Anti-Coagulants

both for thrombus and hyperlipidemia

Blood coagulation/hemostasis

necessary to prevent excessive hemorrhage from damaged blood vessels

Thrombogenesis

the abnormal formation of blood clots, or thrombi

Thrombus formation

may lead directly to vessel occlusion and tissue infarction

T

t/f
A piece of thrombus may dislodge, creating an embolism that causes infarction elsewhere in the body, such as lungs or brain

Hyperlipidemia

cholesterol and other lipids are progressively deposited onto arterial walls, forming plaque like lesions indicative of atherosclerosis

Fibrinogen

factor I

Factor II (Prothrombin)

for Heparin (Ila) & Warfarin synthesis

factor III

Tissue Thromboplastin

factor IV

Calcium

factor V

Proaccelerin

factor VII

Proconvertin

factor VIII

Antihemophilic Factor (AHF)

factor IX

Christmas Factor, plasma thromboplastin component (PTC)

factor X

Stuart-Power Factor

factor XI

Plasma thromboplastin antecedent (PTA)

factor XII

Hageman factor

factor XIII

Fibrin Stabilizing factor

Factor X (Stuart-Prower factor)

for Heparin (Xa) & Warfarin synthesis

plasminogen

for Thrombolytic enzymes, aminocaproic acid

clotting factors

proteolytic enzymes synthesized in the liver that remain in an inactive form until there is some injury

platelets

help reinforce the clot by sticking to the fibrin mesh

Tissue plasminogen activator

converts plasminogen to plasmin

thrombus formation

Lack of breakdown would enable clots to proliferate at an excessive rate, leading to \______________________

anticoagulants

- inhibit synthesis and function of clotting factors
- used primarily to prevent and treat venous thromboembolism

antithrombotics

- inhibit platelet aggregation and platelet-induced clotting
- used primarily to prevent arterial thrombus formation

thrombolytics

- facilitate clot dissolution
- used to reopen occluded vessels in arterial and venous thrombosis

anticoagulant

used primarily in the treatment of abnormal clot formation in the venous system

deep vein thrombosis (DVT)

primary indication for anticoagulant therapy

pulmonary embolism

secondary indication for anticoagulant therapy

Heparin

* primary drug used in the initial treatment of venous thrombosis.
* works by potentiating the activity of a circulating protein known as antithrombin III and accelerating the induced activation of these clotting factors, reducing thrombogenesis.
* larger sugar like molecule that is poorly absorbed from the GIT.
* administered parenterally via IV infusion or repeated IV injection, subQ injection is ideal as it causes less bleeding

Low Molecular Weight Heparin (LMWH)

- subcutaneous administration of this is safer because it causes less bleeding, easier and more convenient than IV administration e.g. enoxaparin, dalteparin, tinzaparin
- used in pediatric age group
- heparin lock helps with clotting

oral anticoagulants

Exert anticoagulant effects by impairing the hepatic synthesis of several clotting factors

Warfarin

- primary drug for oral anticoagulants
- prevents reductive metabolism of the inactive vitamin K epoxide back to its active hydroxyquinone form
- crosses the placenta readily and can cause hemorrhagic disorder in the fetus, serious birth defects characterized by
abnormal bone deformation.

Coumarin anticoagulants

blocks the Y carboxylation of several glutamate residues in prothrombin and factors VIl, IX and X as well as the endogenous anticoagulant proteins C and S

8 to 12 hours

delay in the action of warfarin (hrs)

Antithrombotic drugs

- primarily inhibit the function of platelets
- used primarily to prevent the formation of arterial clots such as those that cause coronary artery occlusion or cerebral infarction

platelets

respond to vascular injury by changing their shape and adhering to another at the site of clot formation

Aspirin

* Suppresses platelet aggregation by **inhibiting the synthesis of prostaglandins and thromboxanes**
* Inhibits the cyclooxygenase enzyme that initiates the synthesis of lipid-like hormones (prostaglandins and thromboxane A2)
* May help prevent the type of stroke caused by cerebral ischemia and infarction but increases the risk of hemorrhagic stroke
* Used to prevent thromboembolism following surgical procedures such coronary artery bypass, arterial grafts, endarterectomy, and valve replacement
* helps maintain patency and prevent reocclusion of vessels following the procedure

increased hemorrhage

side effect due to chronic use of Aspirin

Clopidogrel & Ticlopidine

* Reduce platelet aggregation by inhibiting the ADP pathway of platelets.
* Thienopyridine derivatives
* No effect on prostaglandin metabolism
* With reported efficacy in the prevention of vascular events among patients with TIA, complete strokes, and unstable angina pectoris.

250 mg bid

Dosage of Ticlopidine for pt’s that cannot tolerate aspirin.

75 mg od

Maintenance dose of clopidogrel which achieves maximum platelet and duration of antiplatelet effect is 7-10 days.

Dipyridamole

* a vasodilator
* inhibits platelet aggregation by impairing adenosine metabolism and or by increasing monophosphate within the platelet the concentration of cyclic adenosine.
* this + aspirin = prevention of cerebrovascular ischemia
* this + warfarin = primary prophylaxis of thromboembolism

Cilostazol

A newer phosphodiesterase inhibitor that promotes vasodilation and inhibition of platelet aggregation and used primarily to treat intermittent claudication.

Sulfinpyrazone

Usually administered to treat gouty arthritis but also has an ability to decrease platelet function by inhibiting prostaglandin synthesis similar to aspirin.

THROMBOLYTIC DRUGS

* Facilitate the breakdown and dissolution of clots that have already formed by converting plasminogen to plasmin.
* Extremely valuable in treating acute MI
* When administered within 3 to 6 hours after onset of symptoms, these drugs can actually re-establish blood flow through occluded coronary vessels often preventing or reversing myocardial damage.
* May produce beneficial effects when injected intravenously which is easier, faster and safer than the intracoronary route.

Streptokinase

* indirectly activates plasmin by binding to the precursor molecule plasminogen and facilitating activation by endogenous mechanisms.


* A protein but not an enzyme synthesized by streptococci that combines with the pro-activator plasminogen.
* One used more frequently as it is cheaper.

Urokinase

* A human enzyme synthesized by the kidney, directly converts plasminogen to plasmin by enzymatically cleaving a peptide bond within the plasminogen molecule.
* Used to resolve acute clot formation in the coronary arteries and other peripheral vessels.

Tissue Plasminogen Activator

* IV administration of t-PA rapidly and effectively initiated clot breakdown by directly activating plasmin
* Commercial synthesis of human t-PA (alteplase) has been made possible through the use of recombinant DNA techniques

Reteplase

* another recombinant human t-PA from which several amino acid sequences have been deleted and less expensive than t-PA

Tenecteplase

* a mutant form of t-PA that has a longer half live and can be given as an IV bolus.

Anistreplase

* Known as **anisoylated plasminogen streptokinase activator complex** (APSAC) Consists of a complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme's active site binds to fibrin where it is then chemically activated so that streptokinase can modify plasminogen and initiate clot breakdown.
* More selective for clots that have already formed with less effect on systemic fibrinolysis.
* Recently discontinued in the USA.

Hemorrhage

* the primary and most serious problem with drugs used to decrease blood clotting- blood in the urine or stools, unexplained nosebleeds or an unusually heavy menstrual flow and back pain or joint pain may be an indication of abdominal or intra joint hemorrhage.

Adverse effect of Heparin

* associated with severe decrease in platelets (thrombocytopenia), may also cause an allergic like reaction especially in individuals who are sensitive to other substances

Adverse effect of Warfarin and Aspirin

* may produce stomach irritation and gastrointestinal distress.

Adverse Effects of Streptokinase and Anistreplase

* associated with hypersensitivity and a febrile reaction in some individuals

Hemophilia

* A hereditary disease in which an individual is unable to synthesize adequate amounts of a specific clotting factor.

hemophilia A

d/t hemophilia VIII

hemophilia B

d/t hemophilia IX

Vitamin K

* needed in the hepatic synthesis of clotting factors II, VII, IX and X wherein it catalyzes the final steps.
* Insufficiency of such results in tan inadequate hepatic synthesis of the clotting factors thus resulting in poor hemostasis and excessive bleeding
* a fat soluble substance found primarily in leafy green vegetables with low dietary requirement because the vitamin is additionally synthesized by bacteria that colonized the human intestine.

Vitamin K1 (phytonadione)

Found in food and also available in oral and paranteral forms

Vitamin K2 (Menaquinone)

Found in human tissues and synthesized by intestinal bacteria.

5:8

* Vitamin K1 is currently administered to all newborns for the first ___ TO _____ days, to prevent the hemorrhagic disease of Vitamin K deficiency which is especially common in preterm **infants.**

Hyperfibrinolysis

results in excessive clot destruction and ineffective hemostasis

Antifibrinolytic

* Inhibit activation of plasminogen (profibrinolysin) to plasmin (fibrinolysin)
* Agents include aminocaproic acid and tranexamic acid (cyclokapron)
* Administered either orally or IV for the acute treatment of hyperfibrinolysis or to prevent clot breakdown in patients with hemophilia who are undergoing surgery.
* Adverse effects include nausea, diarrhea, dizziness and headache

Hyperlipidemia

* Abnormally high concentration of lipids in the blood stream


* One of the primary causes of cardiovascular disease in industrialized nations


* Causes deposition of fatty plaque like lesions on the walls of large and medium-sized arteries which can lead to thrombosis and infarction.


* Caused by poor diet and lifestyle as well as by several genetic conditions.

HDL

* considered beneficial by removing cholesterol from the arterial wall

IDL, LDL, VLDL

* harmful cholesterols because they transport and deposit cholesterol onto the arterial wall.

HMG- CoA Reductase Inhibitors

* Also called "statins"


* Act by inhibitiong an enzyme known as 3-hydroxy-3methyl-glutaryl coenzyme A (HMG-CoA) reductase
* Catalyze one of the early steps of cholesterol synthesis, and drugs that inhibit HMG-CoA reductase decrease cholesterol production especially in liver cells.
* Decrease hepatic cholesterol biosynthesis -> more surface receptors for LDL cholesterol to be synthesized -> increase in the breakdown of LFL cholesterol and decrease in the synthesis of VLDL
* Improv plasma lipid profiles by decreasing plasma LDL cholesterol and VLDL concentration
* Neuromuscular side effects such as myalgia, myositis, fatigue/ weakness and paresthesisas

Niacin or Vitamin B3

* Decreases VLDL and LDL levels and often increases HDL levels significantly
* Inhibits VLDL secretion, in turn decreasing production of LDL
* Has no effect on bile acid production
* Inhibits the intracellular lipase of adipose tissue via receptor-mediated signaling.
* Catabolic rate for HDL is decreased.
* Useful in patients with combined hyperlipidemia and in those with dysbetalipoproteinemia
* Most effective agent for increasing HDL
* Most patients require 2՞6g of niacin daily for treatment of heterozygous familial hypercholesterolemia (a hereditary disease)
* Should be given in divided doses with meals starting with 100mg 2x or 3x daily and increasing gradually.
* Adverse effects include cutaneous vasodilation and sensation of warmth \n

Fibric acid derivatives (fibrates)

* Increase the breakdown of triglyceride rich lipoproteins such as LDL and IDL
* Increase lipolysis of lipoprotein triglyceride via LPL
* Useful in hypertriglyceridemia in which VLDL predominate and in dysbetalipoproteinemia
* Should be avoided in patients with hepatic or renal dysfunction.
* Fibric acid derivatives (fibrates)

cholesterol gallstones

Use of fibrates shows modest increase in the risk of \__________

Bile Acid Binding Resin

- Attaches to bile acids within the GIT lumen and increases fecal excretion of these acids
- Leads to decreased plasma cholesterol concentration because cholesterol breakdown is accelerated to replace the bile acid that are lost in the feces
- Used in treatments of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage
- Also used in combination with other frugs to achieve further hypocholesterolemic effect
_ May be helpful in relieving pruritus in patients who have cholestasis and bile salt accumulation

Inhibitors of intestinal sterol absorption

- Primary clinical effect is reduction of LDL levels
- Effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile
- Experience reveals a low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor
- Myositis hass been reported rarely