Opioids absorption

The state-of-the-art approach to controlled release opioid therapy is to provide formulations which exhibit zero order pharmacokinetics and have minimal peak to trough fluctuation in opioid levels with repeated dosing. This zero order release provides very slow opioid absorption, and a generally flat serum concentration curve over time. A flat serum concentration is generally considered to be advantageous because it would in effect mimic a steady-state level where efficacy is provided but side effects common to opioid analgesics are minimized. 

Casein refers to a family of proteins, namely, ttgi-, 0. 2-, p-, and k-caseins (Table 5.1). Digestion of a- and p-caseins leads to production of peptides that may bind to opioid receptors that exist in the nervous, endocrine, immime, or gastrointestinal system (Kampa et ah, 1996 Meisel, 2004). These compoimds may modulate absorption processes in the gut and can potentially affect gastrointestinal fimction through transit... 

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

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 pulmonary absorption and metabolism of an opioid tetrapeptide was investigated in the IPL and in rats in vivo by Tronde and co-workers [68, 140], The lung metabolism, compared after airway and vascular delivery, was consistently showed to be higher after airway delivery indicating some first-pass... 

Initial studies of brain delivery based on the chimeric peptide strategy used the absorptive-mediated uptake of cationized albumin which was chemically coupled to the opioid peptide P-endorphin [80] or its metabohcaUy stabilized analogue [D-Ala ]P-endorphin. Tracer experiments in which the chimeric peptide was labelled in the endorphin moiety provided evidence of internalization by isolated brain capillaries and transport into brain tissue in vivo [81]. 

Spasmolytics. N-Butylscopolamine (p. 104) is used for the relief of painful spasms of the biliary or ureteral ducts. Its poor absorption (N.B. quaternary N absorption rate <10%) necessitates parenteral administration. Because the therapeutic effect is usually weak, a potent analgesic is given concurrently, e.g., the opioid meperidine. Note that some spasms of intestinal musculature can be effectively relieved by organic nitrates (in biliary colic) or by nifedipine (esophageal hypertension and achalasia). 

Opioids such as diamorphine, pethidine, and pentazocine strongly inhibit gastric emptying and greatly reduce the absorption rate of paracetamol. Codeine, however, has no significant effect on paracetamol absorption. Morphine and diamorphine have been shown to reduce the absorption of antiarrhyth-mics such as mexiletine in patients with myocardial infarction. 

Decreasing intestinal motility will favor the intestinal absorption of water. For this purpose the activity of opioids can be employed. Also combinations of opioid agonists with muscarinic receptor antagonists are used for this purpose. 

Pharmacokinetics plays a very important role in the manner in which opioids are abused. Morphine and many of its derivatives are slowly and erratically absorbed after oral administration, which makes this route suitable for long-term management of pain but not for producing euphoria. In addition, opioids undergo considerable first-pass metabolism, which accounts for their low potency after oral administration. Heroin is more potent than morphine, although its effects arise primarily from metabolism to morphine. The potency difference is attributed to heroin s greater membrane permeability and resultant increased absorption into the brain. 

The antidiarrheal activity of codeine results from two actions. First, there is a decrease in the propulsive contractile activity of the small and large intestines, which delays the forward movement of the contents of the intestines. Second, codeine causes an increase in the absorption of water from the intestinal contents. These gastrointestinal effects are mediated by specific opioid receptors in the gut (as we will see in... 

Antimotility drugs are opioid drugs. They increase small bowel smooth muscle tone and segmentation activity. They also reduce propulsive movements and decrease intestinal secretions while increasing absorption. They mediate these actions through p receptors. 

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. 

Pharmaceutical interactions and modified absorption will not be described here, as they are relatively unimportant in anaesthetic practice, where few drugs are given by the oral route. However, it should be noted that the absorption of drugs from the jejunum may be delayed by drugs, such as opioids or atropine, which reduce gastric motility. 

As previously noted, opioids have significant constipating effects (see Chapter 31). They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements and the gastrocolic reflex. Although all opioids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most. 

Loperamide, 4 mg initially, then 2 mg after each loose stool, not to exceed 8 mg daily Imodium A-D, various generic Loperamide, a synthetic opioid, acts on intestinal smooth muscle to decrease motility allowing for absorption of water and electrolytes. Poorly penetrates the CNS and has a lower risk of side effects compared with diphenoxylate or opiates. Not considered a controlled substance. 

It has been suggested that y-turns are present in the solution structures of several peptides, and furthermore implicated in their bioactive conformations 101 including brady-kinin, 111 substance P,1121 cyclic somatostatin analogues, 131 cyclolinopeptide, 141 and the 6-opioid receptor bound conformation of enkephalin. 151 Yet, despite the fact that y-tums are frequently hypothesized to represent important features of secondary structure 161 based upon computational,1171 IR absorption,1181 NMR spectroscopic,119 201 and X-ray diffraction crystallographic determinations,1211 verification of the role of this predicted secondary structural element remains a difficult, but nonetheless critical step. 

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