Morphine physiological actions

Ormosia dasycarpa Jacks. Ormosine, CjoHaaNg, m.p. 85-7°, long needles methiodide (abnormal) picrate, m.p. 178° (dec.). Ormosinine, CjaHaaNj, m.p. 208-5° methiodide, needles, m.p. 245°. Morphine-like in physiological action (Hess and Merck, Ber., 1919, 52,1976). 

The change in structure from morphine to apomorphine profoundly changes its physiological action. The central depressant effects of morphine are much less pronounced, and the stimulant effects are enhanced greatly, thereby producing emesis by a purely central mechanism. It is administered subcutaneously to obtain emesis. It is ineffective orally. Apomorphine is one of the most effective, prompt (10 to 15 minutes), and safe emetics in use today. Care should be exercised in its use. however, bccau.se it may be depressant in already-depressed patients. It is currently cla.ssified as an "orphan drug" for use in Parkinson s disease. 

The next correlation was found in Scotland where Crum Brown and Fraser (1869) made a major discovery. They showed that several alkaloids, when quaternized, lost their characteristic pharmacological properties (many of them spasmogenic or convulsant) and acquired the muscle-relaxing powers of tubocurarine (2.6) (itself a quaternary amine), whose site of action had been shown to lie at the jimction between nerve and voluntary muscle, a few years earlier, by Claude Bernard (1856). Strychnine, bruceine, thebaine, codeine, morphine, nicotine, atropine, and coniine were quaternized into curarimimetic substances, by reaction with methyl iodide. The Scottish authors wrote There can be no reasonable doubt that a relation exists between the physiological action of a substance and its... 

P-Endorphin. A peptide corresponding to the 31 C-terminal amino acids of P-LPH was first discovered in camel pituitary tissue (10). This substance is P-endorphin, which exerts a potent analgesic effect by binding to cell surface receptors in the central nervous system. The sequence of P-endorphin is well conserved across species for the first 25 N-terminal amino acids. Opiates derived from plant sources, eg, heroin, morphine, opium, etc, exert their actions by interacting with the P-endorphin receptor. On a molar basis, this peptide has approximately five times the potency of morphine. Both P-endorphin and ACTH ate cosecreted from the pituitary gland. Whereas the physiologic importance of P-endorphin release into the systemic circulation is not certain, this molecule clearly has been shown to be an important neurotransmitter within the central nervous system. Endorphin has been invaluable as a research tool, but has not been clinically useful due to the avadabihty of plant-derived opiates. 

Most often only one form shows correct physiological and pharmacological action. For example, only one enantiomer of morphine is active as an analgesic, only one enantiomer of glucose is metabolized in our body to give energy and only one enantiomeric form of adrenaline is a neurotransmitter. 

Examples of neuropeptides are endorphins and enkephalins, sometimes called naturally occurring opioid peptides because of their ability to bind to the same receptors as morphine. In this family of neuropeptides, there are at least 10 to 15 substances with purported actions on such diverse physiological systems as pain response, memory and learning, appetite, and temperature regulation. 

Toxins in general are potent poisons. Nevertheless, the selectivity of action of some of these toxins means they have been harnessed in medical therapeutics (and even more widely in experimental pharmacology and physiology). Toxins that have been, or still are. us in medicine include atropine, botulinum toxin, cardiac glycosides, coichidne, eserine, hyoscine, picrotoxin, morphine, ouabain, strychnine, veratridine, vinca alkaloids and many more. All these work by an action at a defined molecular site, whether ion channel, neurotransmitter receptor, enzyme, pump or intracellular organelle. Those toxins that work at nonneuronal, or not specifically at neuronal sites (e.g. cholera toxin, pertussis toxin, cardiac glycosides, phospholipases) are discussed under TOXINS. 

Substitution of tetrazol-5-one for the thiophene ring in sufentanil results in a decrease in potency ( 25 times that of morphine) and a decrease in the pKa of the resultant compound, alfentanil (Table 24.4). The lower pKa of alfentanil results in a lower percentage of the drug existing in the ionized form at physiological pH. Being more un-ionized, alfentanil penetrates the blood-brain barrier faster than other fentanyl derivatives and has a faster onset and shorter duration of action. Alfentanil is 99% metabolized in the liver and has a half-life of only 1.3 hours. Alfentanil is available as an intravenous dosage form for use in ultrashort anesthetic procedures. 

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