Narcotic analgetics (opiates, opioids) Morphine

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1 Analgesic agents, analgesic drugs, painkillers arcotic analgetics (opiates, opioids) Opium alkaloids Analgesic: a drug bringing about insensibility to pain without loss of consciousness. Pain: physiological (e.g. burning, cut) inflammatory (e.g. infections) neuropathic (injury to CS or periferal nervous system) Classification arcotic analgesics Opiates and morphinomimetics; onnarcotic analgesics onsteroid anti-inflammatory agents (analgesic antipyretics); Paracetamol/acetaminophen group. 181 Selective depression of CS to relieve severe pain. Opium from poppy and its properties was known by Sumerians (~4000 B.C.) Pulvis opii - to treat diarrhea Tinctura opii (laudanum) 70% alcohol extract of opium to treat strong diarrhea G.L.Patrick: An Introduction to Medicinal Chemistry, pp Wilson & Gisvold pp Papaver somniferum 182 Mixture of ~25 alkaloids: Isoquinoline 183 Morphine Morphine Morphine Morphine Morphine sulfate Morphini hydrochloridum Morphini sulfas Production: - earlier from opium. - method of Janos Kabay (Hungary): extraction of morphine (+ other alkaloids) from "poppy straw by dilute H 2 SO 4 and precipitation with H 4 OH. Structure-activity relationships: Isolated from the seed capsules by Sertürner (1804, Paderborn, Germany) ring perdendicular ring system, the aromatic one is planar

2 Morphine SAR E OH C 6 Basic atom used as different salts. B O D Linked by a C2 chain to C-13. A 1 Quaternary C-13 in S -configuration. Blockade of phenolic OH decreases analgesic activity, increases antitussive activity (but cross BBB easier) Blockade or removal of the alcoholic OH increases CS depressant activity. The ether bridge (ring D) is not required. Demethylation of -17 or increasing the aliphatic chain decreases potency or results in competitive antagonists. Aromatic ring is absolutely necessary OH Morphine pharmacology As an analgesic in hospital settings to relieve pain in myocardial infarction pain in sickle cell crisis pain associated with surgical conditions, pre- and postoperatively Relief of severe chronic pain, e.g. cancer (palliative care) pain from kidney stones Significantly reduces gut motility, causing constipation. Antitussive activity. Contraindications: acute respiratory depression renal failure. 188 Morphine pharmacology Adverse effects Respiratory depression overdoses kill. Highly addictive substance, both psychologically and physically. Dependence serious withdrawal symptoms. Most commonly abused narcotic analgesic. Mode of action Opiate alkaloids morphine and codeine bind most strongly to the opioid µ-receptor high affinity for enkephalins and betaendorphin as well. Responsible for euphoria and respiratory depression. κ-receptor: responsible for analgesia and sedation. δ-receptor: binding site of the endogen painkillers enkephalins. Morphine binds strongly as well. 189 Endorphins, enkephalins Metabolism Semisynthetic morphine derivatives Endorphin = endogenous morphine" Endogenous opioid polypeptide compounds produced by the pituitary gland and the hypothalamus (Hughes, 1975). They produce analgesia and a sense of wellbeing, bind to the δ-receptor. Apomorphine Apomorfini hydrochloridum Methionin-enkephalin: Tyr Gly Gly Phe Met Classic use: very strong emetic, induces vomiting in a few minutes (subcutan administration 0.1 mg/kg). Treatment of erectyle disfunction of men. (Uprima sublingual tablets, 3 mg). Dopaminergic agonist. Treatment of Parkinson s disease

3 Diacetyl morphine, heroin Very strong analgesic. Very quick and strong addiction. Prohibited in most countries. Ethylmorphine Ethylmorphini hydrochloridum Ethylmorphine Analgesic activity is ~ 1/6 that of the morphine. Less dependence. Used in painkiller tablets (toothache etc.) Oxycodone 14-Hydroxi-dihydrocodeinone Used as strong sedative, analgesic narcotic and antitussive. Popular with drug users and addicts. Acts as -demethyl metabolite (noroxycodone) Chemical transformations of thebaine CH 3 Diprenorphine Buprenorphine Synthesis: Etorphine Immobilon OH OMe O OCH 3 Diprenorphine: used to reverse the effects of the superpotent opioid analgesics such as etorphine. ~100 x more potent than nalorphine more active than morphine. Licenced only for veterinary use. Most often used to immobilize elephants and other large mammals. Buprenorphine: ~25 x more potent analgesic than morphine. Transdermal formulation ("patch") for chronic pain

4 Codeine Codeinium Codeine hydrochlorid dihydrate Codeini hydrochloridum dihydricum Codeine phosphate hemihydrate Codeini phosphas hemihydricus Codeine Strong antitussive + some analgesic activity. Applied in combination with expectorants, bronchodilators. Absorbs well from the g.i. tract. Sometimes a drog of abuse, may induce dependence. ~ 0.2% in opium, produced synthetically. Dihidrocodeine hydrogentartarate Dihydrocodeini hydrogentartaras Stronger antitussive than codeine alorphine hydrogenchloride alorphine Antagonistic effect against morphine Undesirable psychotic effect, replaced by other derivatives. Morphine antagonists aloxone aloxonum -Allyl-14-hydroxy-7,8- dihydronormorphinone altrexone altrexonum Antaxon,, emexin,, Revia Morphine antagonists Synthetic morphine analogs 203 For treating narcotic overdosage and narcotic addicts (to block the effect of heroine)

5 Morphinane dervatives Benzomorphane derivatives Phenylpiperidine derivatives Levorphanol Dextrometorphane ot relevant group Pethidine (I) Meperidine hydrochl. (USA) Pethidini hydrochloridum Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate Excellent examples of enantiomers with different biologal activities. Levorphanol: 5 x more potent analgesic than morphine (+ adverse effects) Potent antitussive without narcotic effects (component of Rhinathiol, Robitussin etc.) Prepared in 1938 as antispasmodic, antimuscarinic (structural resemblance to atropin). Analgesic effect was discovered almost accidentally. Somewhat weaker analgesic than morphine, no hypnotic effect + papaverin-like depression of smooth muscle pain is due to spasmic condition of intestines, uterus, bladder, kidney stones etc. 208 Synthesis Pethidine Phenylpropylamine derivatives Like other opioid drugs, pethidine has the potential to cause physical dependence or addiction. In fact, pethidine may be more addictive than other opioids because of its exceptionally rapid onset of action and associated "rush. Methadone Methadonii hydrochloridum Dolophine,, Amidone,, etc. CH 3 H + Cl - * CH 3 CH 3 O Analgesic (chronic pain, stronger than morphine), antitussive and a maintenance anti-addictive for use in patients on opioids. Stabilises the condition of the patient by stopping and preventing the opioid withdrawal syndrome. Good oral bioavailability, oral administration no need top use needles

6 Other, synthetic major analgetics Fentanyl (citrate) Fentanylum O Tramadole Analgesic activity 50 x morphine. Rapid onset. Used as neuroleptanalgesic in surgery in combination with droperidol. Strong analgesic, but does not induce morphine-like side effects