MODE OF ACTION

• Block the action of endogenous catecholamines (Adrenaline) & (NA) in particular,

• On B-adrenergic receptros, part of sympathetic nervous system

• There are three known types of beta receptor, B1, B2, & B3 receptors

BETA BLOCKERS

β-ADRENERGIC RECEPTORS

• β1-adrenergic receptors are located mainly in the heart & in the kidney

• β2-adrenergic receptors are located mainly in the lungs, GIT, liver, uterus, vascular smooth muscle, & skeletal muscle

• β3-adrenergic receptors are located in fat cells

β STIMULATION

• Stimulation of β1 receptors at HEART induces a positive chronotropic & inotropic effect on the heart and increases cardiac conduction velocity & automaticity.

• Stimulation of β1 receptors in the kidney causes renin release

• Stimulation of β2 receptors induces smooth muscle relaxation, induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle

• Stimulation of β3 receptor induces lipolysis.

• Differ in intrinsic sympathomimetic activity, in CNS effects, and in pharmacokinetics

• Beta 1 selective (Cardioselective) – Acebutalol, Atenolol, Bisoprolol, Esmolol, Metoprolol

• Non-selective ( Beta 1 & 2) – Nadolol, Penbutolol, Pindolol, Propranolol, Timolol

BETA ANTAGONISTS

SELECTIVE BETA 1 ANTAGONISTS

• Acebutalol• Atenolol• Metoprolol• Esmolol (short half life)

– Selectively block beta 1 (Cardioselective)– To lower B.P. in hypertension– Increase exercise tolerance in angina– Also useful for patient with diabetic hypertensive

patients who are receiving insulin/oral hypoglycemic agents

INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA)

• Some beta blockers (e.g. oxprenolol, pindolol, penbutolol, and acebutolol) exhibit intrinsic sympathomimetic activity (ISA)

• These agents are capable of exerting low level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist.

INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA)

• Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound such norepinephrine)

ANTAGONISTS WITH PARTIAL AGONIST ACTIONS

• Pindolol• Acebutalol• Not pure blockers, weakly stimulate both beta

1 & 2 (intrinsic sympathomimetic activity)• Decreased metabolic effects• Uses : hypertension with moderate

bradycardia/ diabetic patients

BETA ANTAGONISTS WITH ADDITIONAL CVS EFFECTS – (3rd GENERATION BETA BLOCKERS)

1. Alpha 1 blockade : Labetalol, Carvedilol, Bucindolol, Bevantolol, Nipradilol

2. Increased production of NO : Celiprolol, Nebivolol, Carteolol, Bopindolol, Nipradolol

3. Beta 2 agonist properties : Celiprolol, Carteolol, Bopindolol

4. Calcium entry blockade : Carvedilol, Betaxolol, Bevantolol

5. Opening of K channels : Tilisolol6. Antioxidant action : Carvedilol

PHARMACOLOGICAL DIFFERENCES

• Agents with intrinsic sympathomimetic action (ISA)– Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol,

pindolol, labetalol• Agents with greater aqueous solubility– Atenolol, celiprolol, nadolol, sotalol

• Agents with membrane stabilizing effect– Acebutolol, betaxolol, pindolol, propranolol

• Agents with antioxidant effect– Carvedilol, nebivolol

INDICATION DIFFERENCES

• Agents specifically indicated for cardiac arrhythmia– Esmolol, sotalol, landiolol

• Agents specifically indicated for congestive heart failure– Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol

• Agents specifically indicated for glaucoma– Betaxolol, carteolol, levobunolol, metipranolol, timolol

• Agents specifically indiciated for myocardial infarction– Atenolol, metoprolol, propranolol

• Agents specifically indicated for migraine prophylaxis– Timolol, propranolol

BETA BLOCKERS IN CVS

1. Angina pectoris2. Myocardial infarction3. Arrhythmias4. Hypertension5. Heart failure

HYPERTENSION• The primary antihypertensive mechanism of beta blockers is

unclear but it may involve reduction in cardiac output (due to negative chronotropic and inotropic effects)

• It may also be due to reduction in renin release from the kidneys, and

• A central nervous system effect to reduce sympathetic activity (for those β-blockers that do cross the blood-brain barrier, e.g. Propranolol)

• Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone system with a resultant decrease in blood pressure due to decreased sodium and water retention

Reduced C.O.Decrease sympathetic outflowReduce renin

ANGINA

• Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand

Reduced workloadDecrease C.O.

ARRHYTHMIAS

• The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade – resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refraction periods

• Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade

ADVERSE EFFECTS

1. Bronchoconstriction (contraindicated in bronchial asthma)2. Arrhythmias (beta blockers should be stopped gradually),

bradycardia, cardiac depression3. Cold extremities, Insomnia, depression, fatigue, Sexual

impairment4. Disturbance in metabolism (care in diabetics)5. Drug interactions – Cimetidine, Furosemide,

Chlorpromazine may potentiate anti-hypertensive effects- Barbiturates, Phenytoin, Rifampin can reduce its effects

DRUG INTERACTIONS WITH BETA BLOCKERS

• Antidiabetic medications: beta blockers may mask signs and symptoms of hypoglycemia

• Calcium channel blockers: (verapamil or diltiazem) has resulted in rare conduction disturbances

• Cimetidine: Cimetidine may increase plasma concentration by 30% in patients receiving beta blocker

• ClonidineL potentiates the blood pressure and heart-rate lowering effects of beta blockers. If combination therapy with clonidine and a beta blocker is terminated, the beta blocker should be discontinued first

• Digoxin: The concentration of digoxin is increased by 15% when used in combination with beta blockers

• Rifampin: Rifampin causes a reduction in the plasma concentration by 770% in patients receiving beta blocker

• Other inhibitors of cytochrome P450 2D6 isoenzyme (fluoxetine, paroxetine, quinidine) May increase plasma concentration in patients receiving beta blocker.

B BLOCKERS AGENT

• Non-selective : Propranolol

• Partial agonist : Acebutalol, Pindolol

• Selective : Acebutalol, Atenolol, Metoprolol

• Both Antagonist a & B : Labetolol, Carvidelol

PROPRANOLOL

• Non selective• It has little intrinsic sympathomimetics action (ISA)

but has strong membrane stabilizing activity• Pharmacological Actions:

1. CVS – diminishes C.O. (negative inotropic chronotropic effects). Directly depress SA & AV nodes

• Beta 1 blockade – reduced C.O., world load, oxygen consumption (useful for treatment of angina)

PROPRANOLOL

2. Periphrical vasoconstriction – blockade of beta 2 mediated vasodilation– Reduced C.O. – decreased B.P. reflex peripheral vasoconstriction

3. Bronchoconstriction – blocking beta 2 receptors ( can precipitate respiratory crisis in asthma/COPD patients)

4. Disturbances in glucose metabolism – beta blockade – decreased glycogenolysis and decrease glucagon secretion. (care in diabetic patient, beta blockers may also attenuate normal physiological responses to hypoglycemia)

5. Increased Na+ retention-due low perfusion to kidney, result Na+ and water retention, leads to increased BP

PHARMACOKINETICS

• Well absorbed, high lipid solubility.

• Propranolol – first pass effect; 25% reached systemic circulation

• CNS effects – present with propranolol, less with Nadolol, Atenolol

THERAPEUTIC USES

1. Hypertension – lowers B.P. by decreasing C.O., reduction in renin release, central – reduce sympathetic action

2. Glaucoma – effective in diminishing intraocular pressure – decrease secretion of aqueous humor from ciliary body

3. Migraine prophylaxis – blockade of catecholamine-induced vasodilation in brain vasculature. Reduced incidence and severity of migraine

4. Hyperthyroidism-effective in blunting the sympathetic stimulation and also useful for the storm (prevent cardiac arrhythmias)

THERAPEUTIC USES

5. Angina Pectoris – decreases oxygen requirement of heart muscle – reduced chest pain on exertion (useful in chronic stable angina)

6. Myocardial Infarction-protective effect on myocardium, reduces infarct size, and hastens recovery

7. Arrhythmias – depress automaticity, prolong AV conduction, decrease HR and contractility

8. Congestive heart failure (worsen in acute heart failure but improve life quality in chronic cases)

9. Anxiety-to control somatic symptoms

ADVERSE EFFECTS

1. Bronchoconstriction – CI for asthma2. Arrythmias – never stopped abruptly.

Tappered down in 1 week slowly. Long term treatment upregulated receptors

3. Nightmares – cross BBB

ATENOLOL

• Is a selective β1 receptor antagonist• Introduced in 1976, atenolol was developed as

a replacement for propranolol in the treatment of hypertension

• Unlike propranolol, atenolol does not pass through the blood-brain barrier thus avoiding various central nervous system side effects

ATENOLOL

• Is one of the most widely used β -blockers in the United Kingdom and was once the first-line treatment for hypertension

• The role for β -blockers in hypertension was downgraded in June 2006 in the United Kingdom to fourth-line, as they perform less appropriately or effectively than newer drugs, particularly in the elderly

• Some evidence suggests that even in normal doses that most frequently used B-blockers carry an unacceptable risk of provoking type 2 DM

ATENOLOL-PHARMACOKINETICS

• The mean elimination half life is 6 hours. However the action of the usual oral dose of 25 to 100 mg lasts over a period of 24 hours. OD Dose

• Atenolol is a hydrophilic drug. The concentration found in brain tissue is approximately 15% of the plasma concentration only. The drug crosses the placenta barrier freely. In the milk of breastfeeding mothers.

• Is almost exclusively eliminated renally and is well removable by dialysis

METOPROLOL

• The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate (where 100mg metoprolol tartrate corresponds to 95mg metoprolol succinate)

• The tartrate is an immediate-release and the succinate is an extended-release

• Genetic Polymorphism CYP2D6 variants

METOPROLOL

• Beta 1 Selective• Moderately lipophilic• With weak membrane stabilizing activity• Short half life, therefore must be taken at least

twice daily or as a slow-release preparation• Decrease heart rate, contractility and cardiac

output, therefore decreasing blood pressure

CARVIDELOL

• Non-selective beta blocker/ alpha-1 blocker indicated in the treatment of mild to moderate congestive heart failure (CHF)

• As an adjunct to conventional treatments (ACE inhibitors and diuretics)

• The use of carvedilol has been shown to provide additional morbidity and mortality benefits in HEART FAILURE

LABETALOL

• Both alpha and beta blocker• Actions: reduce B.P. esp. pregnancy induced

hypertension (PIH) and Pre Eclampsia• Used in hypertensive emergency• Does not alter serum lipid/ blood glucose

level, does not cause reflex tachycardia• Adverse effects: orthostatic hypotension,

dizziness

BETA BLOCKERS REVIEW

• For more than 3 decades, beta-blockers have been widely used in the treatment of hypertension and are still recommended as first-line agents by national and international guidelines

• Recent meta-analyses indicate that, in patients with uncomplicated hypertension, compared with other antihypertensive agents, first-line therapy with beta-blockers was associated with an increased risk of stroke especially in the elderly

• With no benefit for the end points of all-cause mortality, cardiovascular morbidity, and mortality.

BETA BLOCKERS REVIEW

• Beta blockers (sometimes written as B-blockers) are a class of drugs used for various indications, but particularly for the management of cardiac arrhytmias and cardioprotection after myocardial infarction

• Whilst once 1st line treatment for hypertension, their role was downgraded in June 2006 in the UK to 4th line as they perform less well than other drugs

• Particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers at usual dose carry an unacceptable risk of provoking type 2 diabetes.

• It is worthwhile to note that the British Hypertension Society has withdrawn its endorsement of beta-blockers as first-line treatment for patients with uncomplicated hypertension.