Norepinephrine drugs increasing

Ultimately, the effects of virtually aU existing antidepressants can be traced to the improvement of neurotransmission in the brain by one or more monoamine neurotransmitters, that is serotonin (5-HT, 4), norepinephrine (NE, 5), and dopamine (DA, 6). By blocking monoamine transporters, which remove the neurotransmitter from the synapse and extracellular space by uptake processes, the drugs increase extracellular levels of the transmitter and cause a cascade of intracellular events leading to the desired CNS effect. 

In a normal resting subject who is receiving no drugs, there is a moderate parasympathetic tone to the heart, and sympathetic activity is relatively low. The ventricular muscle receives little, if any, parasympathetic innervation. As the blood pressure rises in response to norepinephrine, the baroreceptor reflex is activated, parasympathetic impulses (which are inhibitory) to the heart increase in frequency, and what little sympathetic outflow there is may be reduced. Heart rate is slowed so much that the direct effect of norepinephrine to increase the rate is masked and there is a net decrease in rate. Under the conditions described, however, the impact of the reflex on the ventricles is very slight because there is no parasympathetic innervation and the preexisting level of sympathetic activity is already low. A further decrease in sympathetic activity therefore would have little further effect on contractility in this subject. Thus, a decrease in heart rate and an increase in stroke volume will occur, and cardiac output will change very little. 

The idea that depression is associated with changes in amine receptor sensitivity is summarized in Figure 7-1. For reasons that are still unclear, depression might occur because of an increase in postsynaptic receptor sensitivity to amine neurotransmitters, particularly norepinephrine and serotonin.4 Antidepressant drugs increase amine transmission by a variety of methods, thereby bringing about overstimulation of the postsynaptic receptor. (The exact method by which these drugs increase amine stimulation is discussed later in this chapter.) Overstimulation... 

Dopamine s role in the coordination of movement can be partially understood by examining Parkinson s disease. This illness is associated with low levels of dopamine in the brain and is characterized by spastic motion of the eyelids as well as rhythmic tremors of the hands and other parts of the body. One method of treating Parkinson s disease is to increase the concentration of dopamine in the brain. This is most effectively accomplished by administering the precursor of dopamine, L-dopa. In order to prevent concentrations of norepinephrine from increasing as well, L-dopa is given in conjunction with a drug that inhibits norepinephrine synthesis. 

Catecholamines are sympathomimetic drugs. These drugs increase heart rate and cardiac output and may produce cardiac arrhythmias. Administration of norepinephrine also results in increased peripheral vascular resistance. Both effects may cause serious... 

Blood pressure effects are unpredictable. The action of these drugs increases circulating levels of norepinephrine and epinephrine, which tend to raise pressure. At the same time, they stimulate the inhibition of central vasoregulatory centers that tend to decrease sympathetic activity. 

Psychostimulant drugs increase the amounts of available norepinephrine and/or dopamine in the CNS. The effects of MAOIs may synergize with the effects of these drugs. Thus, psychostimulant drugs should be used cautiously in conjunction with MAOIs. 

L-dopa is taken into both dopaminergic and noradrenergic nerve terminals, both in the CNS and periphery. Thus, peripheral levels of dopamine and norepinephrine may increase with administration of the drug, resulting in effects on the cardiovascular system, renal blood flow, and skeletal muscle function. 

As discussed, a number of studies have examined the effect of vasoactive drugs on percutaneons absorption. We therefore limit this discnssion to the more detailed investigations. Mnch of this early work was undertaken nsing both the IPPSF (Riviere and Williams, 1991) and anesthetized weanling pig model (Riviere etal., 1992). They reported that the vasodilator tolazoline significantly increased lidocaine flux compared to that observed in vitro, whereas norepinephrine (a vasoconstrictor) sigruficantly decreased lidocaine flux in the IPPSF (Riviere and Williams, 1991). Tolazoline shortened and norepinephrine increased the mean absorption time. Neither of these effects conld be replicated in the in vitro model. Their subsequent work in the anesthetized pig model showed that, in tissue samples taken 4 h after a 1-h iontophoretic treatment period, tolazoline had decreased underlying tissue concentrations of lidocaine, and norepinephrine had increased tissue levels compared to those observed when lidocaine was administered alone (Riviere etal., 1992). Subsequently, Williams and Riviere (1993) used a three-compartment pharmacokinetic model to describe these results. 

Epinephrine itself does find some use in clinical medicine. The drug is used in order to increase blood pressure in cases of circulatory collapse, and to relax the bronchial muscle in acute asthma and in anaphylactic reactions. These activities follow directly from the agent s physiologic role. The biogenetic precursor of epinephrine, norepinephrine, has activity in its own right as a mediator of sympathetic nerve action. (An apocryphal story has it that the term nor is derived from a label seen on a bottle of a key primary amine in a laboratory in Germany N ohne... 

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

MISCELLANEOUS ANTIDEPRESSANTS. An uncommon but potentially serious adverse reaction of trazodone is priapism (a persistent erection of die penis). If not treated within a few hours, priapism can result in impotence The nurse instructs the patient to report any prolonged or inappropriate penile erection. Use of the drug is discontinued immediately and the primary care provider notified. Injection of a-adrenergic stimulants (eg, norepinephrine) may be helpful in treating priapism. In some cases, surgical intervention may be required. Venlafaxine may cause an increase in die blood pressure. A sustained increase in die blood pressure may indicate that die dosage of venlafaxine needs to be decreased. 

The antidiuretic effects of vasopressin may be decreased when die agent is taken witii die following drugs lithium, heparin, norepinephrine, or alcohol. Antidiuretic effect may be increased when die drug is used witii carbamazepine, clofibrate, or fludrocortisone... 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

Phentermine decreases food intake, and hence weight, by increasing norepinephrine and dopamine release in the central nervous system. This drug is indicated for short-term use—no more than a few weeks—in addition to lifestyle modifications in obese patients with a BMI of 30 kg/m2 or greater or a BMI of 27 kg/m2" or greater in the presence of other risk factors.38... 

Against this backdrop, researchers reported evidence that iproniazid, the antitubercular drug that was to become the first antidepressant, might increase norepinephrine and serotonin levels in the brain. How did it have this effect Recall that some of the neurotransmitter molecules released by a neuron are destroyed by enzymes in the synaptic cleft between the sending presynaptic neuron and the receiving postsynaptic neuron. When the neurotransmitter is a monoamine - like norepinephrine and serotonin - this process is called monoamine oxidase (MAO). As early as 1952 researchers at the Northwestern University Medical School in Chicago reported that iproniazid inhibited the oxidation of monoamines. This meant that iproniazid was a... 

The answer is that there are two ways in which neurotransmitter levels might be increased. One is to inhibit their destruction after they have been released into the synaptic gap. That is how MAOIs are supposed to work. Recall, however, that after a neurotransmitter is released, some of its molecules are reabsorbed by the presynaptic neuron that released them in a process that is called reuptake . Blocking this reuptake process should also increase the level of neuro transmitters in the brain. In 1961, Julius Axelrod, who later received the Nobel Prize in Medicine for his work on the release and reuptake of neurotransmitters, reported that imipramine, as well as a few other drugs, inhibited the reuptake of norepinephrine in cats. Two years later he reported that these drugs also inhibited the reuptake of serotonin.13... 

The biochemical theory of depression is in a state of crisis. The data just do not fit the theory. The neurotransmitter depletion studies that I described earlier in this chapter show that lowering serotonin or norepinephrine levels does not make most people depressed. When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree. And the effect of anti-depressants, which was the basis for proposing the chemical-imbalance theory in the first place, turns out to be largely a placebo effect. 

MAOI (Monoamine Oxidase Inhibitors) will intensify and prolong the effects of NN-DMT, however this is never recommended. Foolish combinations of MAOIs and other drugs can lead to serious health problems and even death. The tryptamines are normally metabolized by an MAO in the body. MAO metabolizes serotonin, norepinephrine, and dopamine. By inhibiting this, MAOIs increase levels of those neurotransmitters. Tyramine will not be metabolized and will cause an increase in tyramine levels in blood. 

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