Medical Pharmacology Topics
The juice of the opium poppy (Papaver somniferus) contains a number of alkaloids. Other opioids are synthetic or semisynthetic, for example meperidine, methadone and fentanyl. These exogenous opioids have phenatherene and piperidine rings sterically at right angles. They exhibit stereospecificity, with the majority of the agonists being levo (-) isomers.
Small structural differences can lead to major differences in activity, including potency and antagonist vs. agonist activity. For example, mu agonists have minimum methyl substitution at the tertiary nitrogen, while antagonists have bulkier carbon chains including either C-C double bonds or cyclic structures.
Exogenous opioids are classified according to their activity as either "pure" agonists, mixed agonists/antagonists at different receptor subtypes, and "pure" agonists. These agents have five main therapeutic actions: analgesia, antitussive, sedation, antidiarrheal and relief of dyspnea.
Opioid agonist can have toxic effects in the CNS and cardiovascular system. Other adverse effects include urinary retention, itching/urticaria (red blotches), and exacerbation of biliary colic (constipation). In general thy are contraindicated in patients with impaired pulmonary or hepatic function, during pregnancy, and when a diminished analgesic response develops.
In the CNS, opioids cause respiratory depression, sedation, nausea, vomiting, stimulation (seizures in children), physical dependence, tolerance, euphoria, dysphoria and miosis. The respiratory depression depends on many pharmacokinetic factors (dosage, administration route, delivery to brain) and patient characteristics (age, tolerance disease).
The symptoms of early mild abstinence syndrome are anxiety, drug request, lacrimation, yawning, piloerection, rhinorrea, dilated pupils, anorexia and tremor. Symptoms of late severe abstinence are vomiting, diarrhea, fever, abdominal pain, hypertension, tachycardia, leukocytosis and insomnia. Abstinence symptoms appear much sooner and with a greater intensity after meperidine withdrawal than morphine. Methadone withdrawal symptoms are delayed much longer than morphine's and are of a lesser intensity.
Mu agonists have minimal effects on the heart, making them good agents for anesthesia in patients with cardiovascular disease. On the other hand, they induce vasodilation, therefore orthostatic hypotension may develop. Kappa agonists like pentazocine and butorphanol can increase pulmonary arterial pressure and heart rate.
Signs of acute opioid poisoning include pinpoint pupils, depressed respiration and coma. Naloxone, an opioid antagonist, is used as antidote. The major detoxification pathway for morphine is glucuronidation.
Pure Agonists As Analgesics
Morphine is the prototype opioid agonist. Morphine, meperidine, methadone and codeine are indicated as analgesics. They reduce both the sensation of pain ad the affective response to pain. Patients often say they still feel pain but do not mind it.They are more effective in the relief of continuous dull pain than sharp acute pain. Opioid agonists modulate pain at many levels of the CNS, and are more effective when administered directly to the spinal cord.
The pharmacology of meperidine is comparable to that of morphine, but meperidine is less potent: 75-100 mg are needed to get analgesia similar to 10 mg of morphine. Its duration of action is also shorter than morphine, and withdrawal symptoms are of more rapid onset (?). Unlike morphine, meperidine at therapeutic doses does not prolong labor, and may in fact slightly increase contractions. Normeperidine, a metabolite of meperidine, can cause CNS excitation, myoclonus, hyperactive reflexes and seizures, especially in patients with renal disease (ere the metabolite accumulates).
Codeine is now the most frequently administered opioid for pain, usually in combination with aspirin or acetaminophen. Tolerance to codeine develops slowly, and it produces less nausea and constipation than morphine. Propoxyphene is 1/2 - 2/3 as potent as codeine and has an analgesic effect similar to aspirin, but still can produce typical opioid toxicity.
Opioids are administered by various routes. The oral route is limited for morphine and some others because of a predominant first pass effect. Absorption is variable by the IV route. There is a rapid onset of action when administered IV, but also a greater potential for toxicity. Using the "standard" dose of opioids is effective only in a portion of patients. The safe dose is often too low to achieve analgesia due to the development of tolerance to the drug.
Intraspinal administration produces pain relief while minimizing side effects and allows use of lower doses. Still, there is a risk of infection and tolerance.
Other uses of Pure Agonists
Opioid agonists act centrally to suppress the cough reflex. Historically codeine was used as antitussive, but it has been replaced by dextromethorphan. Dextromethorphan is the d-isomer, therefore lacks analgesic or addictive properties because it does not act on neither mu, delta or kappa receptors but others (?). It also has less GI side effects than codeine.
Paregoric, lomotil and loperamide are opioid agonists used to treat diarrhea and dysentery. They delay gastric emptying and reduce peristaltic activity. Paregoric is an opium tincture, an oral dose being equivalent to 2-4 mg of morphine. Lomotil is a mixture of the opioid agonist diphenoxylate (insoluble in water) and atropine (to prevent abuse). Loperamide is poorly absorbed and has a low abuse potential.
Opioid agonists are used to relief dyspnea associated with acute left ventricle failure and pulmonary edema, but are contraindicated in other forms of dyspnea such as asthma.
Several opioids are used as anesthetic adjunctives because they cause analgesia and sedation: fentanyl, sufentanyl and alfentanyl. Fentanyl, a primarily mu agonist, is used IM or IV in balanced anesthesia (?), especially for cardiac patients. Fentanyl is much more potent and more lipid soluble than morphine, therefore it is more rapidly absorbed and of shorter duration of action. (available as a patch).
Sufentanyl and alfentanyl are 5-10 times more potent than fentanyl and more lipid soluble. They are used in epidural or spinal analgesia. They also have much greater affinity for mu receptors than morphine.
Methadone is equipotent to morphine as an analgesic, but it is primarily used in detoxification and to diminish abstinence syndrome due to the long delay of symptoms and their lesser intensity compared to morphine's.
Partial Agonists and Mixed Agonist/Antagonists
Some opioids are either partial agonists or mixed agonists/antagonists at opioid receptors. In general, the mixed agonists are antagonists at mu receptors and agonists at kappa receptors. These agents do produce analgesia by their action at kappa receptors, and may be used to substitute mu agonists when tolerance develops to the analgesic effect.
All mixed agonists have abuse potential. While exhibiting opioid agonist action in normal subjects, in patients physically dependent on mu agonists the mixed agonists/antagonists precipitate withdrawal. In subjects acutely intoxicated with mu opioids, mixed agonist/antagonists lessen severe CNS depression. Respiratory depression can be enhanced in patients with mild opiate intoxication or under an unrelated CNS depressant like barbiturates. Major side effects of the mixed agonists/antagonists include dysphoria, anxiety and nightmares.
The mixed agonists include pentazocine, nalbuphine, butorphanol and buprenorphine. Pentazocine is a weak antagonist (partial agonists) at mu receptors and an agonist at kappa receptors. The analgesic effects of pentazocine are similar to morphine. At high doses pentazocine increases pulmonary arterial pressure and heart rate. Pentazocine induces tolerance and dependence but at a different rate than morphine.
At normal therapeutic dose, butorphanol causes respiratory depression similar to morphine, but as the dose increases the respiratory depression is less profound than with morphine. Major side effects of butorphanol are drowsiness, weakness and sweating, although it is less psychotomimetic than pentazocine.
Nalbuphine does not increase blood pressure nor cardiac workload as seen with pentazocine or butorphanol. Buprenorphine is a partial mu agonist with similar side effects as morphine but 25-50 times more potent than morphine as an analgesic.
The "pure" antagonists at opioid receptors are naloxone and naltrexone. Naloxone does not have a substantial pharmacology at normal doses other than antagonizing opioid actions at all receptor subtypes. It is used primarily in diagnosis and treatment of opioid overdose, but it is short acting and can precipitate withdrawal symptoms in dependent patients. Naloxone does not enhance opioid-induced respiratory depression and may prove useful in hypotension associated with shock.
Naltrexone has a higher oral efficacy and longer duration of action than naloxone. It has been approved as adjunctive in the management of detoxified addicts and may prove useful in treating compulsive opioid users. It was also recently approved to treat alcoholism.
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