before you study the mechanism of action of drugs I think it's important that you
understand the concept of pharmacokinetics and pharmacodynamics so
this lecture is all about pharmacokinetics and the easiest way to
remember what pharmacokinetics refers to is to think of it in terms of what
the body does to a drug so let's think about it when you either swallow a
tablet or apply a cream on your skin the first thing that takes place is
absorption so the drug has to absorb and once it gets absorbed either through
skin or through stomach it gets into your bloodstream and then from there it
gets distributed into the fluids outside and inside the cells so once the drug
gets distributed all over the body the body starts metabolizing it basically
modifying the drug so that it's easy to excrete this is done primarily by a
liver but it can also be done by other tissues so for simplicity drug passes
through liver gets biotransformed and finally it gets eliminated so
elimination is the last step in which drug and its metabolites get excreted
primarily in bile urine and feces so now let's quickly recap what we learned
about pharmacokinetics well first drug has to get absorbed secondly once it
reaches systemic circulation it gets distributed outside and inside the cells
then it starts to get metabolized and liver plays important role in that
finally drug gets eliminated now let's break down these steps
and let's talk about them in a little bit more detail there's many routes by
which we can administer a drug such as parenteral topical nasal rectal etc but
unless the drug is given IV it must cross some membrane before it gets into
systemic circulation so absorption of drugs can happen in four different ways
first through passive diffusion secondly through facilitated diffusion thirdly
through active transport and finally through endocytosis so let's talk about
passive diffusion first most drugs are absorbed by passive diffusion in passive
diffusion drugs simply move from area of high concentration to area of lower
concentration so if it's a water-soluble molecule it will easily move through a
channel or a pore that's in the membrane now on the other hand if it's lipid
soluble it will just easily pass through a membrane without any help whatsoever
so now let's move on to a facilitated diffusion so other drugs especially
larger molecules will pass with the help of carrier proteins just like in passive
diffusion they also move from area of high concentration to area of low
concentration and the only difference is that they actually need a little bit of
help from the carrier proteins that are in the membrane let's move on to active
transport some drugs are transported across membrane via active energy
dependent transport unlike passive and facilitated diffusion energy for this
process is derived from ATP when ATP undergoes hydrolysis to ADP there is a
high energy that comes from breaking of phosphate bond lastly in endocytosis
drugs of very large size get transported via engulfment by cell membrane because
of their large size they wouldn't fit in a channel or a pocket of a carrier
protein
you also need to remember that absorption is not exactly that
straightforward it's a variable process depending on pH surface area and blood
flow and this also leads us to a concept of bioavailability so let me ask you a
question if you take a 100 milligram oral tablet how much of it gets actually
absorbed in unchanged form the answer is it's not a 100 percent this is
because unlike drug given intravenously oral medication gets metabolized in gut
and in the liver and good portion of it gets cleared out before it reaches
systemic circulation the cool thing is that once we administer drug either
orally or intravenously we can then measure the plasma drug concentration
over time so a drug given IV would start at a concentration of 100 percent
because it bypasses the whole absorption process however a drug given orally
would have to get absorbed first and then some of it would get eliminated
before it even reaches systemic circulation
therefore it's curve would look a little different once we can graph this
phenomenon we can then find areas under these curves also known as AUC AUC is
really helpful in making comparisons between formulations and routes of
administration so finally knowing all that bioavailability is simply AUC for
the oral drug over AUC for the IV drug times 100 once the drug gets absorbed it
then gets distributed from circulation to the tissues distribution process is
dependent on a few different factors such as lipophilicity so highly
lipophilic drug will dissolve through some membrane much easier than the
hydrophilic drug next we have blood flow some organs such as brain receive more
blood flow than for example skin so if a drug can pass through blood-brain
barrier it will accumulate much faster in the brain as opposed to in the skin
next we have capillary permeability for instance capillaries in the liver have
lots of slit junctions through which large proteins can pass on the other
hand in the brain there are no slit junctions at all so
it's more difficult for a drug to pass through next we have binding to plasma
proteins and tissues so due to their chemical properties some drugs will
accumulate in some tissues more than the others
also many drugs will bind to albumin which is a major drug binding protein
that will significantly slow the distribution process finally we need to
factor in the volume of distribution which is theoretical volume that the
drug would have to occupy in order to produce the concentration that's present
in blood plasma so volume of distribution can be calculated by taking amount of
drug in the body and dividing it by concentration of drug in blood plasma so
for example high molecular weight drugs tend to be extensively protein bound and
don't pass through the capillaries as easy as smaller molecules thus they have
higher concentration in blood plasma and lower volume of distribution typically
opposite is true for lower molecular weight drugs especially the lipophilic
ones which will distribute extensively into tissues and will result in larger
volume of distribution so the bottom line is volume of distribution helps
predict whether the drug will concentrate largely in the blood or in
the tissue this is really helpful in estimating drug dosing for example if
drug has large volume of distribution we would need to administer a larger dose
to achieve desired concentration the last step in the pharmacokinetic process
is elimination which refers to clearing of a drug from the body mainly through
hepatic renal and biliary route so the total body clearance is simply the sum
of individual clearance processes most of drugs are eliminated by first order
kinetics which means that the amount of drug eliminated over time is directly
proportional to the concentration of drug in the body what this means is that
for example starting with 1000 milligrams of a drug the amount eliminated per
each time period will be different but the fraction will be constant so in this
example per each time period constant of 16 percent of a drug gets eliminated
however the milligram amount changes and if we were to collect
these samples and plot them the graph would produce a curve that looks
something like this now there are few drugs such as Aspirin
that are eliminated by zero order kinetics which means that the amount of
drug eliminated is independent of drug concentration in the body so the rate of
elimination is constant and if we were to take 1000 milligrams again as an
example this time amount of drug eliminated is the same per each time
period which is 200 milligrams but the fraction the percentage is different and
if we were to graph it the zero order elimination would produce a straight
line also the cool thing about these graphs is that if we can plot them it's
easy to determine half-life of a drug from them so a half-life is simply the
time that is required to reduce drug concentration in plasma by a half this is
important piece of information which along with the volume of distribution it
can tell us a lot about duration of action of a drug half-life also helps us
predict steady state concentrations so when doses of a drug are repeatedly
administered a drug will accumulate in the body until the rate of
administration equals the rate of elimination this is what we call steady
state so if we were to graph it when after each additional dose the peak and
trough concentrations stay the same we know we reached steady state this is
typically attained in about 4 to 5 half-lives the reason why we are
interested in steady state is because we want concentration of a drug high enough
to be effective but not too high to be toxic so the goal is to maintain steady
state concentration within therapeutic range now there are situations
such as life-threatening infections during which we can't waste time getting
to steady-state so to compensate for accumulation time large loading dose can
be administered on treatment initiation to reach desired concentration more
rapidly now the most important route of elimination is through kidney
which excrete drugs into the urine however a kidney can't efficiently get rid
of lipid soluble drugs as there a passively reabsorbed and that's where
the liver comes to the rescue by transforming lipophilic drugs into water
soluble substances that are then easily removed by kidneys liver accomplishes
that mainly through two metabolic reactions called phase 1 and phase 2
now let's talk about these reactions in more details so phase 1 reactions are
all about making a drug more hydrophilic these reactions involve
introduction or unmasking of a polar functional group so in phase 1 we are
going to see oxidation hydrolysis and reduction it's also important to
remember that most of these reactions are catalyzed by cytochrome p450 enzymes
now if metabolites from phase 1 are still too lipophilic they can undergo
conjugation reaction which involves addition of a polar group and this is
what happens in phase 2 so in phase 2 we are going to see
glutathione conjugation acetylation sulfation and glucuronidation these
reactions produce polar conjugates which cannot diffuse across membranes
therefore they're easily eliminated from the body now let's go back to cytochrome
p450 this large family of enzymes is essential for the metabolism of drugs
and although I wouldn't recommend anyone to memorize all of them there are few
that are worth remembering because they catalyze vast majority of phase 1
reactions and these are the following CYP 3A4 and 5 CYP 2D6 CYP 2C8 and 9
and CYP 1A2 many drug interactions arise from drug's ability to induce or
inhibit these enzymes some of the important inducers include Phenytoin
Carbamazepine Rifampin alcohol with chronic use barbiturates and St. John's Wort
and good mnemonic that you can use to remember these is
"PCRABS" on the other hand some of the important inhibitors are grapefruit
protease inhibitors azole antifungals Cimetidine macrolides
with exception of Azithromycin Amiodarone nondihydropyridine calcium
channel blockers such as Diltiazem and Verapamil and again good mnemonic that
you can use to remember these is "GPACMAN" and with that I wanted to thank
you for watching and I hope you enjoyed this video