Drugs Affecting Coagulation

Anticoagulant, Antiplatelet, and Thrombolytic Drugs

Hemostasis Stage 1 Formation of Platelet Plug

Platelet aggregation Stage 2 Coagulation

Intrinsic system Extrinsic system You tube video

https://www.youtube.com/watch?feature=player_embedded&v=xNZEERMSeyM

Process of Coagulation

Blood Vessel Injury

Local vasoconstriction seals off small injury

Platelet aggregation forms a platelet plug

Hageman factor is activated

Intrinsic pathway converts prothrombin to thrombin to seal system

Extrinsic pathway clots the blood that has leaked out of the vascular system

Damaged Vessel Endothelium Stimulates Platelets to Cause Platelet Adhesion

Types of Blood Disorders

Thromboembolic disorder

Conditions that predispose a person to the formation of clots and emboli

Hemorrhagic disorder

Condition in which excess bleeding occurs

Anticoagulant TherapiesA. Antiplatelet

1. Aspirin 2. Thienopyridines Clopidogrel (Plavix), Prasugrel (Effient) ,Tichlopidine (Tichlid) 3. GP IIb/IIIa Inhibitors Abciximab (Reopro),Eptifibitide (Integrilin) ,Tirofiban (Aggrastat)

B. Anticoagulants 1. Unfractionated Heparin 2. LMWH

a. Enoxaparin (Lovenox) b. Dalteparin (Fragmin) 3. Direct Thrombin Inhibitors

a. Bivalrudin (Angiomax) b. Argatroban 4. Factor Xa Inhibitors

a. Fondaparinux (Arixtra) 5. Vitamin K Antagonists

(Warfarin, Coumadin)

C. Fibrinolytics

Actions of Anticoagulants

Antiplatelet Alter the formation of the platelet plug

Anticoagulants Interfere with the clotting cascade and thrombin

formation

Thrombolytic drugs Break down the thrombus that has been formed by

stimulating the plasmin system

Classification of Cyclooxygenase Inhibitors

Drugs with anti-inflammatory properties NSAIDs (nonsteroidal anti-inflammatory

drugs) Aspirin, celecoxib, ibuprofen, and naproxen

Drugs without anti-inflammatory properties Acetaminophen

Antiplatelet Drugs

Aspirin (ASA) Inhibition of cyclooxygenase

Ticlopidine (Ticlid) ADP receptor antagonists

Tirofiban (Aggrastat) GP IIb / IIIa receptor antagonists

Antiplatelets-Aspirin

Action

Inhibit platelet adhesion and aggregation by blocking receptors sites on the platelet membrane-irreversible inhibition of cycloxyenase, an enzyme required by platelets to synthesize thromboxane A2 (TXA2)

Anagrelide: blocks the production of platelets in the bone marrow

Indications

Reduce risk of recurrent TIAs or strokes; reduces death or nonfatal MI; MI and anginal prophylaxis; anti-inflammatory, analgesic, and antipyretic effects

Pharmacokinetics Well absorbed and bound to plasma proteins Metabolized in the liver and excreted in the urine

Aspirin

Nonselective inhibitor of cyclooxygenaseTherapeutic uses Analgesic, antipyretic, anti-inflammatory Suppression of platelet aggregation

Protects in thrombotic disorders Dysmenorrhea Cancer prevention Prevention of Alzheimer’s disease

Antiplatelet (cont.)Contraindications

Allergy,

Pregnancy, and lactation

Anemia, postpartum hemorrhage, may prolong labor

Caution

Reye’s syndrome

Bleeding disorder, recent surgery, closed head injury

Adverse effects

Bleeding

Headache, dizziness, and weakness

GI distress

Drug-to-drug interaction Anticoagulants: warfarin and heparin Glucocorticoids Alcohol Ibuprofen ACE inhibitors and ARBs

Clopidogrel (Plavix)

Therapeutic uses Prevents blockage of coronary artery stents Reduces thrombotic events in patients with

acute coronary syndromes MI, ischemic stroke, and vascular death

Similar adverse effects to those of aspirinUse with caution in combination with other drugs that promote bleeding

Direct Thrombin Inhibitors

Direct inhibition of thrombin (unlike heparin, which enhances the activity of antithrombin)

Dabigatran- Etexilate (2010)

Oral prodrug- GI Conversion to Dabigatran

Advantages: doesn’t require monitoring of anticoagulation little risk of adverse interactions same dose can be used for all patients regardless of age

or weight

Other Antiplatelet Drugs

Dipyridamole

Dipyrindamole + aspirin

Aggrenox

Cilostazol

Anticoagulants

Argatroban (Acova)

Used to treat thrombosis in heparin-induced thrombocytopenia

Bivalirudin (Angiomax)

Used with aspirin to prevent ischemic events in patients undergoing trans luminal coronary angioplasty

Direct Thrombin Inhibitors

Hiruden Analog: Bivalirudin (Angiomax) Prevents clot formation (combined with aspirin) in patients

with unstable angina who are undergoing coronary angioplasty Mechanism of action

Facilitates the actions of antithrombin Prevents conversion of fibrinogen to fibrin Prevents activation of factor XIII

Adverse effects Bleeding Back pain Nausea, headache

Other Direct Thrombin Inhibitors

Lepirudin (Refludan)Argatroban (formerly known as Acova)Desirudin (Ipravask)Dabigatran (Pradaxa)

Selective Factor Xa Inhibitors

Produce selective inhibition of factor XaFondaparinux Activation of antithrombin Injection

Rivaroxaban Binds directly with factor Xa to cause

inactivation Oral

Rivaroxaban (Xarelto)

Oral anticoagulant approved in 2011Does not require laboratory monitoring Patients who received rivaroxaban were found to be much less likely to experience DVT, VTE, PE, or death

Anticoagulants

Warfarin (Coumadin) Maintains a state of anticoagulation when the patient is

susceptible to potentially dangerous clot formation

Heparin (generic) Inhibits the conversion of Prothrombin to thrombin

Antithrombin (Thrombate III) Used for hereditary Antithrombin III deficiencies and

replacement therapy in congenital Antithrombin III deficiency

Anticoagulants

Action

Interfere with the normal cascade of events involved in the clotting process

Pharmacokinetics

Vary based on the drug

Contraindications

Allergy and conditions that could be compromised by increased bleeding tendencies

Pregnancy, renal, and hepatic disorders

Cautions

CHF, thyrotoxicosis, senility, and psychosis

Anticoagulants (cont.)

Adverse effects Bleeding GI upset Hepatic dysfunction Alopecia, dermatitis, bone marrow suppression, and

prolonged and painful erectionDrug-to-drug interactions Heparin and oral anticoagulants, salicylates,

penicillins, and cephalosporins Heparin and nitroglycerine Warfarin: number of documented interactions

Heparin

Rapid acting anticoagulantUses Pulmonary embolism Stroke Vein thrombosis

Adverse Effects Hemorrhage Thrombocytopenia Hypersensitivity reactions

Low-Molecular-Weight Heparins

Inhibit thrombus and clot formation by blocking factors Xa and Iia

Do not greatly affect thrombin, clotting, or prothrombin times; therefore, they cause fewer systemic adverse effects

Block angiogenesis, the process that allows cancer cells to develop new blood vessels

Are indicated for specific uses in the prevention of clots and emboli formation after certain surgeries or bed rest

Warfarin (Coumadin)

Oral anticoagulantAntagonist Vitamin KEffects synthesis - Factors VII, IX, X, and prothrombinUses Prevents thrombosis formation

Adverse Effects Hemorrhage

Coumadin(Warfarin)

https://www.youtube.com/watch?feature=player_embedded&v=ucP1OEOGO5E

Patient education video for monitoring and taking Coumadin.

Thrombolytic Drugs

Streptokinase Binds plasminogen

Uses Myocardial infarction Deep vein thrombosis Massive pulmonary emboli

Adverse Effects Bleeding Hypotension Fever

Thrombolytic Therapy

Action – to dissolve clots

Thrombolytics Alteplase -Tissue plasminogen activator Reteplase Streptokinase Urokinase Anistreplase

Thrombolytic Agents

Action

Activate plasminogen to plasmin, which in turn breaks down fibrin threads in a clot to dissolve a formed clot

Indications Acute MI, pulmonary emboli, and ischemic stroke

Pharmacokinetics

Drugs must be injected and are cleared from the body after liver metabolism

Contraindications Allergy

Any condition that worsens through dissolution of clots Pregnancy and lactation

Streptokinase (Streptase)

Binds to plasminogen to form active complexTherapeutic uses Acute coronary thrombosis (acute MI) Deep venous thrombosis (DVT) Massive pulmonary emboli

Adverse effects Bleeding – excessive fibrinolysis can be reversed with IV

aminocaproic acid (Amicar) Antibody production Hypotension Fever

Thrombolytic Drugs

Streptokinase (Streptase); Alteplase (tPa)Major adverse effect – bleeding (minor oozing to life-threatening amount) Likely sites of bleeding

Recent wounds, needle puncture sites, invasive procedure sites

Anticoagulants increase the risk for hemorrhageBlood replacement may need to be considered

Thrombolytic Agents (cont.)

Adverse effects Bleeding Cardiac arrhythmias Hypotension Hypersensitivity: rash, flushing, bronchospasm, and

anaphylactic reaction

Drug-to-drug interactions Anticoagulants Antiplatelet

Bleeding Disorders Treated With

Clotting Factors

Hemophilia Genetic lack of clotting factors that leaves the patient

vulnerable to excessive bleeding from any injury

Liver disease Clotting factors and proteins needed for clotting are not

produced

Bone marrow disorders Platelets are not formed in sufficient quantity to be

effective

Antihemophilics

Actions Replace clotting factors that are either genetically

missing or low in a particular type of hemophilia

Indications Prevent blood loss from injury or surgery and to treat

bleeding disorders

Pharmacokinetics Replace normal clotting factors; they are processed as

such by the body

Antihemophilics (cont.)Contraindications

Allergy

Factor IX in the presence of liver disease

Lactation

Caution

Pregnancy

Adverse effects

Risks associated with use of blood products

Headache, flushing, fever, chills, and lethargy

Nausea and vomiting

Stinging, itching, and burning at the site of injection

Systemic Hemostatic Agents

Action Stop the natural plasminogen clot-dissolving

mechanism by blocking its activation or by directly inhibiting plasmin

Indication Prevent or treat excess bleeding in hyperfibrinolytic

states

Pharmacokinetics Vary for each drug

Systemic Hemostatic Agents

Contraindications

Allergy

Acute DIC

Caution

Cardiac disease, renal or hepatic dysfunction, pregnancy, and lactation

Systemic Hemostatic Agents

Adverse effects

Excessive clotting

CNS: hallucinations, drowsiness, dizziness, headache, and psychotic states

GI: nausea, cramps, and diarrhea

Weakness, fatigue, malaise, and muscle pain

Aprotinin: cardiac arrhythmias, MI, CHF, and hypotension

Drug-to-drug interactions

Heparin

Oral contraceptives and estrogen

Drugs for Deficiency Anemia

Anemia decrease in erythrocytes (RBC) Number Size Hemoglobin content

Causes Blood loss Hemolysis Bone marrow dysfunction

Red Blood Cell Development

Stage 1 – Proerythroblasts Lacks hemoglobin

Stage 2 – Erythroblasts Gains hemoglobin

Stage 3 – Reticulocytes Immature erythrocytes

Stage 4 - Erythrocytes Maturity

Iron Deficiency Anemia

Most common nutritional anemia

Iron essential to hemoglobin

Daily requirements

Dietary sources

Iron supplements

Iron Deficiency Anemia-Causes

Imbalance in iron uptake and iron demand

Microcytic, hypochromic anemia

Causes Pregnancy Infancy and early childhood Chronic blood loss

Iron Preparations

Ferrous Sulfate Indications Administration Drug Interactions

Adverse Effects GI disturbances Staining of teeth Toxicity

Dosage Formula for Iron

Mg Iron =

0.66 x kg body weight x(100- hemoglobin value in g/dl)

14.8

Vitamin B12 Deficiency

Vitamin B12 (Cobalamins)

Essential for synthesis of DNA

Absorption requires intrinsic factor

Daily requirement

Dietary sources

Diagnostic tests

Vitamin B12 Deficiency – Causes and Consequences

Causes Regional enteritis Celiac disease Lack of intrinsic factor

Consequences Megaloblastic anemia Neurologic damage GI disturbances

Vitamin B12 Preparations - Cyanocobalamin

Cyanocobalamin Administration

Oral, parenteral, intranasal Adverse Effects

Hypokalemia Long term treatment

With lack of intrinsic factor, Vitamin B12 lifelong

Folic Acid Anemia

Folic Acid Found small intestine Daily requirements Dietary sources Administration

Folic Acid Anemia- Causes and Consequences

Causes Poor dietMalabsorption syndrome

ConsequencesMegaloblastic anemiaNeural tube defects

Hematopoietic and Thrombopoietic Growth Factors

Acts on bone marrow to stimulate formation of blood cells

Types Hematopoietic growth factor

RBC’s, WBCs Thrombopoietic growth factor

Platelets

Epoetin Alfa (Erythropoietin)

Epoetin alfa (Epogen) Hematopoietic growth factor Recombinant DNA technology

Uses Chronic renal failure HIV-infected patients Chemotherapy

Adverse Effects Hypertension

Filgrastim (Neupogen)

Filgrastim Hematopoietic growth factor Recombinant DNA technology

Uses Chemotherapy Bone marrow transplant Chronic neutropenia

Adverse Effects Bone pain

Oprelvekin (Interleukin – 11)

Oprelvekin (Neumega) Thrombopoietic growth factor Recombinant DNA technology

Uses Chemotherapy

Adverse Effects Fluid Retention Cardiac Dysrhythmias