Pharmacology Lecture 1 PDF

1 Rani Tachijian AbdulMalik AlMa’aytah Mohammad Abusido Hebah Khraisat The color code for these modified slides: Black text: the professor’s slides Underlined Black text: what the professor has read from the slides Green text: what the professor has mentioned during the lecture but...

1 Rani Tachijian AbdulMalik AlMa’aytah Mohammad Abusido Hebah Khraisat The color code for these modified slides: Black text: the professor’s slides Underlined Black text: what the professor has read from the slides Green text: what the professor has mentioned during the lecture but isn’t written in his slides Purple text: extra information that may be useful Highlighted text: information thought to be of greater importance Drugs Used in Clotting Disorders In this lecture, we shall discuss drugs which: Reduce clotting – Antiplatelets – Anticoagulants – Thrombolytics Facilitate clotting Pharmacology, Examination and Board Review Doctor's notes: Discussing these drugs and concepts is crucial, as bleeding is a common and significant issue that we will frequently encounter during our clinical years. The same applies to thrombosis. Many of the drugs covered in this lecture are widely used by patients and can often be considered baseline medications for them as they could have a history cardiovascular diseases (CVDs) including MI (myocardial infarction), angina, cardiac arrhythmia, pulmonary embolism, deep vein thrombosis, stroke, brain hemorrhage etc. Even if the patient was a smoker and disease-free, they might require antiplatelets, and the same goes for hypertensive patients without a disease (I believe the doctor meant diseases other than hypertension). These disease-free individuals that have viable risk factors take antiplatelet drugs as prophylactic agents (medications used to prevent the occurrence of diseases) in order to reduce the chance of later developing CVDs. Doctor's notes: Hemostasis (blood clot formation during wound healing) is normally a physiological process that takes place during our lives, to heal wounds and stop bleeding. However, in many cases, this hemostasis can be excessive and even pathological rather than a process to stop bleeding, resulting in the formation of blood clots that cause shortage of blood supply (ischemia) or resulting in completely cutting off supply to tissues by blocking blood vessels (infarction). This pathological condition is known as thrombosis. So, for example, in the case of atherosclerosis, hyperlipidemia will form lipid deposits (plaques) in the walls of arteries, inevitably leading to the rupture/fissure of these plaques, causing an injury in the blood vessels. This injury will lead to the exposure of the collagen fibers present in the artery’s wall, recruiting platelets and initiating healing which is signaled by certain mediators such as thromboxane, ADP, and other factors. Doctor's notes: Consistency in healing is important to our bodies. Remember, we always have a balance between opposite processes: sympathetic and parasympathetic functions, coagulation factors and anticoagulation factors (antiplatelets, thrombolytics...). But why do we need balance in this case? Because, sometimes, during the healing process, thrombi and coagulation factors escape from the healing site, leading to the clotting of unrelated the vessels in our bodies, an undesired effect. In other cases, clotting factors may not be enough to stop bleeding in time in order to heal injured blood vessels. Therefore, this necessitates the need to interfere by either increasing or decreasing antithrombotic substances, antiplatelets, or anticoagulants depending on the case (in short, it is important to facilitate and balance between clotting in cases of bleeding or blood thinning in cases of thrombosis).  Plaques are sites of abnormal/excessive lipid deposition in the walls of arteries. Unstable plaques activate Plaque Fissure or platelets Rupture Platelet Since they are filled with Adhesion lipids, the sites of these plaques are weaker than the rest of the artery wall, Platelet making them much more Activation susceptible to ripping open (rupture/fissure). Platelet Aggregation This rupture in the arterial wall initiates a clotting process similar to any injury that occurs in blood vessels. In this case, Thrombotic the clotting leads to thrombus formation that may occlude the Occlusion whole flow in the artery. Doctor's notes: Watch this video to save yourself a ton of time. The first event that occurs after collagen exposure (due to plaque rupture) is what we call platelet activation to start coagulation, leading to platelet aggregation. Platelets group and aggregates start to form due to them attaching to a protein called von Willebrand Factor (vWF) secreted by endothelial cells which binds to exposed collagen fibers at the site of injury. Platelets have receptors which bind these vWFs, leading to their recruitment, subsequent activation, and self-activation. But what does platelet self- activation mean? Platelets that bind to vWF become activated, increasing intracellular Ca2+ concentrations which ultimately leads to exocytosis of stored vesicles, a process called degranulation, releasing granules containing adenosine diphosphate (ADP) and thromboxane A2. Doctor's notes: Let's focus on ADP here: it has receptors on platelets called P2Y12 which help platelets become more sensitive to activation. ADP can also bind to the same platelet that released it and cause further degranulation, activating even more platelets and itself (hence the phrase self-activation, similar to autocrine activity). Following the binding of ADP to its P2Y12 receptor, it increases the platelet’s susceptibility to become activated, further increasing degranulation. The key component in this process is cyclic AMP (cAMP). Activation of the P2Y12 receptor inhibits cAMP production. Decrease in cAMP is essential because high concentrations of cytosolic cAMP prevent platelet activation by controlling Ca2+ levels. Clinically speaking, the effects of mediators such as ADP and thromboxane are not favorable, especially in patients with atherosclerosis whose coronary arteries are injured. An important note here: antiplatelets aren’t used to treat an already-formed blood clot, they prevent the formation of clots in the future (prophylactic). 1) A group of drugs that inhibit the function of ADP is known as ADP-receptor blockers which are significant drugs to prevent platelet aggregation. Doctor's notes: Fibrinogen also binds to activated platelets and plays a role in platelet aggregation; it binds receptors called GpIIb/IIIa on one platelet and then another platelet binds to this same fibrinogen by its own receptor, forming an aggregate. 2) Another group of drugs interferes with aggregation by blocking GpIIb/IIIa receptors, preventing fibrinogen-based platelet aggregation. Doctor's notes: Another method to interfere with platelet function is by interfering with thromboxane A2 production. Remember, phospholipases function on cell membranes, produce arachidonic acid (AA) which is used by cyclooxygenases (COX-2 primarily, (the doctor didn't really focus on this)) which synthesizes prostaglandins and leukotrienes. Thromboxane A2 is a derivative of these products, a molecule that is active in platelets with a function similar to ADP (it plays a role in platelet self-activation by binding receptors on platelets). 3) Aspirin (acetylsalicylic acid) is the third drug that can be used as an antiplatelet for its ability to inhibit thromboxane A2 production. 4) The last method is by increasing cytosolic cAMP (remember its inhibitory effect on Ca 2+ release and degranulation) by inhibiting its metabolizer, the enzyme phosphodiesterase. Note: cAMP has a vasodilatory effect also on blood vessels and, thus, it functions as antiplatelet and vasodilator at the same time, which makes it useful in strokes and myocardial infarctions. Doctor's notes: Several factors of coagulation play a role in forming blood clots as well in what is known as the coagulation cascade. This cascade has two separate pathways; intrinsic and extrinsic pathways. The intrinsic pathway is activated by coagulation factors in the blood while the extrinsic pathway is activated by tissue factors. Both of these pathways eventually result in the activation of factor X, leading to a common shared pathway that involves the activation of prothrombin (factor II) into thrombin. Thrombin then causes the conversion of fibrinogen (factor I) into fibrin which is the vital component in forming the fibrin mesh, creating a clot. Doctor's notes: Drugs that inhibit the formation of the fibrin mesh and the clot are known as anticoagulants. Examples of anticoagulants are heparin, warfarin, dabigatran, rivaroxaban. Anticoagulants are therapeutic; on the other hand, drugs used in the earlier step that interfere with coagulation mediators such as ADP and thromboxane (aspirin, clopidogrel, dipyridamole..) are part of the antiplatelets class and have a prophylactic function. For example, if the patient presents with deep vein thrombosis, we TREAT it with anticoagulants, you can't use antiplatelets if the clot has already formed. Another important note: antiplatelets are PROPHYLACTIC used in ARTERIES (coronary, pulmonary, etc..) while anticoagulants are THERAPEUTIC used in VEINS (clots are more common in veins). Doctor's notes: On the other hand, drugs that function by breaking up already formed clots are known as thrombolytic agents (they perform thrombolysis). There is a physiological process which takes place naturally in our bodies to treat clots after they form (such as in the case of strokes and myocardial infarction). This process is known as fibrinolysis, performed by the enzyme tPA, tissue plasminogen activator. This enzyme converts plasminogen into plasmin, which acts like scissors, cutting off pieces of the fibrin mesh one at a time, allowing blood to flow. Although this enzyme is naturally occurring in ّ ‫) ُت‬. our body, it can also be administered as a treatment intravenously (‫سمى هذه اإلبرة إبرة الحياة‬ tPA is given in cases of MI if the patient has been in that condition for 6-12 hours. In the case of stroke however, it should be administered only if the patient has been in the condition for 3-4 hours, because hypoxia would occur after that and brain cells would die. This is why it is so important to pay attention to timing the treatment.  Platelet Inhibitors These drugs prevent platelet activation. (1) Inhibition of prostaglandin synthesis (aspirin), (2) Inhibition of ADP-induced platelet aggregation (Ticlopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor), (3) Blockade of glycoprotein IIb/IIIa receptors on platelets (abciximab, tirofiban, and eptifibatide). (4) Phosphodiesterase inhibitor (Dipyridamole ?? and cilostazol). All of these drugs are antiplatelets. They are very important prophylactic agents and are commonly used First used in 1830 and first approved for medical use in 1891! Aspirin MOA: Blocks COX→ inhibits conversion of AA into TXA2. Indications: -prophylactic in transient cerebral ischemia. -to reduce recurrence of MI. -in angina. A daily dose of 100 mg. Adverse effects: hemorrhagic stroke, GIT bleeding. Doctor's notes: A very important distinction between aspirin and other drugs is that it binds irreversibly to COX inside platelets to prevent thromboxane A2 production. That’s why we don’t have baby profen or baby voltaren but we have baby aspirin. The daily dose is 80-100mg. You should know that aspirin should NOT be given to peptic ulcer patients at a dose of 325mg which is the analgesic dose (pain-relief dose, anti-inflammatory dose is 975mg, taken 3 pills per day). As for profen, we use 200mg for headaches. If used for toothaches where there is an inflammation, we need to use a +400mg dose to relieve the pain AND treat the inflammation. The same goes for diclofenac and other NSAIDs: the higher the dose, the stronger the anti-inflammatory effect. It's important to understand that it is a DOSE-DEPENDENT effect. Using NSAIDs in a low dose treats a moderate headache. Increasing the dose treats a moderate, sometimes severe, headache with inflammation. So, the next time you see Advil (Ibuprofen) at 200mg, 400mg and 600mg, you should know that the dose depends on the condition you are trying to treat. Headache? 200mg. Toothache? 400mg. Sprained ankle? 600mg to prevent swelling. Doctor's notes: Aspirin at 325mg can be taken with caffeine to relieve a headache. For rheumatoid arthritis, it is given at 975mg, 3 times per day, 3 pills per time (9 pills daily). To prevent stomach pain, it is best to use it side to side with PPIs (proton pump inhibitors). Why do we use aspirin in the previously mentioned conditions? Why not ibuprofen? Because aspirin's effect is irreversible. A daily dose of 100mg is enough to give the desired outcome: inhibition of platelet aggregation. This will continue until new platelets are produced in compensation of the lost old inhibited platelets. So, when is the right time to perform a major surgery on a patient using aspirin? 2, 3 or 4 days later? We perform it after 6 days from the last dose to allow for the turnover of platelets and prevent bleeding. One last thing regarding aspirin is Reye's syndrome; it is important not to prescribe aspirin to patients aged under 19 with a viral infection. Well, do we prescribe 100mg aspirin to peptic ulcer patients? The doctor informed us that there is no evidence to suggest it is either harmful or beneficial; therefore, we will not be asked about in the exam but, to be safe, don't prescribe them aspirin.  Ticlopidine & Clopidogrel Remember this Useful in patients who cannot tolerate aspirin or who failed aspirin. MOA: block ADP receptors on platelet. Indications: -prevent vascular events in patients with transient ischemic attacks (TIA), maintenance dose. -unstable angina, maintenance dose. -prevent thrombotic stroke, maintenance dose. -to prevent thrombosis in patients undergoing placement of a coronary stent, loading dose. Clopidogrel is given to stop platelet aggregation. Its commercial name is Plavix ®. Important question: Do we take it with aspirin ( Is it allowed )? Yes, we always use aspirin with it. Aggregation depends on ADP & thromboxane A2, so we use aspirin & clopidogrel together to have a dual activity preventing the aggregation (they have different mechanisms, more mechanisms result in better effects), there also isn’t a crossover between their side effects, at least at the level of bleeding & peptic ulceration. Clopidogrel, prasugrel & ticagrelor have the same MOA & indications. A loading dose is administered to quickly achieve a steady state of the drug, which is essential for it to be effective, particularly in emergencies. For preventing vascular events in cases of unstable angina or thrombotic stroke, a maintenance dose is given: 75mg for normal patients and 150mg for those with abnormal conditions. Reminder: Loading dose: A dose of medication, often larger than subsequent doses, administered for the purpose of establishing a therapeutic level of the medication. Maintenance dose: After the loading dose is given the another dose is given to maintain the steady- state drug conc. / plateau. Such dose is known as maintenance dose. Note: Cardiac catheterization is the insertion of a catheter into a chamber or vessel of the heart. In cases of myocardial infarction, catheterization is used to place metallic stents to open narrow/blocked arteries. When a catheter is used for a blocked coronary artery and a metal stent is inserted, the procedure ruptures the artery, exposing collagen and vWF. This triggers platelet binding and the feedback loop involving ADP and TXA2, which can lead to blood vessel closure. To prevent platelet aggregation, a loading dose of 300mg must be given before the procedure; if the catheterization is scheduled for the next day, 300mg should be administered the day before and 75mg on the day of surgery. If the surgery is on the same day, the 300mg dose should be given 3 hours prior to the procedure, since Tmax is 1.5-2 hours. While clopidogrel theoretically has a half-life of 7-8 hours, in practice, its effects last 2-3 days due to its strong receptor binding. The effects of both clopidogrel and aspirin last for about six days, so they should be stopped six days before any major surgery. Notice how management varies depending on the procedure, if the procedure is catheterization, antiplatelets such as Clopidogrel must be administered along with Aspirin. In the cases of surgery however, Aspirin and Clopidogrel must both be discontinued.  Ticlopidine & Clopidogrel Note that all the side effects of Adverse effects: these medications Ticlopidine are related to Hemorrhage: common among all antiplatelets & anticoagulants. bleeding! Leucopenia: should monitoring WBCs during the first 3 The likelihood of months. It is rare to happen & usually with ticlopidine. bleeding increases Thrombotic thrombocytopenic purpura (TTP) with higher doses administered. Clopidogrel - fewer than with ticlopidine Neutropenia. TTP Thrombotic: thrombosis. Thrombocytopenia: decreased number of platelets. Purpura: the black circles or lines under the skin due to closing or blocking of small blood vessels. Adverse effects depend on dose. Thrombotic thrombocytopenic purpura (TTP) is a potential adverse effect associated with ticlopidine use, although it can occur with other medications, albeit less frequently. TTP results from the turnover of platelets combined with the inhibition of the ADAMTS13 protease, which normally cleaves vWF. When this protease is inhibited, vWF accumulates, leading to small platelet aggregations in the capillaries between arteries and veins. These aggregates block blood flow to various areas, manifesting as dark circles on the skin. Doctor said that these details of the disease aren’t required. The body identifies ticlopidine as an autoimmune suppressant, similar to an allergy but less severe and without anaphylaxis. The immune system recognizes ticlopidine bound to the surface of platelets through haptens, which can trigger autoimmune effects on platelets, leading to immune mediated thrombocytopenia (ITP). These side effects occur in 2-3% of patients taking ticlopidine, which is considered relatively high, while only about 0.5% of those using clopidogrel, prasugrel, or ticagrelor experience them. This information is gathered by checking the patient’s platelet count before starting the medication and again after one month. And if it is extremely low, you need to remove all the autoimmune antibodies by plasma replacement. Please note that TTP and ITP are two different diseases; in TTP, thrombocytopenia is caused by the consumption of platelets to form clots, whereas in ITP, it is caused by an autoimmune reaction. All those drugs are orally administered (aspirin , clopidogrel,…) except for Cangrelor (IV ) Cangrelor is very important in emergency cases such as in MI when urgent catheterization is necessary and the patient requires the antiplatelet effect as soon as possible. The immediate effect of cangrelor is possible due to its IV administration (works within 30 minutes). However, it is more likely to cause bleeding.  Ticlopidine & Clopidogrel Dose: -Ticlopidine: 250 mg BID orally. -Clopidogrel: oral loading dose 300 mg, maintenance dose 75 mg once daily. Because of less side effects & more convenient dosing with clopidogrel, it is preferred over ticlopidine  ( P2Y12 )ADP receptors blockers Remember this Cangrelor (Kengreal) IV (not a prodrug) Clopidogrel (Plavix) Prodrug ?????? Prasugrel (Effient) bleeding Hypertension (8%), hypotension (4%), atrial fibrillation (3%), bradycardia (3%), Remember this Ticagrelor (Brilinta) not a prodrug bleeding and shortness of breath (dyspnoea) 6-7% Ticlopidine (Ticlid) not used any more (TTP)  Warning Clopidogrel was issued a black box warning from the FDA on 12 March 2010, as the estimated 2–14% of the US population who have low levels of the CYP2C19 liver enzyme needed to activate clopidogrel may not get the full effect (won’t get activated). Tests are available to predict if a patient would be susceptible to this problem or not Testing is either through PCR or using a device called multiplate, you need to draw the patient’s blood & apply clopidogrel to it, in order to know the level of inhibition of platelet aggregation and to know if the patient is a poor, intermediate, or fast metabolizer of clopidogrel. Clopidogrel is a prodrug that requires activation by the enzyme CYP2C19. The CYP2C19 gene is polymorphic, meaning it has single nucleotide polymorphisms (genetic variations where, for example, A can become T or C can become G). Depending on these polymorphisms, the enzyme's activity can vary: it may be induced in ultra-rapid metabolizers, reduced in intermediate metabolizers with one allele lost, or severely diminished in poor metabolizers who have lost both alleles. Administering clopidogrel to poor metabolizers as an antiplatelet medication poses significant risks, particularly for patients undergoing stenting. In these cases, clopidogrel may be ineffective as prophylaxis, effectively leaving patients without any antiplatelet protection, which greatly increases the risk of clot formation within the stent. The likelihood of bleeding as a side effect of clopidogrel is low. To address this issue, prasugrel came out. It is also a prodrug, but it is activated by CYP3A4, CYP3A5, or CYP3A6, which provides multiple pathways for activation. This makes it less likely for patients to be poor metabolizers of prasugrel. However, prasugrel still has m side effects, including an increased risk of bleeding, hypertension, hypotension, and bradycardia, making it not an ideal choice. An alternative non-prodrug antiplatelet medication is ticagrelor (Brilinta), which can be used instead. While it is effective, it is associated with a higher risk of bleeding compared to clopidogrel and can cause dyspnea, likely due to immune responses triggered by weakened platelets. Abciximab, eptifibatide, & tirofiban. Glycoprotein IIb/IIIa inhibitors: Abciximab is a humanized monoclonal antibody directed against IIb/IIIa complex - Fibrinogen works binds to Eptifibatide & Tirofiban inhibit ligand binding to IIb/IIIa GpIIb/IIIa receptors for clot receptor by their occupancy of the receptor. formation and these drugs inhibit this function. ➔ All Inhibit bridging of platelet by fibrinogen. - This is the most powerful treatment but it isn’t used often Approved for use in percutaneous coronary intervention due to high risk of bleeding. (PCTA) & in ACSs. - You have to know Abciximab, it The three agents are administered parenterally is used in Jordan instead of cangrelor.  Dipyridamole: MOA: -inhibits phosphodiesterase→ ↑ cAMP→ potentiates effects of prostacyclin→ platelet inhibition. -dipyridamole is also a coronary vasodilator. Indications:-with aspirin for prophylaxis in angina. -with warfarin to inhibit embolization from prosthetic heart valves. Degranulation occurs when Ca2+ levels are high & cAMP levels are low (cAMP inhibits Ca2+), If cAMP is high—> Ca2+ influx decreases preventing degranulation. If you want to stop platelet aggregation, you have to stop the break down of cAMP by inhibiting phosphodiesterase. The drug Dipyridamole is a weak drug but it has a beneficial effect on coronary arteries as a vasodilator. It inhibits phosphodiesterase to increase cAMP, thus reducing Ca2+, which leads to dilation of coronary arteries. So dipyridamole is both an antiplatelet agent and a vasodilator, particularly for coronary arteries. All vasodilators can cause headaches, as they dilate blood vessels in the brain, which might be sensed by specific receptors triggering pain. They also cause hypotension which might also cause attribute to headaches.  Ticlopidine P Abciximab Glycoprotein IIb/IIIa receptor complex PAF  Anticoagulants Coagulation Cascade Series of steps Precursor proteins in plasma are activated by proteolysis Activated proteins activate other proteins Plasma contains protease inhibitors like Antithrombin III (ATIII), protein C, and S that rapidly inactivate coagulation proteins as they escape from site of vessel injury. Patients with conditions such as deep vein thrombosis or myocardial infarction can’t be treated using antiplatelet drugs (specifically if the MI patients are not undergoing catheterization) since they are primarily prophylactic agents. These patients require therapies using thrombolytic agents or using anticoagulants in order to break down the formed clots. Our bodies are balanced between coagulation factors (e.g., factors from 2-10) and anticoagulation factors (protein S, protein C & antithrombin 3), if this balance is disrupted, either coagulation or severe bleeding occurs, so you need to monitor the drugs to avoid both overdose and underdose.  This file has been edited! Slide 11: Aspirin targets the enzyme cyclooxygenase, which is responsible for the synthesis of prostaglandins (from which thromboxane A2 is derived) and leukotrienes. Slide 22: A maintenance dose of clopidogrel is used to prevent the occurrence of vascular events in patients with unstable angina (as well as in patients that’ve suffered from a TIA or thrombotic stroke).