An ideal prodrug is pharmacologically inactive but is converted to an active drug through metabolic or chemical means. It rapidly transforms to the active drug only at the desired site and has nontoxic metabolic byproducts. Prodrugs can improve drug properties like solubility, stability, absorption, and can target drugs to specific sites through enzymatic activation. Common prodrug approaches include carrier-linked, mutual, and bioprecursor prodrugs which utilize ester, amide or other hydrolyzable linkages.
Definition: Antiviral agents are substances used in the treatment and prophylaxis of disease caused by viruses.
Classification:
A] Agents involves the inhibition of early stage of viral replication (Adamantane derivatives)
Admantane
Amantadine
Rimantadine
Tromantadine
B] Interferon:
Tilorane
ABPP (Bromopirimine)
CP20,961
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.
Definition: Antiviral agents are substances used in the treatment and prophylaxis of disease caused by viruses.
Classification:
A] Agents involves the inhibition of early stage of viral replication (Adamantane derivatives)
Admantane
Amantadine
Rimantadine
Tromantadine
B] Interferon:
Tilorane
ABPP (Bromopirimine)
CP20,961
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.
Tetracyclines BY Dr. P. Ravisankar M. Pharm., Ph.D.Dr. Ravi Sankar
Tetracyclines by Dr. P. Ravisankar M. Pharm., Ph.D.
Definition
Introduction
Classification
Historical background
Sources
Chemistry
SAR of tetracyclines
Mechanism of action of tetracyclines
Spectrum of activity
Uses of tetracyclines
Side effects of tetracyclines
These are antibiotics having a macrocyclic
lactone ring with attached sugars. Erythromycin
is the first member discovered in the 1950s,
Roxithromycin, Clarithromycin and Azithromycin
are the later additions. Antimicrobial spectrum is narrow,
includes mostly gram-positive and a few gramnegative
bacteria, and overlaps considerably with
that of penicillin G. Erythromycin is highly active
against Str. pyogenes and Str. pneumoniae, N.
gonorrhoeae, Clostridia, C. diphtheriae and
Listeria, but penicillin-resistant Staphylococci
and Streptococci are now resistant to erythromycin
also.
All cocci readily develop resistance
to erythromycin, mostly by acquiring the
capacity to pump it out. Resistant Enterobacteriaceae
have been found to produce an erythromycin
esterase. Alteration in the ribosomal binding
site for erythromycin by a plasmid encoded
methylase enzyme is an important mechanism of
resistance in gram-positive bacteria. All the above
types of resistance are plasmid mediated. Change
in the 50S ribosome by chromosomal mutation
reducing macrolide binding a
Leprosy is the disorder for which the effective agents are used to treat leprosy. This presentation will drive you through in detail concepts of the medicines used in the treatment, with effective visualisation/ pictures.
Anti-Neoplastic agents(Anti-cancer drugs)-History-Mechanism of actions-Classifications,SAR,Synthesis and Uses.(Medicinal chemistry)
P.Ravisankar
Vignan Pharmacy College
Vadlamudi. Guntur-A.P. India.
Classification and Synthesis of Sulpha drugs, Anti Viral Drugs, Anti Fungal Agents, Anti Tubercular Agents, Anti leprotic Agents, Antiamoebic Agents, Anthelmintics, Anti Malarial Drugs, Anti cancer Drugs
Tetracyclines BY Dr. P. Ravisankar M. Pharm., Ph.D.Dr. Ravi Sankar
Tetracyclines by Dr. P. Ravisankar M. Pharm., Ph.D.
Definition
Introduction
Classification
Historical background
Sources
Chemistry
SAR of tetracyclines
Mechanism of action of tetracyclines
Spectrum of activity
Uses of tetracyclines
Side effects of tetracyclines
These are antibiotics having a macrocyclic
lactone ring with attached sugars. Erythromycin
is the first member discovered in the 1950s,
Roxithromycin, Clarithromycin and Azithromycin
are the later additions. Antimicrobial spectrum is narrow,
includes mostly gram-positive and a few gramnegative
bacteria, and overlaps considerably with
that of penicillin G. Erythromycin is highly active
against Str. pyogenes and Str. pneumoniae, N.
gonorrhoeae, Clostridia, C. diphtheriae and
Listeria, but penicillin-resistant Staphylococci
and Streptococci are now resistant to erythromycin
also.
All cocci readily develop resistance
to erythromycin, mostly by acquiring the
capacity to pump it out. Resistant Enterobacteriaceae
have been found to produce an erythromycin
esterase. Alteration in the ribosomal binding
site for erythromycin by a plasmid encoded
methylase enzyme is an important mechanism of
resistance in gram-positive bacteria. All the above
types of resistance are plasmid mediated. Change
in the 50S ribosome by chromosomal mutation
reducing macrolide binding a
Leprosy is the disorder for which the effective agents are used to treat leprosy. This presentation will drive you through in detail concepts of the medicines used in the treatment, with effective visualisation/ pictures.
Anti-Neoplastic agents(Anti-cancer drugs)-History-Mechanism of actions-Classifications,SAR,Synthesis and Uses.(Medicinal chemistry)
P.Ravisankar
Vignan Pharmacy College
Vadlamudi. Guntur-A.P. India.
Classification and Synthesis of Sulpha drugs, Anti Viral Drugs, Anti Fungal Agents, Anti Tubercular Agents, Anti leprotic Agents, Antiamoebic Agents, Anthelmintics, Anti Malarial Drugs, Anti cancer Drugs
Prodrugs an approach to solve problems related to admeJyotsna Patil
prodrugs an approach to overcome problems related to ADME, for MPharm students
sub- modern pharmaceutical and medicinal chemistry
branch- quality assurance
Basic concepts of Prodrug & their application in pharmacy fieldsSHUVAM SAR
Definition of prodrugs along with their uses in pharmacy have been discusses here in brief. Also includes the basic objectives of their formulation with examples.
drug metabolism, phase I metabolism, biotransformation, Xenobiotics- substances foreign to body
Non polar lipid soluble compounds are made polar lipid insoluble, so that they are easily excreted.
Advantages of metabolism
Termination of drug action
↓ toxicity
Reduced lipophilicity.
Renal / biliary excretion ↑
↑ water solubility
↑ polarity
↑ excretion
Loss of phsiological activity
Active drug → more active drug
Non Active drug → active drug
Active drug → inactive drug
BIOTRANSFORMATION REACTIONS - 2 TYPES
Phase I / Non synthetic / Functionalization
A functional group is generated
Metabolite – active or inactive
Phase II / Synthetic / Conjugation
Metabolite is usually inactive
BIOTRANSFORMATION REACTIONS - 2 TYPES
Phase I / Non synthetic / Functionalization
A functional group is generated
Metabolite – active or inactive
Phase II / Synthetic / Conjugation
Metabolite is usually inactive
Depending upon nature and localisation of enzymes which catalyse reaction –
Microsomal enzymes
Non- Microsomal enzymes
Oxidation of alcohol
ethanol→ acetaldehyde → acetic acid →TCA cycle → CO₂
Eg.
chloral hydrate → trichloroacetic acid
mefenamic acid → hydroxy methyl derivative
ALIPHATIC HYDROXYLATION
Hydroxyl group added to drug
RCH2CH3 O RCHOHCH3
Salicylic acid to Gentisic acid
Ibuprofen
Tolbutamide, Chlorpropamide,
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
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
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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.
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.
Title: Sense of Taste
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 structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
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.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?
Prodrug_ Dr. M. Rudrapal
1. In 1958, Albert coined the term “Prodrug”………….
A pharmacologically inactive compound that is
converted to an active substance (drug) by either
chemical or metabolic means in vivo
(biotransformation).
Prodrug-drug transformation could be enzymatic
and nonenzymic or chemical e.g., oxidation,
reduction, hydrolysis etc.).
Prodrug-drug conversion could occur before,
during, after absorption or at a specific site in the
body.
Ideally, conversion happens as soon as the target
site is reached.
2. The prodrug design approach is also referred
as Drug Latentiation.
An ideal prodrug:
Should not have intrinsic pharmacological
activity
Should rapidly transform into the active form
where desired
Metabolic fragments, apart from the active
drug should be nontoxic
3. A. Pharmaceutical applications:
1. Improvement of taste (e.g. Chloramphenicol-Palmitate, Sulfisoxazole-Acetyl)
2. Improvement of odor (e.g. Ethyl mercaptan (foul smell), -Phthalate ester)
3. Reduction of G. I. irritation (e.g.Salicylic acid-Aspirin, Kannamycin-Pamoate)
4. Reduction of pain on injection (Clindamycin, low solubility-Phosphate ester)
5. Enhancement of drug solubility and dissolution rate (hydrophilicity)
e.g. Metrodidazole-Amino acid ester
6. Enhancement of chemical stability
(e.g. Azacytidine-Bisulfite (Stable at acidic PH, more water soluble)
B. Pharmakokinetic applications:
1. Enhancement of bioavailability (lipophilicity) e.g. Bacampicillin (98% OB)
2. Prevention of presystemic metabolism e.g. Triamcinolone acetonide
3. Prolongation of duration of action e.g. Testosterone cypionate (i.m depot)
4. Reduction of toxicity e.g. Sulindac (sufoxide)-sulfide (active)
5. Site specific drug delivery (Drug-targeting) e.g. Acyclovir (Anti-HIV
bioprecursor)
Reasons for Prodrug /Applications of prodrug approach
4. Types of prodrugs
Carrier-linked prodrug (or simple prodrug):
an active drug covalently linked to an inert removable carrier or
transport moiety (usually hydrolyzable group such as ester, amide,
etc.)
Bipartate prodrug: one carrier (inert) attached to one drug
Tripartate prodrug (Double prodrug (or) pro-prodrug: one carrier
connected to a drug through a linker (diseter of pilocarpic acid)
Mutual prodrug: two synergistic drugs attached to each other
(Benorylate-Aspirin+Paracetamol)
Bioprecusor or metabolic precursors:
Inert molecules obtained by chemical modification of the active drug
but do not contain a carrier.
6. Carrier-linked prodrugs
A. Alcohols and carboxylic acids
(Ester prodrug)
Carrier/promoiety is lipophilic in nature
Lipophilicity of active drug is greatly modified
Lipophilicity: Prodrug > active drug
Esterase are ubiquitous (hydrolytic cleavage)
Example:
Chloramphenicol palmitate Chloramphenicol (in blood)
7. Drug C
O
O Promoiety
or
Drug O C Promoiety
O
Drug C
O
OH
Drug OH Promoiety
+ OH Promoiety
C
O
HO+
Ester prodrug: Drug molecule contains either alcohol or
carboxylic acid functionality
Esterase enzymes: Capable of hydrolysing ester linkage of
prodrugs
Ester hydrolase/Lipase/Cholesterol esterase/Ach esterase etc.
8. Non-polar (lipophilic carrier) alcohol or
carboxylic acid (Promoiety)
Decreased water solubility i.e., hydophilicity
Benefits:
Increased absorption (% OB, lipophilic form)
Example:
Dipivefrin HCl, prodrug (diester of pivalic acid) of
Epinephrine, Adrenomimetic, used in Open-angle
glaucoma
Has 10 times more ocular penetrability than active
drug
Nadolol: Diacetate ester is 20 times more lipophilic
and 10 times more readily absorbed ocularly
9. Decreased dissolution (greater stability in
g.i.f-->absorption)
Example:
Chloramphenicol palmitate, Antibacterial
Reduced solubility in saliva and lower
affinilty to taste receptors, bitterness is
reduced
11. Reduction of dosage (increased OB,
increased lipophilicity)
Example: Becampicillin is as effective as
ampicillin in just 1/3rd the dose of latter.
12. Ester linkage: Catechol hydroxyl groups of epinephrine with
pivalic acid
Increased lipophilicity allows high intraocular concentration
Hydrolysis of ester function occurs then in eye to generate the
active form, epinephrine
OH
NH2O
OO
O
Cl
OH
NH2HO
HO
Cl
OH
O
Epinephrine
Pivalic acidDipivefrin HCl
Esterase
+
14. Polar alcohol or carboxylic acid (Promoiety)
Increased water solubility i.e., hydrophilicity
Benefit :
Increased parenteral administration
Reduction of pain at the site of injection (Clindamycin-Phos)
Example: Chloramphenicol succinate
Chloraphenicol has low water solubility
Succinate ester has increased solubility in the administered
solvent, and facilitate parenteral administration
16. Some common examples of
ester prodrugs
Chloramphenicol palmitate
N-Acetyl sulfisoxazole
N-Acetyl sulfamethoxypyridazine
Erythromycin estolate (lauryl sulfate salt of
erythromycin propianate)
Clindamycin palmitate
17. Polar Drug - Soluble in g.i.t -> destabilization in
acid
Caridacillin (a ∞-indalol ester)-Carbenicillin
(antibiotic)
Stable at gastric pH (low solubility)
Stable at pH >7.0 in intestine and hydrolyzed under
such condition
20. C. Azo linkage:
H2N N N S
O
O
NH2
NH2
Azoreductase
H2N S
O
O
NH2
NH2
Prontosil
H2NNH2
Sulfanilamide
(active drug)
+
1. Prontosil
21. 2. Sufasalazine
HO
HOOC
N N S
O
O
NH
N
Sulfasalazine
Azoreductase
HO
HOOC
NH2 H2N S
O
O
NH
N
+
Aminosalicylic acid Sulfapyridine
22. C. Carbonyl
Schiff base increase lipophilicity
Oxime increase hydrophilicity
oxazolidines, thioxazolidines adjust lipophility.
23. More examples of Carrier-linked Bipartate Prodrugs
A. For Increased Water Solubility
R= R’=H, Prednisolone
R= CH3, R’=H, Methylprednisolone
Both are water-insoluble
Ideal prodrug: shelf life > 2 yrs;
activated < 10 min in vivo
Prodrug: R=CH3, R’=COCH2CH2CO2Na
shelf life<48hrs, others > 2 yrs
R=H, R’=phosphate, good
H3N
O
O
HN
O
O
H3N
R
O
Bezocaine
Local anesthetic
Low solubility
Bezocaine prodrug
stable, long shelf life
high solubility, activated readily
MeHO
Me
R
OH
O
O
OR'
24. B. For Improved Absorption and Distribution
Cortisosteroid
Inflammation,
Allergy
Pruritic skin conditions
Epinphrine, R = H
Antiglaucoma
25. C. For site specificity
OH
OH CH2 CH
COOH
NH C
O
CH2CH2 CH
NH2
gama-Glutamyl DOPA (Prodrug)
gama-Glutamyl transferase
OH
OH CH2 CH
COOH
NH2 C
O
CH2CH2 CH
NH2
COOHOH+
DOPA (Bioprecursor) Glutamic acid
CO2
OH
OH CH2CH2NH2
DOPAMINE
Renal vasodilation
by increasing renal blood flow
L-aromatic amino acid decarboxylase
(treatment of renal hypertension)
Selectively accumulate in the
kidneys & bind to specefic
receptor
(released active drug locally)
COOH
26. D. For Stability E. Prolonged Release
H3C N
R
O
CH3
Naltrexone(R=H), opiod addiction
Not stable in the first pass
R= CO-o-NO2Ph, bioavailability 45
times
R= CO-o-AcOPh, bioavailability 28
times
Tolmetin sodium(R=O-Na+),
antiarthritis
Peak concentration duration: 1
hr.
R= NHCH2COOH, peak
duration: 9 hrs.
ORO
OH
N
O
27. F. To Minimize Toxicity G. To Encourage Patient
Acceptance
H. Elimination of
Formulation Problems
Aspirin: gastric irritation
and bleeding
When R=CH2CONR1R2, no
problems
Sulfa drug: pediatric
antibiotics, bitter taste
(R=H)
When R=CH3CO,
tastless
Prodrug for formaldehyde:
release HCHO in acidic
condition
Used as urinary tract
antisep
28. Carrier-linked Tripartate prodrugs
(Double prodrug approach)
Double ester approach: Penicillin/ Cephalosporin esters
An additional ester or carbamate function is incorporated into the
molecule
Advantages are:
To improve the absorption or to reduce dissolution
And subsequent acid-catalysed decomposition (in the stomach)
These drugs are orally active
Examples: Cefpodoxime Proxetil, Cefuroxime Axetil, Ampicillin,
Becampicillin
32. OH
H3C
HO
+
17alpha-Estradiol, steroid portion
Helps to concentrate the drug in the
prostate
Antiandrogenic effect, slows the growth of
cancer cells
NH
Cl
Cl
+ CO2 + PO4
-2
+ 2Na
Normustard
Alkylating agent
Cytotoxic effect
33. Bioprecursor prodrugs
In vivo reactions that can activate a bioprecursor
• Oxidative activation
• Reductive activation
• Nucleotide activation
• Phosphorylation activation
• Decarboxylation activation
34. Oxidative activation
Oxidative activation ( by Cyt. P450): NSAID Nabumetone
Exhibits reduced gastric irritation compared with other NSAIDs
It contains no acidic functionility and produce no gastric irritation while
passing through the stomach
Subsequently absorbed through intestine, and metabolized in liver to
produce active drug O
CH3
H3CO
Nabumetone
Prodrug
COO
H
H3CO
Active drug
Oxidative bioactivation
Cyt P450
36. Reductive activation
Antineoplastic agent mitomycin C, used in bladder and
lung cancer.
Mitomycin C contains a quinone functionality that
undergoes reduction to give a hydroquinone.
Hydroquinone has an e-withdrawing effect on the e-
pair of the N atom, which allows the e to participate in
the expulsion of methoxide ion and, subsequently,
The loss of carbamate to generate a reactive species,
which may alkylate DNA.
37.
38. Phosphorylation activation
Acyclovir, antiviral drug
Genital herpes simplex virus
infection
Incorporated into DNA as a G
after triple phosphorylation in
infected cells
Acyclovir (R=H)
R=triphosphate, recognized as a dG by
viral DNA polymerase
but not recognized by normal cellular
DNA polymerase
39. Nucleotide activation
Anticancer agent, Acute childhood leukemias
de novo DNA synthesis
Incorporated into DNA after nucleotide formation
40. Site specific chemical delivery system
The drug may lead to undesirable toxic effects in the nontarget
tissues
The problem can be overcome by targeting the drug to its site of
action
The approach of prodrug design is one of the several
approaches of drug targeting
Site-specific chemical delivery requires that the prodrug to
reach the target site
Specific enzymatic or chemical process exists at the target site
The conversion of prodrug to the active drug takes place at the
target site
41. Examples
1. Antiviral drug: Iodoxuridine
Iodoxuridine (prodrug) is specific for those sites at which it serves as a
substrate for phosphorylating enzymes found in viruses.
The prodrug is readily abale to penetrate into the virus, and the increased
polarity of the phosphorylated derivative would serve to retain that active
species inside the virus.
The phosphorylated species: active antiviral agent
The active phosphorylated species is incorporated into viral DNA, disrupting
viral replication and thus producing the antiviral effect.
43. 2. Urinary tract antiseptic: Methenamine
The increased acidity (low pH) of the urine
promotes the hydrolysis to formaldehyde, active
antibacterial agent.
The rate of hydrolysis at plasma (pH 7.4) is low
preventing systemic toxicity from formaldehyde.
Dissolution in stomach and premature hydrolysis
in the highly acidic environment of the stomach
can be prevented by enteric-coating (tablet).
45. 3. L-Dopa
L-Dopa: Site specific chemical delivery system delivering the
drug dopamine into the brain.
L-Dopa is transported into the CNS by an active transport
system and once across the BBB, the L-Dopa undergoes
decarboxylation to yield the active metabolite, dopamine.
Direct systemic administration of dopamine does not produce
significant brain levels of the drug due to its high polarity, and
poor membrane permealibility, as well as it facile metabolic
degradation by oxidative deamination.