β Adrenergic Blocking Drugs - Pharmacological Actions

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Chapter: Essential pharmacology : Antiadrenergic Drugs (Adrenergic Receptor Antagonists) And Drugs For Glaucoma

These drugs inhibit adrenergic responses mediated through the β receptors.


PHARMACOLOGICAL ACTIONS

 

1. 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 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 the subendocardial area (which is the site of ischaemia 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 fibres and decreases automaticity rate of diastolic depolarization in ectopic foci is reduced, specially if it had been augmented by adrenergic stimuli. The AV 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 rereversal 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:

 

·        Reduced NA release from sympathetic terminals due to blockade of β 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. However, pindolol does not decrease plasma renin activity but is an effective antihypertensive.

 

·        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 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 longterm 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.

 

4. Local Anaesthetic

 

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

 

5. 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 hypoglycaemia—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.

 

6. Skeletal muscle

 

Propranolol inhibits adrenergically provoked tremor. This is a peripheral action exerted directly on the muscle fibres (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.

 

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 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—equi-effective 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.

 

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.

 

INDERAL, CIPLAR 10, 40, 80 mg tab, 1 mg/ml inj., BETABLOC 10, 40 mg tab.

 

INTERACTIONS

 

·     Additive depression of sinus node and AV conduction with digitalis and verapamil — cardiac arrest can occur. However, propranolol has been safely used with nifedipine.

 

·     Propranolol delays recovery from hypoglycaemia due to insulin and oral antidiabetics. Warning signs of hypoglycaemia mediated through sympathetic stimulation (tachycardia, tremor) are suppressed. In some cases BP rises due to unopposed α action of released Adr.

 

·     Phenylephrine, ephedrine and other α agonists present in cold remedies can cause marked rise in BP due to blockade of sympathetic vasodilatation.

 

·     Indomethacin and other NSAIDs attenuate the antihypertensive action of β blockers.

 

·     Cimetidine inhibits propranolol metabolism. However, the dose range of propranolol is wide, and this may not be clinically significant.

 

·     Propranolol retards lidocaine metabolism by reducing hepatic blood flow.

 

·     Propranolol increases bioavailability of chlorpromazine by decreasing its first pass metabolism.

 

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