Opioid Analgesics Opioid Analgesics

Constituents of Opium Opium poppy contains over 40 opium alkaloids, including morphine (up to 20%), narcotine (about 5%), codeine (about 1%), and papaverine (about 1%).

History of Morphine in the U.S. Doctors had long hunted for effective ways to administer drugs without ingesting them. Taken orally, opium is liable to cause unpleasant gastric side-effects. The development of the hypodermic syringe in the mid-nineteenth century allowed the injection of pure morphine. Both in Europe and America, members of high society and middle-class professionals alike would jack up daily; poor folk couldn't afford to inject drugs.

History of Morphine Use in the U.S. Morphinism became rampant in the USA after its extensive use by injured soldiers on both sides of the Civil War. In late nineteenth-century America, opiates were cheap, legal and abundant. In the judgement of one historian, America became "a dope fiend's paradise". Moreover it was believed that injecting morphine wasn't addictive.

How Does Morphine Work? There are at least three different opioid receptors in the CNS: mu, delta, and kappa Morphine is an agonist at all three receptors, but seems to prefer the mu receptor Thus, agonists of the mu receptor (which act as powerful analgesics) are classified as “morphine like”.

Side effects of morphine Morphine has many side effects. The most dangerous is respiratory depression. Other central nervous system side effects of morphine are cough suppression, sedation, and dependence leading to addiction. Morphine also has an effect on the muscle of the bowel and urinary tract, causing the sphincter to contract and reduce the peristalsis (the wavelike movements of the bowel muscle that propel its contents forwards). This results in a delayed emptying of the stomach, constipation, and may also lead to urinary retention.

Structure of Morphine

‘Tinkering’ with the structure of morphine produced heroin

Heroin The two hydroxyl groups of morphine are converted to acetate esters, producing diacetylmorphine, or heroin. Heroin crosses the blood-brain-barrier much more quickly than morphine, Once across the BBB, brain esterases rapidly cleave the acetate esters back to hydroxyl groups In particular the C3 hydroxyl group is needed for analgesic (and euphoric) activity.

Heroin is addictive because it crosses the BBB more quickly than morphine.

Heroin Addiction Heroin use frequently leads to dependency. Ceasing heroin use after continuous use for as little as three days can cause withdrawal symptoms In repeat users, tolerance develops However, tolerance for the euphoric effect develops more rapidly than tolerance for the respiratory depression, thus leading to the (unanticipated) cessation of breathing in the user.

How do these drugs work? http://thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03_m_par_heroine.html#drogues

Manufacture of codeine Up to 90% of the morphine isolated from opium is commercially converted into codeine by methylation.

Codeine is demethylated back to morphine in the liver To experience the painkilling properties of codeine the body must first convert it into morphine. (Unlike morphine), Codeine is readily absorbed by the gastrointestinal tract, becoming quickly transported to various tissues throughout the body.

Codeine Through O-demethylation the codeine is converted into morphine and through N-demethylation it becomes norcodeine. The metabolism rate is approximately 30 mg of codeine in an hour and about 90% of the drug will be excreted from the body within a day. In most people, only about 10% of codeine is transformed into morphine.

The C3 hydroxyl group is necessary for activity The C3 hydroxyl group is necessary for activity. (The methyl ether is only 0.1% as active)

Codeine is a useful cough suppressant The antitussive and analgesic attributes of codeine also enable it to work as a cough suppressant, especially with dry, non-productive coughs. It does this by inhibiting the receptor in the cough centre of the medulla oblongata and acting on the brain to reduce the cough reflex, without the suppression of the respiratory centre. Codeine increases the viscosity of bronchial secretions and has a drying effect on the respiratory tract.

‘Tinkering’ with the morphine structure can produce useful painkillers