Alkaloids opioid analgesics - morphine

【Chemical structure and structure-activity relationship】 morphine (morphine) from the molecular structure of four parts: ① to retain four of the double bond hydrogenation nuclear Philippines (ring A, B, C); ② nuclear talks with the Philippine Central B fused with the N-methyl-piperidine ring; ③ A ring connected with the ring of C-bridged; ④ A ring-a-ring with the C-alcohol. Hydroxy-methyl hydrogen atoms had been replaced, the analgesic effect of reduced (such as codeine); tertiary nitrogen has been replaced by allyl, the analgesic effect not only weakened, and become the antagonist of morphine, such as morphine and C-na -Rod (Table 18-1). 【】 Process in the body after oral easily absorbed from the gastrointestinal tract, but obviously the elimination of first pass, low bioavailability, it is commonly used drug injection. 30 minutes after subcutaneous injection of 60% has been absorbed. About 1 / 3 and plasma protein binding. Not a combination of rapid distribution of morphine in the body, through the blood-brain barrier and only a small amount, but enough to play a central role in pharmacology. Mainly in the liver and glucose combined with acid and failure, the combination of materials and the combination is not a small amount of morphine in the 24 hours since most of the renal excretion. Plasma t1/22.5 ~ 3 hours. There is a small amount of morphine by the excretion of the breast, but also through the placenta into the fetus in the body. 】 【Pharmacological effects of morphine analgesic is a representative of a major role in the central nervous system and gastrointestinal smooth muscle. 1. Central nervous system (1) analgesic, sedative morphine has a strong analgesic effect of selective, subcutaneous injection of 5 ~ 10mg that is able to significantly reduce or eliminate the pain, but the sense of feeling and not be affected. Morphine for pain are a variety of effective, and the continuity of chronic dull pain is greater than the effect of intermittent sharp pain. There are obvious effects of morphine sedation; and by the elimination of pain caused by anxiety, tension, fear, and other emotional responses, and thus significantly increase the pain tolerance. With the ease pain and the emotional impact of emerging euphoria (euphoria). If the outside world quiet, it will enable patients to fall asleep. High-dose (15 ~ 20mg) when analgesic effects sedative more obvious. A drug delivery, sustainable analgesic effect of 4 to 5 hours. Analgesic effect of morphine has been part of research, pharmacology and scholars in China in the early 1960s, reported trace of morphine injected into rabbits around the third ventricle can cause pain; have been proved beyond injected morphine in the third ventricle to the end of the first end of the fourth ventricle Analgesic effect of neural structures are most effective pain is part of periaqueductal gray (map) 18-1. (2) inhibit the treatment of respiratory volume of morphine can suppress breathing, so that the respiratory rate slowed down, lower tidal volume; increase the dose, the enhanced inhibition. Acute poisoning can slow down the respiratory rate to 3 to 4 times / min. Morphine to reduce the respiratory center of the sensitivity of blood CO2 tension, at the same time, adjustment of the bridge in the brain respiratory center also is a disincentive. (3) inhibition of morphine antitussive cough center, antitussive effect. (4) Hitomi morphine can be reduced, needle-like characteristics of the poisoning of their pupils. Morphine can cause nausea and vomiting. 2. Anti-diarrhea and digestive tract can be morphine-induced constipation. The main reason is the excitement of morphine gastrointestinal smooth muscle, to increase their tension. Even reach spasm. As the antrum and the upper part of the tension to improve duodenum, inhibited peristalsis, delayed gastric emptying; small intestine and large intestine smooth muscle tension increased, so that the advance-decline peristalsis, to postpone the adoption of chyme; ileocecal valve and the anal sphincter to increase tension, intestinal Contents through the obstruction; In addition, morphine inhibit the secretion of digestive juice, so slow to digest food; plus morphine on the central inhibition, so that patients would be intended to slow, causing constipation. The amount of morphine treatment caused by biliary sphincter of Oddi spastic contraction, so that the bile duct obstruction emptying, gallbladder pressure improved, can result in abdominal discomfort or even Biliary Colic. Atropine can be part of the mitigation. 3. Morphine cardiovascular system and blood vessels to expand the capacity of resistance to blood vessels caused by orthostatic hypotension, and its step-down is due to make its central sympathetic to reduce tension, peripheral arteries caused by the expansion. Step-down effect may be part of the fight against antihistamines, so the effect of morphine and in part related to the release of histamine. Morphine inhibited breathing, so that the CO2 accumulation in the body, the brain caused by blood vessels and the expansion of intracranial hypertension. 4. Other treatment can increase the amount of morphine bladder sphincter tension, lead to urinary retention; pituitrin also promote the release of antidiuretic hormone; high dose of morphine to bronchial contraction. 】 【Mechanism available information shows that there exists in the body "anti-pain system", which enkephalin neurons, and enkephalin opioid receptor form. Depolarization or enkephalin stimulate the nerve pathway can cause the release of enkephalin and dependent on calcium. Under normal circumstances, there are about 20% to 30% of the opioid receptors and enkephalin, the feeling of pain control plays a role in maintaining the normal pain threshold, to play a physiological function of pain, analgesics are excited about the role of the opioid receptor , The activation of the brain "anti-pain system" to block transmission of pain, have a central analgesic effect. 1. Opioid receptors and endogenous opioid-like substances in the early 1970s have confirmed the opioid receptors in the brain, and a variety of analgesics and opioid receptor affinity with their analgesic effect between a high degree of correlation. Opioid receptor in the brain are widely distributed and uneven, the higher the density of receptor sites, such as spinal cord glial zone, the inside of the hypothalamus, the ventricle and the periaqueductal gray and are introduced to the pain stimulus, the integration of pain and feelings The neural structure; and the highest density of receptors on the brink of nuclear systems, as well as blue plaques, and is more emotional and mental activities related to the brain. In the brain to build a nuclear pre-opioid receptor may be related to reduced pupil-related. Extension of the brain NTS Department of opioid receptors and antitussive drugs, respiratory depression, central sympathetic reduce the tension. After a brain stem area, NTS, the vagus nerve back, and other parts of the nuclear-opioid receptor with gastrointestinal activity. Their muscle enterovirus have opioid receptors. The discovery prompted opioid receptor in the brain may be the endogenous opioid-like substances in the near future in the brain that is isolated from two-five, that is, methionine-enkephalin (M-enkephalin) and the brain leucine FQ (L-enkephalin), in which the brain's opioid receptor distribution and the distribution of similar, and with the opioid receptor was created three-dimensional combination of specific morphine-like role, which could be morphine antagonist naloxone The antagonism. Following the discovery enkephalin, and isolated from the pituitary of several large peptides, known as the endorphin (endorphins), such as β-endorphin (β-endorphin) and dynorphin (dynorphin A). Has found that nearly 20 kinds of opium alkaloids and the role of similar peptides, known collectively as the opioid peptides in (or with opioid). With opioid neurotransmitter or may be neuromodulator (that is, the regulation of neurotransmitter release of the material) or nerve hormone, the body plays a machine in pain or feeling of endogenous pain-control system, as well as regulation of cardiovascular and gastrointestinal function The role, such as the sensory nerve endings in the spinal opioid receptors have been found, the experimental data enkephalin may be prompted by inhibiting the release of a sensory nerve endings excitatory transmitter (P material) so as to interfere with pain impulse into the hub (Figure 18 -- 2). As for the morphine-type drugs mechanism of action may be with different brain regions of opioid receptors, opioid peptides and simulation with good results. 2. Multi-opioid receptor, and its effects through the subtype of opioid receptor binding experiments, is that the opioid receptor can be divided into μ, δ, κ, and σ-, μ, δ-σ and the 1 and 2 can be divided into two subtypes. The type of excitement when the effects of different; with a variety of different types of opioid-opioid receptor affinity, that is leucine enkephalin and dynorphin were κ receptor δ and the endogenous ligand, Μ and σ receptor and receptor endogenous ligand is not yet clear. Morphine-based drugs to different affinity and intrinsic activity is not exactly the same, some drugs are agonists (such as morphine, pethidine); some antagonists (such as naloxone); some type of drug is antagonistic Drugs, and another type is the exciting part of the drug or agonists (such as pentazocine, C-morphine, buprenorphine) (Table 18-2). Recently, research indicates that opioid receptors may exist between allosteric, such as morphine and the combination of receptors (μ) and with the combination of enkephalin receptors (δ) is a protein molecule or a complex combination of different Points; β-endorphin combination of two points, or N-terminal point of enkephalin and C-terminal point of morphine; on one point to the role of allosteric effects of the combination of the other point performance. Clinical 【】 1. Analgesic morphine for pain are a variety of effective, but there are easy addiction for a long time, so in addition to cancer pain can be long-term, short-term generally only be used for other analgesics invalid at the time of acute sharp pain, such as severe trauma, burns and so on. The pain caused by myocardial infarction, normal blood pressure, can be used painkiller morphine; In addition, morphine and a sedative to expand the role of blood vessels, reduce patient anxiety and emotional burden on the heart, more conducive to treatment. 2. Cardiogenic asthma for all of a sudden left heart failure and acute pulmonary edema caused by difficulty in breathing (cardiac asthma), with the exception of application of cardiac glycosides, aminophylline and inhaled oxygen, intravenous morphine can often produce good results. Its mechanism of action of morphine is due to the expansion of peripheral vascular and reduce peripheral resistance; At the same time, its sedative effect in favor of the elimination of patients with anxiety and fear of emotions; thus reduce the load of the heart. In addition, the respiratory center of morphine to reduce CO2 sensitivity, so that the rapid shallow breathing to ease. However, shock, coma and a serious insufficiency of lung function were banned. 3. Anti-diarrhea apply to acute and chronic consumption so as to alleviate the symptoms of diarrhea. May choose to use opium or compound tincture tincture camphor; such as bacterial infections, should take anti-bacterial drugs. 【Adverse reactions】 1. The amount of morphine treatment in some cases can cause dizziness, nausea, vomiting, constipation, difficulty urinating, Biliary Colic, respiratory depression, drowsiness, and other side effects. 2. Repeated many times in a row easy application of morphine tolerance and addiction, drug once, that is, withdrawal symptoms occur, for the performance of the excitement, insomnia, crying, runny nose, sweating, tremors, vomiting, diarrhea, or even collapse, the sense of Loss, and so on. If the amount of morphine given treatment, the symptoms disappear immediately. Morphine addicts in pursuit of euphoria and avoid withdrawal symptoms caused by the pain often means access to morphine (referred to as "compulsive drug-seeking behavior"), have done great harm. So on and so on morphine addiction and drug use should be strictly controlled, and the state has promulgated the "Regulations on Narcotic Drugs" strict management. Morphine tolerance and addiction have the nerve tissue was mainly due to the adaptability of morphine; and morphine addiction and withdrawal symptoms is directly linked to the nuclear blue plaque, from the nuclear norepinephrine neurons, And there are opioid-receptor; morphine or enkephalin can inhibit the blue plaque nuclear discharge, when the animals on morphine tolerance or addiction, the core discharge also tolerance, once out of morphine, speed up the discharge, at the same time Withdrawal symptoms, suggesting that withdrawal symptoms and blue plaque of nuclear norepinephrine neuron activity related to enhanced. It is reported that can inhibit the discharge of the blue plaque nuclear clonidine alleviate the symptoms of morphine withdrawal. 【】 Performance of acute poisoning for coma, pupil extremely narrow (severe hypoxia when mydriasis), a high degree of respiratory suppression, to reduce blood pressure and even shock. Respiratory paralysis is the main cause of death. Required artificial respiration, oxygen rescue; morphine antagonist naloxone on morphine respiratory depression of the significant effects of drugs such as null and void, then the diagnosis of suspected morphine poisoning. 】 【Contraindication of morphine through the placenta or the fetus or newborn milk inhibit breathing and at the same time be able to confront oxytocin on the uterus and excited to extend the role of the birth process (reasons unknown), it is prohibited in the labor breast-feeding women, analgesics and pain. Due to inhibit breathing and a cough reflex, as well as inhibiting the release of histamine due to bronchial contraction, it is prohibited in patients with asthma and lung disease. Traumatic brain injury caused by the increased intracranial pressure in patients with liver function in patients with severely decreased banned.