Classification of -adrenergic receptor antagonists

B-adrenergic receptor antagonists or B-receptor blockers are the drugs that selectively and
competitively block the actions of catecholamines mediated through B-receptor stimulation.

Classification on pharmacokinetic basis:

B-receptor blockers can be classified according to their relative solubility in lipids and in water.

1. Lipid soluble drugs:

- Rapidly absorbed (across lipoprotein membrane)

- Undergo moderate (timolol) to extensive (propranolol,

labetalol) first pass metabolism

- Having shorter half life (2-6 hours)

- Extensively metabolized (hydroxylated, conjugated), with most metabolites appearing in the urine.

Example:

Propranolol, labetalol , timolol, pindolol (non selective),Metoprolol (selective)

2. Water soluble drugs:

- Incomplete oral absorption

- No significant first pass metabolism

- Longer acting (t1/2 6-20 hours)

- Not extensively metabolized and is largely excreted unchanged in the urine.

Example:

Nadolol (non selective),Atenolol (selective)

Classification on pharmacodynamic basis:

• Nonselective B-(B1+B2) adrenergic receptor antagonists: They have equal affinity for B1 and B2
receptors.

Propranolol,Labetalol,Nadolol,Timolol,Pindolol.

• Selective B 1

-adrenergic receptor antagonists: They have a greater affinity for the B1 receptors of the heart than for
B2 receptors in other tissues.

Atenolol,Metoprolol,Esmolol,Acebutolol
Cardioselective B-antagonists:Cardioselective B-antagonists are drugs that have a greater affinity for the
B1 -receptors of the heart than for  B2 -receptors in other tissues. Such cardioselective agents should
provide two important therapeutic advantages.

The first advantage would be the lack of an antagonistic effect on the B2 -receptors in the bronchi.
Theoretically, this would make B1 -blockers safe for use in patients who have bronchitis or bronchial
asthma.

The second advantage would be the absence of blockade of the vascular B2 -receptors, which mediate
vasodilatation. This would be expected to reduce or eliminate the increase in peripheral resistance that
sometimes occurs after the administration of nonselective B-antagonists.

Atenolol / Metoprolol

Atenolol / Metoprolol is a B1 -selective adrenergic antagonist. It is approximately equipotent to

propranolol in inhibiting stimulation of  B1 -adrenoceptors such as those in the heart but 50 to 100 fold
less potent than propranolol in blocking B 2 -receptors.

Although atenolol / metoprolol is in other aspects very similar to propranolol, its relative
cardioselectivity may be advantageous in treating hypertensive patients who also suffers from asthma.

Studies of small number of asthmatic patients have shown that atenololol causes less bronchial
constriction than propranolol at doses that produce equal inhibition of  B1 -adrenocepotor responses.
Atenolol / Metoprolol decreases blood pressure primarily as a result of a decrease in cardiac output.

The major therapeutic effect of atenolol is on the cardiovascular system. B1 receptor is present in
myocardium. Atenolol blocks the  1 receptor in heart. Since catecholamines have positive chronotropic
and inotropic actions, -adrenergic antagonist atenolol slows the heart rate and decreases myocardial
contractility → ↓ cardiac output → ↓ blood pressure.

PROPANOLOL:

Propranolol is a competitive -adrenergic antagonist.It has equal affinity for  1 and  2 receptors; thus,
it is a nonselective -adrenergic receptor antagonist. Propranolol decreases blood pressure primarily as
a result of a decrease in cardiac output.
The major therapeutic effect of propranolol is on the cardiovascular system. 1 receptor is present in
myocardium. Propranolol blocks the 1 receptor in heart.

Nonselective -adrenergic antagonists such as propranolol block  2 -adrenergic receptors in bronchial

smooth muscle.This usually has little effect on pulmonary function in normal individuals.

However, in patients with asthma or chronic obstructive pulmonary disease, such blockade can lead to
life-threatening bronchoconstriction.

H2 BLOCKER:

H2 -receptor antagonists or H2 blockers Extensive pharmacological analysis suggests the existence of

mainly two types of histamine-receptors: H1 and H2 . H2 -receptors are located on the cell membrane of
acid-secreting cells (parietal) of the gastric mucosa and mediate the gastric acid secretory actions of
histamine. Drugs which selectively and competitively antagonize most of the actions of histamine that
are mediated by H2 -receptors are called H2 receptor blockers. e.g. ranitidine, nizatidine, famotidine etc.

Physiological regulation of acid secretion by the parietal cell / Physiology of acid secretion: Gastric acid
is secreted from parietal cells located mainly in the upper portion (fundus) of the stomach and is
stimulated by three endogenous substances: gastrin, acetylcholine, and histamine.

In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells.
Chemistry of H2 -receptor antagonists or H2 blockers : The H2 receptor antagonists in clinical use are
histamine congeners that contain a bulky side chain in place of the ethylamine moiety. Early
representatives of the group, such as burimamide and cimetidine (the first compound released for
general use) retain the imidazole ring of histamine.

This ring is replaced in more recently developed compounds by a furan (ranitidine) or a thiazole
(famotidine, nizatidine). Structures of some H2 antagonists are given below:
Pharmacodynamics / Mechanism of action of H2 receptor antagonists: The H2 receptor antagonists
exhibit competitive inhibition at the parietal cell H2 receptor and suppress basal (fasting), nocturnal and
meal-stimulated acid secretion.

H2 receptor antagonists reduce acid secretion stimulated by histamine as well as by gastrin and
acetylcholine through two mechanisms: First, histamine released from ECL cells by gastrin or
acetylcholine is blocked from binding to the parietal cell H2 receptor.
Second, direct stimulation of the parietal cell by gastrin or acetylcholine results in diminished acid
secretion in the presence of H2 receptor blockers. It appears that reduced parietal cell cAMP levels
attenuate the intracellular activation of protein kinase by gastrin or acetylcholine.

SYNTHESIS OF RANITIDINE:

Metabolism of ranitidine: Excretion of the drug and its metabolites is largely in urine: 30 – 70% of a
dose is found unchanged in the urine and the S- and N-oxides and desmethylranitidine are detectable in
urine within 24 h of dosing.
PENICILLIN:

Advantages of semi-synthetic penicillins over Penicillin G:

1. Less allergic reactions.

2. Suitable oral forms (acid resistance e.g. ampicillin, amoxicillin, cloxacillin).

3. Broad spectrums (e.g. amoxicillin, Ticarcillin).

4. B-lactamase resistant (e.g. methicillin, cloxacillin)

5. More and adequate plasma half life.

Ampicillin:

• Ampicillin (- Aminobenzylpenicillin) is a semisynthetic penicillin.

• Antibacterial spectrum is broader than that of penicillin G.

• It is resistant to acid but susceptible to -lactamase hydrolysis.

Amoxycillin:

• Amoxycillin (-Amino-p-hydroxybenzylpenicillin) is a semisynthetic penicillin.

• Antibacterial spectrum is broader than that of penicillin G. Its antibacterial spectrum is nearly identical
to that of ampicillin.

• It is resistant to acid but susceptible to -lactamase hydrolysis.

Comparative study between ampicillin and amoxicillin:

Orally administered amoxycillin possesses significant advantages over ampicillin, Thus amoxycillin has
largely replaced ampicillin for the treatment of certain systemic and urinary tract infections for which
oral administration is desirable.

Cephalosporins

The cephalosporins are -lactum antibiotics isolated from Cephalosporium species or prepared
semisynthetically. Most of the antibiotics introduced since 1965 have been semisynthetic
cephalosporins.

Natural cephalosporins isolated from Cephalosporium acremonium are not potent enough to be a useful
antibiotic.
Advantages of semisynthetic cephalosporins:

• increased acid stability

• improved pharmacokinetic properties, particularly better oral absorption

• broadened antimicrobial spectrum

• increased activity against resistant microorganisms (as a result of resistance to enzymatic destruction).

• decreased allergenicity and • increased tolerance after parenteral administration

Classification of cephalosporins on the basis of their antimicrobial properties: On the basis of spectrum
of antimicrobial activity, cephalosporins are classified into four groups or generations such as first,
second, third and fourth generation cephalosporins.

First- generation cephalosporins: The first-generation cephalosporins have good activity against gram-
positive organisms and relatively modest activity against gram-negative microorganisms.This group
includes cephalexin, cephradine, cefadroxil etc. These drugs are very active against gram-positive cocci,
including pneumococci, streptococci and staphylococci.

Second-generation cephalosporins: The second-generation cephalosporins have somewhat increased

activity against gram-negative microorganisms, but are much less active than the third generation
agents.Members of this group include cefuroxime, cefamandole, cefaclor etc.

Third-generation cephalosporins: Third-generation cephalosporins generally are less active than first-
generation agents against gram-positive cocci, but they are much more active against gram-negative
microorganisms such as Enterobacteriaceae, including B-lactamase-producing strains of haemophilus
and neisseria. This group includes ceftriaxone, cefixime, cefotaxime etc.
Fourth-generation cephalosporins: Fourth generation cephalosporins have an extended spectrum of
activity compared to the third generation and have increased stability from hydrolysis by chromosomal
B-lactamases (eg, those produced by enterobacter). Fourth-generation agents have particular
therapeutic usefulness in the treatment of infections due to aerobic gram-negative bacilli which are
resistant to thirdgeneration cephalosporins. Cefepime is an example of a so-called fourth-generation
cephalosporin.

Mechanism of action of cephalosporins: Cephalosporins inhibit bacterial cell-wall synthesis in a manner

similar to that of penicillin.