Bisoprolol

Structural formula
	Structural formula without stereoisomerism
General
Non-proprietary name	Bisoprolol
other names	( RS ) -1- [4- (2-isopropoxyethoxymethyl) phenoxy] -3-isopropylamino-2-propanol ( IUPAC )
Molecular formula	C 18 H 31 NO 4
External identifiers / databases
EC number	613-980-5
ECHA InfoCard	100.108.941
PubChem	2405
ChemSpider	2312
DrugBank	DB00612
Wikidata	Q412515
Drug information
ATC code	C07 AB07
Drug class	β-receptor blockers
Mechanism of action	selective blockade of β 1 receptors
properties
Molar mass	325.45 g · mol -1
Physical state	firmly
Melting point	100 ° C (as hemifumarate)
solubility	Water: 2.24 g l −1 (25 ° C)
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Caution
H and P phrases	H: 302
	P: no P-phrases
Toxicological data	100 mg kg −1 ( LD 50 , mouse , oral ) ; 0.143 mg kg −1 ( TD Lo , human , oral ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Bisoprolol is a drug from the group of selective β ₁ -adrenoreceptor blockers ( beta blockers for short ). It is used to treat high blood pressure , angina pectoris , chronic heart failure and tachycardia . From a chemical point of view, it is a phenol ether , see adjacent formula.

Clinical information

Application areas (indications)

Bisoprolol is used to treat arterial hypertension, angina pectoris and chronic heart failure. To improve compliance and to simplify therapy, bisoprolol is available in a fixed combination with the diuretic hydrochlorothiazide and the calcium antagonist amlodipine in different strengths.

Contraindications

The drug should not be taken in the case of slow heart arrhythmias ( bradycardia ), the use of MAO inhibitors , hypotension , severe heart failure with incipient cardiogenic shock and diabetes mellitus .

In bronchial asthma or other chronic obstructive pulmonary dysfunction, the drug should be used with caution.

Adverse effects (side effects)

Bisoprolol can cause numerous side effects. Possible side effects are classified according to their frequency.

Common side effects: drop in blood pressure , drop in heart rate ( bradycardia ), loss of appetite , nausea , vomiting , circulatory disorders , fatigue , headache , confusion , dizziness , increased sweating , mood changes , hallucinations and delusions, sleep disorders , muscle spasms and bronchospasm

Uncommon side effects: blurred vision, dry eyes and conjunctivitis

Rare side effects: exacerbation of psoriasis , disorder of libido and erectile dysfunction , joint inflammation, hair loss and ringing in the ears

Pharmacological properties

Bisoprolol is a long-acting β-blocker that preferentially binds to β ₁ -adrenoreceptors . It lowers the heart rate and has a negative inotropic effect . Because of its lipophilicity , bisoprolol also has a central nervous effect. Like carvedilol , it does not display intrinsic sympathomimetic activity ( ISA ).

After oral administration, the β-blocker is rapidly absorbed with a bioavailability of around 90%. The consumption of doses in the range from 10 to 100 mg lead to the maximum plasma concentration after about 3 hours. The half-life is 10 to 11 hours, with half of the substance being eliminated unchanged via the kidneys, the rest being eliminated via degradation in the liver. The active ingredient is used as a racemate , the enantiomers of active ingredients usually having different pharmacological properties and effects.

Market importance

With around 515 million DDD , bisoprolol was the second most frequently used β-blocker in Germany after metoprolol in 2007. Overall, the number of prescribed doses (according to DDD) of beta blockers almost tripled between 1998 and 2007.

chemistry

synthesis

The synthesis of bisoprolol can take place in a three-step reaction.
In the first step , the two alcohols 1 and 2 condense to form the ether 3 . The second step is a nucleophilic substitution that creates the oxirane 4 . This then reacts in the last step of the reaction - the ring opening of the oxirane - with isopropylamine to form bisoprolol ( 5 ):

Stereoisomerism

The compound is chiral and is used as a racemate ; i.e., used as a 1: 1 mixture of the two enantiomers . The active stereoisomer ( eutomer ) is the ( S ) form. The table shows both stereoisomers. They differ in the position of the hydrogen atom, which in this representation either goes into the plane of the drawing or protrudes out of the plane of the drawing :

Bisoprolol stereoisomers
( S ) -enantiomer	( R ) -enantiomer

Trade names

Monopreparations

Bilol (CH), Bisacardiol (A), Bisocor (A), Bisoprolol (D), Concor (D, A, CH), Concor COR (D, A), Rivacor (A), numerous generics (D, A, CH )

Combination preparations

In combination with hydrochlorothiazide : Concor plus (D, CH), Bilol comp (CH), Lodoz (CH), Rivacor plus (A), generics (D, A, CH);

In combination with amlodipine : bisodipine (D)

Individual evidence

↑ ^a ^b ^c Entry on bisoprolol in the ChemIDplus database of the United States National Library of Medicine (NLM) .
↑ ^a ^b data sheet bisoprolol hemifumarate salt from Sigma-Aldrich , accessed on March 13, 2011 ( PDF ).
^ Entry on bisoprolol in the DrugBank of the University of Alberta .
^ Entry on bisoprolol by Cora Health, accessed June 25, 2018.
↑ Beate Blümer-Schwinum, Hermann Hager, Franz von Bruchhausen, E. Nuremberg, Peter Surmann: Hagers Handbook of Pharmaceutical Practice, Volume 7, Materials A – D. 5th edition, Birkhäuser / Sprinter, 1995, ISBN 978-3-540-52688-9 , pp. 497-499.
↑ Ariëns, EJ. (1984): Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology . In: Eur J Clin Pharmacol . 26 (2); 663-668; PMID 6092093 .
^ Dieter Paffrath, Ulrich Schwabe: Drug Ordinance Report 2008: Current data, costs, trends and comments. Springer, 2008, ISBN 978-3-540-69218-8 , p. 439.
↑ Axel Kleemann ; Jürgen Engel; Bernhard Kutscher; Dietmar Reichert: Pharmaceutical Substances - Syntheses, Patents and Applications of the most relevant APIs. , 5th edition, Georg Thieme Verlag KG, 2009, ISBN 978-3-13-558405-8 , pp. 162-163.
↑ Joni Agustiana, Azlina Harun Kamaruddina, Subhash Bhatiaa: Single enantiomeric -blockers — The existing technologies , Process Biochemistry 45 ( 2010 ) 1587-1604, doi: 10.1016 / j.procbio.2010.06.022 .

[ChemIDplus-1] Entry on bisoprolol in the ChemIDplus database of the United States National Library of Medicine (NLM) .

[Sigma-2] ta sheet bisoprolol hemifumarate salt from Sigma-Aldrich , accessed on March 13, 2011 ( PDF ).

[3] Entry on bisoprolol in the DrugBank of the University of Alberta .

[4] Entry on bisoprolol by Cora Health, accessed June 25, 2018.

[hager-5] Beate Blümer-Schwinum, Hermann Hager, Franz von Bruchhausen, E. Nuremberg, Peter Surmann: Hagers Handbook of Pharmaceutical Practice, Volume 7, Materials A – D. 5th edition, Birkhäuser / Sprinter, 1995, ISBN 978-3-540-52688-9 , pp. 497-499.

[Ariëns-6] Ariëns, EJ. (1984): Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology . In: Eur J Clin Pharmacol . 26 (2); 663-668; PMID 6092093 .

[7] Dieter Paffrath, Ulrich Schwabe: Drug Ordinance Report 2008: Current data, costs, trends and comments. Springer, 2008, ISBN 978-3-540-69218-8 , p. 439.

[Kleemann-8] Axel Kleemann ; Jürgen Engel; Bernhard Kutscher; Dietmar Reichert: Pharmaceutical Substances - Syntheses, Patents and Applications of the most relevant APIs. , 5th edition, Georg Thieme Verlag KG, 2009, ISBN 978-3-13-558405-8 , pp. 162-163.

[Agustiana-9] Joni Agustiana, Azlina Harun Kamaruddina, Subhash Bhatiaa: Single enantiomeric -blockers — The existing technologies , Process Biochemistry 45 ( 2010 ) 1587-1604, doi: 10.1016 / j.procbio.2010.06.022 .