kinetics exam 3

Question 1

During a multiple-dose schedule the more recent a missed dose is, the less the effect the omission has on the current plasma drug concentration.

A
True

B
False

Answer 1

false! according to slide 24, it will have a greater effect!

Question 2

PLASMA CONCENTRATION-TIME COURSE
AFTER ONE ORAL DRUG ADMINISTRATION

Answer 2

onset of action = when the drug reaches the minimum effective concentration

peak time = the time it takes to reach the peak concentration

duration = the time in which the drug is above the minimum effective concentration

intensity = the window between the peak concentration and the minimum effective concentration

therapeutic window = the window between the minimum toxic concentration and the minimum effective concentration

Question 3

predicted plasma drug con concentrations for multiple-dose regimen using the superposition principle

Answer 3

taking/giving the patient the same dose at certain time intervals and as a result will result in a total dose after adding the doses taken previous to the one given

Question 4

towards a steady state

Answer 4

taking a dose at different time intervals will increase the concentration in the body and keep it at a steady state

tou symbol:
At a steady state, concentrations will rise and fall according to a repeating pattern as long as we continue to administer the drug at the same dose level and with the same time period between doses.
This repeated dosing period is often called the dosing interval and is abbreviated using the Greek letter tau (τ).

Question 5

Predicting Plasma Drug Accumulation

Answer 5

It is assumed:
– that a first-order process eliminates the drug
– that early doses do not affect the pharmacokinetics of later doses
i.e. the pharmacokinetics of later doses are only superimposed (stacked on top of) on those of earlier ones (the principle of superposition)

• Also, the entire 0 Cpdt for a single dose administration is equal to nn+1Cpdt for any dosing interval at a steady state in a multiple-dosing case - so
• the area under the curve of the first dose is equal to the area under the curve of any dose interval at steady state

Question 6

Predicting Plasma Drug
Accumulation II

Answer 6

Based on the principle of superposition, the concentration-time curve in a multiple-dosing case can be predicted from the concentration-time data of a single-dose administration

• *Ref Table 8.1; if a constant dose is given at constant periods, the plasma concentrations after each dose consist of the same data obtained after the single dose. For each time point, then, the predicted plasma concentration is the sum of the residual concentration resulting from each previous dose
• The prediction holds even if the dosing interval is not fixed

Question 7

Situations In Which Superposition Would Not Be Valid

Answer 7

The drug does not follow linear kinetics see Table 9.1 for examples

• A Drug’s carrier system gets saturated (for instance, the drug is eliminated by a saturable enzymatic process and so follows Michaelis- Menten kinetics. Recall Vmax and KM)
• There is enzyme induction
• There is enzyme inhibition
• The patient’s disease condition changes significantly between doses

Question 8

Drug Accumulation

Answer 8

Multiple dosing is intended to keep plasma drug levels within the therapeutic window - which is always the goal!

• The dose and the time between doses () may be adjusted to achieve this.
• Accumulation will not occur if a second dose is given at an interval longer than that required for the elimination of the previous dose
• A steady state should eventually be achieved during accumulation (Cmax and Cmin should remain the same from dose to dose)
• There is no accumulation if at steady state Cmax is the same as for (Cn=1)max for the first dose.
• For drug safety, Cmax should always be less than the minimum toxic dose

Question 9

Drug Accumulation II

Answer 9

the drug accumulation index:
R = (Cinfinity)max/(Cn=1)max

R = D0/VD[1 - e^-ktou]/(D0/VD)

R = (1/1 - e ^-k(τ))

Thus, accumulation depends not on the dose, but on the dosing interval (which is tau) and the elimination rate constant which is k

• The time required to attain a steady state is dependent on the elimination half-life but is independent of dose or interval between doses
• Average steady-state Plasma Concentration =[AUC]t1^t2/ tau

Question 10

Drug Accumulation III

Answer 10

The time required to attain one-half of the steady-state plasma levels (the accumulation t1/2):

t1/2acc = t1/2(1 + 3.3log (ka/ka-k))

• For IV infusion administration ka is rapid&raquo_space;>k

t1/2acc = t1/2(1 + 3.3log(ka/ka))
i.e. for an IV-administered drug
t1/2acc = t1/2

Thus t1/2acc is dependent on the elimination t1/2 but not on dose or dose intervals

Question 11

Drug Accumulation IV

Answer 11

The time needed to reach 90% and 99% steady-state concentrations is 3.3 t1/2 and 6.6 t1/2 respectively.

• The number of doses needed to reach steady-state is dependent on t1/2 and .
  (specifically, it is for 99% steady state)
  (6.6 x t1/2)/tau

Question 12

interrelation of elimination half life, dosage interval, maximum plasma concentration, and the time to reach steady-state plasma concentration

Answer 12

table 8.3

Question 13

Relation Between Loading Dose
and Accumulation Index

Answer 13

Maintenance Dose (DM ) = Loading Dose (DL) – Amount of Drug
Remaining at end of Dosing interval

DL = DM x (1/1-e^ktau)

You would recall the accumulation index
R = 1/(1 - e^ktau)

So the loading dose is the product of the maintenance dose and the accumulation index.

Question 14

the dose of sulfisoxazole (Gantrisin, Roche) recommended for an adult female patient (age 26 years, 63 kg) with a urinary tract infection was 1.5 g every 4 hours. The drug is 85% bound to serum proteins. The elimination half-life of this drug is 6 hours and the apparent volume of distribution is 1.3 L/kg. Sulfisoxazole is 100% bioavailable.

Answer 14

a.Calculate the steady-state plasma concentration of sulfisoxazole in this patient.

b.Calculate an appropriate loading dose of sulfisoxazole for this patient.

c.Gantrisin (sulfisoxazole) is supplied in tablets containing 0.5 g of the drug. How many tablets would you recommend for the loading dose?

d.If no loading dose was given, how long would it take to achieve 95%–99% of steady state?

Question 15

Drug Accumulation:
Repeated IV Injections

Answer 15

For a one-compartment open model following first-order
kinetics, after a single dose:
DB = D0e^-ktau

• So given that the interval between a first and second dose is
  tau: DB = D0e^-ktau
• The fraction of the dose remaining in the body:
  f = DB/D0 = e^-ktau

Thus f depends on k and tau e.g. f is large if tau is small.

Question 16

Drug Accumulation:
Amount of Drug in the Body

Answer 16

• The maximum amount of drug in the body:
  Dmax = D0/(1-f)

Since the difference between the maximum and minimum amounts of drug in the body is equal to the administered dose (D0):
Dmin = Dmax - D0

Where F= fraction of dose absorbed (NB: for an IV dose F=1), the average amount of drug in the body at steady-state:
Dav = FD0/ktau

The respective concentrations can be determined by dividing the amounts by the apparent volume of distribution

Question 17

A new drug is to be given by multiple IV bolus injections to a patient such that drug steady-state concentrations should be maintained between a maximum of 20 and a minimum of 1 mg/L.

Assume a one-compartment linear
the model applies to this drug in this concentration range. The elimination rate constant and apparent volume of distribution for this drug in this patient are 0.223 hr-1 and
40.6 L, respectively.

Calculate the dosing interval that will exactly achieve this concentration requirement.
Also, calculate the maintenance dose.

Question 18

problem to solve! slide 22 of multiple dosages

Question 19

table

Question 20

table

Question 21

Drug Accumulation: Plasma Level Equations

Answer 21

Cmax = C^0p/(1 - e^-ktau)

Cmin = (C^0pe^-ktau)/(1-e^-ktau)

Cav = (FD0/VDktau)

….

Question 22

Drug Accumulation: Plasma Level Equations II

Answer 22

After administering n i.v.doses (time  between doses), the plasma concentration at time t after the nth dose is given by:
CP = (D0/VD)(1-e^-nktau)

• At steady-state, e-nk approaches zero:
  CP^infinity = D0/VD(1/1-e^ktau)e^-ktau

Question 23

problem to solve

Question 24

Non-Compliance:
Dose Skipped?

Answer 24

When a dose is missed, the concentration that should have been contributed by the missing dose ((D0/VD)e-ktmiss) is subtracted from the concentration at time t after the nth dose (given that time is time tmiss since that scheduled
dose). For i.v.:
CP = D0/VD[(1 - e^nktau/1 - e^ktau)e^-kt - e^-ktmiss]

Or at steady-state (where n is very large):
CP^infinity = D0/VD(e^-kt/ 1- e^-ktau) - D0/VD e^-ktmiss

NB: The more recent a missed dose is, the greater the effect it will have on the current plasma concentration.

• Missed doses greater than 5 half-lives later should be omitted because of their minimal impact

Question 25

problem to solve

Question 26

Non-Compliance: Wrong Time or Wrong Dose?

Answer 26

When a dose is late, the dose not taken on schedule should be regarded as a missed dose and subtracted as before. However, when the dose in question is actually taken (early or late) it is taken into account as follows for
i.v.:
CP = D0/VD(1 - e^-nktau/1 - e^-ktau) -e -ktmiss + e-tactual)

where tactual is the time since the dose is question was actually taken
* If a wrong dose (hopefully non-lethal) is given, Cp may be determined with the right dose and the correction made by subtracting the contribution due to the wrong dose

Question 27

problem to solve

Question 28

Repeat IV Infusions

Answer 28

Intermittent short IV infusions prevent transient extreme high plasma levels of a drug and so are better tolerated even though steady-state may not be attained.

where R is the infusion rate. Since R = D/tinf
(D is size of infusion; tinf is the duration of infusion) After any specified time t of IV infusion,

The concentration at any specified time t after IV infusion given Cstop is the concentration when infusion stops

Question 29

problem to solve

Question 30

table

Question 31

table

Question 32

Repeat Oral (Or Extravascular)
Administrations

Answer 32

• Recall, for a single dose, the plasma concentration at the time

where F is the fraction of drug absorbed and ka is the first-order rate constant for absorption.

After dosing n times ( intervals), the plasma concentration at time t:

At steady-state, n approaches infinity and e-nka approaches zero.

Question 33

Repeat Oral (Or Extravascular) Administrations II

Question 34

Repeat Oral (Or Extravascular) Administrations III

Answer 34

tp corresponds to a time after many doses (i.e. n approaches infinity); also tp corresponds to a peak concentration

• tp is the repeat-dosing equivalent of a tmax for a single dose at a steady state.

Question 35

Example

Answer 35

A drug is given by multiple oral dose of 30 mg every 6 hours. Assume a one compartment linear model applies to this drug in this concentration range. The Clearance and VD for this drug in this patient are 10.7 L/hr and 52.3 L, respectively. For this dosage form and patient
-1
the bioavailability is 0.63 and ka is 1 hr
Assume that e-ka *  approaches 0 and ka&raquo_space; k. Calculate the expected Cpaverage, Cpmin value and a ‘very’ approximate Cpmax value at steady state.

Question 36

Example

Answer 36

A drug is to be given by multiple oral doses every 24 hr. After consideration of the patient’s clinical condition it is decided that the average drug concentrations should be maintained at 9 mg/L. Assume a one compartment linear model applies to this drug in this concentration range. For this dosage form and patient, the bioavailability is 0.65 and the absorption rate constant is 1 hr-1. The half- life and VD for this drug in this patient are 4.3 hr and 35.7 L, respectively. Calculate the dose that will achieve this average concentration of 9 mg/L.

Question 37

Example

Answer 37

A drug was given by multiple oral doses of 200 mg every 6 hr. Assume a one compartment linear model applies to this drug in this concentration range. For this dosage form and patient the bioavailability is 0.67 and the
-1
absorption rate constant is 3.21 hr
VD for this drug in this patient (63.1 kg) are 0.155 hr-1 and 0.53 L/kg, respectively. Calculate the average drug concentration.
* Solution:………….

Question 38

Loading Dose Determination

Answer 38

Used to achieve the desired plasma concentration (C ) av
promptly, circumventing the delay that the processes of absorption and elimination introduce.

• Dose Ratio = DL/D0

When the dosage interval is equal to the half-life, the dose ratio has value 2.

Question 39

Bioavailability

Answer 39

Estimation of ka (in multi-dose regimens ) is difficult because of superposition of doses

• Determination of bioavailability is possible at steady-
  
  state (Cav , AUC0 , tmax and Cmax ).
• First sample should be taken just before the administration of the second dose, thereafter, samples should be taken regularly after the administration of each dose
• Multi-dose regimen bioavailability studies can reveal changes that would not be obvious in a single-dose study e.g. the existence of non-linear pharmacokinetics, drug-induced malabsorption syndrome etc…

Question 40

Bioequivalence

Answer 40

A multiple dose study can be designed to ascertain bioequivalence. Equal doses of a test and reference product may each be administered repeatedly in turn (two-way cross- over) to steady state, separated by a time period required to completely eliminate the drug from the body.

• The AUC and Cmax of the test product should be within 80 -125% of the corresponding values for the reference product using a 90% confidence interval.

Question 41

relation Between Loading Dose
and Accumulation Index

Answer 41

Maintenance Dose (DM ) = Loading Dose (DL) – Amount of Drug Remaining at end of Dosing interval

So the loading dose is the product of the maintenance dose and the accumulation index.

Question 42

Circulatory System and Distribution

Answer 42

Drug is borne by blood (via blood vessels) to the site of action

• Volume of blood pumped by the heart per minute (cardiac output) is important
• Cardiac output = stroke volume X heart rate
• At rest, average cardiac output (due to 69 left ventricle contractions per minute) is 5.5 L per minute
• Blood pressure = cardiac output X peripheral resistance
• Left ventricle contraction produces a systolic blood pressure of 120 mmHg, and moves blood at 300 mm/sec through the aorta

Question 43

Water Volumes in 70 kg Adult

Answer 43

intracellular water volume: 27

interstitial water volume: 12

plasma water volume: 3

blood cell water volume: 2

total blood volume 5L

Question 44

Factors Affecting Drug Entry Into
Tissues

Answer 44

Physicochemical nature of cell membranes:

Protein + bi-layer of phospholipid

Under certain pathophysiological conditions (e.g. burns and meningitis) permeability could change

Unique features of tissue such as blood-brain barrier

• The physicochemical properties of the drug:
  Lipophilic drugs traverse cell membranes more easily than polar ones

Small molecules traverse membranes more easily than larger ones or those forming drug-protein complexes

Question 45

Diffusion

Answer 45

Most drugs enter cells by way of spontaneous passive diffusion

• Passive diffusion is temperature-dependent and governed by Fick’s Law of Diffusion. The rate of
  drug diffusion

Where h=thickness of membrane; A=surface area of membrane; D=diffusion constant; K=lipid-water partition coefficient;Cp=drug concentration in plasma; Ct=drug concentration in tissue

*negative sign because there is a net transfer of drug from the capillary lumen to the extracellular fluid and tissue

Question 46

Hydrostatic Pressure

Answer 46

The pressure difference between capillaries entering and those leaving tissue

• Hydrostatic (filtration) pressure is caused by capillary blood pressure being higher than that of tissue at the arterial end
• This is responsible for the transfer of water-soluble drugs penetrating spaces between endothelial cells
• Blood pressure of tissues higher than venous capillaries (creating ‘absorptive’ pressure), so filtrate gets transferred to venous capillary

Question 47

Distribution

Answer 47

Distribution may be flow limited (such as in congestive heart failure) or diffusion limited (such as during inflammation when there is increased capillary permeability)
* The first-order distribution constant for a drug into an organ:
kd = Q/VR

concentration in the organ to that in the venous blood
* R may be estimated from the oil/water partition coefficient (Po/w). A drug with high Po/w will have a high R
* Thus large blood flow (Q) decreases distribution time; a large volume
Q VR
kd
Where Q=blood flow to the organ; V= volume of the organ; R=ratio of drug
(V) increases distribution time.
* The first-order distribution half-life:
td1/2 = 0.693/kd

Question 48

Accumulation

Answer 48

R indicates the extent to which an organ accumulates a drug. A high R (due to either protein binding or high solubility of the drug in the tissue) means it takes longer
for distribution to be complete
*e.g. flutamide, digoxin

• A high level of accumulation in tissues results in: a long elimination half-life (e.g. etretinate, DDT); plasma levels may not correlate well with pharmacodynamic action if tissue is target tissue*
• Mechanisms of accumulation: dissolution in lipids, reversible binding to biomolecules (e.g. proteins, melanin, calcium), irreversible binding to biomolecules (e.g. in cancer chemotherapy purine/pyrimidine drugs that bind to nucleic acids), enzymatic or active transport systems

Question 49

image

Question 50

Drug Protein Binding

Answer 50

Irreversible binding to protein sometimes occurs when an activated form of a drug attaches to a protein via a covalent bond (e.g. acetaminophen hepatotoxicity, chemical carcinogenesis)

• Reversible binding (typical) is usually due to weak bonds such as hydrogen bonds and van der Waals forces
• Protein-bound drugs are usually not active pharmacologically
• Protein-bound drugs are usually not able to cross cells or cell membranes

Question 51

Drug Protein Binding II

Answer 51

Drug-protein binding may be allosteric: There can be cooperativity in protein binding i.e. binding of first drug molecule can affect the binding of successive molecules to the same protein molecule (e.g. O2 binding to Hb)

• Drug protein binding can result in non-linear pharmacokinetics
• Drug protein binding can result in a “depot” effect (longer duration of action).

Question 52

Factors Affecting Protein Binding

Answer 52

Drug properties: physicochemical properties and quantity of drug in body

• Protein properties: physicochemical properties and the quantity of protein available for binding
• Drug-protein affinity: Ka.
• Drug-drug interactions: competition for binding site; the binding of one drug alters affinity of protein for another drug e.g. after ASA acetylates lysine in albumin, albumin’s capacity to bind other anti-inflammatory drugs changes
• Disease condition of patient: may reduce blood-protein binding (e.g. in hepatic disease)

Question 53

Drug Protein Binding:
Blood Proteins- Albumin

Answer 53

albumin: MW 65kDa.
* Largely responsible for maintaining the osmotic pressure of blood.
* Weak acidic drugs (e.g. salicylates, penicillin), free fatty acids, bilirubin, and some hormones (e.g. cortisone, thyroxine) bind to albumin.
* Albumin has several binding sites for which different drugs compete. For instance, sulfonamides, phenytoin, valproic acid and phenylbutazone compete for Binding Site I; medium chain fatty acids, probenecid , benzodiazepines and some penicillins compete for Binding site II

Question 54

Drug Protein Binding: Blood Proteins- Globulins

Answer 54

1-acid glycoprotein (AAP or orosomucoid): A globulin, 44kDa.
* Many basic drugs (e.g. propranolol, lidocaine) bind to AAP.
* Globulins (, , and ) have low capacity and high affinity for endogenous substances such as corticosteroids.
* Also Immunoglobulins (IgG)

Question 55

Drug Protein Binding: Blood Proteins- Lipoproteins

Answer 55

Lipoproteins: MW 200 – 3400 kDa.
* Include very-low-density- (VLDL), low- density- (LDL), and high-density- lipoproteins (HDL).
* Bind to and transport plasma lipids to the liver.

Question 56

Drug Protein Binding: Blood Proteins- RBCs

Answer 56

Some drugs bind strongly to RBCs.
* For such, the hematocrit influences the total amount of drug in the blood.
* Binding to albumin reduces binding to RBCs.

Question 57

Apparent Volume of Distribution

Answer 57

Any undetected source that reduces the plasma drug concentration increases the apparent volume of distribution. Such sources include binding to proteins within tissues and binding of metabolites to tissues following metabolism of drug
* A VD greater than combined plasma volume and body water indicates that this could be the situation

Question 58

Drug Protein Binding: VD

Answer 58

Generally speaking, drugs with little plasma protein binding have large fu (unbound drug fraction), diffuse more into tissues and so have large VDs.
* High protein binding in blood reduces penetration to targets of action in tissues. Generally from:
DB= VPCP + VtCt

(Where Vp and Vt are the plasma and tissue volumes, Cp and Ct are the plasma and tissue drug concentrations)

Question 59

Drug Protein Binding: VD

Answer 59

We get:
Vapp = VP = Vt(fu/fut)

(Where Vapp=apparent distribution volume, fut=unbound drug fraction in
tissue)
* The products of tissue volumes of other organs and (fu/fut) can be added to the RHS of the equation if more tissues are involved
* The volume of distribution, fu and fut should only be measured under equilibrium conditions (drug concentrations between the plasma and tissue equilibrate)

Question 60

problem to solve

Question 61

Drug Protein Binding: Drug Elimination

Answer 61

For drugs excreted mainly by filtration in the kidney, as plasma protein binding increases, so does the elimination half-life
* For drugs eliminated by active renal secretion, the elimination half-life can be short even with high protein binding (recall secretion preferentially strips blood protein of drug)
* Drugs eliminated by both renal and biliary secretion, there is poor correlation between plasma protein binding and clearance

Question 62

Drug Protein Binding: Distribution and Elimination II

Answer 62

Some drugs (e.g. dirithromycin) have high Cl and VD and
low k i.e. large VD assures a long t1/2.
* With others, a low VD assures a long t1/2.
* Some drugs (e.g. propranolol) are eliminated even when they are protein-bound i.e. they are non-restrictively eliminated. In these elimination may not be exclusively hepatic.
* Others (e.g. phenylbutazone and piroxicam) are restrictively eliminated. Generally they have small hepatic extraction ratios (ER < fu) and do not have first pass effects

Question 63

PROTEIN BINDING KINETICS

Answer 63

Based on the law of mass action (the rate of a chemical reaction is proportional to the product of the concentrations of reactants):
* For: protein + drug protein-drug-complex,

[P] + [D]  [PD]

• The association (affinity) constant:
  Ka = [PD]/[P][D]

Given the ratio:
Ka 
r = moles of bound drug/ total moles of protein
r = [PD]/[PD]+[P]

Question 64

PROTEIN BINDING KINETICS II

Answer 64

Where there are n identical binding sites per
protein molecule:

Sometimes a protein molecule can have more than one kind of binding site for a drug (e.g. binding of salicylic acid
to albumin). For such:

Question 65

PROTEIN BINDING KINETICS III

Answer 65

• The dissociation constant

Kd = 1/Ka

Preceding equation may be expressed in terms of
Kd as follows:
r = n[D]/Kd+[D]

Question 66

problem to solve

Question 67

Graphical Methods of Determining Ka: Double Reciprocal Plot

Answer 67

Assuming 1 type of binding site and no protein-protein interaction,from earlier equation:

Thus a plot of 1/r against 1/[D] gives a slope of 1/nKa and a y-intercept of 1/n. Since both r and [D] can be determined, Ka may be calculated this way.

Question 68

Graphical Methods of Determining Ka: Scatchard Plot

Answer 68

Thus a plot of r/[D] versus r (a Scatchard plot) gives a line of slope –Ka.
Graphical Methods of Determining Ka: Scatchard Plot

A non-linear plot would suggest complexities exist e.g. there could be more than one type of binding site

Question 69

Graphical Methods of Determining Ka: Where Protein Concentration is Unknown

Answer 69

Where [D] is the concentration of bound drug and [PT]is the total protein concentration

Thus a plot of [D]/[D] versus [D] gives a straight line with slope –Ka.
* NB: The ratio of bound drug concentration to free drug concentration ([D]/[D]) depends on the affinity constant (Ka) and on [PT] (which can change during disease).

Question 70

Factors Affecting Plasma Protein Concentration

Answer 70

Protein synthesis
* Protein catabolism
* Distribution of albumin between vascular and extravascular space
* Age
* Disease

Question 71

table

Question 72

table

Question 73

Protein Concentrations and
Disease

Answer 73

The quality of protein synthesized may be altered during liver or kidney disease or as a result of a genetic defect:This could alter the Ka.
* Albumin levels decrease in liver disease
* During kidney disease, accumulated metabolites (such as uric acid and urea) could compete with drugs for protein binding
* Severe burns could increase movement of albumin into extracelular fluids, resulting in reduced levels in the plasma

Question 74

At constant protein levels, all available binding sites get bound even at low drug
concentrations i.e. at low drug concentrations, the fraction of bound drug is high. After saturation free drug levels rapidly increase.

Answer 74

THE EFFECT OF PROTEIN SATURATION

Question 75

Protein Concentrations and
Disease

Answer 75

The fraction of drug bound:

From equations this equation and

Thus, any changes in protein or free drug concentration (such as could occur during a disease) impacts the pharmacokinetics of a drug

Question 76

Displacement from Binding

Answer 76

Drug displacement from binding to protein or other biomolecules (e.g. melanin or DNA) can result from competition
* Displacement from plasma protein binding increases level of free drug and therefore therapeutic effect (as well as the potential for toxicity)
* Clinical effect of displacement from plasma protein binding may be minimal if distribution or elimination dilute the resulting rapid rise in free drug levels
* Displacement of endogenous ligands such as hormones have little practical significance because of the existence of feedback mechanisms (except in newborn babies e.g. kernicterus)

Question 77

Displacement from Binding II

Answer 77

Displacement from plasma protein binding is most significant for drugs that are more than 95% protein-bound and have a narrow therapeutic index *example on page 243 (5th Edition Page 292 ) and Table 10.15
* Such displacement causes an increase in the VD and t1/2
* Consider a drug that gets displaced from plasma protein binding which then gets into tissue to which it has high affinity. The volume of distribution would increase but so
would the elimination half-life. Displacement has no effect on clearance (recall Cl = 0.693VD/t1/2) or mean steady-state concentration (if multiple doses are administered)

Question 78

table

Question 79

Low Extraction Drug and Protein
Binding

Answer 79

For a low-extraction drug, changes in protein binding have consequence.
* Generally, organ clearance:

where Qorgan is blood flow, fu is fraction of free drug
unchanged Clint is intrinsic clearance
* In the case of a low-extracting drug, Qorgan&raquo_space;> fuClint and so:
* Cl  fuClint
* i.e. organ clearance depends on intrinsic clearance (which is flow independent) and fu.

Question 80

Low Extraction Drug Exposure

Answer 80

where FH is the hepatic bioavailability and QH the hepatic blood flow

where FG and Fabs are the fraction of drug that gets across the gut wall unchanged and the fraction of drug that gets absorbed to the gut wall respectively.

For an unbound drug,

• i.e. unbound drug exposure (AUCoral ) is independent of fu

Question 81

High Extraction Drug Protein Binding and Exposure

Answer 81

for a high-extracting drug, hepatic Cl (ClH) is flow-dependent, and protein binding is clinically important
* For high-extracted drugs

• The systemic exposure of unbound drug:

i.e. changes in binding may be important clinically

Question 82

What’s In a Name?

Answer 82

Generic name (established non-proprietary common name of active ingredient): e.g. acetaminophen
* Chemical name (used by organic chemists; indicates structure): e.g. p-acetamidophenol (p-hydroxyacetaniline)
* Brand name (privately owned trade name of a drug): e.g. tylenol

Question 83

Plasma Observations

Answer 83

“Bioavailability” is a reference to the rate and extent to which a drug is absorbed.
* The F and ka are direct measures of bioavailabilty but are too variable (recall why) to be useful for this purpose.
* FromanoralCpvrstcurve,theCmax,tmaxandAUCare used (as indirect measures) to determine the bioavailability of a drug.
– Cmax,is a measure of rate and extent of absorption tmax is a measure of the rate of absorption
– AUC is a measure of the extent of absorption

Question 84

plasma level-time curve

Question 85

linear relationship

Question 86

Urine Observations

Answer 86

If absorption is greater for one drug product than another, then more of the first product should appear in the urine (for most drugs elimination is first order).
* Enough time should be allowed for the collection of the amount of absorbed drug in the urine (about five t1/2s)
* AU is the total amount of absorbed drug that is ultimately excreted unchanged
* AU is a measure of the extent of drug absorption

Question 87

plasma level time curves

Question 88

Relative Bioavailability

Answer 88

This compares the extent of absorption of a test product (generic drug) with a standard or reference product
* The systemic availability of a drug in a given drug product relative to its availability in a standard formulation (such as the Reference Listed Drug)
* For two products given at the same dose:

Relative Bioavailability 

Question 89

Relative Bioavailability II

Answer 89

• If the doses are not the same,

Relative Bioavailability

A high relative bioavailability means two products may be considered bioequivalent. It does not necessarily mean that either product is well absorbed

Question 90

Absolute Bioavailability

Answer 90

This is a reference to the fraction of the oral dose (of an individual product) that is absorbed.
* For the same drug dose given po and iv:

Absolute Bioavailability

Question 91

problem to solve

Question 92

Bioavailability Studies Rationale

Answer 92

these contribute to assure that standards of safety and effectiveness of a drug (identity, strength, purity etc..) are met.
* For new generic products (as well as new formulations of old drugs) FDA requires in vitro and/or in vivo studies of bioavailability along with essential pharmacokinetic parameters (such as t1/2, rates of absorption, excretion and metabolism) are met.
* Data from bioavailability studies help determine appropriate dose regimens

Question 93

Bioequivalence

Answer 93

Bioequivalent drug products show similar bioavailability when studied under similar conditions
* Bioequivalenceisdemonstratedbyestablishingthat no statistical difference exists among Cmax, tmax and AUC for the test and reference products
* Analysis of Variance (ANOVA) is a commonly used test (level of probability of < 0.05 and a power of 80% certainty). The average parameter value of the test product should be within 20% of that of the reference product

Question 94

Bioequivalence II

Answer 94

FDA: “The rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses”
* Or: where there is no difference in the extent of absorption but a significant difference in the rate of absorption that is intentional, reflected in the label and is medically insignificant

Question 95

Bioequivalence Studies

Answer 95

Typically single-dose (usually following an overnight fast), two-treatment, randomized cross over design. Plasma sample taken just before dose and at regular intervals thereafter. Food intervention studies and multiple-dose studies are sometimes performed

Question 96

table

Question 97

Bioequivalence Studies II

Answer 97

Latin square. Each subject receives each drug product only once, with sufficient time between product administrations to allow for : 1. full description of Cmax, tmax and AUC and 2. elimination of product from the body

– Replicated crossover design: estimates within- subject variance for both products. FDA recommends a four-period, two-sequence, two- formulation design

Question 98

table

Question 99

table

Question 100

Generic Substitution

Answer 100

Generic Substitution: Dispensing an unbranded product or a different brand in place of a prescribed product.
* Same dosage form, same active ingredient, different manufacturer.
* If permitted by prescriber
* The FDA publishes a list of drug products: Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book.
* Overall classification: A (deemed therapeutically equivalent) or B (inadequate evidence of bioequivalence)
* Two-letter codes used

Question 101

table

Question 102

Pharmaceutical Substitution

Answer 102

• Pharmaceutical Alternatives: same therapeutic entity but presented as different salts, complexes or esters. Also different dosage forms (e.g. elixirs, capsules and tablets) and strengths by a single manufacturer.
• Pharmaceutical Equivalents: same active ingredient, same amount of it, same dosage form for the same route of administration. Must meet same uniformity, disintegration and dissolution rates where applicable. May differ in features such as packaging, shape, color, release mechanism, excipients and some labeling details
• The process of dispensing a pharmaceutical alternative in place of a prescribed product.
• Needs prescriber approval

Question 103

Therapeutic Substitution

Answer 103

Therapeutic alternatives: different active ingredients share same indications and used for same therapeutic objectives e.g. ibuprofen instead of ASA
* Therapeutic equivalents: are pharmaceutic equivalents that are expected to have the same clinical effect and safety profile
* Therapeutic substitution involves the use of a therapeutic alternative

Question 104

Drug Review Process

Question 105

Drug Review Process II

Answer 105

Contrast New Drug Applications (NDAs) and Abbreviated New drug Applications (ANDAs)
* NDAs must have animal and clinical data along with bioavailablity data.
* ANDAs do not need these but must have bioequivalence data

Question 106

Biopharmaceutics Classification System

Answer 106

Used to predict in vivo absorption based on solubility and permeability characteristics
* Jw = PwCw
* Jw= drug flux (mass/area/time), Pw=permeability of membrane, Cw= drug concentration at intestinal membrane surface

Question 107

Biopharmaceutics Classification System II

Answer 107

According to the BCS, drug substances are classified as follows:
Class 1: high solubility–high permeability
Class 2: low solubility–high permeability
Class 3: high solubility–low permeability
Class 4: low solubility–low permeability

Question 108

Criteria Proposed by FDA for Consideration of BCS-Based Biowaivers of Immediate-Release Generic Drug Products

Question 109

table

Question 110

Recall: Mechanisms of Drug Movement III

Answer 110

Carrier-Mediated Transport
– Intestinal examples
– Facilitated Diffusion: carrier-mediated, moves along concentration gradient, requires no energy expenditure
– Active Transport: carrier-mediated, requires energy * VesicularTransport:exocytosis,endocytosis
* Pore Transport
* Ion-Pair Formation: e.g. propranolol + oleic acid, resulting in neutral (and so more lipophilic entity)

Question 111

Specialized Mechanisms of
Intestinal Absorption

Answer 111

Recall: anatomy and physiology of digestive system
* Lipid diffusion of unioinized molecule
* Aqueous diffusion of low molecular weight molecules
* Co-absorption with Lipids: some highly lipid soluble drugs are absorbed from the gut along with long chain fatty acid and their monoglycerides, fat-soluble vitamins and cholesterol e.g. griseofulvin
* Active Transport: some drugs are similar to nutrients that are naturally actively transported e.g. levodopa and methyldopa are taken up by an amino acid transport system, some anticancer drugs compete with pyrimidines for active transport system.
* Pinocytosis: some large M wt drugs (e.g. the complex of intrinsic factor and vitamin B12) are taken up by pinocytosis.

Question 112

table

Question 113

table

Question 114

Factors Affecting Gut Absorption:
pH

Answer 114

pH of gastric contents affects the degree of ionization of a drug and therefore its absorption. Drugs that are more than 0.01% ionized are only slowly and erratically absorbed
* The considerations can be complicated. Example of acidic drug ASA: 1/3 to 2/3 absorbed in the stomach despite low pH because of limitations of solubility. The rest of the dose is absorbed in the intestine.

Question 115

Factors Affecting Gut Absorption: Area of Absorbing Surface

Answer 115

Most absorption takes place in the small intestine (as opposed to the stomach) because the area of absorbing surface (about 200 m2, including the microvilli).
* Although the pKa of a drug may favor gastric absorption per unit area over intestinal, a good proportion may be absorbed in the intestine because of the surface area size

Question 116

Factors Affecting Gut Absorption: Dissolved Drug Concentration

Answer 116

Recall, for solid oral dosage forms, disintegration and dissolution must precede absorption
* First order absorption process depends on the concentration of dissolved drug
* Highest concentration is achieved on an empty stomach
* Lower concentrations are achieved with meals

Question 117

Factors Affecting Gut Absorption: GI Secretions

Answer 117

Gastric Acid: hydrolyzes a number of esters. This results in inactivation for certain drugs or the activation of certain other drugs (e.g. chlorazepate diazepam)
* Enzymes: proteolytic enzymes break up polypeptide drugs e.g. insulin, oxytocin

Question 118

Factors Affecting Gut Absorption: Bacterial Metabolism of Drugs

Answer 118

Commensal bacteria resident in the gut produce enzymes that could act on drugs or drug metabolites
* For instance, they act on glucuronide conjugates, the liberated drug moiety may then proceed along the enterohepatic shunt

Question 119

Factors Affecting Gut Absorption:
Metabolism During Absorption

Answer 119

Sulfate conjugating enzymes present in the intestinal mucosa can cause the inactivation of certain drugs (e.g. chlorpromazine) during absorption
* Amino acid decarboxylase and monoamine oxidase in the gut mucosa can inactivate part of an orally administered dose of levodopa (used to treat Parkinsonism). The rest of the dose can be decarboxylated in the periphery with only 1% entering the brain intact to be converted to dopamine. This is prevented by concomitant administration of the dopa decarboxylase inhibitor carbidopa. (Carbidopa does not enter the brain).
* Hydrolytic enzymes in the gut mucosa can inactivate glyceryl trinitrate (so given s/l). Hydrolysis of drugs such as ASA and dexamethsone phosphate does not result in loss of pharmacologic activity

Question 120

Factors Affecting Gut Absorption: Clearance After Absorption

Answer 120

Blood supply via the sub-mucosal capillaries is the limiting factor for the absorption of lipid-soluble drugs
* The faster the removal of a drug from its site of absorption (blood side), the greater the concentration gradient. This facilitates absorption either by lipid or aqueous diffusion.

Question 121

Factors Affecting Gut Absorption:
GI Motility

Answer 121

Non-propulsive Movements: contribute to solid dosage form disintegration and dissolution
* Propulsive Movements and Transit Time: determine the contact time between dissolved drug and absorbing surface.
– For drugs that are poorly absorbed from the intestine, drugs that increase contact time (e.g. opiates and anticholinergics) increase absorption.
– For drugs that are not absorbed in the stomach, slowing the rate of gastric emptying (e.g. by a fatty meal) slows the rate of absorption; stimulating gastric emptying (e.g. metoclopramide) increases the rate of absorption.

Question 122

Factors Affecting Gut Absorption: Disorders

Answer 122

In some patients, Crohn’s disease (inflammation of the distal small intestine and colon) causes a decrease in absorption of certain drugs (e.g. trimetoprim) and an increase in the absorption of others (e.g. clindamycin)
* In some patients, Celiac disease (inflammation mainly of the proximal small intestine) causes a decrease in absorption of certain drugs (e.g. digoxin) and an increase in the absorption of others (e.g. clindamycin)
* In achlorhydria patients (low level of acids in stomach), weakly basic drugs cannot form soluble salts and so precipitate out. HIV-AIDS patients show increased gastric transit time, achlorhydria and diarrhea
* In heart failure patients, reduced blood flow to the gut and reduced intestinal motility result in decreased and/or erratic drug absorption.

Question 123

Factors Affecting Gut Absorption:
Drug Interactions

Answer 123

Most interactions result in decreased absorption. Insoluble chelates can form if tetracyclines (or ciprofloxacin) are administered along with iron preparations or antacids or foods containing polyvalent cations.
* Anticholinergics (or drugs with anticholinergic effects) slow gastric emptying and so delay absorption
* Proton pump inhibitors may render the stomach achlorhydric.
* Non-absorbable ion-exchange resins such as cholestyramine can adsorb other drugs and so reduce their absorption.
* In some cases absorption is enhanced e.g. allopurinol increases iron absorption (by inhibiting a limiting transport system)

Question 124

Factors Affecting Gut Absorption: Enteric Shunts

Answer 124

• First Pass Effect
• Enterohepatic Shunts
• Other Enteric Shunts
  – Saliva (e.g. clonidine)
  – Gastric juice (e.g. quinine)
  – Bronchial secretions (e.g. bialamicol)

Question 125

Factors Affecting Gut Absorption:
Food and Nutrients

Answer 125

Food can interact physically or chemically with a drug (especially if the drug is taken shortly after a meal)
* Fatty food can reduce the absorption of certain drugs (e.g. sildenafil) and increase the absorption of others (e.g. griseofulvin)
* Food can stimulate bile flow (and result in double peaks)
* Food can cause a delay in gastric emptying (and result in double peaks)
* Food can change the gut pH
* Food can change the metabolism of a drug in the lumen
* On the other hand, food can reduce a drug’s irritation to the gut mucosa

Question 126

chart

Question 127

Factors Affecting Gut Absorption: Food and Nutrients II

Answer 127

Vitamin B12-Intrinsic factor complex is carried to the ileum, binds to a receptor. There is a separation and Vitamin B12 gets absorbed.
* Grapefruit juice can increase drug bioavailability:
– inhibits the pre-systemic absorption of certain drugs (inhibits the intestinal efflux transporter P- glycoprotein)
– inhibits certain cytochrome P450 enzymes (gut and/or liver) involved in metabolism

Question 128

chart

Question 129

Sublingual and Buccal Administrations

Answer 129

Absorptionintocirculationisdirect, circumventing the possibility of first pass effects
* Lipid soluble molecules are rapidly absorbed by this route. Useful for “emergency” drugs like glyceryl trinitrate and isoprenaline.
* Absorption of ionizable drugs, generally speaking, can be increased by suppressing their ionization e.g. by using a buffer

Question 130

Rectal and Vaginal Mucosa

Answer 130

Suppositories are solid but soften and melt at body temperature
* Drugs absorbed through the rectal mucosa get into the vena cava and so avoid first pass effects; enemas get into the colon and may reach the ileum and so may be subject to first pass effects
* Vaginal preparations are generally intended for local effects. However, absorption through the vaginal mucosa occurs

Question 131

Conjuctival and Nasal Mucosa

Answer 131

Drugs designed for conjuctival instillation generally act locally.
* Absorption occurs to some extent.
* Nasal drug delivery could be used for local or systemic effects.
* Nasal mucosa have a rich supply of blood vessels and can deliver a rapid therapeutic effect.

Question 132

Absorption after Inhalation

Answer 132

The lung has a large absorption surface.
* The airways filter inhaled matter to remove foreign material.
* Droplet size (aerosolization helps) and velocity of application control the extent to which inhaled material can penetrate the airways. Devices, such as spacers, can improve depth of inhalation.

Question 133

Absorption Through the Skin

Answer 133

Both local and systemic effects are possible; highly lipid soluble drugs penetrate the dermis; hydrophilic/ionizable drugs are impeded (unless driven through by some means e.g. electrophoresis)

Question 134

Absorption Following Parenteral Injections

Answer 134

Subcutaneous (hypodermic) and intramuscular:
– Subq injections are more painful because of rich sensory innervation of skin
– Larger volumes may be given i.m.
– Drug is disseminated after passage through capillary (M wt < 3000 or intermediate) or lymphatic (M wt > 20 000 or intermediate) endothelium.
* Intravenous: recall bolus administration and infusions. Drugs that may otherwise be irritating to tissues may be administered by this means.

Question 135

Absorption Following Parenteral Injections II

Answer 135

Others
- intradermal (used e.g. for test sera),
- intraperitoneal (rarely used in man; large absorption area so diffusion into blood is rapid);
- intrathecal (given into subarachnoid space for local action on meninges or spinal nerve roots);
- Intra-arterial (used e.g. in animal experiments to localize administration to a specific organ);

• intracardiac(e.g.duringcardiacsurgerywhenheart is exposed)