These drugs inhibit adrenergic responses mediated through the α adrenergic receptors without affecting those mediated through β receptors.
α ADRENERGIC BLOCKING DRUGS
These drugs inhibit
adrenergic responses mediated through the α adrenergic receptors
without affecting those mediated through β receptors.
Classification
I.
Nonequilibrium type
a.
βHaloalkylamines—Phenoxybenzamine.
II.
Equilibrium type (competitive)
A. Nonselective
a.
Ergot alkaloids—Ergotamine,
Ergotoxine
b.
Hydrogenated ergot
alkaloids—Dihydroergotamine
(DHE), Dihydroergotoxine
c.
Imidazolines—Tolazoline,
Phentolamine
d.
Miscellaneous–Chlorpromazine
B. α1 selective—Prazosin, Terazosin, Doxazosin, Tamsulosin
C. α2 selective—Yohimbine
·
Blockade of vasoconstrictor α1 (also α2) receptors reduces
peripheral resistance and causes pooling of blood in capacitance vessels → venous return and
cardiac output are reduced → fall in BP. Postural reflex is interfered with → marked hypotension
occurs on standing → dizziness and syncope. Hypovolemia accentuates the hypotension.
The α blockers abolish the
pressor action of Adr, which then produces only fall in BP due to β mediated vasodilatation—vasomotor reversal of Dale. Pressor and
other actions of selective α agonists (NA, phenylephrine) are suppressed.
·
Reflex tachycardia occurs due to fall in mean
arterial pressure and increased release of NA due to blockade of presynaptic α2 receptors.
·
Nasal stuffiness and miosis result from
blockade of α receptors in nasal
blood vessels and in radial muscles of iris respectively.
·
Intestinal motility is increased due to
partial inhibition of relaxant sympathetic influences— diarrhoea may occur.
·
Hypotension produced by α blockers can reduce
renal blood flow → g.f.r. is reduced and more complete reabsorption of Na+ and water
occurs in the tubules → Na+ retention and increase in blood volume.
This is accentuated by reflex increase in renin release mediated through β1 receptors.
·
Tone of smooth muscle in bladder trigone,
sphincter and prostate is reduced by blockade of α1 receptors (mostly of
the α1A subtype) → urine flow in patients with
benign hypertrophy of prostate (BHP) is improved.
·
Contractions of vas deferens and related
organs which result in ejaculation are coordinated through α receptors—α blockers can inhibit
ejaculation; this may manifest as impotence.
·
The α blockers have no effect on adrenergically
induced cardiac stimulation, bronchodilatation, vasodilatation and most of the
metabolic changes, because these are mediated predominantly through β receptors.
Apart
from these common effects, most of which manifest as side effects, many α blockers have some
additional actions. Their pharmacological profile is also governed by their
central effects and by the relative activity on α1 and α2 receptor subtypes.
Only the distinctive features of different α blockers are
described below.
Phenoxybenzamine It cyclizes
spontaneously in the body giving
rise to a highly reactive ethyleniminium intermediate which reacts with adrenoceptors
and other biomolecules by forming strong covalent bonds. The α blockade develops
gradually (even after i.v. injection) and lasts for 3–4 days.
In isolated preparations
of vascular smooth muscle, low concentrations cause DRC of NA to shift to right
without suppression of maxima
(till spare receptors
are available); higher concentrations progressively flatten the DRC and nonequilibrium
antagonism is manifested. Increased release of NA from sympathetic nerves (due
to α2 blockade) occurs and
reflex tachycardia is prominent in intact animals. Partial blockade of 5HT,
histaminergic and cholinergic receptors, but not β adrenergic receptors,
can be demonstrated at higher doses.
The fall in BP caused
by phenoxybenzamine is mainly postural because venodilatation is more prominent
than arteriolar dilatation. In recumbent subjects cardiac output and blood flow
to many organs are increased due to reduction in peripheral resistance and
increased venous return. It tends to shift blood from pulmonary to systemic
circuit because of differential action on the two vascular beds. It also tends
to shift fluid from extravascular to vascular compartment. Phenoxybenzamine is
lipid soluble, penetrates brain and can produce CNS stimulation, nausea and
vomiting on rapid i.v. injection. However, oral doses produce depression,
tiredness and lethargy. Major side effects are postural hypotension,
palpitation, nasal blockage, miosis, inhibition of ejaculation.
Pharmacokinetics
Oral
absorption of phenoxybenzamine is erratic and incomplete; i.m. and s.c.
injections are very painful—should not be given. Though most of the
administered dose is excreted in urine in 24 hours, small amounts that have
covalently reacted remain in tissues for long periods. Chronic administration
leads to accumulation in adipose tissue.
Dose: 20–60 mg/day oral; 1
mg/kg by slow i.v. infusion over 1
hour; used primarily in pheochromocytoma, occasionally in secondary shock and peripheral
vascular disease.
FENOXENE 10 mg cap, 50
mg/ml inj.
Natural And Hydrogenated Ergot Alkaloids Ergot alkaloids are
the adrenergic antagonists with which Dale demonstrated the vasomotor reversal
phenomenon. The amino acid alkaloids ergotamine
and ergotoxine are partial agonists
and antagonists at α
adrenergic, serotonergic and dopaminergic receptors.
The amine alkaloid ergometrine has no α blocking activity.
The natural ergot alkaloids produce long lasting vasoconstriction which
predominates over their α blocking action—peripheral vascular insufficiency
and gangrene of toes and fingers occurs in ergotism. Ergotoxine is a more
potent α blocker and less potent vasoconstrictor than
ergotamine. Hydrogenation reduces vasoconstrictor and increases α blocking activity.
The α blockade produced by
clinical doses of ergot alkaloids is low grade and short lasting; they are not
employed for this purpose. The principal use is in migraine. Diagnostic use of
ergotamine has been made to precipitate ECG signs of ischaemia in coronary
artery disease. Dihydroergotoxine has been used as a cognition enhancer.
Tolazoline It is an imidazoline compound with complex pharmacological properties. The α blocking action is
only modest and short lasting. In addition, it is a direct vasodilator and
stimulates the heart.
Tolazoline
also blocks 5HT receptors, has a histamine like gastric secretagogue and ACh
like motor action on intestines. It was used in peripheral vascular diseases
and pulmonary hypertension of the newborn.
Phentolamine This congener of tolazoline is a rapidly acting α blocker with short
duration of action (in minutes). It equally blocks α1 and α2 receptors—NA release
is increased and venodilatation predominates over arteriolar dilatation. It is
used as a quick and short acting α blocker for diagnosis and intraoperative
management of pheochromocytoma and for control of hypertension due to clonidine
withdrawal, cheese reaction, etc. It is the most suitable α blocker for local
infiltration to counteract vasoconstriction due to extravasated NA/DA during
their i.v. infusion.
Dose: 5 mg i.v. repeated as
required;
REGITINE, FENTANOR 10
mg/ml inj.
Prazosin It is first of the highly selective α1 blockers having α1 : α2 selectivity ratio
1000:1. All subtypes of α1 receptor (α1A, α1B, α1D) are blocked equally.
It blocks sympathetically mediated vasoconstriction and produces fall in BP
which is attended by only mild tachycardia; NA release is not increased due to
absence of α2 blockade.
Prazosin dilates
arterioles more than veins. Postural hypotension is less marked, occurs
especially in the beginning, which may cause dizziness and fainting as ‘first
dose effect’. This can be minimized by starting with a low dose and taking it
at bedtime. Subsequently tolerance develops to this side effect. Other α blocking side effects
are also milder. It also inhibits phosphodiesterase which degrades cAMP. Rise
in smooth muscle cAMP could contribute to its vasodilator action.
Prazosin is effective
orally (bioavailability ~60%), highly bound to plasma proteins (mainly to α1 acid glycoprotein),
metabolized in liver and excreted primarily in bile. Its plasma t½ is 2–3
hours; effect of a single dose lasts for 6–8 hours.
Prazosin is primarily
used as an antihypertensive (see Ch.
40). Other uses are—Raynaud’s disease and prostatic hypertrophy—blocks α1 receptors in bladder
trigone and prostate and thus improves urine flow, reduces residual urine in
bladder.
PRAZOPRES 0.5, 1.0 and
2.0 mg tabs. Start with 0.5–1 mg at bedtime; usual dose 1–4 mg BD or TDS. MINIPRESS XL: Prazosin
GITS (gastrointestinal therapeutic system) 2.5 mg and 5 mg tablets; 1 tab OD.
Terazosin It is chemically and pharmacologically similar
to prazosin; differences are higher bioavailability (90%) and longer plasma t½
(~12 hr); a single daily dose lowers BP over 24 hrs. Terazosin is more popular
for use in BHP due to single daily dose and a probable apoptosis promoting
effect on prostate.
HYTRIN, TERALFA,
OLYSTER 1, 2, 5 mg tab; usual maintenance dose 2–10 mg OD.
Doxazosin Another long acting (t½ 18 hr) congener of
prazosin with similar pharmacological profile, used in hypertension and BHP.
Dose: 1 mg OD initially,
increase upto 8 mg BD;
DOXACARD, DURACARD,
DOXAPRESS 1, 2, 4 mg tabs.
Tamsulosin This uroselective α1A/α1D blocker (α1A : α1B affinity 7–38 fold)
has been found as effective as terazosin in improving BHP symptoms. Because α1A subtype predominate
in the bladder base and prostate, while α1B receptors are
dominant in blood vessels, tamsulosin does not cause significant changes in BP
or HR at doses which relieve urinary symptoms. No increase in adverse
cardiovascular events, including postural hypotension has been noted. Dizziness
and retrograde ejaculation are the only significant side effects. Its plasma t½
is 6–9 hrs, but the modified release (MR) cap needs only once daily dosing. It
appears to be a better tolerated α1 blocker for BHP.
CONTIFLO–OD
0.4 mg Cap, URIMAX, DYNAPRES 0.2, 0.4 mg MR cap; 1 cap (max 2) in the
morning with meals. No dose titration is needed in most patients.
Trimazosin is a less potent
congener of prazosin. Alfuzosin is a α1 blocker used primarily
in BHP, but is subtype nonselective.
Indoramine
and Urapidil are α1 blockers chemically distinct from prazosin; are being used as antihypertensive in some
countries.
Yohimbine An alkaloid from West
African plant Yohimbehe.
It is a relatively selective
α2 blocker with short duration of action. Also blocks 5HT receptors. Heart rate
and BP are generally elevated due to increased central sympathetic outflow as
well as peripheral NA release. Other CNS effects include excitation, tremor,
ADH release (antidiuresis), nausea and vomiting. It may cause congestion of
genitals and has been claimed to be an aphrodisiac. This effect is only
psychological, but can overcome psychogenic impotence in some patients. There
are no valid indications for clinical use of yohimbine.
Chlorpromazine
and some other neuroleptics have additional α adrenergic blocking
activity—cause fall in BP, nasal stuffiness and inhibition of ejaculation as
side effect.
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