P-Receptor agonists

Picenadol opioid analgesic (-r)-isomer (3.S,4R) p-receptor agonist (-)-isomer (3R.4.5) weak p-receptor antagonist... 

Major gastrointestinal effects include decreased gut motility and changes in secretion of gastric and intestinal fluids. Morphine and most p receptor agonists cause pupillary constriction. Some tolerance to this effect may develop, but addicts with high opioid levels will still have miosis. Respiratory depression is the usual cause of death from opioid overdose. 

Methadone is a p receptor agonist with special properties that make it particularly useful as a maintenance agent. Rehably absorbed orally, it does not reach peak concentration until about 4 hours after administration and maintains a large extravascular reservoir (Kreek 1979). These properties minimize acute euphoric effects. The reservoir results in a plasma half-life of 1—2 days, so there are usually no rapid blood level drops that could lead to withdrawal syndromes between daily doses. Effective blood levels are in the range of 200-500 ng/mL. Trough levels of 400 ng/mL are considered optimal (Payte and Khouri 1993). There is wide variability among individuals in blood levels with identical doses (Kreek 1979), and some have inadequate levels even with doses as high as 200 mg/day (Tennant 1987 Tenore 2003). 

Isoproterenol (104) is an important agent for classification because of its selective p-receptor agonist activity. It is of special interest that its chronotropic (increase in heart rate) and inotropic (increase in force of contraction) effects exceed that of epinephrine it is also used in the management of mild to moderate asthma due to its bronchodilating effect, resulting in increased vital capacity of the lungs. 

Butorphanol tartrate is a weak partial p-receptor agonist, 3.5-5 times as potent as morphine. The incidence of psychotomimetic effects is relatively low. The recommended doses are 1-4 mg intramuscularly every 3-4 h or 0.5-2 mg intravenously. Respiratory depression produced by butorphanol 2 mg IV is similar to that of 10 mg morphine. However, there is a ceiling effect for respiratory depression, and near-maximum depression occurs after 4 mg in normal adults. In healthy volunteers, butorphanol 0.03-0.06 mg-kg-1 produces no significant cardiovascular changes. However, in patients with cardiac disease, progressive increases in cardiac index and pulmonary artery pressure occur, and butorphanol should be avoided in patients with recent myocardial infarction. Butorphanol is metabolised mainly in the liver to inactive metabolites. The terminal half-life is 2.5-3.5 h. 

Dobutamine is a directly acting synthetic catecholamine with predominant effects at pi receptors. It has weak 32 and a effects. It is a racemic mixture and both stereoisomers are p-adrenoceptor agonists. The (+) isomer is approximately ten times more potent as a p-receptor agonist than the (-) isomer, which is mainly responsible for the o-adrenoceptor activity. Unlike dopamine, dobutamine does not act by releasing noradrenaline or via dopaminergic receptors. 

Opium derivatives, such as morphine and codeine phosphate, have been used for a iong time, but the piperidine derivatives loperamide (Imodium) and diphenoxylate (Lomotii) are now preferred. Both are p-receptor agonists, iargeiy devoid of centrai opiate-iike effects, and reiativeiy insoiubie in water, so that parenterai use and abuse are aimost impossibie. 

VAN-H36 (Vita-Invest) is a serotonin and noradrenaline reuptake inhibitor and p-receptor agonist (i.e. has a pharmacological profile of action similar to tramadol). It is in early clinical development as an analgesic. 

Hoffmeister, F. and Tettenbom, D. Calcium agonists and antagonists of the dihydropyridine type Antinociceptive effects, interference with opiate-p-receptor agonists and neuropharmacological actions in rodents, Psychopharmacology 1986, 90, 299-307. 

This situation became particularly acute with respect to the development of illicit analogs of fentanyl to derive heroin substitutes. Fentanyl is a synthetic opioid, a p-receptor agonist, and is about 100-200 times more potent than morphine as an analgesic. As with other narcotic analgesics, respiratory depression is the most significant acute toxic effect of the fentanyl derivatives. Fentanyl analogs can be 80-1000... 

Isoprenaline (isopropylnoradrenaline) is a nonselective p-receptor agonist, i.e. it activates both Pj-and Pj-receptors. It relaxes smooth muscle, including that of the blood vessels, has negligible metabolic or vasoconstrictor effects, but a vigorous stimulant effect on the heart. This latter is its main disadvantage in the treatment of bronchial asthma. Its principal uses are in complete heart block and occasionally in cardiogenic shock (h3rpotension). 

Pharmacodynamic. The effect on the blood pressure of s5unpathomimetics having both a- and P-receptor agonist actions is increased by block of p-... 

Meperidine is a p receptor agonist that is one-tenth as potent as morphine and has a shorter duration of effect. Its effects in the horse are similar to those described for morphine and it is used primarily as an anesthetic adjimct, or along with other sedatives for standing chemical restraint or anesthetic premedication. The recommended dose rate is 0.6-1.0mg/kg i.v. in combination with either acepromazine (0.05 mg/kg) or xylazine (0.5-1.0mg/kg). 

Carfentanil is the most potent opioid available commercially for use in veterinary medicine. It is a p, receptor agonist that is 10000 times as potent... 

There is now a search going on for orally active opiate structures which can act as antagonists at the p, receptor, agonists at the k receptor, and have no activity at the a receptor. Some success has been obtained, especially with the compounds shown in Fig. 12.34, but even these compounds still suffer from certain side-effects, or lack the desired oral activity. 

Finally, the investigational use of new pharmacotherapeutics such as thromboxane synthase inhibitors, vasodilator prostaglandin infusions, antioxidants, and P-receptor agonists in the treatment of microvascular permeability edema is well covered in several reviews (Demling, 1982 McMillan and Boyd, 1982 Persson et al., 1982). 

Fentanyl is a synthetic opioid related to the phenylpipe-ridines. The actions of fentanyl and its congeners, sufentanil, remifentanil, and alfentanil, are similar to those of other p,-receptor agonists. 

Ephedrine is both an a- and a p-receptor agonist in addition, it enhances release of norepinephrine from sympathetic neurons and therefore is a mixed-acting sympathomimetic drug. It contains two asynunetrical carbon atoms only /-ephedrine and racemic ephedrine are used clinically. 

The structural formulas of meperidine, a phenylpiperi-dine Meperidine is predominantly a p-receptor agonist, and it exerts its chief pharmacological action on the CNS and the neural elements in the bowel. It is no longer recommended for the treatment of chronic pain because of concerns over metabolite toxicity. It should not be used for longer than 48 hours or in doses greater than 600 mg/day. 

In subjects dependent on low doses of morphine (60 mg/day), nalbuphine precipitates an abstinence syndrome. Prolonged administration of nalbuphine can produce physical dependence. The withdrawal syndrome is similar in intensity to that seen with pentazocine. The potential for abuse of parenteral nalbuphine in subjects not dependent on p-receptor agonists probably is similar to that for parenteral pentazocine. 

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