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RECENT AND OLD FACTS ABOUT b-BLOCKERS
BHAVIN DALAL*, AMIT SHAH**, PRANAV DALAL***
*Assistant Professor of Medicine, BJ Med College, Ahmedabad. **Resident of Medicine, MPSMC, Jamnagar. ***Resident of Medicine, NHLMMC, Ahmedabad.
It is not wrong to say that this is an era of b-blockers for faculty of cardiology. b-blockers are marvellous drugs decreasing morbidity and mortality. They are not indicated only for cardiac disorders, but are utilised for variety of other disorders also. There are more than dozen b-blockers available in market, and newer and newer drugs are coming in the same group with advantageous properties. So thorough understanding and cautious use is very much needed.
A. Physiology of b-Receptors
Type of on b-receptors Site Effects stimulation b1
(E=NE)
Heart Increase heart rate (SA node)
Increase conduction velocity
Increase myocardial
contractility Increase oxygen
consumption Increase automaticity
(AV node and muscle)1Adipose tissue Lipolysis b2
(E > NE)
Skeletal muscle2
Skeletal muscle
vasculature
Bronchial
Smooth Muscle
Uterus Liver
Bladder
(detrusor muscle)
Intestinal smooth
muscle PancreasTremors2
Vasodilatation in skeletal
muscle Bronchodilatation
Uterine relaxation (Pregnant)
Hypokalaemia and
hepatic glycogenolysis3
Relaxation
Relaxation
Increase
insulin secretionb3 [4] Brown adipose tissue Heat production b1/b2 [5] Blood 1. Anti inflammatort effect [Inhibition of release of autecoides histamine, (leukotrienes) from mast cells]
2. Platelet aggregation
B. Effects of b-Receptor Stimulation-
E Catecholamines (1st messenger transmitter) C F Attachment over b-receptor causes b-receptor stimulation C Stimulation of G-protein M Stimulation of adenyl cyclase I Increase Cyclic AMP (2nd messenger transmitter) C F Stimulation of protein kinase-A • Cardiac effects; • Bronchial dilatation
• Skeletal vasodilatation
• Release of glucose and potassium from liver
C. Classification of b-blockers
Drugs Partial agonist
(ISA)c (PACO)Membrane Stabilizing Effect
(Quinidine like activity)Division-1 Non selective (b1+b2)blockers Group I Oxprenolol + + Group II Propranolol — + Group III Pindolol + — Group IV — — Sotalol Timolol Nadolol Division-II b1 selective blockers
[ b]Group I Acebutolol + + Group IV Atenolol — — (AMBE) Metoprolol
Bisoprolol
Betaxolol
Esmolol
Division III Non selective
b-blockers + alpha 1 blockers
Group III Labetalol
Carvedilol [d]+ —
a. May be used in the management of arrhythmia.
b. b1 selectivity means 50 times more of the blocker is required to achieve the same blockade of b2 receptor as of the b1 receptor. Therefore as the dose rises the selectivity is reduced.[7,8]
c. Less chances of bradycardia, less effects on serum lipids and better tolerated in patients of PVD.[9] little or no effect on resting HR. Not much useful in thyrotoxicosis, IHSS, aortic dissection and tachyarrhythmias.
d. Compare to the labetolol carvedilol has a ratio of alpha 1 to b-blockers of 1:10. On milligram to milligram basis carvedilol is about 2 to 4 times more potent than propranolol. Carvedilol has also anti oxidant and anti proliferative activities.[9]
e. Celiprolol has antagonistic action for B1 and partial agonistic activity for b2.[10]
D. Pharmacokinetics
Absorption : All the drugs are well absorbed after oral administration. Peak concentration occurs 1 to 3 hours after ingestion.
Bioavailability : Propranolol undergoes extensive hepatic metabolism. Its bioavailability is very low.
Duration and clearance : Most of the b-blockers have half-life in the range of 2-5 hours, except esmolol has half life of 8-10 minutes and nadolol has longest half life of 24 hrs. Lipophilic drugs (Propranolol, Metoprolol) have low plasma half life, while hydrophilic drugs (Atenolol, Acebu tolol, Bisoprolol) have long plasma half life. Hepatic failure prolongs the half life of Lipophilic drugs, while renal failure prolongs the half life of hydrophilic drugs. Atenolol achieves peak concentration within 2-4 hours after oral ingestion.
E. Therapeutic Uses [10]
1. Cardiac Uses
(a) Conditions
* Angina pectoris
* Hypertension
* Heart failure
* Neuro circulatory asthenia
* Prolonged QT syndrome
* Reversal of LVH
* Ventricular outflow obst. (Fallot’s tetrology, HOCM)
* Myocardial infarction
* Congestive Cardiomyopathy
* Tachyarrhythmias
* Mitral stenosis and MVP
* Digitalis intoxication
* Arotic dissection
Selectivity Partial agonistic
activityLipid solubility Half life (hrs) Doses (mg) Propranolol None No High 3.5-6 80-480 Labetelol None Yes Moderate 5 600-1200
2 mg/min ivCarvedilol None No — 7-10 3.125-50 Sotalol None No Low 12 — Timolol None No Moderate 4-5 — Metoprolol b1 No Moderate 3-4 100-200
5-15 mg/min ivAtenolol b1 No Low 6-9 50-100 Bisoprolol b No Low 9-12 — Celiprolol b1 Yes — 4-5 100-200 Esmolol b1 No Low 10 min 500
50 mg/min iv
(b) Mechanisms of usefulness of b-blockers in cardiac conditions
* Reduces myocardial O2 demand by reducing heart rate and force of contraction.
* Longer diastolic filling time increases coronary perfusion time.
* Reduces peripheral resistance.[11]
* Decreases the slope of phase 4 depolarisation as well as spontaneous firing rate of sinus or ectopic pacemakers.[10]
* Reduces cardiac output.
* Reduces plasma renin.[11]
(c) Doses
Usual doses are mentioned in Table. Usually b-blockers are started in low dose and increased till maximum tolerable doses. Doses should be reduced if,
* SBP < 100 mm of Hg
* HR < 60/min.
* Basal rales > 10 cm from diaphragm
* PR interval > 24 m sec.
Myocardial infarction [12]
Early (within 6 hrs (or at most 12 h) of onset) use reduces morbidity and mortality. (iv for 24 hrs then oral for 3-4 weeks).
—Cardiac work is reduced, resulting in a reduction in infarct size by upto 25% and protection against cardiac rupture. b-blockers reduce mortality by 25%.—Metoprolol and atenolol are equally approved. Metoprolol 5 mg iv every 5 minutely for maximum of 3 doses followed by oral administration.—Contraindication to early use include bradycardia, hypotension and LVF.
Late use for secondary prevention of another myocardial infarction. The drug is started between 4 days and 4 weeks after the onset of infarct and is continued for at least 2 years.
Hypertension
- b-lockers decrease SCD. Little interference with homeostatic reflexes. Labetelol is used in hypertensive emergencies.
- Mechanisms explaining usefulness of b-blockers as antihypertensive are (1) decrease cardiac output (2) decrease NE release at postganglionic sympathetic nerve endings (3) decrease renin secretion (4) suppressed central sympathetic output.
Congestive cardiomyopathy [ 13]
Metoprolol and Carvedilol, could improve symptoms, ventricular function and functional capacity while reducing the need for hospitalization.
Trials of carvedilol showed mortality benefit in patients with NYHA II-III heart failure when the drug was used in addition to diuretics, angiotensin-converting enzyme inhibitors and digoxin.
Possible mechanism for b-blocker benefit in chronic heart failure include (1) an up regulation of impaired b-receptors expression in the heart (2) improvement in impaired baroreceptor functioning that can inhibit excess sympathetic outflow (3) decreased NA (4) decreased cardiotoxic effects of catecholamines.
2. Endocrine Uses
Thyrotoxicosis
b-blockers control tremors, palpitation, tachycardias and nervousness. These effects presumably related to adenoreceptor and perhaps to the inhibition of conversion of T4 to T3. Propranolol can be used with thyroid strom.b-blockers prolongs time of ankle jerk relaxation which misguides if the reflex is being relied on diagnosis and treatment of hypothyroidism.
Phaeochromocytoma
Blockade of b-agonist effects of circulating catecholamines is useful. Always used in combination with alpha-adrenoreceptor blocker. Only small doses of a b-blocker are required.
3. CNS Uses
*b-blockers are used in anxiety with somatic symptoms.
*b-blockers can be used in alcohol and opioid withdrawal syndrome, SAH, essential tremor.
*b-blockers can be used in migraine prophylaxis. Reduces recurrence of migraine by 60% of patients. If no response within 4-6 weeks, drug should be discontinued.
4. Other Uses
Glaucoma
b-blockers reduce the intra-ocular pressure by reducing production of the aqueous humour by the ciliary body which is physiologically activated by cyclic AMP. Timolol is usually used, locally in doses of 1 mg and systemically in doses of 10-60 mg/day.
Portal hypertension
Reduces the chance of variceal bleeding. Reduces portal venous pressure by splanchnic vessel vasoconstriction and by reducing portal blood flow by reducing cardiac output. Dose is adjusted to decrease the heart rate by 25%.
F. Concomitant Disease and Choice of b-Blockers
1.Respiratory disease : Cardio selective b-blockers are used.
2.Cardio vascular disease : In sick sinus syndrome b-blockers are dangerous.
3.Active peripheral vascular disease : e.g. Raynaud’s phenomena - b-blockers are relatively contra-indicated.
4.Renal disease : b-blockers may reduce GFR. They are excreted by kidney so in renal failure doses are changed.
5.Liver disease : Avoid b-blockers with high first pass metabolism like propranolol.
6.Pregnancy : It may depress vitals of foetus and causes uterine artery vasoconstriction. Labetolol and Atenolol can be used. Alpha methyldopa preferred.
7.Surgical : It is prophylactically used to prevent anaesthetic tachycardia.
8.Smokers : b-blockers are less effective in reducing coronary events.
9.Diabetes mellitus : Non selective b-blockers causes (1) impairment of counter regulatory metabolic responses during hypoglycaemia and (2) masking of symptoms of hypoglycaemia. So cardio selective agents are preferred.
G. Adverse Effects
1.CNS : Sedation, sleep disturbances, depression, psychotic reactions, nightmares, impotence, lethargy, headache.
2.CVS : Bradycardia, congestive cardiac failure, hypotension, hypertension in phaeochromocytoma (due to preexisting alpha effect), AV nodal block, decrease in exercise tolerance (due to decreased cardiac output).
3.Others : Bronchospasm, rash, fever, drug allergy, hyperkalaemia in diabetics and uraemia, hyperuricaemia, decrease HDL/LDL ratio.
4.Rare side effects : uveitis, sclerosing cholangitis, peritonitis, purpura, agranulocytosis.[14]
5.Abrupt withdrawal syndrome : Abrupt withdrawal can cause exacerbation of MI angina, arrhythmias and SMI. So patients on chronic b-blockers therapy should be tapered of this therapy slowly.
OVERDOSE
Overdose including self-poisoning, causes bradycardia, heart block, hypotension and low output shock. Death is more likely with agents having membrane stabilizing action. Bronchoconstriction can be severe, even fatal.
Rational treatment includes:
1.Atropine (1-2 mg iv as 1 or 2 bolus doses) to eliminate the unopposed vagal activity that contributes to bradycardia. For long lasting bradycardia TPI can be done.
2.Glucagon, which has cardiac inotropic and chronotropic actions independent of the b-adrenoceptors (dose 5-10 mg iv followed by infusion of 1-10 mg/hr) to be used at the outset in severe cases.[15]
3.If there is no response, iv injection or infusion of a b-adrenoceptor agonist is used, e.g. isoprenaline (4 mcg/min, increasing at 1-3 min intervals until the heart rate is 50-70 beats/min).
4.Other sympathomimetics may be used as judgement counsels, according to the desired receptor agonist actions (b1, b2, alpha) required by the clinical condition, e.g. dobutamine, dopamine, dopexamine, noradrenaline, adrenaline.
5.For bronchoconstriction salbutamol may be used.
REFERENCES
1.Laurence DR. Adrenergic mechanism, Clinical Pharmacology, 8th edition. 1997; Pg. 414
2.Laurence DR. Adrenergic mechanism, Clinical Pharmacology. Pg. 414.
3.Laurence DR. Adrenergic mechanism, Clinical Pharmacology. Pg. 414.
4Lewis Landsberg. Harrison’s principle of internal medicine, 13th edition. Pg. 416.
5.Laurence DR. Adrenergic mechanism, Clinical Pharmacology. Pg. 414.
6.Laurence DR. Adrenergic mechanism, Clinical Pharmacology. Pg. 440.
7.Laurence DR. Adrenergic mechanism, Clinical Pharmacology. Pg. 446.
8.Hurst’s the Leen, Campaign Handbook, 9th edition. Pg. 695.
9.Hurst’s the Leen, Campaign Handbook, 9th edition. Pg. 696.
10.Hurst’s the Leen, Campaign Handbook, 9th edition. Pg. 698.
11.Hurst’s the Leen, Campaign Handbook, 9th edition. Pg. 697.
12.Laurence DR. Adrenergic mechanism, Clinical Pharmacology. Pg. 439.
13.Hurst’s the Leen, Campaign Handbook, 9th edition. Pg. 699.
14.Hurst’s the Leen, Campaign Handbook, 9th edition. Pg. 701.
15.Laurence DR. Adrenergic mechanism, Clinical Pharmacology. Pg. 442.
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