Healthcare in India

 Antiadrenergic Drugs (Adrenergic Receptor Antagonists) and Drugs for Glaucoma

These are drugs which antagonize the receptor action of adrenaline and related drugs. They are competitive antagonists at a or b or both a and b adrenergic receptors and differ in important ways from the “adrenergic neurone blocking agents”, which act by interfering with the release of adrenergic transmitter on nerve stimulation. These differences are given in Table 10.1

a ADRENERGIC BLOCKING DRUGS

These drugs inhibit adrenergic responses mediated through the a adrenergic receptors without affecting those mediated though b receptors.

CLASSIFICATION

I.          onequilibrium type
(i) b-Haloalkylamines-Phenoxybenzamine
II.         Equilibrium type (competitive)
A.        Nonselective

• Ergot alkaloids-Ergotamine, Ergotoxine
• Hydrogenated ergot alkaloids-Dihydroergotamine (DHE), Dihydroergotoxine
• Imidazolines-Tolazoline, Phentolamine
• Miscellaneous-Chlorpromazine

B.        a1 selective-Prazosin, Terazosin, Doxazosin, Tamsulosin
C.        a2 selective-Yohimbine

GENERAL EFFECTS OF a BLOCKERS

• Blockade of vasoconstrictor a1 (also a2) 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 a blockers abolish the pressor action of Adr, which then produces only fall in BP due to b2 mediated vasodilatation-vasomotor reversal of Dale. Pressor and other actions of selective a 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 a2 receptors.
• Nasal stuffiness and miosis result from blockade of a 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 a 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 rennin release mediated through b1 receptors.
• Tone of smooth muscle in bladder trignone, sphincter and prostate is reduced by blockade of  a1 receptors (mostly of the a1A 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 a receotirs-a blockers can inhibit ejaculation; this may manifest as impotence.

The a blockers have no effect on adrenergically induced cardiac stimulation, bronchodilation, vasodilatation and most of the metabolic changes, because these are mediated predominantly through b receptors.

Apart from these common effects, most of which manifest as side effects, many a blockers have some additional actions. Their pharmacological profile is also governed by their central effects and by the relative activity on a1 and a2 receptor subtypes. Only the distinctive features of different a blockers are described below.

Phenoxybenzamine : It cyclizes spontaneously in the body giving rise to a highly reactive ethyleniminium intermediate which reacts with a adrenoceptors and other biomolecules by forming strong covalent bonds. The a 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 a2 blockade) occurs and reflex tachycardia is prominent in intact animals. Partial blockade of 5-HT, histaminergic and cholinergic receptors, but not b 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 differntial 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. njection. 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 hours; 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 a blocking action-peripheral vascular insufficiency and gangrene of toes and fingers occurs in ergotism. Ergotoxine is a more potent a blocker and less potent vasoconstrictor than ergotamine. Hydrogenation reduces vasoconstrictor and increases a blocking activity.

The a 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 complx pharmacological properties. The a blocking action is only modest and short lasting. IN addition, It is a direct vasodilator and stimulates the heart.
Tolazoline also blocks 5-HT receptors, has a histamine like gastric secretagogue and Ach like motor action on intestines. It was used in peripheral vascular diseases and pulmonary hypertesion of the newborn.
Phentolamine : This congener of tolazoline is a rapidly acting a blocker with short duration of action (in minutes). It equally blocks a1 and a2 receptors – NA release is increased and veno dilatation predominates over arteriolar dilatation. It is used as a quick and short acing a 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 a blocker for local infiltration to counteract vasoconstriction due to extravasated NA/DA during their i.v. infusion.

Dose : 5 mg i.v. repeated as reuired;
REGITINE, FENTANOR 10 mg/ml inj.
Prazosin : It is first of the highly selective a1 blockers having a1 : a2 selectivity ration 1000:1. All subtypes of a1 receptor (a1A, a1B, a1D) 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 a2 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 a 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 a1 acid glycoprotein), metabolized in liver and excreted primarily in bile. Its plasma t ? is 2-3 hours; effect of a single dose lasts for 6-8 hours.

Prazosin is primarily used as an antihypertensive. Other uses are-Raynaud’s disease and prostatic hypertrophy-blocks a1 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.-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 t ? (-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 (t? 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 a1A/a1D blocker (a1A : a1B affinity 7-38 fold) has been found as effective as terazosin in improving BHP symptoms. Because a1A subtype predominate in the bladder base and prostate, while a1A 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 t? is 6-9 hrs, but the modified release (MR) cap needs only once daily dosing. It appears to be a better tolerated a1 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 a1 blocker used primarily in BHP, but is subtype nonselective.
Indoramine and urapidil are a1 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 a2 blocker with short duration of action. Also blocks 5-HT 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 a adrenergic blocking activity-cause fall in BP, nasal stuffiness and inhibition of ejaculation as side effect.