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Friday 17 April 2020

Sulphonamides and Sulfones || B.Pharm VI Semester (3rd Year 2nd Sem.) || Medicinal Chemistry-III

STUDY MATERIAL

Pharma Wisdom Jobs 23:17:00 0

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Historical development of Sulfonamides:

Building on Ehrlich’s early work, Gerhard Domagk, a medical doctor employed by a German dye manufacturer made a breakthrough discovery by finding that a dye known as prontosil, dosed orally, was effective in curing life threatening streptococci infections in humans. He made the discovery in a desperate, but successful attempt to save his daughter who was dying of a streptococci infection.

German bacteriologist and pathologist who was awarded the 1939 Nobel Prize for Physiology or Medicine for his discovery (announced in 1932) of the antibacterial effects of Prontosil, the first of the sulfonamide drugs.

Chemistry of Sulfonamides:

- Recognized since 1932.

- In clinical usage since 1935.

First compounds found to be effective antibacterial agents in safe dose ranges.

- Chemically, it is a molecule containing the sulfonamido (sulfanilamide, SO₂NH2) functional group attached to aniline.

- Structurally related to p-amino benzoic acid (PABA).

- Chemical Modification of the sulphonamide structure has given rise to several important groups of drugs.

- This group is also present in other non-antibacterial compounds like

Oral Hypoglycemic – Sulphonyl ureas

Diuretics – Thiazides (Furosemide)

Anti Mycobacterial - Sulphones

Glucoma -Acetazolamide

- All sulfa are white crystalline powder except Sulfaquinoxaline (yellow).

- Sulfa generally are weak organic acid, insoluble in water but much more soluble in alkaline aqueous sol. than in neutral or acidic.

- The spectrum of all sulfonamides is generally the same.

- Sulfonamide inhibit both Gram-positive & Gram negative bacteria, Nocardia, Actinomyces spp, & some Protozoa as Coccidia & Toxoplasma spp. & Streptococcus, Staphylococcus, Salmonella, Pasteurella, & E. coli .

- Sulfa used to treat or prevent acute systemic or local infections.

Mechanism of Sulfonamides :

- Sulfonamide molecular structure is similar to p-Amino benzoic acid (PABA) which is needed in bacteria organisms as a substrate of the enzyme dihydro pteroate synthetase for the synthesis of Tetra Hydro Folic acid (THFA).

- Folic acid - synthesized from PABA, pteridine and glutamate.

- All sulfonamides are analogs of PABA.

- All sulfa drugs are bacteriostatic.

SAR of Sulfonamides:

Structure of Sulphonamides could be divided in to four parts:

1.) Para amino group

2.) Aromatic Ring

3.) Sulphonamide group

4.) N1-Substitution

1. Para Amino Group:

- The para amino group is essential for the activity and must be unsubstituted.

- It should be always substituted on para position of aromatic ring other wise anti bacterial activity is lost.

2. Aromatic Ring:

- It is the minimal structural requirement for the antibacterial activity.

- It should be always para substituted.

- Replacement of Aromatic ring by other ring systems or the introduction of additional substituents on it decreases or abolish activity.

3. Sulphonamide group:

- Sulphonamide group along with aromatic ring is essential for the antibacterial activity.

- Sulphur atom should be directly linked to aromatic ring.

- The amino & Sulphonyl groups on the benzene ring are essential & should be in 1,4-position.

- Exchange of the -SO2NH group by –CO-NH reduce the activity.

4. N1-Substitution:

- Sulphonamide nitrogen should be primary or secondary.

- R could be substituted with hydrogen, aromatic ring or heterocyclic ring.

- Substitution of Aromatic Heterocyclic nuclei at N¹ - yields highly potent compounds.

- N¹ –Di substitution in general leads to inactive.

Classification of Sulphonamides:

Sulfonamide Structures:

Synthesis of Sulfacetamide:

Synthesis of Sulfamethoxazole:

Adverse Effects:

- Produce mild-to-moderate nausea, vomiting, headache and mental depression.

- Produce hypersensitivity reactions (rashes, fever, eosinophilia).

- Rarely cause Stevens-Johnson Syndrome, erythema multiforme associated with lesions of skin and mucous membranes.

- Produce Kernicterus (bilirubun-induced brain dysfunction) in neonates because of the displacements of bilirubin form serum albumin binding site.

- Sever adverse effects includes hepatitis, bone marrow depression and crysalluria

Folate Reductase Inhibitors:

TRIMETHOPRIM:

- Trimethoprim is selective inhibitor of bacterial DHFR

- Individually they both are bacteriostatic but the combination is bactericidal

CO-TRIMOXAZOLE:

Fixed dose combination

SULPHAMETHAXAZOLE : TRIMETHOPRIM (5 : 1)

- SEQUENTIAL BLOCK.

- Broad spectrum bactericidal combination.

- Delays the development of bacterial resistance

Synthesis of Trimethoprim:

Sulfones:

A sulfone is a chemical compound containing a sulfonyl functional group attached to two carbon atoms. The central hexavalent sulfur atom is double-bonded to each of two oxygen atoms and has a single bond to each of two carbon atoms, usually in two separate hydrocarbon substituents.

Dapsone (diamino diphenyl sulfone, DDS), It was discovered by German chemists Fromm and Wittmann in 1908, Was not utilized as a treatment until decades later.

Dapsone is used to treat dermatitis herpetiformis (a skin condition) and leprosy.

It is also used with other drugs to treat Hansen's disease.

Dapsone is commonly used in combination with rifampicin and clofazimine for the treatment of leprosy

Synthesis of Dapsone:

Note: All information copyright @ www.pharmawisdom.co.in

Prepared By:
S.Seetaramswamy, M.Pharm
Assoc. Prof.
Dept. Pharmaceutical Chemistry

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Drugs acting on Autonomic Nervous System (Sympathomimetic agents & Adrenergic Antagonists) || B.PHARM SEMESTER IV (2nd Year 2nd Sem.) || Unit-2 || Medicinal Chemistry-I

STUDY MATERIAL

Pharma Wisdom Jobs 23:30:00 2

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The nervous system is a complex network of nerves and cells that carry messages to and from the brain and spinal cord to various parts of the body.

The Central nervous system is made up of the brain and spinal cord and The Peripheral nervous system is made up of the Somatic and the Autonomic nervous systems.

Adrenergic Neurotransmitters are 3 types

Collectively called catecholamines

1. Noradrenaline (NA) - at postganglionic sympathetic sites (except sweat glands, hair follicles) & in certain areas of brain.

2. Adrenaline (Adr) - secreted by adrenal medulla

3. Dopamine (DA) - transmitter in basal ganglia, limbic system, CTZ, anterior pituitary.

Biosynthesis of Catecholamine

Steps in the synthesis of Catecholamines (CAs)

- Synthesis of CAs

- Storage of CAs

- Release of CAs

- Uptake of CAs

- Metabolism of CAs

All belong to super family of G-protein-coupled receptors.

Adrenergic receptors are classified into two types

Sympathomimetic drugs / Adrenergic Agonist

Adrenergic drugs are medications that stimulate certain nerves in your body. They do this either by mimicking the action of the chemical messengers epinephrine and norepinephrine or by stimulating their release. These drugs are used in many life-threatening conditions, including cardiac arrest, shock, asthma attack, or allergic reaction.

Sympathomimetic agents that partially or completely mimic the actions of norepinephrine (NE) or Epinephrine (Epi).

They are also called as Sympathomimetic drugs / Adrenomimetic Drugs / Adrenergic Agonist / Adrenoreceptor Agonists

Classification of Sympathomimetic Drugs:

They are chemically classified into two main categories
A) Catecholamines
B) Non-catecholamines

SAR of Adrenergic Agonists / β-phenylethylamines / Sympathomimetic Agents/ Arylethanolamines
1. Structure required for Activity

a) Phenyl Ethylamine as parent compound

b) Catechol or Aromatic Ring

c) β-carbon hydroxy & amino terminal

Replacement of meta hydroxyl of catechol increases β2 selectivity and decreases metabolism by COMT.

Removal of para hydroxyl group from epinephrine produce selective α1 agonist.

Substitution at nitrogen

The nature of amino substituent determines α / β receptor selectivity.

As the size of alkyl group on nitrogen increases, activity at α-receptor decreases and activity at β -receptor increases.

Synthesis of Phenylephrine:

Synthesis of Salbutamol:

Therapeutic Uses of Sympathomimetic Agents:

A – Anaphylactic Shock – Exp: Epinephrine

B – Bronchial Asthma – Exp: Salbutamol, Terbutaline, Isoprenaline, Epinephrine

C – Cardiogenic shock – Exp: Dobutamine / Cardiac Arrest - Exp: Epinephrine

D – Delay of Parturition – Exp: Terbutaline, Ritodrine / Delay absorption of Local Anesthetics – Exp: Adrenaline

H – Hypertension – Exp: Clonidine

M – Migraine – Exp: Clonidine

N – Used as CNS stimulant in Narcolepsy – Exp: Amphetamine

N – Nasal Decongestion – Exp: Ephedrine, Phenylephrine, Methoxamine

P – Premature labor – Exp: Salbutamol

Sympatholytic drugs / Adrenergic Antagonist

The agents which antagonise the action of Sympathomimetic agents or sympathetic stimulations are called Sympatholytic agents.

Alpha adrenergic blockers / Alpha Antagonists

Alpha & Beta Antagonists are prevent the interaction of endogenous neurotransmitter NE or Sympathomimetics with corresponding adrenergic receptors.

Bind specifically to alpha receptors and interfere with catecholamine and Sympathomimetic action.

Role of Alpha-1 & Alpha-2 Antagonists

Alpha-1:

- Vasoconstriction

- Increased peripheral resistance

- Increased blood pressure

Alpha-2:

- Inhibition of Norepinephrine release

- Inhibition of insulin release

Classification of Alpha Blockers:

Structures of Alpha Blockers

Synthesis of Tolazoline:

Therapeutic Uses of Alpha-Adrenergic Blockers:

Hypertension - alpha-1 selective

• Pheochromocytoma (Conditions associated with increased sympathetic activity)

• Hemodynamic shock

• Peripheral vascular disease – Raynaud’s

• Congestive heart failure (CHF)

• Benign prostatic hyperplasia (BPH)

• Pulmonary hypertension – tolazoline

Beta adrenergic blockers / Beta Antagonists

Bind selectively to beta receptors

Interfere with ability of catecholamines or Sympathomimetics to

provoke beta receptors (heart, smooth muscle of airway and blood vessel).

Propranolol is standard beta antagonist drug to which all beta

antagonists are compared.

Role of Beta-1 & Beta-2 Antagonists

Beta-1:

- Tachycardia

- Increased lipolysis

- Increased myocardial contractility

Beta-2:

- Vasodilation

- Bronchodilation

Classification of Beta Blockers:

Structures for Beta Blockers:

Synthesis of Propranolol:

SAR of Beta Blockers / Adrenergic Antagonists / Sympatholytic Agents/ Aryloxy Propanolamines

1. OCH₂ group is placed between the aromatic ring and ethanolamino side chain, which is essential for the activity.

2. The hydroxyl bearing carbon of the aryloxy prpanolamine side chain play critical role in the interaction of β-antagonist drugs with β-receptor.

3. Alkyl Amino group is must be a secondary amine for optimal activity.

4. Isopropyl and t-butyl groups present on the amino group provides nucleophilicity to the amino group. E.g: Atenolol

5. The two carbon chains are essential for activity.

6. N, N-disubstitution decreases the beta blocking activity.

7. The aromatic ring and it substituent is the primary determinant of β1 antagonist activity.

8. Alkenyl groups present in the ortho position on aryl ring gives good beta antagonist activity. E.g: Oxprenolol, Alprenolol

9. Most of the derivatives have different aryl group like Phenyl, Naphthalene & Indole. E.g: Atenolol, Propranolol & Pindolol

Therapeutic Uses of Beta-Adrenergic Blockers:

Note: All information copyright @ www.pharmawisdom.co.in

Prepared By:
S.Seetaramswamy
Assoc. Prof.
Dept. Pharmaceutical Chemistry

For More Pharma Study Materials - Click Here

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Why GMP? An explanation of Good Manufacturing Practice...!!

STUDY MATERIAL

Pharma Wisdom Jobs 14:11:00 3

GMP refers to the Good Manufacturing Practice Regulations published by the FDA under the Federal Food, Drug, and Cosmetic Act. As a response to concerns about substandard drug manufacturing practices occurring at the time, Congress enacted the 1962 Drug Amendments. These amendments instructed the FDA to require all drugs to be made according to Good Manufacturing Practice (GMP) as defined under FDA 21 CFR Part 210-211.

The first set of Good Manufacturing Practices (GMP) regulations were published in 1963. These regulations are meant to guide companies in the production of safe and effective drugs. The regulations outlined in the GMPs are the minimum requirements necessary to ensure safe and effective products.

In this blog we'll discuss the definition of GMP, various regulatory components, and why it's important for companies in the life sciences space.

Trained inspectors for the FDA examine facilities around the world, including those facilities that produce the active ingredients and final products. The FDA also reviews consumer and industry complaints filed about the drug, using these reports to identify sites that could benefit from inspection.

About GMP

GMP is a set of regulations that ensures the quality of drugs, medical devices, blood, and some types of food. The regulations cover manufacturing, facilities and controls for the manufacturing, processing, packaging or holding of a drug product.

When discussing current good manufacturing practices, many agencies use the acronym cGMP, with the letter ‘c’ standing for ‘current.’ This nomenclature reminds companies to use the most up-to-date technologies and systems in order to comply with current regulations. Many older GMP practices, specifically those designed to prevent errors, mix-ups and contamination, are now outdated and inadequate.

About Part 210 and 211

21 CFR Part 210 and 211 outline the manufacture, processing, packing, or holding of a drug specifically, although supporting companies and services can benefit by compliance with these standards as well.

Part 210.2 applies to drug products intended for human use and lays out definitions for terms used within the document. Part 211 describes important issues.

Its 11 sub-parts discuss all sections of drug manufacturing operations:

1. General Provision

2. Organization and Personnel

3. Building and Facilities

4. Equipment

5. Control of Components and Drug Product Containers and Closures

6. Production and Process Controls

7. Packaging and Labeling Controls

8. Holding and Distribution

9. Laboratory Controls

10. Records and Reports

11. Returned and Salvaged Drug Product

Each section of code outlines a different GMP activity. 211.22 details the responsibilities of a quality control unit, for example, while 211.25 discusses personnel qualifications, 211.28 deals with sanitation, clothing, protective apparel, hygiene and health habits and 211.34 offers guidelines on working with consultants. Part 1271 subparts C and D describes donor-eligibility and applicable current good tissue practice procedures for owners and operators of establishments engaged in the recovery, donor screening, donor testing and other types of testing, processing, storage, labeling, packaging, or distribution of human cells, tissue samples, and cellular and tissue-based products (HCT/Ps).

What GMP Means for Companies in the Life Sciences Space

GMP regulations address a wide range of production activities, including starting materials, sanitation and cleanliness of the premises, equipment verification, and process validation. GMP regulations even extend into human resources and general offices, offering practice guidelines for record keeping, personnel qualifications, complaints, training, and personal hygiene of staff working in regulated areas. GMP requires documented proof of consistent adherence to established procedures at every step in the production process.

While stringent in their requirement for quality, most GMP regulations are open-ended and flexible in that they allow individual companies the latitude to decide on the best way to implement the controls necessary to achieve the highest quality within each organization. Failure to comply with these regulations may result in regulatory action for the drug and for the company responsible for the failure.

Virtually every person in the United States is affected by the quality of pharmaceuticals. Nearly 70 percent of Americans take a prescription drug, according to Mayo Clinic, and almost half take two. The use of non-prescription or over-the-counter (OTC) drugs and supplements is also widespread. cGMPs are important because consumers cannot easily detect an unsafe or ineffective product simply by looking, smelling or touching it. GMP testing, typically performed on small samples from a batch, ensures that the rest of the batch provides the high quality medication or supplementation desired by these consumers.

What is Good Manufacturing Practices (GMP)?

GMP (Good Manufacturing Practice) is part of a quality system covering the manufacture and testing of pharmaceutical dosage forms or drugs and active pharmaceutical ingredients, diagnostics, foods, pharmaceutical products, and medical devices. GMPs are guidance that outlines the aspects of production and testing that can impact the quality of a product.

Quality Assurance / GMP Objectives

Quality Assurance is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice.

The system of quality assurance appropriate to the manufacture of pharmaceutical products to ensure that:
Pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) and good clinical practice (GCP)
Production and control operations are clearly speciﬁed in a written form and GMP requirements are adopted
Managerial responsibilities are clearly speciﬁed in job descriptions
Arrangements are made for the manufacture, supply and use of the correct starting and packaging materials
All necessary controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations, and validations are carried out
The ﬁnished product is correctly processed and checked, according to the deﬁned procedures
Pharmaceutical products are not sold or supplied before the authorized persons have certiﬁed that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of pharmaceutical products
Satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored by the manufacturer, distributed, and subsequently handled so that quality is maintained throughout their shelf-life
Deviation/complain and recalls are reported, investigated and recorded
There is a system for approving changes that may have an impact on product quality
Regular evaluations of the quality of pharmaceutical products should be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement

What is GMP in Pharmaceutical Products?

Good manufacturing practice is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization.

GMP is aimed primarily at diminishing the risks inherent in any pharmaceutical production. Such risks are essentially of two types: cross contamination (in particular of unexpected contaminants) and mix-ups (confusion) caused by, for example, false labels being put on containers.

Good Manufacturing Practice is concerned with both production and quality control.

Under GMP:

>All manufacturing processes are clearly deﬁned, systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their speciﬁcations

>Critical steps of manufacturing processes and significant changes to the process are validated;

All necessary facilities for GMP are provided, including

Appropriately qualiﬁed and trained personnel Adequate premises and space Suitable equipment and services Appropriate materials, containers and labels Approved procedures and instructions; Suitable storage and transport; Adequate personnel, laboratories and equipment for in-process controls Instructions and procedures are written in clear and unambiguous language, speciﬁcally applicable to the facilities provided Operators are trained to carry out procedures correctly Records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the deﬁned procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected; any signiﬁcant deviations are fully recorded and investigated Records covering manufacture and distribution, which enable the complete tracing history of the batch, are retained in a comprehensible and accessible form Proper storage and distribution of the products minimizes any risk to their quality are in place and documented A system is available to recall any batch of product from sale or supply

Complaints about marketed products are examined; the causes of quality defects investigated, and appropriate measures taken in respect of the defective products to prevent recurrence
no batch of product is released for sale or supply prior to certification by an authorised person that it is in accordance with the requirements of the relevant authorisations

Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory.

The basic requirements of Quality control are that:

Adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes;
Samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control;

Test methods are validated;

Records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated;
The finished products contain active ingredients complying with the qualitative and quantitative composition of the marketing authorisation, are of the purity required, and are enclosed within their proper containers and correctly labelled;
Records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;
All batch of product are completely analyzed and approved in accordance with the requirements of the relevant authorization
Sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.