This document discusses β-lactam antibiotics, specifically penicillins. It covers the chemistry and classification of penicillins, including natural vs. semi-synthetic penicillins. The structure-activity relationship of penicillins is examined in depth, focusing on factors that influence spectrum of activity, acid stability, and bacterial resistance, such as penicillinase production. Extended-spectrum penicillins like ampicillin and carbenicillin are described as having activity against gram-negative bacteria through the introduction of ionizable groups that increase polarity and membrane permeability. Resistance mechanisms include bacterial production of beta-lactamase enzymes that deactivate penicillins by hydrolyzing the beta-lactam ring.
002. Cephalosporins for students 2023 Prof. P. Ravisankar.pdfDr. Ravi Sankar
Cephalosporins, Why Cephalosporins? Advantages of cephalosporins over penicillin, Mechanism of action of cephalosporins, Classification of cephalosporins, Structures of some important cephalosporins and cephamycins, Oximinocephalosporins, SAR of cephalosporins,Hydrolytic reactions, degradation and stability of cephalosporins, Uses of cephalosporins, Comparison between 6-APA and 7-ACA and penam and cepham.
002. Cephalosporins for students 2023 Prof. P. Ravisankar.pdfDr. Ravi Sankar
Cephalosporins, Why Cephalosporins? Advantages of cephalosporins over penicillin, Mechanism of action of cephalosporins, Classification of cephalosporins, Structures of some important cephalosporins and cephamycins, Oximinocephalosporins, SAR of cephalosporins,Hydrolytic reactions, degradation and stability of cephalosporins, Uses of cephalosporins, Comparison between 6-APA and 7-ACA and penam and cepham.
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
Aminoglycosides(medicinal chemistry by p.ravisankar)Dr. Ravi Sankar
Aminoglycosides,Aminocyclitols,Source,Structures of streptomycin,Dihydrostreptomycin,A mention of other aminoglycoside antibiotics,Acid hydrolysis,Mechanism of action,SAR,Dihydrostreptomycin and its importance,therapeutic uses, toxicity.
Dear students, you can watch the Complete chapter of antibiotics in these videos as per PCI syllabus
1)Antibiotics-History & Introduction
https://www.youtube.com/watch?v=xdKch...
2)Easy Learning Of Chapter - β-Lactam antibiotics-Cephalosporin
https://www.youtube.com/watch?v=D7b5g...
3)Learn Complete Topic -β-Lactam antibiotics(Penicillin) in Medicinal Chemistry
https://www.youtube.com/watch?v=qXQ3S...
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
Aminoglycosides(medicinal chemistry by p.ravisankar)Dr. Ravi Sankar
Aminoglycosides,Aminocyclitols,Source,Structures of streptomycin,Dihydrostreptomycin,A mention of other aminoglycoside antibiotics,Acid hydrolysis,Mechanism of action,SAR,Dihydrostreptomycin and its importance,therapeutic uses, toxicity.
Dear students, you can watch the Complete chapter of antibiotics in these videos as per PCI syllabus
1)Antibiotics-History & Introduction
https://www.youtube.com/watch?v=xdKch...
2)Easy Learning Of Chapter - β-Lactam antibiotics-Cephalosporin
https://www.youtube.com/watch?v=D7b5g...
3)Learn Complete Topic -β-Lactam antibiotics(Penicillin) in Medicinal Chemistry
https://www.youtube.com/watch?v=qXQ3S...
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
The cephalosporins are β-lactam antibiotics isolated from Cephalosporium spp. or prepared semisynthetically
Most of the antibiotics introduced since 1965 have been semisynthetic cephalosporins.
Beta lactam antibiotics, PCI syllabus for B.Pharm.Purna Nagasree K
This ppt contains beta lactum antibiotics for B.pharm people. the mechanism of action, classification was well explained. Degradations and generations of penicillins and cephalosporins was covered.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
1. Page 1 of 18
β-LACTAM ANTIBIOTICS
A. PENICILLINS
1. Benzyl penicillins
a. Penicillin G
i. benzylpenicillin sodium,
ii. Procaine benzylpenicillin,
iii. Benzathine penicillin
2. Phenoxy-penicillins (oral penicillins)
a. Penicillin V
b. Propicillin
3. Penicillinase resistant penicillins (anti-staphylococcal penicillins)
a. Oxacillin
b. Dicloxacillin
c. Flucloxacillin
4. Aminobenzyl penicillins
a. Ampicillin
b. Amoxicillin
5. Ureidopenicillins (broad-spectrum penicillins)
a. Mezlocillin
b. Piperacillin
6. ß-Lactam/ ß-lactamase inhibitors
a. sulbactam & Ampicillin
b. Clavulanate & Amoxicillin
c. Tazobactam & Piperacillin
d. Sulbactam in free combinations
B. Cephalopsorins
2. Page 2 of 18
β- Lactam Antibiotics- Penicillin(s)
1. Chemistry and nomenclature:
A β- lactam is a cyclic amide with four atoms in its ring.
As the name “lactam” indicates cyclic amide which is generally considered as
analogous to the name “lactone” which is indicated for cyclic esters.
In an older nomenclature, α was designated to the second carbon in an
aliphatic carboxylic acid/ or a carbon bears functional group such as
carboxyllic acids, and β to the third, and so on- as shown in above structure.
The contemporary name for this ring system is azetidinone.
The penicillin subclass of β -lactam antibiotics is characterized by the
presence of a substituted 5-membered thiazoldine ring fused to the β -lactam
ring.
Nomenclature:
Two different numbering approaches are used for the fused bicyclic heterocyclic
system of penicllin of beta lactam class.
1. The Chemical Abstracts system initiates the numbering with the sulfur atom
and assigns the ring nitrogen the 4-position. Thus, penicillins are named as
4-thia-l-azabicyclo[3.2.0]heptanes,
3. Page 3 of 18
2. The numbering system adopted by the USP is the reverse of the Chemical
Abstracts procedure, assigning number 1 to the nitrogen atom and number 4
to the sulphur atom.
Three simplified forms of penicillin nomenclature have been adopted for
general use.
o The first uses the name “penam” for the unsubstituted bicyclic system,
including the amide carbonyl group,
o Thus, penicillins according to the Chemical Abstracts system as 5-
acylamino-2,2-dimethylpenam-3-carboxylic acids.
o The second, more frequently, uses the name “penicillanic acid” is 2, 2-
dimethyl and 3-carboxyl.
3. A
third form, uses trivial nomenclature to name the entire 6-
carbonylaminopenicillanic acid (6-APA) portion of the molecule penicillin and
then distinguishes compounds on the basis of the R group of the acyl portion
of the molecule.
Example:
4. Page 4 of 18
o penicillin G - benzylpenicillin,
o penicillin V - phenoxymethylpenicillin,
o methicillin is 2,6-dimethoxyphenylpenicillin, and so on.
1.1 Sterochemistry of penicillin
The penicillin molecule contains three chiral carbon atoms (C-3, C-5, & C-6).
PC’s are the cis relationship between
o the two hydrogens at positions 5 and 6, a
o free 3-carboxylate and a 6-amide.
The carbon atom bearing the
o acylamino group (C-6) has the L configuration,
o Whereas the carbon to which the carboxyl group is attached has the D
configuration.
o Thus, the acylamino and carboxyl groups are trans to each other, with
the former in the α and the latter in the β orientation relative to the
penam ring system.
The absolute stereochemistry of the penicillins is designated 3S:5R:6R, as
shown below/ above
5. Page 5 of 18
The atoms composing the 6-aminopenicillanic acid (6-APA) portion of the
structure are derived biosynthetically from two amino acids,
o L-cysteine (S-1, C-5, C-6, C-7, and 6-amino) and
o L-valine (2,2-dimethyl, C-2, C-3, N-4, and 3-carboxyl).
Amino acid components of 6-
aminopenicillanic acid (6-APA)
structure
2. Classification (according to source/ synthesis way)
There are several ways to classify penicillin antibiotic of beta lactam class. Few are
enlisted below
Natural penicillins Semi-synthetic penicillins
– Extracted from the cultural
solution of penicillia.
– Prototype is penicillin G
– Is pH sensitive. Therefore
not given orally.
– Effective against G+ve
– Susceptible to penicillinase
– Produce by growing Penicillium in culture
so that only the nucleus is synthesized.
– Attach R group in lab. OR
– Grow Penicillium, extract replace R by/
with required R group.
– Have broader spectrum.
– Effective against G-ve cells, too.
– Are not resistant to penicillinases
Classification according to SAR
Class Example
Aminopenicillins Ampicillin, Amoxicillin
Acid-stable Penicillin V
Penicillinase-resistant oxacillin
Extended/ broad -spectrum Ampicillin, Amoxicillin
Antistaphylococcal nafcillin, Oxacillin, Dicloxacillin
Anti-Pseudomonal [Carboxy] Ticarcillin, [Ureido] Piperacillin,
carbenicillin,
Beta-lactamase inhibitors clavulanic acid, sulbactam, tazobactam
6. Page 6 of 18
o Resistance to penicillin
decreased permeability to penicillins
Alteration of the number or nature of porins in the cell
envelope
Changes in the affinity of PBPs for penicillins/ Altered PBP
binding due to mutation
Degradation of antibiotics/ Penicllins by Beta lactamase
7. Page 7 of 18
3. Structure–Activity Relationship
The chemical substituent’s attached to the penicillin nucleus can greatly influence
the
the spectrum of activity/broadened spectrum
stability of the penicillin in terms of
o in gastric juice &
o drug stability on the shelf or in the GI tract (in vivo),
o against bacterial resistance- improve stability toward bacterial
metabolism (beta lactamase),
Chemical Degradation
Bacterial Resistance
Penicillinase-Resistant Penicillins
Extended-Spectrum Penicillins
Protein Binding
Allergy to Penicillins
Common SAR requirements/ requisites
• The strained (β-lactam ring is essential)
• The free carboxylic acid is essential
• The bicyclic system is important
– confers strain on the β-lactam ring—the greater the strain, the greater
the activity,
– but the greater the instability of the molecule to other factors.
• The acylamino side-chain is essential
• The stereochemistry of the bicyclic ring with respect to the acylamino side-
chain is important.
3.1 SAR for acid stable PC
– Acid-catalyzed degradation in the stomach contributes strongly to the poor
oral absorption of penicillin.
– Thus, efforts to obtain penicillins with improved pharmacokinetic and
microbiological properties have focused on acyl functionalities that would
8. Page 8 of 18
minimize sensitivity of the β-lactam ring to acid hydrolysis while
maintaining antibacterial activity.
– Substitution of an electron-withdrawing group in/at the α-position of
benzylpenicillin markedly stabilizes the penicillin to acid-catalyzed hydrolysis.
– Thus,
o phenoxymethylpenicillin-PC-V,
o α -aminobenzylpenicillin-ampicillin, &
o α-halobenzylpenicillin
are significantly more stable than benzylpenicillin in acid solutions.
– As α-aminobenzylpenicillin (ampicillin) exists as the protonated form in acidic
(as well as neutral) solutions, and the ammonium group is known to be
powerfully electron-withdrawing.
Comparative Acid resistance to penicillin’s
Poor Fair Good
PC-G, Methicillin,
carbenicillin, ticarcilllin,
piperacillin, mezlocillin
Nafcillin
PC-V, oxa, clox, dicloxacilllin,
ampi & amoxy
3.2 Bacterial Resistance
3.2.a-Bacterial enzymes responsible for resistance
– Enzymes penicillinases is the nonspecific name, is of two general types:
o β-lactamases &
o acylases.
– By far, the more important of these are the β-lactamases, enzymes that
catalyze the hydrolytic opening of the β-lactam ring of penicillins to produce
inactive penicilloic acids.
Penicillin resistant bacteria possess β-lactamase enzymes which
deactivate the drug by opening the β-lactam ring
9. Page 9 of 18
– Some bacteria, in particular most species of G-ve bacilli, are naturally
resistant to the action of penicillins.
– The well-known resistance among strains of Staphylococcus aureus is due to
β-lactamase production.
– Specific acylases (enzymes that can hydrolyze the acylamino side chain of
penicillins) have been obtained from several species of G-ve bacteria,
however their probable involvement in resistance is yet to be revealed.
– Another important resistance mechanism, especially in G-ve bacteria, is
decreased permeability to penicillins which might be contributed by one of
the followings
o Alteration of the number or nature of porins in the cell envelope
o Changes in the affinity of PBPs for penicillins.
o Altered PBP binding has been demonstrated in non–β-lactamase-
producing strains of penicillin-resistant Neisseria gonorrhoeae and
methicillin-resistant S. aureus (MRSA).
3.2.b-Penicilinase-Resistant Penicillins
In general, increasing the steric hindrance at the α-carbon of the acyl group
increased resistance to staphylococcal β-lactamase, with maximal resistance
being observed with quaternary substitution.
(↑ Steric hindrance↑ resistance beta-lactamase—max with 4°/ quaternary
substitution)
o More productive in terms of antibacterial potency, was the observation
that the α-acyl carbon could be part
o of an aromatic (e.g.,phenyl or naphthyl) or
o heteroaromatic (e.g., 4-isoxazoyl)
o Substitutions at the ortho positions of a phenyl ring
– e.g., 2,6-dimethoxy [methicillin]) or
– the 2-position of a 1-naphthyl system (e.g., 2-ethoxyl [nafcillin])
10. Page 10 of 18
Steric factors that assure β-lactamase resistance, however, do not necessarily
also confer stability to acid. As Methicillin> penicillin G (more labile to acid-
catalyzed hydrolysis).
Bulkier substituents are required to confer effective beta-lactamase
resistance among five-membered–ring heterocyclic derivatives.
o Thus, members of the 4-isoxazoyl penicillin family (e.g., oxacillin,
cloxacillin, and dicloxacillin) require both the 3-aryl and 5-methyl
(3-methyl and 5-aryl) substituents for effectiveness against beta-
lactamase–producing S. aureus.
o The isoxazoyl penicillins, particularly those with an electronegative
substituent in the 3-phenyl group (cloxacillin, dicloxacillin, and
floxacillin), are also resistant to acid-catalyzed hydrolysis of the beta-
lactam, for the reasons described previously.
(Bulkier substituents- five-membered–ring effectiveness against beta-lactamase–producing S.
aureus)
The β-lactamase–resistant penicillins tend to be comparatively lipophilic
molecules that do not penetrate well into Gram-negative bacteria.
The same amino group that enhanced stability in acidic conditions also results
in their relatively poor absorbance through the walls of the GI.
and as a result diarrhoea is a common side effect, as they will act upon and
diminish the numbers of essential bacteria present in the intestines.
For penicillin derivatives in general it has been found that hydrophobic side
chains asserts
o good activity against G+ve bacteria (ex)
o but poor activity against G-ve strains (ex)
For penicillins containing hydrophilic side chains the reverse is true;
o good activity is observed against G-ve bacteria and
o relatively poor activity against G+ve species.
Β- lactamase resistance against S aureus
Yes No
Methi, Nafi, Oxa, Cloxa,
Diclo
PC-G, PC-V, Ampi, amoxy,
Carben, Ticarci, Mezlo, Pipara
11. Page 11 of 18
3.2.c Extended-Spectrum Penicillins
Semi synthetic penicillins have provided significant advance by the following
manners
The introduction of an ionized or polar group into the α-position of the side
chain benzyl carbon atom of penicillin G confers activity against G-ve bacilli.
Hence, derivatives with an ionized α-amino group, such as ampicillin and
amoxicillin, are generally effective against such
o G-ve genera as
o Escherichia, Klebsiella, Haemophilus, Salmonella, Shigella, &
o non–indole-producing Proteus.
o Furthermore, activity against penicillin G–sensitive, G+ve species is
largely retained.
The introduction of α-amino group in ampicillin (or amoxicillin) creates an
additional chiral centre, which extends spectrum of activity.
o Extension of the antibacterial spectrum applies only to the D-isomer
>L-isomer or benzylpenicillin (which are equiactive) against various
species of the aforementioned genera of G-ve bacilli (D>L 2-8 times).
o Hydrophilic penicillins, such as ampicillin, penetrate G-ve bacteria
more readily than penicillin G, penicillin V, or methicillin.
o α-Hydroxy substitution also yields “expanded-spectrum” penicillins
with activity and stereoselectivity similar to that of the ampicillin group.
o Note that α-amino benzyl penicillins exist as zwitterions over a
broad pH range and, as such, are considerably less polar than
carbenicillin.
Incorporation of an acidic substituent at the α-benzyl carbon atom of PC-G
o imparts clinical effectiveness against G-ve bacilli
o extends the spectrum of activity (against organisms resistant to
ampicillin).
Thus, α-carboxybenzylpenicillin (carbenicillin) is active against
o ampicillin-sensitive, G-ve species and
o additional G-ve bacilli of the genera Pseudomonas, Klebsiella,
Enterobacter, indole-producing Proteus, Serratia, and Providencia.
12. Page 12 of 18
o Carbenicillin is active against both β-lactamase–producing and non–β-
lactamase-producing strains of G-ve bacteria.
o The potency of carbenicillin against most species of penicillin G-
sensitive, G+ve bacteria is several orders of magnitude lower than that
of either penicillin G or ampicillin; (carbe<PC-G & Ampi)
o presumably because of poorer penetration of a more highly ionized
molecule into these bacteria.
o This increased polarity is apparently an advantage for the
penetration of carbenicillin through the cell envelope of G-ve
bacteria.
This selective penetration of ampi, amoxi & carbenicillin is believed to take
place through the porin channels of the cell membrane.
A series of α-acylureido–substituted penicillins, exemplified by, exhibit
greater activity against certain G-ve bacilli than carbenicillin.
oThe acylureidopenicillins are, however, superior to carbenicillin against
Klebsiella spp., Enterobacter spp., and P. aeruginosa.
oMore facile penetration through the cell envelope of these particular
bacterial species is the most likely explanation for the greater potency.
oThe acylureidopenicillins, unlike ampicillin, are unstable under acidic
conditions; therefore, they are not available for oral administration.
13. Page 13 of 18
Table:-Summarised SAR of penicillin’s for Extended spectrum of activity
Name of PC Structural change Change in activity
Ampicillin &
amoxicillin,
ionized α-amino group are generally effective against such
G-ve genera as Escherichia, Klebsiella,
Haemophilus, Salmonella, Shigella, and
non–indole-producing Proteus.
Ampicillin α-amino group creates
an additional chiral
center.
D-isomer, > L-isomer or benzylpenicillin
(2-8 times)
Hydrophilic penicillins, penetrate G-ve bacteria > penicillin G,
V, or methicillin
Amoxicillin α-OH substitution also
yields
“expanded-spectrum” with activity and
stereoselectivity similar to that
of the ampicillin group
Ampi> amoxy (2-5 times more active & acid stable)
Carbenicillin
α-Carboxybenzyl
penicillin
Incorporation of an
acidic substituent at
the α-benzyl carbon
atom of penicillin G
also imparts clinical effectiveness
against G-ve bacilli &, furthermore,
extends the spectrum of activity to
include organisms resistant to ampicillin.
Active against ampicillin-sensitive, G-ve
species & G-ve bacilli of the genera
Pseudomonas, Klebsiella, Enterobacter,
indole-producing Proteus, Serratia, &
Providencia.
active against both β-lactamase–
producing & non–β-lactamase-producing
strains of G-ve bacteria.
Against most species of penicillin G-sensitive, G+ve bacteria
penicillin G or ampicillin,> carbenicillin (is several orders of magnitude lower)
presumably because of poorer penetration of a more highly ionized molecule
into these bacteria.
azlocillin,
mezlocillin, and
piperacillin
α-acylureido–
substituted penicillins,
Exhibit greater activity against certain
Gram-ve bacilli than carbenicillin; More
facile penetration through the cell
envelope
azlocillin, mezlocillin, and piperacillin> carbenicillin (certain G-ve bacilli)
15. Page 15 of 18
MOA (PBP & D-alanine cross linking)
Penicillins have a structural resemblance to two D-alanine residues linked
together, and
are mistaken by the transpeptidase enzyme for D-Ala-D-Ala, and thus
incorporated into the active site.
Once bound, the b-lactam carbonyl is attacked by the serine hydroxyl, and
ring opening occurs to leave the penicillin covalently bound to the enzyme.
The bulky thiazolidene ring now blocks access to the active site by either a
pentaglycine chain or water. As a result the penicillin becomes irreversibly
bound to the transpeptidase enzyme, preventing it from functioning properly.
This results in incomplete cell walls that are much more fragile and porous,
and eventually lead to swelling followed by cell lysis and death.
All β-lactam antibiotics* binds to PBPs, which are requisite for cell
wall synthesis of bacteria. PBPs are members of transpeptidases (a subgroup
of enzymes).
Table:- Different classes of PBP’s & their role in bacterial cell wall synthesis/
formation
PBP class/
PBM
Type of enzyme Role Result of inhibition
PBPs 1a &1b-
first-generation
cephalosporins
Transpeptidases
in peptidoglycan
synthesis associated with
cell elongation
results in spheroplast
formation & rapid cell
lysis-
PBP 2-
Amdinocillin
only to PBP -2
CP’S
involved in maintaining
the rod
shape of bacilli
results in ovoid /round
forms that undergo
delayed lysis
PBP 3????-
Doubtful-
whether
inhibition of
PBP 3 is
lethal to
bacterium.
PC-G & CP’S
required for septum
formation
during cell division
in the formation of
filamentous forms
containing rod-shaped
units that cannot
separate.
PBPs 4 through
6
Carboxypeptidases
responsible for
the hydrolysis of D-
alanine–D-alanine
terminal peptide
bonds of the cross-linking
peptides
Apparently not lethal to
the bacterium, even
though cleavage of the
terminal D-alanine bond
is required before
peptide cross-linkage.
17. Page 17 of 18
Unit of activity measurement
Penicillin Units for assay
1. The commonly known unit value to measure the activity is the Oxford unit:
1 Oxford unit is defined as the smallest amount of penicillin that will show the
ability to inhibit (in vitro), the growth of a strain of Staphylococcus in 50 mL of
culture medium under specified experimental conditions.
2. The other is United States Pharmacopoeia (USP) defines unit as the
antibiotic activity of 0.6 µg of penicillin G sodium reference standard.
The weight to unit correlation of the penicillin differs/changes with the acyl
substituent and with the salt formed of the free acid, accordingly-
Penicillin salt form of the free acid equivalent to units
1 mg of penicillin G sodium 1,667
1 mg of penicillin G procaine 1,009
1 mg of penicillin G potassium 1,530
Precautions
(Drug-drug interaction/ Drug excipients interaction & allergy)
Because penicillins are inactivated by metal ions such as zinc and copper, it has
been suggested that the phosphates and the citrates combine with these metals to
prevent their existence as free ions in solution
Combination of penicillin & aminoglycoside {PC & AG}
(Good but be careful!!!!!)
The low toxicity of carbenicillin (and the penicillins in general), however,
usually permits (in the absence of allergy) the use of such high doses without
untoward effects.
Furthermore, carbenicillin (and other penicillins), when combined with
aminoglycosides,
o exerts a synergistic bactericidal action against bacterial species
sensitive to both agents, frequently allowing the use of a lower dose
18. Page 18 of 18
of the more toxic aminoglycoside than is normally required for
treatment of a life-threatening infection.
o The chemical incompatibility of penicillins and aminoglycosides
requires that the two antibiotics be administered separately;
otherwise, both are inactivated.
o It has been showed that acylation of amino groups in the
aminoglycoside by the β-lactam of the penicillin occurs.
Combination of penicillin & clavulinic acid {PC & CA}
Combination of penicillin & lactobacillus {PC & LB}