Opioid Analgesics Opioid Analgesics
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Opioid AnalgesicsOpioid 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%).
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
O
HOH
NH
CH3
CH3O
Codeine (5X LESS potent than morphine)
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
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
HO- Group is needed for activity
HO- Group not important to activity
‘Tinkering’ with the structure of morphine produced heroin
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16 O
AcOH
NH
CH3
AcO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)Heroin (Diamorphine)(2X as potent as morphine)(Conversion of two -OH groups to -OAcfacilitates crossing of the BBB)
Easily enzymatically hydrolyzed to AcOH and HO-ArHO- Group is needed for activity
HO- Group not important to activity
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.
O
AcOH
NH
CH3
AcO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Heroin (Diamorphine)(2X as potent as morphine)(Conversion of two -OH groups to -OAcfacilitates crossing of the BBB)THIS IS A PRODRUG
Easily enzymatically hydrolyzed to AcOH and HO-Ar
O
AcOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Esterases
(in the brain)
ACTIVE DRUG
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.
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
O
HOH
NH
CH3
CH3O
Codeine (5X LESS potent than morphine)
CH3I
Base
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 methyl ether is only 0.1% as active)
O
HOH
NH
CH3
CH3O
Codeine (5X LESS potent than morphine)
Inefficiently converted to HO group in the liver
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
HO- Group is needed for activity
HO- Group not important to activity
Liver
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
O
OH
NH
CH3
RO
R = H Hydromorphone (Dilaudid)(5X MORE potent than morphine)
R = CH3 Hydrocodone(approx. half as potent as morphine orally)
oxidized OH
Reduced C=C
O
OOH
NH
CH3
HO
-OH group increases potencyOxymorphone(10X MORE potent than morphine)
oxidized OH
Reduced C=C
O
OOH
NH
CH3
CH3O
-OH group increases potencyOxycodone (Percocet)(equal to morphine in potency)
CH3 group reduces potency
Reduced C=C
oxidized OH