USES OF α BLOCKERS / difference between adverse effects and contraindications / β ADRENERGIC BLOCKING DRUGS NOTES

1. Pheochromocytoma :

                                           It is a tumour 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.v. 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, both false positive and false negative results are possible. Therapeutic Surgical removal of the tumour is the firstline therapeutic approach. Phenoxybenzamine can be used as definitive therapy for inoperable and malignant pheochromocytoma. Prazosin is an alternative. When surgical removal of the tumour is contemplated, it is desirable to give phenoxybenzamine orally for 1–2 weeks preoperatively and infuse it i.v. during surgery. The rationale is:

• Due to excess circulating CAs blood volume is low (they shift fluid from vascular toextravascular compartment). Treatment with a blocker normalizes blood volume and distribution of body water.
• Handling of the tumour during surgery may cause outpouring of CAs in blood → marked rise in BP. This is prevented by phenoxybenzamine given pre and intraoperatively. Alternatively, phentolamine or sodium nitroprusside (a rapidly acting vasodilator) drip can be instituted during the operation
• Removal of the tumour is often attended by marked fall in BP, because blood vessels dilate and the blood volume is low. This does not happen if volume has been restored before hand with the aid of an α blocker. 

2. Hypertension :

                               α blockers other than those selective for α1 (prazosin-like) 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 that due to cheese reaction in patients on MAO inhibitors.

3. 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:

• α1 adrenergic blockers (prazosin like): they decrease tone of prostatic/bladder neck muscles.
• 5-αreductase inhibitor (finasteride/dutasteride) which arrest growth/reduce size of prostate (see Ch. 21).

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 α1 blockers 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 α1 blockers 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 few years due to disease progression. They may be used concurrently with finasteride.

Terazosin, doxazosin, alfuzosin and tamsulosin are the preferred α1 blockers because of once daily dosing. There is some evidence that terazosin and doxazosin promote apoptosis in prostate. Tamsulosin appears to cause fewer vascular side effects because of relative α1A/α1D selectivity.

4. Peripheral vascular diseases  :

                                                         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. Calcium channel blockers are also effective, and preferred by some due to fewer side effects.

5. 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. Priapism 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. Oral sildenafil is the preferred drug now, and PIPE therapy should 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. Some β blockers like metoprolol, atenolol, etc. preferentially block β1 receptors, while few others have additional α1 receptor blocking and/ or vasodilator properties

   The pharmacology of propranolol is described as prototype.

PHARMACOLOGICAL ACTIONS :

1. CVS :

(a) 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 fibres 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 perfusion of the subendocardial area (which is the site of ischaemia in angina patients) is not affected. The overall effect in angina patients is improvement of O2 supply/ demand status; exercise tolerance is increased.

                    Propranolol abbreviates refractory period of myocardial fibres and decreases automaticity— rate of diastolic depolarization in ectopic foci is reduced, specially if it had been augmented by adrenergic stimuli. The A-V conduction is slowed. 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 methylxanthines or glucagon.

(b) 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. Propranolol 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 normotensives. Total peripheral resistance (t.p.r.) is increased initially (due to blockade of β mediated vasodilatation) and c.o. is reduced, so that there is little change in BP. With continued treatment, resistance vessels gradually adapt to chronically reduced c.o, so that t.p.r. decreases and both systolic and diastolic BP gradually fall to some extent. This is considered to be the most likely explanation of the antihypertensive action. Other mechanisms that may contribute are:

•  Reduced NA release from sympathetic terminals due to blockade of b receptor mediated facilitation of the release process. 
• 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.
• Central action reducing sympathetic outflow. However, β blockers which penetrate brain poorly are also effective antihypertensives. 

2. Respiratory tract :

                                           Propranolol increases bronchial resistance by blocking dilator 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.

3. CNS  :

                     No overt central effects are produced by propranolol. However, subtle behavioural 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 (see p. 495).

4. Local anaesthetic :

                      Propranolol has membrane stabilizing (Na+ channel blocking) property and is a potent local anaesthetic. However, it is not a clinically useable local anaesthetic due to irritant action. Ocular irritation and corneal anaesthesia occurs when it is instilled in the eye, making it unsuitable for ocular use.

5. Metabolic :

                        Propranolol blocks adrenergically induced lipolysis and consequent increase in plasma free fatty acid levels. Plasma triglyceride level and LDL/HDL-CH ratio tend to increase during propranolol therapy. Glycogenolysis in heart, skeletal muscles and liver that occurs due to sympathetic stimulation is attenuated. As such, recovery from insulin hypoglycaemia that involves sympathetic stimulation is delayed. Though there is no effect on normal blood sugar level, prolonged propranolol therapy may impair carbohydrate tolerance by decreasing insulin release. 

6. Skeletal muscle :

                                  Propranolol inhibits adrenergically provoked tremor. This is a peripheral action exerted directly on the muscle fibres (through β2 receptors). Propranolol also 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.

7. 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.

8. Uterus :

                    Relaxation of uterus in response to isoprenaline and selective β2 agonists is blockedby 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, therefore equieffective oral doses vary considerably. Propranolol 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: its own oral bioavailability is increased and its t½ is prolonged (by about 30%) on repeated administration. Bioavailability of propranolol is higher when it is taken with meals because food decreases its first pass metabolism. Since metabolism of propranolol is saturable, higher bioavailability and prolongation of t½ is noted when high doses are given.

                                     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. Dose: Oral—10 mg BD to 160 mg QID (average 40–160 mg/day). Start with a low dose and gradually increase according to need; i.v.—2 to 5 mg injected over 10 min with constant monitoring. It is not injected s.c. or i.m. because of irritant property.

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 and its congeners.

2. Propranolol delays recovery from hypoglycaemia due to insulin and oral antidiabetics. Warning signs of hypoglycaemia mediated through sympathetic stimulation (tachycardia, tremor) are suppressed.

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. Propranolol retards lidocaine metabolism by reducing hepatic blood flow.  

ADVERSE EFFECTS AND CONTRAINDICATIONS :

Propranolol can produce many adverse effects, but mostly they are mild; β blockers are, in general, well tolerated drugs. 

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 certain β1 blockers is now established therapy to prolong survival.

2. Bradycardia: It is the most common side effect, 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. The β1 selective agents may be safer in this regard. 

4. Propranolol exacerbates variant (vasospastic) 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. Propranolol is better avoided in diabetics, because risk of hypoglycaemic episodes may be increased. However, the b1 selective agents may be less risky. Carbohydrate tolerance may be impaired in prediabetics. 

6. Plasma lipid profile is altered on longterm use: total triglycerides tend to increase while HDL-cholesterol falls. This may enhance risk of coronary artery disease. Cardioselective β blockers and those with intrinsicsympathomimetic 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 appears to be due to upregulation 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 may be felt 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 may be noticed during winter due to blockade of vasodilator β2 receptors. Peripheral vascular disease is worsened. 

11. Side effects not overtly due to β blockade are—g.i.t. upset, lack of drive, nightmares, forgetfulness. Incidence of mental depression was found to be higher among patients taking β blockers, especially the lipid soluble agents like propranolol. Male patients more frequently complain of sexual distress.