Lecture 2 - Physicochemical Properties in Relation to Drug Action Flashcards
part 1
Before a pharmacological response can be obtained, the drug must have what 6 qualities?
-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
in order to produce a pharmacological response, the drug must
“survive attachment and storage to alternate inert sites”
explain what this means
“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
what are 2 conflicting statements in the 6 requirements for a pharmacological response to be obtained?
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
explain how a potential drug must be able to endure metabolic attack in order to produce the desired effects
-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
the site of action of a drug is often located where?
WITHIN the cell
Drug + receptor –> ________—->_______
drug-receptor complex —> pharmacological response
are drugs administered orally vs parenterally structurally similar?
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
what a drug is administered, it undergoes…..
these process are influenced by WHAT
ADME
absorption, distribution, metabolism, excretion
influenced by the physicochemical properties of the drug
When a drug enters circulation, where does it go from there?
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
what route of administration can most easily use labile (easily changed) functional groups?
parenteral, but mainly INTRAVENOUS injections. bypasses 1st pass effects and acidic conditions of the stomach
for a drug to be orally active, it must be soluble in __________
GI FLUID (water)
a drug’s ability to dissolve in GI fluid is influenced by several factors such as what 5 things
-chemical structure
-particle size
-particle surface area
-crystal form
-tablet coating
give a specific example of how chemical modification can be used to facilitate the drug’s ability to reach its target site
olsalazine is the chemically modified ORALLY ACTIVE prodrug of Mesalamine, which is orally INACTIVE
olsalazine gets bioreduced at the large intestine to form Mesalamine
the creation of the prodrug Olsalazine is an example of modifying the ____ profile of a drug
AD profile (absorption and distribution)
Olsalazine is used for what?
to treat ulcerative colitis
which methods of administration place the drug directly into systemic circulation?
4 parenteral routes:
intravenous
intraarterial
intraspinal
intracerebral
which parenteral methods of administration do NOT place the drug directly into circulation?
what happens instead?
subcutaneous
intramuscular
intraperitoneal
instead, a depot is produced and the drug enters circulation from there
name the 3 MOST IMPORTANT physicochemical properties that affect the ABSORPTION and DISTRIBUTION characteristics of a drug
-solubility
-partition coefficient
-dissociation at body pH
drugs are ionized at varying pH’s, depending on what?
their chemical structure
name 10 commonly found polar functional groups in drug molecules.
which are acidic, basic, and neutral?
Which are the most polar?
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
explain how a hydroxyl group can differ
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
at body pH, which of the 10 polar groups are most soluble?
amine and carboxylic acid
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
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
what is a “hybrid of an amine and ester”
carbamate
what functional group is a carbonyl connected to 2 amines
urea
polar functional groups facilitate the formation of ______ and help in_____
hydrogen bonds, solubilizing the drug in an aqueous medium
water solubility of a molecule can be increased by what 2 things?
-attaching polar functional groups
-salt formation
give 11 examples of polar functional groups/salts that can be added to a molecule to increase water solubility
-sodium succinate
-tartarate
-maleate
-HCl
-phosphate
-sulfate
-fumarate
-citrate
-Na+
-K+
-Ca++
as mentioned, salt formation is a method of increasing water solubility of a molecule
what is the exception to this rule?
salts of organic bases INCREASE THE LIPOPHILICITY (decreased water solubility)
as mentioned, salts of organic bases are unique because they increase the lipophilicity of the molecule
how is this used to our advantage?
used to increase the duration of action
give 2 examples of organic bases
benzathine and procaine
give a specific class of drugs that uses the salts of organic bases to increase the duration of action
systemic anesthetics
what is the rate limiting condition of a drug reaching its site of action?
the movement of drugs through a series of membranes
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
partition coefficient
true or false
only passive transport is involved in the transport of drugs across biological membranes
false – both active and passive, BUT most drugs rely on their lipophilicity to passively diffuse through the membrane
active passage involves a ____ system, such as what 3 things?
a CARRIER SYSTEM such as enzymes, amino acids, or Na+/K+ ions
true or false
energy is used by the body in active transport
TRUE
What kinds of naturally occurring things are absorbed through an active absorption process?
vitamins, amino acids, and sugars
natural dietary components and cellular metabolites are absorbed by active or passive diffusion?
ACTIVE (ie: vitamins, amino acids, and sugars)
how are drugs that resemble metabolic precursors/intermediates transported into the cell?
through ACTIVE TRANSPORT
give 4 examples of drugs that resemble metabolic precursors/intermediates
-methyldopa
-5-flurouracil
-penicillamine
-levodopa
explain how the drug 5-flurouracil is a drug resembling a metabolic precursor/intermediate
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
explain how levodopa (L-dopa) is an example of a drug that resembles a metabolic precursor/intermediate
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
what is the reason for using the metabolic precursor to dopamine as a drug, and not just using dopamine itself?
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)
name the 3 ways in which active passage differs from passive diffusion
-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
