Xanthine Derivatives

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Chapter: Medicinal Chemistry : CNS Stimulants

CNS Stimulants - Xanthine Derivatives - Synthesis and Drug Profile - a. Caffeine b. Theophylline and Theobromine (Theobid, Theopa, Broncordil) i. Theophylline hydrate ii. Theobromine c. Aminophylline (Aminophyline, Minophyl) d. Pentoxyphylline (Flexital, Pentovas, Trental) - Structure, Properties, uses, Synthesis, Assay, Storage, Dosage forms, Dose


SYNTHESIS AND DRUG PROFILE



Xanthine Derivatives

The naturally occurring xanthine derivatives are caffeine, theophylline, and theobromine. These agents generally cause mild CNS stimulation, and relax -smooth muscles, so it is used in the treatment of asthma. All xanthine derivatives produce diuresis by increasing glomerular filtration and blocking tubular reabsorption of sodium ions. It stimulates the medullary centre and overcomes fatigue.

Mode of action: These agents have mild stimulant action and increase the epinephrine secretion and enhance the neural activity in several areas of the brain. These agents act by producing antagonism of adenosine receptor. Adenosine is a neuromodulator, which influences numerous functions in the CNS and the blocking is responsible for stimulation.


a. Caffeine


Properties and uses: It exists as a white crystalline powder or silky white crystals, sublimes readily, sparingly soluble in water, freely soluble in boiling water, and slightly soluble in ethanol. It dissolves in the concentrated solutions of alkali benzoates or salicylates. Caffeine acts on the higher centres of the CNS and produces a condition of wakefulness. It stimulates the respiratory centre, increases rate and depth of respiration. The diuretic action of caffeine is weaker than theophylline. Caffeine is used along with ergotamine in the treatment of migraine.

Assay: Dissolve the sample by heating in anhydrous acetic acid. Allow to cool, add acetic anhydride, and 20 ml of toluene. Titrate with 0.1 M perchloric acid and determine the end point potentiometrically.

Synthesis

Route I. From: Dimethylurea and cyanoacetic acid


Route II. From: Uric acid


Dosage forms: Aspirin and caffeine tablets B.P., Caffeine citrate injection B.P., Caffeine citrate oral solution B.P.


b. Theophylline and Theobromine (Theobid, Theopa, Broncordil)


Synthesis: They can be synthesized by adopting the above route described for caffeine with the suitable reagents.


i. Theophylline hydrate

Properties and uses: It exits as white, crystalline powder, slightly soluble in water, sparingly soluble in ethanol. It dissolves in solutions of alkali hydroxides, in ammonia, and in mineral acids. Used as nonselective phosphodiesterase inhibitor (xanthine) and in the treatment of reversible airways obstruction.

Assay: Dissolve the sample in water, add 0.1 M silver nitrate, and shake. Add bromothymol blue solution as indicator and titrate with 0.1 M sodium hydroxide.

Dose: For acute bronchospasm: Adult: As conventional tablet: 5 mg/kg every 6–8 h. Child: As conventional tablet: 5 mg/kg every 4–6 h. For chronic bronchospasm: Adult: As conventional dosage form: 300–1000 mg in divided doses, every 6–8 h daily. As modified-release preparations: 175–500 mg every 12 h.

Dosage forms: Aminophylline injection B.P., prolonged-release theophylline tablets B.P.


ii. Theobromine

Properties and use: It is a white powder, very slightly soluble in water and in ethanol, slightly soluble in ammonia. It dissolves in dilute solutions of alkali hydroxides and in mineral acids. Theobromine is used as diuretic and used in the treatment of angina pectoris and hypertension. It is a nonselective phosphodiesterase inhibitor (xanthine) and used in the treatment of reversible airways obstruction.

Assay: Dissolve the sample in boiling water, cool to 50°C–60°C and add 0.1 M silver nitrate and titrate with 0.1 M sodium hydroxide using phenolphthalein solution as indicator, until a pink colour is obtained.


c. Aminophylline (Aminophyline, Minophyl)


Properties and uses: A white or slightly yellowish powder, sometimes granular, freely soluble in water (the solution becomes cloudy through absorption of carbon dioxide), practically insoluble in ethanol. It is used in the treatment of bronchial asthma, acts as a nonselective phosphodiesterase inhibitor and in the treatment of reversible airways obstruction.

Assay for Ethylenediamine

Dissolve the sample in water, to this add bromocresol green solution as indicator. Titrate with 0.1 M hydrochloric acid until a green colour is obtained.

Assay for Theophylline

Heat the weighed quantity of the sample to constant mass in an oven at 135°C. Dissolve the residue by heating in water; allow to cool, adding 0.1 M silver nitrate and shake. Add bromothymol blue solution as indicator and titrate with 0.1 M sodium hydroxide.

Dose: The usual dose is oral 300–600 mg/day.

Dosage forms: Aminophylline injection B.P.


d. Pentoxyphylline (Flexital, Pentovas, Trental)


Synthesis


Uses: It is used in the relief of bronchospasm in asthma.

Dose: The usual dose is 400 mg, thrice daily with meals.


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