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Timoptic Pharmacology, Pharmacokinetics, Studies, Metabolism - Timolol Maleate
Timoptic Pharmacology, Pharmacokinetics, Studies, Metabolism - Timolol Maleate
CLINICAL PHARMACOLOGY
Tablets
Timolol maleate is a beta1 and beta2 (non-selective)
adrenergic receptor
blocking agent
that does not have significant
intrinsic sympathomimetic, direct myocardial
depressant, or local anesthetic
activity.
Pharmacodynamics
Clinical pharmacology studies have confirmed the beta-adrenergic
blocking activity as shown by (1) changes in resting
heart rate
and response of heart
rate to changes in posture;
(2) inhibition of
isoproterenol-induced tachycardia; (3) alteration of the response
to the Valsalva maneuver
and amyl nitrite administration;
and (4) reduction
of heart rate
and blood pressure changes on exercise.
Timolol maleate decreases the positive
chronotropic, positive
inotropic, bronchodilator, and vasodilator
responses caused by beta-adrenergic receptor agonists. The magnitude
of this decreased response
is proportional to the existing sympathetic
tone and the concentration
of timolol maleate at receptor sites.
In normal volunteers,
the reduction in heart
rate response
to a standard exercise was dose
dependent over the test
range of 0.5 to 20 mg,
with a peak reduction
at 2 hours of approximately 30% at higher doses.
Beta-adrenergic receptor
blockade reduces cardiac
output in both healthy
subjects and patients with heart
disease. In patients with
severe impairment of myocardial
function beta-adrenergic
receptor blockade
may inhibit the stimulatory effect
of the sympathetic
nervous system
necessary to maintain adequate cardiac
function.
Beta-adrenergic receptor
blockade in the bronchi
and bronchioles results in increased airway resistance
from unopposed parasympathetic
activity. Such an effect
in patients with asthma
or other bronchospastic conditions is potentially dangerous.
Pharmacokinetics and Metabolism
Timolol maleate is rapidly and nearly completely absorbed (about
90%) following oral ingestion.
Detectable plasma levels
of timolol occur within one-half hour and peak plasma
levels occur in about one to two hours. The drug half-life
in plasma is approximately
4 hours and this is essentially unchanged in patients with moderate
renal insufficiency. Timolol
is partially metabolized by the liver
and timolol and its metabolites are excreted by the kidney. Timolol
is not extensively bound
to plasma proteins; i.e.,
<10% by equilibrium
dialysis and approximately
60% by ultrafiltration. An in vitro hemodialysis
study, using 14C timolol added to human
plasma or whole blood,
showed that timolol was readily dialyzed from these fluids; however,
a study of patients with renal
failure showed that
timolol did not dialyze
readily. Plasma levels following oral
administration are about half those following intravenous
administration
indicating approximately 50% first pass metabolism. The level of
beta sympathetic
activity varies widely among individuals, and no simple
correlation exists
between the dose of plasma
level of timolol maleate and its therapeutic
activity. Therefore, objective clinical
measurements such as reduction
of heart rate
and/or blood pressure
should be used as guides in determining the optimal dosage for each
patient.
Ophthalmic Solutions and Ophthalmic Gel Forming Solution
Mechanism of Action
Timolol maleate is a beta1 and beta2 (non-selective)
adrenergic receptor
blocking agent
that does not have significant
intrinsic sympathomimetic, direct myocardial
depressant, or local anesthetic
(membrane-stabilizing) activity.
Beta-adrenergic receptor
blockade reduces cardiac
output in both healthy
subjects and patients with heart
disease. In patients with
severe impairment of myocardial
function, beta-adrenergic receptor
blockade may inhibit
the stimulatory effect
of the sympathetic
nervous system
necessary to maintain adequate cardiac
function.
Beta-adrenergic receptor
blockade in the bronchi
and bronchioles results in increased airway resistance
from unopposed parasympathetic
activity. Such an effect
inpatients with asthma
or other bronchospastic conditions is potentially dangerous.
Timolol maleate, when applied topically on the eye, has the action
of reducing elevated as well as normal
intraocular pressure,
whether or not accompanied by glaucoma. Elevated intraocular
pressure is a major
risk factor in the pathogenesis
of glaucomatous
visual field
loss. The higher the level of intraocular
pressure, the greater the likelihood of glaucomatous visual field
loss and optic
nerve damage.
The precise mechanism
of the ocular hypotensive
action of timolol maleate
is not clearly established at this time. Tonography and fluorophotometry
studies of timolol maleate in man
suggest that its predominant action
may be related to reduced aqueous
formation. However, in some studies, a slight increase in outflow
facility was also observed.
Additional Information for Ophthalmic Solutions:
The onset of reduction
in intraocular pressure
following administration
of timolol maleate can usually be detected within one-half hour
after a single dose. The maximum
effect usually occurs
in one to two hours and significant
lowering of intraocular
pressure can be maintained
for periods as long as 24 hours with a single dose. Repeated observations
over a period of one
year indicate that the intraocular
pressure-lowering effect
of timolol maleate is well maintained.
Pharmacokinetics
In a study of plasma
drug concentration
in six subjects, the systemic exposure to timolol was determined
following once daily administration of timolol maleate in the morning
(twice daily for the preservative-free ophthalmic solution). The
mean peak plasma
concentration
following this morning dose
was 0.28 ng/ml for the ophthalmic
gel forming solution, and
0.35 ng/ml for the ophthalmic
solutions.
CLINICAL STUDIES
Tablets
Clinical studies indicate that timolol maleate at a dosage
of 20-60 mg/day reduces blood
pressure without causing
postural hypotension
in most patients with essential
hypertension. Administration of timolol maleate to patients with
hypertension results
initially in a decrease in cardiac output, little immediate
change in blood pressure,
and an increase in calculated peripheral resistance. With continued
administration
of timolol maleate, blood pressure
decreases within a few days, cardiac
output usually remains
reduced, and peripheral
resistance falls
toward pretreatment
levels. Plasma volume may decrease or remain unchanged during therapy
with timolol maleate. In the majority of patients with hypertension
timolol maleate also decreases plasma renin
activity. Dosage adjustment
to achieve optimal antihypertensive effect may require a few weeks.
When therapy with timolol maleate is discontinued, the blood
pressure tends to return
to pretreatment
levels gradually. In most patients the antihypertensive
activity of timolol maleate is maintained with long-term therapy
and is well tolerated.
The mechanism of
the antihypertensive
effects of beta-adrenergic receptor blocking agents is not established
at this time. Possible mechanisms of action include reduction
in cardiac output, reduction
in plasma renin
activity, and a central
nervous system
sympatholytic
action.
A Norwegian multi-center, double-blind study compared the effects
of timolol maleate with placebo
in 1884 patients who had survived the acute phase of a myocardial
infarction. Patients with systolic
blood pressure below 100
mm Hg, sick
sinus syndrome
and contraindication
to beta blockers, including
uncontrolled heart failure,
second or third degree
AV block and bradycardia
(<50 beats per minute),
were excluded from the multi-center trial. Therapy with timolol
maleate, begun 7 to 28 days following infarction, was shown to reduce
overall mortality; this was primarily attributable to a reduction
in cardiovascular
mortality. Timolol maleate significantly reduced the incidence
of sudden death (deaths
occurring without symptoms or within 24 hours of the onset of symptoms),
including those occurring within one hour, and particularly instantaneous
deaths (those occurring without preceding symptoms). The protective
effect of timolol maleate
was consistent regardless of age, sex
or site of infarction.
The effect was clearest
in patients with a first infarction
who were considered at a high risk of dying, defined as those with
one or more of the following characteristics during the acute
phase: transient left
ventricular failure,
cardiomegaly, newly appearing atrial
fibrillation or
flutter, systolic hypotension,
or SGOT (ASAT) levels greater than four times the upper limit
of normal. Therapy with timolol maleate also reduced the incidence
of non-fatal reinfarction. The mechanism
of the protective
effect of timolol maleate
is unknown.
Timolol maleate was studied for the prophylactic
treatment of migraine
headache in placebo-controlled clinical
trials involving 400 patients, mostly women between the ages of
18 and 66 years. Common migraine
was the most frequent diagnosis. All patients had at least two headaches
per month at baseline. Approximately
50 percent of patients
who received timolol maleate had a reduction
in the frequency of migraine
headache of at least
50 percent, compared to a similar decrease in frequency in 30 percent
of patients receiving placebo. The most common cardiovascular
adverse effect was bradycardia
(5%).
Ophthalmic Solutions
In controlled multiclinic studies in patients with untreated intraocular
pressures of 22 mmHg or greater, timolol maleate 0.25% or 0.5% administered
twice a day produced a greater reduction
in intraocular pressure
than 1, 2, 3, or 4% pilocarpine solution
administered four times a day or 0.5, 1, or 2% epinephrine
HCl solution administered
twice a day.
In these studies, timolol maleate was generally well tolerated
and produced fewer and less severe side
effects than either pilocarpine or epinephrine. A slight reduction
of resting heart
rate in some patients receiving
timolol maleate (mean reduction
2.9 beats/minute standard
deviation 10.2) was
observed.
Ophthalmic Gel Forming Solution
In controlled, double-masked, multicenter clinical
studies, comparing timolol maleate ophthalmic
gel forming solution
0.25% to timolol maleate ophthalmic solution
0.25% and timolol maleate ophthalmic
gel forming solution 0.5%
to timolol maleate ophthalmic
solution 0.5%, timolol
maleate ophthalmic gel forming solution
administered once a day was shown to be equally effective in lowering
intraocular pressure
as the equivalent
concentration
of timolol maleate ophthalmic
solution administered
twice a day. The effect
of timolol in lowering intraocular
pressure was evident
for 24 hours with a single dose of timolol maleate ophthalmic
gel forming solution. Repeated
observations over a period
of six months indicate that the intraocular
pressure-lowering effect of timolol maleate ophthalmic
gel forming solution
was consistent.
Timolol maleate ophthalmic
gel forming solution
administered once daily had a safety profile
similar to that of an equivalent
concentration
of timolol maleate ophthalmic
solution administered
twice daily. Due to the physical characteristics of the formulation,
there was a higher incidence of transient
blurred vision in patients
administered timolol maleate ophthalmic gel forming solution. A
slight reduction in
resting heart
rate was observed in some
patients receiving timolol maleate ophthalmic
gel forming solution 0.5%
(mean reduction 24
hours post-dose 0.8 beats/minute, mean
reduction 2 hours post-dose 3.8 beats/minute). (See ADVERSE
REACTIONS.)
Timolol maleate ophthalmic
gel forming solution
has not been studied in patients wearing contact
lenses.
ANIMAL PHARMACOLOGY
No adverse ocular effects
were observed in rabbits and dogs administered timolol maleate topically
in studies lasting one and two years respectively.
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