Opioid Derivatives

The constipating effects of morphine and certain other opioid derivatives have been recognized for some time. These drugs produce a general decrease in GI motility, and they may also reduce fluid loss by increasing the absorption of salt and water or by decreasing fluid and electrolyte excretion from the GI tract.44 The exact manner in which opioids exert these effects, however, is not known. As indicated in Chap- 

Opioid derivatives used to treat diarrhea are listed in Table 27-3. Opium tincture (laudanum) and camphorated opium tincture (paregoric) are naturally occurring opiates that are very potent inhibitors of peristalsis. These natural agents are still available for treating diarrhea, but they have essentially been replaced by newer opioids such as diphenoxylate and loperamide. These newer opioids are somewhat less potent but may produce fewer side effects. 

Attapulgite Donnagel, others 1.2-1.5 gm after each loose bowel movement 

Kaolin, Pectin Kao-Spen, Kapectolin 60-120 mL regular-strength suspension after each loose, bowel movement 

Bismuth salicylate Pepto-Bismol, others 525 mg every half hour to 1 hour or 1050 mg every hour if needed 

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Opiates and opioid derivatives delay the transit of intraluminal content or increase gut capacity, prolonging contact and absorption. The limitations of the opiates are addiction potential (a real concern with long-term use) and worsening of diarrhea in selected infectious diarrheas. 

The aminothiazole ring of the novel opioid derivative 191 is produced on reaction of the corresponding amine with potassium thiocyanate and bromine in acetic acid (Equation 126) <2004JME1886>. 

Other treatment is aimed mainiy at decreasing discomfort. Buiking agents, such as methyiceiiuiose, bran, etc., may be of use, but the mainstay of treatment of diarrhoea is opioid derivatives. These act mainiy by an action at p receptors, siowing transit time and thus aiiowing more time for absorption of fluids. They may aiso have an effect directiy on the epitheiiai ceiis of the bowei to reduce secretion and/or increase reabsorption. 

The opioid derivatives most commonly used as antitussives are dextromethorphan, codeine, levopropoxyphene, and noscapine (levopropoxyphene and noscapine are not available in the USA). They should be used with caution in patients taking monoamine oxidase inhibitors (see Table 31-5). Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions. Importantly, due to increasing reports of death in young children taking dextromethorphan in formulations of over-the-counter "cold/cough" medications, its use in children less than 6 years of age has been banned by the FDA. Moreover, due to variations in the metabolism of codeine, its use for any purpose in young children is being reconsidered. 

Naloxone Narcotic drugs, other opioid derivatives A specific antagonist of opioids 1-2 mg initially by IV, IM, or subcutaneous injection. Larger doses may be needed to reverse the effects of overdose with propoxyphene, codeine, or fentanyl derivatives. Duration of action (2-3 hours) may be significantly shorter than that of the opioid being antagonized. 

During the late 1930s some 4-phenylpiperidine derivatives were examined as potential spasmolytics on the basis of their chemical relationship to atropine. The antinociceptive properties of one member, ethyl 1-methyl-4-phenyl-piperidine-4-carboxylate, was detected in screening tests and the compound was subsequently introduced into clinical use by Eisleb and Schaumann in 1939. The compound, well known as pethidine in Europe and meperidine in North America (proprietary names include Demerol, Dolantin, and Dolosal), was soon in widespread use for the relief of pain, and it is remarkable how pethidine, the original non-opioid-derived opioid analgesic, has retained its popularity for many years in the face of competition from other synthetic analgesics introduced since 1939. 

The most widely used approach to treating opioid addiction is methadone maintenance. Methadone, shown in Figure 14.44, is a synthetic opioid derivative that has most of the effects of other opioids, including euphoria, but differs in that it retains much of its activity when taken orally. This means that doses are very easy to control and monitor. The withdrawal symptoms of methadone are also far less severe, and the addict may be slowly weaned off the opioid without excessive stress. An addict may be freed of physical dependence in a matter of months. The psychological dependence, however, usually persists throughout the individual s life, which is why the relapse rate is so high. 

Oxycodone is a semisynthetic opioid derived from thebaine and used for oral pain relief. It is commonly formulated as an immediate-re lease medication with acetaminophen or aspirin. A con-trolled-release oxycodone formulation is used for the treatment of moderate to severe pain it provides controlled drug delivery over 12 h. The oral bioavailability of this formulation is 60 to 87%.35 The results of clinical studies of patients with postoperative and cancer pain show that oxycodone has a potency 1.5 times that of morphine. 

Hydrocodone is a semisynthetic opioid derived from codeine.18It is utilized as an analgesic and antitussive available for oral administration, often in combination with acetaminophen or ibuprofen. As a rule, potent analgesics containing a methoxyl group at position 3 (e.g., hydrocodone, K, = 19.8 nM) bind the mu receptor relatively weakly, but their O-demethylated metabolites (such as hydromorphone, Kt = 0.6 nM) bind more strangely. As with oxycodone, the possibility exists that some of their ability to relieve pain may actually derive from their active metabolites 48... 

Opioid derivatives Difenoxine Motofen1 2 mg initially, 1 mg after each loose stool or every 3-4 hrs... 

Buprenorphine is a semisynthetic, highly lipophilic opioid derived from thebaine. It is 25 to 50 times more potent than morphine. 

Answer B. Docusate is a stool-softening laxative that facilitates mixing of oil and water via its surfactant properties. Drugs that have muscarinic blocking effects, like scopolamine and the antihistamines diphenhydramine and promethazine, tend to cause constipation by decreasing GI motility. Loperamide is an opioid derivative, with no analgesic activity, used in the treatment of diarrheal states. 

The opioid peptides isolated from mammalian tissue are known collectively as endorphins, a word that is derived from a combination of endogenous and morphine. The opioid alkaloids and all of the synthetic opioid derivatives are exogenous opioids. Interestingly, the isolation of morphine and codeine in small amounts has been reported from mammalian brain (9). The functional significance of endogenous morphine remains unknown. 

Those interested in an in-depth understanding of the SAR for p receptor antagonists should be aware that properly substituted N-methyl-4-phenylpiperidines, N-methyl-6,7-benzomorphans, and even nonphenolic opioid derivatives that have good antagonist activity are known. 

The number of Americans abusing prescription drugs doubled from 7.8 million in 1992 to 15.1 million in 2003. The painkiller hydrocodone was used by 7.4% of college students in the United States in 2005. It is a semisynthetic opioid derived from two of naturally occurring opiates, codeine and thebaine. Production of this drug has increased in recent years. In Scandinavia, flunitrazapam, a sedative, is sold as Rohypnol, and it is widely known as a date-rape drug. ... 

Maher-Loughnan GP, Macdonald N, Mason AA et al (1962) Controlled trial of hypnosis in the symptomatic treatment of asthma. Br Med J 2 317-321 Manocha R, Marks GB, Kenchington P et al (2002) Sahaja yoga in the management of moderate to severe asthma A randomized controlled trial. Thorax 57 110-115 May AJ, Widdicombe JG (1954) Depression of the cough reflex by pentobarbitone and some opioid derivatives. Br J Pharmacol 9 335-340... 

The term opioids refers to these and other derivatives of naturally occurring opium (eg, morphine, heroin, codeine, and hydrocodone) as well as new, totally synthetic opiate anaiogs (eg, fentanyl, butorphanol, meperidine, and methadone Table 11-43). A wide variety of prescription medications contain opioids, often in combination with aspirin or acetaminophen. Dextromethorphan (see p 183) is an opioid derivative with potent antitussive but no analgesic or addictive properties. Tramadol (Ultram )... 

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