Morphine, oral bioavailability

The opium alkaloid morphine is representative for this group of opiates and also for other opioid analgesics. Morphine is a full agonist for both the jx and the k receptors. It is used to relieve severe acute pain, or chronic pain in terminally ill patients. Its oral bioavailability varies from 15% to 35% and its... 

Like morphine, codeine is a naturally occurring opioid found in the poppy plant. Codeine is indicated for the treatment of mild to moderate pain and for its antitussive effects. It is widely used as an opioid antitussive because at antitussive doses it has few side effects and has excellent oral bioavailability. Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect It is one of the most commonly used opioids in combination with nonopioids for the relief of pain. The administration of 30 mg of codeine in combination with aspirin is equivalent in analgesic effect to the administration of 65 mg of codeine. The combination of the drugs has the advantage of reducing the... 

Methadone Slow-acting agonist of M-opioid receptor Acute effects similar to morphine (see text) Substitution therapy for opioid addicts High oral bioavailability half-life highly variable among individuals (range 4-130 h) Toxicity Respiratory depression, constipation, miosis, tolerance, dependence, and withdrawal symptoms... 

Pharmacokinetic properties Codeine (Sindrup and Brosen, 1995) has a good oral bioavailability. The compound is extensively metabolized by O- and N-demethylation followed by glucuronidation. The main metabolites are norcodeine, morphine and hydrocodeine and their glucuronides. There are indications (Yue et al., 1997), that the analgesic effect is reduced in persons with low CYP2D6 activity (poor metabolizers). 

Pharmacokinetic properties Ethylmorphine (Aasmundstad et al., 1995) has a reasonable oral bioavailability. Like codeine, it is metabolized by O- and N-desalkylation, leading to nor-ethylmorphine, morphine, nor-morphine, and the respective glucuronides. 

Pharmacokinetic properties Levomethadone (Olsen et al., 1977) is readily absorbed from the intestinal tract and has high oral bioavailability. The compound is much more lipophilic than morphine and binds to plasma protein in the... 

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. 

In Figure 2.4 the serum concentrations of three tablet forms of a drug are compared with its IV form. As you can see, tablets A and B have approximately the same bioavailability (AUC). Tablet C, on the other hand, has significantly less. Poor oral bioavailability can obviously influence a drug s ideal mode of delivery. It is because of poor oral bioavailability (approximately 25 percent) of heavily charged weak bases, such as the opiates (pKa values in the range of 8.0-9.0), that heroin and morphine abusers resort to injection of the drugs to maximize their effects. 

For drugs that have poor oral bioavailability, rectal administration of prodrugs can increase their absorption. For example, nalbuphine is an analgesic with potency approximately 0.5-0.9 that of morphine. It is used for the relief of moderate to severe pain from a variety of causes, e.g., surgery, trauma, cancer, kidney, or biliary colic pain. Oral bioavailability of nalbuphine was poor, e.g., around 6% in experimental dogs. Rectal administration of nalbuphine-3-acetylsalicylate in the same animals enhanced the bioavailability 4- to 5-fold to around 28%. In addition, the plasma half-life of nalbuphine after rectal administration of the prodrug was prolonged. 

Morphine satisfies all of Lipinskis rules and has an oral bioavailability in human beings of 33%. 

Morphine undergoes first-pass metabolism in the liver (low oral bioavailability). One of its metabolites, morphine-6-glucuromde, is highly active, contributing greatly to analgesia and causing possible toxicity in renal dysfunction. 

Morphine p agonist— strong (full) +++ +++ +++ Prototype of the class, marked sedation, poor oral bioavailability, histamine release... 

Chlorpromazine increases the respiratory-depressant effects of meperidine, as do tricyclic antidepressants this is not true of diazepam. Concurrent administration of drugs such as promethazine or chlorpromazine also may greatly enhance meperidine-induced sedation without slowing clearance of the drug. Treatment with phenobar-bital or phenytoin increases systemic clearance and decreases oral bioavailability of meperidine this is associated with an elevation of the concentration of normeperidine in plasma. As with morphine, concomitant administration of an amphetamine has been reported to enhance the analgesic effects of meperidine and its congeners while counteracting sedation. 

IMPAIRED HEPATIC CLEARANCE OF DRUGS The effect of liver disease on the hepatic biotransformation of drugs cannot be predicted from any measure of hepatic function. Thus, even though the metabolism of some drugs is decreased with impaired hepatic function, there is no quantitative basis for dose adjustment other than assessment of the clinical response and plasma concentration. The oral bioavailability of drugs with extensive first-pass hepatic clearance (e.g., morphine, meperidine, midazolam, and nifedipine) may be increased in liver disease. 

This drug is a full agonist at opioid receptors. It has excellent oral bioavailability, analgesic activity equivalent to that of morphine, and a longer duration of action. Withdrawal signs on abrupt discontinuance are milder than those with morphine (A) Fentanyl... 

Opioid analgesic synthetic, equivalent to morphine in efficacy but orally bioavailable. Strong agonist at mu opioid receptors blocks muscarinic receptors. Tox see morphine normeperidine accumulation may cause seizures. 

A) Analgesic actions of methadone are reversed by naloxone Codeine has antitussive effects at subanalgesic doses Morphine has limited oral bioavailability... 

Codeine is the monomethyl ether of morphine. It is metabolised to morphine, and possesses accordingly a morphine-like activity spectrum, although its potency is five to ten times weaker. It shows good oral bioavailability and is frequently used for the treatment of low to medium levels of pain, and also to suppress the urge to cough. Its potential for addiction at therapeutic doses is low. 

Oxycodone is structurally similar to codeine while pharmacodynamically comparable to morphine in onset and duration of action. It is approximately 1.5 times more potent than morphine with equivalent effectiveness in equianalgesic dosages. Oxycodone has high oral bioavailability (60%) compared with morphine (20-30%), which is the most notable difference between these drugs. It also explains why oxycodone has a rapid analgesic onset and onset-to-peak effect. In clinical practice oxycodone does not release significant amounts of histamine and may cause less sedation than equivalent doses of morphine. 

Although early studies showed oxycodone CR and morphine CR to be essentially equivalent milligram for milligram, oxycodone CR has been shown to have a higher bioavailability than morphine, resulting in an equianalgesic ratio of approximately 2 mg oral oxycodone to 3 mg oral morphine. Because of its greater oral bioavailability, patients may require lower doses compared to morphine. 

Unlike morphine and meperidine, methadone is well absorbed from the gastric mucosa, and has high oral bioavailability of around 75% (36-100%). It can be detected in blood 15-45 minutes after oral administration, and peak plasma concentration is achieved at 2.5-4 hours. Methadone is highly bound to plasma proteins, in particular to al-acid glycoprotein. 

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