Exam 1 - Lecture 3 & 4, Drug ADME Flashcards

1
Q

Structure and physiochemical properties of cell membranes

A

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.

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2
Q

Factors determining diffusion of drugs across membrane

A

Concentration gradient (Fick’s law”

Lipid solubility of drug, many drugs weak acids or bases

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3
Q

Drug ionization acids

A

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

If pH is above pKa -> 50% ionized

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4
Q

Drug transport bases

A

If pH is lower than pKa -> 50% ionized

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

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5
Q

Drug trapping

A

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

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6
Q

Body fluids in which pH differences from blood pH cause trapping

A

stomach (pH 1.9-3)

small intestine (pH 7.5 -8)

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7
Q

Rates of permeation

A

log P > -5.0 = good permeation

log P < -5.0 = bad permeation

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8
Q

Active transport

A

requires energy, selective, saturable

can operate against electrochemical gradient

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9
Q

Facilitated transport

A

no energy required

cannot operate against electrochemical gradient

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10
Q

Facilitated transport transporters

A

NET, SERT, VMAT

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11
Q

Active transport transporters

A

MDR1 ( transport xenobiotics out of cells)

MRP1 ( Leukotriene secretion)

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12
Q

Factors that modify absorption

A

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

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13
Q

Oral administration

A

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)

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14
Q

sublingual administration

A

special form of oral drug admin

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

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15
Q

IV administration

A

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

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16
Q

IM administration

A

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

17
Q

SC administration

A

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

Disadvantages:
possible pain, necrosis at injection site

18
Q

Topical administration

A

at mucous membranes - absorption is rapid

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

19
Q

Inhalation administration

A

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

20
Q

Intrathecal administration

A

injection into spinal subarachnoid space

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

21
Q

Intra-arterial

A

for high local conc of drug in certain tissue

22
Q

Intraperitoneal

A

used in experimental lab procedures, rarely used clinically

23
Q

Drug route + bioavailability

A
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
24
Q

Factors which contribute to unequal distribution of drugs

A

BBB, drug reservoirs

25
Q

Drug distribution factors BBB

A

Capillary endothelium lacks intracellular pores

Astrocyte “glial feet” surround capillaries

“tight junctions” between endothelial cells

26
Q

Plasma protein binding as reservoir

A

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)

27
Q

Fat as a reservoir

A

many lipid soluble drugs conc in fat

a “stable” reservoir since blood flow is low

28
Q

Renal excretion

A

most important route

Ionized, polar form better eliminated than unionized

29
Q

3 proceses in kidney excretion

A

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

30
Q

Maintenance dose

A

Dosing Rate/F X Dosing interval

Dosing rate = Clearance X Target Conc

F = f X (1 - ER)

ER = CLliver / Q

31
Q

Loading dose

A

Volume of Distribution X Target Conc

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

32
Q

Bioavailability

A

the fraction of unchanged drug reaching the systemic circulation

33
Q

Zero - Order kinetic processes

A

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

34
Q

1st order kinetic processes concept equation

A

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
35
Q

Capacity - limited elimination

A

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

concentration keeps rising as dosing continues

36
Q

Flow - dependent elimination

A

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

37
Q

T1/2

A

time required for 50% completion of the process

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

k X T1/2 = 0.693

38
Q

Clearance

A

measure of the ability of body to eliminate drug

CL = rate of elimination / C

39
Q

Volume of distribution

A

measure of apparent space in body available to contain drug

V = Amount of drug in body / C