Exam 1 - Lecture 3 & 4, Drug ADME

Question 1

Structure and physiochemical properties of cell membranes

Answer 1

Lipid bilayer with protein embedded…

Polar, ionized groups of molecules located on surfaces

Hydrophobic, non-polar lipid side chains oriented toward inside of membrane bilayer

Membrane contains aqueous channels of small diameter so permit passage only of water of small water-soluble molecules or ions

Most drugs must cross membrane by diffusion through it, therefore they must dissolve in lipid layer.

Question 2

Factors determining diffusion of drugs across membrane

Answer 2

Concentration gradient (Fick’s law”

Lipid solubility of drug, many drugs weak acids or bases

Question 3

Drug ionization acids

Answer 3

If pH is lower than pKa -> 50% non-ionized

If pH is above pKa -> 50% ionized

Question 4

Drug transport bases

Answer 4

If pH is lower than pKa -> 50% ionized

If pH is above pKa -> 50% non-ionized

Question 5

Drug trapping

Answer 5

Weak acids excreted faster in alkaline urine

Weak bases excreted faster in acidi urine

Drug diffuses across membrane, then becomes ionized and trapped so cant be reabsorbed and thus gets excreted

Question 6

Body fluids in which pH differences from blood pH cause trapping

Answer 6

stomach (pH 1.9-3)

small intestine (pH 7.5 -8)

Question 7

Rates of permeation

Answer 7

log P > -5.0 = good permeation

log P < -5.0 = bad permeation

Question 8

Active transport

Answer 8

requires energy, selective, saturable

can operate against electrochemical gradient

Question 9

Facilitated transport

Answer 9

no energy required

cannot operate against electrochemical gradient

Question 10

Facilitated transport transporters

Answer 10

NET, SERT, VMAT

Question 11

Active transport transporters

Answer 11

MDR1 ( transport xenobiotics out of cells)

MRP1 ( Leukotriene secretion)

Question 12

Factors that modify absorption

Answer 12

Lipid solubility and degree of ionization

Dissolution rate - solubility at absorption site

Concentration at site of absorption

Circulation to site of absorption

Area of absorptive surface

Molecular size

Question 13

Oral administration

Answer 13

Advantages: safest, most convenient and economical, no special devices

Disadvantages: low pH or food can alter absorption are, patient compliance

weak acids best absorbed in stomach (pH 1)
weak bases best absorbed in intestine (pH 1-7)

Question 14

sublingual administration

Answer 14

special form of oral drug admin

absorption across oral mucosa of certain non-ionized, lipid soluble drugs

Question 15

IV administration

Answer 15

Advantages: speed, accuracy, control, useful in emergency situations, titrate dosage, can give large volume

disadvantages: no turning back, must inject slowly, risk of adverse effect from too rapid injection

Question 16

IM administration

Answer 16

Advantages:
can control rate of absorption, suitable for depot-type injection, less pain than s.c.,

sites with highest blood flow allow fastest absorption.

slow absorption from oils or other vehicles

Question 17

SC administration

Answer 17

Advantages:
can control rate of absorption; suitable for insoluble suspensions, pellet implants

Disadvantages:
possible pain, necrosis at injection site

Question 18

Topical administration

Answer 18

at mucous membranes - absorption is rapid

at skin surface - most drugs not readily absorbed; proportional to lipid solubility at epidermis

Question 19

Inhalation administration

Answer 19

absorption across pulmonary alveolar epithelium

rapid access to circulation due to large surface area

major means by which toxic substances enter body; allergens and environmental contaminants

Question 20

Intrathecal administration

Answer 20

injection into spinal subarachnoid space

for admin to cerebrospinal axis of drugs which do not cross BBB

Question 21

Intra-arterial

Answer 21

for high local conc of drug in certain tissue

Question 22

Intraperitoneal

Answer 22

used in experimental lab procedures, rarely used clinically

Question 23

Drug route + bioavailability

Answer 23

IV = 100%, most rapid onset
IM = 75-100%, larger volumes more often feasible 
SC = 75-100%, smaller volumes than IM
Oral = 5-100%, most convenient
Rectal = 30 - <100%, less 1st pass than oral
Inhalation = 5 - <100%, rapid onset
Transdermal = 80 - <100%, used for lack of 1st pass

Question 24

Factors which contribute to unequal distribution of drugs

Answer 24

BBB, drug reservoirs

Question 25

Drug distribution factors BBB

Answer 25

Capillary endothelium lacks intracellular pores

Astrocyte “glial feet” surround capillaries

“tight junctions” between endothelial cells

Question 26

Plasma protein binding as reservoir

Answer 26

many drugs bind to albumin

binding usually reversible, provides depot

plasma protein binding limits conc of free drug in tissues

as unbound drug conc falls, protein bound drug is freed; process prolongs drug effect

protein binding capacity limited, therefore saturable

drugs can compete for binding sites, displacement of 1 can increase activity of other (adverse drug interactions)

Question 27

Fat as a reservoir

Answer 27

many lipid soluble drugs conc in fat

a “stable” reservoir since blood flow is low

Question 28

Renal excretion

Answer 28

most important route

Ionized, polar form better eliminated than unionized

Question 29

3 proceses in kidney excretion

Answer 29

Glomerular filtration:
blood filtered, unbound drug passes through pores into filtrate, protein bound drug cannot pass pores and remains in blood

Active tubular secretion:
ionized drug actively transported from blood into proximal tubule

Passive reabsorption:
unionized drug can passively diffuse out of proximal and distal tubules back into blood

Question 30

Maintenance dose

Answer 30

Dosing Rate/F X Dosing interval

Dosing rate = Clearance X Target Conc

F = f X (1 - ER)

ER = CLliver / Q

Question 31

Loading dose

Answer 31

Volume of Distribution X Target Conc

promptly raises the concentration of drug in plasma to the target concentration

Question 32

Bioavailability

Answer 32

the fraction of unchanged drug reaching the systemic circulation

Question 33

Zero - Order kinetic processes

Answer 33

Constant amount of drug is processed per unit time, rate is constant, independent of drug concentration and encountered rarely

Question 34

1st order kinetic processes concept equation

Answer 34

Constant fraction (or %) of drug is processed per unit time. rate of process is exponential

ka = rate constant for absorption
ke = rate constant for elimination

Question 35

Capacity - limited elimination

Answer 35

If dosing exceeds elimination capacity, steady state cannot be achieved.

concentration keeps rising as dosing continues

Question 36

Flow - dependent elimination

Answer 36

Drugs cleared very readily by organ of elimination, so that any clinically realistic concentration of the drug is eliminated on 1st pass.

These drugs are known as “high-extraction” drugs

Question 37

T1/2

Answer 37

time required for 50% completion of the process

in 4 half-times, 95% drug gone/ process complete

k X T1/2 = 0.693

Question 38

Clearance

Answer 38

measure of the ability of body to eliminate drug

CL = rate of elimination / C

Question 39

Volume of distribution

Answer 39

measure of apparent space in body available to contain drug

V = Amount of drug in body / C