Lecture 2 -Lecture 3 Flashcards
most drugs pass through biological membranes according to what?
their partition coefficients
what does “foreign organics” mean
explains most drug molecules
the higher the partition coefficient……
the higher the lipophilicity, and thus the easier it is to cross the membranes
how do you calculate the partition coefficient of a drug?
PC = solubility in organic phase/solubility in aqueous phase
can anything other than lipophilic substances diffuse through the biological membrane?
YES – there is a specialized situation in which water, ions, and low MW polar compounds can diffuse through AQUEOUS CHANNELS in the membrane
the biological membranes are highly _____
lipophilic
true or false
more lipophilic = worse absorption
FALSE – better absorption (more drug goes into cell)
compare the relative partition coefficients of phenobarbital, secobarbital, barbital, and pentobarbital
what does this mean about their % absorption?
HIGHEST PC = secobarbital
pentobarbital
phenobarbital
LOWEST PC = barbital
this means that secobarbital has the highest % absorbed (50%) and barbital has the lowest % absorbed (10%)
true or false
the higher the partition coefficient of a drug, the higher the % absorbed
TRUE
In general, as the PC increases, % drug absorbed also increases.
HOWEVER……
the lipophilicity of the drug should be OPTIMUM (not too high, not too low)
give 3 things that can happen if a drug is too lipophilic
-it may become INSOLUBLE in biological fluids and start clumping
-it may be lost to neutral fats
-it may undergo rapid metabolism
give 2 things that can happen if a drug is too hydrophilic
-it cannot pass through biological membranes readily
-it is excreted rapidly
modifying a drug to increase lipophilicity is favorable but…..
only up to a certain extent (don’t want too lipophilic bc the drug may become insoluble in body fluids and start clumping, be lost to neutral fats, or undergo rapid metabolism)
is the target of a drug usually extracellular or intracellular
intra
most drugs are….
weak acids or weak bases
“degree of ionization” can be represented by…
pka
most drugs are weak acids or weak bases and their ____ and _____ of the environment influence their LIPID/WATER SOLUBILITIES
most drugs are weak acids or bases and their PKA (degree of ionization) and PH OF THE ENVIRONMENT influence their lipid/water solubilities
true or false
passing in/out of biological membranes is important for drug delivery
TRUE
unionized molecules possess higher _____ (water or lipid?) solubility
lipid
unionized molecules pass most membrane barriers _____(more or less readily) than ionized molecules.
MORE READILY
give 2 reasons why unionized molecules pass most membrane barriers more readily than ionized molecules
- the lipoprotein that forms the cell membrane is highly charged. therefore, ionized molecules will either be REPELLED or BOUND TIGHTLY (depending on opposite or like charges) which decreases membrane penetration
- ionized molecules get hydrated and thus increase in size – larger in size than their corresponding unionized species which makes it harder to cross the membrane
explain the Bronsted-Lowry theory of acids and bases
(include: what an acid and a base are, what happens when they undergo a reaction)
an acid is any substance capable of yielding a proton
a base is any substance capable of accepting a proton
when an acid gives up a proton to a base, it is converted to its conjugate base
when a base accepts a proton from an acid, it is converted to its conjugate acid form
give the formula of methylamine.
is it an acid or base?
CH3NH2
base.
when it accepts a proton, it becomes CH3NH3+ (methylammonium)
what is the ionized form of acetic acid
CH3COO- (acetate)
give the Henderson-Hasselbalch equation
pH = pka + log [A-]/[HA]
give the variation of the Henderson-Hasselbalch equation that can be used to calculate the pka of weak acids and bases
pka=pH + log [protonated form]/[unprotonated form]
protonated form = HA
unprotonated form = A-
“protonated form” does this mean it’s ionized or unionized?
it depends on if the substance is a base or an acid
when bases are protonated, they’re converted to their ionized form (BH+)
When acids are protonated, they’re converted to their unionized form (HA)
what does %I mean
% ionized
when pH = pka, what can you say about % ionization?
% ionized = % unionized
50%-50%
when pH <pka, what can you say about % ionization?
what area in the body mimics these conditions?
when pH<pka, protonated forms predominate
stomach has these conditions
the pka for acidic drugs is usually around what value?
3
in an acidic environment, will basic drugs be ionized or unionized?
what does this mean?
ionized – therefore, basic drugs are not well absorbed in the stomach
when pH>pka, do protonated or deprotonated forms predominate?
what area of the body has these conditions?
deprotonated forms predominate
these are the conditions of the small intestine
in the small intestine, which are more likely to be absorbed better – weakly acidic or weakly basic drugs as compared to the stomach?
the small intestine has a higher pH in the stomach.
deprotonated forms predominate.
weakly basic drugs will be unionized and are thus better absorbed
give a representation by using letters of a protonated acid and an unprotonated acid, as well as a protonated base and an unprotonated base
protonated acid – HA
deprotonated acid – A-
deprotonated base – B
protonated base – BH+
in terms of letters, what is the unionized form of an Acid, and what is the unionized form of a base
unionized acid = HA
unionized base = B
the distribution of a drug between the ionized and unionized form depends on…
the pH of the medium and the pka of the drug
ka=…
concentration of products/concentration of reactants
true or false
most drug molecules reach the site of action
FALSE
most drug molecules do NOT survive to reach the site of action.
why?
they can undergo 4 different things that prevent reaching the site of action
-protein binding
-binding to neutral fats
-drug metabolism
-excretion
name 4 sites of loss for drugs before they reach the site of action.
explain them too
-protein binding – many drugs are highly protein bound and will bind to a serum protein like albumin. they must be free in order to reach the site of action
-binding to neutral fats – especially if the drug is very lipophilic
-drug metabolism – especially the case for oral drugs. 1st pass effects (liver) destroys most of the drug (especially if very lipophilic)
-excretion – water soluble drugs go straight out in urine and dont need to be metabolized
drug metabolism is a site of loss for drugs.
for which drugs is this most relevant?
oral drugs because of 1st pass effects
for which drugs is excretion the biggest concern as a site of loss?
very water soluble drugs – go straight into urine and aren’t even metabolized
most and almost all drugs bind to albumin in the blood plasma in a _____ fashion
REVERSIBLE
the drug can unbind if free drug clears (through excretion/metabolism/reaches site of action) to maintain equilibrium
true or false
protein binding to albumin is NOT unidirectional
true - it can unbind
drug-protein binding is due to what force(s)?
ionic and/or nonionic bonding
is drug-protein binding selective or nonselective?
nonselective
when a drug undergoes protein binding, it cannot cross the membranes, and is said to be _____
INACTIVE
Can a drug that is bound to protein be metabolized or excreted?
explain
NO.
therefore, protein binding can be used to our advantage to prolong the duration of the drug’s activity
give an example of a drug that uses its protein binding affinity to prolong the duration of action
trypanocide suramen
this is an anti-parasite that binds to the protein (can’t be metabolized when bound)and slowly releases in order to increase the duration of action. bound drug serves as a depot - slow release, and long duration of action
what is the clinical significance of drug-protein binding?
bound drugs and endogenous substances (substances within the body) can be displaced by other drugs, leading to DRUG INTERACTIONS
Give 2 examples of drug interactions related to drug-protein binding
warfarin (anticoagulant) is displaced from its albumin-binding sites by several drugs such as phenylbutazone, clofibrate, and sulfonamides
bilirubin (breakdown byproduct of blood cells) is protein bound and can be displaced by sulfonamides and other organic anions. issue for fetus and newborn
why is the protein-binding interaction of warfarin a significant concern?
warfarin has a narrow therapeutic index, meaning anything that alters its blood concentration can be dangerous.
many drugs (ie phenylbutazone, clofibrate, and sulfonamides) have albumin binding sites so this is a big clinical concern. the binding is not very specific in the case of albumin
the sulfonamides are ___ ___
organic anions
organic anions displace what from its protein binding site?
also, give a specific example of a drug that is an organic anion
displace bilirubin
sulfonamides
