Biochemistry Of ‘Primary-Secondary’ Actions Of Drugs Disproves The Concepts Of Stuart Close
Stuart N. Close in his ‘Lectures on Philosophy’ (Chapter 13) pp 184-5 says:
“The homeopathic doctrine of dosage, like the law of cure was based upon the discovery of the opposite action of large and small doses of medicine. It is another application in medicine of Law of Mutual Action – the third Newtonian law motion – “Action and Reaction are Equal and Opposite”. Every one at all acquainted with the action of drugs knows, for example, that Ipecac in large doses causes nausea and vomiting and in small doses, under certain conditions, will cure the same; that Opium in large doses will cause a deep sleep or narcosis, and in small doses, under certain conditions, will cure the same.”
I disagree with Stuart Close regarding his concepts of ‘primary-secondary’ actions of drugs.
I cannot see any substance in the comparison of homeopathic principle and newton’s laws of motion.Newton’s law is related with the action of ‘mechanical force on material bodies’, where as homeopathy deals with an entirely different subject. The principle “for every action there is an equal and opposite reaction’ is applicable to the interaction of ‘material bodies and mechanical forces’. Even if a great homeopath like Stuart Close says that homeopathy “is another application in medicine of Law of Mutual Action – the third Newtonian law motion”, it amounts to utter nonsense. He interprets homeopathy as well as newton’s law in a very absurd way through this statement. How can anybody with sound reasoning say that the phenomenon of ‘Opium in large doses causing deep sleep and in small doses cure the same’ is similar to ‘for every action there is an opposite reaction’?Newton’s law has nothing in it comparable to action of ‘Opium in large doses causing deep sleep and in small doses cures the same’. Anybody with minimum common sense would realize that Stuart Close has used a wrong comparison here.
Stuart Close says: “Closely allied to this is the so-called primary and secondary action of drugs, in which we see many drugs, in the first or primary stage of their action producing one group of symptoms, and in the second stage a directly opposite set of phenomena; as when the deep sleep of the primary action of Opium is followed by much longer lasting wakefulness; or where the diarrhea induced by a cathartic is followed by a longer lasting constipation. This applies, of course, only to drugs given in tangible form and considerable quantities, in what are called “physiological doses”.
How can anybody say the phenomenon of “so-called primary and secondary action of drugs, in which we see many drugs, in the first or primary stage of their action producing one group of symptoms, and in the second stage a directly opposite set of phenomena” is “closely allied to” the phenomenon of “opium in large doses causing deep sleep and in small doses cure the same”. First phenomenon is related with ‘large dose’ getting antidoted by ‘small dose’ of same drug, where as second phenomenon is related with “action of opium causing deep sleep followed by much longer lasting wakefulness”.
The logic of Stuart close has obviously misfired in both these statements.
In fact, the ‘effects of large doses being antidoted by small dose of same substance’, on which the principle of ‘similia similibus curentur’ is built up, is related with the known phenomenon of ‘molecular inhibitions getting removed by competitive affinity of similar molecules’. But the “action of opium causing deep sleep followed by much longer lasting wakefulness” is related with the phenomenon of ‘nerve receptors getting blocked by accumulation of ligand molecules, thereby initiating feedback mechanisms’ inducing the up-regulation of glutamate and other pathways in the brain induced by the over-activation of opioid receptors, thereby exert an opioid-opposing effect and so reduce the effects of opioid drugs by altering downstream pathways.
Both are different, and cannot be compared to one another.
In any discussion regarding the ‘primary-secondary’ actions of homeopathic drug substances, the phenomenon of ‘opium causing excessive sleep and constipation, later followed by profound sleeplessness” is always cited as an example.
Opium contains two main groups of alkaloids. Phenanthrenes such as morphine, codeine, and thebaine are the main narcotic constituents. Isoquinolines such as papaverine and noscapine have no significant central nervous system effects
To understand the biochemistry of ‘primary- secondary’ actions of opium, we should learn the biochemical processes involving μ-opioid receptors.
Read from Wikipedia: “The μ-opioid receptors (MOR) are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide (MOP) receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ (mu) refers to morphin
MOR can mediate acute changes in neuronal excitability via “disinhibition” of presynaptic release of GABA. Activation of the MOR leads to different effects on dendritic spines depending upon the agonist, and may be an example of functional selectivity at the μ receptor. The physiological and pathological roles of these two distinct mechanisms remain to be clarified. Perhaps, both might be involved in opioid addiction and opioid-induced deficits in cognition.
Activation of the μ receptor by an agonist such as morphine causes analgesia, sedation, slightly reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation. Some of these side effects, such as sedation, euphoria and decreased respiration, tend to lessen with continued use as tolerance develops. Analgesia, miosis and reduced bowel motility tend to persist; little tolerance develops to these effects.
As with other G protein-coupled receptors, signalling by the mu opioid receptor is terminated through several different mechanisms, which are upregulated with chronic use, leading to rapid tachyphylaxis. The most important regulatory proteins for the mu opioid receptor are the β-arrestins Arrestin beta 1 and Arrestin beta 2, and the RGS proteins RGS4, RGS9-2, RGS14 and RGSZ2.
Long-term or high dose use of opioids may also lead to additional mechanisms of tolerance becoming involved. This includes downregulation of mu opioid receptor gene expression, so the number of receptors presented on the cell surface is actually reduced, as opposed to the more short-term desensitisation induced by β-arrestins or RGS proteins. Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect and so reduce the effects of opioid drugs by altering downstream pathways, regardless of mu opioid receptor activation.
Opioid overdoses kill through apnea and fatal hypoxia, often aggravated by simultaneous use of alcohol, benzodiazepines or barbiturates. Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses. However tolerance to respiratory depression is lost just as quickly during withdrawal. Many overdoses occur in people who misuse their medication after being in withdrawal long enough to lose the tolerance to respiratory depression. Less commonly, massive overdoses have been known to cause circulatory collapse.
Opioid overdoses can be rapidly reversed with any of several opioid antagonists: naloxone, or naltrexone, differing primarily in their duration of action and potency. While commonly referred to as antagonists, and when used to treat an overdose they do appear to function as such, naloxone & naltrexone are inverse agonists”.
So-called secondary actions of opioid substances such as opium can be explained by the phenomenon up-regulation of glutamate and other pathways in the brain induced by the over-activation of opioid receptors, thereby exert an opioid-opposing effect and so reduce the effects of opioid drugs by altering downstream pathways, regardless of mu opioid receptor activation. In effect, the ‘primary-action’ of opioids finally lead to ‘secondary actions’, which are totally in reverse direction.
This is the biochemical mechanism underlying the ‘primary-secondary actions’ of ‘opioid’ substances.
Similar way, we can explain this phenomenon of ‘primary-secondary’ actions regarding any drug substance in terms of modern biochemistry, by studying the molecular pathways affected by the constituent molecules of those drug substances. There is nothing ‘mysterious’ in it. We need not drag any ‘dynamic’ ‘vital force’ into it.