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wondering
06-28-2009, 02:39 PM
Dr. Mariano,

Have you ever used Clonidine to help reduce norepinephrine to reduce anxiety. Does this have the same effect on dopamine - i.e. do side effects include lower libido, ED, etc.

While I consider psychotherapy to help with anxiety, I wonder if there are ANY medical interventions that dont have sexual side effects.

thanks again.

DrMariano
06-28-2009, 10:59 PM
Dr. Mariano,

Have you ever used Clonidine to help reduce norepinephrine to reduce anxiety. Does this have the same effect on dopamine - i.e. do side effects include lower libido, ED, etc.

While I consider psychotherapy to help with anxiety, I wonder if there are ANY medical interventions that dont have sexual side effects.

thanks again.

Remember that I am a psychiatrist. A psychiatrist can use a far greater range of medications than most physicians.

I am very familiar with Clonidine and certainly use it as part of my toolkit.


CLONIDINE:

Clonidine and its sister, Guanfacine, are Adrenergic alpha-2 receptor selective agonists. They are also I1 Imidazoline Receptor agonists. Note that anytime the world "selective" is used, this means that it also works on other receptors but prefers one versus the other. "Selective" is a weasel word in pharmacology.

The I1 Imidazoline receptors in many functions including control of blood pressure, pain management, etc., though they usually don't include anxiety, alertness, wakefulness functions like the adrenergic receptors do. Agonists of I1 Imidazoline receptors reduce blood pressure and helps reduce pain.

Adrenergic receptors have subtypes, which include the Alpha-1, Alpha-2, Beta-1, and Beta-2 receptors. Adrenergic receptors respond to both norepinephrine (noradreline) and epinephrine (adreneline). Alpha-2 receptors occur primarily in the brain. Alpha-2 receptors are both pre-synaptic and post-synaptic.

The pre-synaptic alpha-2 receptor is of interest since stimulating it reduces norepinephrine output from norepinephrine-releasing neurons of the norepinephrine system in the nervous system (which originates from the locus ceruleus and the lateral tegmental field). It functions like a thermostat, providing negative-feedback inhibition of norepinephrine output.

Clonidine, by stimulating alpha-2 receptors, reduces norepinephrine output from the norepinephrine system. Guanfacine (Tenex) is weaker in this regard and is thus not as sedating.

Clonidine only works 80% of the time on alpha-2 receptors. 20% of the time, it works like norepinephrine as an agonist on the other receptors. In the body, it actually acts as a stimulant 100 % of the time, just like norepinephrine, rather than acting as an anti-norepinephrine. But its ability to reduce norepinephrine signaling in the nervous system generally outweighs the stimulant part - for most people. It's stimulant effects can lead to side effects such as dry mouth, constipation. The norepinephrine-reducing action in the central nervous system causes sedation, dizziness, reduction in cardiac outflow (a consideration in treating patients with congestive heart failure).

Clonidine has many uses. In general medicine, it is primarily used to reduce blood pressure. It is also used as a pre-anesthetic agent. In psychiatry, it can be used for the treatment of migraine, nicotine addiction, opiate withdrawal, menopausal flushing, attention deficit/hyperactivity disorder, posttraumatic stress disorder, Tourette Syndrome, panic and anxiety disorders. In clinical use, I haven't found it as useful for anxiety since it can cause excessive daytime sedation.

Regarding sexual function, if the dose is too high, it also will reduce libido and the ability to have an orgasm. Norepinephrine also participates in sexual function - such as providing the excitement of sex and in trigger the orgasm. Inhibiting norepinephrine too much would not only reduce sex drive, but make one too sleepy to have sex in the first place.

Clonidine does not work with everyone. For example, some people become more anxious or do not sleep at all despite treatment with Clonidine. I hypothesize some people have a variant Alpha-2 receptor where Clonidine and norepinephrine do not fit fully well. This results in a nervous system which tends to be shifted to a high stressed state. The thermostate, so to speak, is broken. Generally, the anti-stress signaling systems can balance this and the person can function well. But after a time, through stresses, aging, etc. these systems lose function, then the person becomes ill.

If the dose of Clonidine is too high, the alpha-2 receptors can become saturated with Clonidine. Any further increase in Clonidine only increases its norepinephrine-like stimulant effects. Thus, past a certain dose, Clonidine works primarily as a stimulant rather than as a norepinephrine-reducing agent. It would cause insomnia, rather than sedation.

Care must be taken when used with stimulants, such as amphetamines. When a stimulant and Clonidine are working simultaneously, the stimulant can overpower Clonidine's alpha-2 agonist effects (it's norepinephrine-reducing effects). This means Clonidine will work primarily as a stimulant which has additive effects with the stimulant medication. This can cause significant problems such as tachycardia or other arrhythmias. A lot of physicians don't realize this, thinking Clonidine only has Alpha-2 agonist effects, not stimulant effects, since the alpha-2 agonist effects are the only ones listed in textbooks. When used in combination, my preference is to limit Clonidine to the evening so that its effects can wear out by the time a stimulant is started in the morning. Then, the simultaneous stimulant effects can be avoided as much as possible. I would avoid giving Clonidine in the daytime along with a stimulant. Since many psychiatrists if not most of them do not take vitals as I do, they may not realize they are causing tachyarrhythmias in the kids they treat with Clonidine and stimulants in the daytime. As I said above, the world "selective" is a weasel-word in pharmacology. A receptor-selective medication is not totally receptor-selective, it works on other receptors as well.

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REGARDING ANXIETY TREATMENTS:

With any medication for anxiety, realize that dosing is important. The higher the dose of ANY treatment for anxiety, the more likely impairment of sexual function or other side effect occurs. Thus, I would reduce the dose to find the minimum dose that doesn't have the unwanted side effect, then add another medication that uses a different mechanism. I call this a complex treatment.

Serotonin Reuptake Inhibitors are very useful for reducing anxiety. If the dose is too high and causes sexual dysfunction, I would simply reduce the dose until this effect is gone, keeping whatever dose is left for reducing anxiety. Then if anxiety is still prominent, I would add another medication with another mechanism of action to attack the problem of excessive anxiety, such as by adding a benzodiazepine or other medication. If an SSRI cannot be used at all, I would choose alternative mechanisms to treat the causes of anxiety.

In regard to anxiety, anxiety can be a side effect itself of increased norepinephrine levels which are a compensation for another problem. For example, when thyroid hormone is low, norepinephrine is increased by the brain in an attempt to improve energy production. Norepinephrine increases the production of 5'-deiodinase enzyme, which then improves conversion of T4 to T3, improving the effectiveness of whatever thyroid hormone is left. In this case, adding thyroid hormone to treatment helps avoid this compensation, thus reducing anxiety. Thus, when examining why a patient is having anxiety, the causes of a compensatory increase in norepinephrine production are important to find. This avoids having to add a medication to the mix since it would help restore normal norepinephrine signaling tone.