Smooth muscle xanthine effects

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

Mechanism of Action A xanthine derivative that acts as a bronchodilator by directly relaxing smooth muscle of the bronchial airways and pulmonary blood vessels. Therapeutic Effect Relieves bronchospasm and increases vital capacity. Pharmacokinetics Rapidly and well absorbed. Protein binding Moderate (to albumin). Extensively metabolized in liver. Partially excreted in urine. Half-life 6-12 hr (varies). 

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. 

Another proposed mechanism is the inhibition of cell surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to cause contraction of isolated airway smooth muscle and to provoke histamine release from airway mast cells. These effects are antagonized by theophylline, which blocks cell surface adenosine receptors. It has also been shown, however, that xanthine derivatives devoid of adenosine-antagonistic properties (eg, enprofylline) may be more potent than theophylline in inhibiting bronchoconstriction in asthmatic subjects. 

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. 

Q10 Other bronchodilator agents include nebulized ipratropium. Ipratropium is a muscarinic receptor antagonist that helps to relax bronchial smooth muscle which has contracted via parasympathetic stimulation. The xanthines theophylline and aminophylline (theophylline ethylenediamine) are alternative bronchodilator agents. These agents may act as phosphodiesterase inhibitors and, although they have been used as bronchodilators for many years, adverse CNS, GI and cardiovascular effects may limit their usefulness. 

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. 

Xanthines are a group of drugs that directly cause relaxation of bronchial smooth muscle and some central respiratory stimulation. They also have a slight diuretic effect. Xanthines are of principle use in the immediate phase reaction of asthma but also have some effect on the late phase reaction. They are used to treat severe acute asthma attacks and chronic asthma, in particular control of nocturnal asthma and early morning wheezing. Xanthines also have some use in chronic bronchitis. 

Caffeine enters the bloodstream about ten minutes after its ingestion and stays in the body for up to twelve hours. Like other alkaloids, caffeine has powerful physiological effects on humans and animals. It stimulates heart muscle and relaxes certain structures that contain smooth muscle, including the coronary arteries and the bronchi. It is a diuretic. Theophylline and theobromine, two other plant alkaloid derivatives of xanthine, have physiological effects similar to those of caffeine. 

Xanthine derivatives have a number of pharmacological properties in common. Five major actions are observed (1) central nervous system and respiratory stimulation, (2) skeletal muscle stimulation, (3) diuresis, (4) cardiac stimulation, and (5) smooth-muscle relaxation. Caffeine (29) increases central nervous system activity and its main effect is on the cerebral cortex, where it acts to produce clear thought and reduce drowsiness and fatigue. The normal dose is 100-200 mg (Cordell, 1981). The oral LD50 in mouse is 127-137 mg/kg the oral LD50 in rat for theobromine (31) is 950... 

The phosphodiesterase which cleaves cyclic AMP to adenylate is found in both particulate and soluble fractions of tissue homogenates, and it is inhibited by pyrophosphate and ATP, as well as by caffeine, theophylline, and theobromine. These three methylated xanthines cause central nervous system and respiratory stimulation, smooth muscle relaxation, diuresis, coronary dilatation, cardiac stimulation, and skeletal muscle stimulation these effects are believed to be due to increased tissue concentrations of cyclic AMP resulting from inhibition of phosphodiesterase activity. 

Incubation of A10 cells, a murine vascular smooth muscle cell line, with xanthine oxidase and purine resulted in an enhancement of adenylate cyclase activation (Tan et al. 1995). The effect of purine and xanthine oxidase was not blocked by coincubation with superoxide dismutase (which catalyses the conversion from superoxide anion to H2O2). This suggests that the generation of the superoxide anion is not involved in the mechanism of enhancement of adenylate cyclase activation. 

It has been proposed that these bronchodUator effects of xantbines result from a relaxant effect on bronchial smooth muscle and that the xanthines regulate the cAMP and cGMP in the smooth muscle via PDE inhibition. 

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