Antiadrenergic Drugs (Adrenergic Receptor Antagonists) and Drugs for Glaucoma / pharmacology Notes Download / bpharma Notes

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 α or β or both α and β adrenergic receptors, and differ in important ways from the “adrenergic neurone blocking drugs”, which act by interfering with storage or release of adrenergic transmitter. These differences are given in Table 10.1.

α ADRENERGIC BLOCKING drugs

These drugs inhibit adrenergic responses mediated through the α adrenergic receptors without affecting those mediated through β receptors.

GENERAL EFFECTS OF a BLOCKERS

1. 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 (injected i.v. in animals), which then produces only fall in BP due to β2 mediated vasodilatation (also see p. 143). This was first demonstrated by Sir HH Dale (1913) and is called vasomotor reversal of Dale. Pressor and other actions of selective α agonists (phenylephrine) are suppressed.

2. Reflex tachycardia occurs due to fall in mean arterial pressure and increased release of NA from cardiac sympathetic neurons due to blockade of presynaptic α2 receptors.

 

3. Nasal stuffiness and miosis result from blockade of α receptors in nasal blood vessels and in radial muscles of iris respectively.

4. Intestinal motility is increased due to partial inhibition of relaxant sympathetic influences— loose motion may occur.

5. 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 expansion of blood volume. This is reinforced by reflex increase in renin release mediated through β1 receptors.

6. 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.

7. Contractions of vas deferens and seminal vesicles which result in ejaculation are coordinated through α receptors. As such, α blockers can inhibit ejaculation; this may manifest as impotence.

   The α blockers have no effect on adrenergic 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. The pharmacological profile of an α blocker is mainly governed by its central effects and by the relative activity on α1 and α2 receptor subtypes. Only the distinctive features of individual α blockers are described below.

Phenoxybenzamine : 

It is a halogenated alkylamine that cyclizes spontaneously in the body giving rise to a highly reactive ethyleniminium intermediate which reacts with α adrenoceptors and other biomolecules by forming strong covalent bonds. The α blockade is of nonequilibrium (irreversible) type and develops gradually (even after i.v. injection) and lasts for 3–4 days till fresh receptors are synthesized.

Partial blockade of 5-HT, histaminergic and muscarinic 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 is 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 on rapid i.v. injection it can produce CNS stimulation, nausea and vomiting. 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 dose administered i.v. 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.

Phenoxybenzamine is used primarily in pheochromocytoma, occasionally in peripheral vascular disease.

FENOXENE 10 mg cap, 50 mg/ml inj. BIOPHENOX 50 mg in 1 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 agonist and antagonist at α adrenergic, serotonergic and dopaminergic receptors.  

The amine alkaloid ergometrine has no α blocking activity.

vity. 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 ergot alkaloids is low grade and clinically not useful. Their principal use is in migraine (see Ch. 12). Dihydroergotoxine has been used as a cognition enhancer (see Ch. 35).

Phentolamine :

 This is a rapidly acting α blocker with short duration of action (in minutes). Because of nonselective α1 and α2 blockade, NA release is increased and tachycardia occurs. Venodilatation predominates over arteriolar dilatation. Phentolamine is used for diagnosis and intraoperative management of pheochromocytoma, as well as 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, because NA release is not increased due to absence of α2 blockade.

Prazosin dilates arterioles more than veins. Postural hypotension is less marked, but may occur in the beginning, causing 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 due to haemodynamic adjustments. Other α blocking side effects (miosis, nasal stuffiness, inhibition of ejaculation) are also milder. For the above reasons, prazosin (also other α1 blockers) has largely replaced phenoxybenzamine. Prazosin, in addition, inhibits phosphodiesterase which degrades cAMP. Increase 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. 41). Other uses are in Raynaud’s disease and benign hypertrophy of prostate (BHP). Prazosin blocks α1 receptors in bladder trigone and prostatic smooth muscle, thereby 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 oral 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. This effect is unrelated to α1 receptor blockade, but may retard the progression of prostatic hypertrophy

HYTRIN, TERALFA, OLYSTER 1, 2, 5 mg tab; start with 1 mg OD, increase if required, usual maintenance dose 2–10 mg OD.

Doxazosin :

Another long acting (t½ 18 hr) congener of prazosin with pharmacological profile, similar to terazosin, including the apoptosis promoting effect on prostate. It is used in hypertension and BHP. 

Dose: 1 mg OD initially, increase upto 8 mg BD;

DOXACARD, DURACARD, DOXAPRESS 1, 2, 4 mg tabs.

 

Alfuzosin :

This short acting (t½ 3–5 hours) congener of prazosin has been specifically developed for symptomatic treatment of BHP, though it is nonselective for α1A, α1B and α1D subtypes. It is not approved as an antihypertensive. The metabolism of alfuzosin is inhibited by CYP34A inhibitors. Concurrent treatment with erythromycin, ketoconazole, ritonavir etc. is to be avoided.

Dose: 2.5 mg BD-QID or 10 mg OD as extended release (ER) tablet.

ALFUSIN, ALFOO 10`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.

Silodosin :

 Another selective a1A blocker developed in Japan, which improves urine flow and relieves symptoms of BHP, but causes little change in BP. Incidence of postural hypotension is low. However, failure of ejaculation is frequent which can cause psychosexual distress. Oral bioavailability is ~30%. it is metabolized by glucuronidation and excreted in urine as well as in faeces. The t½ averages 13 hours.

Dose: 4–8 mg OD; RAPILIF, SILODAL 4, 8 mg caps.

Yohimbine :

An alkaloid from the West African plant yohimbe. It is a relatively selective α2 blocker with short duration of action. It blocks 5-HT receptors as well. Heart rate and BP are generally elevated due to increased central sympathetic outflow as well as enhanced peripheral NA release. It may cause congestion in genitals and is considered 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 significant α adrenergic blocking activity—cause fall in BP, nasal stuffiness and inhibition of ejaculation as side effect.

There are no valid indications for clinical use of yohimbine. Chlorpromazine and some other neuroleptics have significant α adrenergic blocking activity—cause fall in BP, nasal stuffiness and inhibition of ejaculation as side effect.