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0:00In the name of God, the Most Gracious,
0:01the Most Merciful.
0:02In this lecture, guys, let’s talk about
0:05one of the very important topics in
0:07cardiovascular pharmacology.
0:09That is, anticoagulant drugs.
0:13Because we will need to use them often,
0:15and of course, they are medications that
0:16come with many notes you must pay
0:17attention to.
0:20Let's start by refreshing your memory on
0:22the physiology information that we must
0:25know and remember.
0:27So that we can build upon it the
0:28pharmacological information that will
0:29follow shortly.
0:31I will remind you that regarding
0:33coagulation, you learned in physiology
0:36that we have something called...
0:40There were about 12.
0:42These 12 factors or proteins act like a
0:45ladder or a cascade.
0:47They exist so that coagulation or blood
0:49clotting can occur.
0:52God, in His wisdom, did not leave the
0:54decision to one, two, or three proteins
0:57; no.
0:59He created 12, and these 12 participate
1:01in the decision to clot because it is a
1:03serious matter.
1:04For a person to develop thrombosis or
1:06clotting, the issue is not simple.
1:09So, the matter must be controlled, and
1:11God placed the control in the hands of
1:1312 factors.
1:15These 12 factors: one starts, then
1:17consults the second, third, and fourth,
1:20until we reach the final decision to
1:22clot, with all of them participating in
1:25the decision.
1:27Okay, for example, let me give you an
1:29example: if someone gets a wound on
1:32their hand or something similar.
1:34And bleeding occurs, it is required that
1:36we perform clotting quickly to stop the
1:38bleeding.
1:39Who is the first factor among the 12 to
1:42notice this? Factor number seven.
1:46Because when factor number seven is
1:48involved, something called factor three
1:50is released from the tissue.
1:53Factor three tells factor seven, "
1:55Listen, there is an injury and bleeding
1:56here, pay attention."
1:59Then factor seven—meaning what factor
2:02three does, which comes from factor
2:04seven—sends to consult factor eight: "
2:06What do you think, factor eight?"
2:10He tells him, "Yes, we really do need to
2:12make a decision."
2:14So now with factor eight, they become
2:16two, and they both send to whom? To the
2:19department manager.
2:21The department manager or the person who
2:23holds the leadership, which is factor
2:26number 10, factor X. Think of it like a
2:29football team; the important player, the
2:31striker, always wears the number 10
2:34jersey, so factor 10 is the department
2:36manager.
2:39"What do you think, factor 10?
2:41We have..." He tells them, "Indeed, the
2:43decision is now mine, you can step out
2:45of the story."
2:48Factor 10 sends to factor...who acts as
2:50the secretary, the secretary for factor
2:5210, which is...
2:57Factor two, which gets activated, then
2:59sends to factor...factor...which is...
3:03He says, "Factor, quickly, quickly,
3:05execute the order!"
3:07It turns into...and it is not...this is
3:10...they are like spider webs that form,
3:14the cells get tangled in them and
3:17trapped, and then it happens and...
3:22Okay, this is if the story started and
3:24factor seven was the one to notice and
3:27start the chain.
3:29Well, if the story is as I told you, and
3:31Factor 7 is the one that starts, then it
3:33signals Factor 8 and sends it to Factor
3:3510, this is what they call...
3:39But the story could happen in another
3:41way; it might not be Factor 7 that
3:44starts it, no.
3:45It could be Factor 12.
3:48For some reason, it starts to notice
3:50that there is a need, a need for us to
3:53act.
3:55Well, Factor 12, when it notices that
3:57there is an issue, it sends a signal to
3:59which factor? It says let's get the
4:00opinion of Factor 11.
4:02Then Factor 11 says, "Yes, you are right
4:04, there really is a problem that
4:05requires clotting." So, whose opinion
4:07should we take next?
4:11The three of them consult each other,
4:13and once they feel there is a real
4:15problem, they send it to the board, to
4:17the manager, which is again Factor 10.
4:22The story proceeds, and Factor 10 tells
4:23them, "You can step out of the story now
4:25, the decision is in my hands."
4:27He sends it to Factor 2, the secretary;
4:29Factor 2 sends it to Factor 1, and we
4:31form the clot. If the one starting the
4:33story or the one noticing it first is
4:35Factor 12, 11, and 9, these are called
4:37...
4:39I don't want you to worry too much about
4:41them, because they are very technical
4:43terms that won't really help you much.
4:46But all I want you to know is that
4:48clotting can start from Factor 7, or it
4:50can start from Factor 12.
4:54Whether it started with Factor 7, which
4:56is drawn in blue for you, or from Factor
4:5912, in both cases, the decision must be
5:02sent to the big man in the subject,
5:04which is Factor 10.
5:08He is the manager I told you about, and
5:10Factor 10, it's like the ball was kicked
5:12to him, just like when you pass the ball
5:14to player number 10. Once the ball
5:15reaches him, the decision is no longer
5:17in the hands of the previous ones; the
5:19decision is now his.
5:21He sends it to Factor 2, and Factor 2
5:23sends it to Factor 1, and we make the
5:25fibrin and we make...
5:28Now, if I ask you, do you understand
5:31this system now? How clotting happens?
5:34If I now want to tell you that we want
5:36to give a drug to prevent or slow down
5:38this process a little bit...
5:43If you tell me, "I want to design this
5:45drug to work on Factor 7, for example,
5:47or Factor 3, 4, or 5," I would say, "
5:49Well, you are talking about...what about
5:51the fact that clotting could happen
5:52through the other pathway, the intrinsic
5:55one?"
5:56You would say, "Oh, I want to design a
5:58drug that works on all of them, on 7, 8
6:00, 9, and so on, and 10 and 11." I would
6:02ask, "Why would you do that? What
6:04compels you to do so?"
6:07Don't we have the common pathway here,
6:08the manager who holds the decision:
6:10Factor 10, Factor 2, and Factor 1?
6:13They are the ones who execute the order
6:15in the end.
6:16What were all these others then? They
6:18were like secretaries consulting with
6:19each other, and once they reached a
6:21decision, as I told you, they would send
6:23Factor 10. So, if we want to design a
6:25drug that works or acts...
6:28Then focus on the common pathway, focus
6:31on the big players, the front-line
6:33strikers. These three strikers, which we
6:36call the common pathway—Factor 10,
6:38Factor 2, and Factor 1—if you inhibit
6:40any of them, the whole system stops.
6:43It’s as if you’ve sidelined the entire
6:45team.
6:47But let me make a small note to get it
6:49out of the way: Factor 1, which is
6:51fibrinogen, is considered the most
6:53important one in the whole chain, and
6:55it's best not to touch it.
6:58Don't design a drug to target Factor 1,
7:00because if you design a drug that
7:02targets and inhibits it, that means the
7:04whole team is basically sidelined, the
7:06whole chain stops, and when the whole
7:08chain stops, it could cause you...
7:13I'll give you a very simple example to
7:15clarify the issue: some snake venoms,
7:18certain types of cobra and other
7:21poisonous snakes, how does their venom
7:23kill? It kills simply by the fact that
7:26as soon as the snake bites the victim,
7:28it causes inhibition of fibrinogen, a
7:30depletion of fibrinogen, which is Factor
7:321. The result is that it immediately
7:35causes...
7:38The victim dies from internal bleeding
7:40because you've, you've, you've inhibited
7:42Factor 1. Playing with Factor 1 is very
7:44dangerous, so it's best to avoid it.
7:47So, what should we focus on now?
7:49On Factor 10, Factor 10 and Factor 2,
7:52which is prothrombin.
7:53It's best that when you design a drug,
7:56it must target one of these two, either
7:58Factor 10 or, what, or Factor 2. These
8:00are the important ones, the common
8:02pathway that concerns us, and as I told
8:04you, stay away from, what?
8:06We can, we can design a drug that works
8:08on 1, it’s not difficult.
8:10But as I told you, if you do, you will
8:12cause...
8:15So, we are done with this diagram to
8:17finish it off, we now understand how it
8:18happens.
8:20And we understood when we design a drug
8:22, what the idea is, meaning what it will
8:24work on more, Factor 10 or Factor...
8:28Let's move on to take the drug examples
8:30we have, we will take two very big
8:32examples.
8:35On the left here.
8:38And Warfarin on the right, and we'll put
8:39them together so that we make it easy
8:41for you while you study.
8:44We'll act as if we're making a table and
8:45go through it together, put, what, every
8:47piece of information and put, what,
8:48compare the two.
8:49Heparin on one side and Warfarin on the
8:51other.
8:53Heparin is, well, it's, there's no, as
8:56for Warfarin on the other side, there's
8:58no, it's, therefore Warfarin is always
9:01in parentheses, what, sometimes we call
9:03it, its 'couma' is what, we mean
9:05Warfarin immediately because there are
9:08no injections of it.
9:11Well, Heparin, its discovery began in
9:14the early twenties of the last century.
9:17They discovered Heparin, they discovered
9:19it’s a substance found in all of our
9:22bodies, stored in, in, in us, especially
9:25in mast cells that are in some tissues,
9:28like, for instance, you find it’s
9:30storing what...
9:33So we discovered it in the twenties.
9:36But we manufacture it now, we extract it
9:38from this and from other things, and we
9:41manufacture it in other ways, and I will
9:43talk to you about other types of heparin
9:45that we produce.
9:47But its original discovery was in a
9:50substance in our body stored in, and by
9:52the way, we discovered later that these
9:55of heparin or carrying, meaning
9:57physically, are the ones stored in.
10:01Because this is an important piece of
10:02information, I will need it in exactly
10:04five minutes, and I will tell you what I
10:05will need it for.
10:07Well, on the other hand, Warfarin, if
10:10you are comparing, Warfarin is something
10:12we created around the mid-fifties of the
10:15last century.
10:17And we did not intend for it to be, well
10:19, it was made for other purposes.
10:22But over time, we discovered it, and it
10:25started to enter medicine, so we use it
10:28.
10:29So, before we leave heparin, as I told
10:32you, there are no tablets of it, it is
10:35all why?
10:38Because if you made heparin tablets and
10:41swallowed them, the [stomach] would
10:43break them down immediately, so we don't
10:45have them.
10:48All the ampoules you see must be taken,
10:51or its [route], or injected under the
10:53skin or taken directly into the vein,
10:56but not by the way, and we will also say
10:59why in a little while.
11:02So, there are no tablets, and it doesn't
11:04cross [the placenta], and this is the
11:06important thing I will tell you about.
11:09It doesn't cross, and every word we say
11:12here we will need in a little while.
11:15Meaning, heparin does not cross, and if
11:17one [pregnant woman] takes it, it does
11:19not cross and does not reach the [fetus
11:21] inside.
11:23Now reverse it when you go to Warfarin,
11:25reverse what you say, look at Warfarin.
11:30Meaning, you swallow the pill, it enters
11:32your body and your blood 100%, and
11:33therefore, since it is like this, when
11:35they found that the pill enters my blood
11:36directly, they said, "Why would we make
11:38injections of it then?"
11:40It is already there, so there are no
11:42longer any injections of it, it is all [
11:44tablets], and it also reaches 100%, and
11:46crosses 100%, meaning it is the opposite
11:47of heparin.
11:49We are saying this because we will build
11:51important information on it, so pay
11:53attention to every word we say.
11:56Let's move to the next one.
11:58On, good.
12:01Come to heparin on the left and let's
12:02talk about.
12:05Now that I have explained to you.
12:08And I told you that in order to disable
12:10, the smart move is to disable what?
12:13Disable factor number two or factor
12:15number.
12:17Disabling any other factor will not help
12:19me much because those are the ones in
12:20charge, as I told you, they are the big
12:22ones.
12:23Heparin, when you give the injection
12:25directly IV and it reaches the blood,
12:28heparin activates a protein in your
12:30blood called.
12:33This.
12:35Is originally created by God.
12:40Meaning, so that this doesn't happen
12:42while you are sleeping and you have a
12:44problem, out of His mercy, God created
12:46for us a protein called.
12:50It prevents—it’s what does this—it’s
12:52what carries out the entire role of
12:54heparin.
12:55When you administer it, it goes and
12:57activates this dormant protein called [
13:00antithrombin], telling it to wake up and
13:02act.
13:03This [antithrombin] then goes and blocks
13:06, as you see in the diagram, it
13:07obstructs the path of several factors
13:10together.
13:11Let’s count them: it will obstruct
13:13factors number two, nine, ten, eleven,
13:16and twelve, preventing them from [
13:18acting]. It tells them "no way, no how.
13:20" Does factor 12 interest you? No, not
13:23really. Factor 11?
13:25No, it doesn't really matter to me, nor
13:27does factor nine.
13:29What matters to me in this story is when
13:31[antithrombin] goes and inhibits factor
13:33[II] and factor X, which I told you
13:35about; those are the ones in charge, the
13:38ones that matter to me.
13:41I want to alert you, may God bless you,
13:42to a very important point: never, ever
13:44say [that heparin directly inhibits
13:45factors] so that no one misleads you in
13:47the [exam] and causes you to make a
13:48mistake.
13:49Never say that heparin goes and inhibits
13:52the [factors] directly; that statement
13:54is wrong. No, heparin doesn't do that.
13:57Heparin works through a mediator; it
13:59goes and activates the mediator called [
14:01antithrombin], and this [antithrombin]
14:04is what goes and inhibits the [factors]
14:06, rendering them [inactive]. So, the
14:08process is indirect.
14:11Now, let's look at the other side and
14:13compare it with warfarin. When you
14:15administer warfarin, let's first see
14:17what happens.
14:19Our liver produces—the 12 factors you
14:21know—four of them are very important and
14:24are produced in the liver, the four you
14:26memorized from physiology, which are
14:291972. 1972, meaning read them from the
14:31right: 2, 7, 9, 10, these four.
14:35The liver produces them all day long,
14:37making these four with the help of
14:39vitamin K. Vitamin K enters the liver
14:42and says, "Well, we want to make these [
14:44factors]." The liver then takes the
14:46vitamin K and uses it for [
14:48carboxylation]. By [carboxylation], it
14:50can produce these four. But vitamin K
14:53sacrifices itself; it enters the liver
14:55to help it produce these four, but it
14:57comes out the other side, as you see in
15:00the drawing and as the arrow points,
15:02oxidized. It sacrifices itself so the
15:05liver can produce the four I mentioned
15:07to you.
15:10Okay, so if all the vitamin K in your
15:12body entered the liver to produce them
15:14and came out the other side spent and no
15:16longer useful, I would need massive
15:18amounts of vitamin K all day long,
15:19because what goes in once is no longer
15:21usable.
15:23No. God has created something else to
15:25restore vitamin K. I am explaining
15:26physiology to you right now, by the way
15:28. I'm explaining something before we
15:30even get into the medication, just to
15:31keep you focused with me.
15:33So, what does God do?
15:35He restores the vitamin K that was
15:37oxidized, bringing it back through a
15:39reverse process to [recycle] it, to [
15:40regenerate] it, so you don't have to
15:42need much vitamin K. This way, the small
15:44amount in your body lasts you a long
15:46time.
15:48How is the oxidized vitamin K, which is
15:49called [vitamin K epoxide], activated
15:51again? By an enzyme inside the liver
15:53also called vitamin K [epoxide reductase
15:55].
15:56The word [reductase].
15:59Meaning the enzyme responsible for the [
16:01regeneration] again is called vitamin K
16:03[epoxide reductase].
16:06Good, so all day long your body or the
16:09liver is busy producing these four,
16:11which are 2, 7, 9, and 10, and every bit
16:13of vitamin K comes out spent from the
16:16other side.
16:19The enzyme restores them again, and
16:20things keep moving like that.
16:23Your body only needs a very small amount
16:25of Vitamin K because it works all day;
16:26every time it oxidizes, it turns back,
16:28and everything keeps going.
16:32All that warfarin does is go to this
16:33enzyme, called the Vitamin K [epoxide
16:35reductase].
16:37Focus now. If warfarin, which is drawn
16:40in black here, inhibits the enzyme
16:42called [epoxide reductase], what will
16:44happen is that Vitamin K enters your
16:46body or the liver, produces some things
16:48, and leaves. Then what? It can’t return
16:51to its active state again.
16:53So, the result is the liver saying, "I
16:55honestly can't do it. The Vitamin K is
16:57spent; we need new Vitamin K." The
16:59enzyme that was recycling it to work
17:01again is broken.
17:03Well, go get us Vitamin K. Look for some
17:05Vitamin K. But there isn't any; the
17:07Vitamin K in our body is limited.
17:09The liver says, "That's it, I'm going to
17:11stop producing these four."
17:13So, warfarin also disrupted the
17:15production of four important factors in
17:17the way I told you, by inhibiting the
17:19enzyme called Vitamin K [epoxide
17:20reductase].
17:23Now look at what those four were. Let's
17:26review: two, seven, nine, and ten. Okay
17:28, does seven matter to you? No, not
17:30really. Does nine matter to you? No, it
17:32really doesn't. Who matters most to you
17:34? Two and ten.
17:35So, in both cases, you notice that
17:37heparin disrupted or worked on many
17:40factors, including two and ten.
17:43And warfarin also worked on many factors
17:45, including two and ten.
17:47Do you notice that all the drugs we are
17:49talking about aim for two and ten, which
17:52I told you are the ones in charge? They
17:55are the big bosses in this matter.
17:59The fundamental difference here is that
18:01heparin works very quickly. When you
18:04give the heparin ampoule,
18:07right away, within a few minutes, it has
18:10[inhibited/affected] everything by
18:12activating [antithrombin] or [acting on
18:15].
18:17Its [half-life] is short; it doesn't
18:20last more than three or four hours at
18:22most.
18:23And then its effect ends; it gets [
18:25metabolized] and finishes.
18:27As for warfarin, if you are paying close
18:29attention, you will find that the
18:31warfarin story I told you needs time to
18:34work. Look, it goes and inhibits the
18:36enzyme called [epoxide reductase].
18:41Well, I have them working in my body,
18:42right? Okay, they will enter the liver,
18:44get [oxidized/spent], and won't be able
18:46to turn back.
18:48By the time the ones in your body get [
18:50spent] and all of them oxidize and can't
18:53return, this process can take 12 hours,
18:55a day, or two days.
18:57So, you might swallow a warfarin pill
18:59today, and its effect won't show until
19:02after a period—for example, 12 hours, a
19:04day, or two days—until all the active
19:06factors that were in the liver oxidize
19:09and can no longer work.
19:11So, this takes a little time.
19:13It's as if I want to point out to you
19:15initially that if I want to [induce
19:17anticoagulation] quickly,
19:20in an emergency, then heparin is the
19:23only choice I have.
19:25If I want to act slowly and calculate
19:28things because the patient is not in a
19:31rush, we give a drug to prevent clotting
19:34gradually, so I have warfarin; this is
19:37different from that.
19:40I also want to tell you something
19:41important, to explain it to you again,
19:43as it comes up along the way.
19:45Back in the day, our professors used to
19:47ask us when we were still students.
19:51They would say, if I have...
19:54And want to send it to the lab for
19:56analysis for any reason, and I don't
19:59want it to clot, because if you take it
20:01and put it in...
20:05And send it on its way, within a short
20:06time it happens, and the blood is ruined
20:08.
20:09They used to ask us, "What should you
20:11add to this sample to prevent clotting?
20:13Should you add heparin or warfarin?" You
20:16answer now, which one works? Obviously,
20:18I cannot add anything but heparin. Why?
20:20Because as soon as I add heparin to the
20:22blood, it activates antithrombin III and
20:23inhibits the...
20:26As for warfarin, no, warfarin does not
20:28work, guys.
20:29For warfarin to work, it acts in the
20:31liver; its site of action is not the
20:33blood. Focus on this point, because it
20:35is very important.
20:37Heparin works immediately; you add
20:39heparin to the blood, and it prevents
20:41its clotting.
20:43But warfarin is not like that; if you
20:45add warfarin to the blood, it will clot
20:47. Why?
20:49Because for warfarin to work, it acts in
20:51the liver by inhibiting the enzyme
20:53called [VKOR] inside the liver.
20:56Therefore, it does not work outside;
20:58this is also one of the important
20:59differences.
21:01As I told you, in both cases, with both
21:03drugs, whether heparin or warfarin, we
21:05prevent clotting or what they call...
21:09But the difference is in the application
21:12when you use it.
21:14If a patient enters the emergency room
21:17with a [condition] or [condition] or...
21:22And you want to catch something quickly
21:24, then you have nothing but heparin,
21:26definitively.
21:27A heparin ampoule contains [units], and
21:30it is calculated by [units] immediately
21:32; we give this patient who is entering
21:35with [condition] one or two ampoules of
21:37heparin.
21:40Then, if I want to continue with heparin
21:42for, say, 48 hours, I give it as an
21:44injection every eight hours
21:46subcutaneously.
21:48Why?
21:49Because the patient who comes in with [
21:50condition] or [condition] or [condition
21:52], the [thrombosis] has already occurred
21:53.
21:54I want you to focus on what I am saying
21:56: the [thrombosis] has occurred, and I
21:58am not giving heparin to dissolve it,
22:00because dissolving it is another story
22:02we will cover in the next lecture.
22:04But why do I give heparin? To prevent
22:06the [extension].
22:10Meaning, if a thrombus has formed now
22:11and the patient arrives with it, and it
22:13is still in its early stages.
22:16I won't dissolve it or anything; I can't
22:18. But I will catch it with heparin to
22:21prevent this thrombus from extending to
22:23the rest of the artery and enlarging.
22:25Instead of it blocking 25%of the artery
22:27, if I leave the patient without heparin
22:30, I will find that after two, three, or
22:32four hours, the entire artery is blocked
22:34. If it was one artery blocked, it could
22:37become two, so I use heparin to prevent
22:39the [extension].
22:42The problem shouldn't escalate into two
22:44or three issues. As I told you, give the
22:48patient one or two IV ampoules quickly,
22:515,000 or 10,000 units, then follow up
22:54every eight hours with a subcutaneous
22:57injection if needed for about 48 hours
23:01or longer, depending on the case. Start
23:04with IV, then continue. Now, let’s move
23:07to the other side.
23:10As I told you, it's a drug that doesn't
23:13work fast; it takes 12 hours, a day, or
23:15two to start working, so it’s never for
23:18emergencies.
23:20We agree on that. Who do we give it to
23:23instead? We give it to prevent clotting
23:26if I'm afraid a patient might be prone
23:30to it.
23:31While Heparin saves you in emergencies,
23:34this one prevents it from happening in
23:36the first place.
23:38Who are these patients?
23:41Anyone I suspect might develop it for
23:43any reason.
23:44I’ll give you examples written in front
23:48of you: patients who have, for instance
23:51, a fracture.
23:53Sometimes orthopedic surgeons use casts
23:55, plates, and screws, and the patient
23:58stays in bed for six months.
24:02A patient stuck in bed for six months
24:04not moving their legs could develop
24:06something called...
24:11If you're worried about that and afraid
24:14it might happen, give them and keep them
24:17on...
24:19Keep them on it for that whole duration
24:20so their leg doesn't develop...
24:24For example, a patient who had surgery
24:26and is also bedridden for a long time,
24:27same thing: keep them on it if you're
24:29afraid they'll develop...
24:31A patient with...
24:36Meaning they have a problem and you’re
24:37worried, you did a CT scan and feel what
24:38they have is...
24:42And you're worried...That it might get,
24:43or something like that. All right, fine
24:45. I went on. Look at every single word.
24:46I'm telling you. Worried it might happen
24:48. Focus on the words "worried it might
24:50happen."
24:52So we put them on it, someone who has,
24:54for example...You're worried because
24:56they had an implant, for example...
24:57People who have had what they call,
24:59which are valves.
25:01Artificial heart valves.
25:05This is a foreign object implanted, and
25:07foreign objects can trigger platelets
25:09because it's something, or it's
25:11sometimes made of plastic, Teflon, or
25:12the like, which might...
25:16That implanted artificial valve, or
25:17perhaps an artificial joint, and you're
25:19worried because this foreign material
25:20might trigger the...
25:24Keep that patient on a tablet every day
25:25as well.
25:27So, you notice here that it’s the
25:29situation that forces me to decide when
25:31to use this and when to use that.
25:34Heparin, as I told you, we use it in
25:37emergencies.
25:40But if you want to maintain the patient
25:42, or prevent, or you're worried that
25:44something might happen...Then no, we’ll
25:45put them on a tablet every day, like,
25:47keep them on it.
25:50Look, I have another important
25:51observation to tell you. Someone might
25:52try to test you on this in an exam here
25:54or there.
25:59Of course, it’s no secret to you that
26:01these are dangerous medications.
26:04The game with them isn't simple; you
26:06must be an expert to handle these drugs
26:08because if heparin, or their levels,
26:11increase a bit.
26:13First, if you are giving them and the
26:15dose is low, it’s as if you didn't do
26:17anything. The patient might end up with
26:19...And the disaster you were afraid of
26:20will happen. Okay, and if it increases?
26:23If it increases, what will happen?
26:25The patient will bleed. So instead of
26:28preventing one problem, you've caused
26:29another.
26:31So, what is the solution? The solution
26:32is that whether it’s heparin or warfarin
26:35, it must be perfectly calibrated.
26:38So the patient doesn't end up with
26:40complications. How do we calibrate it
26:42perfectly?
26:44They said we should periodically test
26:46patients on heparin or warfarin. If they
26:49are on heparin, we do a...
26:54If they are on warfarin, we do an...
26:59What is the idea behind the test? I
27:01won't bore you with clinical pathology
27:03or go deep into the tests, just a very
27:05simple piece of information.
27:08When you give heparin or warfarin, what
27:10is the goal? Is the goal to disable the
27:13...or the...if you say this, you are
27:15wrong immediately. If I am examining you
27:18and you tell me this, that I am giving
27:21heparin or warfarin to disable...then
27:23you are...
27:26You are off-track. Why? Because if you
27:29say I am disabling the..., it means you
27:31are putting the patient at risk of...
27:33And I told you a while ago that the
27:35venom of some snakes kills by causing
27:36...
27:39By causing...so the patient bleeds and
27:41suffers from...
27:44Instead, we give heparin and warfarin,
27:46guys, to slow down...Focus now, draw 100
27:49lines under "slow down," not "prevent."
27:53If, for example, it happens in how many
27:56seconds?
27:58If we say this measures the speed of...
28:00we take blood, add something called
28:03factor three, and add calcium to the
28:05blood to see when it clots.
28:09If you take blood from a normal person
28:11and add calcium and tissue factor three
28:14, it happens in 12 seconds.
28:17The clotting that happens within 12
28:19seconds is normal. Normal for me and for
28:21you. If you take blood and add calcium
28:24and factor three. It happens in 12
28:26seconds.
28:28It is called...So, you and I consider
28:31that for a normal human, it happens
28:34within 12 seconds; that is normal.
28:40When I give you...I don't want to
28:42prevent clotting, I want it to happen,
28:46but instead of 12 seconds, let it take
28:4924 seconds, or up to 30 seconds at most
28:52.
28:54If it happens within 24 seconds, it’s as
28:55if you have...
28:58Right? Instead of happening in 12
28:59seconds, it happens in 24 seconds, as if
29:01you slowed it down a bit.
29:02It’s as if you want to say that the...
29:07It’s what makes the PT or the clotting
29:09time happen, meaning instead of
29:11happening in 12 seconds, it happens in
29:1424 or 30 seconds, so two and a half
29:16times as long.
29:18So if I ask you what is the therapeutic
29:20range?
29:22You tell me it’s the range that makes
29:24...
29:29It becomes, or three, even three is a
29:31bit much, no, let’s stick to two to two
29:34and a half.
29:38Meaning instead of 12 seconds, it
29:40becomes 24 or 30 seconds, so I am
29:42essentially slowing down the clotting,
29:44not preventing it entirely.
29:46Just so you are aware of this.
29:48And in the case of Warfarin, as I say, I
29:49repeat again, if you are giving Warfarin
29:51, the test you perform is called INR.
29:55If you have the patient on Heparin, the
29:58test you will perform is the PTT or APTT
30:00.
30:03Now, if the dosage increases beyond,
30:05whether it’s Warfarin or it exceeds its
30:07natural limit, and you didn't do a check
30:10and you gave the dose and it came out
30:12high, brace yourself for what follows.
30:14The first thing, the first thing you
30:16will expect, you’ll find the patient who
30:18takes Warfarin or is on Warfarin comes
30:21to the clinic and says, "Doctor, I was
30:23praying yesterday and I had a nosebleed
30:25while I was prostrating," or suddenly
30:27you find the patient had an issue, look
30:29at their eye and find it red, with
30:31subconjunctival hemorrhage.
30:35Or you find the skin starting to develop
30:37blue patches, all of this happens.
30:39By the way. For example, gum bleeding.
30:45And I don't know, hematuria. All of this
30:46is from the anticoagulant.
30:48But this is not your primary problem.
30:50Meaning if this was your main problem,
30:52it’s solvable, it’s manageable.
30:53But as it happens, well, like this.
30:55Meaning they say I have a nosebleed. Or
30:57I have blue spots on my skin or
30:58something. No, you could be afraid of
31:00internal bleeding.
31:02That is the dangerous part.
31:04Meaning it happens, for example.
31:06It happens in the brain. It happens in,
31:07I don't know, the stomach.
31:10It happens in the abdomen.
31:11I mean to say that even if the situation
31:13looks easy from the outside. I am afraid
31:15of internal bleeding.
31:17So what? If the dose increases on you,
31:19internal bleeding will happen, and the
31:21fear is greater than...
31:23Brain and so on. So what is the solution
31:25? What is the solution? You made a
31:27mistake, sir, fine. We all make mistakes
31:28. You made a mistake and gave an
31:29overdose.
31:30Medicine. And it turned out to be too
31:32much and caused the patient bleeding.
31:33How do we rescue them? How do we catch
31:34it? Let’s look at Heparin.
31:36At the beginning, I told you that
31:38Heparin carries its negative charge.
31:41So we manufactured a protein to bind to
31:44it.
31:46You know that Heparin carries a negative
31:48charge, so we manufactured a protein.
31:49Carrying a positive charge. They said
31:50it’s very simple.
31:52Give the protein that carries the
31:52positive charge.
31:53The positive charges bind with the
31:55negative charges on the Heparin. And
31:56they neutralize each other, and goodbye
31:57, that’s it. And that way, I have
31:58blocked the effect of the Heparin. Good
32:00? We called this protein Protamine
32:02Sulfate. Protamine, why did we call it
32:03Protamine? Why Prota-mine? Because you
32:06know that anything "proto" means...The
32:08name comes from the fact that it’s
32:09positively charged.
32:11So it was called Protamine for this
32:12reason, because it is positively charged
32:13.
32:17This protein binds to 100 units, so for
32:19example, if I told you exactly what you
32:21need.
32:23If I gave, for example, an ampoule of
32:25Heparin 5000 units, then how much
32:27Protamine do I need for it? So you need
32:2950; these 50 correspond to the ampoule
32:31of heparin you mistakenly gave the
32:33patient, which turned out to be an
32:35overdose.
32:36Now let's look at the case of warfarin;
32:39I told you it works by depleting vitamin
32:41K from your body and liver.
32:43Every time vitamin K enters the reaction
32:45, it comes out the other side inactive,
32:48right? And the enzyme that was supposed
32:50to recycle it has been disabled by it.
32:51So what is the solution? The solution is
32:53, if I gave warfarin and it was too much
32:55for the patient and they started
32:56bleeding, I have no choice but to
32:58administer vitamin K externally.
33:03There are many vitamin K ampoules
33:04available under various names.
33:06I give it to the patient.
33:09It's written as 10 mg IV, but 10 mg is
33:11actually a bit too much; I can give 3 to
33:145 mg IV immediately because this active
33:16vitamin K goes to the liver, stimulating
33:19it to produce clotting factors,
33:21effectively ending the role of warfarin
33:23.
33:25So if asked for the antidote to heparin
33:27, say it definitively without hesitation
33:30: protamine sulfate IV. What is the
33:33antidote to warfarin? Definitive answer
33:35: 3 to 5 mg of IV vitamin K. Now let's
33:38continue with the rest of the adverse
33:40effects. I told you about bleeding and
33:43how to solve it. Now, for the rest of
33:46the adverse effects of heparin on the
33:48left, heparin causes a mistake that many
33:51doctors sometimes make. I told you
33:54heparin is taken in two ways: either
33:56subcutaneously or IV in emergencies if
33:59I'm in a hurry, but never IM, meaning
34:01intramuscular. Never, ever intramuscular
34:04. Why?
34:06Because if you give a heparin injection
34:08intramuscularly, the injury caused by
34:10the needle tip entering the muscle is
34:13minor. Look at how thin the needle tip
34:15is. However, this minor injury in a
34:18muscle full of blood vessels will not
34:20close. The muscle will keep bleeding
34:22because wherever you injected the
34:25heparin, the heparin will disable the
34:27clotting system, and the needle site
34:29will keep bleeding and form a hematoma.
34:32So, never give heparin...I will show you
34:34a picture now of the mistakes that
34:37happen; I'll show it to you right away.
34:39Thus, heparin causes a hematoma if given
34:42IM. So,
34:44Absolutely not.
34:47Two important things in a row; never
34:48forget them for the rest of your life.
34:49Put a million lines under them, not just
34:50two—a million lines.
34:54I am talking about heparin-induced
34:57thrombocytopenia, meaning heparin lowers
35:00the count of platelets in the blood.
35:05But where does the heparin take them?
35:06Where does it send or remove them? They
35:08are circulating in the blood, and I gave
35:10an injection. How does it work?
35:12Heparin causes your body to form
35:17Then these go and stick to
35:21the wall.
35:24And when the antibody sticks to the wall
35:27, every platelet passing by gets stuck
35:29to it.
35:31You know, it acts like a magnet,
35:33attracting and sticking them to the wall
35:35.
35:36Over time, you find most of the
35:38platelets circulating in your blood are
35:41stuck to it. Who made them stick there?
35:44When it formed
35:47So, among the things heparin causes that
35:50we really, really, really don't like is
35:52this issue, and this is what will lead
35:54us to invent drugs later on to, you know
35:56, counteract the heparin so it doesn't
35:59cause this issue.
36:02Moving to the other side, why does
36:04osteoporosis happen?
36:07Because it inhibits the proteins that
36:09stimulate it.
36:14You know, there are cells that build
36:17bone, and there are proteins that
36:19activate them.
36:23On the other hand, there are others that
36:26activate cells that eat or dissolve bone
36:28.
36:31So, what does heparin do over time?
36:33It affects the balance we all have
36:37between...
36:40...and the bone-building cells known as
36:44...
36:47...the process of osteoporosis or bone
36:49resorption, the cells called...we all
36:51have a balance between these two
36:53processes.
37:00There is a harmony between the two, and
37:02we all experience both.
37:06But over time, it stops the proteins
37:08responsible for...and activates other
37:11types of proteins responsible for...
37:17What is the result?
37:19It takes...and over time, what happens?
37:22The patient develops osteoporosis.
37:26The last thing was hair loss, which
37:29isn't a big deal if ignored, but I will
37:32never forgive you if you forget that
37:35heparin must not be injected...
37:40One thing I won't forgive you for, two
37:42...
37:44Because it is very dangerous, and
37:46sometimes heparin inhibits...and when it
37:49inhibits, it becomes another story.
37:52This is very important because some
37:53patients need to be on...
37:57So we worry about...Now, let's move to
38:00the other side, the...We already agreed
38:03that both cause...and we are done with
38:06that.
38:08Regarding..., sometimes it causes
38:10something called...I will show it to you
38:13now.
38:16You find a patient taking...after
38:18starting a course from a cardiologist,
38:21for example, who prescribed one pill
38:23daily,
38:24starts developing severe blue spots or
38:27something like...or sometimes even a
38:30kind of...you see a blue area that turns
38:33black as if...because...sometimes
38:36inhibits the production of an important
38:39protein called Protein C. This Protein C
38:42is responsible for the...of the...in the
38:45...so when it inhibits this protein, it
38:48happens in the very thin...under the
38:51skin.
38:52The...get blocked, and consequently, the
38:55area in the...dies, turns blue first,
38:57changes color, and...happens.
39:01Sometimes, what causes this? The...
39:04It sometimes bleeds in the area, turns
39:06black, and...occurs.
39:10Number two can also be what is written
39:12underneath...
39:15Meaning, if a pregnant woman takes it
39:17for a long period, especially in the...
39:19I am talking about the stage of...which
39:22is the formation of organs in the body,
39:24the first two or three months, which is
39:27the...if she takes...during that time,
39:29it causes...
39:33You find the...of the child who will be
39:35born, and it shows clearly in the...in
39:37the...area.
39:38The area where it shows most, I will
39:41show you a picture now of a child born
39:43to a mother who took a lot of...during
39:45the first period of...I will show you a
39:48characteristic shape to the point that
39:50they call it...
39:53So when you see this child's appearance
39:55, you know that the mother was taking
39:57...during the...period, so that is not
39:59good.
40:01I mentioned earlier that it crosses the
40:04placenta, and it doesn't just do that,
40:06it can also cause fetal problems; the
40:09fetus in the mother's womb might be
40:11affected without her knowing, leading to
40:14stunted growth, and the child is born
40:17with defects.
40:21All this can be caused by it because it
40:23crosses the placenta, and lastly, if a
40:26patient is on one of those drugs that
40:28...
40:30I mean, if you have a patient on it and
40:32you stop it suddenly; it was inhibiting
40:35the enzyme called what?
40:37The one I told you about.
40:41As soon as you stop it suddenly, the
40:43liver starts working with all its might
40:45to produce clotting factors violently
40:47because you have inhibited it for months
40:48or years, and suddenly you stopped.
40:51So the liver starts producing those four
40:53factors it was deprived of very
40:55aggressively.
40:57The patient then enters a
40:58hypercoagulable state and develops
40:59thrombosis.
41:02You find they get a brain stroke or
41:04something else; it causes a major
41:06problem.
41:07That is why it is a drug you must use
41:10with extreme caution if a patient is on
41:13it. If you intend to stop warfarin for
41:16any reason, do it with extreme caution.
41:19This, sir, is a view of an error where
41:22heparin was taken.
41:24Look at what it did; this blue area you
41:27see, if you go inside, you will find the
41:30muscle filled with blood, causing a
41:32major issue, and this might actually
41:35need to be opened surgically to drain
41:37what is inside.
41:41The next picture is the patient who took
41:44warfarin and, by bad luck, it caused
41:46skin necrosis, as I told you.
41:50Warfarin sometimes inhibits the
41:51production of a protein called Protein C
41:53, which is responsible for
41:55anticoagulation.
41:57Which is this, under the skin.
42:01When Protein C is inhibited, clots form
42:04under the skin in that area, and as I
42:06said, you get this necrosis, which is
42:09what warfarin does. By the way, heparin
42:12can also do this sometimes, but much,
42:14much less often than warfarin; warfarin
42:17is the one famous for it.
42:20This third image is of a child born to a
42:22mother who was taking warfarin.
42:24Notice this—these are different children
42:26, not just one, and they have a very
42:28distinctive look as you can see right
42:30here; why do they look like that?
42:34Look at the face, it is very
42:35characteristic; the nose is not formed
42:36well because warfarin causes nasal
42:38hypoplasia.
42:41So the nose is not formed properly, and
42:42you find that the nose has a very unique
42:44shape in these children.
42:46It's not just the nose; you will find
42:48issues with the skull and other bones,
42:50but it is very visible in the nose and
42:52the eyes. By the way, the eyes are very
42:55narrow, as if they were drawn with a pen
42:57; this appearance is very characteristic
43:00and they call it Fetal Warfarin Syndrome
43:02.
43:06Now, let me tell you a new story,
43:08because it’s clear that both heparin and
43:11warfarin had their pros and cons.
43:14We are trying to develop ourselves,
43:17create newer, more modern drugs, and
43:19avoid these drawbacks. Let’s start with
43:22heparin and try to avoid the flaws in
43:25the way I’m about to describe.
43:29Look at the image on the left, for
43:31example; these blue granules you see are
43:33heparin stored in mast cells, stained
43:35blue.
43:38When they examined heparin closely with
43:40a scanning electron microscope to see
43:43its molecules, they found that natural
43:45heparin stored in mast cells is
43:47heterogeneous.
43:49You find very small granules, as you can
43:52see, and also very large ones. The
43:55molecular weight of heparin is not
43:58constant or uniform; you find granules
44:00with a molecular weight of, say, 3,000
44:03Daltons, and other molecules or granules
44:07at 10,000 or 30,000 Daltons.
44:09This lack of uniformity in molecular
44:12weight and size is what makes heparin do
44:15things that are...You saw that when it
44:17activated anti-thrombin III, it went on
44:20to disable how many factors?
44:23Count them: factor 12, 11, 9, 10, and 2
44:25, right? And not only that, it caused
44:28the body to form antibodies against
44:30platelets, making platelets stick to the
44:33endothelium from the inside, which
44:35reduces their active count circulating
44:38in the blood.
44:41That’s not all; it also disrupted
44:44osteogenesis, accelerated osteolysis,
44:47and caused osteoporosis. Where did all
44:49these problems come from? They stem from
44:52...
44:55It’s because it’s heterogeneous.
44:58As I told you, the weight ranges from
45:003,000 to 30,000 Daltons.
45:03This lack of homogeneity makes heparin
45:04act as if it's hitting multiple spots
45:06inside your body; it's not specific.
45:08You might ask, "Well, what then?" I will
45:11ask you, "What was it that you actually
45:12needed?"
45:13Didn’t you need, when you want to
45:16disable or slow down coagulation, to
45:18focus on factor 10 or factor 2?
45:21Wasn't that what we started talking
45:23about?
45:25Alright, sir, let's find out exactly
45:28which part of heparin, which specific
45:31molecular weight, is responsible for
45:34inhibiting factor 10.
45:39Scientists kept working on this until
45:41they found what, within those
45:42heterogeneous heparin molecules, is
45:43responsible.
45:46The molecules specifically responsible
45:49for inhibiting factor 10 are the small
45:53molecules—the tiny blue ones you see in
45:56this picture.
45:59They decided to isolate them, separating
46:01them using chemical methods and
46:03centrifugation.
46:06They tested it; they isolated the small
46:08heparin molecules and tried them out,
46:10finding they only worked on factor 10.
46:13They said, "That’s perfect."
46:16This way, it will be safer and won't go
46:19around affecting other unnecessary
46:21factors.
46:22It won't be hitting factors 12, 9, or 11
46:24anymore; that won't happen. And that's
46:26not all.
46:27And it won't go and cause, nor will it
46:29...
46:31It won't...
46:34And it also won't cause the problems
46:35that heparin used to cause.
46:38Starting around the eighties, they began
46:40to develop new types of heparin.
46:42What did they call them, guys? The ones
46:45on the right here.
46:48That abbreviation you see right there.
46:50It has become the most widely used today
46:53, which is the LMWH. I’ve already
46:56explained its theory to you; it works on
46:59Factor Xa, meaning these are the small
47:01molecules within heparin that we
47:04isolated to make them work only on that
47:07factor and avoid other problems.
47:10Here are their forms on the market.
47:14This type is called enoxaparin, a kind
47:17of LMWH, and here is another type on the
47:20bottom right called dalteparin.
47:23Enoxaparin is Clexane, and many of you
47:26have seen this Clexane in hospitals and
47:28seen how much we use it.
47:30Clexane comes in pre-filled syringes,
47:32already set up. There are 2,000-unit,
47:356,000-unit, and 4,000-unit versions,
47:37depending on what I need.
47:40It is very famous and, of course, safer
47:43than heparin, with less risk of HIT.
47:47Both Clexane and Fragmin, or enoxaparin
47:50and dalteparin, are more widely used now
47:53than heparin, though naturally, the
47:56better the drug, the higher the price.
48:01This table provides a simple comparison
48:03between them.
48:06Notice the word "heterogeneous" which we
48:08use a lot, because the regular heparin I
48:11mentioned has molecules that are not
48:13uniform—their molecular weight ranges
48:16from 3,000 to 30,000 Daltons.
48:19So, they call it a mixed bag.
48:23By comparison, the Low Molecular Weight
48:25Heparin on the right, no, that...
48:28I only took the small molecules from the
48:31heparin to use, so its molecular weight
48:33is less than 8,000, or some books even
48:35say less than 6,000 Daltons.
48:38Regarding...
48:41Heparin used to hit Factor X and other
48:43factors, and would go to the platelets
48:45and cause issues. This won't happen with
48:48LMWH because it will be...
48:53It doesn't stick to the endothelium, it
48:55doesn't cause HIT, so I won't need to
48:58monitor it constantly out of fear of
49:00complications.
49:02Not only that, but its duration of
49:05action is also longer.
49:07Meaning, with regular heparin, I need
49:09three injections a day for the patient,
49:11one every eight hours.
49:13But with LMWH, it’s just one injection a
49:15day because its half-life is 24 hours.
49:19And as I told you, it won't cause
49:21bleeding and won't cause HIT—meaning all
49:24risks are lower with what?
49:27With LMWH.
49:29But at the expense of...
49:32It is more expensive.
49:34I'll also say a few words about what's
49:37new before we finish, because in
49:39pharmacology, new drugs are actually
49:41being released every single day.
49:45I talked to you about heparin and LMWH
49:47because a medical student must study and
49:50know them.
49:52However, every day we keep coming up
49:54with alternatives for both.
49:57For example, we are in agreement here
49:59for the third and fourth time: I
50:01emphasize that the two most important
50:03ones I want to target are Factor 10 and
50:05Factor 2, which is thrombin.
50:08Targeting either of these alone is
50:10enough to do the job you want and stop
50:12the coagulation cascade without causing
50:15us many issues.
50:17So they have now invented or created
50:19medications for us just like heparin.
50:23We have two medications that are almost
50:26exactly like heparin.
50:29There is a medication that is exactly
50:31like heparin, perfectly.
50:33But it doesn't cause us...I mean, it
50:36doesn't cause—well, it is even less than
50:39heparin—it doesn't cause—you'll tell me
50:42heparin didn't cause it, yes it didn't,
50:45but this one is even less than that;
50:48meaning it is safer than heparin, which
50:50is an injection like heparin, taken just
50:53like it, one injection per day.
50:57They came back and said, "Okay, we don't
50:59want injections. I wonder, can we make
51:01something that works like heparin—like
51:02low molecular weight—and goes to inhibit
51:04factor 10 alone without anything else,
51:06but make it easy for the patient?" They
51:08made it.
51:09They made Rivaroxaban, which is in front
51:10of you here.
51:12It is also like low molecular weight; it
51:14inhibits the factor, but it is...
51:18They came back and said, "Okay, we are
51:20done with the factor. I wonder, can we
51:21make things that work on factor 2 alone
51:23, which is prothrombin?" Yes, they did,
51:25and they named this family what you see
51:27in blue down here.
51:30Because thrombin is factor 2.
51:32So they said we will inhibit factor 2
51:34alone, and that's it, so they made a
51:35drug called Argatroban, which is written
51:37up there for you.
51:41The difference between Argatroban and
51:42Dabigatran is that Argatroban is an
51:44injection and Dabigatran is oral. Of
51:46course, we always prefer oral.
51:47Injections are given only when we are in
51:49an emergency—something urgent—we use
51:51injections, but if we are not in a rush
51:52, we take our time and use the oral,
51:54which is better.
51:56So Dabigatran down here, this is the new
51:58one.
51:59It works on number two, inhibits factor
52:02number two, and disrupts the clotting
52:04system just like low molecular weight,
52:06but it doesn't cause the problems of the
52:09heparin family, the most important of
52:11which is what?
52:14Because the most important thing, or the
52:16thing that annoyed me most about heparin
52:18—it actually annoyed me a lot—heparin
52:20and its family annoyed me a lot, but the
52:22thing that annoyed me the most is...
52:26It's bothersome, and sometimes it causes
52:28us problems.
52:30So Dabigatran and Argatroban, all these
52:31new medications in front of you are made
52:33specifically to be alternatives to
52:35heparin.
52:37Without causing us...
52:40And as I told you, some of them work on
52:42factor X alone, like the two above.
52:45And there are two that work on factor 2
52:46, like Argatroban and Dabigatran.
52:50I want to tell you about a story; I told
52:51you that if heparin or warfarin levels
52:53increase, there is a solution for them.
52:55Remember, a while ago I said if heparin
52:57increases, the solution is to give what
52:59? Protamine sulfate.
53:01And if warfarin increases, you give
53:03Vitamin K. But what about these
53:04medications?
53:06Focus now on the drug called Dabigatran
53:08, which is the one we use the most now.
53:10This Dabigatran works on factor 2, good
53:13. What if it increases in my patient?
53:14What if I have a patient on Dabigatran
53:16and he starts bleeding?
53:18I went to check his INR and found
53:19everything is broken; the INR is eight
53:20or nine, and the patient is bleeding
53:21from everywhere.
53:23What do I treat him with?
53:24For Dabigatran, which is this new drug,
53:26they have now made antibodies, special
53:28monoclonal antibodies, that as soon as
53:30you give them IV, they immediately go
53:32and bind to the Dabigatran molecule and
53:34stop its function.
53:36Like its antidote. The, the, the, what
53:38are those antibodies called, sir?
53:41Pronounce it just as I do, because it's
53:42a long name, you won't be able to say it
53:44.
53:45Idarucizumab. It's like you're saying it
53:47, like you're saying the sentence "I
53:49dare you, seezumab." Meaning, "I dare
53:51you, Seezumab" or "Seezumab."
53:54Because the drug's name is actually
53:56Idarucizumab. Pronounce it like this:
53:58Idarucizumab.
54:00This Idarucizumab is a monoclonal
54:02antibody specifically for treating what
54:04? Dabigatran overdose.
54:07So, keep your eyes peeled for those MCQs
54:09.
54:10If they say heparin overdose, tell them
54:11, "Easy, I'll solve it with protamine
54:13sulfate."
54:14If they say, "Well, the warfarin is too
54:15high," easy, I'll solve it with vitamin
54:17K, give 5 milligrams IV or IM.
54:19What about dabigatran? Easy, we’ll give
54:22that thing called Idarucizumab, which is
54:24the antibody.
54:27Now let's talk about pregnancy; just a
54:28couple of words because this is
54:29important to us. In pregnancy, for
54:31example, if a woman has an artificial
54:33heart valve and is on anticoagulants,
54:35then gets married and becomes pregnant.
54:38Don't you dare tell me to stop the
54:39anticoagulant; don't ever say that,
54:40because if you do, it means a disaster
54:42will happen. Because if a woman is on an
54:44anticoagulant and you stop it during
54:45pregnancy, she will develop
54:47hypercoagulability and enter into
54:48thrombosis and a catastrophe. So what is
54:50the solution?
54:51You will keep her on heparin or warfarin
54:53, but with the following observations.
54:55I told you that we cannot give warfarin
54:57in the first three months because it can
54:58cause fetal warfarin syndrome since it
55:00crosses the placenta.
55:02Also, it can cause CNS hemorrhage
55:04because it crosses the placenta. Okay,
55:06so I’ll use heparin? Okay, go ahead, use
55:09heparin. Which heparin? It’s very good,
55:12it’s even better than heparin because
55:15...actually, wait, if you keep her on it
55:18for a long time it could cause—wait, you
55:21just said it doesn't?
55:24It doesn't do it like heparin, meaning
55:26not to the same extent as heparin, but
55:29over time I still worry about her bones
55:32, especially since this woman will be on
55:34it for nine months.
55:37If she takes it for nine months, yes,
55:39the chance is lower than with heparin,
55:42but it’s still possible.
55:44So what’s the solution? We can't use
55:47heparin because of the nine months, and
55:50we can't use [warfarin] because it
55:53crosses the placenta and causes—you know
55:56what. So what is the solution? The
55:59solution is right here in front of you,
56:02which is...
56:05The American College of Chest Physicians
56:08said, "Sir, for any woman who needs a
56:11fixed protocol that you can memorize, we
56:14will follow this: for the first 13 weeks
56:17of pregnancy—let's consider pregnancy 40
56:20weeks—for the first 13 weeks we will use
56:24[Low Molecular Weight Heparin]."
56:26It's good, because these are the 13 very
56:29dangerous weeks for fetal development.
56:35The fetus's organs are forming during
56:38this period, the 13-week period, or
56:41loosely, the first two and a half months
56:44, and then we stop.
56:47We stop it and switch to...
56:51Up to week 34, meaning from week 13 to
56:53week 34, we keep them on—but wait,
56:55you'll tell me it's dangerous. No, sir,
56:58the danger period has passed.
57:01The danger period is the first two and a
57:03half months, which are the first 13 or
57:0515 weeks, that's when we administer them
57:07.
57:08Once we pass that period, switch to
57:10warfarin. So, why don't we continue it?
57:12We said because of osteoporosis, because
57:14of the fear of osteoporosis.
57:16Okay?
57:18Well, we finished 34 weeks, stop the
57:20warfarin now and switch back to—
57:22goodness, why are we doing this?
57:24I mean, why this game of musical chairs
57:26? Why? Why are we constantly switching
57:27from here to there?
57:28Because I cannot continue with warfarin
57:30until the time of delivery.
57:32Birth is at 40 weeks, I cannot give a
57:35woman warfarin in the final weeks of
57:37pregnancy, why?
57:40Because warfarin can easily cross the
57:42placenta and cause CNS hemorrhage in the
57:44final weeks.
57:46So from week 34 until week 40, you are
57:49worried about the CNS, and you know that
57:52warfarin was—so we will follow a fixed
57:54protocol like this, any woman who needs
57:57it:
58:00We will give it to her for the first 13
58:01weeks.
58:05Then we switch from 13 to 34, that
58:07period in the middle, we switch to
58:09warfarin, then stop warfarin at 34 weeks
58:11and continue until the time of delivery
58:13.
58:16This way, we avoided the nine-month
58:18period of giving it the whole nine
58:20months; we interrupted them with
58:21warfarin in the middle.
58:24And after delivery, then I am free to
58:26use the new things and the new things I
58:28explained to you, slowly and carefully,
58:31and stabilize the patient.
58:38And I won't take much of your time, but
58:39it’s all logical.
58:42I mean, these are drugs that increase
58:43blood thinning.
58:44So you will be wary of what I am about
58:45to tell you. A patient who has:
58:49Suppose the patient is already bleeding
58:51, then these drugs are contraindicated
58:52for them.
58:55Like I told you, if they are bleeding,
58:56these things are forbidden for them.
58:59Someone, for example, who has had:
59:04Maybe three weeks or even three months
59:06ago, my friend.
59:07Okay, or they had, for example, a brain
59:10hemorrhage within the last three months
59:12.
59:13These drugs are strictly prohibited.
59:15Because you will cause—and you could
59:17potentially reawaken the area that was a
59:20surgery site or a location, you will
59:22increase it, or if they had an operation
59:25too, stay away from it because it could
59:27increase their—people who have:
59:33I mean, no, stabilize their blood
59:34pressure first, because if they take it
59:36while their blood pressure is very high
59:37, they might bleed at any second, and if
59:39they bleed, you won't be able to save
59:40them at all.
59:42Because with high blood pressure and the
59:43bleeding that will occur, you won't be
59:44able to save that patient.
59:45Someone who has, for example:
59:48Or is bleeding every little while,
59:50getting it every little while. I mean a
59:52patient, for example, who is bleeding
59:53every little while. Do you think that a
59:54patient who is bleeding every little
59:56while from—or bleeding from—giving them
59:57—well, it is naturally forbidden, of
59:58course, because you will—to the wound
1:00:00that is occurring there, and the patient
1:00:01will bleed from it. To the wound that is
1:00:03happening there, and the patient will
1:00:04bleed from it.
1:00:08It’s like someone with a colon issue who
1:00:10is bleeding every little while, it’s the
1:00:11same, it’s forbidden too.
1:00:13People who have—or—all these are
1:00:15forbidden.
1:00:16A woman, for example, who has something
1:00:18called:
1:00:20What does that mean?
1:00:22It means—well, she has something that
1:00:25threatens her pregnancy.
1:00:27I mean, for example, she has—or she has
1:00:29—which makes her pregnancy something
1:00:31that could happen to her at any moment.
1:00:34So stay away from the woman who has this
1:00:36constantly, because she is always going
1:00:38to her gynecologist saying, "Doctor, I
1:00:40had some drops of blood while pregnant,
1:00:42" well of course that’s dangerous. So we
1:00:44never give it at all to these women or
1:00:46these people.
1:00:49Just as I told you as well.
1:00:52Not in [the] nor in [the], so just
1:00:53memorize it like that.
1:00:55[The] should not be taken in the first
1:00:56two and a half months of [the], nor
1:00:58should it be taken in the last month or
1:01:00month and a half of [the]; it is only
1:01:01taken during the period in the middle, [
1:01:03the].
1:01:05And with that, guys, we have finished
1:01:07today's lecture. God willing, in the
1:01:09next lecture we will talk about another
1:01:10topic called.

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