Pharmacology – PHARMACOKINETICS (MADE EASY)
28
August

By Adem Lewis / in , , , , , , , , , , , , , , , , , , , , , , /


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


100 thoughts on “Pharmacology – PHARMACOKINETICS (MADE EASY)

  1. why my nursing school taught me:
    zero order drug half life = Initial Conc./2K
    First order drug half life= 0.693/K
    that means zero order drug elimination depends on the dose
    while first order drug is constantly eliminating

    This is opposite to yours! WHY?!!! I am so confused.

  2. wow…wow…wow…all the lectures of speed pharmacology are just super awesome…I start enjoying pharma..thanku so much sir

  3. His accent reminds me of Doctor Doofenshmirtz from Phineas and Ferb! (This is not an insult, you're an amazing instructor thank you).

  4. Such an informative and simple way to illustrate the complex concepts of pharmacokinetics, thanks man.

  5. This is so helpful to study my Biopharamaceutics. Your videos are so helpful to me as a Pharmacy student ๐Ÿ˜ญ๐Ÿ˜ญ๐Ÿ˜ญ thank you. Its so easy to understand

  6. These are gems sir! Awesome videos! Can you please upload something regarding neurotransmitters and antiepileptic drugs?

  7. Amazing video. Very informative. I was wondering if you could make a video with a stepwise tutorial of the phase 1 and phase 2 mechanisms of elimination. My professorโ€™s explanation is a little wonky. Thanks ๐Ÿ‘๐Ÿป๐Ÿ‘๐Ÿป๐Ÿ‘๐Ÿป๐Ÿ‘๐Ÿป๐Ÿ‘๐Ÿป

  8. Thank you very much for the video! It is very understandable and useful. May I have a question unrelated to the topic? Speaker (lecturer) where are you from? What is your accent?

  9. the most fun part of these videos are that i'm imagining doofenshmirtz from phineas and ferb teaching us. please tell me i'm not the only one!

  10. My question is, if a drug has a half life of say 66 hours, and you were to take it every 24 hours (everyday indefinitely); how does the drug not build up in your system or else otherwise over-tax your liver in effort to breakdown the drug fast enough in order not to over-accumulate, since it is being taken again and again every 24 hours?

  11. To be honest, he is much better than any doctor/teacher <3 thank you for these videos <3

  12. JUST BLOWED my whole mind away!!! You expained in 5 min the best way I knew than 5 years in my med school.

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