ββ-Adrenergic Blocking Agents-Adrenergic Blocking Agents All the clinically available All the clinically available β β -blockers are -blockers are

competitive antagonistscompetitive antagonists. . NonselectiveNonselective ββ-blockers act at both -blockers act at both ββ11 and and ββ22

receptors, whereas receptors, whereas cardioselective cardioselective ββ antagonists primarily antagonists primarily block block β β 11 receptors. receptors.

[Note:There are [Note:There are no clinically useful no clinically useful ββ22 antagonistsantagonists]]

Although all Although all β β -blockers lower blood pressure -blockers lower blood pressure in hypertension,in hypertension, they do not induce postural they do not induce postural hypotension, because the hypotension, because the αα-adrenoceptors -adrenoceptors remain functional.remain functional.

Therefore, Therefore, normal sympathetic controlnormal sympathetic control of the of the vasculature is maintainedvasculature is maintained..

β β -Blockers are also effective -Blockers are also effective in treating: in treating: angina,angina, cardiac arrhythmias,cardiac arrhythmias, myocardial infarction,myocardial infarction, congestive heart failure, congestive heart failure, hyperthyroidism, hyperthyroidism, and glaucoma,and glaucoma, as well as serving in the as well as serving in the prophylaxis of migraine prophylaxis of migraine

headaches.headaches.

A. Propranolol(Inderal)A. Propranolol(Inderal) A A nonselective nonselective ββ antagonist antagonist Propranolol :Propranolol : is the is the ββ-adrenergic -adrenergic

antagonist antagonist and blocks both and blocks both ββ11 and and ββ22

receptors. receptors. Sustained-release preparations Sustained-release preparations for for

once-a-day dosing are available.once-a-day dosing are available.

• Actions:Actions:

•Cardiovascular:Cardiovascular:• Propranolol Propranolol diminishesdiminishes cardiac output, cardiac output,

having both having both negative inotropic and negative inotropic and chronotropic effects. chronotropic effects. The resulting The resulting bradycardia .bradycardia .

• Cardiac output, work, and oxygen Cardiac output, work, and oxygen consumption consumption are are decreaseddecreased by blockade of by blockade of ββ11

receptors; receptors; these effects are these effects are useful in the useful in the treatment of angina .treatment of angina .

• Peripheral vasoconstriction:Peripheral vasoconstriction:– The The reduction in cardiac outputreduction in cardiac output leads to leads to decreased decreased

blood pressure.blood pressure.

• This This hypotension hypotension triggers triggers

a reflex peripheral a reflex peripheral

vasoconstrictionvasoconstriction that is reflected in that is reflected in reduced blood reduced blood flow to the periphery. flow to the periphery.

• On balance, there is a gradual On balance, there is a gradual reduction of both reduction of both systolic and diastolicsystolic and diastolic blood pressures blood pressures in in hypertensive patients.hypertensive patients.

No postural hypotension occursNo postural hypotension occurs, , because the because the αα11-adrenergic receptors -adrenergic receptors

that control vascular resistance that control vascular resistance are are unaffected.unaffected.

• Bronchoconstriction:Bronchoconstriction:• Blocking Blocking β β 22 receptors receptors in in

the lungs of susceptible the lungs of susceptible

patients causes patients causes contraction contraction

of the bronchiolar smooth muscleof the bronchiolar smooth muscle . .

• This can precipitate a respiratory crisis in This can precipitate a respiratory crisis in patients with patients with chronic obstructive chronic obstructive pulmonary disease (COPD) or asthma. pulmonary disease (COPD) or asthma. • are thus are thus contraindicated in patients with contraindicated in patients with

COPD or asthma.COPD or asthma.

• Increased NaIncreased Na++ retention retention: : • Reduced blood pressure Reduced blood pressure causes causes a decrease in a decrease in

renal perfusionrenal perfusion, resulting in an , resulting in an increase in increase in NaNa++ retention and plasma volume . retention and plasma volume .

• In some cases, this compensatory response In some cases, this compensatory response tends to tends to elevate the blood pressureelevate the blood pressure. .

• For these patients, For these patients, β β -blockers are often -blockers are often combined with a combined with a diuretic to prevent Nadiuretic to prevent Na++ retention.retention.

• By inhibiting By inhibiting ββ receptors, receptors, renin production renin production is is also preventedalso prevented, , contributing to Nacontributing to Na+ + retention.retention.

• Disturbances in glucose metabolism:Disturbances in glucose metabolism:

• ββ-blockade leads to :-blockade leads to :

• 1-1-decreaseddecreased glycogenolysis glycogenolysis and and decreased decreased glucagon secretion.glucagon secretion.

• Therefore, if a Type I (insulin-dependent) Therefore, if a Type I (insulin-dependent) diabetic diabetic is to be given propranololis to be given propranolol, , very very careful monitoring of blood glucosecareful monitoring of blood glucose is is essential, essential, because hypoglycemia may occur because hypoglycemia may occur after insulin injection. after insulin injection.

2- 2- β β -Blockers also -Blockers also attenuate attenuate the the normal normal

physiologic response to hypoglycemia.physiologic response to hypoglycemia.

• Therapeutic effects:Therapeutic effects:1- In Hypertension: 1- In Hypertension:

Propranolol Propranolol does does not reduce blood pressure not reduce blood pressure in people with normal blood pressure.in people with normal blood pressure.

Propranolol lowers blood pressure Propranolol lowers blood pressure in in hypertension patients by several different hypertension patients by several different mechanisms of action:mechanisms of action:

1.1.Decreased cardiac output Decreased cardiac output is the primary is the primary mechanism.mechanism.

2. decreased sympathetic 2. decreased sympathetic outflow from the outflow from the CNS .CNS .

2- Glaucoma:2- Glaucoma: •ββ-Blockers, topically applied -Blockers, topically applied Timolol,Timolol,

•are effective in diminishing intraocular are effective in diminishing intraocular pressure in glaucoma. pressure in glaucoma.

•This occurs by This occurs by decreasing the secretion decreasing the secretion of of aqueous humor aqueous humor by the by the ciliary body. ciliary body.

•Many patients with glaucoma have been Many patients with glaucoma have been maintained with these drugs for years. maintained with these drugs for years.

• They They neitherneither affect the affect the ability of the eye ability of the eye to focus for near vision to focus for near vision

• nor nor change change pupil size, pupil size, as do the as do the cholinergic drugs.cholinergic drugs.

• However, in an However, in an acute attack of acute attack of glaucoma, glaucoma, pilocarpinepilocarpine is still the drug of is still the drug of choice. choice.

• The The β β -blockers are only used to treat this -blockers are only used to treat this disease chronically.disease chronically.

3-Migraine: 3-Migraine:

•Propranolol is also effective in Propranolol is also effective in reducing reducing migraine migraine when used prophylactically.when used prophylactically.

•ββ-Blockers are valuable in the treatment -Blockers are valuable in the treatment of of chronic migraine, chronic migraine, in which they in which they decrease the decrease the incidence and severity of incidence and severity of the attacks.the attacks.

4- Hyperthyroidism:4- Hyperthyroidism:

• Propranolol and other Propranolol and other β β -blockers are -blockers are effective in effective in blunting the widespread blunting the widespread sympathetic stimulation that occurs in sympathetic stimulation that occurs in hyperthyroidism.hyperthyroidism.

•In acute hyperthyroidism, In acute hyperthyroidism, β β -blockers -blockers may be may be lifesaving lifesaving in protecting against in protecting against serious cardiac arrhythmias.serious cardiac arrhythmias.

5- Angina pectoris: 5- Angina pectoris:

•Propranolol Propranolol decreases the oxygen decreases the oxygen requirement of heart muscle requirement of heart muscle and, and, therefore, is effective in reducing the therefore, is effective in reducing the chest chest pain on exertion pain on exertion that is common in that is common in angina.angina.

• Propranolol Propranolol is therefore useful in the is therefore useful in the chronic management of chronic management of stable angina, stable angina, but but not not for acute treatment. for acute treatment.

6- Myocardial infarction: 6- Myocardial infarction: •Propranolol and other Propranolol and other β β -blockers -blockers have a have a protectiveprotective effect on the effect on the myocardium. myocardium.

•Thus, patients who have Thus, patients who have one myocardial one myocardial infarction appear to be infarction appear to be protected against a protected against a second heart attacksecond heart attack by prophylactic use of by prophylactic use of ββ--blockers. blockers.

•In addition, administration of a In addition, administration of a ββ-blocker -blocker immediately following a immediately following a myocardial myocardial infarction infarction reducesreduces infarct size and hastens infarct size and hastens recovery. recovery.

• Propranolol also Propranolol also reduces the reduces the incidence of sudden arrhythmic incidence of sudden arrhythmic death death after myocardial infarction.after myocardial infarction.

• Adverse effects:Adverse effects:1- 1- Bronchoconstriction: Bronchoconstriction:

Propranolol has a Propranolol has a seriousserious and and potentially potentially lethal side lethal side effect when administered to effect when administered to an an asthmatic asthmatic ..

•Deaths by asphyxiation Deaths by asphyxiation for asthmatics for asthmatics administered the drug. administered the drug.

•Therefore, propranolol must never be used in Therefore, propranolol must never be used in treating any individual with COPD or asthma.treating any individual with COPD or asthma.

2- Arrhythmias: 2- Arrhythmias:

•Treatment with Treatment with ββ-blockers must -blockers must

never be never be stopped quickly stopped quickly because because

of the risk of precipitating of the risk of precipitating cardiac cardiac arrhythmiasarrhythmias, which may be severe. , which may be severe.

•The The ββ-blockers must -blockers must be tapered off be tapered off gradually for 1 week. gradually for 1 week.

•Long-term treatment with a Long-term treatment with a ββ antagonist leads antagonist leads to to up-regulation of the up-regulation of the ββ-receptor-receptor. .

•On stop of therapy, the increased receptors On stop of therapy, the increased receptors can worsen angina or hypertension.can worsen angina or hypertension.

3- Disturbances in metabolism:3- Disturbances in metabolism:• β β -Blockade leads to decreased -Blockade leads to decreased glycogenolysis and decreased glucagon glycogenolysis and decreased glucagon secretion.secretion. Fasting hypoglycemia may Fasting hypoglycemia may occur. occur.

4- Drug interactions: 4- Drug interactions: •Drugs that Drugs that interfere with the metabolism interfere with the metabolism of of propranolol, such as cimetidine, fluoxetine propranolol, such as cimetidine, fluoxetine (inhibit (inhibit metabolismmetabolism), may ), may potentiate its potentiate its antihypertensive effects.antihypertensive effects.

• Conversely, those that Conversely, those that stimulate its stimulate its metabolism,metabolism, such as barbiturates, phenytoin, such as barbiturates, phenytoin, and rifampin, and rifampin, can decrease its effectscan decrease its effects..

B- Timolol and Nadolol:B- Timolol and Nadolol: Nonselective Nonselective β β antagonistsantagonistsTimolol and Nadolol also block Timolol and Nadolol also block ββ11- and - and ββ22- -

adrenoceptors and are more adrenoceptors and are more potent than potent than propranolol.propranolol. Nadolol has a very long duration of action Nadolol has a very long duration of action .. Timolol reduces Timolol reduces the production of aqueous the production of aqueous humor in the eye. It is used humor in the eye. It is used topicallytopically in the in the treatment of treatment of chronic open-angle glaucoma chronic open-angle glaucoma and, and, occasionally, for occasionally, for systemicsystemic treatment of treatment of hypertension.hypertension.

C-C- Acebutolol, Atenolol, and Esmolol: Acebutolol, Atenolol, and Esmolol: Selective Selective ββ11 antagonists antagonists

Drugs that block the Drugs that block the ββ11 receptors receptors have been have been

developed to eliminate developed to eliminate the unwanted the unwanted bronchoconstrictor effect (bronchoconstrictor effect (β β 22 effect) effect) of of

propranolol seen among propranolol seen among asthmatic patients. asthmatic patients. This cardioselectivity is thus most at low doses This cardioselectivity is thus most at low doses

and is lost at high doses.and is lost at high doses.

• Therapeutic use in hypertension: Therapeutic use in hypertension: • The The cardioselective cardioselective β β -blockers are useful in -blockers are useful in

hypertensive patients with hypertensive patients with impaired impaired pulmonary function.pulmonary function.

• Because these drugs have Because these drugs have less effect on less effect on peripheral vascular peripheral vascular ββ22 receptors receptors, the , the coldness coldness

of extremitiesof extremities (a common side effect of (a common side effect of β β --blocker therapy) blocker therapy) is less frequent. is less frequent.

• Cardioselective Cardioselective β β -blockers are useful in -blockers are useful in diabetic hypertensive diabetic hypertensive patients who are patients who are receiving receiving insulin or oral hypoglycemic agents.insulin or oral hypoglycemic agents.

Pindolol and Acebutolol: Pindolol and Acebutolol: (Antagonists with partial agonist (Antagonists with partial agonist activity)activity) Actions:Actions:

• Cardiovascular:Cardiovascular: are are not pure antagonistsnot pure antagonists; they ; they have the have the ability to weakly stimulate both ability to weakly stimulate both ββ11 and and ββ22

receptors and are said to have intrinsic receptors and are said to have intrinsic sympathomimetic activity (ISA).sympathomimetic activity (ISA).

• These partial agonists These partial agonists stimulate the stimulate the ββ receptor receptor to which they are bound,to which they are bound, yet they yet they inhibit inhibit stimulation stimulation by the more potent endogenous by the more potent endogenous catecholamines, epinephrine and norepinephrine. catecholamines, epinephrine and norepinephrine.

• Decreased metabolic effects: Decreased metabolic effects:

• Blockers with Blockers with ISA ISA minimize the minimize the disturbancesdisturbances of lipid and carbohydrate of lipid and carbohydrate metabolism that are seen with other metabolism that are seen with other β β --blockers.blockers.

• Therapeutic use in hypertension:Therapeutic use in hypertension:• β β -Blockers with ISA -Blockers with ISA are effective in hypertensive are effective in hypertensive

patients patients with with moderate bradycardia, moderate bradycardia, • because a because a further further decrease in heart decrease in heart rate rate is is

less pronounced with these drugs.less pronounced with these drugs.• Carbohydrate metabolism Carbohydrate metabolism is is less affected less affected

with Acebutolol and pindolol with Acebutolol and pindolol than it is with than it is with propranolol, making them valuable in the propranolol, making them valuable in the treatment of diabetics. treatment of diabetics.

Drugs Affecting Neurotransmitter Drugs Affecting Neurotransmitter Release or UptakeRelease or Uptake

amphetamine and tyramine, amphetamine and tyramine, they exert their they exert their effects effects indirectly on the adrenergic neuron indirectly on the adrenergic neuron by by causing the causing the release of neurotransmitter from release of neurotransmitter from storage vesicles.storage vesicles.

Similarly, some agents act on the Similarly, some agents act on the adrenergic adrenergic neuron :neuron :

either to interfere with either to interfere with neurotransmitter release neurotransmitter release or to alter the or to alter the uptake of the neurotransmitter into uptake of the neurotransmitter into

the adrenergic nerve. the adrenergic nerve.

A. ReserpineA. Reserpine Reserpine a plant alkaloid, Reserpine a plant alkaloid, blocks the blocks the

MgMg2+2+/adenosine triphosphate /adenosine triphosphate (dependent (dependent transport of biogenic amines) transport of biogenic amines) norepinephrine, dopamine, and serotonin norepinephrine, dopamine, and serotonin from the cytoplasm into from the cytoplasm into storage vesicles storage vesicles in the adrenergic nerves in the adrenergic nerves of all body of all body tissues.tissues.

This causes the ultimate depletion of biogenic This causes the ultimate depletion of biogenic amines. amines.

Sympathetic functionSympathetic function, in general, is , in general, is impaired impaired because of decreased release of because of decreased release of norepinephrine. norepinephrine.

The drug has a The drug has a slow onset, a long duration slow onset, a long duration of of action, and action, and effects that persist for many days effects that persist for many days after discontinuation.after discontinuation.

GuanethidineGuanethidine blocks the release blocks the release of of stored norepinephrine stored norepinephrine as as

well as well as displacesdisplaces norepinephrine from storage norepinephrine from storage vesicles vesicles (thus producing a transient increase (thus producing a transient increase in in blood pressure).blood pressure).

This leads to gradual depletion of This leads to gradual depletion of norepinephrine in nerve endings except norepinephrine in nerve endings except for those in the CNS. for those in the CNS.

Guanethidine commonly causes Guanethidine commonly causes orthostatic hypotension orthostatic hypotension ..

Supersensitivity to norepinephrine due to Supersensitivity to norepinephrine due to depletion of the amine can result in depletion of the amine can result in hypertensive crisis in patients with hypertensive crisis in patients with pheochromocytoma.pheochromocytoma.

C. CocaineC. Cocaine Although cocaine inhibits norepinephrine Although cocaine inhibits norepinephrine

uptake, it is an adrenergic agonist.uptake, it is an adrenergic agonist. norepinephrine accumulate in the norepinephrine accumulate in the

synaptic space ,resulting in enhancement synaptic space ,resulting in enhancement of sympathetic activity and potentiation of sympathetic activity and potentiation the action of epinephrine, norepinephrine.the action of epinephrine, norepinephrine.