Antipyretic Analgesics Remedial Agents Lower Temperature Body Pyrexia Biology Essay

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Antipyretic analgesics are remedial agents that lower the temperature of the body in pyrexia. Pyrexia is a condition where the temperature of the body rises to levels above the normal body temperature. They exert their action on the heat regulating centre of the hypothalamus. Salicylates, aminophenol analogues, anilines, pyrazolones and quinoline derivatives are the common group of compounds used as antipyretic analgesics.

Antipyretics are agents which essentially help to reduce fever to normal body temperature. The drug substances in this category possess the ability to alleviate the sensation of pain threshold ranging from mild to severe status. Many substances in this category have been removed from the market because of various side effects seen such as skin problems, cardiac irregularities, jaundice and methemoglobinemia.

Analgesics may be defined as 'agents that relieve pain by elevating the pain threshold without disturbing consciousness or altering sensory-modalites'.(Medicinal Chemistry, K. Ashutosh, 2005). The mechanism by which these analgesics act can mainly be attributed to the presence of opiate receptors located in selected parts of the CNS associated with pain regulation. These opiate receptors are located specifically in the medial thalamus, layers I and II in the spinal cord and the brainstem's vagus nuclei.

The drug is completely absorbed from the upper part of the gastrointestinal tract following oral absorption. Within one or two hours maximum plasma level concentration is reached. Only a fraction opf the drug os bound to plasma protein, the rest (approximately 99.8%) is metabolised and converted to acetyl p-aminophenol. The first step in the metabolism of phenacetin is O- deethylation by cytochrome P450 1A2. Some of this metabolised drug is conjugated with glucorinioc acid or sulfate ions. Aboy 0.1% is changed to p-phenetidin by deacetylation. 3.5% of the total ingested dose is found in the urine within 24 hours in the form of free aminophenol and and about 74% in the form of conjugated N-acetyl- p- aminophenol.

1.1.8. Dose: Typical doses of 300-500mg a day lead to analgesic effects.

1.1.9. Contraindication:

Phenacetin is already withdrawn from the market but still general contraindication may be pointed out as:

Should not be taken by patients having hypertension.

Patients having renal insufficiency should avoid the drug as it has adverse effects on the kidney and may worsen the condition.

1.1.10 Adverse and toxicological effects:

Phenacetin was withdrawn from the market because of its severe abuse and carcinogenic effects. Some adverse effects can be pointed out as:

Nephrotoxicity and renal failure after prolonged use is seen.

It has severe carcinogenic effects and may lead to cancer.

Another toxic effect of phenacetin is that it converts haemoglobin to methemoglobin and sulfhemoglobin within the blood cells lading to reduction in erythrocyte survival time. This ultimately may lead to less haemoglobin available for oxygen transportation and lead to chronic anoxemia.

It may cause intravascular hemolysis.

High concentrations of phenacetin may have depressant effects on the cardiovascular system circulation and nervous system which may lead to vascular collapse and shock.

1.2 Salicylamide

1.2.1. Iupac Name: 2-hydroxy benzamide

1.2.2. Structural Formula: C7H7 NO2

1.2.3. Molecular mass: 137.1g/mol

1.2.4. Salicylamide has been used historically as an antipyretic anangesic but is not used considerably today (Hart 1946). It is described as an amide of salicylic acid. It is prepared by reacting methyl salicylate with ammonia. In humans it has antipyretic analgesic and even anti-inflammatory effects similar to salicylic acid. (Insel, 1990).

Figure: 2.1 Chemical structure of Salicylamide

1.2.5 Properties:

Salicylamide appears as a white or pink crystalline powder or as needle shaped crystals having faintly bitter taste and is odourless. It has a melting point of 140 0C.It is sparingly soluble in water but soluble in ethanol, chloroform and ether. It is soluble in a solution of alkalis. It is stable, light sensitive. It is incompatible with strong bases and strong oxidising agents. It darkens on exposure to air (Chemicalbook).

1.2.6. Mechanism of Action:

1.2.7. Therapeutic use:

Salicylamide is used as an antipyretic analgesic. It also has a mild sedative action. It has negligible anti-inflammatory effect. It is used in multidrug combinations for treatment of a variety of mild pain conditions including musculoskeletal, soft tissue and joint disorders. It is also used in arthiritic conditions.

1.2.8: Pharmacokinetics of salicylamide:

Salicylamide is readily absorbed when given orally. It undergoes significant first pass metabolism. It is seen widely distributed in the body as it is lesser bound to plasma proteins. It has a half life of about 1 hour as seen from urinary excretion data. It gets rapidly excreted in the urine mainly as sulphate and glucuronide conjugates. Only trace amounts are excreted unchanged.

1.2.9. Adult dose:

Salicyclamide is given in doses of about 1 to 2.5 grams daily, usually with other analgesics. It is also applied topically in about concentrations of about 5%.

1.2.10. Contraindication:

1.2.11 Adverse effect:

1.3. Nuclear magnetic resonance spectroscopy:

1.3.1 Definition: Nuclear magnetic resonance spectroscopy (NMR spectroscopy) is a powerful technique used for elucidating the structures of organic molecules. It involves the absorption of electromagnetic radiation in the radio frequency range of 4-900 MHz. The basic principle underlying Nuclear magnetic resonance spectroscopy is that atomic nuclei have quantised spin states which may be differentiated in the presence of strong magnetic field. A variety of information about a compound can be obtained from an NMR spectrum.

1.3.2. Principles: In NMR, radiation in radiofrequency region is used to excite atoms, usually protons or carbon-13 atoms. The spins of the excited atoms switches the alignment from with an applied magnetic field to against an applied magnetic field. The absorption of energy results from the application of energy in the form of radio frequency, orthogonal to the applied magnetic field which results in transitions between the allowed states resulting in whole the phenomenon taking place. The range of frequencies required for excitation and the complex splitting patterns produced are due to the chemical structure of the molecule. The corresponding frequency of the absorbed energy depends on the nuclei and also its electronic environment. (Traficante 1996).

1.3.3. Theory of NMR: It was suggested by Pauli that certain magnetic nuclei could have spin as well as magnetic moment from rotation around their axes. He suggested that the nuclei could align themselves with or opposed to the magnetic field. The angular moment of the spinning charge is expressed by the spin quantum number, I. The spin quantum number can be a half integer or an integer and is expressed in units of h/2Ï€, where h is Planck's constant. Any nuclei which has I > 0 when placed in a magnetic field will assume a maximum number of orientations equal to 2I+1. Now, I= 1/2 for a proton, therefore two orientations exist: aligned with field (low energy) and aligned opposed to the field (high energy).

The separation of the energy levels or spin states is a function of the external magnetic field (H0), the spin quantum number (I) and nuclear magnetic moment (µ).

E= µ H0/I

1.3.4. Basic terms and concepts in NMR:

1.3.4.1: Absorption and relaxation: NMR spectroscopy can be distinguished from other forms of spectroscopy in that it has equal populations in the higher and lower energy states. The population of the two states is governed by the Boltzmann distribution in the absence of an applied magnetic field. For absorption to occour , there must be an excess population in the lower state. This excess in NMR is slight, the phenomenon of saturation occours readily as the the lower states is depleted.

The population in the upper state also depends on the phenomenon known as relaxation, which refers to any process that removes any nuclei from an excited state. Two basic relaxation mechanisms are operative in NMR: spin-spin relaxation and spin-lattice relaxation.

1.3.4.2: Chemical Shift: The term chemical shift is used to describe the unique magnetic field strength required to achieve resonance for any given proton. The required magnetic field is influenced by the electromagnetic environment of the proton. Shielding is said to occour when these fields counteract the applied magnetic field. Shielding can be reduced by the presence of electron withdrawing substituents such as oxygen or halogens. The protons attached to electronegative substituients are said to be deshielded and require less magnetic field strength to achieve resonance.

1.3.5: Types of NMR: There are basically two types of NMR techniques namely 1H or Proton NMR and 13C NMR.

1.3.6. Application:

It can be used for fingerprinting mixtures

It can be used to determine the residual structures of unfolded proteins.

It can be used for direct detection of hydrogen bonding interactions.

It can be used for research in polymer chemistry and physics. (Michigan state university).

www2.chemistry.msu.edu/facilities/nmr/900Mhz/MCSB_NMR_applications.html

Used for the chemical analysis of molecular structures.

It is used for the characterisation of physical properties of matter in materials science. (Bernhard Blümich, 2005)

NMR is successfully used for the characterisation of the exact structure of raw materials and finished products.

NMR is used for metabolic studies.

1.3.7. Strength: NMR provides a lot more information about molecular structure of a compound than any other technique. (Jens Duus 2000)

Can be used detect very fine structural components, works for organic and inorganic compounds, is qualitative and quantitative, versatile.

1.3.8. Limitations:

It is a relatively insensitive technique compared to the other spectroscopic techniques as it requires more than 5mg of sample for proton nuclear magnetic resonance (NMR) and more than 20mg for carbon-13 NMR.

The instrumentation for NMR is very expensive and difficult to operate. A specialist operator is required to operate this instrument, although automation is increasingly available for routine methods. (Jens Duus 2000)

Overall, it is a very expensive, time consuming process and the spectra take long time to interpret.

Figure 1.3. NMR sample tube placed in a spinner, (Norell, Inc. 2008)modified.

1.4. Infrared spectroscopy:

1.4.1 Definition:

IR is a technique based on the vibrations of the atoms of a molecule.An IR spectrum is obtained by passing Ir radiation through a sample and determining what fraction of the incident radiation is absorbed at a particular energy.The energy at which any peak in an absorption spectrum appears corresponds to the frequency of a vibration of a part of the sample molecule.

( Ref : Biological applications of IR Spectroscopy by Barbara Stuart, David J. Ando)

1.4.2. Principles: Electromagnetic radiations ranging between 400cm-1 and 4000cm-1 (2500 and 20000 nm) are passed through a sample. The bonds present in the molecule sample absorb the radiation which causes them to stretch or bend. The wavelength of the radiation absorbed is characteristic of the bond absorbing it. (Koichi Nishikida 1995)

1.4.3. Application:

It is used to check the identity of a compound in synthetic chemistry.

It is used to check the presence or absence of a carbonyl group, which is difficult to check by any other method.

Can be used to characterise samples in the solid and semi-solid states such as creams and tablets and identification of raw materials and product quality, moisture and solvent content in drying or solvent removal processes, residual drug carryover in manufacturing facilities, mixing quality evaluation, and imaging of tablets and packaging systems. .

Can be used to detect polymorphs of drugs (polymorphs are different crystal forms of a molecule that have different physical properties such as solubility and melting point, which may be important in the manufacturing process and bio-availability). (Stuart 2004)

IR is used in interpretation of the spectra of drugs with the help of FTIR for identification of drugs , excipients and the raw materials used in manufacture. ( Ref : Biological applications of IR Spectroscopy by B. Stuart)

A qualitative fingerprint check for the identity of raw material used in manufacturing and as well as for identifying drugs.

It has been used for analysis of fine chemicals, polymers gasoline and pharmaceuticals, both with dispersive and Fourier-Transform (FT-NIR) based instrument.

FTIR is used for structural elucidation of penicillins. ( Ref : Biological applications of IR Spectroscopy by B.Stuart)

1.4.4. Strengths:

For every compound being studied , it provides a fingerprint which is unique to the compound.

The matching of the compound to its standard fingerprint can be carried out as the instruments are computer controlled. (James Robertson 1999)

IR process is quite cheap, versatile and is an easy method to identify functional groups.

1.4.5. Limitations:

There is a difficulty in sample preparation and interpretation.

It can only detect gross impurities in samples.

Sample preparation requires a degree of skill, particularly when potassium bromide disk needs to be prepared. (James Robertson 1999)

It is a time consuming method and sample recovery is not possible.

1.5. Mass spectrometry:

1.5.1. Mass spectrometry is an analytical technique that measures the mass-to-charge ratio (m/z) of gas-phase ions formed from molecules. The mass spectrometer measures the mass to charge ratio of the gas phase ions and gives the abundance of ionic species. Mass spectroscopy is a destructive method of analysis wher the sample cannot be recovered. Mass spectroscopy is a highly sensitive technique and requires very less sample compared to other spectroscopic techniques.

1.5.2. Principle: The basic principle of mass spectroscopy the generation of ions by a suitable method, then separate these ions by their mass-to-charge ratio and then detect them quantitatively and qualitatively. The first step in mass spectroscopic analysis is the production of charged molecules or molecular fragments. These are generated in a high-vacuum region, or immediately prior to sample introduction, using a variety of methods for ion production. The molecules are bombarded with a high energy beam of electrons. Due to this bombardment the molecules are broken up into many fragments. Now, each kind of ion has a mass to charge ratio which is measured by the mass spectrometer. (Morrison and Boyd

The mass spectrometric instrument consists of an ion source, a mass analyzer and a detector. The block diagram in Fig. shows the different parts of a mass spectrometer.

Diagram courtesy: American society of Mass spectroscopy, 2001.

There are a number of methods that can be used for ionisation of the sample as described in Table 1.1.

Table 1.1 Methods of ionisation in mass spectroscopy, (Chemical Education Group SA Branch n.d.) modified.

Method

Description

Chemical ionization (CI)

By either a proton or hydride transfer, a reagent ion reacts with the analyte molecules, to form ions.

CH4+ + CH4 --> CH5+ + CH3 ; CH3+ + CH4 --> C2H5+ + H2

Electron impact (EI)

An electron beam, from a tungsten filament, knocks an electron off of analyte atoms or molecules to create ions

Electrospray ionization (ESI)

The ESI source consists of a very fine needle. Sample solution is dispersed into a fine aerosol. The droplets carry charge when the exit the capillary and, as the solvent evaporates, highly charged analyte ions are left behind

Laser ionization (LIMS)

A laser pulse causes both vaporization and ionization of the sample.

Matrix-assisted laser desorption ionization (MALDI)

MALDI is an LIMS method of vaporizing and ionizing large molecules such as proteins or DNA fragments. The sample is dispersed in a solid matrix such as nicotinic acid and a UV laser pulse targets the matrix which carries some of the large molecules into the gas phase in an ionized form

Plasma-desorption ionization (PD)

Decay of 252Cf produces two fission fragments of which one strikes the sample knocking out 1-10 analyte ions and the other strikes a detector

Resonance ionization (RIMS)

One or more laser beams are tuned in resonance to transitions of a gas-phase atom or molecule to create an ion

Thermal ionization (TIMS)

A sample in its elemental form is deposited on a metal ribbon, such as Pt, and an electric current heats the metal to a high temperature

Fast-atom bombardment (FAB)

A high-energy beam of neutral atoms, like Xe or Ar, strikes a solid sample causing desorption and ionization

Plasma and glow discharge

Plasma is a hot, partially-ionized gas that excites and ionizes atoms. A glow discharge is a low-pressure plasma maintained between two electrodes

1.5.3. Applications:

It is used for determining and also confirming the structure of drugs and raw materials used for manufacture.

It can be used for characterising impurities in drugs and formulation excipients by conjunction with either gas chromatography (GC-MS) or liquid chromatography (LC-MS)

Mass spectrometry has become an important tool in proteomics, which is currently a major tool in drug discovery. (Yinon 1995)

It is an important method for the characterization of proteins.

1.5.4. Strength:

It is the best method for getting rapid identification of trace impurities, which is ideally carried out using chromatographic in conjunction with high-resolution mass spectrometry so that elemental compositions can be determined.

With the advent of electro spray mass spectrometry and the re-emergence of time of flight mass spectrometry the technique will be of major use in the quality control of therapeutic antibodies and peptides. (Gross 2004)

1.5.5. Limitations:

MS is not currently used in routine quality control (QC) but is placed in a research and development (R&D) environment, where it is used to solve specific problems arising from routine processes or in process development.

The instrumentation is expensive and requires support by highly trained personnel and regular maintenance. However, limitations are gradually being removed. (Gross 2004)

The greater the MS instrument's resolution, the greater its usefulness for analysis

Finding the correct parent peak in the mass spectra may be difficult.

2. EXPERIMENTAL SECTION

2.1 Aim: The synthesis and characterisation of Analgesic Antipyretic drugs:

1. Phenacetin.

2. Salicylamide.

The experiment also includes the characterisation of Phenacetin and Salicylamide by Mass spectroscopy, FT-Infrared spectroscopy and NMR spectroscopy.

2.2. Synthesis of Phenacetin:

2.2.1. Chemicals used: p-aminophenol, acetic anhydride, sodium ethoxide, rectified spirit, ethyl iodide, water.

2.2.2. Instruments used: round bottom flask equipped with a reflux condenser, water bath, beakers, measuring cylinders, vacuum filter, filter paper, electronic weighing machine, etc.

2.2.3. Procedure:

Suspend 11g (0.1 mol) of p-aminophenol in 30 mol of water contained in a 250-ml beaker or conical flask and add 12 ml (0.127 mol) of acetic anhydride. Stir (or shake) the mixture vigorously and warm on a water bath. The solid dissolves. After 10 minutes, cool, filter the solid acetyl derivatives at the pump and wash with a little cold water. Recrystallise from hot water (about 75ml) and dry upon filet-paper in the air. The yield of p-hydroxyacetanilide, m.p. 169 0C (1), is 14g (93%).

Warm a flask on water bath until solution is complete. Cool the mixture and add 10g (0.066 mol) of p-hydroxyacetanilide. Introduce 15g (8 ml, 0.1 mol) of ethyl iodide slowly through the condenser and reflux the mixture for 45-60 minutes. Pour 100 ml of water through the condenser at such a rate that the crystalline product does not separate; if crystals do separate, reflux the mixture until they dissolve. Then cool the flask in an ice batch: collect the crude phenacetin with suction and wash with a little cold water. Dissolve the crude product in 80ml of rectified spirit; if the solution is coloured, add 2g of decolourising carbon, boil and filter. Treat the clear solution with 125 ml of hot water and allow to cool. Collect the pure phenacetin at the pump and dry in the air. The yield is 9.5g (80%), m.p. 137 0C.

Note : (1) if the m.p. is unsatisfactory, dissolve the product in dilute alkali in the cold and then reprecipitate it by the addition of acid to the neutralisation point. This procedure will eliminate traces of the diacetate of p-aminophenol which may be present; the acetyl group attached to nitrogen is not affected by cold dilute alkali; but that attached to oxygen is readily hydrolysed by the reagent.

2.3. Synthesis of Salicylamide:

2.3.1. Chemicals used: salicylic acid, dry methanol, conc. sulphuric acid, water, sodium hydrogen carbonate, magnesium sulphate, conc. ammonia, hydrochloric acid.

2.3.2. Instruments used: round bottom flask equipped with a reflux condenser, water bath, beakers, measuring cylinders, vacuum filter, fluted filter paper, electronic weighing machine, separatory funnel, still head with 360 0C thermometer, air condenser.

2.3.3. Procedure:

Step 1. Use 28g (0.2 mol) of salicylic acid, 64g (81 ml, 2 mol) of dry methanol and 8 ml of concentrated sulphuric acid. Reflux the mixture for at least 5 hours. (1). Distil off the excess of alcohol on a water bath (rotary evaporator) and allow to cool. Pour the residue into 250 ml of water contained in a separatory funnel and rinse the flask with a few ml of water which are also poured into the speratory funnel. If, owing to the comparatively slight difference between the density of the ester and of water, difficulty is experienced in obtaining a sharp separation of the lower ester layer and water, add 10-15 ml of carbon tetrachloride (2) and shake the mixture in the funnel vigorously; upon standing the heavy solution of methyl benzoate in the carbon tetrachloride separates sharply and rapidly the bottom of the separatory funnel.. Run off the lower layer carefully, reject the upper aqueous layer, return the methyl benzoate to the funnel and shake it with a strong solution of sodium hydrogen carbonate until all free acid is removed and no further evolution of carbon dioxide occurs. Wash once with water and dry by pouring into a small dry conical flask containing about 5g of magnesium sulphate. Stopper the flask, shake for about 5 minutes and allow to stand for at least half an hour with occasional shaking. Filter the methyl salicylate solution through a small fluted filter paper directly into a round -bottomed flask fitted with a still-head carrying a 360 0C thermometer and an air condenser. Add a few boiling chips and distil from a air bath; raise the temperature slowly at first until all carbon tetrachloride has passed over and then heat more strongly. Collect the pure methyl salicylate (a colourless oil of delightful fragrance, 'oil of wintergreen') at 221-224 0C; the yield is 25g (81%). The ester may also be distilled under reduced pressure; the b.p is 115 0C/20mmHg and a 2 0C fraction should be collected.

Step 2. 2 ml (2.3g) of methyl slayicyalte and 20ml of concentrated ammonia (28% NH3) are placed in a 50 ml round bottom flask and stoppered tightly and shaken thoroughly. The ester may be dispersed lower by the addition of a wetting agent (.01g) e.g. Charcoal etc, but that is not necessary. The mixture is set aside for a week. During this time the ester phase disappears. The clear solution is transferred to a beaker and diluted with 50 ml water. The diluted solution is neutralised with hydrochloric acid. The liberated amide precipitates as the solution cools. The precipitate is collected by suction, washed with 50 ml water (used in small portion) and dried; m.p. is 136/137 0C yield is 70 %.

2.4. FT Infra-Red Spectroscopy

FT infra-red spectra were recorded on a Perkin Elmer, Paragon 1000 FT-IR spectrometer (Figure 2.1). The spectra were recorded at a resolution of 1 cm-1 in the 450-4000 cm-1 range. A dry nitrogen gas purge was maintained in the sample compartment to facilitate a simpler background subtraction. The samples which were solid in nature were examined as pressed KBr discs which were prepared by triturating the sample thoroughly with potassium bromide and spectra were recorded over the 4000-450 cm-1 region. The instruments used to prepare the potassium bromide discs with the sample were thoroughly cleaned so as to avoid any cross contamination.

Figure 2.1. Image of Perkin Elmer, Paragon 1000 FT-IR spectrometer

2.5. Mass Spectrometry

All the samples needed to be examined by the mass spectroscopic method were dissolved in an appropriate solvent and then were run on VG-QUATTRO, where the inlet probe was heated. Mass spectra were obtained using electrospray ionization (ESI) method of ionization. The source consists of a very fine needle. The sample solution is dispersed into a fine aerosol. When the droplets exit at the capillary end they carry a charge and as the solvent gets evaporated, highly charged analyte ions are left behind.

In positive ion mode, ESI usually produces multiply charged ions [M + nH]n+. The ions in solution state are transferred to gaseous state at atmospheric pressure by ESI. The sample flows through a capillary tube to which a high voltage is applied. There is a strong electric field due to the counter electrode. The sample emerging from the tip is dispersed into an aerosol of highly charged droplets. Positive ions will accumulate at the surface of the liquid and will move towards the negative collector electrode if a positive potential is applied to the capillary. As they move towards the electrode they are either subjected to heat or heated nitrogen gas due to which the solvent evaporates and the droplets reduce in size. The droplet breaks down into smaller particles when electrostatic repulsion is greater than surface tension of the liquid and the charged sample ions free from solvent are released from droplets (Lee 2005).

Figure 2.2. Image of Mass spectrometer

2.6. Nuclear Magnetic Resonance

Samples (+)-3, 6-bis-(aminoxymethyle)-2, 5-piperazinedione and 3, 6-dimethylene-2, 5-piperazinedione were analyzed using proton NMR spectroscopy and C13 spectroscopy. Samples were run in a Jeol EX, 270 MHz FT NMR Spectrometer, incorporating a Tuneable H-5/270 probe. Samples were dissolved in DMSO d6 (~20mg/ml) and placed into a 5 mm o.d. borosilicate glass NMR tube. The NMR tube was loaded into the instrument and spun at 15 Hz. Samples were locked and shimmed with respect to the deuteriated solvent. 1H spectra were acquired using a single pulse experiment, with a relaxation delay of 4 seconds, the number of spectral accumulations was 32 scans.

Fig. 2.3. Image of NMR Spectrometer

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