Thrombolysis alteplase pharmacodynamics and pharmacokinetics
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THROMBOLYSIS Alteplase: Pharmacodynamics and Pharmacokinetics. Dr Kevin Reiling. Tissue Plasminogen Activator. Coagulation Factors. Fibrinolysis. Plasminogen. Fibrinogen. Plasmin. Fibrin. Coagulation and Fibrinolysis. Natural Regulatory Balance.

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Thrombolysis alteplase pharmacodynamics and pharmacokinetics

THROMBOLYSISAlteplase: Pharmacodynamics and Pharmacokinetics

Dr Kevin Reiling


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Tissue Plasminogen Activator

Coagulation Factors

Fibrinolysis

Plasminogen

Fibrinogen

Plasmin

Fibrin

Coagulation and Fibrinolysis


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Natural Regulatory Balance

Fibrinolysis - tissue plasminogen activator (tPA) - streptokinase

- urokinase

Inactivation of procoagulant enzymes

Activated clotting factor clearance


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Fibrinolysis

Injured endothelial cells

Plasminogen activators

Plasmin cleaved from plasminogen

Fibrin degrades


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Plasmin

Plasminogen

Primary


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Tissue Plasminogen Activators: 

Family of thrombolytic drugs used in acute myocardial infarction, cerebrovascular thrombotic stroke and pulmonary embolism.

Alteplase

Retaplase, smaller derivative of recombinant tPA that has increased potency and is faster acting than rtPA.

Tenecteplase, greater binding affinity for fibrin than rtPA.


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Thrombolytic drugs dissolve blood clots by activating plasminogen, which forms a cleaved product called plasmin. Plasmin is a proteolytic enzyme that is capable of breaking cross-links between fibrin molecules, which provide the structural integrity of blood clots. Because of these actions, thrombolytic drugs are also called "plasminogen activators" and "fibrinolytic drugs." 


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

The removal of the clot is caused by plasmin cleavage of the fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Primary Structure of Tissue Plasminogen Activator (tPA) fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

C2569H3928N746O781S40

Elimination by liver endothelium cells

Stimulation of protease by fibrin

Fibrinolytic drug

Elimination by Hepatocyte

Alteplase (Actilyse; Activase; rtPA) is a recombinant form of human tPA

Binding to fibrin

Clot-buster

Splitting of Plasminogen


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Pharmacokinetics fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

ADME

Broken down in digestive system, so?

Exercise and vasoactive substances such as epinephrine, vasopressin, desmopressin, niacin or alcohol, increase endogenous levels, so?

Endogenous levels = 4–6 ng/mL, so?

Natural constituent of bloodstream relatively inactive with a VD approximating to plasma volume.


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Pharmacokinetics fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

ME

Metabolism – poorly understood but principally hepatic with most occurring with the hepatocytes.

First reading – 60

Second reading – 26 @ 5 minutes later

Third Reading – 12 @ another 5 minutes later

Half-life?


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Pharmacokinetics fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

Rapidly cleared 550-680 mL/minute from plasma giving an initial distribution phase half life (t½α) <5 min and in the terminal elimination phase (t½β) ~40 min.

Thus > 50% of t-PA is cleared from plasma within 5 minutes after discontinuance of an IV infusion and approximately 80% is cleared within 10 minutes.


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Giving us fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

Continuous infusion.

Recommended dose 0.9 mg alteplase/kg body weight (maximum of 90 mg) over 60 minutes, with 10% of the total dose administered as an initial intravenous bolus.

Not indicated <18 years >80 years.

????


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Risks fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

Plasmin breaks down fibrin = fibrin degradation products (FDPs).

FDPs compete with thrombin = slow down the conversion of fibrinogen to fibrin (and thus slows down clot formation).

Secondary impact tPA – binds circulating plasminogen


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Risks fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

Lysis of normal haemostatic plugs - bleeding

Intracranial haemorrhage, absolute risk is increased 6% in patients of first 10 days, maximal during the first 36 hours after treatment. (c.f. 3 month overall risk reduction of 11% )


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Other risks fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

Potential interactions with anticoagulants, ACE inhibitors, platelet function altering drugs etc.

Cholesterol embolisms

Immune problems – plasmin also cleaves C3 component of complement system


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

  • Contraindications? fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

  • Blood glucose < 50 or > 400 mg/dl

  • More with Dr Fotherby


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Have we missed anything important? fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease.

Within 3 hours of the stroke.

The efficacy of thrombolytic drugs depends on the age of the clot. Older clots have more fibrin cross-linking and are more compacted or in plain English older clots are more difficult to dissolve.

Beyond that time, the efficacy diminishes and higher doses are generally required to achieve desired lysis and the great the risk of unwanted complications.


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Alteplase is recommended for the treatment of acute ischaemic stroke when used by physicians trained and experienced in the management of acute stroke. It should only be administered in centres with facilities that enable it to be used in full accordance with its marketing authorisation.


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Near future developments? ischaemic stroke when used by physicians trained and experienced in the management of acute stroke. It should only be administered in centres with facilities that enable it to be used in full accordance with its marketing authorisation.

Completion of major EU trials – 2008.

Increased tPA window – better scanning equipment = not all neurons die after 3 hours potentially pushing window to 8 hours.

Delay progression – combination therapy – oxygen.

Desmoteplase - "Even at nine hours, patients had significant long-term clinical benefits”


Thrombolysis alteplase pharmacodynamics and pharmacokinetics

Competency framework ischaemic stroke when used by physicians trained and experienced in the management of acute stroke. It should only be administered in centres with facilities that enable it to be used in full accordance with its marketing authorisation.

“the time of the onset of stroke has been recorded and has full understanding of the importance of this in relation to thrombolysis”

“Understands the pharmacodynamics and pharmacokinetics of thrombolytic treatment with rtPA”

“Understands the potential for unwanted effects “