Opioid Analgesic

Opioids are natural, semi synthetic or synthetic compounds which show interaction with opioid receptors (mu, kappa and delta) and have morphine like effect. Opioid analgesic: These are the agents which show analgesic (decrease pain) effect without induction of sleep. LIKE ENDORPHINS OPIOIDS ARE INHIBITORY IN NATURE: THEY DECREASE JUNCTIONAL RELEASE OF NEUROTANSMITTER (GLUTAMATE, NORADRENALINE, DOPAMINE, 5-HT)
CLASSIFICATION OF OPIOIDS:
v  Natural ·         Pure agonist- A.      Strong agonist: Morphine B.       Weak agonist: Codeine	v  Semisynthetic ·         Pure agonist: Strong agonist:                Heroin                Oxycodone Pholocodeine Ethylmorphine			v  Synthetic 1.       Pure agonist: A.      Strong agonist- Fentanyl Alfentanil Pethidine (Meperidine) Methadone Remifentanil Sufentanil B.      Weak agonist: Dextropropoxyphene 2.       Agonist at mu site and antagonist at kappa site: buprenorphine 3.       Antagonist at mu site and agonist at kappa site: Pentazocine Cyclazocine Butorphanol Nalorphine 4.       Others (weak mu receptor agonist): Tramadol-
Action of opioid receptors:
Mu		Kappa			Delta
·         Analgesia		·         Analgesia			·         Analgesia
·         Respiratory depression		·         Respiratory depression			·         Respiratory depression
·         Decrease G.I.I motility (Constipation)		·         Decrease G.I.T motility(Constipation)			·         Decrease G.I.T motility(Constipation)
·         Sedation		·         Sedation			·         No sedation
·         Euphoria		·         Dysphoria			·         Increase prolactin and growth hormone release
·         Show Physical dependence and psychological dependence for morphine		·         Show Physical dependence and psychological dependence for nalorphine			·         Decrease acetylcholine and dopamine neurotransmitter release
·         Miosis (Pin point pupil)		·         Show Psychomimetic action
Pharmacological Action of pure Opioid Agonist:			Pharmacological Action of Partial Opioid Agonist (agonist as well as antagonist):
·         e.g. Morphine, Codeine, Pethidine, Methadone, Oxycodone, Dextropropoxyphene, Fentanyl			·         e.g. Pentazocine, Buprenorphine, Butorphanol, Nalorphine
·         Analgesia (by action on mu, kappa, delta receptor)- morphine strong analgesic			·         Pentazocine: mu receptor partial agonist/antagonist and  kappa  receptor agonist – cause hallucination (psychosis), anxiety ·         analgesia ·         drug abuse is less ·         cardiac stimulation, vomiting,sedation ·         Dependence (physical dependence and psychological dependence-drug abuse) ·         tolerance
·         Emesis			·         Buprenorphine- partial agonist for mu receptor and antagonist for kappa and delta receptor- as analgesic, for opioid withdrawn ·         BUPRENORPHINE IS 25 TIMES MORE POTENT THAN MORPHINE ·         analgesia ·         sedation, vomiting,miosis ·         Dependence (less physical dependence and psychological dependence-drug abuse) ·         less tolerance
·         Respiratory depression			·         Butorphanol- mu receptor partial agonist and  kappa  receptor agonist- cause more sedation than morphine ·         BUTORPHANOL IS MORE POTENT THAN PENTAZOCINE ·         analgesia ·         sedation, cardiac stimulation ·         Dependence (physical dependence and psychological dependence-drug abuse)
·         Suppress cough			·         Nalorphine-mu receptor antagonist and kappa receptor agonist ·         analgesia ·         dysphoria ·         psychotomimetic effect
·         Constriction of pupil –miosis- pin point pupil (Pethidine cause mydriasis)
·         Euphoria (by  action  on mu receptor)
·         Dysphoria (by action on kappa receptor)
·         Constipation
·         Sedation (less sedation with Fentanyl and Pethidine)
·         Convulsions
·         Dependence (physical dependence and psychological dependence-drug abuse)
·         Tolerance (emesis, euphoria, dysphoria, analgesia, respiratory depression, sedation, cough suppression) but tolerance not develops against constipation, miosis and convulsions.
·         Cause bronchoconstriction
·         Withdrawl symptoms develop if suddenly stop drug.
Uses: 1.       They are used as analgesic but less effective in inflammatory pain (NSAIDS effective) 2.       For cough suppression: Codeine, Pholcodeine, Dextromethorphan 3.       In diarrdhea: they cause constipation that’s why use for non-infective diarrhoea- Diphenoxylate,  Loperamide(metabolite of Diphenoxylate) 4.       As general anaesthetic: Fentanyl 5.       Pethidine is  used to reduce shivering after general anaesthesia 6.       Morphine also used in Myocardial Infarction and as premedication in anaesthesia.
Important points: Least potent Opioid: Dextropropoxyphene and Pethidine Morphine metabolite: Morphine-3-glucuronide and Morphine -6- glucuronide accumulate in renal failure person and due to accumulation cause convulsions. There is no tolerance develop to opioid effects like convulsions, constipation, pin point pupil. Endogenous opioids: Endorphins (act on mu receptor), Enkephalins (act on delta receptor), Dynorphins (act on kappa receptor) Pethidine cause mydriasis Long acting opioid: Methadone (also act by blocking NMDA receptor and slow development of  dependence) Physical or psychological dependence chances are less with the use of Pentazocine, Codeine and Buprenorphine. Morphine contraindicated in head injury patient. Fentanyl 100 times more potent than morphine Codeine 10 times less potent than morphine (codeine act as partial agonist at mu receptor) Heroin 3 time more potent than morphine Fentanyl and sufentanil are highly lipophilic (rapid and short duration of action) Dextropropoxyphene has poor antitussive and constipation effect. Tramodol: Also inhibit reuptake of nor adrenaline and serotonin (other than Opioid action). Morphine used in pregnant woman cause apnoea in foetus Naloxone used for  ACUTE morphine poisoning MORPHINE DE-ADDICTION-For morphine withdrawal OR DE-ADDICTION use methadone ( long acting and orally effective) AND FOR TREATMENT OF WITHDRAWL SYMPTOMS USE CLONIDINE OR BETA BLOCKERS

Action of Opioid drugs on Opioids Receptors:

Drug	Mu Agonistic action	Kappa Agonistic action	Delta Agonistic action
Morphine	+++	+	+
Fentanyl	+++	----	----
sufentanil	+++	+	+
Butorphanol	Partial agonist (+)	+++	----
Buprenorphine	Partial agonist (+)	antagonist	----
Pentazocine	Partial agonist/Antagonist (+)	++	----
Methadone	+++	----	----
levorphnol	+++	----	----
Endorphin	+++	----	+++
Enkephalin      endogenous	++	----	+++
Dynorphin	+	+++	+
Nalorphine	Antagonist(+++)	++	----
Tramadol	+	----	----

+ (weak), ++ (medium), +++ (strong)

Opium- papaver somniferum: phenantherene and benzoisoquinoline alkaloids
Analgesic alkaloid Morphine (Phenantherene) Codeine  (Phenantherene)	Nonanalgesic alkaloid Thebaine (Phenantherene) Papaverine (Benzoisoquinoline) Noscapine (Benzoisoquinoline)