PHENOTHIAZINES

Synthetic chemistry improved the specificity and power of these drugs by making different substitutions. Drugs such as Compazine, Thorazine, and Mellaril are synthetic variations of the phenothiazine class. Depending on the different ions that are attached, for instance adding Cl- or F- to R2, we can increase antipsychotic potency. The classic phenothiazine is Chlorpromazine (Thorazine). The basic pharmacologic effect of these drugs is a general interference with transmission in different receptors.



This is a very complicated figure that looks so complex that you may just give up and say “to hell with it.” What this figure shows are different psychoactive drugs and the concentrations that they are effective at. These different colored areas represent the different receptors such as dopamine, 5-HT2, muscarine, etc. How can we know what drugs interact with what receptors? The author doesn’t know himself, he just copied from another author… what they do to figure this out is mash out brain (of a rat, hopefully) and measure radioactively how drugs bind to particular receptors. When I look at this figure, I see that these drugs act on all receptors! They are not specific. But maybe some are specific depending on the dose, for specific receptors. All of the drugs more or less specifically affect the dopamine receptors. But they very often affect the other receptors also, so we must expect some secondary effects. Also there is a more subtle thing, the dopamine D2 receptor is more commonly associated with these things. But in one case (we’ll see later) the D4 is more involved… so maybe D4 is the real one.


So you can walk away and say “He told me a lot of confusion.” But I told you the reality. So take this with you: these drugs do have some lack of specificity, but nevertheless the dopaminergic receptors are most commonly affected, and the D2 is usually more affected.


Generally speaking, another thing that the anti-psychotics do is interfere with mental activity; for instance the ability to perform conditioned reflexes is interfered with. We know this by testing rats; when given some of these drugs they will not be able to learn conditioned responses like associating a light with a shock, whereas normal rats will learn to associate the two and behave accordingly.



So focusing on the dopamine business, it is an analog of norepinephrine. So you still have the chemical reactions for the transformation of tyrosine into DOPA and then Dopamine, then you have storage of dopamine and release. The antipsychotic activities are mostly focused on D2, therefore they prevent signaling coming after D2 and you have an interference with dopaminergic stimulation of the CNS.



There is one further indication that the control on psychosis is dependent on anti-dopaminergic activity, due to the fact that if you measure the concentration of these drugs in the CSF and compare to the effects in blocking the psychosis, you get a linear relationship. So it seems that D2 is involved except for Clozapine… but in this case it is the D4 receptor, which is also a little more specific than D2.


So if we take an animal and give it these drugs, we see a paradoxical response of increased activity. But after 2-3 weeks of treatment, you get a paralysis, or block of lower activity. So that’s where the therapeutic effects show up. The therapeutic effect of positive control of schizophrenia is due to lowering the activity of dopaminergic bundles coming from the midbrain. So we have certainly made a case for the dopamine blocking activity of the psychotic drugs.


What we find in addition is a cholinergic block, because of the fact that other receptors (in addition to the dopamine receptors) are involved. So people who are taking these drugs will have xerostomia, and other anti-cholinergic symptoms such as difficulty urinating (in men) or constipation. These drugs also block central vomiting receptors. At one time, pregnant women were treated with anti-psychotics to counter the effects of morning sickness—anti-psychotics have effects on the medullary receptors associated with vomiting. Dopaminergic transmission is instrumental in the working of the extra-pyramidal system. The extra-pyramidal system controls involuntary movement; very often people on anti-psychotics develop strange movements.

Category: Pharmacology Notes