2. BISOPROLOL
PHARMACOLOGICAL AND CLINICAL
DEPICT
UNIVERSITY OF VETERINARY AND ANIMAL
SCIENCES, LAHORE
ASADULLAH, R. Ph.
1st Semester ,Department of Pharmacology

3. Objective & Goal
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.

4. What is Bisoprolol?
HISTORY AND APPROVAL
PHARMACOLOGICAL PROPERTIES
THERAPEUTIC INDICATION
CONTRAINDICATION /AR
TOXICOLOGICAL STUDY

5. What is Bisoprolol?
HISTORY AND APPROVAL
PHARMACOLOGICAL PROPERTIES
THERAPEUTIC INDICATION
CONTRAINDICATION /AR
TOXICOLOGICAL STUDY

6. BISOPROLOL FUMERATE:
• 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.

7. Receptor Location Pathway
Beta1 Postsynaptic effector cells, especially heart, Stimulation of adenylyl
lipocytes, brain; presynaptic adrenergic and cyclase, increased cAMP
cholinergic nerve terminals, juxtaglomerular
apparatus of renal tubules, ciliary body
epithelium
Beta2 Postsynaptic effector cells, especially smooth Stimulation of adenylyl
muscle and cardiac muscle cyclase and increased
cAMP.
Beta3 Postsynaptic effector cells, especially lipocytes; Stimulation of adenylyl
heart cyclase and increased
cAMP1

10. Heart
Mechanism of Action:
Beta-blockers antagonise the
Sympathetic Beta
effects of sympathetic influence blockers
nerve stimulation or
circulating catecholamines
chronotropy ↓ heart rate
• Heart
Beta-blockers bind to beta-
adrenoceptors located in Ionotropy ↓ contractility
cardiac nodal tissue, the
conducting system, and
contracting myocytes. ↓ conduction
dromotropy
velocity

11. • 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.

12. What is Bisoprolol?
HISTORY AND APPROVAL
PHARMACOLOGICAL PROPERTIES
THERAPEUTIC INDICATION
CONTRAINDICATION /AR
TOXICOLOGICAL STUDY

13. 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.

14. What is Bisoprolol?
HISTORY AND APPROVAL
PHARMACOLOGICAL PROPERTIES
THERAPEUTIC INDICATION
CONTRAINDICATION /AR
TOXICOLOGICAL STUDY

15. 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

16. 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

17. 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

18. 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.

19. 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

20. 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).

21. 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 .

22. What is Bisoprolol?
HISTORY AND APPROVAL
PHARMACOLOGICAL PROPERTIES
THERAPEUTIC INDICATION
CONTRAINDICATION /AR
TOXICOLOGICAL STUDY

23. Clinical Uses:
 Treatment of Essential Hypertension :
Effective in both resting and exercise induced hypertension ,have greater
patient compliance due to after 24 hr administration schedule.

24. • 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

25. Treatment of angina pectoris in
coronary heart disease
• 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.

26. Treatment of Chronic heart faliure
• 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

27. What is Bisoprolol?
HISTORY AND APPROVAL
PHARMACOLOGICAL PROPERTIES
THERAPEUTIC INDICATION
CONTRAINDICATION /AR
TOXICOLOGICAL STUDY

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

29. Special consideration
 Cardiac Failure:
depression of myocardial contractility and precipitate more severe
failure.
 Abrupt cessation:
Exacerbation angina pectoris, MI, ventricular arrhythmia
 Bronchospasm
 Anesthesia and Major Surgery
anesthetic depress myocardial function,risk of hypotension or
bradychardia
 Diabetes and Hypoglycemia
Beta-blockers may mask symptoms of hypoglycemia, particularly
tachycardia
 Thyrotoxicosis
 may mask clinical signs of hyperthyroidism, such as tachycardia.

30. Adverse Reaction:
Potentially Fatal: Non Fetal:
o AV block, bradycardia. • Increased sweating
o bronchospasm, • Arthralgia
o hypoglycaemia, • Insomnia, depression
o hypotension, • Cough, dysnea
o orthostatic • Nausea, vomiting,
hypotension, diarrhea
o Rebound phenomenon

31. What is Bisoprolol?
HISTORY AND APPROVAL
PHARMACOLOGICAL PROPERTIES
THERAPEUTIC INDICATION
CONTRAINDICATION /AR
TOXICOLOGICAL STUDY

32. TOXICITY
The 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 for
6 months at daily doses of 15, 50 and 150mg/kg. 10 mg/kg was
not toxic for beagles after daily administration for 6 months.

34. Success is a journey not destination and there is no
final destination in improvement journey