β-blocker drug (Antiadrenegic drug)treatment for IHD

By:Dr.Zharif

β-blocker drug (Antiadrenegic drug)treatment for IHD

Purpose of treatment :

1.Improve quality of life

2.Improve outcome of life

β-blocker drug (Antiadrenegic drug)

General Mechanism of action

block the action of endogenous catecholamines (epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular),

on β-adrenergic receptors, part of the sympathetic nervous system which mediates the fight or flight response.

Action of β adregenic receptor (part of sympathethic nerves system)

-three known types of beta receptor, designated β₁, β₂ and β₃.

a) β₁-Adrenergic receptors are located mainly in the heart and in the kidneys.

b) β₂-Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle.

c) β₃-receptors are located in fat cells

Respiratory system(β2 agonists receptor)

1.bronchodilation

2. Increase Respiratory Secretions

Cardiovascular system

Heart(β1 agonists receptor)

1.Increase heart rate

2.Increase AV conduction

3.Increase BP -rise in systolic and diastolic-NA

-rise in systolic and fall diastolic-Iso

Blood vessel(β2 agonists receptor)

1.Vasodilation

Eye(β2 agonists receptor)

1.Increase secretory activity of ciliary epithelia(caution to patient with glaucoma)

2.Increase Intraocular Pressure

GIT(not clinical significant)

1.Reduced peristalsis

2.Sphincter constricted

Bladder

1.Relaxed detrussor muscle

Uterus

1.Decrease contraction of uterus

Metabolic

1.Increase glycogenolysis- hyperglycaemia,hypelactidemia(β2)

2.Decrease insulin

3.Increase lipolysis

4.Increase lipid profile in plasma

5.Transient hyperkalemia followed by hypokalemia

CNS

Not produce any effect on CNS because poorly penetration in brain (hydrophilic)

Lipophilic drugs

Lipophilic drugs (metoprolol, propranolol, timolol) are

rapidly and completely absorbed from the gastr

ointestinal

tract but are extensively metabolised in the gut wall

and in the liver (first pass effect), so that the

ir oral

bioavailability is low (10–30%). These drugs may accumulate

in patients with reduced hepatic blood flow (i.

e.,

elderly, congestive heart failure, liver cirrhosis). Lipophilic

drugs present short elimination half-lives (1-5 h)

and they easily enter the central nervous sys

tem (CNS),

which may account for a greater incidence of

central

side-effects.

Hydrophilic drugs

Hydrophilic drugs (atenolol, esmolol) are absorbed incompletely

from the gastrointestinal tract and are excreted

unchanged or as active metabolites by the kidney.

They have longer half-lives (6–24 h), and do not interact

with other liver-metabolised drugs. They barely cross the

blood–brain barrier. Elimination half-life is increased

when glomerular filtration rate is reduced (i.e., elderly,

renal insufficiency).

Mechanism of action in IHD

The prevention of the cardiotoxic effects of catecholamines plays

The following mechanisms are also considered:

(a) Antihypertensive action.

Associated with a decrease in cardiac

output, inhibition of the release of renin and production

of angiotensin II, blockade of presynaptic a-adrenoceptors

that increase the release of norepinephrine from

sympathetic nerve terminals and decrease of central

vasomotor activity.1–9

(b) Anti-ischaemic action

b-blockers decrease myocardial oxygen demand by reducing

heart rate, cardiac contractility, and systolic

blood pressure.10 In addition, prolongation of diastole

caused by a reduction in heart rate may increase myocardial

perfusion.

(c) Reduction of renin release and

angiotensin II and aldosterone production by blocking of

b1-adrenoceptors on renal juxtaglomerular cells.

(d)Improvement of left ventricular structure and function,

decreasing ventricular size and increasing ejection fraction.

6–8 b-blockers may improve cardiac function because

they:

(i) reduce heart rate, prolong diastolic filling

and coronary diastolic perfusion time,

(ii) decrease myocardial

oxygen demands,

(iii) improve myocardial energetics

by inhibiting catecholamine-induced release

of free fatty acids from adipose tissue,

(iv) upregulate

b-adrenergic receptors

(v) reduce myocardial

oxidative stress.1;11;12

(e) The antiarrhythmic effect, the

result of direct cardiac electrophysiological effects

(reduced heart rate, decreased spontaneous firing of

ectopic pacemakers, slowed conduction and increased

refractory period of AV node),

reduces the sympathetic

drive and myocardial ischaemia, improves baroreflex

function and prevents catecholamine-induced hypokalemia.

Other mechanisms include:

Inhibition of cardiac apoptosis mediated via the activation of the b-adrenergic

pathway,

Inhibition of platelet aggregation,

Reduction of the mechanical stress imposed on t

he plaque,

Preventing plaque rupture

Resensitization of the b-adrenergic pathway and changes in myocardial gene expression,

i.e., an increase in sarcoplasmic reticulum calcium ATPase, mRNA and a-myosin heavy chain mRNA and a decrease in b-myosin heavy chain mRNA levels.15

exhibit antioxidant properties and inhibit vascular smooth

muscle cell proliferation.

Other Indication

· Hypertension

· Angina

· Mitral valve prolapse

· Cardiac arrhythmia

· Congestive heart failure

· Myocardial infarction

· Glaucoma

· Migraine prophylaxis

· Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism

· Essential tremor

· Phaeochromocytoma, in conjunction with α-blocker

also been used in the following conditions

· Hypertrophic obstructive cardiomyopathy

· Acute dissecting aortic aneurysm

· Marfan syndrome (chronic treatment with propranolol slows progression of aortic dilation and its complications)

· Prevention of variceal bleeding in portal hypertension

· Possible mitigation of hyperhidrosis

· Social anxiety disorder and other anxiety disorders

Adverse effect

Cardiovascular

1.Reduce heart rate,

2.Extreme bradycardia and AV block.

3.Impaired sinusnode function and AV-node conduction

4.Produce cold extremities and Raynaud’s phenomenon and worsen the symptoms in patients with severe peripheral vascular disease.

5.Coronospasm

Metabolic

Hypoglycaemia -In patients with insulin-dependent type I diabetes nonselective

b-blockers mask and selective b-blocker should therefore be preferred at

least in insulin dependent patients

In one study carvedilol decreased the new onset diabetes in

patients with heart failure.

Pulmonary

Increase in airway resistance and are contraindicated in patients with

asthma or bronchospastic chronic obstructive pulmonary

disease.

Central effects

Central effects (fatigue, headache, sleep disturbances,

insomnia and vivid dreams, depression) are less common

with hydrophilic drugs

In some patients the fatigue may

be related to a decrease in blood flow to skeletal muscles;

in other cases, it may be secondary to a central effect.

Sexual dysfunction

Impotence and loss of libido.

Abrupt discontinuation of b-blockers after chronic

treatment can lead to rebound symptoms (i.e., hypertension,

arrhythmias, exacerbated angina)

This increased risk is related with upregulation of badrenoceptors during chronic treatment

Contraindications

1. Asthma,
2. Symptomatic hypotension
3. Bradycardia
4. Severe decompensated heart failure
5. Chronic obstructive lung disease without bronchospastic activity
6. Peripheral vascular disease are not considered as absolute contraindications and high risk patients may obtain a significant benefit from this therapy.
7. Patients with heart failure and bradycardia due to sick sinus node or second or third degree AV-block may benefit from pre-treatment with pacemaker in order to tolerate b-blockers, although this approach has, however, not been formally tested.
8. Diabetes or intermittent lower limb claudication are not absolute contraindications for b-blockers use

I. Non-selective β₁, β₂ adrenergic antagonists

Carteolol + Low 2.5–20 mg once/twice daily

Nadolol 0 Low 40–320 mg once daily

Penbutolol + Moderate 20–80 mg once/twice daily

Pindolol ++ High 10–40 mg twice daily

Propranolol 0 High + 40–180 mg twice daily

Sotalol 0 Low +

Timolol 0 High 5–40 mg twice daily

II. Selective β₁adrenergic antagonists

Acebutolol + Moderate 200–800 mg once/twice daily

Atenolol 0 Low + 25–100 mg once daily

Betaxolol 0 Moderate 5–20 mg once daily

Bisoprolol 0 Moderate 2.5–10 mg once daily

Celiprolol + Moderate 200–600 mg once daily

Esmolol 0 Low Only i.v.

Metoprolol 0 High 50–100 mg once/twice daily

Nevibolol 0 2.5–5 mg once daily

III. α1- and β₁-adrenergic antagonists

Bucindolol + Moderate 25–100 mg twice daily

Carvedilol_ 0 Moderate 3.125–50 mg twice daily

Labetalol + Low 200–800 mg twice daily

ISA: Intrinsic Sympathomimetic Activity;

i.v.: Intravenous administration possible; AMI: Acute Myocardial Infarction; CHF: Chronic Heart Failure.

Acute Myocardial Infarction (AMI)

Intravenous dosing of b-blockers

Drug Loading dose Maintenance dose

Atenolol 5 ю 5 mg Oral, 50–100 mg/day

Esmolol 0.5 mg/kg over 1–5 min 0.05–0.3 mg/kg/min

Labetalol 20 mg in 2 min 2–10 mg/min

Metoprolol 2.5–5 mg i.v. bolus over 2 min; up to three doses Oral, 25–100 mg/12 h

Propranolol 0.15 mg/kg 0.10–0.20 mg/kg/min oral, 80–240 mg/day

Practical guidance on using b-adrenergic blockers in heart failure

Who should receive b-blocker therapy

_ All patients with chronic, stable heart failure

_ Without contraindications (symptomatic hypotension or bradicardia, asthma)

What to promise

Treatment is primarily prophylactic against death and new hospitalisations for cardiovascular reasons. Some patients will

experience improvement of symptoms.

When to start

_ No physical evidence of fluid retention (use diuretics accordingly)

_ Start ACE-I first if not contraindicated

_ In stable patients, in the hospital or in outpatient clinics

_ NYHA class IV/severe CHF patients should be referred for specialist advice

_ Review treatment. Avoid verapamil, diltiazem, antiarrhythmics, non-steroidal anti-inflamatory drugs

Beta-blocker

_ Bisoprolol, carvedilol or metoprolol

Dose

_ Start with a low dose

_ Increase dose slowly. Double dose at not less than 2 weekly intervals

_ Aim for target dose (see above) or, if not tolerated, the highest tolerated dose

Starting dose mg Target dose mg

Bisoprolol 1.25 once daily 10 once daily

Carvedilol 3.125 twice daily 25–50 twice daily

Metoprolol CR/XL 12.5–25 once daily 200 once daily

Monitoring

_ Monitor for evidence of heart failure symptoms, fluid retention, hypotension and bradycardia

_ Instruct patients to weigh themselves daily and to increase their diuretic dose if weight increases

Problem solving

_ Reduce/discontinue b-blocker only if other actions were ineffective to control symptoms/secondary effects

_ Always consider the reintroduction and/or uptitration of the b-blocker when the patient becomes stable

_ Seek specialist advice if in doubt.

Symptomatic hypotension (dizziness, light headedness and/or confusion)

_ Reconsider need for nitrates, calcium channel blockers and other vasodilators

_ If no signs/symptoms of congestion consider reducing diuretic dose

Worsening symptoms/signs (increasing dyspnoea, fatigue, oedema, weight gain)

_ Double dose of diuretic or/and ACE-I.

_ Temporarily reduce the dose of b-blockers if increasing diuretic dose does not work

_ Review patient in 1–2 weeks; if not improved seek specialist advice

_ If serious deterioration halve dose of b-blocker

_ Stop b-blocker (rarely necessary; seek specialist advice)

Bradycardia

_ ECG to exclude heart block

_ Consider pacemaker support if severe bradycardia or AV block or sick sinus node early after starting b-blockers

_ Review need, reduce or discontinue other heart rate slowing drugs, e.g., digoxin, amiodarone, diltiazem

_ Reduce dose of b-blocker. Discontinuation rarely necessary

Severe decompensated heart failure, pulmonary oedema, shock

_ Admit patient to hospital

_ Discontinue b-blocker if inotropic support is needed or symptomatic hypotension/bradycardia is observed

_ If inotropic support is needed, levosimendan may be preferred

Reference
1. Cycle clinical farmacology 6th year RSMU
2.Essential of Medical Pharmacology,KD Tripathi,JAYPEE
3.wikipedia
4.Escardio(Europian Society of Cardiology)