Side effects activity Respiratory depression

The history of this class of analgesics might have stopped there were it not for the manifold ancillary activities shown by that molecule. Although still one of the most widely used agents for treatment of severe pain, morphine is a drug that must be used with caution. Side effects include respiratory depression, induction of constipation, and sometimes marked sedation. The one property that most severely limits use of this drug is its propensity to induce physical dependence in patients subjected to more than casual exposure. 

Unfortunately, nalorphine has hallucinogenic side-effects resulting from the activation of a non-analgesic receptor, and is therefore unsuitable as an analgesic, but for the first time a certain amount of analgesia had been obtained without the side-effects of respiratory depression and tolerance. 

Another agent of this general type is nalmefene (47) Despite their useful characteristics, opiates display tolerance, addiction, abuse, and some toxic side effects Antagonists combat some of these effects, most notably respiratory depression and addiction Nalmefene reputedly has significant oral activity as a narcotic antagonist The synthesis of nalmefine concludes by Wittig olefination of naltrexone (46) to nalmefene (47) This molecular transformation resulted in a significant increase in oral potency as well (141... 

Mediates its effects by activating the microopioid receptor it shows equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. 

Medications with serotonergic activity may also have other monaminergic or sympathomimetic activity. Combining MAOIs with these medications may result in a complex side effect profile. For example, combining meperidine or dextromethorphan with MAOIs may result in respiratory depression, in addition to symptoms of serotonin excess. Furthermore, interactions between MAOIs and tricyclic antidepressants (TCAs) more commonly result in potentiating shared adverse events such as othostatic hypotension, as opposed to hyperadrenergic crises or the serotonin syndrome. 

Nalbuphine hydrochloride is structurally related to oxymorphone and naloxone. It is approximately equipotent with morphine. Nalbuphine is metabolised in the liver to inactive metabolites. The plasma terminal half-life is approximately 5 h. The onset of analgesia is within 2-3 min of intravenous administration and 15 min after intramuscular injection, and lasts 3-6 h with an adult dose of 10 mg. With equi-analgesic doses, similar degrees of respiratory depression to that of morphine occur up to a dose of approximately 0.45 mg-kg-1. With higher doses a ceiling effect occurs. Sedation, possibly mediated by K-receptor activation, occasionally occurs. The incidence of psychotomimetic side effects is lower than with pentazocine. The abuse potential is low, but is can cause withdrawal symptoms in opioid-dependent subjects. It has occasionally been used to reverse opioid-induced respiratory depression. 

Opioids in the different parts of the limbic system suppress the emotional component of pain and the pain suffering. Opioids in the formatio reticularis inhibit the pain-induced activation of autonomous functions, e.g. increase in respiration, increase in blood pressure and sweating. The inhibitory actions at the formatio reticularis are responsible for the major side-effects of the opioids such as respiratory depression, bradycardia and the central component of gastrointestinal inhibition. 

Side-Effects The most common side-effects are nausea, vomiting and dizziness. Other vegetative side-effects include sweating, hypotension and drowsiness. The compound is reported to be relatively free of respiratory depressant activity, which was attributed to selective binding to a subtype (p-1) of the opioid receptor... 

The opiates are perhaps the oldest drugs known to man. Opium contains a complex mixture of almost 25 alkaloids. The principal alkaloid in the mixture, and the one responsible for analgesic activity, is morphine, 11. Pure morphine is especially good for treating dull, constant pain, and periodic pain. Unfortunately, it has a large number of side effects, which include the depression of the respiratory center, excitation, nausea, euphoria, dependence, and others [6]. 

Although treatment of mild to moderate pain can typically be accomplished with nonnarcotic analgesics such as acetaminophen or aspirin, treatment of severe pain often requires use of an opioid analgesic such as morphine. These drugs are associated with serious side effects, however, most notably addiction liability and respiratory depression, which limit their clinical usefulness. Therefore there has been an intensive effort to find new analgesics that retain the effectiveness of morphine, but do not have the undesired side effects. As a result, a wide variety of compounds with opioid activity have been identified and significant strides have been made in understanding the mechanisms of opioid action. 

Codeine is partially demethylated in the body to morphine, which may contribute to its antitussive activity but also accounts for its liability to cause sedation, respiratory depression (although this is not normally a problem at OTC doses), constipation and addiction. Pholcodine has a generally better side-effect profile than codeine, and dextromethorphan is claimed to be virtually free from side-effects. 

It is usually assumed that the side-effects of a drug are due to interactions with additional receptors other than the one we are interested in. These interactions are probably due to the molecule taking up different conformations or shapes. If we make the molecule more rigid so that it takes up fewer conformations, we might eliminate the conformations which are recognized by undesirable receptors, and thus restrict the molecule to the specific conformation which fits the desired receptor. In this way, we would hope to eliminate such side-effects as dependence and respiratory depression. We might also expect increased activity since the molecule is more likely to be in the correct conformation to interact with the receptor. 

---