Antiplatelet medications

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Introduction0:00–0:36

Antiplatelet medications prevent blood clot formation during hemostasis, where hemo means blood, and stasis means to halt or stop.
Hemostasis is divided into primary hemostasis, where circulating cell fragments called platelets form a plug at the site of an injured blood vessel, and secondary hemostasis, which involves multiple coagulation factors working together to form a fibrin mesh to stabilize the platelet plug.
Antiplatelet medications inhibit the steps of primary hemostasis to prevent the platelet plug from forming.Primary hemostasis can be further divided into five steps: endothelial injury, exposure, adhesion, activation, and aggregation.

Physiology0:36–2:29

Endothelial injury is when the innermost layer of the artery, called the endothelium, gets damaged. The second step is exposure, where the damaged endothelium exposes the underlying collagen.
The underlying collagen and endothelial cells then release a protein called Von Willebrand's factor, or vWF, that binds to this collagen.
The third step is adhesion where circulating platelets bind to the vWF via a surface protein called GPIB. The fourth step is activation, where platelets become active after binding to vWF.
First, the platelet changes shape and its membrane forms tentacle-like arms allowing it to grab onto other platelets. Second, platelets release more vWF, as well as serotonin, a tiny molecule that attracts more platelets to the area.
Third, the platelets also release adenosine diphosphate or ADP, and thromboxane A2, or TXA2. These two molecules can activate other platelets that haven’t bound to vWF.
ADP and TXA2 also cause platelets to express new surface proteins called GPIIb/IIIa, which is needed for the fifth step, aggregation.
Now each platelet has multiple GPIIb/IIIa receptors that can bind to circulating proteins called fibrinogen. When two platelets attach to the same fibrinogen protein, they are linked together.
This allows platelets to rapidly aggregate at the site of injury, and form a large platelet plug that can stop the bleeding.
Now, antiplatelet medications interfere at different steps during this process. Aspirin, the NSAID or non-steroidal anti-inflammatory drug, has antiplatelet effects by blocking the synthesis of thromboxane A2, which activates platelets.

Aspirin2:29–3:56

Aspirin accomplishes this by irreversibly inhibiting the activity of cyclooxygenase enzymes, abbreviated COX-1 and COX-2, via acetylation.
This is where an acetyl group made up of two carbons, three hydrogens, and an oxygen is permanently attached to the enzyme.
When COX-1 and COX-2 get inhibited, thromboxane A2, which is a downstream product of the cyclooxygenase pathway can no longer be produced.
Aspirin, as an antiplatelet medication, gets used in a low dose form of 75-325 milligrams in several clinical situations to prevent clots from worsening.
325 milligram aspirin tablets are used for the treatment of acute strokes and myocardial infarctions, or heart attacks. Low doses of aspirin in the form of 81 mg tablets also gets used for the prophylaxis or prevention of future heart attacks in high risk individuals.
Aspirin, when used as an antiplatelet in low dose formulations, carries the risk of developing gastric ulcers, as well as bleeding.
Aspirin can also cause allergic reactions at low doses. Patients with aspirin allergy can develop bronchoconstriction, or narrowing of the airways, causing shortness of breath and wheezing.
Like thromboxane A2, ADP is also a potent platelet activator. So the ADP receptor inhibitors like clopidogrel, prasugrel, ticlopidine, cangrelor, and ticagrelor also interfere with platelet function.

ADP Receptor Inhibitors3:56–6:14

Ticlopidine, clopidogrel, and prasugrel are first metabolized by the liver, and their active metabolites bind irreversibly to the platelet P2Y12 ADP receptor, and prevent ADP from binding.
Without ADP, the platelets will not express GPIIb/IIIa on their surface and thus, will not aggregate together. Ticagrelor doesn’t need to be activated by the liver since it’s not a prodrug.
Ticagrelor binds reversibly and in a non-competitive manner--meaning it binds to the receptor in an area outside of the active site where ADP normally binds.
This decreases the receptors affinity for ADP, leading to decreased platelet activation. The ADP receptor inhibitors are used in combination with aspirin for the treatment of acute coronary syndrome, which is a spectrum of symptoms that arise when there is limited blood flow to the heart.
They are also effective for preventing ischemic strokes and myocardial infarctions in people with atherosclerosis, and can be used inplace of aspirin if the person has an aspirin allergy.
In fact, clopidogrel is considered equally effective as aspirin. Additionally, the medication clopidogrel has been used in combination with aspirin as a pretreatment to prevent clots from forming for people undergoing coronary stenting.
This is a procedure where blocked vessels in the heart are kept open using a tube shaped device. In terms of toxicity, the ADP receptor inhibitors increase the risk of bleeding like other antiplatelet medications, but they can also cause a condition called thrombotic thrombocytopenic purpura, where microthrombi form in small blood vessels, causing ischemic damage to various organs.
The platelets also get depleted in the process, which leads to bleeding under the skin, forming purple bruises called purpura.
The medication ticlopidine, is rarely used now, because it can cause a very serious condition called neutropenia, or low levels of a type of immune cell called neutrophils, and increases the risk of serious infections.The phosphodiesterase inhibitors cilostazol and dipyridamole also work by interfering with platelet aggregation.

Phosphodiesterase Inhibitors6:14–7:31

They inhibit an enzyme called phosphodiesterase III inside of platelets. This enzyme normally breaks down a molecule called cyclic adenosine monophosphate, or cAMP.
When cAMP increases inside a platelet, the platelet does not respond to ADP, so it doesn’t activate. Additionally, these medications inhibit phosphodiesterase III inside of vascular smooth muscle cells and inhibit the breakdown of cyclic guanosine monophosphate or cGMP.
Increased levels of cGMP inside prevents the smooth muscle cells in vessels from contracting, which results in vasodilation.
Because of this property, cilostazol is used primarily for the treatment of peripheral artery disease and coronary artery disease where there’s significant blockage in the arteries of the lower extremities and heart.
They are also used with aspirin for secondary prevention of ischemic stroke by inhibiting clot formation in cerebral arteries.
In terms of side effects, the phosphodiesterase inhibitors can cause dizziness, headaches, palpitations, and gastrointestinal disturbances.The next step, platelet aggregation, is inhibited by the glycoprotein IIb/IIIa inhibitors eptifibatide, tirofiban, and abciximab.
These medications work by binding directly to the IIb/IIIa receptor and prevent fibrinogen from cross linking platelets together.
The medication abciximab is a monoclonal antibody, or identical proteins made by the immune system that bind to a specific antigen.Now, the glycoprotein IIb/IIIa inhibitors, mainly abciximab, get used as pretreatment to prevent ischemic complications for people undergoing interventional coronary procedures.

Glycoprotein IIB/IIIa Inhibitors7:31–8:33

These medications are all associated with an increased risk of bleeding, and thrombocytopenia, or low platelets. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts!
Since platelets are similar to saucers, let’s use flying saucers for the mnemonic. There’s a UFO that’s activated its tractor beam and under the UFO’s tractorbeam, let’s have a broken bike carrying an oxygen tank for cyclooxygenase.
The bike broke down when the distracted rider rode over a spring, for aspirin, which got stuck in the wheel. The rider was injured in this incident and he’s got a bloody stain on his stomach representing bleeding gastric ulcers, and red spots on his arm representing the hives-like rash from the allergic reaction.

Memory Palace8:33–11:23

Next, for the adenosine diphosphate receptor, let’s use an alien transmitter with 2 phosphorescent radar dishes. The ADP receptor inhibitors will be the aliens operating this machine, one of whom looks like a pig-dog hybrid for clopidogrel.
The other two alien abominations are goofing off; there’s a pidgeon that’s tickling itself with its horrible tentacles for ticlopidine, and an alligator doing the same for ticagrelor.
Their ration on earth is a big pile of sugar representing prasugrel. For side effects of these drugs, let’s have a pile of tiny, crashed, purple UFOs next to them for thrombotic thrombocytopenic purpura.
Under the tentacled pigeon is a neutrophil that’s been pecked to death since ticlopidine causes neutropenia. For the enzyme phosphodiesterase, let’s use a disaster, like an earthquake.
Lot’s of tents are by the crack in the earth representing increased cAMP. For the two phosphodiesterase inhibitors, there’s an alien mole with a pyramide on his head for diperidamole, and he’s playing a space cello for cilostazol.
The crack in the earth caused by this monster is wider at one end with a lot of blood-like lava gushing out to represent vasodilation.
The side effects are represented by the campers; one is vomiting in terror, another one is clutching at his chest for palpitations, and one fainted due to dizziness and bumped his head, giving him a headache.
Next let’s look at a group of UFOs releasing a swarm of mutant bugs consisting of 2 bees and 3 ants, which represent the IIb/IIIA inhibitors.
These bugs wiped out humanity and the medications here include eptifibatide, which is a tombstone with the word “epitaph” written on it, an old tire for tirofiban, and 3 old alphabet blocks with A, B, and C on them for abciximab.
For the side effects, there is a crashed saucer representing low platelets, or thrombocytopenia. All right, as a quick recap antiplatelet agents are medications that interfere with the first step of hemostasis which is platelet plug formation.
Aspirin works by blocking thromboxane A2. ADP receptor inhibitors prevent platelet aggregation by decreasing the expression of glycoprotein IIb/IIIA, while IIb/IIIa inhibitors attach to these proteins directly and prevent fibrin from binding.
Finally, phosphodiesterase inhibitors decrease the breakdown of cAMP which is a potent inhibitor of platelet aggregation.
Antiplatelet medications are used to treat and prevent a variety of conditions caused by blood clots. These include acute coronary syndromes like heart attacks, ischemic strokes, and claudication.
The major side effect for antiplatelet medications is an increased risk of bleeding, and some could cause thrombocytopenia.But wait, there's more: Here's a mind map with all of the mnemonics from the video.

Review11:23–12:22

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers at the end.
V3 a while to be 3 and have attached to these proteins directly and prevent fibrin from binding. Finally, phosphodiesterase Inhibitors decrease, the breakdown of Camp, which is a potent inhibitor of platelet aggregation.
Antiplatelet medications are used to treat and prevent a variety of conditions caused by blood clots. These include acute coronary syndromes like heart attacks ischemic Strokes in claudication.
The major side effect for antiplatelet medications is an increased risk of bleeding and some could cause thrombocytopenia.

Mind Map12:22–12:36

But wait, there's more, here's a mind map with all of the mnemonic from the video. Go ahead and pause a video so you can test yourself to see what you remember.
Stay tuned for the answers at the end.