Chemical Science of CSIR Syllabus

Related tags: chemical analysis, syllabus questions, Mass spectroscopy
PAPER 1– SECTION A
1. General information on science and its interface with society to test the candidate’s awareness of science, aptitude of scientific and quantitative reasonsing.
2. COMMON ELEMENTRY COMPUTER SCIENCE ( Applicable to all candidates offering subject areas ).
3. History of development of computers, Mainframe, Mini, Micro’s and Super Computer Systems.
4. General awareness of computer Hardware i..e. CPU and other peripheral devices ( input / output and auxiliary storage devices ).
5. Basic knowledge of computer systems, software and programming languages i.e. Machine language, Assembly language and higher level language.
6. General awareness of popular commercial software packages like LOTUS, DBASE, WORDSTAR, other Scientific application packages.

PAPER 1 – SECTION B
1. Structure and Bonding : Atomic orbitals, electronic configuration of atoms ( L – S coupling ) and the periodic properties of elements ; ionic radii, ionization potential, electron affinity, electronegativity; concept of hybridization. Molecular orbitals and electronic configuration of homonuclear and heteronucelar diatomic molecules. Shapes of polyatomic molecules; VSEPR, theory. Symmetry elements and point groups for simple molecules. Bond lengths, bond angles, bond order and bond energies. Types of Chemical Bond ( weak and strong ) intermolecular forces, structure of simple ionic and covalent solids, lattice energy.
2. Acids and Bases : Bronsted and Lewis acids and bases, pH and pKa, acid-based concept in non-acqueous media ; HSAB concept. Buffer solution.
3. Redox Reactions : Oxidation numbers, Redox potential, Electrochemical series, Redox indicators.
4. Energetics and Dynamics of Chemical Reactions : Law of conservation of energy, Energy and entheipy of reactions. Entropy, free-energy, relationship between free energy change and equilibrium. Rates of chemical reactions (first-and second-order reactions). Arrhenius equation and concept of transition state. Mechanisms, including SN 1 and SN 2 reactions, electron transfer reactions, catalysis. Coiligative properties of solutions.
5. Aspects of s, p, d, f, Block Elements : General characteristics of each block. Chemical principles involved in extractions and purification of iron, copper, lead, zinc and aluminium. Coordination chemistry; structural aspects, isomerism, octahedral and tetrahedral crystal – field splitting of dorbitals. CFSE, magnetism end colour of transition metal ions. Sandwich compounds, metal carbonyls and metal clusters. Rare gas compounds, non-stoichiometric oxides. Radio activity and transmutation of elements, isotopes and their applications.
6. IUPAC Nomenciature of Simple Organic and Inorganic Compounds.
7. Concept of Chirality : Recognition of symmetry elements and chiral structures; R – S nomenciature, diastereoisomerism in acyclic and cyclic systers; E – Z isomerisms. Conformational analysis of simple cyclic ( chair and boat cyclo hexanes ) and acyclic systems. Interconversion of Fischer, Newman and Sawhorse projections.
8. Common Organic Reactions and Mechanisms : Reactive intermediates, Formation and stability of carbonium ions, carbanians, carbenes, nitrenes, radicals and arynes. Nucleophilic, electrophilic, radical substitution, addition and elimination reactions. Familiar name reactions : Aldol, Perkin, Stobbe, Dieckmann condensations; Holmann, Schmidt, Lossen, Curtius, Backmann and Fries rearrangements; Reimer – Tiemann, Reformatsky and Grignard reactions. Diels – Aider reactions; Clasien rearrangements; Friedeal – Crafts reaftions; Witting reactions; and robinson annulation. Routine functional group transformations and interconversions of simple functionalities. Hydroboration, Oppenaur oxidations; Clemmensen, Wolff-Kishner, Meerwein – Ponndorf – Verley and Birch reductions.
9. Elementary principles and applications of electronic, vibrational, NMR, EPR and Mass Spectral techniques to simple structural problems.
10. Data Analysis : Types of errors, propagation of errors, accuracy and precision, least-squares analysis, average standard deviation.

11. Statistical Tharomodynamics : Thermodynamic probability and entropy; Maxwell – Boltzmann, Bose – Einstein and Fermi – Dirac statistics. Partition function; rotational translational, vibratioanl and electronic partition functions for diatomic molecules; calculations of thermodynamic functions and equilibrium constants. Theories of specific heat for solids.
12. Non-equilibrium Thermodynamics : Postulates and methodologies, linear laws, Gibbs equation, Onsager reciprocal theory.
13. Reaction Kinetics : Methods of determining rate laws. Mechanisms of photochemical, chain and oscillatory reactions. Collision theory of reaction rates; steric factor, treatment of unimolecular reactions. Theory of absolute reaction rates, comparison of results with Eyring and Arrhenius equations, ionic reactions; salt effect. Homogeneous catalysis and Michaelis – Menten kinetics; heterogeneous catalysis.
14. Fast Reaction : Luminescence and Energy transfer processes. Study of kinetics by stopped flow technique, relazation method, flash photolysis and magnetic resonance method.
15. Macromolecules : Number – average and weight average molecular weights ; determination of molecular weights. Kinetics of polymerization. Stereochemistry and mechanism of polymerization.
16. Solids : Dislocation in solids, Schottky and Frenkel defects, Electrical properties; insulators and semiconductors; superconductors, band theory of solids, Solid-state reactions.
17. Nuclear Chemistry : Radioactive decay and equilibrium. Nuclear reactions ; Q value, cross sections, types of reactions, Chemical effects of nuclear transformations; fission and fusion, fission products and fission yields. Radioactive technique; tracer technique, neutron activation analysis, counting techniques such as G. M. ionization and proportional counter.
18. Chemistry of Non-transition Elements : General discussion on the properties of the non-transition elements; special features of individual elements; synthesis, properties and structure of their halides and oxides, polymorphyism of carbon, phosphorus and sulphur. Synthesis, properties and structure of boranes, carboranes, borazines, silicates carbides, silicones, phosphazenes, sulphur-nitrogen compounds; peroxo compounds of boron, carbon and sulphur; oxy acids of nitrogen, phosphours, sulphur and halogens, interhalogens pseudohalides and noble gas compounds.
19. Chemistry of Transition Elements : Coordination chemistry of transition metal ions ; Stability constants of complexes and their determination; stabilization of unusual oxidation states. Stereochemistry of coordination compounds. Ligandfield theory, splitting of d-orbitals in low-symmetry environments. Jahn – Teller effect; interpretation of electronic spectra including charge transfer spectra ; spectrochemical series, nephelauxetic series ,Magnetism; Dia-, para-, ferro- and antiferromagnetism, quenching of orbital angular moment, spinorbit copling, inorganic reaction mechanisms; substitution reactions, trans effect and electron transfer reactions, photochemical reaction of chromium and ruthenium complexes. Fluxional molecules iso-and heteropolyacids ; metal clusters. Spin crossover in coordination compounds.
20.Chemistry of Lanthanides and Actinides : Spectral and magnetic properties; Use of lanthanide compounds as shift reagents.
21. Organometallic Chemistry of Transition Elements : Synthesis, structure and bonding, organometallic reagents in organic synthesis and in homogeneous catalytic reactions ( hydrogenation, hydroformayalation, isomerisation and polymerization ); pl-acid metal complexes, activation of small molecules by coordination.
22. Topics in Analytical Chemistry : Adsorption partition, exclusion electrochromatography, Solvent extraction and ion exchange, methods. Application of atomic and molecular absorption and emission spectroscopy in quantitative analysis Light scattering techniques including nephelometry and Raman spectroscopy. Electroalytical techniques: voltammetry, cyclit, voltammetry, polarography, amperometry, coulometry and comductometry ion-elective electrodes. Annodic stripping voltammetry; TGA, DTA, DSC and online analysors.
23. Bioinorganic Chemistry : Metal ions in Biology, Molecular mechanism of ion transport across membranes; ionophores. Photosynthesis, PSL, PSH; nitrogen fixation, oxygen uptake proteins, cytochromes and ferrodoxins.
24. Aromaticity : Huckel’s rule and concept of aromaticty (n) annulences and heteroannulenes, fulterenes (C60).
25. Stereochemistry and conformational Analysis : Nwere method of asymmetric synthesis ( including enzymatic and catalytic nexus ), enantio and diastereo selective synthesis. Effects of conformation on reactivity in acyclic compounds and cyclohexanes.
26. Selective Organic Name Reactions : Favorskli reaction; Stork enamine reaction; Michael addition, Mannich Reaction; Sharpless asymmetric epoxidation; Ene reaction, Barton reaction, Holmann-Loffer-Freytag reaction, Shapiro reaction, Baeyer-Villiger reaction, Chichibabin reaction.
27. Mechanisms of Organic Reactions : Labelling and Kinetic isotope effects, Hamett equation, ( sigma-rho ) relationship, non-classical carbonium ions, neighbouring group participation.
28. Pericyclic Reactions : Selection rules and stereochemistry of electrocyclic reactions, cycloaddition and sigmatropic shifts, Sommelet, Hauser, Cope and Claisen rearrangements.
29. Heterocyclic Chemistry : Synthesis and reactivity of furan, thiophene, pyrrole, pyridine, quinoline, isoquinoline and indole; Skraup synthesis, Fisher indole synthesis.30. Reagents in Organic Synthesis : Use of the following reagents in organic synthesis and functional group transformations ; Complex metal hybrids, Gilman’s reagent, lithium dimethycuprate, lithium disopropylamide (LDA) dicyclohexylcarbodimide. 1,3 – Dithiane (reactivity umpolung), trimethysilyl iodide, tri-n-butyltin hybride, Woodward and provost hydroxylation, osmium tetroxide, DDQ, selenium dioxide, phase transfer catalysts, crown ethers and Merrified resin, Peterson’s synthesis, Wilkinson’s catalyst, Baker yeast.
31. Chemistry of Natural Products : Familiarity with methods of structure elucidation and biosynthesis of alkaloids, terponoids, steroids, carbohydrates and proteins.
32. Bio-organic Chemistry : Elementry structure and function of biopolymers such as proteins and nucleric acids.
33. Photochemistry : Cis – trans isomeriation, Paterno – Buchi reaction, Norrish Type I and II reactions, photoreduction of ketones, di-pimethane rearrangement, photochemistry of areanes.
34. Spectroscopy : Applications of mass, UV – VIS, IR and NMR spectroscopy for structural elucidation of compound.

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Mechanism of Diels-Alder reaction

Diels-Alder reaction

This reaction was discovered by two German chemists named Otto Diels and Kurt Alder. Conjugated dienes undergo a cycloaddition reaction with multiple bonds to form unsaturated six-membered rings. This reaction involves the 1,4-addition of a diene and a dienophile. This reaction proved to be of great importance as yield was 100% and hence they received the Nobel Prize in 1950.






Reaction mechanism
The Diels-Alder reaction is a thermal cycloaddition whose mechanism involves the sigma-overlap of the pi-orbitals of the two unsaturated systems. There is not a single mechanism for all Diels-Alder reaction. At first approximation, we can divide them into two classes:

1.Synchronous and symmetrical (concerted) mechanisms when the two new bonds are formed simultaneously. In the transition state, the two forming bonds have the same lengths. The combination of ethylene and butadiene is one example.
2.Multistage (non-concerted) and asynchronous mechanisms. The transition state is a di-radical, one bond being formed, the other not.

Real mechanisms are a mixture of these two extremes, one bond being more properly formed and thus shorter than the other.
















To have an idea of the mechanism and to calculate the activation energy of a reaction, we have to find its transition state, using a gradient minimization. The transition state of the Diels-Alder addition of butadiene and ethylene shows that it looks like the reactants. It is called an early transition state.
Typically, the Diels-Alder reaction works best when either the diene is substituted with electron donating groups (like -OR, -NR2, etc) or when the dienophile is substituted with electron-withdrawing groups (like -NO2, -CN, -COR, etc).

Conformational requirements of the diene
One quirk of the Diels-Alder reaction is that the diene is required to be in the s-cis conformation in order for the Diels-Alder reaction to work. The s-cis conformation has both of the double bonds pointing on the same side of the carbon-carbon single bond that connects them. In solution, the carbon-carbon single bond in the diene that connects the two alkenes is constantly rotating, so at equilibrium there is usually some mixture of dienes in the s-trans conformation and some in the s-cis conformation. The ones that are at that moment in the s-trans conformation do not react, while the ones in the s-cis conformation can go on to react.






Because of the Diels-Alder's requirement for having the diene in a s-cis conformation, dienes in rings react particularly rapidly because they are "locked" in the s-cis conformation. Unlike dienes in open chains in which there is usually some proportion of the diene in the unreactive s-trans conformation, dienes in rings are held in the reactive conformation at all times by the constraints of the ring, making them react faster.







Stereochemistry of Diels-Alder reaction
If the dienophile is disubstituted (substituted twice), there is the possibility for stereochemistry in the product. In the Diels-Alder reaction, you end up with the stereochemistry that you started with. In other words, if the substituents started cis (on the same side) on the dienophile, they end up cis in the product. If they started trans (opposite sides) on the dienophile, they end up trans in the product.

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Photochromic materials

Photochromic materials


Photochromic molecules can belong to various classes: triarylmethanes, stilbenes, azastilbenes, nitrones, fulgides, spiropyrans, naphthopyrans, spiro-oxazines, quinones.




Spiropyrans and Spriooxazines

Spiro-mero photochromism.
One of the oldest, and perhaps the most studied, families of photochromes are the spiropyrans.

Very closely related to these are the spirooxazines.

For example, the spiro form of an oxazine is a colorless leuco dye; the conjugated system of the oxazine and another aromatic part of the molecule is separated by a sp³-hybridized "spiro" carbon. After irradiation with UV light, the bond between the spiro-carbon and the oxazine breaks, the ring opens, the spiro carbon achieves sp² hybridization and becomes planar, the aromatic group rotates, aligns its π-orbitals with the rest of the molecule, and a conjugated system forms with ability to absorb photons of visible light, and therefore appear colorful. When the UV source is removed, the molecules gradually relax to their ground state, the carbon-oxygen bond reforms, the spiro-carbon becomes sp³ hybridized again, and the molecule returns to its colorless state.

This class of photochromes in particular are thermodynamically unstable in one form and revert to the stable form in the dark unless cooled to low temperatures. Their lifetime can also be affected by exposure to UV light. Like most organic dyes they are susceptible to degradation by oxygen and free radicals. Incorporation of the dyes into a polymer matrix, adding a stabilizer, or providing a barrier to oxygen and chemicals by other means prolongs their lifetime.

Diarylethenes

Dithienylethene photochemistry

The "diarylethenes" were first introduced by Irie and have since gained widespread interest, largely on account of their high thermodynamic stability. They operate by means of a 6-pi electrocyclic reaction, the thermal analog of which is impossible due to steric hindrance. Pure photochromic dyes usually have the appearance of a crystalline powder, and in order to achieve the color change, they usually have to be dissolved in a solvent or dispersed in a suitable matrix. However, some diarylethenes have so little shape change upon isomerization that they can be converted while remaining in crystalline form.

Photochromic quinones

Some quinones, and phenoxynaphthacene quinone in particular, have photochromicity resulting from the ability of the phenyl group to migrate from one oxygen atome to another. Quinones with good thermal stability have been prepared, and they also have the additional feature of redox activity, leading to the construction of many-state molecular switches that operate by a mixture of photonic and electronic stimuli.

Inorganic photochromics

Many inorganic substances also exhibit photochromic properties, often with much better resistance to fatigue than organic photochromics. In particular, silver chloride is extensively used in the manufacture of photochromic lenses. Other silver and zinc halides are also photochromic.

Fulgides

Triarylmethanes

Triphenylmethane, or triphenyl methane, is the hydrocarbon with the formula (C6H5)3CH. This colorless solid is soluble in nonpolar organic solvents, but not water. Triphenylmethane has the basic skeleton of many synthetic dyes called triarylmethane dyes, many of them are pH indicators, and some display fluorescence. A trityl group in organic chemistry is a triphenylmethyl group Ph3C, e.g. triphenylmethyl chloride — trityl chloride

Examples of triarylmethane dyes are bromocresol green or malachite green

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Photochromism

Photochromism

Photochromism is the reversible transformation of a chemical species between two forms by the absorption of electromagnetic radiation, where the two forms have different absorption spectra. Trivially, this can be described as a reversible change of color upon exposure to light. The phenomenon was discovered in the late 1880s, including work by Markwald, who studied the reversible change of color of 2,3,4,4-tetrachloronaphthalen-1(4H)-one in the solid state. He labeled this phenomenon "phototropy", and this name was used until the 1950s when Yehuda Hirshberg, of the Weizmann Institute of Science in Israel proposed the term "photochromism".Photochromism can take place in both organic and inorganic compounds, and also has its place in biological systems (for example retinal in the vision process).


Photochromism does not have a rigorous definition, but is usually used to describe compounds that undergo a reversible photochemical reaction where an absorption band in the visible part of the electromagnetic spectrum changes dramatically in strength or wavelength. In many cases, an absorbance band is present in only one form. The degree of change required for a photochemical reaction to be dubbed "photochromic" is that which appears dramatic by eye, but in essence there is no dividing line between photochromic reactions and other photochemistry. Therefore, while the trans-cis isomerization of azobenzene is considered a photochromic reaction, the analogous reaction of stilbene is not. Since photochromism is just a special case of a photochemical reaction, almost any photochemical reaction type may be used to produce photochromism with appropriate molecular design. Some of the most common processes involved in photochromism are pericyclic reactions, cis-trans isomerizations, intramolecular hydrogen transfer, intramolecular group transfers, dissociation processes and electron transfers (oxidation-reduction).
Another somewhat arbitrary requirement of photochromism is that it requires the two states of the molecule to be thermally stable under ambient conditions for a reasonable time. All the same, nitrospiropyran (which back-isomerizes in the dark over ~10 minutes at room termperature) is considered photochromic. All photochromic molecules back-isomerize to their more stable form at some rate, and this back-isomerization is accelerated by heating. There is therefore a close relationship between photochromic and thermochromic compounds. The timescale of thermal back-isomerization is important for applications, and may be molecularly engineered. Photochromic compounds considered to be "thermally stable" include some diarylethenes, which do not back isomerize even after heating at 80 C for 3 months.

Since photochromic chromophores are dyes, and operate according to well-known reactions, their molecular engineering to fine-tune their properties can be achieved relatively easily using known design models, quantum mechanics calculations, and experimentation. In particular, the tuning of absorbance bands to particular parts of the spectrum and the engineering of thermal stability have received much attention.

Sometimes, and particularly in the dye industry, the term "irreversible photochromic" is used to describe materials that undergo a permanent color change upon exposure to ultraviolet or visible light radiation. Because by definition photochromics are reversible, there is technically no such thing as an "irreversible photochromic"—this is loose usage, and these compounds are better referred to as "photochangable" or "photoreactive" dyes.

Apart from the qualities already mentioned, several other properties of photochromics are important for their use. These include
Quantum yield of the photochemical reaction. This determined the efficiency of the photochromic change with respect to the amount of light absorbed. The quantum yield of isomerization can be strongly dependent on conditions (see below).

Fatigue resistance. In photochromic materials, fatigue refers to the loss of reversibility by processes such as photodegradation, photobleaching, photooxidation, and other side reactions. All photochromics suffer fatigue to some extent, and its rate is strongly dependent on the activating light and the conditions of the sample.

Photostationary state. Photochromic materials have two states, and their interconversion can be controlled using different wavelengths of light. Excitation with any given wavelength of light will result in a mixture of the two states at a particular ratio, called the "photostationary state". In a perfect system, there would exist wavelengths that can be used to provide 1:0 and 0:1 ratios of the isomers, but in real systems this is not possible, since the active absorbance bands always overlap to some extent.

Polarity and solubility. In order to incorporate photochromics in working systems, they suffer the same issues as other dyes. They are often charged in one or more state, leading to very high polarity and possible large changes in polarity. They also often contain large conjugated systems that limit their solubility.

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Fischer Indole Synthesis

Fischer Indole Synthesis

Overall Reaction

This oldest indole synthesis method transforms aryl hydrazones to indoles and requires elevated temperatures and the addition of Brønsted or Lewis acids.

This reaction is good for preparing 2-, 3-, 5-and 7-substituted indoles but is poorer for the preparation of 4- and 6-substituted indoles, due to lack of regioselectivity.

Mechanism of Fischer Indole Synthesis

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Drug Screening

Screening and Design

The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening (HTS), wherein large libraries of chemicals are tested for their ability to modify the target.
For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor (see antagonist and agonist): if the target is a protein kinase, the chemicals will be tested for their ability to inhibit that kinase.

Another important function of HTS is to show how selective the compounds are for the chosen target. The ideal is to find a molecule which will interfere with only the chosen target, but not other, related targets. To this end, other screening runs will be made to see whether the "hits" against the chosen target will interfere with other related targets - this is the process of cross-screening. Cross-screening is important, because the more unrelated targets a compound hits, the more likely that off-target toxicity will occur with that compound once it reaches the clinic.

It is very unlikely that a perfect drug candidate will emerge from these early screening runs. It is more often observed that several compounds are found to have some degree of activity, and if these compounds share common chemical features, one or more pharmacophores can then be developed. At this point, medicinal chemists will attempt to use structure-activity relationships (SAR) to improve certain features of the lead compound:
increase activity against the chosen target
reduce activity against unrelated targets
improve the "drug-like" or ADME properties of the molecule.

This process will require several iterative screening runs, during which, it is hoped, the properties of the new molecular entities will improve, and allow the favoured compounds to go forward to in vitro and in vivo testing for activity in
the disease model of choice.

While HTS is a commonly used method for novel drug discovery, it is not the only method. It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon (so-called "me too" drugs). Other methods, such as virtual high throughput
screening, where screening is done using computer-generated models and attempting to "dock" virtual libraries to a target, are also often used.

Another important method for drug discovery is drug design, whereby the biological and physical properties of the target are studied, and a prediction is made of the sorts of chemicals that might (eg.) fit into an active site. Novel pharmacophores can emerge very rapidly from these exercises.

Once a lead compound series has been established with sufficient target potency and selectivity and favourable drug-like properties, one or two compounds will then be proposed for drug development. The best of these is generally called the lead compound, while the other will be designated as the "backup".

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Drug design | construction of drug molecule

Drug design

Drug design is the approach of finding drugs by design, based on their biological targets. Typically a drug target is a key molecule involved in a particular metabolic or signalling pathway that is specific to a disease condition or pathology, or to the infectivity or survival of a microbial pathogen.
Some approaches attempt to stop the functioning of the pathway in the diseased state by causing a key molecule to stop functioning.
Drugs may be designed that bind to the active region and inhibit this key molecule.
However these drugs would also have to be designed in such a way as not to affect any other important molecules that may be similar in appearance to the key molecules. Sequence homologies are often used to identify such risks.
Other approaches may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state.
The structure of the drug molecule that can specifically interact with the biomolecules can be modeled using computational tools.
These tools can allow a drug molecule to be constructed within the biomolecule using knowledge of its structure and the nature of its active site.
Construction of the drug molecule can be made inside out or outside in depending on whether the core or the R-groups are chosen first. However many of these approaches are plagued by the practical problems of chemical synthesis.Newer approaches have also suggested the use of drug molecules that are large and proteinaceous in nature rather than as small molecules.
There have also been suggestions to make these using mRNA. Gene silencing may also have therapeutical applications.

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Rational drug design | method of drug design

Rational drug designing

Unlike the historical method of drug discovery, by trial-and-error testing of chemical substances on animals, and matching the apparent effects to treatments, rational drug design begins with a knowledge of specific chemical responses in the body or target organism, and tailoring combinations of these to fit a treatment profile.
Due to the complexity of the drug design process two terms of interest are still serendipity and bounded rationality.
Those challenges are caused by the large chemical space describing potential new drugs without side-effects.
A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as x-ray crystallography and NMR spectroscopy.
This approach to drug discovery is sometimes referred to as structure-based drug design. The first unequivocal example of the application of structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide which was approved in 1995.
Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive leukemias (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). Imatinib is substantially different from previous drugs for cancer, as most agents of chemotherapy simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.

The activity of a drug at its binding site is one part of the design. Another to take into account is the molecule's druglikeness, which summarizes the necessary physical properties for effective absorption. One way of estimating druglikeness is Lipinski's Rule of Five.

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Beta blocker | Clinical use

Beta blocker

Beta blockers (sometimes written as β-blockers) are a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias and cardioprotection after myocardial infarction.
Whilst once first-line treatment for hypertension, their role was downgraded in June 2006 in the United Kingdom to fourth-line as they do not perform as well as other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers especially in combination with thiazide-type diuretics carry an unacceptable risk of provoking type 2 diabetes.

Propranolol was the first clinically useful beta adrenergic receptor antagonist. Invented by Sir James W. Black it revolutionized the medical management of angina pectoris and is considered to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.


Pharmacology

Beta blockers block the action of endogenous catecholamines (epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular), on β-adrenergic receptors, part of the sympathetic nervous system which mediates the "fight or flight" response.

There are three known types of beta receptor, designated β1, β2 and β3. β1-Adrenergic receptors are located mainly in the heart and in the kidneys. β2-Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3-receptors are located in fat cells.


β-Receptor antagonism
Stimulation of β1 receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β1 receptors on the kidney causes renin release. Stimulation of β2 receptors induces smooth muscle relaxation (resulting in vasodilation and bronchodilation amongst other actions), induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle. Stimulation of β3 receptors induces lipolysis.

Beta blockers inhibit these normal epinephrine-mediated sympathetic actions, but have minimal effect on resting subjects. That is, they reduce the effect of excitement/physical exertion on heart rate and force of contraction, dilation of blood vessels and opening of bronchi, and also reduce tremor and breakdown of glycogen.

It is therefore expected that non-selective beta blockers have an antihypertensive effect. The
antihypertensive mechanism appears to involve: reduction in cardiac output (due to negative chronotropic and inotropic effects), reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity.

Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand.

The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade – resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade.

Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone system with a resultant decrease in blood pressure due to decreased sodium and water retention.


Intrinsic sympathomimetic activity
Some beta blockers (e.g. oxprenolol and pindolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.

Agents with ISA are not used post-myocardial infarction as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.

α1-Receptor antagonism
Some beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism of both β- and α1-adrenergic receptors, which provides additional arteriolar vasodilating action.


Other effects
Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep disturbance caused by some agents.Beta blockers protect against social anxiety: "Improvement of physical symptoms has been demonstrated with beta-blockers such as propranolol; however, these effects are limited to the social anxiety experienced in performance situations."Beta blockers can impair the relaxation of bronchial muscle (mediated by beta-2) and so should be avoided by asthmatics.


Clinical use
Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below.

Indications for beta blockers include:
Hypertension
Angina
Mitral valve prolapse
Cardiac arrhythmia
Congestive heart failure
Myocardial infarction
Glaucoma
Migraine prophylaxis
Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism
Essential tremor
Phaeochromocytoma, in conjunction with α-blocker


Beta blockers have also been used in the following conditions:
Hypertrophic obstructive cardiomyopathy
Acute dissecting aortic aneurysm
Marfan syndrome (chronic treatment with propranolol slows progression of aortic dilation and its complications)
Prevention of variceal bleeding in portal hypertension
Possible mitigation of hyperhidrosis
Congestive heart failure
Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition, studies in the late 1990s showed their positive effects on morbidity and mortality in congestive heart failure. Bisoprolol, carvedilol and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure.
The beta blockers are a benefit due to the reduction of the heart rate which will lower the myocardial energy expenditure. This is turns prolongs the diastolic filling and lengthens coronary perfusion.Beta blockers have also been a benefit to improving the ejection fraction of the heart despite an initial reduction in it.
Trials have shown that Beta blockers reduce the absolute risk of death by 4.5% over a 13 month period. As well as reducing the risk of mortality, the number of hospital visits and hospitalizations were also reduced in the trials.

Anxiety and performance enhancement
Some people, particularly musicians, use beta blockers to avoid stage fright and tremor during public performance and auditions. The physiological symptoms of the fight/flight response associated with performance anxiety and panic (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand. Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration.

Since they lower heart rate and reduce tremor, beta blockers have been used by some Olympic marksmen to enhance performance, though beta blockers are banned by the International Olympic Committee (IOC). Although they have no recognisable benefit to most sports, it is acknowledged that they are beneficial to sports such as archery and shooting.


Adverse effects
Adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, abnormal vision, decreased concentration, hallucinations, insomnia, nightmares, clinical depression, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema.
Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares, depression) are more common in agents with greater lipid solubility, which are able to cross the blood-brain barrier into the CNS. Similarly, CNS adverse effects are less common in agents with greater aqueous solubility (listed below).
Adverse effects associated with β2-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β1-selective (often termed "cardioselective") agents, however receptor selectivity diminishes at higher doses.
A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a patient's risk of developing diabetes whilst ACE inhibitors and Angiotensin II receptor antagonists (Angiotensin Receptor Blockers) actually decrease the risk of diabetes.[12] Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta-blockers as first-line treatment of hypertension due to the risk of diabetes.
Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha adrenergic stimulant overdose. The blockade of only beta receptors increases hypertension, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha adrenergic system stimulation unopposed.The appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are vasodilators like nitroglycerin, diuretics like furosemide and alpha blockers like phentolamine.


Examples of beta blockers

Dichloroisoprenaline, the first beta blocker.

Non-selective agents
Alprenolol
Carteolol
Levobunolol
Mepindolol
Metipranolol
Nadolol
Oxprenolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol

β1-Selective agents
Acebutolol
Atenolol
Betaxolol
Bisoprolol[16]
Esmolol
Metoprolol
Nebivolol

Mixed α1/β-adrenergic antagonists
Carvedilol
Celiprolol
Labetalol

β2-Selective agents
Butaxamine (weak α-adrenergic agonist activity)


Side Effects / Health Consequences
Low Blood Pressure
Slow Heart Rate
Impaired Circulation
Loss of Sleep
Heart Failure
Asthma
Depression
Sexual Dysfunction
Nausea
Headaches
Dizziness
Muscle Cramps

Comparative information


Pharmacological differences

Agents with intrinsic sympathomimetic action (ISA)
Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol

Agents with greater aqueous solubility
Atenolol, celiprolol, nadolol, sotalol

Agents with membrane stabilising activity
Acebutolol, betaxolol, pindolol, propranolol

Agents with antioxidant effect
Carvedilol
Nebivolol

Indication differences

Agents specifically indicated for cardiac arrhythmia
Esmolol, sotalol

Agents specifically indicated for congestive heart failure
Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol

Agents specifically indicated for glaucoma
Betaxolol, carteolol, levobunolol, metipranolol, timolol

Agents specifically indicated for myocardial infarction
Atenolol, metoprolol, propranolol

Agents specifically indicated for migraine prophylaxis
Timolol, propranolol

Propranolol is the only agent indicated for control of tremor, portal hypertension and esophageal variceal bleeding, and used in conjunction with α-blocker therapy in phaeochromocytoma.

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