Antiadrenergic Drugs (Adrenergic Receptor Antagonists) and Drugs for Glaucoma

 Chapter-10 

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 neurine blocking agents”, which act by interfering with the release of adrenergic transmitter on nerve stimulation.

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

β-Halo alkylamines—Phenoxybenzamine.

II. Equilibrium type (competitive)

Nonselective

1. Ergot alkaloids—Ergotamine, Ergotoxine 
2. Hydrogenated ergot alkaloids—Dihydroergotamine (DHE), Dihydroergotamine 
3. Imidazolines—Tolazoline, Phentolamine 
4. Miscellaneous–Chlorpromazine

• α1 selective—Prazosin, Terazosin, Doxazosin, Tamsulosin 

• α2 selective—Yohimbine

GENERAL EFFECTS OF α BLOCKERS

• 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 Ard, which then produces only fall in BP due to β2 mediated vasodilatation—vasomotor reversal of Dale. Pressor and other actions of selective α agonists (NA, phenylephrine) are suppressed.

1. Reflex tachycardia occurs due to fall in mean arterial pressure and increased release of NA due to blockade of presynaptic α2 receptors.
2. Nasal stuffiness and miosis result from blockade of α receptors in nasal blood vessels and in radial muscles of iris respectively.
3. Intestinal motility is increased due to partial inhibition of relaxant sympathetic influences— diarrhea may occur.
4. 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.
5. 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.
6. 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 adrenergic ally 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 ethylenimine intermediate which reacts with α adrenoceptors and other biomolecules by forming strong covalent bonds. The α blockade develops gradually (even after i.e., 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 5-HT, 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 vasodilatation 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.e. 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; a.m. and sac 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 (see Ch. 12). Diagnostic use of ergotamine has been made to precipitate ECG signs of ischemia in coronary artery disease. Dihydroergotamine 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 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 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 vasodilatation 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.e., 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

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 up to 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.

• Tramazoline is a less potent congener of prazosin. Alfuzosin is a α1 blocker used primarily in BHP but is subtype nonselective.

• Indolamine and Urapidil are α1 blockers chemically distinct from prazosin; are being used as antihypertensive in some countries.

Yohimbine

• An alkaloid from West African plant Yohimbe he. It is a relatively selective α2 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 α adrenergic blocking activity—cause fall in BP, nasal stuffiness and inhibition of ejaculation as side effect.

USES OF α BLOCKERS

Pheochromocytoma

• It is a tumor of adrenal medullary cells. Excess CAs are secreted which can cause intermittent or persistent hypertension. Estimation of urinary CA metabolites (VMA, normetanephrine) is diagnostic. In addition, pharmacological tests can be performed.

• Phentolamine test Inject phentolamine 5 mg i.e. over 1 min in recumbent subject. A fall in BP > 35 mm Hg systolic and/or > 25 mm Hg diastolic is indicative of pheochromocytoma. However, it is not very reliable and both false positive and false negative results are obtained.

• Provocative tests have been performed by injecting histamine, methacholine or glucagon—which provoke release of CAs and cause marked rise in BP if pheochromocytoma is present. These tests are dangerous; phentolamine must be available to counteract excessive rise in

• Therapeutic Phenoxybenzamine can be used as definitive therapy for inoperable and malignant tumors. When surgical removal of the tumor is contemplated, it is desirable to give phenoxybenzamine orally for 1–2 weeks preoperatively and infuse it i.e., during surgery because:

1. Due to excess circulating CAs blood volume is low (they shift fluid from vascular to extravascular compartment). Treatment with α blocker normalizes blood volume and distribution of body water. 
2. Handling of the tumor during surgery may cause outpouring of CAs in blood → marked rise in BP. This is prevented by phenoxybenzamine given pre and intraoperatively. Alternatively, phentolamine drip can be instituted during the operation. 
3. Removal of the tumor is often attended by marked fall in BP as blood vessels dilate and the blood volume is low. This does not happen if volume has been restored beforehand with the aid of an α blocker.

Hypertension

• α blockers other than those selective for α1 like prazosin have been a failure in the management of essential hypertension, because vasodilatation is compensated by cardiac stimulation. Moreover, postural hypotension, impotence, nasal blockage and other side effects produced by nonselective α blockers are unacceptable. However, phentolamine/phenoxybenzamine are of great value in controlling episodes of rise in BP during clonidine withdrawal and cheese reaction in patients on MAO inhibitors.

Benign hypertrophy of prostate (BHP)

• The urinary obstruction caused by BHP has a static component due to increased size of prostate and a dynamic component due to increased tone of bladder neck/prostate smooth muscle. Two classes of drugs are available:

1. α1 adrenergic blockers (prazosin like): decrease tone of prostatic/bladder neck muscles. 
2. 5-α reductase inhibitor (finasteride): arrest growth/reduce size of prostate

• Since activation of α1 adrenoceptors in bladder trigone, prostate and prostatic urethra increases smooth muscle tone, their blockade relaxes these structures, reducing dynamic obstruction, increasing urinary flow rate and causing more complete emptying of bladder in many patients of BHP.
• Voiding symptoms (hesitancy, narrowing of stream, dribbling and increased residual urine) are relieved better than irritative symptoms like urgency, frequency and nocturia. The α1blockers afford faster (within 2 weeks) and greater symptomatic relief than finasteride which primarily affects static component of obstruction and has a delayed onset taking nearly six months for clinical improvement. The α1blockers do not affect prostate size but are more commonly used. However, effects last only till the drug is given. Even with continued therapy, benefit may decline after several years due to disease progression. They may be used concurrently with finasteride.

Secondary shock 

• Shock due to blood or fluid loss is accompanied by reflex vasoconstriction. If volume replacement fails to reverse this (extremities remain pale and cold, pulse pressure does not improve), therapy with an α blocker (phenoxybenzamine i.e.) can help by:

1.  Counteracting vasoconstriction.
2. Shifting blood from pulmonary to systemic circuit. 
3.  Returning fluid from extravascular to the vascular compartment so that cardiac output improves

Peripheral vascular diseases 

• α blockers do increase skin and to some extent muscle blood flow in normal individuals, but these drugs are largely disappointing in peripheral vascular diseases when obstruction is organic (Buerger’s disease). However, when vasoconstriction is a prominent feature (Raynaud’s phenomenon, acrocyanosis), good symptomatic relief is afforded by prazosin or phenoxybenzamine.

Congestive heart failure (CHF) 

• The vasodilator action of prazosin can afford symptomatic relief in CHF in the short-term, but long-term prognosis is not improved.

Papaverine/Phentolamine Induced Penile Erection (PIPE) therapy for impotence 

• In patients unable to achieve erection, injection of papaverine (3–20 mg) with or without phentolamine (0.5–1 mg) in the corpus cavernosum has been found to produce penile tumescence to permit intercourse. However, the procedure requires skill and training. Priapism occurs in 2–15% cases, which if not promptly treated leads to permanent damage. This is reversed by aspirating blood from the corpus cavernosum or by injecting phenylephrine locally. Repeated injections can cause penile fibrosis. Other complications are—local haematoma, infection, paresthesia and penile deviation. This therapy should therefore be reserved for selected situations with proper facilities.

β ADRENERGIC BLOCKING DRUGS

• These drugs inhibit adrenergic responses mediated through the β receptors.

• The dichloro derivative of isoprenaline was the first compound found in 1958 to block adrenergic responses which could not be blocked till then by the available adrenergic antagonists. However, it was not suitable for clinical use. Propranolol introduced in 1963 was a therapeutic breakthrough. Since then, drugs in this class have proliferated and diversified.

• All β blockers are competitive antagonists. Propranolol blocks β1 and β2 receptors but has weak activity on β3 subtype. It is also an inverse agonist reduces resting heart rate as well.

 CLASSIFICATION

Nonselective (β1 and β2)

1. Without intrinsic sympathomimetic activity Propranolol, Sotalol, Timolol.
2. With intrinsic sympathomimetic activity Pindolol 
3. With additional α blocking property Labetalol, Carvedilol

Cardioselective (β1) 

Metoprolol, Atenolol, Acebutolol, Bisoprolol, Esmolol, Betaxolol, Cicloprolol, Nebivolol.

 

The pharmacology of propranolol is described as prototype.

PHARMACOLOGICAL ACTIONS

 CVS

• Heart Propranolol decreases heart rate, force of contraction (at relatively higher doses) and cardiac output (c.o.). It prolongs systole by retarding conduction so that synergy of contraction of ventricular fibers is disturbed. The effects on a normal resting subject are mild, but become prominent under sympathetic overactivity (exercise, emotion). Ventricular dimensions are decreased in normal subjects, but dilatation can occur in those with reduced reserve—CHF may be precipitated or aggravated.

• Cardiac work and oxygen consumption are reduced as the product of heart rate and aortic pressure decreases. Total coronary flow is reduced (blockade of dilator β receptors), but this is largely restricted to the subepicardial region, while the subendocardial area (which is the site of ischemia in angina patients) is not affected. Overall effect in angina patients is improvement of O2 supply/demand status; exercise tolerance is increased.

• Propranolol abbreviates refractory period of myocardial fibers and decreases automaticity—ate of diastolic depolarization in ectopic foci is reduced, especially if it had been augmented by adrenergic stimuli. The A-V conduction is delayed. At high doses a direct depressant and membrane stabilizing (quinidine like) action is exerted, but this contributes little to the antiarrhythmic effect at usual doses. Propranolol blocks cardiac stimulant action of adrenergic drugs but not that of digoxin, Ca2+, methylxanthines or glucagon.

• Blood vessels Propranolol blocks vasodilatation and fall in BP evoked by isoprenaline and enhances the rise in BP caused by Adr—there is re-reversal of vasomotor reversal that is seen after α blockade. It has no direct effect on blood vessels and there is little acute change in BP. On prolonged administration BP gradually falls in hypertensive subjects but not in normotensive. Total peripheral resistance (t.p.r.) is increased initially (due to blockade of β mediated vasodilatation) and c.o. is reduced—little change in BP. With continued treatment, resistance vessels gradually adapt to chronically reduced c.o. so that t.p.r. decreases—both systolic and diastolic BP fall. This is considered to be the most likely explanation of the antihypertensive action. Other mechanisms that may contribute are:

1.  Reduced NA release from sympathetic terminals due to blockade of β receptor mediated facilitation of the release process. 
2. Decreased renin release from kidney (β1 mediated): Propranolol causes a more marked fall in BP in hypertensives who have high or normal plasma renin levels, and such patients respond at relatively lower doses than those with low plasma renin. However, pindolol does not decrease plasma renin activity but is an effective antihypertensive. 
3. Central action reducing sympathetic outflow. However, β blockers which penetrate brain poorly are also effective antihypertensives.

Respiratory tract 

• Propranolol increases bronchial resistance by blocking β2 receptors. The effect is hardly discernible in normal individuals because sympathetic bronchodilator tone is minimal. In asthmatics, however, the condition is consistently worsened, and a severe attack may be precipitated

CNS 

• No overt central effects are produced by propranolol. However, subtle behavioral changes, forgetfulness, increased dreaming and nightmares have been reported with long-term use of relatively high doses. Propranolol suppresses anxiety in short term stressful situations, but this is due to peripheral rather than a specific central action.

Local anesthetic 

• Propranolol is as potent a local anesthetic as lidocaine but is not clinically used for this purpose because of its irritant property.

Metabolic 

• Propranolol blocks adrenergically induced lipolysis and consequent increase in plasma free fatty acid levels. Plasma triglyceride level and LDL/HDL ratio is increased during propranolol therapy. It also inhibits glycogenolysis in heart, skeletal muscles and in liver (inconsistently), which occurs due to Adr release during hypoglycemia—recovery from insulin action is delayed. Though there is no effect on normal blood sugar level, prolonged propranolol therapy may reduce carbohydrate tolerance by decreasing insulin release.

Skeletal muscle 

• Propranolol inhibits adrenergically provoked tremor. This is a peripheral action exerted directly on the muscle fibers (through β2 receptors). It tends to reduce exercise capacity by attenuating β2 mediated increase in blood flow to the exercising muscles, as well as by limiting glycogenolysis and lipolysis which provide fuel to working muscles.

Eye 

• Instillation of propranolol and some other β blockers reduces secretion of aqueous humor, i.o.t. is lowered. There is no consistent effect on pupil size or accommodation.

Uterus 

• Relaxation of uterus in response to isoprenaline and selective β2 agonists is blocked by propranolol. However, normal uterine activity is not significantly affected.

PHARMACOKINETICS

• Propranolol is well absorbed after oral administration but has low bioavailability due to high first pass metabolism in liver. Oral: parenteral dose ratio of up to 40:1 has been found. Interindividual variation in the extent of first pass metabolism is marked—equieffective oral doses vary considerably. It is lipophilic and penetrates into brain easily.

• Metabolism of propranolol is dependent on hepatic blood flow. Chronic use of propranolol itself decreases hepatic blood flow—oral bioavailability of propranolol is increased and its t½ is prolonged (by about 30%) on repeated administration. Bioavailability of propranolol is more when it is taken with meals because food decreases its first pass metabolism. Higher bioavailability and prolongation of t½ also occur with high doses because metabolism of propranolol is saturable.

• A number of metabolites of propranolol have been found, of which the hydroxylated product has β blocking activity. The metabolites are excreted in urine, mostly as glucuronides. More than 90% of propranolol is bound to plasma proteins.

INTERACTIONS

1. Additive depression of sinus node and A-V conduction with digitalis and verapamil — cardiac arrest can occur. However, propranolol has been safely used with nifedipine.
2. Propranolol delays recovery from hypoglycemia due to insulin and oral antidiabetics. Warning signs of hypoglycemia mediated through sympathetic stimulation (tachycardia, tremor) are suppressed. In some cases, BP rises due to unopposed α action of released Adr.
3. Phenylephrine, ephedrine and other α agonists present in cold remedies can cause marked rise in BP due to blockade of sympathetic vasodilatation.
4. Indomethacin and other NSAIDs attenuate the antihypertensive action of β blockers. 
5.  Cimetidine inhibits propranolol metabolism. However, the dose range of propranolol is wide, and this may not be clinically significant.
6. Propranolol retards lidocaine metabolism by reducing hepatic blood flow.
7. Propranolol increases bioavailability of chlorpromazine by decreasing its first pass metabolism.

ADVERSE EFFECTS AND CONTRAINDICATIONS

1.  Propranolol can accentuate myocardial insufficiency and can precipitate CHF/edema by blocking sympathetic support to the heart, especially during cardiovascular stress. However, when compensation has been restored, careful addition of a β1 blocker is now established therapy to prolong survival. 
2. Bradycardia: resting HR may be reduced to 60/min or less. Patients of sick sinus are more prone to severe bradycardia. 
3. Propranolol worsens chronic obstructive lung disease, can precipitate life-threatening attack of bronchial asthma: contraindicated in asthmatics. 
4. Propranolol exacerbates variant (Prinzmetal’s) angina due to unopposed α mediated coronary constriction. In some patients, even classical angina may be worsened if ventricular dilatation and asynergy of contraction occurs—specially with high doses.
5. Carbohydrate tolerance may be impaired in prediabetics. 
6. Plasma lipid profile is altered on long term use: total triglycerides and LDL-cholesterol tend to increase while HDL-cholesterol falls. This may enhance risk of coronary artery disease. Cardioselective β blockers and those with intrinsic sympathomimetic activity have little/no deleterious effect on blood lipids.
7. Withdrawal of propranolol after chronic use should be gradual, otherwise rebound hypertension, worsening of angina and even sudden death can occur. This is due to supersensitivity of β receptors occurring as a result of long-term reduction in agonist stimulation.
8. Propranolol is contraindicated in partial and complete heart block: arrest may occur.  
9. Tiredness and reduced exercise capacity: due to blunting of β2 mediated increase in blood flow to the exercising muscles as well as attenuation of glycogenolysis and lipolysis.  
10. Cold hands and feet, worsening of peripheral vascular disease are noticed due to blockade of vasodilator β2 receptors.
11. Side effects not overtly due to β blockade are— g.i.t. upset, lack of drive, nightmares, forgetfulness, rarely hallucinations. Male patients more frequently.

OTHER β BLOCKERS

• A number of β blockers have been developed having some special features. Their comparative properties are presented. The associated properties with their significance can be summarized as:

• Cardioselectivity (in metoprolol, atenolol, acebutolol, bisoprolol, nebivolol). These drugs are more potent in blocking cardiac (β1) than bronchial (β2) receptors. However, selectivity is only relative and is lost at high doses. Their features are:

1. Lower propensity to cause bronchoconstriction, but even these drugs should be avoided, if possible, in asthmatics.
2. Less interference with carbohydrate metabolism and less inhibition of glycogenolysis during hypoglycemia—safer in diabetics. However, tachycardia in response to hypoglycaemia is blocked.
3. Lower incidence of cold hands and feet, less chances of precipitating Raynaud’s phenomenon. 4.
4.  No/less deleterious effect on blood lipid profile.
5. Ineffective in suppressing essential tremor (it occurs through β2 action on muscle fibres). 
6. Less liable to impair exercise capacity.

• Partial agonistic (intrinsic sympathomimetic) action (in pindolol, acebutolol). These drugs themselves activate β1 and/or β2 receptors submaximally. The benefits of this property are controversial.

1. Bradycardia and depression of contractility at rest are not prominent, but exercise tachycardia is blocked; may be preferred in those prone to severe bradycardia (elderly patients; sick sinus) or with low cardiac reserve.
2. Withdrawal is less likely to exacerbate hypertension or angina; continued agonistic action oβ receptors (of the drug itself) prevents development of supersensitivity. 
3. Plasma lipid profile is not/less worsened. 
4. Not effective in migraine prophylaxis—they dilate cerebral vessels. 
5. Not suitable for secondary prophylaxis of MI.

• Membrane stabilizing activity (in propranolol, oxprenolol, acebutolol). This activity is claimed to contribute to the antiarrhythmic action but appears to be significant only at high doses.

Lipid insolubility (atenolol, sotalol)

• 1. They are less likely to produce central effects.

• They are incompletely absorbed orally, but do not undergo first pass metabolism and are primarily excreted unchanged in urine: are longer acting (t½ 6–20 hours) and tend to be effective in a narrow dose range. In contrast, the lipid soluble agents are primarily metabolized in liver and have shorter t½ (2–6 hours).

Salient features of important β blockers are given below:

• Sotalol Nonselective β blocker with lower lipid solubility. It has additional K+ channel blocking and class III antiarrhythmic property. SOTAGARD 40, 80 mg tab

• Timolol It is the β blocker preferred for topical use in eye Orally it is a potent β blocker—has been used in hypertension, angina and prophylaxis of myocardial infarction.

• Betaxolol, Levobunolol, Cartiolol and Metipranolol are β blockers employed exclusively for topical application to the eye.

• Pindolol A potent β blocker with prominent intrinsic sympathomimetic activity. It has been used primarily as antihypertensive: may be advantageous in patients who develop marked bradycardia with propranolol. Chances of rebound hypertension on withdrawal are also less. The effective dose range is rather narrow. PINADOL 5 mg tab, VISKEN 10, 15 mg tab.

• Metoprolol It is the prototype of cardioselective (β1)blockers; nearly 50 times higher dose is needed to block isoprenaline induced vasodilatation. It is less likely to worsen asthma but is not entirely safe. It may be preferred in diabetics receiving insulin or oral hypoglycaemics. Patients who complain of cold hands and feet while on propranolol do better on metoprolol. First pass metabolism of metoprolol is less marked than propranolol, but 90% or more is ultimately metabolized before excretion. There are slow and fast hydroxylates of metoprolol (CYP2D6 alleles); the former may require a lower dose.

• Side effects of metoprolol are milder. It is generally given orally, but i.v. injection (5–15 mg) has been used in myocardial infarction provided bradycardia is absent.

• S(–) Metoprolol is the active enantiomer, now available as a single enantiomer product. It is to be used at half the dose as the recemate. Dose: 12.5–50 mg OD–BD.

• Atenolol A relatively selective β1 blocker having low lipid solubility. It is incompletely absorbed orally, but first pass metabolism is not significant. Because of longer duration of action, once daily dose is often sufficient. Side effects related to CNS action are less likely. No deleterious effects on lipid profile have been noted. Effective dose for most individuals falls in a narrow range. It is one of the most commonly used β blockers for hypertension and angina.

• S(–) Atenolol This pure active enantiomer is effective at half the dose and may be better tolerated.
• Acebutolol Another cardioselective agent with significant partial agonistic and membrane stabilizing properties. Effect on resting heart rate is less. The side effect profile is like that of metoprolol. Acebutolol is rapidly metabolized to an active metabolite diacetolol which is primarily excreted by kidney and has a longer t½ (8–12 hours). As such, a single daily dose is sufficient in many patients.
• Bisoprolol A cardioselective β blocker lacking intrinsic sympathomimetic activity; suitable for once daily administration in angina, hypertension and CHF. CONCOR, CORBIS 5 mg tab; ½ to 2-tab OD.

• Esmolol It is an ultrashort acting β1 blocker devoid of partial agonistic or membrane stabilizing actions. It is inactivated by esterases in blood; plasma t½ is < 10 min; action disappears 15–20 min after terminating i.v. infusion—degree of β blockade can be titrated by regulating rate of infusion. Rapid onset, short lasting fall in BP attends i.v. infusion of esmolol.

• A loading dose of 0.5 mg/kg is given followed by 0.05–0.2 mg/kg/min infusion. It has been used to terminate supraventricular tachycardia, episodic atrial fibrillation or flutter, arrhythmia during anaesthesia, to reduce HR and BP during and after cardiac surgery, and in early treatment of myocardial infarction.

•  Cicloprolol It is a selective β1 blocker having additional weak β2 agonistic activity which reduces vascular resistance and holds promise of safety in asthmatics. Nonadrenoceptor media ted vasodilatation (probably due to NO production) adds to its antihypertensive action. Dose: 200–600 mg OD; CELIPRES 100, 200 mg tab.

• Nebivolol This highly selective β1 blocker also acts as a NO donor, produces vasodilatation and has the potential to improve endothelial function, which may delay atherosclerosis. In contrast to older β blockers, hypotensive response to nebivolol has a rapid onset. It has been used in hypertension and CHF.

USES

Hypertension 

• β blockers are relatively mild antihypertensives. All agents, irrespective of associated properties, are nearly equally effective. They are one of the first-choice drugs because of good patient acceptability and cardioprotective potential.

Angina pectoris 

• All β blockers benefit angina of effort. Taken on a regular schedule they decrease frequency of attacks and increase exercise tolerance. High doses, however, may worsen angina in some patients by increasing ventricular size and reducing coronary flow.

Cardiac arrhythmias

• β blockers suppress extrasystoles and tachycardias, especially those mediated adrenergically (during anaesthesia, digitalis induced)—may be used i.v. for this purpose. They control ventricular rate in atrial fibrillation and flutter, but only occasionally restore sinus rhythm. Esmolol is an alternative drug for paroxysmal supraventricular tachycardia

Myocardial infarction (MI) 

• In relation to MI, β blockers have been used for two purposes: (a) Secondary prophylaxis of MI: There is now firm evidence of benefit. Long-term use after recovery from MI has been found to decrease subsequent mortality by 20%.

1. By preventing reinfarction
2. By preventing sudden ventricular fibrillation at the second attack of M

High risk patients (those who had large infarcts) should be put on β blockers (if there are no haemodynamic contraindications) for at least 2 years. β blockers with partial agonistic action are less suitable for this purpose. Myocardial salvage during evolution of MI: Administered i.v. within 4–6 hours of an attack followed by continued oral therapy. β blockers—

1. May limit infarct size by reducing O2 consumption—marginal tissue which is partially ischemic may survive. 
2. May prevent arrhythmias including ventricular fibrillation

• However, β blockers can be given to only those patients not in shock or cardiac failure and who have heart rate > 50/min with not higher than first degree heart block (P-R interval < 0.24 sec). In megatrials such therapy has been found to reduce mortality by 20–25%.

Congestive heart failure 

• Although β blockers can acutely worsen heart failure, several studies have reported beneficial haemodynamic effects of β1 blockers over long-term in selected patients with dilated cardiomyopathy. Introduced gradually and maintained for long term, these drugs retard the progression of CHF and prolong life. The benefit may result from antagonism of deleterious effects of sympathetic overactivity on myocardium. Overactivation of cardiac β1 receptors has been found to exert toxic effects on the heart by accelerating myocyte apoptosis and promoting functionally unfavorable remodeling. Certain β1 blockers, used appropriately along with other measures, is now established as standard therapy for most mild to moderate CHF patients. However, they should not be given to patients with marked fluid retention and to those requiring i.v. vasodilators or i.v. inotropic drugs

Dissecting aortic aneurysm 

• β blockers help by reducing cardiac contractile force and aortic pulsation.

Pheochromocytoma

• β blockers may be used to control tachycardia and arrhythmia but should never be administered unless an α blocker has been given before, otherwise dangerous rise in BP can occur. They suppress cardiomyopathy caused by excess CAs. 

Thyrotoxicosis 

• Propranolol rapidly controls sympathetic symptoms (palpitation, nervousness, tremor, fixed stare, severe myopathy and sweating) without significantly affecting thyroid status. It inhibits peripheral conversion of T4 to T3 and is highly valuable during thyroid storm. Major use, however, is preoperatively and while awaiting response to antithyroid drugs/ radioactive iodine.

Migraine 

• Propranolol is the most effective drug for chronic prophylaxis of migraine

Anxiety 

• Propranolol exerts an apparent antianxiety effect, especially under conditions which provoke nervousness and panic, e.g., examination, unaccustomed public appearance, etc. This is probably due to blockade of peripheral manifestations of anxiety (palpitation, tremor) which have a reinforcing effect. It is largely ineffective in anxiety neurosis but may benefit somatic symptoms.

Essential tremor 

• Nonselective β blockers have now an established place in treating essential tremor. However, they do not benefit parkinsonian tremor.

Glaucoma 

• Ocular β blockers are widely used for chronic simple (wide angle) glaucoma; also used as adjuvant in angle closure glaucoma (see below).

Hypertrophic obstructive cardiomyopathy

• The subaortic region is hypertrophic. Forceful contraction of this region under sympathetic stimulation (exercise, emotion) increases outflow resistance which has incapacitating haemodynamic consequence. β blockers improve c.o. in these patients during exercise by reducing left ventricular outflow obstruction, though they have little effect while at rest.

α + β ADRENERGIC BLOCKERS

• Labetalol It is the first adrenergic antagonist capable of blocking both α and β receptors. There are 4 diastereomers of labetalol, each of which has a distinct profile of action on subtypes of α and β receptors. The commercial preparation has equal parts of each diastereomer and displays β1 + β2 + α1 blocking as well as weak β2 agonistic activity. The β blocking potency is about 1/3 that of propranolol, while α blocking potency is about 1/10 of phentolamine.

• Labetalol is 5 times more potent in blocking β than α receptors. As such, effects of a low dose resemble those of propranolol alone while at high dose they are like a combination of propranolol and prazosin. Fall in BP (both systolic and diastolic) is due to α1 and β1 blockade as well as β2 agonism (vasodilatation). Relatively high doses reduce both c.o. and t.p.r. Heart rate is unchanged or slightly decreased. In contrast to propranolol, limb blood flow increases with labetalol. It has also been shown to inhibit NA uptake by adrenergic nerve endings. Labetalol is orally effective but undergoes considerable first pass metabolism.

• It is a moderately potent hypotensive and is especially useful in pheochromocytoma and clonidine withdrawal; can also be used in essential hypertension. Most important side effect is postural hypotension, but this is significant only in some patients. Failure of ejaculation and other side effects of α and β blockers can also occur, but plasma lipid levels are not altered. Rashes and liver damage have been reported.
• Carvedilol It is a β1 + β2 + α1 adrenoceptor blocker; produces vasodilatation due to α1 blockade as well as calcium channel blockade and has antioxidant property. It has been used in hypertension and is the β blocker especially employed as cardioprotective in CHF. Oral bioavailability of carvedilol is 30%. It is primarily metabolized and has a t½ of 6–8 hrs. CHF: Start with 3.125 mg BD for 2 weeks, if well tolerated gradually increase to max. of 25 mg BD. Hypertension/angina: 6.25 mg BD initially, titrate to max. of 25 mg BD.

DRUGS FOR GLAUCOMA

• Glaucoma is a group of diseases characterized by a progressive form of optic nerve damage. This is generally associated with raised (> 21 mmHg) intraocular tension (i.o.t), but the etiology is unknown and there are many risk factors. The chief therapeutic measure is to lower i.o.t. to target level, either by reducing secretion of aqueous humor or by promoting its drainage. The site of formation and pathway of drainage of aqueous humor as well as sites of action of antiglaucoma drugs is illustrated in Fig. 10.1. Major amount of aqueous (~90%) drains through the trabecular route, while ~10% fluid passes into the connective tissue spaces within the ciliary muscle—then via suprachoroidal into episcleral vessels (uveoscleral outflow). Glaucoma is seen in two principal clinical forms:

Open angle (wide angle, chronic simple) glaucoma

• It is probably a genetically predisposed degenerative disease affecting patency of the trabecular meshwork which is gradually lost past middle age. The i.o.t. rises insidiously and progressively. Ocular hypotensive drugs are used on a long-term basis and constitute the definitive treatment in majority of cases.

β Adrenergic blockers 

• Topical β blockers are one of the first line drugs, but PG F2α analogues are increasingly used now. In contrast to miotics, the β blockers donot affect pupil size, tone of ciliary muscle or outflow facility, but lower i.o.t. by reducing aqueous formation. This probably results from down regulation of adenylyl cyclase due to β2 receptor blockade in the ciliary epithelium and a secondary effect due to reduction in ocular blood flow. They are as effective as miotics and produce less ocular side effects. Ocular β blockers are lipophilic with high ocular capture (to reduce systemic effects) and have no/weak local anaesthetic activity (to avoid corneal hypoesthesia and damage).

• Ocular side effects of β blockers viz. stinging, redness and dryness of eye, corneal hypoesthesia, allergic blepharoconjunctivitis and blurred vision are generally mild and infrequent. Their major limitation are the systemic adverse effects that occur due to absorption through nasolacrimal duct. Lifethreatening bronchospasm has been reported in asthmatics. Bradycardia, accentuation of heart block and CHF are likely, especially in the elderly. In fact, all adverse effects and contraindications of systemic β blocker therapy. apply to ocular β blockers as well.

• Timolol It is the prototype of ocular β blockers; is nonselective (β1 + β2) and has no local anaesthetic or intrinsic sympathomimetic activity. The ocular hypotensive action (20–35% fall in i.o.t.) is smooth and well sustained. After chronic use, effect on i.o.t. persists for 2–3 weeks following discontinuation. This feature, in contrast to pilocarpine drops, gives a high level of clinical safety, i.e., 1 or 2 missed doses will not affect i.o.t. control. However, upto 30% cases of open angleglaucoma fail to achieve the desired level of i.o.t. with timolol alone and may need additional medication.
• GLUCOMOL, OCUPRES, IOTIM, LOPRES 0.25% and 0.5% eye drops; start with 0.25% drops BD, change to 0.5% drops in case of inadequate response.

• Betaxolol It is β1 selective blocker offering the advantage of less bronchopulmonary and probably less cardiac, central and metabolic side effects. In addition, it may exert a protective effect on retinal neurons independent of i.o.t. lowering, possibly by reducing Na+/Ca+ influx. However, it is less efficacious in lowering i.o.t. than timolol, because ocular β receptors are predominantly of the β2 subtype. Transient stinging and burning in the eye is more common with it. Most ophthalmologists prefer to start with betaxolol and change over to timolol (or a similar drug) only if i.o.t. control is insufficient or there is local intolerance to betaxolol.

• OPTIPRESS, IOBET 0.5% eye drops; 1 drop in each eye BD.

• Levobunolol It has been introduced as a once daily alternative to timolol. The ocular and systemic effects are very similar to timolol except for longer duration of action.

α Adrenergic agonists 

• Adrenaline Applied topically 0.5–1% Adr can lower i.o.t., but response is variable due to poor corneal penetration. The i.o.t. reduction is due to increased uveoscleral outflow and β2 receptor mediated increased hydraulic conductivity of trabecular filtering cells. Reduction in aqueous formation can result from α2 and α1 receptor activation in ciliary body. Adrenaline frequently produces ocular smarting and vasoconstriction followed by reactive hyperemia. It is not used now because of ocular intolerance and possible systemic effects

• Dipivefrine It is a prodrug of Adr; penetrates cornea and is hydrolysed by the esterases present there into Adr. Though better tolerated and longer acting than Adr, dipivefrine still produces significant ocular side effects. It is used only as add on therapy in poorly controlled patients. PROPINE 0.1% eye drop; 1 drop in each eye BD.

• Apraclonidine It is a polar clonidine congener which does not cross blood-brain barrier, but applied topically (0.5–1%) it lowers i.o.t. by ~25%. It decreases aqueous production by primary α2 and subsidiary α1 action in the ciliary body. Itching, lid dermatitis, follicular conjunctivitis, mydriasis, eyelid retraction, dryness of mouth and nose are common side effects. Its use is restricted to control of spikes of i.o.t. after laser trabeculoplasty or iridotomy.

• Brimonidine This recently introduced clonidine congener is more α2 selective and more lipophilic than apraclonidine. It lowers i.o.t. by 20–27% by reducing aqueous production and by increasing uveoscleral flow. Ocular side effects are similar to but less frequent than with apraclonidine. Because of weaker α1 action, side effects like mydriasis, eyelid retraction, conjunctival blanching—hyperemia are less prominent, but dry mouth, sedation and small fall in BP have been noted.

Prostaglandin analogues

• Low concentration of PGF2α was found to lower i.o.t without inducing ocular inflammation. It actsby increasing uveoscleral outflow, possibly by increasing permeability of tissues in ciliary muscle or by an action on episcleral vessels. An effect on trabecular outflow is also possible. Ciliary body COX-2 is down regulated in wide angle glaucoma indicating a physiological role of PG in aqueous humor dynamics.

• Latanoprost Instilled in the eye, this PGF2α derivative has shown efficacy similar to timolol (i.o.t. reduction by 25–35%) and the effect is well sustained over long-term. It reduces i.o.t. in normal pressure glaucoma also. Though ocular irritation and pain are frequent, no systemic side effects are reported. Blurring of vision, increased iris pigmentation, thickening and darkening of eyelashes have occurred in some cases.

• Because of good efficacy, once daily application and absence of systemic complications, PG analogues have become the first-choice drugs in developed countries. High cost limits their use in resource poor countries.

• LACOMA, XALATAN 0.005% eye drops, one drop in each eye OD in the evening; LACOMA-T with timolol 0.5% eye drops. (To be stored in cold) Unoprostone, Travoprost and Bimatoprost are other ocular PG analogues.

Carbonic anhydrase inhibitors 

• Acetazolamide (see Ch. 41) Oral treatment with acetazolamide (0.25 g 6–12 hourly) reduces aqueous formation by limiting generation of bicarbonate ion in the ciliary epithelium. It is used to supplement ocular hypotensive drugs for short term indications like angle closure, before and after ocular surgery/laser therapy. Systemic side effects—paresthesia, anorexia, hypokalemia, acidosis, malaise and depression restrict longterm use to few cases in which target i.o.t. is not achieved even by concurrent use of 2–3 topical drugs.

• Dorzolamide (2% eyedrops TDS) It is a topically useful carbonic anhydrase inhibitor developed to circumvent systemic side effects of acetazolamide. It lowers i.o.t. by ~20%; somewhat less efficacious than timolol. Ocular stinging, burning, itching and bitter taste are the side effects.

• Dorzolamide is used only as add on drug to topical β blockers/PG analogues, or when these drugs are contraindicated. DORTAS, DORZOX 2% eye drops.

Miotics:

• Till the 1970s topical pilocarpine and/or antiChEs were the standard antiglaucoma drugs. However, because of several drawbacks, they are now used only as the last option. In open angle glaucoma, they lower i.o.t. by increasing ciliary muscle tone thereby improving patency of trabeculae.

• The current approach to treatment of open angle glaucoma can be summarized as—start monotherapy with latanoprost or a topical β blocker; if target i.o.t. is not attained either change over to the alternative drug or use both the above concurrently. Brimonidine/dorzolamide/dipivefrine are used only when there are contraindications to PG analogues/β blockers, or to supplement their action. Topical miotics and oral acetazolamide are added only as the last resort.

Angle closure (narrow angle, acute congestive) glaucoma

• It occurs in individuals with a narrow iridocorneal angle and shallow anterior chamber. The i.o.t. remains normal until an attack is precipitated, usually by mydriasis. The i.o.t. rises rapidly to very high values (40–60 mmHg). It is an emergent condition; failure to lower i.o.t. quickly may result in loss of sight.
• Vigorous therapy employing various measures to reduce i.o.t. is instituted.

1. Hypertonic mannitol (20%) 1.5–2 g/kg or glycerol (10%): infused i.v. decongest the eye by osmotic action. A retention enema of 50% glycerine is also sometimes used.
2. Acetazolamide: 0.5 g i.v. followed by oral twice daily is started concurrently. 
3. Miotic: Once the i.o.t. starts falling due to the above i.v. therapy, pilocarpine 1–4% is instilled every 10 min initially and then atlonger intervals. Contraction of sphincter pupillae changes the direction of forces in the iris to lessen its contact with the lens and spreads the iris mass centrally → pupillary block is removed and iridocorneal angle is freed. However, when i.o.t. is very high, the iris muscle fails to respond to miotics; tension should be reduced by other measures before miotics can act.
4. Topical β blocker: Timolol 0.5% is instilled 12 hourly in addition.
5.  Apraclonidine (1%)/latanoprost 0.005% instillation may be added.

• Drugs are used only to terminate the attack of angle closure glaucoma. Definitive treatment is surgical or laser iridotomy. Few cases, who have chronic narrow angle glaucoma, may be treated with a miotic/other ocular hypotensive drug for long periods, but often surgery/laser therapy is ultimately required.