ADRENOCEPTOR

Adrenoceptor blocking agents or adrenoceptor antagonists are drugs that inhibit responses mediated by Adrenoceptor activation caused by epinephrine and related drugs. They also block (less completely) effects of adrenergic nerve stimulation. On the other hand, adrenergic neurone blocking drugs act on adrenergic neuronal membrane or contents and block (more completely) the effects of adrenergic nerve stimulation. However, they do not block the effects of injected epinephrine; they actually may potentiate its effect.

Adrenoceptor antagonists are competitive antagonists at alpha or beta adrenergic receptors. So they are classified as alpha adrenoceptor blocking agents and beta adrenoceptor blocking agents.

ALPHA RECEPTOR BLOCKING DRUGS

These drugs inhibit adrenergic responses mediated through alpha-adrenergic receptors. They do not affect those responses mediated through beta-receptors.

Classification of Adrenoceptor drugs

I. Selective alpha-Adrenoceptor blockers

• Alpha-i blockers: Prazosirt, alfuzosin, terazosin, doxazosin, trimazosin, indoramin.
• Alpha-2 blockers: Yohimbine, idazoxan.
• Selective alpha-iA blocker: Tamsulosin

II. Non-selective alpha-adrenoceptor blocker

a. Reversible

• Imidazoline: Tolazoline, phentolamine
• Ergot alkaloids: Ergotamine, ergotoxine
• Hydrogenated ergot alkaloids: Dihydroergotanfine
• Phenothiazine: Chlorpromazine.

b. Non-reversible

• Beta haloalkyl amine: Phenoxybenzamine, dibenamine.

General Effects of Alpha-Adrenoceptor Blockers

1. These Adrenoceptor drugs cause fall in blood pressure by blocking alpha-vasoconstrictor receptors. So there occurs reduction in peripheral resistance and pooling of blood in capacitance vessels. Due to this, venous return and cardiac output are reduced and blood pressure is decreased. They also interfere with postural reflex; so there occurs marked hypotension on standing and individual suffers with dizziness and syncope. Hypovolemia accentuates the hypotension. Pressor and other actions of selective alpha-agonists (norepinephrine, phenylephrine) are also antagonized. They block pressor action of epinephrine by blocking alpha vasoconstrictor receptors. So after their administration epinephrine causes fall in blood pressure due to beta mediated vasodilatation. This phenomenon is called vasomotor reversal of Dale.

2. Reflex tachycardia occurs due to fall in mean arterial pressure and increased release of noradrenaline due to blockage of presyriaptic cs.2-receptors.

3. They cause miosis and nasal stuffiness due to blockage of alpha-receptors in radial muscles of iris and in nasal blood vessels, respectively.

4. Diarrhea may occur due to partial inhibition of relaxant sympathetic influences and increased intestinal motility.

S. They may’ cause sodium retention and increase in blood volume due to reduction in renal blood flow and glomerular filtration rate as a result of hypotension. So there occurs more complete re-absorption of Na and water in the tubules.

6. Alpha-Adrenoceptor blocking agents inhibit ejaculation and may lead to impotence.

Most of these common effects are manifested as side effects such as palpitation, postural hypotension, nasal stuffiness, diarrhoea, fluid retention, inhibition of ejaculation and impotence.

Imidazoline

Tolazoline: It is a competitive antagonist of alpha-adrenoceptor. It causes fall in blood pressure due to direct action on vascular smooth muscles and partly due to competitive blockade of alpha-adrenoceptor. It has histamine like action on gastrointestinal motility. In therapeutic doses, it causes cardiac stimulation. It is fairly well absorbed from gastrointestinal tract on oral administration and is excreted by kidney mostly unchanged. It is mainly used in Raynaud’s disease, thromboangitis obliterance, frostbite, etc. Oral dose is 25 to 50 mg thrice a day.

Phentolamine: It is also a competitive antagonist of alpha-adrenoceptor. Its normal therapeutic doses, it does not block other receptors. However, very large doses of phentolamine can block the action of 5-HT also. It has a quick onset of action and short duration of action. It produces vasodilatation and fall in blood pressure by blocking the alpha-adrenoceptor on the vascular smooth muscles.

It is mainly used as a preliminary test (Regitine test) in the diagnosis of pheochromocytoma. An intravenous injection of 5 mg phentolamine causes a sizeable fall in blood pressure, if it is high due to large quantities of catecholamines circulating in the blood. A fall of 35/25 mm Hg is diagnostic. False positive results do occur. Hence if the test is positive, further investigations like estimation of urinary VMA are necessary.

Ergot alkaloids: Ergot (Claviceps purpurea) is a fungus that grows on rye. The alkaloids of ergot are divided into two groups:

a. Amino acid alkaloids: Ergotamine and ergotoxine (mixture of ergocristine, ergokryptine, and ergocornine). Also called peptide alkaloids.

b. Amine alkaloid: Ergonovine.

Erogotamine and erogotoxin possess alpha-receptor blocking, oxytocic and partial agonistic activity on alpha-receptors. The vasoconstrictor action of these alkaloids is partly due to partial alpha-agonistic activity as well as also due to direct action on the vascular smooth muscles. So this action is opposite to the indirect alpha blocking action. The semisynthetic hydrogenated derivatives are dihydroergotamine and hydergine. They are devoid of oxytocic, partial alpha agonistic and direct vasoconstrictor actions and are primarily alpha-receptor blockers. Ergonovine (ergometrine), Ergotamine is a potent vasoconstrictor and it is, therefore, used in migraine headache. It is preferred to be given by subcutaneous or intramuscular routes because of the poor oral absorption (0.25—0.5 mg). It is also used by sublingual route (2—4 mg). Caffeine acts synergistically with ergotamine in controlling the pulsations of cranial arteries and in relieving migraine. Tablets composed of 1 mg ergotamine and 100 mg caffeine are often used.

Erogotamine and other ergot preparations cause nausea, vomiting, vascular insufficiency and gangrene (due to excessive use) of extremities.

Beta haloalkylamines are phenoxybenzamine and dibenamine. They produce an irreversible competitive antagonism of alpha adrenoceptor of long duration (14—48 hr). It is also called non-equilibrium type of blocked because in the later stages it is not altered by increasing the concentration of the catecholamines at the receptor sites. Out of the two, phenoxybenzamine is used because dibenamine is more toxic. Phenoxybenzamine can also block the responses of acetylcholine, histamine and 5-HT. It inhibits reuptake of released NA by presynaptic adrenergic nerve terminals. It causes more tachycardia, palpitation, and increase in cardiac output than prazocin because of its action on cc2 receptors and inhibition of NA reuptake.

It is mainly used in the treatment of pheochromocytoma. In addition to usual side effects, it causes sedation, fatigue and nausea because it crosses blood—brain barrier being lipid soluble.

Prazosin: It is an extremely potent and highly selective cc receptor blocker. It has no action on presynaptic cz2 receptors. A central effect decreasing sympathetic flow to heart has also been observed. It is more effective in the treatment of hypertension when given in combination with a diuretic which corrects retention of salt and fluid caused by prazocin.

Dose: 1 mg 2—3 times a day.

Terazosin: It is related to prazosin. Its plasma half-life is longer (12 hrs) than prazosin (3—4 hrs) as it undergoes very little first pass metabolism in liver.

Dose: 2—10 mg once daily.

Other long acting once daily administered selective cz1 blockers are trimazosin and doxazosin. Doxazosin is also used in benign prostate hyperplasia.

Indoramin is a selective, competitive cc1- antagonist. It also competitively antagonises H1 and 5-HT receptors. It is used in hypertension and to decrease incidence of Raynaud’s phenomenon. Sedation, dry mouth and failure of ejaculation may occur as side effects.

Important uses of alpha-blockers

Hypertension Selective alpha-i blockers like prazosin, terazosin, trimazosin, doxazosin are used Secondary shock ct-blocker with fluid replacement (Due to blood or fluid loss)

a. Phenotolamine test for diagnosis

b. Phenoxybenzamine for inoperable and malignant tumours

c. Phenoxybenzamine for 1—2 weeks preoperatively and continue it during surgical removal of the tumour

For symptomatic relief, tolazoline, prazosin and phenoxybenzamine may be used. To increase urinary flow and complete emptying of bladder prazosin, terazosin or tamsulosin may be used. Congestive heart failure Prazosin affords improvement for short period.

Pheochromocytoma

Peripheral vascular diseases Benign hypertrophy of prostate  an amine alkaloid, is primarily an oxytocic and is used for the same purpose.

Urapidil is a selective a1 antagonist. It also has weak a2-agonist and 5-HT1-agonistic actions. It is recommended for the treatment of hypertension. It is extensively metabolized. It has a half-life of 3 hours.

Tamsulosin has higher affinity for alA subtype of a1 receptors. These receptors predominate in the bladder base and prostate. So it is an uroselective drug and used to relieve urinary symptoms of benign hyperplasia of prostate. Significant side effects are dizziness and retrograde ejaculation. Its modified release capsule is required to be given once daily.

Yohimbine: It is an indolealkylamine alkaloid obtained from a West African tree. It readily crosses the blood—brain barrier and selectively blocks ot2 receptors and facilitates the release of NA at the synaptic cleft. It is not used therapeutically.

BETA-ADRENOCEPTOR BLOCKING AGENTS

Beta-adrenoceptor blocking agents are synthetic analogues of isoprenaline. Adrenoceptor drugs selectively and competitively block the actions of catecholamines mediated through beta- receptor stimulation.

Classificationof adrenoceptor drugs

I. Non-selective

• Beta blocker with membrane stabilizing activity, e.g. propranolol

• Beta blockers with membrane stabilizing activity and intrinsic sympathomimetic property, e.g. oxprenolol, pindolol, alprenolol

• Specific beta blockers without intrinsic sympathomimetic activity, e.g. timolol, nadolol

• With additional alpha blocking property, e.g. labetalol, dilevalol

II. Cardioselective (l) blocker, e.g. metoprolol, atenolol, acebutolol, esmolol, betaxolol, bisoprolol, celiprolol, nabivolol

Pharmacokinetics: On oral administration, beta blockers are absorbed. In most of the cases, bioavailability is 30—50% except pindolol (90%). These drugs are metabolized in the liver and are excreted in urine. The plasma t½ of most of the beta blockers is between 3 and 6 hours. But nadolol has a t½ of 14—24 hours, atenolol 6—9 hours and esmolol only in minutes. So atenolol is given once a day and esmolol by i.v. infusion. Since propranolol has been thoroughly investigated and has been widely used, it will be discussed in detail as prototype of this group.

Propronolol

Although it exists in levo- and dextro-form, the commercial preparation is however, recemic. It is highly lipophilic. On oral administration, it is completely absorbed and is extensively metabolized (first-pass effect) in the liver. One of the metabolites (4-OH- propranolol) is biologically active. Its plasma half-life is 4—6 hours. It crosses the blood— brain barrier and 90% binds with plasma protein. The drug and its metabolites are excreted in urine.

Pharmacological Actions of adrenoceptor drugs

Cardiovascular system: Its effects on cardiovascular system are dose dependent and can be antagonized by isoprenaline. It blocks cardiac I3 receptors and produces bradycardia, decrease in cardiac contractility, automaticity and cardiac output; oxygen consumption is decreased and there is increase in exercise tolerance. It depresses the heart due to membrane stabilizing action. So it is not used in presence of congestive heart failure.

ECG shows prolongation of PR interval and slow AV conduction. Antiarrhythmic effect of propranolol is due to beta-blocking activity and not to membrane stabilization.

Blood pressure: Although propranolol has no effect on blood pressure of normotensive individuals, it produces slowly developing fall in blood pressure of hsypertensive patients. Its antihypertensive effect is due to:

• Bradycardia and decreased cardiac output which occur as a result of blockade of

receptors in heart; with continued treatment total peripheral resistance decreases due to gradual adaptation of resistance vessels to chronically reduced cardiac output

• Blockade of presynaptic I2 receptors (facilitatory to adrenergic neurons) leads to reduced norepinephrine release from sympathetic terminals

• Inhibition of release of renin from juxtaglomerular cells of kidney (Imediated)

• Central action reducing sympathetic outflow by blocking presynaptic f3 receptors centrally

• Stimulation of prostacycline synthesis in vascular beds

• Increase in natriuretic peptide secretion caused by n-blockade

Respiratory system: Propranolol increases airway resistance, so it is contraindicated in patients of asthma and other forms of respiratory insufficiency.

Eye: Propranolol reduces formation of aqueous humour by decreasing cAMP formation and thus decreases intraocular pressure. It has local anaesthetic effect on conjunctiva, but not used for this purpose because of its irritant property.

Central nervous system: Propranolol produces sedation, lethargy, depression, disturbed sleep and increased dreaming because it crosses the blood—brain barrier. In a high dose (1—2 g), it produces antipsychotic effect by direct membrane stabilizing effect or antiserotonin action. Propranolol decreases anxiety in short-term stressful situations due to peripheral rather than a central action.

Metabolic effects: Propranolol antagonizes catecholamine induced gJycogenolysis and lipolysis mediated by beta-receptors. It increases VLDL and lowers plasma HDL levels (undesirable effect). So it is better to be given along with prazosin in hypertensive patients because prazosin increases HDL levels.

Skeletal muscle: Propranolol blocks facilitatory presynaptic 12 receptors and antagonizes adrenaline induced tremor.

Other Beta Blockers

The pharmacological actions of other beta blockers are similar to that of propranolol. The individual differences are due to pharmacokinetic peculiarities, receptor selectivity, membrane stabilizing and intrinsic sympathomimetic (partial agonistic) actions. Beta-blockers with partial agonistic activity can be used in the presence of congestive heart failure while those causing membrane stabilization are not indicated. Cardioselective f3 blocker does not affect pulmonary ventilation and tissue perfusion, so it can be used with great caution in patients with bronchial asthma. They are also preferred in patients suffering from diabetes mellitus or peripheral vascular spasmodic diseases.

Pindolol is a potent beta blocker having prominent intrinsic svmpathomimetic activity. It is useful to treat hypertensive patients who develop marked bradycardia with propranolol. Ouccrrence of withdrawal rebound hypertension is less. However, it has narrow effective dose range.

Oxprenolol and alprenolol have similar pharmacological profile as that of pindolol, but are less potent and short acting.

Timolol (non-selective beta blocker): Used as eyedrop in cases of wide angle glaucoma to decrease intraocular pressure. It has no effect on ciliary muscle and pupillary size.

Nadolol is a long acting beta blocker which is used to treat hypertension. It has less central side effects and is given once daily.

Metoprolol (cardioselective beta blocker):

It is well absorbed on oral administration; undergoes first-pass metabolism in liver; protein binding is 12%; plasma half-life is 3—4 hours; and the metabolites are excreted by the kidney.

Dose: 100—200 mg.

Atenolol (potent blocker): It has no central action in therapeutic doses. On oral administration, 46—62% is absorbed; plasma half-life is 6—9 hours and is excreted mainly by kidney.

Dose: 50—100 mg per day.

Esmolol (selective J3 blocker) is given by i.v. infusion because it has an ultrashort half- life of 10 minutes due to rapid hydrolysis of its ester linkage.

Bisoprolol is a cardioselective beta blocker without intrinsic sympathomimetic activity. It is used once daily in angina and hypertension

Celiprolol is a selective 3 blocker with weak 132 agonistic activity. It reduces vascular resistance and somewhat safe in asthmatics

Acebutolol is useful in patients with low cardiac reserve because it produces less myocardial depression and bradycardia due to partial beta agonistic activity. The abnormality in lipid profile is also less than with propranolol.

Nebivolol is a cardioselective 13 blocker and a nitric oxide (NO) donor. It produces vasodilatation and improves endothelial function.

Labetalol: It has both ct1 and j3 blocking activity. On oral administration, it is well absorbed and rapidly metabolized in liver. It reduces both systolic and diastolic blood pressure. It is useful in the treatment of hypertension, rebound hypertension after sudden withdrawal of clonidine and pheochromocytoma. Oral dose is 50 mg BD; increased up to 100—200 mg TDS.

Dilevalol is 3—4 times more potent in blocking 3. 12 receptors but 6 times less potent in blocking cs receptors than labetalol. Like labetalol it is an effective antihypertensive by oral route and can be injected i.v. to produce predictable hypotension during emergencies. Dose: 200—800 mg orally daily.

Carved ho! is also adrenoceptor blocker. It produces vasodilatation due to a1 blockade as well as direct action. It also has antioxidant action. It is used in hypertension and as cardioprotective in congestive heart failure.

Therapeutic Uses of adrenoceptor Beta Blockers

1. Essential hypertension: Beta blockers are now considered as the first line drug in the treatment of essential hypertension. They are usually combined with diuretics which contribute to the hypotensive effect by a different mechanism and also prevent development of tolerance.

2. All beta blockers are used in the prophylaxis of angina pectoris of effort to reduce the number and severity of attacks. However, it is not effective in variant or unstable angina where vasospasm is the causative factor.

3.When beta blockers are used for several years in patients of myocardial ischaemia they decrease the incidence and recurrence of myocardial infarction due to beta blockade effect, prevention of platelet aggregation, promotion of fibrinolysis and prevention of sudden ventricular fibrillation at the second attack of myocardial infarction.

4. Propranolol is effective in all supraventricular tachycardias associated with high levels of circulating catecholamines, e.g. halothane or cyclopropane anaesthesia, thyrotoxicosis, pheochromocytoma and also in digitalis toxicity due to its ability to increase refractory period of AV node and direct membrane stabilizing action.

5. Since beta blockers increase the stroke volume as a result of slowing of heart, it is used to relieve congestion and dyspnoea associated with Obstruction of ventricular outflow in the presence of hypertrophic cardiomyopathy, mitral stenosis with tachycardia, dissecting aortic aneurysm and Fallot’s tetralogy.

6. Propranolol and nadolol ase useful in portal hypertension to reduce bleeding from oesophageal varices and gastric erosion.

7. Propranolol is used to reduce tachycardia, tremor, cardiac irregularities, sweating nervousness and raised BMR in cases of thyrotoxicosis.

8. Pheochromocytoma: Beta blockers may be employed in combination with alpha adrenoceptor blocker in pheochromocytoma during removal of the tumour, to prevent excessive cardiac stimulation by catecholamines released from the tumour. Labetalol may also be used in this condition.

9. Glaucoma: Timolol (0.25—0.5%) is used as an eyedrop in cases of wide angle glaucoma to reduce intraocular tension.

10. Neurological disorders: Propranolol has been found to be useful in:

• Reducing the frequency and severity of migraine
• Reducing anxiety states by inhibiting somatic manifestations of anxiety such as palpitation, tachycardia, sweating and diarrhoea
• Reducing the central adrenergic over activity during alcohol withdrawal
• The treatment of essential tremor

Adverse reactions: Beta blockers may cause following adverse reactions:

• Extreme bradycardia and hypotension
• Precipitate or worsen congestive heart failure due to withdrawal of cardiac sympathetic derives.
• Precipitate or worsen bronchial asthma
• Propranolol may cause fatigue, depression, sleep disturbances and vivid dreams.
• Abrupt withdrawal of beta blockers may result in a rebound phenomenon (severe angina or myocardial infarction) and death may occur in patients of ischaemic heart disease.
• Beta-blockers potentiate the hypoglycaemic action of insulin and oral anti diabetic agents.

Contraindications: Beta blockers are contraindicated in:

• Mental depression
• Incipient heart failure and heart block
• Anesthesia with cardiac depressant drugs. In the following conditions, beta blockers are contraindicated except selective blockers which may be tried with care if needed the most:
• Bronchial asthma
• Peripheral vascular spasmodic diseases
• Insulin dependent diabetes mellitus.

Points for Dental Students

Beta adrenoceptor blocking agents are widely used drugs. So if a patient on beta blocker comes to a dentist, he should be careful prescribing other drugs due to important drug interactions. For example, the effect of beta blockers is increased by furosemide, cimetidine, hydralazine, etc. and decreased by phenytoin, rifampin, indomethacin and other NSAIDs, etc.

Further, beta blockers enhance the hypoglycemic effects of insulin and oral hypoglycemic agents; sympathomimetics (non-selective) increase pressor response due to availability of unopposed functional vasopressor alpha-receptors. This is important in dental practice when adrenaline containing local anaesthetic solution is used to a patient on propranolol. If per chance adrenaline is absorbed in sufficient concentration there can occur serious rise in blood pressure leading to even hypertensive crisis.

To treat ventricular arrhythmias, xylocaine is infused i.v. in large doses in coronary care units. In such cases, co-administration of propranolol is contraindicated to avoid xylocaine toxicity which occur due to:

(i) inhibition of oxidation of xylocaine and (ii) decreased hepatic blood flow leading to reduced delivery of xylocaine for metabolism.

TO REMEMBER

1. Alpha-receptor blocking drugs inhibit adrenergic responses mediated through aipha-adrenergic receptors.

2. Tolazoline is a competitive antagonist of aipha-adrenoceptor. It is used in Raynaud’s disease, thromboangitis obliterance, frostbite, etc.

3. Phentolamine is used as a preliminary test (Regitine test) in the diagnosis of pheochromocytoma. A fall of blood pressure by 35/25 mm Hg is diagnostic.

4. Ergotamine is a potent vasoconstrictor which is used in migraine headache.

5. Phenoxybezamine causes irreversible competitive antagonism of alpha adrenoceptor of long duration. It is mainly used in the treatment of pheochromocytoma.

6. Prazocin, terazocin, doxazocirt, trimazocin, indormin and urapidil are extremely potent and highly selective c receptor blocker which have no action on presynaptic ct2 receptors. They are used to treat hypertension along with a diuretic.

7 Beta-adrenoceptor blocking agents are synthetic analogues of isoprenaline. They selectively and competitively block the actions of catecholamines mediated through beta-receptor stimulation.

8. Beta-adrenoceptor blocking agents are used to treat essential hypertension, angina pectoris, myocardial ischaemia, supraventricular tachycardia, hypertrophic cardiomyopathy, portal hypertension, thyrotoxicosis, pheochromocytoma, glaucoma and neurological disorders.

9. Beta blockers are contraindicated in mental depression, incipient heart failure, heart block, bronchial asthma, peripheral vascular diseases, insulin dependent diabetes mellitus.

10. Important beta blockers other than propranolol are metoprolol (cardio-selective beta-blocker), atenolol (potent l3 blocker), esmolol (selective blocker) and timolol (non-selective beta-blocker; used in wide angle glaucoma). Nebivolol is a cardioselective 13 blocker and a nitric oxide donor.

11. Acebutolol and pindolol are useful in patients with low cardiac reserve.

12. Labetalol, dilevalol, carvedilol have both and beta blocking activity. They are useful in the treatment of hypertension, rebound hypertension after sudden withdrawal of clonidine and pheochromocytoma.