DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

326 nadolol is its relatively long t 1/2
. It can be used to treat
hypertension and angina pectoris. Unlabeled uses have
included migraine prophylaxis, parkinsonian tremors,
and variceal bleeding in portal hypertension.
SECTION II
NEUROPHARMACOLOGY
Absorption, Fate, and Excretion. Nadolol is very soluble in water
and is incompletely absorbed from the gut; its bioavailability is
~35%. Interindividual variability is less than with propranolol. The
low lipid solubility of nadolol may result in lower concentrations of
the drug in the brain as compared with more lipid-soluble β receptor
antagonists. Although it frequently has been suggested that the incidence
of CNS adverse effects is lower with hydrophilic β receptor
antagonists, data from controlled trials to support this contention are
limited. Nadolol is not extensively metabolized and is largely
excreted intact in the urine. The t 1/2
of the drug in plasma is ~20 hours;
consequently, it generally is administered once daily. Nadolol may
accumulate in patients with renal failure, and dosage should be
reduced in such individuals.
Timolol
Timolol (BLOCADREN, others) is a potent, non-selective
β receptor antagonist. It has no intrinsic sympathomimetic
or membrane-stabilizing activity. It is used
for hypertension, congestive heart failure, acute MI,
andmigraine prophylaxis. In ophthalmology, timolol
has been used in the treatment of open-angle glaucoma
and intraocular hypertension. Its mechanism of action
in treating open angle glaucoma is not precisely known;
but the drug appears to reduce aqueous humour production
through blockade of β receptors on the ciliary
epithelium.
Absorption, Fate, and Excretion. Timolol is well absorbed from
the GI tract. It is metabolized extensively by CYP2D6 in the liver
and undergoes first-pass metabolism. Only a small amount of
unchanged drug appears in the urine. The t 1/2
in plasma is ~4 hours.
Interestingly, the ocular formulation of timolol (TIMOPTIC, others),
used for the treatment of glaucoma, may be extensively absorbed
systemically (Chapter 64); adverse effects can occur in susceptible
patients, such as those with asthma or congestive heart failure. The
systemic administration of cimetidine with topical ocular timolol
increases the degree of β blockade, resulting in a reduction of resting
heart rate, intraocular pressure, and exercise tolerance (Ishii et al.,
2000). For ophthalmic use timolol is available combined with other
medications (e.g., with dorzolamide or travoprost). Timolol also provide
benefits to patients with coronary heart disease: in the acute
post MI period, timolol produced a 39% reduction in mortality in
the Norwegian Multicenter Study.
Pindolol
Pindolol (VISKEN, others) is a non-selective β receptor
antagonist with intrinsic sympathomimetic activity.
It has low membrane-stabilizing activity and low
lipid solubility. It is used to treat angina pectoris and
hypertension.
Although only limited data are available, β blockers with
slight partial agonist activity may produce smaller reductions in resting
heart rate and blood pressure. Hence, such drugs may be preferred
as antihypertensive agents in individuals with diminished
cardiac reserve or a propensity for bradycardia. Nonetheless, the
clinical significance of partial agonism has not been substantially
demonstrated in controlled trials but may be of importance in individual
patients. Agents such as pindolol block exercise-induced
increases in heart rate and cardiac output.
Absorption, Fate, and Excretion. Pindolol is almost completely
absorbed after oral administration and has moderately high bioavailability.
These properties tend to minimize interindividual variation in
the plasma concentrations of the drug that are achieved after its oral
administration. Approximately 50% of pindolol ultimately is metabolized
in the liver. The principal metabolites are hydroxylated derivatives
that subsequently are conjugated with either glucuronide or
sulfate before renal excretion. The remainder of the drug is excreted
unchanged in the urine. The plasma t 1/2
of pindolol is ~4 hours; clearance
is reduced in patients with renal failure.
β 1
SELECTIVE ADRENERGIC RECEPTOR
ANTAGONISTS
Metoprolol
Metoprolol (LOPRESSOR, others) is a β 1
-selective receptor
antagonist that is devoid of intrinsic sympathomimetic
activity and membrane-stabilizing activity.
Absorption, Fate, and Excretion. Metoprolol is almost completely
absorbed after oral administration, but bioavailability is relatively
low (~40%) because of first-pass metabolism. Plasma concentrations
of the drug vary widely (up to 17-fold), perhaps because of genetically
determined differences in the rate of metabolism. Metoprolol
is extensively metabolized in the liver, with CYP2D6 the major
enzyme involved, and only 10% of the administered drug is recovered
unchanged in the urine. The t 1/2
of metoprolol is 3-4 hours,
but can increase to 7-8 hours in CYP2D6 poor metabolizers. It
recently has been reported that CYP2D6 poor metabolizers have a
5-fold higher risk for developing adverse effects during metoprolol
treatment than patients who are not poor metabolizers (Wuttke et al.,
2002). An extended-release formulation (TOPROL XL) is available for
once-daily administration.
Therapeutic Uses. Metoprolol has been used to treat essential hypertension,
angina pectoris, tachycardia, heart failure, vasovagal syncope,
and as secondary prevention after myocardial infarction, an
adjunct in treatment of hyperthyroidism, and for migraine prophylaxis.
For the treatment of hypertension, the usual initial dose is
100 mg/day. The drug sometimes is effective when given once daily,
although it frequently is used in two divided doses. Dosage may be
increased at weekly intervals until optimal reduction of blood pressure
is achieved. If the drug is taken only once daily, it is important
to confirm that blood pressure is controlled for the entire 24-hour
period. Metoprolol generally is used in two divided doses for the
treatment of stable angina. For the initial treatment of patients
with acute myocardial infarction, an intravenous formulation of