THROMBOLYSIS

Alteplase: Pharmacodynamics and Pharmacokinetics

Dr Kevin Reiling

Coagulation and Fibrinolysis

Tissue Plasminogen Activator
Coagulation Factors

Plasminogen
Fibrinogen

Plasmin
Fibrin

Fibrinolysis

Natural Regulatory Balance

Fibrinolysis - tissue plasminogen activator (tPA)
- streptokinase - urokinase

Inactivation of procoagulant enzymes Activated clotting factor clearance

Fibrinolysis
Injured endothelial cells

Plasminogen activators
Plasmin cleaved from plasminogen Fibrin degrades

Primary

Plasmin Plasminogen

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.

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."

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.

Primary Structure of Tissue Plasminogen Activator (tPA)

Elimination by liver endothelium cells Stimulation of protease by fibrin

C2569H3928N746O781S40

Elimination by Hepatocyte

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

Binding to fibrin

Splitting of Plasminogen

Clot-buster

Pharmacokinetics

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 = 46 ng/mL, so?

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

Pharmacokinetics

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?

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

Giving us
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. ????

Risks
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

Risks
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% )

Other risks
Potential interactions with anticoagulants, ACE inhibitors, platelet function altering drugs etc. Cholesterol embolisms

Immune problems plasmin also cleaves C3 component of complement system

Contraindications?
Blood glucose < 50 or > 400 mg/dl More with Dr Fotherby

Have we missed anything important?

Within 3 hours of the stroke.
The efficacy of thrombolytic drugs depends on the age of the clot. Older clots have more fibrin crosslinking 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.

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.

Near future developments?

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

Competency framework
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