Opiates gastrointestinal effects

There are a number of side-effects of opiates that are due to their actions on opiate receptors outside the central nervous system. Opiates constrict the pupils by acting on the oculomotor nucleus and cause constipation by activating a maintained contraction of the smooth muscle of the gut which reduces motility. This diminished propulsion coupled with opiates reducing secretion in the gut underlie the anti-diarrhoeal effect. Opiates contract sphincters throughout the gastrointestinal tract. Although these effects are predominantly peripheral in origin there are central contributions as well. Morphine can also release histamine from mast cells and this can produce irritation and broncho-spasm in extreme cases. Opiates have minimal cardiovascular effects at therapeutic doses. 

Cholecystokinin CCKa (CCKj) Human cDNA Anorexia, gastrointestinal disorders, pancreatitis, satiety, diabetes, obesity, nociception, schizophrenia, Parkinson s disease, addiction, cancer Pancreatic enzyme secretion, potentiation of opiate analgesia, gallbladder contraction, gut motility, growth promoting effects on some tumors, dopamine release... 

Some of the commonly used antitussives are listed in Table 26-1. As shown in the table, codeine and similar opiate derivatives suppress the cough reflex by a central inhibitory effect.21,124 Other nonopioid antitussives work by inhibiting the irritant effects of histamine on the respiratory mucosa or by a local anesthetic action on the respiratory epithelium. The primary adverse effect associated with most antitussives is sedation. Dizziness and gastrointestinal upset may also occur. 

Meperidine has replaced morphine to a large extent in medical practice because of the physician s reluctance to use an opiate and the belief that meperidine manifests less undesirable side effects than does morphine. However, both of these assumptions are ill founded. Addiction to meperidine is much less amenable to treatment than is addiction to morphine. Meperidine, similar to morphine and codeine, causes spasm of the upper gastrointestinal tract and typical attacks of biliary colic in biliary tract disease. Meperidine, in doses giving an equal analgesic effect, induces as much respiratory depression as does morphine. Similar to morphine, it also crosses the placental barrier and must therefore be used cautiously in the latter stages of labor. 

Scientific research has shown that methadone and other opiates have specific areas, or sites, that they attach to in order to exert their influence on the brain and body. These sites, called receptors, are classified as mu, delta, and kappa, depending on what body functions they influence. Opiate activation of mu and delta receptors seems to influence mood, respiration, pain, blood pressure, and gastrointestinal functions. Kappa receptors appear to be more involved in the perception and aversion to pain. The degree of methadone s effect on these receptors can vary widely between individuals, however, there are certain effects that are almost universal. 

Miosis is a characteristic symptom of opiate administration, and while tolerance develops to many of the pharmacological effects of this class of drugs, tolerance to the miotic effects occurs at a much slower rate. Miosis is due to an excitatory action of the autonomic segment of the nucleus of the oculomotor nerve, an effect attributed to the stimulation of the mu receptors. In general, it would appear that the actions of morphine and its analogues on the brain, spinal cord and gastrointestinal tract are due to stimulation of the mu receptors. 

Pharmacological studies with selective agonists have shown that opioid control of intestinal electrolyte transport is predominantly mediated by delta opioid receptors [58], while the gastrointestinal propulsion is under the control of mu receptors [59,60]. The antidiarrheal effects of NEP inhibitors, such as acetorphan, the prodrug of thiorphan, have been compared to those of an opiate agonist, loperamide, in a model of castor oil-induced diarrhea in rats. When administered peripherally, they produced a delayed onset of diarrhea with no reduction in the gastrointestinal transit [61,62], as is commonly observed with loperamide [63],... 

Analgesics. Opiates can precipitate hepatic encephalopathy in patients with decompensated liver disease. If required to control postoperative pain, doses should be reduced to 25-50% of normal. Constant intravenous infusions should be avoided if the patient is not to be insidiously overdosed. Codeine can precipitate hepatic encephalopathy by its constipating effect alone. Aspirin and other NSAIDs may exacerbate impaired renal function and fluid retention by inhibiting prostaglandin synthesis and may also precipitate gastrointestinal bleeding. 

Heroin s primary toxic principle is its profound ability to depress the central nervous system (CNS). Opioid analgesics bind with stereospecific receptors at many sites within the CNS. Heroin, similar to other opioids, exerts its pharmacologic effect by acting at mu, kappa, and delta receptors in the brain. Although the precise sites and mechanisms of action have not been fully determined, alterations in the release of various neurotransmitters from afferent nerves sensitive to painful stimuli may be partially responsible for the analgesic effect. Activities associated with the stimulation of opiate receptors are analgesia, euphoria, respiratory depression, miosis, and reduced gastrointestinal motility. 

Morphine is the prototype for the class of natural and synthetic opioid analgesics and its toxicity stems mainly from its extensive effect on the central nervous system (CNS), principally that of a descending depression. Opioids interact with stereospecific and saturable binding sites mostly located in the CNS. Interaction with the opioid receptors mimics the actions of endogenous enkephalins and endorphins. Morphine is a pure opiate agonist and exerts its activity primarily on the mu receptor. Activity also appears to involve an alteration in the release of neurotransmitters, such as the inhibition of acetylcholine, norepinepherine, and dopamine. These actions result in the therapeutic effects of analgesia, sedation, euphoria, and decreased gastrointestinal motility however, in toxic amounts they can lead to... 

Opioid antagonists (Table 7.4), predominantly naloxone, are used clinically to reverse the effects of opiates in overdose or postoperative sedation. Naltrexone, which has oral bioavailability, is used for the treatment of narcotic addiction and alcohol dependence. As discussed below (Section 2.2.2.1), peripherally selective antagonists are being evaluated for treatment of constipation and other gastrointestinal side effects associated with opioid agonist use. 

Loperamide is an opiate drug that decreases motility of the intestine. It does not cross the blood-brain barrier easily and therefore does not have the central nervous system effects (euphoria, respiratory depression, nausea and vomiting and dependence) of other opiates. Loperamide is prescribed to counteract gastrointestinal side effects (diarrhoea) of therapeutic radiography. 

Primarily effects on the gastrointestinal system. These include decreased bowel motility and decreased gastric acid secretion. It is also believed that there is a vestibular component to the emetic action of opiate drugs. 

Physical addiction is receptor-mediated. Opiates exhibit tolerance, so a progressive increase in dose must be maintained over time in order to continue to achieve desired effects. This effect is manifested by a decrease in receptor number and sensitivity. Upon withdrawal, the receptor number and relative sensitivity to endogenous opiates is insufficient for normal bodily function. In addition, opiates affect all organ systems, particularly the heart and skeletal muscle. Abrupt withdrawal may precipitate convulsions and cardiovascular/cardiopulmonary abnormalities, particularly as a result of altered levels of norepinephrine. Gastrointestinal disturbances may also be manifested, and, because nociceptive levels are also affected, hyperalgesia may also result. 

Discuss the effects of opiate agonists on the gastrointestinal system. 

For example, tolerance develops rapidly to the euphoria produced by opioids such as heroin, and addicts tend to increase their dose in order to reexperience that elusive high. In contrast, tolerance to the gastrointestinal (GI) effects of opiates develops more slowly. The discrepancy between tolerance to euphorigenic effects (rapid) and tolerance to ejfects on vital functions (slow), such as respiration and blood pressure, can lead to potentially fatal accidents in sedative abusers. 

Caseinomorphins. Several peptides with opioid activity have been isolated from enzymatic digests of milk proteins (see Fox and Flynn, 1992). Such peptides were first isolated from enzymatic digests of casein and characterized as a family of peptides containing 4-7 amino acids with a common N-terminal sequence, H.Tyr.Pro.Phe.Pro-, and 0-3 additional residues (Gly, Pro, He), i.e. residues 60-63/6 of -casein, and hence were called caseinomorphins (P-CM) 4 to 7, respectively. P-CM-5 is the most effective of these peptides, which are 300-4000 times less effective than morphine. P-CMs are very resistant to enzymes of the gastrointestinal tract (GIT) and appear in the contents of the small intestine following ingestion of milk. -CN f60-70 also has weak opiate activity but may be hydrolysed to smaller, more active P-CMs by peptidases in the brush border of the GIT. 

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