NTA Level 5 • Semester 1 • PST05104

Pharmacodynamics of Anticoagulants

Pharmacology and Therapeutics • Source Session/Topic 35

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Session 35: Pharmacodynamics of Anticoagulants

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

By the end of this session students are expected to be able to:

Describe mechanism of action of Anticoagulants

Describe drug interactions associated with Anticoagulants

Describe side effects of Anticoagulants

Describe contraindications of Anticoagulants

Resources Needed:

Flip charts, marker pens, and masking tape

Black/white board and chalk/whiteboard markers

Computer and LCD projector

SESSION OVERVIEW

Step

Time

Activity/

Content

Step

Time

Activity/

Content

Step

Time

Method

Content

Method

05 minutes

Presentation

Introduction, Learning tasks

40 minutes

Presentation/

Mechanism of Action of Anticoagulants

40 minutes

Buzzing

Mechanism of Action of Anticoagulants

Buzzing

20 minutes

Presentation/

Drug Interactions Associated with

20 minutes

brainstorming

Anticoagulants

brainstorming

Anticoagulants

20 minutes

Presentation

Side Effects of Anticoagulants

PST 05104 Pharmacology & Therapeutics

277

NTA Level 5 Semester 1 Facilitator Guide

15 minutes

Presentation/

Contraindications of Anticoagulants

15 minutes

Brainstorming

Contraindications of Anticoagulants

Brainstorming

05 minutes

Presentation

Key Points

05 minutes

Presentation

Evaluation

10 minutes

Presentation

Assignment

PST 05104 Pharmacology & Therapeutics 278 NTA Level 5 Semester 1 Facilitator Guide

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Mechanism of Action of Anticoagulants (40 minutes)

Activity: Buzzing (5 minutes)

ASK students to pair up and buzz on the following question for 2 minutes

How do Anticoagulants produce their pharmacological effects?

ALLOW few pairs to respond and let other pairs add on points not mentioned

WRITE their response on the flip chart/board

CLARIFY and SUMMARIZE by using the content below

Anticoagulants

Heparins:

o Heparin is a sulphated acidic mucopolysaccharide that is widely distributed in the body.

o The unfractionated preparation is extracted from the lung or intestine of ox or pig, and is a mixture of polymers of varying molecular weights.

o Since the structure is variable, the dosage is expressed in terms of units of biological activity.

o Low-molecular-weight heparins (LMWH) are fragments or short synthetic sequences of heparin with much more predictable pharmacological effects, and monitoring of their anticoagulant effect is seldom needed.

o They have largely replaced unfractionated heparin in therapy.

Unfractionated Heparin(UFH)

o Unfractionated heparin has been replaced by LMWH for most indications, but remains important for patients with impaired or rapidly changing renal function.

o Treatment is monitored by measuring the activated partial thromboplastin time (APTT) four to six hours after starting treatment and then every six hours, until two consecutive readings are within the target range, and thereafter at least daily.

o Dose adjustments are made to keep the APTT ratio (i.e. the ratio between the value for the patient and the value of a control) in the range 1.5–2.5.

o Mechanism:

PST 05104 Pharmacology & Therapeutics 279 NTA Level 5 Semester 1 Facilitator Guide

The main action of heparin is on the coagulation cascade. It works by binding to antithrombin III, a naturally occurring inhibitor of thrombin and other serine proteases (factors IXa, Xa, XIa and XIIa), and enormously potentiating its inhibitory action.

A lower concentration is required to inhibit factor Xa and the other factors early in the cascade than is needed to antagonize the action of thrombin, providing the rationale

for low-dose heparin in prophylaxis.

o As an antithrombin drug, it inhibits platelet activation by thrombin

Low Molecular Weight Heparins (LMWH)

Low-molecular-weight heparins (LMWH) preferentially inhibit factor Xa.

They do not prolong the APTT, and monitoring (which requires sophisticated factor

Xa assays) is not needed in routine clinical practice, because their pharmacokinetics

are more predictable(less protein binding and first-order kinetics) than those of unfractionated.

LMWH (e.g. enoxaparin and dalteparin) are at least as safe and effective as unfractionated products, except in patients with renal impairment.

Thrombocytopenia and related thrombotic events and antiheparin antibodies are less common than with unfractionated preparations.

Once-daily dosage makes them convenient, and patients can administer them at home,

reducing hospitalization.

However, LMWH are eliminated solely by renal excretion, unlike unfractionated heparin; as a consequence, unfractionated heparin should be used rather than low-molecular-weight preparations in patients with significant renal dysfunction.

Mechanism: as discussed on UFH

Direct Factor Xa Inhibitors: Rivaroxaban:

Direct factor Xa inhibitors are agents that inhibit clotting by inhibiting a specific

component of the coagulation cascade.

Factor Xa converts prothrombin to thrombin (factor IIa). Thrombin is an enzyme that catalyses the final step in the coagulation cascade, the conversion of fibrinogen to fibrin.

Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by factor XIII.

In addition to converting fibrinogen to fibrin, thrombin also activates factor XIII; thus thrombin not only catalyses the creation of the key component of the clot, it also

facilitates the provision of structural rigidity to the clot.

Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation cascade. In addition, thrombin activates platelets, leading to their aggregation.

Direct factor Xa inhibitors directly inhibit the conversion of prothrombin to thrombin

without using antithrombin III as an intermediary.

The direct inhibition of thrombin formation results in an anticoagulant effect.

PST 05104 Pharmacology & Therapeutics 280 NTA Level 5 Semester 1 Facilitator Guide

Direct Factor Xa Inhibitors: Rivaroxaban::

o Direct factor Xa inhibitors are agents that inhibit clotting by inhibiting a specific component of the coagulation cascade.

Direct Thrombin Inhibitors: Parenteral: Hirudin, Bivalirudin and Desirudin Oral: Dabigatran, Ximelagatran and Argatroban

o Thrombin (factor IIa) is an enzyme that catalyses the final step in the coagulation cascade, the conversion of fibrinogen to fibrin.

o Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by factor XIII.

o Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation cascade. Thrombin also has antiplatelet effects.

o Thrombin has an active site as well as two other sites, referred to as exosite 1, which binds fibrin, and exosite 2, which binds heparin.

o Direct thrombin inhibitors all bind to thrombin directly at its active site. The bivalent inhibitors (-irudins) also bind at exosite 1 (hence the term ―bivalent‖, indicating two binding sites), while the univalent inhibitors only bind at the active site.

o The univalent thrombin inhibitors (e.g., argatroban and dabigatran) and bivalirudin all bind reversibly, whereas the other bivalent inhibitors bind thrombin irreversibly.

o The net result of this binding is that the effects of thrombin are inhibited. The inhibition of thrombin results in an anticoagulant effect.

Vitamin K Antagonists: Warfarin

o Vitamin K antagonists are a family of naturally derived anticoagulants, which are also known as coumarins.

o Vitamin K is key cofactor in the hepatic activation of four coagulation factors. The four vitamin K-dependent clotting factors are II, VII, IX, and X (Figure 16-4).

o To act as a cofactor, vitamin K must be in its reduced form, vitamin K hydroxyquinone. The enzyme vitamin K epoxide reductase (VKOR) converts vitamin K to its reduced form.

o Warfarin inhibits the enzyme VKOR. Blocking formation of the reduced form of vitamin K inhibits the activation of these four clotting factors.

o These clotting factors vary in their half-lives (6 to 50 hours), with factor II having the longest half-life and factor VII having the shortest. This delays the onset of action of warfarin, as one must wait until these clotting factors have been mostly depleted before the full anticoagulant effects have been achieved.

o There is significant genetic variability in responses to warfarin owing to variants in 2C9 that metabolize the drug less efficiently and to variants in VKOR.

PST 05104 Pharmacology & Therapeutics 281 NTA Level 5 Semester 1 Facilitator Guide

STEP 3: Drug Interactions Associated with Anticoagulants (20 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are drug interactions associated with Anticoagulants?

ALLOW few students to respond

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

Vitamin K Antagonists: Warfarin

o Potentially important pharmacodynamic interactions with warfarin include those with antiplatelet drugs.

o Aspirin not only influences haemostasis by its effect on platelet function, but also increases the likelihood of peptic ulceration, displaces warfarin from plasma albumin, and in high doses decreases prothrombin synthesis.

o Broad-spectrum antibiotics potentiate warfarin by suppressing the synthesis of vitamin K1 by gut flora.

o Several pharmacokinetic interactions with warfarin are of clinical importance. Several non-steroidal anti-inflammatory drugs (NSAIDs) and dextropropoxyphene inhibit warfarin metabolism.

o The gastrotoxic and platelet-inhibitory actions of the NSAIDs further increase the risk of serious haemorrhage.

o Cimetidine (but not ranitidine) and amiodarone also potently inhibit warfarin metabolism and potentiate its effect, as do other inhibitors of hepatic cytochrome P450, such as erythromycin, ciprofloxacin and omeprazole.

o Drugs that induce hepatic microsomal enzymes, including rifampicin, carbamazepine and phenobarbital, increase warfarin metabolism and increase the dose required to produce a therapeutic effect; furthermore, if the dose is not reduced when such concurrent therapy is discontinued, catastrophic over-anticoagulation and haemorrhage may ensue.

STEP 4: Adverse Effects of Anticoagulants (20 minutes)

Heparin

o Heparin Induced Thrombocytopenia Syndrome (HITS): Antibodies against platelet factor 4 are produced and bind to platelets. Platelets get activated and sticky, and this causes: Thromboses (multiple),Platelet consumption resulting in thrombocytopenia and bleeding as a result of thrombocytopenia

o Hemorrhage can be reversed with protamine.

o Osteoporosis occurs with long-term therapy; the cause is unknown.

PST 05104 Pharmacology & Therapeutics 282 NTA Level 5 Semester 1 Facilitator Guide

Hyperkalemia: Although not a common occurrence, heparin can cause increased serum potassium; it is more likely to occur in patients with diabetes or renal disease.

In this regard the action of heparin is similar to that of spironolactone, which is an

aldosterone blocker classified as a K-sparing diuretic.

Fever: Rarely, heparin can cause a drug fever.

Heparins provide a safe and important alternative to teratogenic warfarin in pregnancy.

For cases of heparin overdose, protamine sulphate is a strongly basic protein that forms a complex with heparin, acting as a chemical antagonist. LMWH does not have an antidote.

Danaparoid works by the same mechanism as the heparins, but it is not structurally related to the heparins; it is therefore considered a heparinoid. Therefore it can be used in the management of patients with heparin-induced thrombocytopenia (HIT) too.

Direct Factor Xa Inhibitors: Rivaroxaban:

Bleeding: As with all anticoagulants, bleeding is the major side effect

Direct Thrombin Inhibitors:

Bleeding: As with all anticoagulants, bleeding is the major side effect

Vitamin K Antagonists: Warfarin

Hemorrhage: Minor: Small cuts, nosebleeds, easy bruising, hematuria (blood in urine), and bleeding gums may occur.

Major: Intracranial bleeding is often catastrophic.

Warfarin therapy is monitored using the International Normalized Ratio (INR),

STEP 5: Description of Contraindications of Anticoagulants (10 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are the contraindications of Anticoagulants? ALLOW few students to respond?

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

Heparin

o Previous heparin-induced thrombocytopenia syndrome (HITS) (see Side Effects) o Coagulopathies: hemophilia, thrombocytopenia (low platelet count)

o Active bleeding: intracranial hemorrhage, gastrointestinal (GI) ulcers, certain cancers

Direct Factor Xa Inhibitors: Rivaroxaban: o Active bleeding

PST 05104 Pharmacology & Therapeutics 283 NTA Level 5 Semester 1 Facilitator Guide

Pregnancy

Patients at increased risk of bleeding: clotting disorders, history of recent hemorrhagic stroke

Direct Thrombin Inhibitors:

Patients who are at high risk of bleeding, such as those with the following conditions: Uncontrolled active bleeding, major bleeding (coagulopathy) disorders

Vitamin K Antagonists: Warfarin

Pregnancy: Warfarin is teratogenic and can also cause fetal bleeding.

Recent events that predispose to bleeding include the following: Surgery and stroke o Platelet disorders (If you have dysfunctional clotting cells and dysfunctional clotting

proteins, there really is not much left to form a clot if you should need it.)

o The anticoagulant effects of warfarin can be reversed by administration of vitamin K. The time required for vitamin K to work is dependent on the time the liver requires to generate more proteins (many hours).

STEP 6: Key Points (5 minutes)

Anticoagulants produce effects through different mechanisms

Most anticoagulants cause bleeding as their main side effect

LMWH have advantages over UFH

STEP 7: Evaluation (5 minutes)

What are the adverse effects of Heparins?

What is the mechanism of action of UFH?

What are contraindications of warfarin?

STEP 8: Take HomeAssignment (10minutes)

Activity: Take Home Assignment (5 minutes)

DIVIDE students in groups or individuals

ASK the students to work on the following Assignment

Prepare a presentation on the mechanism of thrombolytc drugs (Give examples of drugs for this pharmacplogical group)

ALLOCATE time for students to do the assignments and submit

REFER students to recommended reference

PST 05104 Pharmacology & Therapeutics 284 NTA Level 5 Semester 1 Facilitator Guide

References

Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.

Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.

Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:

Jaypee Brothers Medical P.

Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.

Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael. (2014). Pharmacotherapy: A Pathophysiologic Approach (9th ed.). New York, McGraw-Hill Education.

Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.

School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).

Dar es Salaam, ARDHI University press.

The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.

The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.

PST 05104 Pharmacology & Therapeutics 285 NTA Level 5 Semester 1 Facilitator Guide

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