Opiates peripheral effects

What are the direct peripheral effects of opiate drugs ... 

Opiates used as antidiarrheals generally do not cross the blood-brain barrier well. They therefore produce peripheral effects, such as slowing of the bowel, but central effects Ce.g.. euphoria and addiction) are not manifested at therapeutic doses. 

R.L. Follenfant, G.W. Hardy, L.A. Lowe, C. Schneider, and T.W. Smith, Antinociceptive Effects of the Novel Opioid Peptide BW443C Compared with Oassical Opiates Peripheral Versus Central Actions. Br. J. Pharmacol., 93, 85-92,1988. 

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. 

Findings continue to accumulate in the field of endogenous opiates, as exemplified by two tetrapeptides isolated from mammalian brain and found to have high affinity and selectivity for p-opioid receptors. These tetrapeptides are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2). A number of synthetic analogues have been prepared with the view to improve their metabolic stability and, in some cases, to limit their access to peripheral opioid receptors. The three synthetic endomor-phin analogues Tyr-D-Ala-Phe-Phe-NH2 (6.84), Tyr-D-Arg-Phe-Phe-NH2 (6.85), and Tyr-D-Arg-Phe-Ape-NH2 (6.86), to be discussed in the next section, have potent antinociceptive effects in in vivo inflammatory tests but exhibit modest effects in the CNS. However, and despite the presence of a D-amino acid and a protected C-terminus, they remained sensitive to enzymatic hydrolysis [211][212],... 

Opiates are the most effective non-specific agents, and the peripheral opiate agonist loperamide may be adequate in most individuals. Whilst giving such empirical treatment the possible need of fluid replacement must be remembered. Opiates are not replacements for oral rehydration fluids (based on salt and glucose) or intravenous rehydration fluids in acute diarrhoea. 

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],... 

Bechara A, Van der Kooy D (1987) Kappa receptors mediate the peripheral aversive effects of opiates. Pharmacol Biochem Behav 28 227-233... 

Giordano J, Rogers L (1989) Peripherally administered serotonin 5-HT3 receptor antagonists reduce inflammatory pain in rats. Eur J Pharmacol 170 83-86 GUck SD, Crane LA (1978) Opiate-like and abstinence-like effects of intracerebral histeimine administration in rats. Nature 273 547-549... 

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. 

OXYCODONE/A CET AMTNOPHEN (Percocet tablets 5 mg oxycodone hydrochloride/325 mg acetaminophen, tablets 7.5 mg oxycodone hydrochloride/500 mg acetaminophen, tablets 10 mg oxycodone hydrochloride/650 mg acetaminophen, Roxicet tablets 5 mg oxycodone hydrochloride/325 mg acetaminophen, solution, oral 5 mg oxycodone hydrochloride/325 mg acetaminophen, Roxicet 5/500 caplets 5 mg oxycodone/500 mg acetaminophen, Roxilox capsules 5 mg oxycodone hydrochloride/500 mg acetaminophen, Tylox capsules 5 mg oxycodone hydrochloride/500 mg acetaminophen) Oxycodone/acetaminophen is an opioid analgesic combination. Acetaminophen inhibits synthesis of prostaglandins and peripherally blocks pain impulse generation, whereas oxycodone binds to opiate receptors in the CNS. Their combination has a synergistic effect in alleviating pain. It is indicated in the relief of moderate to moderately severe pain. 

Prometh with codeine syrup 10 mg codeine phosphate and 6.25 mg promethazine hydrochloride) Promethazine competitively antagonizes histamine at H,-receptor sites and prodnces sedative as well as antiemetic effects. Codeine stimnlates opiate receptors in the CNS in addition to cansing respiratory depression, peripheral vasodilation, inhibition of intestinal peristalsis, stimulation of the chemoreceptors that cause vomiting, increased bladder tone, and suppression of cough. They are indicated in the temporary relief of coughs and upper respiratory tract symptoms associated with allergy or the common cold. 

Opiates delay parturition and prolong labor by decreasing the tone of the uterus. This effect is mediated by both peripheral and central mechanisms. 

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