Alteplase Pharmacology

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 Stimulation of protease C2569H3928N746O781S40

endothelium cells by fibrin
Elimination by Hepatocyte Fibrinolytic drug
Alteplase (Actilyse;
Binding to fibrin Activase; rtPA) is a
recombinant form of
human tPA
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 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.
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

Alteplase Pharmacology

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THROMBOLYSIS

Fibrinolysis - tissue plasminogen activator (tPA)

Inactivation of procoagulant enzymes

Activated clotting factor clearance

Injured endothelial cells

Plasmin cleaved from plasminogen

Retaplase, smaller derivative of recombinant tPA that

Tenecteplase, greater binding affinity for fibrin than

Elimination by liver Stimulation of protease C2569H3928N746O781S40

Elimination by Hepatocyte Fibrinolytic drug

Broken down in digestive system, so?

Exercise and vasoactive substances such as

Endogenous levels = 46 ng/mL, so?

Natural constituent of bloodstream relatively

Metabolism poorly understood but principally

Rapidly cleared 550-680 mL/minute from plasma

Thus > 50% of t-PA is cleared from plasma within 5

Recommended dose 0.9 mg alteplase/kg body weight

Not indicated <18 years >80 years. ????

FDPs compete with thrombin = slow down the

Secondary impact tPA binds circulating

Lysis of normal haemostatic plugs - bleeding

Intracranial haemorrhage, absolute risk is

Potential interactions with anticoagulants, ACE

Blood glucose < 50 or > 400 mg/dl

More with Dr Fotherby

Within 3 hours of the stroke.

The efficacy of thrombolytic drugs depends on the

Beyond that time, the efficacy diminishes and higher

Completion of major EU trials 2008.

Increased tPA window better scanning equipment =

Delay progression combination therapy oxygen.

Desmoteplase - "Even at nine hours, patients had

the time of the onset of stroke has been

Understands the pharmacodynamics and

Understands the potential for unwanted effects

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