

Basic Kinetics Definition:
 the temporal & spatial distribution of a substance in a system
 measurement of Cp/time
 you know a graph is measuring the kinetics of a substance because time is on the Xaxis & plasma concentration (Cp) is on the Yaxis

One Compartment Model
treats the body as one homogeneous volume in which mixing is INSTANTANEOUS; Input and output are from this one volume

Two Compartment Model
 when a drug distributes unevenly in the body, specifically it might move more quickly to a certain organ or part of the body than others
 this model involves 2 distinct distribution phases
 1. initial distribution to specific areas of the body
 2. followed by equilibration of the substance throughout the entire body

What are the two main compartments of a Two Compartment Model
 Compartment 1 (central): blood (plasma) & well perfused organs (eg. liver, kidney)
 Compartment 2 (peripheral): poorly perfused tissues (eg. muscle, lean tissue, fat)

First Pass Metabolism (Presystemic Extraction)
 a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation as a result of decreased absorption mediated by the liver &/or gut wall
 four primary systems that cause the first pass effect: enzymes of the GI lumen, gut wall enzymes, bacterial enzymes, & hepatic enzymes

Extravascular
 describes a drug administered any way except intravenously
 eg. orally, transdermally, sublingually, topically, etc.

When looking at a kinetics graph, how can you tell if a drug is administered extravascularly or intravenously?
 extravascularly: a LAG TIME will be seen between the drug being administered and it showing up in the plasma; something must happen before the drug is detected in blood
 intravenously: drug concentration should be detected immediately upon administration

C_{max}
 peak plasma concentration
 the point where rates of drug absorption, distribution, & clearance are at EQUILIBRIUM
 preceded by the absorptive phase and followed by the distribution phase

T_{max}
 the time when peak concentration is reached
 (Xaxis value of Cmax data point)

AUC
 area under the plasma concentration curve
 systemic exposure to a drug

Bioavailability
 the fraction of drug absorbed systemically after administration
 drugs administered intravenously have a bioavailability of 100%
 For drugs administered via other routes (extravascular), bioavailability is more commonly less than 100%

How is bioavailability calculated?
 F
 fractional bioavailability of a drug
 to calculate F you must know the plasma concentration achieved when a drug is administered intravenously (CANNOT just use oral administration data)
 F = AUC_{oral} / AUC_{IV}
 the closer F is to 1, the greater the drug is absorbed systemically after administered extravascular

What is the main determinant of whether or not the FDA approves a GENERIC equivalent to a previously approved brand name drug?
 Bioavailability, or F value
 the generic version needs to exhibit a similar rate & extent of absorption as the original brand name drug
 AUC, C_{max} and T_{max} should all be statistically similar as well

What could cause a lower F value for a generic attempting to mimic the bioavailability of a name brand drug?
 1. poor absorption (isn't lipophilic)
 2. efflux transport (by Pglycoprotein)
 3. presystemic extraction (either by hepatic enzymes or enteric CYP3A enzymes in GI mucosa)

Why is it important to monitor the blood level of some drugs, but not others?
 because some have a narrow therapeutic range  also is different for different people
 the #s that define therapeutic ranges are population averages & not specific for individuals
 'every time a drug is given it's a mini experiment in the person it's given'

Why is the therapeutic range of antithrombotics (Heparin, Warfarin) measured differently from other drugs?
 because their serum concentration is useless, what matters is their effect on the body: whether or not they prevent blood clotting
 monitoring such drugs is pharmacodynamic, not pharmacokinetic

Volume of Distribution
 a number that gives us an idea of the POTENTIAL for a drug to distribute throughout the body
 tends to be a measure of lipophilicity*
 it's a proportionality constant that relates the amount of drug in the body to the concentration of drug in the plasma
 it's not a real number, but a hypothetical value used to describe potentials of drug distribution

Volume of Distribution Calculations for an IV Drug
 Vd = Dose [mass/concentration > volume]
 Cp
 aka the drug dose (D)
 plasma concentration (Cp)
 expressed in units of VOLUME (Liters)
 Vd: a GOOD MARKER OF DRUG LIPOPHILICITY

How would you calculate the Vd of a drug administered extravascularly instead of intravenously?
 bioavailability must be taken into account
 Vd = (Dose x F)
 Cp

What does a low Vd (volume of distribution) indicate?
a low Vd indicates that a drug isn't in a central compartment (blood stream) but ELSEWHERE in the body

How many nanograms in 1 milligram?
 10^{9} ng = 1 mg
 10^{12} ng = 1 kg

What does Vd (volume of distribution) FAIL to express?
 WHERE the drug is
 it just reflects peripheral tissue uptake

Steady State
 refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination
 is reached at a time that is 45 times a drug's halflife after regular dosing is started

Why is it useful to know the Vd of a drug?
 so the LOADING DOSE can be calculated
 this way a desired serum concentration can be achieved immediately (eg. for drugs  like antibiotics  that need to start working immediately)

Loading Dose Calculation
 D_{L} = Vd * Cp_{desired} [vol * conc > mass]
 dosage given when a drug is needed immediately because it allows therapeutic range to be reached almost right away in a patient
 loading doses are used frequently for antibiotics to combat serious bacterial infections

How is a desired plasma concentration maintained after the loading dose is given?
 by giving an additional maintenance dose
 the maintenance dose is given at a rate proportional to the elimination rate of the loading dose
 this way the amount of drug in the plasma remain constant because it's being replaced at the same rate at which it is being used up or lost (* assuming the drug exhibits firstorder elimination behavior)

Clearance Calculations
 Cl = dose rate = Q * E
 Cp_{steady state}
 units = volume/time, eg. mL/min (NO mass units)
 total volume of plasma from which drug is removed per unit time

Clearance
 the quantitative capacity for the body to remove a drug
 determined by blood flow to the organ that functions to metabolize/clear the drug from the system (Q) & the efficiency of the organ in extracting the drug from the bloodstream (E)

Whole Body Clearance
 the volume of plasma cleared of its drug content per unit of time
 for drugs that exhibit firstorder elimination, the RATE of elimination of a drug can vary as the concentration changes, but clearance will remain constant

What can be calculated if we know the clearance?
estimation of the time it takes to remove a drug from the body

What is clearance NOT?
 clearance is not the RATE of drug removal
 it's a component of it, but not the rate itself

Q
blood flow to the organ that metabolizes or clears the drug

E (Extraction Ratio)
how effectively an organ extracts the drug from the bloodstream

Other Equations for Cl (clearance)
 Cl = dose/AUC
 Cl = Vd x k [from half life formula]
 Cl = Q x E
 Cl = elimination rate/Cp
 Cl = maintenance dose rate/Cp

How can the amount of drug eliminated from the plasma by that organ per unit time be calculated?
by knowing 1) the value for clearance by the organ responsible for removing the drug & 2) the plasma concentration of the drug in question

Upper Limit
 the maximum possible clearance value
 is equal to blood flow to the clearing organ, as clearance can't exceed the amount of blood entering the organ
 eg. blood flow to the liver is 1500 mL/min
 maximal hepatic clearance (UL) of a drug susceptible to this route of elimination cannot exceed 1500 mL/min

When given 2 plots of drug concentration per unit time, how can one determine which plot for a given patient exhibits more efficient clearance?
 the plot with a LOWER AUC (area under the curve) indicates the drug is cleared more efficiently
 a high AUC value indicates low drug clearance and therefore high systemic exposure to said drug
 a slow clearance could be due to age, or compromised capacity of the organ system responsible for removing drug

What are the most common routes by which a drug is cleared from the body?
 1. renal filtration (kidney)
 2. metabolism: usually hepatic, but sometimes is done through the GI mucosa
 pathway of excretion usually elucidated during early studies

With the exception of what organ is specific organ clearance generally difficult to measure?
 filtration through the kidneys
 * but hepatic clearance is the most common route of drug clearance as it's the primary site of drug metabolism

Glomerular Filtration Rate (GFR)
 describes the flow rate of filtered fluid through the kidney
 important to take into consideration if a drug is excreted by renal filtration
 GFR = (140 – age) * IBW
 72 x Scr
 for females multiply result by 0.85

IBW
 ideal body weight
 to calculate GFR using the Cockroft & Gault equation IBW is measured in kg

Scr
serum creatinine; measured to determine kidney function

Creatinine Clearance Rate (CCr or CrCl)
the volume of blood plasma that is cleared of creatinine per unit time (mL/min); is a useful measure for approximating the GFR

How is a drug dose adjusted if the CrCl is greater than 60?
100% of recommended dose is given every 6 hours

How is a drug dose adjusted if the CrCl is between 3060?
5075% of recommended dose is given every 812 hours

How is a drug dose adjusted if the CrCl is less than 30?
50% of recommended dose is given every 24 hours

ChildPugh Score
 used as an indicator of liver function & a patient’s ability to metabolize drugs
 the HIGHER the score, the more likely the patient is to require a smaller drug dosage


Zeroorder Behavior
 involves a constant amount of drug removal per unit time
 once the elimination mechanisms becomes saturated, elimination becomes zeroorder

Zeroorder Elimination
 rate of elimination is constant & independent of plasma concentration of drug
 drug clearance is dependent on drug concentration as a constant amount of drug is eliminated per unit of time
 this usually occurs when the elimination process is saturated
 few drugs used clinically exhibit zeroorder behavior

What are two 'drugs' whose Km's are well below their therapeutic ranges?
 alcohol
 phenytoin (dilantin, an anticonvulsant)
 aka they exhibit zeroorder elimination behavior
 such drugs possess nonlinear kinetics, since plasma concentrations change more or less than expected upon changes in doses

Firstorder Behavior
 involves a constant fraction of drug removal per unit time
 when drug concentrations are low enough that the elimination mechanisms are not saturated, elimination is usually firstorder

Firstorder Elimination
 rate of elimination depends and is directly proportional to plasma concentration of drug
 drug clearance however is independent of drug concentration (a constant fraction of drug is eliminated per unit of time)
 most drugs use exhibit firstorder behavior at therapeutic concentrations
 such drugs possess linear kinetics since drug concentrations change in proportion to dose changes

Drug Elimination Behavior & Enzyme Kinetics
 *note: do not confuse behaviors during drug administration (above graph) with those during drug elimination

% drug cleared = fixed; amount = variable
 FIRSTORDER BEHAVIOR
 Rate is proportional to Cp
 Clearance is independent of Cp
 Constant fraction eliminated per unit time
 Applicable to most drugs
 the Cp << Km

% drug cleared = variable; amount = fixed
 ZEROORDER BEHAVIOR
 Rate is constant & independent of Cp
 Clearance is dependent on Cp
 Constant amount eliminated per unit time
 Applicable to few drugs
 the Cp >> Km

Halflife
 the time required for plasma CONCENTRATION of a drug to decrease by one half after absorption and distribution are complete [*only applies to drugs that follow firstorder kinetics]
 when elimination follows firstorder behavior the halflife of a drug is constant and independent of both dose administered & route of administration

Why is knowing the halflife of a drug useful?
 it is important for determining how long it takes to remove a given dose of a drug from the plasma
 it is important for determining the time to steady state concentration w/ continual administration of a drug (by either continuous infusion or multiple discreet doses)

For a drug that exhibits firstorder kinetics, after how many half lives will more than 95% of it be eliminated from the body?
 after 5 halflives have passed
 after 5 half lives such a drug would also be within 5% of the maximal steady state concentration

However the majority of drug is removed after about how many half lives have passed?
 he says 4 in lecture
 aka it would take ~40 hours to remove ~90% of a drug that has a halflife of 10 hours

How may halflife be graphically determined?
 from a semilog scale of plasma concentration vs. time when the data is linear (aka after the drug has been absorbed)
 can determine halflife by simply looking at the plot and estimating the time it takes for the plasma concentration at any point during the decay to fall by 50%

Halflife Calculations
 t_{1/2} = ln 2 ln 2 = 0.693
 k k = Cl / Vd
 t_{1/2} = 0.693 * Vd
 Cl
 [most biologically accurate eqn]
 t_{1/2} = 0.693 / k k = ln (C1/C2)
 Δtime
 t_{1/2} = 0.693 * Δt ...
 ln (C_{1}/C_{2})

What else can be calculated from a graph of plasma concentration vs. time?
 the volume of distribution IF we know the dose administered:
 Vd = Dose
 Cp_{0}
 *always use initial plasma concentration (C_{0}) from the graph when calculating Vd

Two Compartment Model
 appears as a biphasic plot (on a semilog scale of plasma concentration vs time), not a linear one
 in the alpha (distribution phase) there is a rapid decrease in plasma concentration of the drug right administration, because it moves from the plasma to other tissue
 a linear decline of the drug concentration occurs after it has equilibrated between the various body compartments & the plasma
 this elimination phase is called the beta phase

How is Vd calculated for a drug that exhibits a two compartment model?
 to find the "initial plasma concentration" of the drug, you extrapolate back to the yaxis using the linear beta phase of the plot
 Vd = Dose
 Cp_{0}

Halflife is a ______________ pharmacokinetic variable:
 halflife is a DEPENDENT pharmacokinetic variable
 its value depends on volume of distribution & clearance, each of which are independent of each other

t_{1/2} = 0.693 * Vd
Cl
 as volume distribution INCREASES, halflife increases (proportional)
 as Cl increases, halflife DECREASES (inversely proportional)
 the drug w/ the longest halflife should have the largest Vd (& vice versa)

In which case is the halflife shorter for a drug given orally or the same drug given parenterally?
 the halflives are the SAME because it's the same drug & halflife is independent of ROUTE of administration
 (*absolute plasma concentrations will be different though)
 also, could use AUC's for PO (oral) & IV to get BIOAVAILABILITY
 F = AUC_{oral} / AUC_{IV}

Css (steady state concentration)
 Css = Dose / Vd
 plasma concentration of drug once a steady state has been achieved
 as a drug infusion progresses there reaches a point at which drug accumulation plateaus and then remains constant = steady state plasma concentration
 at steady state the rate of drug administration is equal to the rate of drug removal

After about how many half lives will a drug obeying firstorder kinetics reach its steady state?
 ~4 half lives
 *TIME to reach the steady state is INDEPENDENT of the dose given (aka giving a lot won't help you reach the drug's steady state any faster, it's dependent on body's ability to metabolize  however if a larger dose is given the plasma concentration will be higher)

How can dose adjustments be made for a drug that obeys firstorder kinetics?
 D_{new}= D_{old}*(Css_{desired} / Css_{observed})
 by basing the adjustments on plasma concentrations
 plasma concentrations of firstorder drugs change IN PROPORTION to dose

The drug concentration reached at steady state is a function of dose administered divided by what?
dose administered / the volume of distribution for that drug

If a drug's steady state concentration is 4 concentration units (mg/mL), what would need to be done to raise its steady state concentration to 8 mg/mL? Lower it to 2 mg/mL?
 8: the infusion rate (Q) would need to be DOUBLED
 2: the infusion rate (Q) would need to be HALVED
 (eg. if Q_{4} = 10 mg/min, to reach an ss conc. of 8, Q > 20 mg/min)


Equation used to calculate plasma concentrations of drugs that exhibit firstorder behavior in a onecompartment model:
 C = C_{0}e^{kt}
 C_{0} = initial concentration
 k = elimination rate constant
 t = time since drug was 1st given

What are the implications of C = C_{0}e^{kt}?
 if you can determine the concentration of a drug in the plasma at any given time and you know k, it is possible to determine what the drug concentration will be at any subsequent time
 it's also possible to determine at what point in time the concentration would fall below some minimum effective level (i.e. when you might given another dose of the drug)

Cmax
describes the maximum plasma concentration of a drug over a dosing interval

Cmin
describes the minimum concentration over the dosing interval

Interdose Fluctuation
 the ratio of the Cmax to the Cmin
 it's dependent on the drug dose & the frequency with which it's given

If a drug exhibits firstorder clearance, what happens if both dose and frequency change in equal proportions?
 the interdose fluctuation should change but the mean steady state plasma concentration should NOT as long as the total dose administered per day remains the same
 eg. if an antibiotic is given orally, 125 mg every 6 hours, mean steady state plasma concentration = 15 mcg/mL
 if the dose & interval were changed to 250 mg every 12 hours or 500 mg every 24 hours, the interdose fluctuation would INCREASE, but the mean steady state concentration would stay the same

What is the only way to obtain perfectly constant plasma levels of a drug?
 a continuous infusion
 for other routes of administration the degree of fluctuation of plasma drug concentrations can be altered by changing the dose interval while holding the dose rate constant
 shorter dose intervals result in less fluctuation than longer dose intervals

CYP450
 the generic name for a group of enzymes responsible for most drug metabolism oxidation reactions
 eg. CYP450 1A2, 2C19, 2D6, 3A4
 they're present mainly in the liver, although CYP450 3A is also present in the GI mucosa

What are some strong inhibitors of the CYP450 system?
 ritonavir (Norvir): HIV protese inhibitor
 macrolide antibiotics (erythromycin aka Zpak)
 azole antifungals
 grapefruit juice*

What are some strong inducers of the CYP450 system?
 rifampin (antibiotic)
 anticonvulsants (carbamazepine/Tegretal, phenytoin/Dilantin, phenobarbital)

Example of a drugdrug interaction:
 Ciprofloxacin & Vitamins
 because the drugs were being taken at the same time, an interaction occurred due to the fact that cipro can form cations with the minerals in vitamins
 this complex results it neither drug being absorbed very well in the GI tract
 *can be avoided by staggering administration times (ideally by at least 4 hours)

What is an example of a drug that requires an acidic environment for optimal absorption?
 azole antifungals
 anything that raises the pH of the stomach or arbitrary environment where such a drug is absorbed affects effectiveness of the medication (because less of it is internalized)
 eg. prilosec suppresses acid production > less of antifungal is absorbed > treatment failure
 difficult to avoid if both drugs are required

Why would you perform therapeutic drug monitoring?
 Drug has a narrow therapeutic window
 There's a relationship between Cp & either efficacy or toxicity
 Drug has a unpredictable doseresponse relationship
 Reliable assay exists
 often done for Antiarrhythmics (digoxin, procainamide), Antibiotics (aminoglycosides), Anticonvulsants (carbamazepine, phenytoin), Antidepressants (amitriptyline, imipramine) & Antithrombotics (heparin, warfarin)

Aminoglycoside
 antibiotics (eg. gentamicin, tobramycin) that are VERY polar/hydrophobic  lends itself to therapeutic drug monitoring
 they cannot be given orally, must be given parenterally using a dosage based on a patient's ideal body weight (unless obese, in which case a dosing weight must be calculated)
 DW = IBW + 0.4(TBW  IBW)
 the rate limiting step of aminoglycosides' halflife = KIDNEY FUNCTION
 there is no hepatic or 1st pass metabolism; the drug is cleared through the kidney in it's original form
 Vd = 0.30.5 L/kg
 therefore the halflife depends on kidney function but usually is around 24 hours if healthy (need to be careful)

