Opioid analgesia and antagonist

History The word opium itself is deriv

ed from the Greek name for juice ,the drug being obtained from the juice of the poppy, Papaver somniferum. Arabian physicians were versed in the use of opium; Arabian trader introduced the drug to the orient, where it was employed mainly for the control of dysenteries. By the middle of the sixteenth century, many of the uses of opium were appreciated.

Opium contains more than 20 distinct alkaloids. In 1806,Sertuner reported that the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams. The discovery of other alkaloids in opium quickly followed that of morphine( codeine by Robiquet in 1832,papaverine by Merck in 1848). by the middle of the nineteenth century ,the use of pure alkaloids rather than crude opium preparation began to spread throughout the medical world.

poppy

In the USA , opioid abuse was accentuated by the unrestricted availability of opium that prevailed until the early years of the 20th century and by the influx of opium-smoking immigrants from the Orient.

opium

• The problem of addiction to opioids stimulated a search for potent analgesics free of addictive potential.

• Just prior to and following World War Ⅱ, synthetic compounds such as meperidine and methadone were induced into clinical medicine, but proved to have typical morphine-like actions.

heroin

Nalorphine ,a derivative of morphine ,was an exception. Nalorphine antagonized the effects of morphine and was used to reverse morphine poisoning in the early 1950s. but the drug is not used clinically as an analgesic because of side effects such as anxiety and dysphoria.

However ,its pharmacological profile ushered in the development of new drugs, such as the relatively pure antagonist naloxone and compounds with mixed actions.

Endogenous opioid peptidesA) Alcohol is thought to stimula

te the release of endogenous opioids, which may produce the euphoric feelings associated with alcohol consumption. B) Endogenous opioids (e.g., beta-endorphin) are released into the synapse (the space between the signaling and target neurons) and C) stimulate activity at opiate receptors, which produces a signal in the target neuron. D) Exogenous opiates such as morphine also stimulate opiate receptors. E) Naltrexone is thought to block opioids from activating opiate receptors.

Multiple opioid receptors• Mu receptors:

– Most of the clinically used opioid are relatively selective for μreceptors, reflecting their similarity to morphine. μ receptors initially were defined by their affinity for morphine. Β-endorphin has high affinity for μreceptors, which also have high affinity for the enkephalins. Dynorphin A also binds to μreceptors potently , but not as potently as to κ1 receptors.

• Kappa receptors:– Dynorphin A is the endogenous ligand for the

κ1 receptors . Unlike κ1 receptors ,which produce analgesia spinally, κ3 receptors relieve pain through supraspinal mechanisms.

• Delta receptors:– The enkephalins are the endogenous ligand

s for the δ receptors. The consequences of stimulating δ receptors with morphine and morphine -like opioid agonists in human beings are unclear. In animals, relatively specific δagonists produce analgesia and positive reinforcing effects at supraspinal sites and antinociception for the thermal stimuli at spinal sites.

Profiles of opioid actions

Morphine and other morphine -like opioid agonists produce analgesia primarily through interaction with μreceptors . Other consequences of μreceptor activation include respiratory depression , miosis, reduced gastrointestinal motility, and feeling of well-being( euphoria)

Classification

Natural opiates: morphine, codeine, papaverine

Synthetic analgesics: meperidine, methadone, fentanyl, anadol, etorphine, pentazocine.

natural opiates

Morphine

pharmacokinetics

Absorption It is well absorbed

from the gastrointestinal tract and but, undergoes a significant first-pass effect. so subcutaneous injection is commonly used.

In addition, readily absorbed from nasal mucosa, intramuscular, and intravenous route

• Distribution – When therapeutic

concentrations of morphine are present in plasma, about one-third the drug is protein bound, although the primary site of action of morphine is in the CNS, in the adult only small quantities pass the BBB.

• Metabolism – The major pathway for t

he metabolism of morphine is conjugation with glucuronic acid to form both active and inactive products. morphine -6-glucuronide, a major metabolite of morphine, has pharmacological actions indistinguishable from those of morphine.

• Excretion – Very little morphine is

excreted unchanged. It is eliminated by glomerular filtraton, primarily as morphine-3-glucuronide ; 90%of the total excretion takes place during the first day.

Pharmacological effects

A)Opiates affect the limbic system, which controls emotions, increasing pleasure, relaxation and contentment. B.) The brainstem controls automatic activity, like breathing or coughing. Opiates can act on the brainstem to stop coughing or slow breathing. C.) The spinal cord transmits pain signals from the body. Opiates act here to block pain messages

CNS effects

• Analgesia and sedation :– Strong analgesia– Effective on various pains: chronic dull pain

and acute sharp pain, especially continued severe dull pain.

– No effects on other senses and consciousness– Sedation – Analgesia with euphoria in partial patients

• Nauseant and emetic effects– Nausea and vomiting produced by morphin

e –like drugs are unpleasant side effects caused by direct stimulation of the chemoreceptor trigger zone(CTZ) for emesis , in the area postrema of the medulla.

Respiratory depression Morphine depresses respiration , at least in

part by virtue of a direct effect on the brainstem respiratory center. The respiratory depression is discernible even with doses too small to disturb consciousness and increases progressively as the dose is increased. In human beings, death from morphine poisoning is nearly always due to respiratory arrest. the diminished respiratory volume is due primarily to slow rate of breathing, and with toxic amounts the rate may fall to 3 or 4 breaths per minute.

• Stops coughing– Morphine and related opioid also depress th

e cough reflex at least in part by a direct effect on a cough center in the medulla.

• Miosis – Morphine and most μ and κ agonists cause co

nstriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil.

Cardiovascular effects

• Peripheral vasodilation to the produce orthostatic hypotension due to inhibition of vasomotor center and promotion of release of histamine.

• Cerebral vasodilation to increase intracranial pressure via depressed respiration and increased blood CO2.

• Shifting of blood from pulmonary to systemic circulation .

• Reduces peripheral resistance so cause decrease work load.

Gastrointestinal effects

• Constipation due to reduced peristalsis and stomach motility as well as increase spasmodic nonpropulsive contraction.

• Decreased biliary and pancreatic secretions to cause indigestion.

• Increased biliary pressure by constriction of Oddi’s sphincter to induce biliary colic.

Other effects

• Bronchoconstriction.• Retention of urine by increasing sphinct

er tone of bladder.

Clinical uses

• Analgesia – Morphine is useful in acute sharp pain , angi

nal pectoris, biliary and kidney colic, etc. morphine should be combined with atropine in the treatment of biliary and kidney colic, and relieve aginal pectoris by analgesic, sedative and vasodilative effects.

• Acute pulmonary edema caused by acute left ventricular failure. Morphine relieves acute pulmonary edema by vasodilation which results in decreased peripheral resistance and increased capacity of peripheral vessels.

• Severe diarrhea.• Relieve of anxiety and depression• Balanced anaesthesia and surgical anaesthesic• Pre anaesthetic medication

Adverse reaction

• Side effects:– Nausea, vomiting ,constipation ,respiratory

depression, dysphoria.

• Tolerance and addiction– Persisting use of morphin

e for 1~2 weeks may produce tolerance and addiction. Addiction include physical dependence and withdrawal syndrome( pupillary dilation, sweating, tachycardia, yawning, fever,etc).

The first and most common used depends on cross-tolerance and consists of transfer to a prescription of opioid medication and then gradual dose reduction.

Cold turkey therapy and Methadone plan

Pharmacological interventions

A second approach to detoxification involve the use of clonidine, a medication approved for the treatment of hypertension . Clonidine , is an α2-adrenergic agonist that decreases adrenergic neurotransmission from the locus ceruleus. Many of the autonomic symptoms of opioid withdrawal such as nausea, vomiting cramp, sweating , tachycardia, and hypertension result from the loss of opioid suppression of the locus ceruleus system during the abstinence syndrome.

Clonidine ,acting via distinct receptors but by cellular mechanism that mimic opioid effects, can alleviate many of the symptoms of opioid withdrawal . However ,clonidine dose not alleviate generalized aches and opioid craving charateristic of opioid withdrawal.

A third method of treating opioid withdrawal is theoretically but not practically useful, it involves activation of endogenous opioid system with medication. The techniques proposed include acupuncture and several methods of CNS activation involving transcutaneous electrical stimulation.

Codeine• Codeine is the 3-

methyether of morphine.

• Pharmacological effects of codeine are similar to those of morphine, but its analgesic potency is ½ of morphine, cough depressant potency is ¼ of morphine.

• Analgesic effect of codeine is stronger than that of aspirin,30mg of codeine is equivalent to 600mg of aspirin.

• Less sedation ,respiratory depression and fewer gastrointestinal effects.

• It is used for mild to moderate pains and severe cough.

• Addiction in long term administration

synthetic analgesia

Pethidine• Pharmacological effects of pethidine are

similar to those of morphine, but less potencies and shorter duration in analgesis(1/10),sedative and respiratory depression. Pethidine has no effect on cough, bronchial and gastrointestinal smooth muscles.

• Pethidine may replace morphine to relieve pains and treat acute pulmonary edema and induce artificial hibernation as one of lytic cocktail components.

• Pethidine has mild adverse effects and produces tolerance and addiction in long-term use.

Methadone

• It is used for analgesia, suppression of withdrawal syndrome, treatment of heroin user.

• Physical dependence of methadone occurs slowly and withdrawal syndrome is less severe.

Fentanyl Analgesic effect of fentanyl is 100 times a

s effective as morphine with short duration and rapid onset, it is mainly used for anesthesia, especially for postoperation pain.

opioid receptor antagonists

• Partial antagonists: pentazocine. It may precipitate a withdrawal syndrome in opioid addicts.

• Full antagonists: naloxone and naltrexone. Naloxone may reverse the acute poisoning effects of opioids agonists and precipitate a withdrawal syndrome in opioid addiction.

Opium Poppy, CrudeOpium, Codeine, Heroin,and Morphine

Morphine PowderedHeroin

Hydromorphone(Dilaudid)