β-ADRENERGIC

BLOCKING AGENTS
(( β-BLOCKERS ))

‫اسماء الثويني‬.‫د‬
Asist.Prof.M.B.ch.B/M.S.C./Ph.D.in Pharmacology and
Therapeutics
‫مقرر فرع االدويه والعالجيات‬
• General Properties:
• The most widely used drugs affecting noradrenergic
transmission.
• All the clinically available β-blockers are competitive
antagonists.
• Nonselective β-blockers act at both β1 and β2 receptors,
• Cardioselective β-antagonists primarily block β1 receptors
• Butoxamine is selective β2 antagonists, but it is not useful
clinically.
• In addition to different selectivity, these drugs also differ in:
 Intrinsic sympathomimetic (partial agonist) activity
 CNS effects
 Local anesthetic effect (membrane stabilizing activity)
 Pharmacokinetics.
• Others :
 Oxprenolol and Alprenolol (non-selective with considerable partial agonist activity)
 Nebivolol (a β1-selective antagonist that also causes vasodilatation through an endothelium-
dependent mechanism via nitric oxide)
 Sotalol (non-selective drug with extended class III antiarrhythmic effects)

• Pharmacological effects:
• Cardiac effects :
•
• Negative inotropic effects
• Negative chronotropic effects.
• ↓ Cardiac output (COP) and O2 consumption
• ↓ S-A and A-V conduction velocity
• All effects are mostly due to β1 blockade & more pronounced
during exercise
• Drugs with partial agonist activity, such as oxprenolol, increase
the heart rate at rest but reduce it during exercise.
• Vascular effects :
• Blockade of β receptors prevents β2-mediated vasodilatation.
• The reduction in COP leads to decreased BP. This hypotension
triggers a reflex peripheral vasoconstriction (cold extremities).
• Reduced blood flow to the periphery.
• Antihypertensive effects :
• Antihypertensive action is more clear in patients with hypertension
(although not normotensive subjects). Gradual fall in arterial pressure that
takes several days to develop fully.
• The mechanism is complex and involves the following:
 Reduction in COP
 Reduction of renin release from the juxtaglomerular cells of the kidney
 A central action, reducing sympathetic activity.
 Carvedilol , labetalol and nebivolol are particularly effective in lowering
blood pressure, because of their additional vasodilator properties.
• Reflex vasoconstriction (α-effect) is preserved, postural hypotension is
less than with many other antihypertensive drugs.
• Bronchoconstriction:
• This can precipitate a severe bronchoconstriction in patients with
chronic obstructive pulmonary disease (COPD) or asthma.
• β-blockers, and in particular nonselective ones, are thus contraindicated
in patients with COPD or asthma.
• Increased Na+ retention:
• Due to decrease in renal perfusion, β-blockers are often combined with
a diuretic to prevent Na+ retention.
• Disturbances in glucose metabolism:
• ↓Glycogenolysis , ↓Gluconeogenesis and ↓glucagon secretion.
• They cause only minor metabolic changes in normal subjects, but important in
diabetic patients:
 β-blockers can cause exercise-induced hypoglycemia
 β-blockers can mask the symptoms of hypoglycemia
•
• Local anesthetic action. "membrane stabilizing action ", is a prominent
effect of several –blockers. Unlikely important after systemic administration of
these drugs
• Pharmacokinetics:
• Most drugs are well absorbed orally; peak concentrations occur 1–3 hours
after ingestion.
• Propranolol undergoes extensive hepatic (first-pass) metabolism; its
bioavailability is relatively low (30 %).
• Most have large volumes of distribution Propranolol and penbutolol are
highly lipophilic and readily cross the BBB.
• Most antagonists have half-lives in the range of 3–10 hours. A major exception
is Esmolol, which is rapidly hydrolyzed and has a half-life of approximately 10
minutes.
• Nadolol is excreted unchanged in the urine and has the longest half-life of any
available antagonist (up to 24 hours).
 • Therapeutic uses
1. Cardiovascular uses: (The main clinical uses)
 Angina pectoris:
• Effective in reducing the chest pain on exertion that is common in angina (except
variant angina).
 Myocardial infarction:
• β-blockers have a protective effect on the myocardium after MI:
o Patients protected against a second attack.
o administration immediately following MI reduces infarct size and hastens
recovery.
o β-blocker also reduces the incidence of sudden arrhythmic death after MI.
 Dysrhythmias :
•
• Effective in both supraventricular and ventricular arrhythmias. (supraventricular
is more)
• β-blockers are class II antiarrhythmic drugs (e.g. propranolol), sotalol is also class III
agent.
 Heart failure :
• In patients with heart disease, blocking β receptors can exacerbate cardiac failure.
Paradoxically, β-receptor antagonists are increasingly being used in low doses to treat
cardiac failure.
• Several mechanisms may contribute, including:
o Inhibition of central sympathetic outflow
o Attenuation of high concentration of catecholamines
o Decrease the heart rate
o Prevention of cardiac hypertrophy (decrease remodeling).
o Up regulation of β receptors.
• Carvedilol and metoprolol are often used
• Hypertension :
•
• β-blockers are effective antihypertensive agents for mild to moderate HTN (no more 1st line)
•
•
•
• 2- Other uses:
•
 Glaucoma:
• Timolol eye drops decreases IOP and used for chronic treatment of open-angle glaucoma (No LA effect)
•
 Thyrotoxicosis:
o Preoperatively or to control symptoms.
o In acute hyperthyroidism (thyroid storm) β -blockers may be lifesaving in protecting against serious
cardiac arrhythmias. Propranolol is the drug of choice.
•
 Migraine prophylaxis :
• Propranolol is effective in reducing migraine episodes when used prophylactically.
•
 Anxiety : , to control somatic symptoms (e.g. palpitations, tremor)
•
 Benign essential tremor (a familial disorder).
• Adverse effects:
•
 Bronchoconstriction.
• asthmatic patients the effect can be dramatic and life-threatening.
• There is an advantage in using β1-selective agents
•
 Cardiac depression.
• Cardiac depression can occur, leading to signs of heart failure, particularly in elderly people.
•
 Bradycardia.
• This side effect can lead to life-threatening heart block.
•
 Arrhythmias. (rebound tachycardia)
• The β -blockers must be tapered off gradually for 1 week. Long-term treatment with a β-antagonist leads to
up-regulation of the β-receptor.
•
 Hypoglycemia.
• This is important to diabetic patients and to other individuals prone to hypoglycemic attacks.
•
• There is an advantage in using β1-selective agents.
•
 Fatigue.
• reduced cardiac output
• reduced muscle perfusion in exercise.
•
 Cold extremities.
• Due to a loss of β-receptor-mediated vasodilatation
• β1-selective drugs are less likely to produce this side effect.
•
 Sexual impairment.
• Some men complain of impaired sexual activity.
• Nebivolol dose not cause impotence
•
 Nightmares.
• mainly with highly lipid-soluble drugs
• Contraindications:
 asthma and other bronchospastic conditions,
 severe bradycardia
 atrioventricular blockade
 severe unstable left ventricular failure.
•
• Individual β-blockers :
•
• Propranolol
• Is the prototype of β-blockers. it is non-selective, highly lipid soluble and has low and
dose-dependent bioavailability, extensive first-pass metabolism in the liver. No detectable
partial agonist action at receptors.
•
• Timolol, Carteolol and nadolol
• Nonselective β-antagonists, more potent than propranolol.
• Nadolol has a very long duration of action.
• Timolol reduces the production of aqueous humor in the eye.
•
• Acebutolol, atenolol, , bisoprolol, betaxolol, celiprolol, esmolol, metoprolol
& nebivolol (Cardioselective β-blockers)
•
• Cardioselectivity is thus most pronounced at low doses and is lost at high doses.
•
• Cardioselective blockers have relatively little effect on pulmonary function, peripheral
resistance, and carbohydrate metabolism.
•
• Preferred in; Asthma, DM & PVD
• Pindolol, oxprenolol, alprenolol and acebutolol
•
• They have intrinsic sympathomimetic activity (ISA), so they stimulate the β receptor to
which they are bound
•
• The result of these opposing actions is a much diminished effect on cardiac rate and
cardiac output compared to that of β -blockers without ISA (rebound effect is also less).
•
• Therapeutic effects :
•
o Effective in hypertensive patients with moderate bradycardia.
o Blockers with ISA are not used as antiarrhythmic agents due to their partial agonist
effect
o These agents are not preferred in angina.
•
•
• Labetalol and carvedilol: (antagonists of both β- and α- R)
• They produce peripheral vasodilatation, and they are therefore useful in treating
hypertensive patients with increased peripheral vascular resistance.
•
• Carvedilol have benefit in heart failure.
•
• Labetalol is useful for treating the elderly hypertensive patient in whom increased
peripheral vascular resistance is undesirable. Labetalol may be employed as an alternative
to methyldopa in the treatment of pregnancy-induced hypertension. Also used in
emergency treatment of hypertension.
•
• Adverse effects: Orthostatic hypotension and dizziness are associated with α1
blockade.
 • Drugs Affecting Neurotransmitter Release
(sympatholytic agents)
• Reserpine
• Reserpine, a plant alkaloid, blocks the vesicular monoamine
transporter of biogenic amines, norepinephrine, dopamine, and
serotonin from the cytoplasm into storage vesicles in the adrenergic
nerves of all body tissues.
•
• It was used as centrally acting antihypertensive drug. The drug
has a slow onset, a long duration of action, and effects that persist
for many days after discontinuation. May cause sever depression.
•
• Guanethidine
• Guanethidine blocks the release of stored noradrenaline.
• Effective in hypertension but cause severe side effects (postural
hypotension, diarrhea, nasal congestion, interferes with male sexual
function, etc.), so now little used.