Monograph: |
PLASMINOGEN ACTIVATOR
Alteplase
A glycosylated protein of 527 residues having the amino acid
sequence of human tissue plasminogen activator (t-PA) and
produced by recombinant DNA technology.
A study by Lee and others' concluded that alteplase should
not be mixed in the same container with dobutamine.
dopamine. glyceryl trinitrate or heparin. as there was evi-
dence of incompatibility, although a subsequent study found
no incompatibility between alteplase and glyceryl trinitrate.;
Another study, by Frazin.' found that dilution of a proprietary
preparation of alteplase (Activase) to 0.09 and 0.16 mg per
mL with 5% glucose injection resulted in precipitation of the
drug. Alteplase is formulated with arginine as a solubilising
agent, and dilution with 5% glucose to concentrations below
0.5 mg of alteplase per mL makes precipitation possible. Di-
lution with 0.9% sodium chloride is possible to concentra-
tions down to 0.2 mg per mL before precipitation becomes a
risk.
Units
The activity of alteplase can be measured in terms of
international units using the second International
Standard for tissue plasminogen activator estab-
lished in 1987, although doses are generally ex-
pressed by weight. The specific activity of alteplase
is 580 000 international units per mg.
Adverse Effects, Treatment, and Precautions
As for Streptokinase. Allergic reactions are
less likely with alteplase and repeated administra-
tion is possible.
Infusion of alteplase produces considerable thrombin genera-
tion which may result from direct activation of the coagula-
tion system by plasmin or by positive feedback of the
coagulation system by clot-bound thrombin. This excessive
thrombin generation was considered a possible cause of my-
ocardial infarction in a patient undergoing thrombolytic ther-
apy with alteplase for venous thrombosis. Infusion of
streptokinase produced no evidence of excessive thrombin
generation.
Hypersensitivity. An anaphylactoid reaction to alteplase
occurred in a patient with a history of atopy. For comment on
this unexpected reaction, see Hypersensitivity under the Ad-
verse Effects of Streptokinase.
Interactions
As for Streptokinase.
Glyceryl trinitrate. Although thrombolytics and nitrates
are both frequently used in acute myocardial infarction one
report has suggested that this combination may result in im-
paired thrombolysis. Concurrent intravenous administration
of alteplase and glyceryl trinitrate to 36 patients with acute
myocardial infarction produced lower plasma-antigen con-
centrations of tissue-plasminogen activator than alteplase giv-
en alone to 11 patients. Reperfusion was sustained in only
44% of patients receiving both drugs compared with 91% of
patients receiving alteplase alone. The authors of a subse-
quent study suggested that these lower plasma concentra-
tions may be due lo increased hepatic metabolism of alteplase
as a result of glyceryl trinitrate's effect of increasing hepatic
blood flow.
Pharmacokinetics
Alteplase is cleared rapidly from the plasma, mainly
by metabolism in the liver.
Uses and Administration
Alteplase is a thrombolytic drug. It is a predomi-
nantly single-chain form of the endogenous enzyme
tissue plasminogen activator and is produced by re-
combinant DNA technology. Like endogenous tis-
sue plasminogen activator. alteplase converts fibrin-
5ound plasminogen to the active form plasmin. re-
sulting in fibrinolysis and dissolution of clots.
Alteplase has relatively
little effect on circulating, unbound plasminogen
and thus may be termed a fibrin-specific agent. Fi-
brin specificity was thought to be required for reduc-
ing the risk of haemorrhage associated with the use
of thrombolytics, although currently available fi-
brin-specific agents do not produce less bleeding
than nonspecific thrombolytics (see Haemorrhage
under Adverse Effects of Streptokinase).
Alteplase is used similarly to streptokinase
in the treatment of thrombo-embolic disorders, par-
ticularly myocardial infarction and venous
thrombo-embolism . Alteplase may also be
used in patients with acute ischaemic stroke.
In the treatment of acute myocardial infarction. al-
teplase is given intravenously as soon as possible af-
ter the onset of symptoms in a total dose of 100 mg;
a total dose of 1.5 mg per kg body-weight is sug-
gested for patients weighing less than 65 kg. The to-
tal dose of 100 mg may be given either over 1%
hours (accelerated or 'front-loaded' alteplase) or
over 3 hours. The accelerated schedule has been rec-
ommended where administration is within 6 hours
of myocardial infarction. while the 3-hour schedule
has been recommended where administration is
more than 6 hours after myocardial infarction. Ad-
ministration over l & 1/2 hours is as follows: 15 mg as
an intravenous bolus, then 0.75 mg per kg body-
weight, up to a maximum of 50 mg, by intravenous
infusion over 30 minutes, followed by the remainder
infused over the subsequent 60 minutes. Adminis-
tration over 3 hours is as follows: 10 mg as an intra-
venous bolus, then 50 mg by intravenous infusion
over I hour. followed by a further 40 mg infused
over the subsequent 2 hours.
In the treatment of pulmonary embolism 100 mg
may be given by intravenous infusion over 2 hours.
In acute ischaemic stroke, alteplase is given within
3 hours of the onset of symptoms in a dose of 0.9 mg
per kg up to a maximum total dose of 90 mg. The
dose is administered intravenously over 60 minutes
with 10% being given as a bolus during the first
minute.
Catheters and cannulas. Alteplase has been used success-
fully to clear thrombi in central venous catheters. Doses
typically employed have been 2 mg injected as a bolus into
the blocked catheter. In two children alteplase in doses of
0.01 to 0.05 mg per kg body-weight per hour intravenously
has been used for venous thrombosis associated with indwell-
ing intravascular catheters.
Intracardiac thrombosis. Alteplase has been used, in a
dose of 100 mg given intravenously over two hours, for
thrombosis of prosthetic heart valves.
Alteplase has been used successfully in a neonate to treat in-
tracardiac thrombosis associated with the use of a central ve-
nous line. A dose of 0.5 mg per kg body-weight given over
10 minutes was followed by infusion of 0.2 mg per kg per
hour for three days.
Micro vessel thrombosis. Alteplase has been used in a
number of conditions where the underlying pathology is oc-
clusion of small blood vessels by micro thrombi.
Purpura and loss of circulation in the hands of a patient recov-
ering from fulminant meningococcemia responded to in-
tra-arterial infusion of alteplase 0.02 to 0.04 mg per kg body-
weight per hour for 22 hours in the right hand, and 0.02 mg
per kg per hour for 11 hours in the left. Perfusion was success-
fully restored to both hands, and full function subsequently
attained in them. Improvement was also achieved when al-
teplase was given to 2 infants with septic shock and purpura
fulminans caused by meningococcal infection.
Six patients with ulcers caused by livedoid vasculitis and
refractory to conventional treatment were treated with al-
teplase 10 mg infused intravenously over 4 hours daily for 14
days. Most ulcers healed rapidly; one patient required retreat-
ment with concomitant anticoagulation.
A 4-year-old girl with haemolytic uraemic syndrome responded to
treatment with an intravenous infusion of alteplase 0.2 mg per
kg per hour for 5 hours, subsequently reduced to 0.05 mg per
kg per hour for 14 days.
Alteplase has been tried in a few patients with veno-occlusive
disease of the liver, a serious complication of bone-marrow
transplantation that may be caused by diffuse thrombi in the
hepatic venules. However, results have been mixed.
Peripheral arterial thrombo-embolism. Thrombolyt-
ics. including alteplase, may be used in the management of
peripheral arterial thrombo-embolism. Alteplase has
been injected intravenously or intra-arterially directly inio the
clot as an alternative to surgical treatment of the occlusion. It
has also been infused intra-arterially lo remove distal clots
during a surgical procedure. Alteplase is claimed to produce
more rapid thrombolysis than streptokinase although studies
have been too small to provide evidence of reduced limb loss
or mortality. The most common dose range is 0.5 to I mg per
hour given intra-arterially. An intravenous dose of 0.5 mg
per kg body-weight per hour for the first hour followed by
0.25 nig per kg per hour until clot lysis occurred has been
used in infants. Where a thrombolytic is used to remove dis-
tal clots during a surgical procedure alteplase has been given
intra-arterially as three doses of 5 mg at IO-minute intervals.
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