Uptake of catecholamines inhibition

The mechanism of the central action of amphetamine continues to be explored and the prevailing evidence points to multiple mechanisms involving catecholamine release, inhibition of catecholamine uptake, MAO inhibition and a direct intrinsic action73-75. Dependence on amphetamine and other stimulant drugs, its clinical manifestations and treatment are the subject of two excellent reviews76,77. 

Dopexamine (Dopacard) is a synthetic analog related to dopamine with intrinsic activity at dopamine Dj and D2 receptors as well as at P2 receptors it may have other effects such as inhibition of catecholamine uptake. It appears to have favorable hemodynamic actions in patients with severe CHF, sepsis, and shock. In patients with low cardiac output, dopexamine infusion significantly increases stroke volume with a decrease in systemic vascnlar resistance Tachycardia and hypotension can occnr, bnt nsnally only at high infusion rates. 

Its euphoric properties are due primarily to inhibition of catecholamine uptake, particularly dopamine, in the CNS. Other local anesthetics do not block the uptake of norepinephrine and do not produce the sensitization to catecholamines, vasoconstriction, or mydriasis characteristic of cocaine. Currently, cocaine is used primarily for topical anesthesia of the upper respiratory tract, where its combination of both vasoconstrictor and local anesthetic properties provide anesthesia and shrinking of the mucosa. Because of its abuse potential, cocaine is listed as a schedule II drug by the U.S. Drug Enforcement Agency. 

A. CNS stimulation and inhibition of catecholamine uptake result in a state of generalized sympathetic stimulation very similar to that of amphetamine intoxication (see p 72). 

Table 15. Inhibition of Catecholamine Uptake INTO Isolated Adrenal Medullary Vesicles by Drugs...

Drug Concentration CuM) Percentage inhibition of catecholamine uptake... 

Methylphenidate (Ritalin) is a behavioural stimulant used for the treatment of narcolepsy and attention deficit hyperactivity disorder (ADHD). It is commonly classified as a non-amfetamine but its nucleus is still present in that structure. The erytliro-racemate, i.e. (2 R,2"S)- and (2 S,2"R)-methylphenidate, shows negligible stimulant activity and is not used. The racemic threo-mcemate is responsible for activity but the (2 R,2"R)-enantiomer (dexmethylphenidate) displayed a more powerful inhibition of catecholamine uptake. 

Ary, T.E., and Komiskey, H.L. Phencyclidine Inhibition of synaptosomal uptake and release of previously accumulated %-catecholamines. Pharmacologist 21 241, abst. no. 506, 1979. 

I. Mechanism of toxicity. The primary actions of cocaine ate local anesthetic effects (see p 74), CNS stimulation, and inhibition of neuronal uptake of catecholamines. 

Relationship between blockade of catecholamine uptake and antisecretory activity - Following the earlier findings that imipr ine inhibits basal gastric secretion in rats, and also reduces acidity and relieves pain in ulcer patients,studies have been published on the antisecretory activity of other compounds that block norepinephrine uptake. 

Lu 3-010 (3,3-dimethyl-l-(3-methylaminopropyl)-l-phenylphthalan), a specific blocker of catecholamine uptake devoid of anticholinergic activity, inhibited both basal and pentagastrin stimulated secretion in the rat.88 studies by Lippmann on Lu 3-010 and another series of com-pounds 9 related to N,N -bis-(l-naphthylmethyl)-l, t-cyclohexane-bis-(methylamine) dihydrochloride (AY 9928) suggest that direct correlation between blockade of catecholamine uptake and antisecretoiy effect is moot. 

Diffutin (see above) has pronounced adaptogenic (anti-stress and anti-anxiety) activity, as well as being a mild CNS depressant (barbiturate potentiation). It also has a marked inotropic effect in perfused frog heart, and shows no arrhythmogenic properties. In addition, it potentiates the contractile response of guinea pig vas deferens to catecholamines, without inhibition of the uptake of adrenalin. At 500 mg/kg, diffutin is nontoxic to dogs. The use of Canscora in Indian medicine as a herbal remedy for certain mental disorders is supported by these observations. 

Prenyl amine (66) was long used in the treatment of angina pectoris, in which condition it was believed to act by inhibiting the uptake and storage of catecholamines in heart tissue. Droprenilamine (69), an analogue in which the phenyl ring is reduced, acts as a coronary vasodilator. One of several syntheses involves simple reductive alkylation of 1,1-diphenyl-propylamine (67) with cyclohexyl acetone (68)... 

The linkage of uptake to the Na+ gradient may be of physiological significance since transport temporarily ceases at the time of depolarization-induced release of catecholamines. The transport of catecholamines can be inhibited selectively by such drugs as tricyclic antidepressants and cocaine. In addition, a variety of phenylethyl-amines, such as amphetamine, are substrates for carrier thus, they can be concentrated within catecholamine-containing neurons and can compete with the catecholamines for transport. 

Prazosin, terazosin, and doxazosin are selective cq-receptor blockers that inhibit catecholamine uptake in smooth muscle cells of the peripheral vasculature, resulting in vasodilation. 

Reserpine causes a breakdown of norepinephrine, dopamine, and serotonin in neuron endings. It weakens intracellular uptake of biogenic amines and reduces the ability if storing them in vesicles. It is possible that reserpine acts on membrane vesicles, irreversibly inhibiting ATP-Mg (adenosinetriphosphate) requiring process that is responsible for the uptake of biogenic amines in intemeuronal vesicles. Breakdown of catecholamines is expressed by a decreased number of intraneuronal serotonin and dopamine. 

On the other hand, theophylline inhibits reverse uptake catecholamine uptake, which can elevate the level of cychc adenosine monophosphate, thus causing a broncholytic effect. Finally, theophylline is an adenosine receptor blocker, and this may be responsible for its broncholytic effect. 

Sympathomimetics are drugs which resemble the phenylalkylamine structure of the catecholamines and induce similar effects as adrenaline and noradrenaline. According to their molecular mechanism there are direct- and indirect-acting sympathomimetic drugs, the latter of which release noradrenaline from and/or inhibit its re-uptake into the presynaptic sympathetic axon. 

There is good evidence that the facilitation of peripheral sympathetic nervous system transmission prcxluced by the amphetamines also occurs in the CNS.The possibihty that amphetamines act indirectly (i.e., by releasing monoamines) at monoaminergic synapses in the brain and spinal cord seems likely. However, amphetamine has effects beyond displacement of catecholamines these include inhibition of neuronal amine uptake, direct stimulation of dopamine and serotonin receptors, antagonism of catecholamine action at certain subtypes of adrenoceptors, and inhibition of monoamine oxidase. Interestingly, none of these actions explains the therapeutic benefit of the amphetamines in hyperkinetic children. 

Synthesis inhibitors block tryptophan hydroxylase, the first rate-determining enzyme in serotonin synthesis. Although p-chlorophenylalanine (4.111) can decrease serotonin levels by more than 90%, this agent does not cause the sedation that is seen after catecholamine depletion with reserpine. Therefore, reserpine, although capable of depleting 5-HT vesicles, causes sedation by a catecholaminergic mechanism that inhibits uptake-2. It acts on the membrane of the synaptic vesicle and seems to prevent 5-HT and catecholamine uptake into the granule. 

Sympathomimetic effects (from NA re-uptake inhibition) and antimuscarinic effects can cause a sinus tachycardia. Postural hypotension may occur as a result of sympatholytic al-adrenoceptor antagonism. With overdoses of these drugs, there is a reduced re-uptake of catecholamines, resulting in arrhythmias and hypertension. Tricyclic compounds have a high... 

Factors that influence the disposition of catecholamines will affect the toxicity. For instance, compounds that inhibit the uptake of noradrenaline reduce the destruction of adrenergic nerve terminals but not of dopaminergic ones. Interference with the oxidative metabolism of catecholamines also influences the toxicity of 6-hydroxydopamine. 

Pemoline, an oxizolidine compound, acts similarly to methylphenidate—through catecholamine uptake inhibition in the CNS (27) with minimal sympathomimetic effects (57). Although pemoline is not the first-line stimulant for the treatment of ADHD, it has been successfully used for the treatment of this disorder in both children and adults (28,30). Pemoline has also been used for the treatment of daytime sleepiness associated with narcolepsy (31), and although it is somewhat effective for this purpose (33), it is not a first-line choice owing to its potentially lethal liver toxicity. 

Tricyclic antidepressants inhibit the uptake of catecholamines, such as adrenaline, into sympathetic neurons and can enhance the cardiovascular effects, so that even the small amounts of adrenaline present as additives in some local anesthetics can have a marked effect on the cardiovascular system. 

Tricyclic antidepressants inhibit the uptake of catecholamines, such as ephedrine, into sympathetic neurons and can enhance their cardiovascular effects (41). 

Fluoxetine has been found to cause selective central nervous system (CNS) neuronal uptake inhibition of serotonin. While fluoxetine may bind to adrenergic, muscarinic, and histaminic receptors, it has not been shown to have the profound effects on catecholamines that are common to tricyclic antidepressant overdose patients. 

---