Transcript 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
endothelium cells
Stimulation of protease
by fibrin
C2569H3928N746O781S40
Fibrinolytic drug
Elimination by Hepatocyte
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 = 4–6 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 (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.
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 “