BISOPROLOL PHARMACOLOGICAL AND

CLINICAL DEPICT

UNIVERSITY OF VETERINARY AND ANIMAL SCIENCES, LAHORE

ASADULLAH, R. Ph.1st Semester ,Department of Pharmacology

To explore the clear understanding of clinical , pharmacological value of Beta adrenergic blocking agent against the

pathological condition treated using them with particular emphasis on BISOPROLOL.

Objective & Goal

What is Bisoprolol?

HISTORY AND APPROVAL

PHARMACOLOGICAL PROPERTIES

THERAPEUTIC INDICATION

CONTRAINDICATION /AR

TOXICOLOGICAL STUDY

What is Bisoprolol?

HISTORY AND APPROVAL

PHARMACOLOGICAL PROPERTIES

THERAPEUTIC INDICATION

CONTRAINDICATION /AR

TOXICOLOGICAL STUDY

• Sympatholytic ,synthetic, beta1-Cardioselective adrenoceptor blocking agent mainly label as antihypertensive agent.

• A racemic mixture , S(-) enantiomer is responsible for most of the beta-blocking activity.

• empirical formula is (C18H31NO4)2

• Molecular weight of 766.97, pKa =9.2• white crystalline powder , approximately equally

hydrophilic and lipophilic, and is readily soluble in water, methanol, ethanol, and chloroform.

BISOPROLOL FUMERATE:

Receptor Location Pathway

Beta1 Postsynaptic effector cells, especially heart, lipocytes, brain; presynaptic adrenergic and cholinergic nerve terminals, juxtaglomerular apparatus of renal tubules, ciliary body epithelium

Stimulation of adenylyl cyclase, increased cAMP

Beta2 Postsynaptic effector cells, especially smooth muscle and cardiac muscle

Stimulation of adenylyl cyclase and increased cAMP.

Beta3 Postsynaptic effector cells, especially lipocytes; heart

Stimulation of adenylyl cyclase and increased cAMP1

Mechanism of Action:Beta-blockers antagonise the

effects of sympathetic nerve stimulation or circulating catecholamines

• HeartBeta-blockers bind to beta-

adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes.

Sympathetic influence

chronotropy

Ionotropy

dromotropy

Beta blockers

↓ heart rate

↓ contractility

↓ conduction velocity

Heart

• Kidney: inhibit the release of renin from juxta-glomerular cells and thereby reduce the activity of the renin-angiotensin-aldosterone system.

• Central and peripheral nervous system: Blockade of beta-receptors in the brainstem and of prejunctional beta-receptors in the periphery inhibits the release of NT and decreases sympathetic activity.

What is Bisoprolol?

HISTORY AND APPROVAL

PHARMACOLOGICAL PROPERTIES

THERAPEUTIC INDICATION

CONTRAINDICATION /AR

TOXICOLOGICAL STUDY

Molecule entity approval:July 31, 1992 FDA approved Duramed Pharmaceutical's application for Zebeta Oral Tablets (Bisoprolol Fumarate)

Generic Approval:

October 25, 2002 by Mutual pharma.

What is Bisoprolol?

HISTORY AND APPROVAL

PHARMACOLOGICAL PROPERTIES

THERAPEUTIC INDICATION

CONTRAINDICATION /AR

TOXICOLOGICAL STUDY

PHARMACOKINETICS• Absorption rate: >90%• Bioavailability: 90%• tmax: 2 –3 h• Metabolism:both liver & kidney• Elimination half-life: 10 –12 h• Clearance: 50% unchanged ,50% metabolised• Excretion: approx. 95% renal, 2% faecal• Renal clearance: 140ml /min• Vd: 3.21/kg• protein binding: ~30%• Placental patency: yes• Passage into milk: yes

Pharmacodynamics:1- B1-selecivity:bisoprolol is more selective for Beta 1 in human bronchus

Hence bronchoconstriction drawback of ancient Beta blockers is overwhelmed .

15-time b1-then b2 31-time b1-then b3-In contrast, atenolol and metoprolol exhibited only 5-time selectivity for b1- versus b2- and b3

2 INTRINSIC SYMPATHOMIMETIC ACTIVITY:• ISA is the property of a drug that causes activation of

adrenergic receptors so as to produce effects similar to stimulation of the sympathetic nervous system. Bisoprolol has no partial agonist activity.

3-Membrane-stabilizing activity:• Bisoprolol has no local anesthetic activity in the

dose range relevant for b-receptor blockade.• Some beta-blockers block sodium channels with

properties similar to those of local anesthetics: they block late current preferentially over peak current and the interaction depends critically on the inactivated state of the channe

4- Renin-angiotensin system:Bisoprolol inhibits basal and stimulated renin secretion.The renin released from the cells of the juxtaglomerular

apparatus leads to formation of angiotensin II. Renin release is stimulated by b1-receptors .

5-Antihypertensive effect:• Bisoprolol had a pronounced antihypertensive effect in all

hypertension models investigated. • Bisoprolol reduced the blood pressure accompanied by only a

slight decrease in heart rate. In comparison with bisoprolol, propranolol had a weaker antihypertensive effect even at a considerably higher dose level.

6-Cardioprotection:• Bisoprolol protects the myocardium from ischemia-related

damage. bisoprolol showed only a small negative inotropic effect.

• 7- Lipid metabolisim:• increase in total cholesterol or LDL-cholesterol and a

decrease in HDL-cholesterol are side effect of non selective beta receptor.

• Bisoprolol generally induces no change in the cholesterol• fractions

8- Carbohydrate metabolism.• Owing to its high b1-selectivity, bisoprolol generally has no• influence on the carbohydrate metabolism.• 9- Insulin sensitivity.• b-blockers are speculated to have a negative impact on

certain parameters of glycemic control such as insulin resistance.

• This is an adaptive physiological phenomenon, when the cellular requirement for glucose is jeopardised in conditions of low glucose availability or high demand (such as fasting, starving, stress or hypoglycemia).

SAFETY

• The performed animal experimental investigations indicated for bisoprolol no unexpected or serious side-effects.

• Even at high doses [30 and 100mg/ kg, single oral administration(rats)], the sedative effects ascribed to b-blockers are less marked with bisoprolol than, for instance, with propranolol .

What is Bisoprolol?

HISTORY AND APPROVAL

PHARMACOLOGICAL PROPERTIES

THERAPEUTIC INDICATION

CONTRAINDICATION /AR

TOXICOLOGICAL STUDY

Treatment of Essential Hypertension :Effective in both resting and exercise induced hypertension ,have greater

patient compliance due to after 24 hr administration schedule.

Clinical Uses:

• As a single daily dose, bisoprolol normalised the blood pressure for 24 hours

• controls exercise-induced blood pressure peaks over 24 hours.

• Control blood pressure peaks which may eventually result in cardiovascular complications, are avoided.

• Long-term treatment of arterial hypertension• Regression of left ventricular hypertrophy

• reduce the number of angina pectoris attacks to a minimum, and to increase the patient’s exercise tolerance

• Bisoprolol increases the myocardial perfusion in coronary artery disease. makes the left ventricular function more economical

• After MI, early administration of a b-blocker without ISA reduces the mortality. b-blockers are established in secondary prevention.

Treatment of angina pectoris incoronary heart disease

• In the past b-blockers were contraindicated in CHF due to negative ionotropic effect.

• Recent studies/ clinical trials have demonstrated improvements in symptoms,

• b-blockers without intrinsic sympathetic activity are efficient in reducing mortality

Treatment of Chronic heart faliure

What is Bisoprolol?

HISTORY AND APPROVAL

PHARMACOLOGICAL PROPERTIES

THERAPEUTIC INDICATION

CONTRAINDICATION /AR

TOXICOLOGICAL STUDY

cardiogenic shock, cardiac failure, second or third degree AV block, and marked sinus bradycardia.

Contraindication

Cardiac Failure:depression of myocardial contractility and precipitate more severe

failure. Abrupt cessation:Exacerbation angina pectoris, MI, ventricular arrhythmia Bronchospasm Anesthesia and Major Surgeryanesthetic depress myocardial function,risk of hypotension or

bradychardia Diabetes and HypoglycemiaBeta-blockers may mask symptoms of hypoglycemia, particularly

tachycardia Thyrotoxicosis may mask clinical signs of hyperthyroidism, such as tachycardia.

Special consideration

Adverse Reaction:Potentially Fatal:o AV block, bradycardia.o bronchospasm, o hypoglycaemia, o hypotension, o orthostatic

hypotension, o Rebound phenomenon

Non Fetal:• Increased sweating• Arthralgia• Insomnia, depression• Cough, dysnea• Nausea, vomiting,

diarrhea

What is Bisoprolol?

HISTORY AND APPROVAL

PHARMACOLOGICAL PROPERTIES

THERAPEUTIC INDICATION

CONTRAINDICATION /AR

TOXICOLOGICAL STUDY

TOXICITYThe toxicological studies revealed no irreversible organ damage.

In animal not cytotoxic nor mutagenic. Although it was embryotoxic at higher doses it was not teratogenic nor carcinogenic in the mouse or rat.

Acute toxicity:• On oral administration the LD50 was 734 for the mouse and 1116 mg/kg for

the rat with a follow-up period of 14 days. On intravenous administration values of 127 (mouse), 53 (rat) and 24 (dog) mg/kg were found.

Chronic toxicity:No toxic effects were detected in rats after oral administration for6 months at daily doses of 15, 50 and 150mg/kg. 10 mg/kg wasnot toxic for beagles after daily administration for 6 months.

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