Xanthine diuretics

Caffeine, theophylline and theobromine are the three important members of the xanthine diuretics, which are commonly foimd in the common beverages viz., coffee Coffee arabica), coca-cola Cola acuminata) and cocoa Theobroma cacao) contain caffeine tea Thea sinensis) contains caffeine and theophylline and cocoa Theobroma cacao) contains theobromine. 

Diuretics—These are drugs which act to increase the output of sodium and water in the urine, and are often used to treat disorders of the heart, kidneys, or liver which cause edema. A majority of the diuretics act up the kidneys by depressing the sodium reabsorbed. Thus, sodium remaining in the urine carries more water out of the body with it. Diuretics include thiazides, furosemide, and ethacrynic acid. Xanthine diuretics are mild diuretics but they are used by many people—perhaps unknowingly—since they are the caffeine, theophylline, and theobromine present in tea, coffee, cola and other soft drinks, cocoa, and many over-the-counter pain relievers. Moreover, water and ethyl alcohol (alcoholic beverages) can act as diuretics by inhibiting the release of ADH. 

In attempts to prepare methylated xanthine analogues with greater therapeutic effectiveness as diuretic and cardiac drugs than theophylline (LXIV) and theobromine (LXV), it was found that some of the intermediate 6-aminouracils (LXVI) showed considerable activity as oral diuretics in experimental animals... 

Theophylline Xanthine Anti-asthmatic, diuretic Camellia sinensis... 

The principal xanthines of medical interest include caffeine, theophylline and aminophylline. Caffeine is synthesized by several plants and was originally isolated from tea in 1838. It is a methylxanthine (Figure 1.12) which stimulates the central nervous system, increasing mental alertness. It also acts as a diuretic and stimulates gastric acid secretion. It is absorbed upon oral administration and is frequently included in drugs containing an analgesic, such as aspirin or paracetamol. 

Since the 1950s, diuretic therapy has changed dramatically. Earlier, the major diuretics were acidforming salts, xanthines, organomercurial compounds, and carbonic anhydrase inhibitors. Either because of toxicity or lack of efficacy, these agents are rarely if ever used. 

Thea assamica Mast T. bohea L. T. cantoniensis Lour. T. chinensis Sims. T. cochinchinensis Lour. T. sinensis L. T. viridis Link. Cha (Tea) (leaf) Caffeine, theophylline, tannic acid, theobromine, xanthine, polyphenols. 33-47.405,406,409 Diuretic effect, increase renal blood flow, stimulate central nervous system, antitumor, prevent lung cancer. 

Camellia sinensis (L.) Kuntze China Caffeine, theophylline, tannic acid, theobromine, xanthine.33,47 Diuretic effect, increases renal blood flow, stimulate central nervous system. 

The xanthines caffeine (40 R1 = R2 = R3 = Me), theophylline (40 R1 = R2 = Me, R3 = H) and theobromine (40 R1 = R3 = Me, R2 = H), which are the stimulants present in tea, coffee, cocoa and many other beverages, have a number of therapeutic uses. They were formerly used as diuretics, theophylline being the most potent, and caffeine is a powerful CNS stimulant useful in treating cases of poisoning by CNS depressants. Caffeine has also been... 

SEs Paradoxical bronchospasm, URI, pharyngitis, back pain Interactions T Effects WTadrenergics T effects OF BBs T risk of hypokalemia W/ corticosteroids, diuretics, xanthines T risk of aiihytlimias W/ MAOIs, TCAs EMS Not for acute asthma, use an inhaled 3-agonist attacks may affect glucose (hyperglycemia) use caution w/ nonselective BBs, may cause severe bronchospasm diuretic use may cause hypokalemia, monitor ECG for signs (flattened T waves) OD May cause profound P-stimulation a cardioselective BB may be useful... 

Methybanthine Diuretics. The meihytxanihine.s are of very limited efficacy when used as diuretics. The excretion of sodium and chloride ions are increased, but the potassium excretion is normal. Even though the methyl xanthines have been demonstrated to have minor direct effects in the renal tubules, it is believed that they exert (heir diuretic effects through increased renal blood flow and GFR. 

The purine alkaloids caffeine, theobromine, and theophylline (Figure 6.135) are all methyl derivatives of xanthine and they commonly co-occur in a particular plant. The major sources of these compounds are the beverage materials such as tea, coffee, cocoa, and cola, which owe their stimulant properties to these water-soluble alkaloids. They competitively inhibit phosphodiesterase, resulting in an increase in cyclic AMP and subsequent release of adrenaline. This leads to a stimulation of the CNS, a relaxation of bronchial smooth muscle, and induction of diuresis, as major effects. These effects vary in the three compounds. Caffeine is the best CNS stimulant, and has weak diuretic action. Theobromine has little stimulant action, but has more diuretic activity and also muscle relaxant properties. Theophylline also has low stimulant action and is an effective diuretic, but it relaxes smooth muscle better than caffeine or theobromine. 

Allopurinol is used to lower uric acid levels in the treatment of primary gout, as a prophylaxis in myeloproliferative neoplastic disease, for investigational purposes in Lesch-Nyhan syndrome, and as an adjunct with thiazide diuretics or ethambutol (see Chapter 24). Allopurinol acts by inhibiting xanthine oxidase, which converts hypoxanthine into xanthine and in turn becomes oxidized into uric acid. 

A number of 8-aryl substituted pyrido[3,4-t/]-l,2,3-triazin-4(3//)-ones have been found to be most efficacious as inhibitors of xanthine oxidase, potential compounds for the treatment of ischemia and gout <88EUP274654>. A number of 3//,4//-pyrido[3,2-e]-l,2,4-triazine and 3/f,4//-pyrido[3,4-e]-1,2,4-triazine 3-acetamides have shown antiinflammatory, diuretic, antihypertensive, and psychotropic effects <89FES279>. During a search for potential antidepressant compounds, the pyrido-1,2,3-triazinone (399) was found to be more active than its isomer (400) <87EJM337>. 

The major bases found in nucleic acids are adenine and guanine (purines) and uracil, cytosine, and thymine (pyrimidines). Thymine is found primarily in DNA, uracil in RNA, and the others in both DNA and RNA. Their structures, along with their chemical parent compounds, purine and pyrimidine, are shown in Figure 10.1, which also indicates other biologically important purines that are not components of nucleic acids. Hypoxanthine, orotic acid, and xanthine are biosynthetic and/or degradation intermediates of purine and pyrimidine bases, whereas xanthine derivatives—caffeine, theophylline, and theobromine—are alkaloids from plant sources. Caffeine is a component of coffee beans and tea, and its effects on metabolism are mentioned in Chapter 16. Theophylline is found in tea and is used therapeutically in asthma, because it is a smooth muscle relaxant. Theobromine is found in chocolate. It is a diuretic, heart stimulant, and vasodilator. 

Xanthines, including caffeine and theophylline, are diuretics they inhibit re-absorption of Na+, increasing the GFR. Alcohol is a diuretic it reduces production of anti-diuretic hormone. 

Methylxanthine is the major purine constituent of human urine (3.1 g in 10001) (1898ZPC(24)364). 3- and 7-Methylpurines are also minor constituents of urine, especially following large doses of caffeine or other methylated xanthines. 1,3-Dimethylxanthine (theophylline) occurs with caffeine in tea leaves and is a powerful diuretic and has been used clinically for this purpose (generally as an adduct with salts of organic acids) and also in the treatment of asthma. 1,7-Dimethylxanthine (paraxanthine) is also an efficient diuretic and, in addition, possesses antithyroid properties (45JCS751). The main purine constituent... 

Lithium is also known to interact in a variety of ways with different classes of diuretic drugs. Thiazide diuretics increase serum lithium concentration by increasing reabsorption of lithium, along with that of sodium, in the proximal tubule. With potassium-sparing diuretics, conflicting results have been reported. Increased serum lithium concentrations may be seen after amiloride. However, the loop diuretic furosemide safely can be combined with lithium with no reduction in renal lithium clearance or consequent increase in serum lithium concentration (191, 192). Other diuretics, for example, carbonic anhydrase inhibitor and xanthine derivatives, decrease serum... 

Carbonic anhydrase inhibitors 165 Osmotic diuretics 166 Potassium-sparing diuretics 167 Xanthines 168... 

Theophylline. The prototypic xanthine, theophylline.h known to promote a weak diuresis by. stimulation of cardiac function and by a direct action on the nephrtrn. Although ii is infircquently used as a diuretic, diuresis may be an ub-served side effect when it is used as a bronchodilator. 

Among the plant derived diuretics, the xanthine derivatives have this mode of action, whereas the osmotic diuretics, mannitol and sorbitol, which produce a glomerular filtration, but not resorption in the tubules, incease the excretion of water. 

XANTHINE-DERIVATIVES (see N06) Theobromine has a stronger diuretic effect than caffeine and theophylline (R03D). 

Theophylline occurs in such a low concentration in all xanthine drugs that extraction is not profitable. Theophylline can be produced by demethylation of caffeine or by total synthesis. Theophylline has a spasmolytic effect on smooth muscles, which is apparent in a pronounced bronchodilating action, hence it is used in asthma either on its own or combined with ethylenediamine to produce aminophylline. Furthermore, theophylline has a diuretic action. 

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