Lecture 2 - Physicochemical Properties in Relation to Drug Action

Question 1

Before a pharmacological response can be obtained, the drug must have what 6 qualities?

Answer 1

-must be soluble in water and transported by body fluids

-pass through many membrane barriers (lipophilic)

-survive attachment and storage to alternate inert sites

-endure metabolic attack

-penetrate to the site of action

-bind to the specific receptors and produce biological effect

Question 2

in order to produce a pharmacological response, the drug must

“survive attachment and storage to alternate inert sites”

explain what this means

Answer 2

“survive attachment” –
albumin is part of our plasma in systemic circulation. many drugs bind to this protein. HOWEVER, only non-bound (free) drugs are available for action.

“survive storage to alternate inert sites”
drug has to get to certain tissues — can’t be bound to albumin in our plasma

Question 3

what are 2 conflicting statements in the 6 requirements for a pharmacological response to be obtained?

Answer 3

the drug must be soluble in water in order to be transported by body fluids, yet the drug must also be somewhat lipophilic to be able to pass membranes

drug has to dissolve in GI fluids and then be transported through GI membrane. has to be a balance between hydrophilicity and lipophilicity

Question 4

explain how a potential drug must be able to endure metabolic attack in order to produce the desired effects

Answer 4

-anything that is ingested undergoes 1st pass effects from the liver. the liver metabolizes everything ingested in order to get rid of foreign chemicals, which is obviously not ideal for drugs

-also, there are enzymes in our plasma that destroy esters and other functional groups

Question 5

the site of action of a drug is often located where?

Answer 5

WITHIN the cell

Question 6

Drug + receptor –> ________—->_______

Answer 6

drug-receptor complex —> pharmacological response

Question 7

are drugs administered orally vs parenterally structurally similar?

Answer 7

NO – structurally different. this is bc parenteral drugs bypass the GI tract and 1st pass effects, so for starters the acidic conditions of the stomach are not a concern for survival of the drug

Question 8

what a drug is administered, it undergoes…..

these process are influenced by WHAT

Answer 8

ADME
absorption, distribution, metabolism, excretion

influenced by the physicochemical properties of the drug

Question 9

When a drug enters circulation, where does it go from there?

Answer 9

a few different fates:

-excreted (if very water soluble)

-goes back and forth between the site of action and circulation

-goes back and forth between circulation and metabolism. after being metabolized, the drug is either excreted or goes back into circulation

-goes back and forth btwn circulation and GI tract

Question 10

what route of administration can most easily use labile (easily changed) functional groups?

Answer 10

parenteral, but mainly INTRAVENOUS injections. bypasses 1st pass effects and acidic conditions of the stomach

Question 11

for a drug to be orally active, it must be soluble in __________

Answer 11

GI FLUID (water)

Question 12

a drug’s ability to dissolve in GI fluid is influenced by several factors such as what 5 things

Answer 12

-chemical structure
-particle size
-particle surface area
-crystal form
-tablet coating

Question 13

give a specific example of how chemical modification can be used to facilitate the drug’s ability to reach its target site

Answer 13

olsalazine is the chemically modified ORALLY ACTIVE prodrug of Mesalamine, which is orally INACTIVE

olsalazine gets bioreduced at the large intestine to form Mesalamine

Question 14

the creation of the prodrug Olsalazine is an example of modifying the ____ profile of a drug

Answer 14

AD profile (absorption and distribution)

Question 15

Olsalazine is used for what?

Answer 15

to treat ulcerative colitis

Question 16

which methods of administration place the drug directly into systemic circulation?

Answer 16

4 parenteral routes:

intravenous
intraarterial
intraspinal
intracerebral

Question 17

which parenteral methods of administration do NOT place the drug directly into circulation?
what happens instead?

Answer 17

subcutaneous
intramuscular
intraperitoneal

instead, a depot is produced and the drug enters circulation from there

Question 18

name the 3 MOST IMPORTANT physicochemical properties that affect the ABSORPTION and DISTRIBUTION characteristics of a drug

Answer 18

-solubility
-partition coefficient
-dissociation at body pH

Question 19

drugs are ionized at varying pH’s, depending on what?

Answer 19

their chemical structure

Question 20

name 10 commonly found polar functional groups in drug molecules.

which are acidic, basic, and neutral?
Which are the most polar?

Answer 20

hydroxyl
ether
aldehyde
ketone
amine (primary, secondary, and tertiary)
amide
ester
carboxylic acid
urea
carbamate

Carboxylic acid is weakly acidic, and amine is weakly basic. all the rest are neutral

amine and carboxylic acid are the most polar, then hydroxyl, and the rest are roughly the same

Question 21

explain how a hydroxyl group can differ

Answer 21

if attached to an aliphatic chain, the molecule is an alcohol. however, if the hydroxyl group is attached to an aromatic ring, it is a phenol

Question 22

at body pH, which of the 10 polar groups are most soluble?

Answer 22

amine and carboxylic acid

Question 23

explain why carboxylic acid and amine are the 2 most polar (and thus most soluble in water) of the 10 polar groups at physiological pH

Answer 23

they are weak acid and a weak base, respectively.
therefore, they partially ionize at a neutral pH. the ionized form is very soluble in water

Question 24

what is a “hybrid of an amine and ester”

Answer 24

carbamate

Question 25

what functional group is a carbonyl connected to 2 amines

Answer 25

urea

Question 26

polar functional groups facilitate the formation of ______ and help in_____

Answer 26

hydrogen bonds, solubilizing the drug in an aqueous medium

Question 27

water solubility of a molecule can be increased by what 2 things?

Answer 27

-attaching polar functional groups
-salt formation

Question 28

give 11 examples of polar functional groups/salts that can be added to a molecule to increase water solubility

Answer 28

-sodium succinate
-tartarate
-maleate
-HCl
-phosphate
-sulfate
-fumarate
-citrate
-Na+
-K+
-Ca++

Question 29

as mentioned, salt formation is a method of increasing water solubility of a molecule

what is the exception to this rule?

Answer 29

salts of organic bases INCREASE THE LIPOPHILICITY (decreased water solubility)

Question 30

as mentioned, salts of organic bases are unique because they increase the lipophilicity of the molecule
how is this used to our advantage?

Answer 30

used to increase the duration of action

Question 31

give 2 examples of organic bases

Answer 31

benzathine and procaine

Question 32

give a specific class of drugs that uses the salts of organic bases to increase the duration of action

Answer 32

systemic anesthetics

Question 33

what is the rate limiting condition of a drug reaching its site of action?

Answer 33

the movement of drugs through a series of membranes

Question 34

since the rate limiting condition for reaching the site of action involves the movement of the drug through a series of membranes, the _____ of a drug has a MAJOR INFLUENCE ON ITS TRANSPORT CHARACTERISTICS

Answer 34

partition coefficient

Question 35

true or false

only passive transport is involved in the transport of drugs across biological membranes

Answer 35

false – both active and passive, BUT most drugs rely on their lipophilicity to passively diffuse through the membrane

Question 36

active passage involves a ____ system, such as what 3 things?

Answer 36

a CARRIER SYSTEM such as enzymes, amino acids, or Na+/K+ ions

Question 37

true or false

energy is used by the body in active transport

Answer 37

TRUE

Question 38

What kinds of naturally occurring things are absorbed through an active absorption process?

Answer 38

vitamins, amino acids, and sugars

Question 39

natural dietary components and cellular metabolites are absorbed by active or passive diffusion?

Answer 39

ACTIVE (ie: vitamins, amino acids, and sugars)

Question 40

how are drugs that resemble metabolic precursors/intermediates transported into the cell?

Answer 40

through ACTIVE TRANSPORT

Question 41

give 4 examples of drugs that resemble metabolic precursors/intermediates

Answer 41

-methyldopa
-5-flurouracil
-penicillamine
-levodopa

Question 42

explain how the drug 5-flurouracil is a drug resembling a metabolic precursor/intermediate

Answer 42

5-flurouracil is fluorinated uracil. it is close enough in structure to uracil to use the same active transport mechanism to get into the cell and cause an effect

Question 43

explain how levodopa (L-dopa) is an example of a drug that resembles a metabolic precursor/intermediate

Answer 43

L-dopa is the natural precursor to dopamine. As a drug, it is used to control Parkinson’s symptoms.
L-dopa gets metabolized into dopamine

Question 44

what is the reason for using the metabolic precursor to dopamine as a drug, and not just using dopamine itself?

Answer 44

if straight dopamine is ingested, it goes nowhere – doesn’t reach the intended site.
administering the chemical precursor allows L-dopa to become dopamine IN THE BODY and is not blocked by things in our body such as the BBB (blood brain barrier)

Question 45

name the 3 ways in which active passage differs from passive diffusion

Answer 45

-the transport of the drug occurs AGAINST the concentration gradient

-At a high drug concentration, the transport mechanism can be SATURATED (no more can pass)

-if there are structurally similar compounds around that closely resemble the drug, there may be competition to be transported