• Executive Summary (an introduction/background to the case study) The clotting cascade is essential in the human body to allow for healing of a broken artery or vein. If we don’t have these clotting factors or clotting cascade it can lead to serious consequences such causing bleeding out eventually leading to death as shown in haemophilia. The clotting cascade consists of primary and secondary haemostasis. Primary haemostasis being the formation vasoconstriction and platelet aggregation at the site of injury and secondary haemostasis being the formation of a clot. In more detail, it starts off with binding of tissue factor VIIa which initiates the coagulation cascade and formation of factor X (thrombin) and eventually fibrin. Platelets …show more content…
are activated by activation of phospholipase A2 leading to the formation of thromboxane A2, ADP and thrombin. On the surface of these platelets are von Willebrand factor and glycoprotein IIb/IIIa which causes platelets to adhere to each other and forming fibrinogen which leads to formation of fibrin, better known as a blood clot. Figure 1. Description of the coagulation cascade and examples of drugs that target specific factors in the coagulation cascade. This process can also be initiated by vitamin K-antagonists (Lüscher, T. et.al, 2015). Sometimes clotting factors can go wrong such as bleeding more easily as shown in the case of haemophilia where there is a defect in the clotting factors that help platelets stick together. Other times people can have an increased tendency to clot leading to blockages of arteries that can cause heart attacks, atherosclerosis or stroke. There are many types of drugs that can interfere with a variety of components of the clotting cascade or platelet activation. Examples of drugs that can affect the clotting cascade are aspirin that targets Thromboxane A2, Clopidogrel which is an ADP receptor inhibitor, warfarin which targets Vitamin K and Edoxaban which targets factor X (thrombin) (Lüscher, and Steffel, 2015). These drugs all prevent platelet aggregation by targeting either the beginning or end of the clotting cascade preventing the process to proceed further. This paper focuses on the pharmacodynamics, pharmacokinetics and adverse effect of Clopidogrel for treatment of thrombosis. • Pharmacodynamic Implications (a description of the mechanism of drug action) Clopidogrel is a prodrug whose action is determined by its biotransformation after being metabolized in the intestine. In order to activate Clopidogrel into its active thiol metabolite it involves a two-step hepatic pathway that involves CYP450 enzymes (Kaufmann, J et.al, 2016). CYP2C19 contributes to 45% of the initial activation (Kaufmann, J et.al, 2016). The thiophen ring is oxidized to 2-oxo-clopiodogrel which results in the opening of the ring and the formation of carboxyl and thiol group (J. Angiolillo, D. et.al, 2007). The thiol group forms a disulphide bridge between 1 or more cysteine residues of the P2Y12 receptor (J.Angiolillo, D. et.al, 2007). Figure 2. Chemical structure of Clopidogrel (Bluet, G. et.al, 2014). This drug selectively and irreversibly binds to the P2Y12 receptor which blocks ADP receptors on platelets blocking the activation of ADP-mediated activation of the glycoprotein GPIIb/IIIa which inhibits platelet aggregation (J.
Angiolillo, D. et.al, 2007). The drug prevents platelet degranulation and release which expands prothrombic and inflammatory mediators while also inhibiting the transformation of GP IIb/IIIa receptor that forms fibrinogen (J. Angiolillo, D. et.al, 2007). Figure 3. This figure shows the mechanism of action of Clopidogrel (Guzman, F. 2008). Clopidogrel inhibits aggregation for 7 to 10 days which is the average lifespan of a platelet, it produces a dosage dependent effect which begin 2 hours after a single dose and the inhibition is approximately 40% to 60% in adults (L. Buck, M. and D, P., 2010). • Pharmacokinetic Implications ( a description of the mechanism of the patient response) Clopidogrel is taken orally and is rapidly absorbed having a bioavailability of 50% (L. Buck, M. and D, P. 2010). Food doesn’t affect its absorption so it is able to be consumed with or without food (Drugs.com. …show more content…
n.d.). Clopidogrel is metabolized by two different mechanisms one being by esterase’s that leads to hydrolysis to an inactive carboxylic acid derivative and the other being mediated by cytochrome P450 enzymes.
The metabolic pathway being mediated by the CYP2C19, CYP3A, CYP2B6 and CYP1A2 enzymes. The maximum concentration with a single dose of 300mg loading dose is twice as high as it is after four days of 75mg maintenance dose which occurs approximately 30 to 60 minutes after dosing. Figure 4. This figure shows metabolic activation of Clopidogrel. Bioavailability is determined by intestinal absorption. 85% converted too inactive metabolites via esterase’s and 15% converted to active thiol-containing metabolite by CYP450 enzymes (Agewall et al., 2013). Conversion to 2-oxo-cloipidogrel is catalysed by CYP2C19, CYP1A2 and CYP2B6 while the second step is catalysed by CYP3A4, CYP2B6, CYP2C19, and CYP2C9 which form the active metabolite and binding to the P2Y12 receptors inhibiting ADP-induced platelet activation (Agewall et al., 2013). After 5 days Drugs.com (n.d.) stated that there was 50% excreted in urine with 46% in faeces with a half-life of approximately 6 hours. Clopidogrel being metabolized by CYP2C19 and using other inhibitors of this enzyme results in reduced plasma concentrations (Drugs.com.
n.d.). • General discussion (discuss alternative treatments and include potential side effects) Alternative treatments should also be taken into such as taking additional drugs such as aspirin that targets thromboxane A2 that blocks the formation of thrombin thus prevents platelets from sticking together (Drugs.com. n.d.). Nitrates, beta-blockers, diuretics or calcium channel blockers are some examples of other drugs that be used in treating thrombosis (Gill and Dalby, 2015). Lifestyle changes need to be changed to prevent any further attacks from happening such as quitting smoking, exercising regularly and eating a healthy diet. Examples of side effects of using these drugs can include chest pain, purple bruise, pain, itching and redness or swelling (Drugs.com. n.d.). Adverse side effects can include severe bleeding, hematoma, gastrointestinal bleeding, angina pectoris, depression, hepatitis or abnormal liver function tests (Drugs.com. n.d.).
In septic patients, increased levels of PAI-1 inhibit plasminogen activator (t-PA), which converts plasminogen to plasmin. Release of fibrin inhibits fibrinolysis by activation of thrombin-activatable fibrinolysis inhibitor (TAFI). In addition, the release of PAF causes platelet aggregation. This combination of inhibition of fibrinolysis, fibrin strand production and platelet aggregation contribute to a state of coagulopathy. This can lead to microcirculatory dysfunction with isolated or multiple organ dysfunction and cell death. Mr Hertz’s coagulation profile showed a fibrinogen level of 5.6 g/L, indicating that coagulopathies were underway in his system.
Coumadin works by inhibiting with how your body uses vitamin K. The metabolism of Coumadin, vitamin K and vitamin K dependant clotting factors take place in your liver. “Coumadin prevents the production of the vitamin K dependent clotting factors and this results in a slower clotting rate.” (National Blood Clot Alliance, 2014)
The liver plays central role in each of these phases of clotting process, as it synthesizes the majority of coagulation factors and proteins involved in fibrinolysis as well as thrombopoietin., which is responsible for platelet production from megakaryocytes. In cirrhosis, liver is badly get damaged. So the production of coagulation factors and proteins is impaired. Many pathological processes associated with cirrhosis, such as portal hypertension and endothelial dysfunction as well as co-morbid conditions, may also alter the coagulation process. Consequently, patients with liver disease as in cirrhosis, have a disturbed balance of procoagulant and anti- coagulant factors which deviates from the normal coagulation cascade.
Hemophilia is a genetic bleeding disorder. People who have hemophilia have a deficiency or an absence of a coagulation protein. A blood clotting factor is deficient or absent. Bleeding is most often into joints, such as the knee, elbow, or ankle, but bleeding can occur anywhere in the body. People with hemophilia bleed longer, not faster.
Viagra is taken orally. It is quickly absorbed into the system and usually reaches its peak concentration in about 30 to 120 minutes. However, as with most orally administered drugs, taking the pill on a full stomach will slow down its absorption (Sildenafil Citrate, par. 5). Viagra is metabolized in the liver by the cytochrome p450 system. It is converted into a metabolite that has properties similar to that of the pre-metabolized drug. Viagra and its metabolite have a "terminal half-life of about 4 hours" (Sildenafil Citrate, par. 4). Finally, Viagra is excreted primarily through feces in the form of metabolites (Sildenafil Citrate, par. 7).
COX-1: Cox-1 is responsible to protect the lining of the stomach and to regulate blood platelets. It also decreases fever and regulates blood platelets promoting blood clotting. NSAIDS and aspirin can be used for inhibition of Cox-1 for the desirable effect of decreasing platelets aggregation, but it can also decrease the protection of stomach lining. As a result, it can cause bleeding and
Pharmacokinetics provides a basis to assess the course of drugs and their effects on the body (Dhillon & Kostrzewski, 2006). The processes of pharmacokinetics can be broken down into the absorption, distribution, biotransformation, and excretion in, through, and out of the body. These are major concepts that guide medication use and dosage selection (Association of Surgical Technologists, 2017).
“Pharmacokinetics (PK) and pharmacodynamics (PD) can be seen as two sides of the same coin. PK and PD have a definite relationship, assessing how much drug gets to the site of action and then what that action is. Both activities are essential in the complete investigation of the interaction between the drug and body, and play significant roles in both drug development and their continual use in the clinical setting (Institute Of Clinical Research, Clinical Pharmacology Special Interest Group, Pharmacokinetics vs. Pharmacodynamics).”
-Wong, D. T., Bymaster, F. P., Horng, J. S., & Molloy, B. B. (1975). A new selective inhibitor
In Blood In Blood Out is a drama directed by Taylor Hackford, and starring Damian Chapa (Miklo), Benjamin Bratt (Paco), and Jesse Borrego (Cruz), produced by Hollywood Pictures. The film was based off everyday life in East Los Angeles, from the 1970’s through the 1980’s. Damian Chapa stars as Miklo in the film, a Mexican-American who wanted to be accepted, not by his skin but for the Mexican within him. Benjamin Bratt (Paco) was the older cousin of Miklo, who learned his lesson throughout the movie and changed his ways. Jesse Borrego (Cruz) is the step-brother of Paco who was a talent artist, who ended up turning to drugs because of back problems caused by a rival gang incident.
Pharmacokinetics describes what the body does to the drug, as opposed to pharmacodynamics which describes what the drug does to the body. Pharmacokinetic information is required to utilize and increase the drug response. The primary pharmacokinetic disposition parameter is clearance. This is really important to have knowledge of this value and its major parts. For example the fractional renal and hepatic elimination and clearance will allow the clinician to prescribe the correct dosage regimen. The accurate dosage regimen could help the clinicians to obtain an average therapeutic concentration and to predict the effects of various disease states. The other pharmacokinetic disposition parameter which can be utilized in vitro is the volume of distribution. The volume of distribution can be measured at steady-state; this may also vary with changes in physiologic and pathologic conditions of the body2. Clearance and volume of distribution would be expected to vary with changes in plasma protein binding. The usage of in vitro setting could help us to measure these modifiable elements. Although plasma concentration measurements are usually easiest to perform via in vitro settings, clarification of parameters in original organism or the hu...
Hemophilia is the result of having factor VIII or factor IX deficiency. Factor VIII and IX are two types of clotting factor which help the body stop a bleed. The KidsHealth article “Hemophilia” explains that when a child falls and scrapes his knee, “platelets go to where the bleeding is and plug up the hole.” These platelets release chemicals that attract proteins called clotting factors to “form fibers [that] make the clot stronger and stop the bleeding.” However, a child with hemophilia is missing one of his twelve clotting factors, which are labeled with roman numerals I through XII, and the clotting factor he does have cannot form strong enough fibe...
platelets on a slide, you would need to have the specimen recollected because of a clot, or
While on that drip, it should have been tested even more frequently to keep check on the dextrose's effects. Yet, several hours would go by without it being tested, at all. I don't know the exact number of times it was usually tested each day because I was very sick and was not keeping track of it. Although, I shouldn't have had to worry about that, since I was in the hospital. I think it was only tested four to six times per day, if even that much.
The five parameters of Liberation Absorption, Distribution, Metabolism and Excretion (LADME for short) are responsible for the changes in concentration of a drug in the body, theory stands that the magnitude of the response requires, and depends on, the concentration of the drug in the fluid the is bathing the target tissue. A deep understanding of these processes is vital in order to provide the correct chemical therapy for a patient. Liberation is the release of the drug from its dosage form and the active ingredient is liberated, for example, the breakdown of capsules in the stomach or mouth. Absorption is the process that involves the movement of the administered compound from the entry site to the bloodstream.