram of tissueBrain and liver concentration rise faster than muscle or fat

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    Enterohepatic circulation

    How does it work?Drug or it's Phase II conjugate excreted in bileDrug reabsorbed or Conjugate cleaved by bacteria and drug reabsorbedWhat does it mean?Volume of distribution of the drug is higherElimination rate for drug is lower in spite of efficient hepatic metabolism / secretionWhy do you care?

    Interrupt to improve drug elimination

    Insecticide poisonings, phenobarbital overdoses, etc.

    Figure 1. Enterohepatic circulation

    Mammary excretion

    How does it work?

    Non-ionic Diffusion (lipid solubility and size dependence)Inflammation reduces barriers to penetration (masititis)Ion trappingnormal milk pH = 6.6 (slightly acidic versus blood).

    Mastitic milk pH is slightly higherWhy do you care?May affect treatment of some bacterial infections of the mammary glandNursing animals may be exposed to toxic concentrations of drug in the milk.

    Salivary excretion

    How does it work?Non-ionic diffusion into salivary secretionsDrug in saliva passes into GI tractWhat does it mean?RuminantsRecycle certain drugs like enteroheptic circulation (prolonged elimination)Trap certain drugs in the rumen pH dependent (enhanced elimination)Non-ruminantsLittle effect on elimination possible

    Drug Elimination

    Biotransformation

    Conversion of a drug entity to a metabolite

    Usually inactivates the druggenerally reduces drug activityMAY activate the drugMajor route of elimination for lipid soluble and protein bound drugs (because other routes are not efficient).

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    Chemical mechanismsOxidation, hydroxylation, hydrolysis, reduction, conjugation (acetylation, glucuronidation, sulfation, etc.)Rates, clearance controlled by...Metabolic activity for a specific drugBlood flow to the organHealth of the organ and health of the circulatory systemOrgans involved

    Liver (most important for most drugs)Lungs (especially for autocoids)Kidneys

    Figure 2. Hepatic metablism, note that the ratio of drug entering the liver to

    that leaving the liver remains constant, despite the change in

    concentration. NOTE: This principle applies to all routes of elimination.

    Bil iary excret ion

    Active secretionDrugs with molecular weights > 300mostly conjugates of original drug

    Passive secretionDrugs with molecular weights < 300biliary concentrations similar to plasma water

    Renal excretion

    Overall renal elimination can be a combination of three processes:(Glomerular filtration + tubular secretion) - passive reabsorption = renal elimination

    Figure 3. Efferent blood supply of the

    nephron enters/leaves the glomerular

    tuft, then bathes the tubule/collecting

    duct before leaving the kidney. A

    PORTION of the plasma water is

    diverted into the nephron as it passes.

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    Nephron image courtesy ofBlausen

    Medical

    Nephron Animation

    Glomerular filtration (all unbound drug - in plasma water - ends up in in GF)

    passive elimination of drug dissolved in plasma waterionized and unionizedNOT protein bound drugTubular secretion (only a few drugs, even protein bound)

    energy dependent excretion by proximal kidney tubuleorganic acid and organic base pumpsincludes protein bound drugscompetition between acids or between basesPassive reabsorption (only a few drugs, small lipid soluble)drug movement from renal tubule back to blood streamlipid soluble drugsunionized drug moleculesnormal concentrating abilityPassive reabsorption can be reduced by disease (accidental) or by therapy (intentional)increases elimination rate of the drugDOES NOT WORK if reabsorption is not an important part of normal elimination

    How?high urine productionreduced tubular concentations of EVERYTHINGreduced contact time with epitheliumalter urine pHionized drug cannot be reabosrbedacids trapped in alkaline urinebases trapped in acid urinerenal elimination of aspirin can go from 2% to 30% of total elimination

    Pharmacokinetic Modeling

    Volume of Distribution

    The volume of fluid that "appears" to contain the amount of drug in the body (based on the plasma concentration).Partially determines the relationship between dose and plasma concentrationDefines the volume of fluid that must be processed by organs of eliminationRoughly describes "tissue penetration"May not equal an actual physiologic space.Equation(s)

    One compartment plot (Figure)

    Cp0 is the plasma concentration at time = 0 (IV adminsitration ONLY)UnitsLiters or milliliters describing whole animalLiters/kg or milliliters/kg

    Table 2. Representative (theoretical) volumes of distribution.

    Scenario Physiologic Space Volume of distribution

    Drug distributed only to plasmawater

    Blood volume = 7% of body weightPlasma water = 55% of bloodvolume

    0.0385 liters/kg

    Drug distributed evenly inextracellular fluid only

    Extracellular fluid volume = 25% ofbody weight

    0.25 liters/kg

    Drug distributed evenly extracellular+ intracellular fluid only

    Intracellular fluid volume = 40% ofbody weight

    0.65 liters/kg

    http://www.blausen.com/http://www.blausen.com/http://www.blausen.com/http://www.blausen.com/http://cpharm.vetmed.vt.edu/VM8314/NephronMovie.swfhttp://cpharm.vetmed.vt.edu/VM8314/NephronMovie.swfhttp://cpharm.vetmed.vt.edu/Images/image021.gifhttp://cpharm.vetmed.vt.edu/Images/image021.gifhttp://cpharm.vetmed.vt.edu/Images/image021.gifhttp://cpharm.vetmed.vt.edu/VM8314/NephronMovie.swfhttp://www.blausen.com/http://www.blausen.com/
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    Drug distributed evenly inextracellular fluid and concentrated3x in intracellular fluid

    Extracellular fluid volume + 3xintracellular fluid volume

    1.45 liters/kg

    Figure 4. 100 mg of a drug is added to a 10 liter fish tank

    filled with water. A sample is taken after equillibrium is

    reached. The chemical properties of the drug control its

    "attraction" to the glass.

    Figure 5. 100 mg of a drug (different drug than figure 4

    above) is added to a 10 liter fish tank filled with water. A

    sample is taken after equillibrium is reached. The

    chemical properties of the drug control its "attraction" to

    the glass.

    Clearance

    (e.g., Hepatic Clearance)

    The volume of plasma water cleared of the drug during a specified time period.Equation(s):Organ clearance is calculated by determining the flow (Q) and the efficiency of extraction

    Total body clearance (Clt) is the sum of all organ clearances

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    Experimentally we determine clearance by determining the Volume of distribution and the elimination rate constant (Figures 5-7)

    Units:Volume / unit time (l/hr, l/min, ml/hr etc) describing whole animalVolume / kilogram / unit time (l/kg/hr, ml/kg/min etc.)

    Rate constant of elimination

    The fraction of the volume of distribution cleared per unit time (or)The slope of the natural log plot of the drug concentration versus time profile(Figure)Equation(s)

    "Produced" by the relationship between the volume of distribution and the total clearance:

    Determined from the slope of the "elimination portion" of the drug concentration vs time profile (curve).

    Units/hr, /min, hr

    -1, min

    -1

    Figure 5. Determining the "pharmacokinetics" of the fish tank.

    Figure 6. Arithmetic plot of dye concentrations versus time.(lz = 0.0693 hrs-1, Vz =1 l/kg, Dose = 100 mg, T1/2 = 10 hrs, Clt =

    0.0693 l/kg/hr).

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    Multiply the concentration by the Vz (Cp X Vz) to determine the amount in the body at each time point. Subtract the amount in the bodyat one time point from the amount in the body at the PREVIOUS time point to determine the amount eliminated during the time"interval."

    Figure 7. Semi-Logarithmic plot of dye concentrations versus

    time.

    (lz = 0.0693 hrs-1, Vz =1 l/kg, Dose = 100 mg, T1/2 = 10 hrs,

    Clt = 0.0693 l/kg/hr).

    Although the amount eliminated from the body is less and less for each time interval, the FRACTION of the amount eliminated duringeach interval is constant. This is demonstrated by the semi-log plot.

    Elimination half-life

    The time for elimination of one half of the total amount in the body.Units

    Hours or minutesApplication(s)Tissue Residues

    At 5 x T1/2 97% has been eliminatedMake sure you use the longest half-life (gentamicin example)Metabolites may be more important than the drugExtremely slow absorption from injection site may be the primary cause of residues.

    Approach to steady stateSteady state exists when defined plasma concentrations (peak, average, trough) are identical following each administered dose duringchronic therapy.

    At 5 x T1/2 concentrations are 97% of steady state values no matter what the dose and interval.Digoxin, maximum effects of digoxin may appear as late as 8 days after therapy is initiatedThe relationship between dose interval and half-life determines the need for a loading dose.

    A loading dose is an initial dose of drug given to shorten the time to reach the steady-state concentrations.

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    Figure 8. Approach to steady state. The figure represents a hypothetical situation in that the dose interval equals the drughalf-life.

    Absorption rate constant

    The absorpt ion rate constant descr ibes the rate of drug m ovement (oral , IM, SC, etc. ) f rom th e dose to the circ ulatory system .Units

    /hr, /min, hr-1

    , min-1

    Appl icat ionIn combination with other factors, ka determines the time required to reach the peak concentration (Cmax) following a dose of drug andthe peak drug concentration.

    Fraction of dose absorbed (F)

    When a drug is administered by any route OTHER than IV, it is rare that the entire dose is absorbed

    OralDestroyed in GI tract, passes out in feces before it is absorbed, binds to ingesta, etc.IMHydrolysis of drug in tissue, drug binding to injection site, abcess formation, etc.UnitsEither percentage of dose or fraction of the dose (59% = 0.59)

    ApplicationThe fraction of the dose absorbed determines a drug's bioavailability (how much gets into the blood stream). Bioavailability is acommon measure used to compare two different drug formulations (tablets vs. elixir) or to compare products sold by two differentmanufacturers (trade name drugs vs. generics).

    Bioequivalence

    Two drug products are bioequivalent if the nature and extent of therapeutic and toxic effects are equal following administrationAlthough similar and related, equal bioavailability (F) does not guarantee bioequivalence.

    Figure 9. Two dose forms of the same drug are depicted.

    These two dose forms have equal bioavailability and they are

    bioequivalent.

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    Figure 10. Two dose forms of the same drug are depicted.

    These two dose forms have equal bioavailability but they

    are NOT bioequivalent.

    Pharmacokinetic Models

    Physiologic models

    Attempt to describe the actual events which control drug absorption, distribution, and eliminationDerived from measurements of drug concentrations in specific fluids (bile, portal and hepatic veins, tissue fluids, urine, etc.).Deal with an organ, a tissue or an organ systemCombined to describe functions and processes

    Mathematic models

    Attempt to accurately predict the time course of drug concentrations in one (usually blood or plasma) or two (urine as well) body

    fluids. Predictions are generally made for tissues which can be sampled from intact patients."Pharmacokinetics" on package inserts represent these kinds of model.Modeling begins with a single dose experiment:

    A dose of drug is administered, samples are taken at timed intervals after dosing, samples are analyzed for drug concentrations.Drug concentrations are then plotted and analyzed mathematically to determine the drug's c learance, the rate constant of elimination,half-life, and the volume of distribution of the drug.

    Body compartments

    DO NOT ASSUME THAT ANY REAL PHYSIOLOGIC BODY SPACE IS BEING DESCRIBED BY MATHEMATICAL MODELS.Central CompartmentBlood volumeOrgans of elimination

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    Peripheral compartment

    Muscle

    Subcutis

    Lung tissue

    Deep compartments

    Fat (poor blood supply, lipid soluble drugs)

    Kidneys (aminoglycosides)

    THE NUMBER OF COMPARTMENTS IS NOT A PHARMACOLOGICAL PROPERTY OF THE DRUG.

    N compartments represents the amount of detail available considering the "experimental conditions".

    Number of samplesSample timingObesity, starvation, dehydration, etc.Difference in rates of distribution into various tissues (2 volumes cannot be separated if individual rate constants are similar).N compartments may be arbitrarily reduced if the level of detail available is unnecessary.Most clinical monitoring reduces "truth" to a one compartment open model

    Figure 7. Linear and semi-logarithmic plots of Pharmacokinetic models. The two compartment models were generated by INCLUDING

    samples at 5, 15, 25 and 30 minutes.

    Dose Dependent Behavior

    For most drugs (99%), it is logical to assume that the relationship between the dose we give and the concentration(s) that the doseproduces in the body are linear. (We double the dose, the concentrations double, the effects double). The PHARMACOKINETICS ofthese drugs are said to be dose-independent.Occassionally, drug dosing behave differently:

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    If the pharmacokinetics of ABSORPTION change when we increase the dose (the absorption rate decreases as the doseincreases -- as would be the case for the "ball" of drug described earlier in these notes under "routes of administration"), thedrug is said to exhibit dose-dependent absorption. Doubling the dose produces less thana doubling of tissueconcentrations and effects.

    If the pharmacokinetics of ELIMINATION change when we increase the dose (clearance and the elimination rate constantdecrease as the dose increases), the drug is said to exhibit dose-dependent elimination . Doubling the doseproduces MORE thana doubling of tissue concentrations and effects.

    Although we have described pharmacokinetics as being "first-order" throughout these notes, the real absorption and eliminationbehavior of drugs obeys Michaelis-Menton kinetics. That is, first-order at "low" doses (most drugs at therapeutic doses), zero-order at

    "high" doses and mixed-order in between.Michaelis-Menton Kinetics

    Order

    Example

    First Order (The pharmacokinetics of MOST drugs is first order at therapeutic doses.)

    A fractionthe dose of drug is absorbed per unit timeA fractionof the amount of drug in the body is eliminated per unit time.Plots

    Arithmetic plots of concentration vs. time will be a curve with a positive deflection (slope becomes less negative with time).A semi-log plot will be a straight line or series of straight lines (multiple compartments).As long as elimination remains first order:There will be a half-life of eliminationIncreasing or decreasing the dose will produce a proportional increase or decrease in the plasma concentration and in drug effect.

    A steady state will be achieved for ANY rate of drug administration.

    Zero order (special dose forms, high concentrations of some drugs)

    A constant amount of drug is absorbed per unit time (or)A constant amount of drug is eliminated per unit timePlots

    Arithmetic plots of concentration vs. time will fall on a straight lineSemi-log plots have a negative deflection (slope becomes more negative with time)If elimination is zero order:

    Drug may accumulate infinitelyThere is no "half-life"

    Abbreviation Term Units Definition

    Clt Clearance, Total l/hr/kg The sum of all individual organ clearances. Usuallydetermined by plasma sampling.

    Clr Clearance, Renal l/hr/kg The clearance "performed" by the kidney.

    Clh Clearance, Hepatic l/hr/kg The clearance "performed" by the liver.

    Cmax Peak plasmaconcentration

    mg/ml (or)mg/liter

    Highest plasma concentration achieved following asingle non-intravenous dose of a drug.

    Cp Plasma concentration mg/ml (or)mg/liter

    Plasma concentration, may be folled by a subscript fortime (Cpt see Cp0 below)

    Cp0 Plasma concentration at

    time zero

    mg/ml (or)

    mg/liter

    The plasma concentration at zero time. Determined

    by extrapolating the plasma concentration versus time"curve" back to the Y (concentration) axis.

    F Fraction of doseabsorbed

    None or % Portion of a non-intravenous dose of drug thatreaches the systemic circulation.

    T1/2 Half life of elimination hrs (or)minutes

    Time required to eliminate 50% of any amount of drugfrom the body.

    Tmax Time of the peak plasmaconcentration

    hrs (or)minutes

    The time that the Cmax (above) is achieved followinga single non-intravenous dose of a drug.

    Vz Volume of distribution L/kg The volume calculated using the intercept of the "z"portion of a curve and the Y axis.

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    Equation Units Application

    hr-1

    , /hr, min-1

    , /minCalculates slope of a line for a natural log plot of plasma concentration versus

    time data.

    liters, milliliters if dose is in mg;

    liters/kg or milliliters/kg if dose

    is in mg/kg

    Extrapolate plasma concentration versus time "curve" back to the Y

    (concentration) axis. The intercept is Cp0. The dose is the intravenous bolus

    dose.

    mg or mg/kg You can calculate the amount of drug in the body at any time =t if you knowthe volume of distribution and the plasma concentration at that time Cpt.

    L/hr/kg or l/hrClearance is calculated following a pharmacokinetic experiment as the

    product of volume of distribution and elimination rate constant.

    hr-1

    , /hr, min-1

    , /min

    In the animal the elimination rate constant is the RESULT of the total body

    clearance of the drug and the volume of distribution into which the drug is

    distributed. (lz is not usually calculated this way).

    5 x T1/2hrs, min.

    Five times the elimination half-life determines:

    97% of the time to reach steady state

    The time to eliminate 97% of the drug


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