OPIOIDS

Dr. Nadeem akhtar

MBBS.M.PhilAsst. Professor PharmacologyAmna Inayat Medical College

Shaikhupura

History

• Opium is the source of morphine obtained from poppy, Papaver somniferum and P album

• It was isolated in 1803 and was named after Morpheus, the Greek god of dreams.

Papver somniferum

Classification

• 1) Agonist: • Strong---Morphine, Heroin,Mepridine, -Methadone,

Fentanyl, Sufentanil.• Moderate---Codeine, Oxycodone, Hydrocodone,

Pholcodeine• Weak---Propoxyphene• 2) MixedAgonist/Antagonist:

Pentazocine,Nalbuphine,Buprenorphine, Butorphenol• Antagonist: Naloxone, Naltrexone,Nalorphine

• Pure agonist: has affinity for binding plus efficacy

• Pure antagonist: affinity for binding but no efficacy

• Mixed agonist: antagonist produces an agonist effect at one receptor and antagonist at other

• Partial agonist: has affinity for binding but low efficacy.

Opioid receptors

• In 1973 a graduate student Candance pert used radioactive morphine to evaluate the location of site of action of morphine, and he found that drug attaches to very specific areas of brain dubbed as opioid receptors

Opioid receptors

• There are opioid receptors within the CNS as well as throughout the peripheral tissues. These receptors are normally stimulated by endogenous peptides (endorphins,enkephalins and dynorphins)

Opioid Receptors

• Mu: µ

• Kappa: К

• Delta: δ

Functions of opiod receptors

• Mu (µ): supraspinal and spinal analgesia, sedation, inhibition of respiration, slow gastrointestinal transit, modulation of hormone and neurotransmitter release

• Kppa (К): supraspinal and spinal analgesia, psychotomimetic effects, slowed gastrointestinal transit

• Delta (δ): supraspinal and spinal analgesia, modulation of hormone and neurotransmitter release

Functions of opiod receptors

• All these receptors possess strong affinity for endogeneous opioid peptides e.g endorphins, enkephalins, and dynorphins

Organ system effects of morphine and its surrogates

• 1)CNS: due to the affinity for µ receptors, they produce analgesia, euphoria, sedation, and respiratory depression and tolerance occur with repeated use.

• a) analgesia: opioid analgesics are unique to reduce both aspects (sensory and affective) of pain.

• b) euphoria: intravenous drug users usually experience pleasant floating sensations with less anxiety ad distress

• c) sedation: induce sleep particularly in elderly as well as with combination of other CNS depressing agents like sedatives & hypnotics

• d) respiratory depression: all opioids produce respiratory depression by inhibiting brain stem respiratory mechanism and depressed response to CO2 challenge.

• e) cough suppression: suppresses cough reflex in this respect codeine is most effective

• f) miosis: constriction of pupils have been seen with all opioid agonists

• g) truncal rigidity: intensification of tone in large trunk muscles have been noted with number of opioids, may be due to spinal action of these drugs.

• h) nausea & vomiting: opioid analgesics can activate chemoreceptors and produce nausea and vomiting.

• i) temperature: homeostatic regulation of body temperature is mediated in part b action of the action of endogenous peptides in the brain.

• 2)Peripheral effects:• a)CVS: no significant effect observed on cvs

with the exception of meperidine which may produce tachycardia.

• b)G.I.T: in large intestine peristaltic waves diminished and causes constipation, more opioids are successfully used for the treatment of the diarrhea (loperamide).

• c) biliary tract: opiods contract biliary smooth muscles which can result in biliary colic.

• d) renal: opioids depress renal function, µ opioids have anti-diuretic action. Ureteral and bladder tone increased due to opioids administration

• e) uterus: peripheral and central actions of opioids reduce uterine contractions and prolong labor.

• f) neuroendocrine: opioids increase the release of ADH, prolactin and somatostatin but inhibit the release of luteinizing hormone.

• g) pruritus: opioids induced pruritus and urticaria more prominently by parenteral use.

Clinical uses of opioid analgesics

• Analgesia: severe pain associated with cancer or other terminal illnesses may be treated successfully. Opioids are often used in obstetric labor.

• Pulmonary edema: morphine can be particularly useful in treating painful myocardial ischemia with pulmonary edema

• Cough: on lower doses cough suppression effect can be obtained.

• Diarrhea: synthetic surrogates diphenoxylate or loperamide are available to control non-infecteous diarrhea.

• Applications in anesthesia: opioids are used in cardiovascular and other high risk surgeries, in which primary goal is to minimize cardiovascular depression.

Mechanism of action

• Activation of peripheral nociceptive fibres causes release of substance P an other pain signaling neurotransmitters from nerve of terminals in the dorsal horn of spinal cord.

• Release of pain signaling neurotransmitters is regulated by endogenous endorphins or by exogenous opioid agonists by acting pre-synaptically to inhibit substance P release causing analgesia.

• Involves changes in transmembrane ion conductance

• Increase potassium conductance• In-activation of calcium channels

Adverse effects

• Severe respiratory depression can occur and may result in death. Other effects include vomiting, dyphoria, histamine enhanced hypotensive effects, increased intracranial pressure, cerebral and spinal ischemia. Care should be taken while prescribing morphine in CLD, CRF.

Tolerance and dependence

• Repeated use produce tolerance to analgesic, euphoric, respiratory and sedative effects of morphine. Physical and psychological dependence readily occur with morphine and other agonists. Withdrawal effects include rhinorrhea, lacrimation, yawning, hyperventilation, hyperthermia, mydriasis, muscular aches and vomiting.

Meperidine

• A synthetic opioid structurally unrelated to morphine.

• Mechanism of action: binds to µ and К receptors.

• Clinical uses: indicated for acute nature of pain, not recommended for long term use

• Adverse effects: large doses can cause anxiety, tremor, muscle twitches.

Methadone

• A synthetic opioid orally effective induces less euphoria and longer duration of action.

• Mechanism of action: acts on µ and NMDA receptors.

• Clinical uses: used as analgesic in neurogenic pain, controlled withdrawal in morphine and heroin abusers.

• Adverse effects: withdrawal effects ,but less toxic than morphine.

Fentanyl

• A synthetic opioid and 100 times more potent than morphine use in anesthesia. The drug has rapid short duration (15-30 mnts). Administered by i.v route but oral mucosal preparations and transdermal patches also available. This is often used in cardiac surgery due to its negligible effects on myocardial contractility.

• Adverse effects: are those of µ receptor agonists

Heroin

• Also called diacetylmorphine three fold increased in potency than morphine. Due to its greater solubility it cross BBB more rapidly than morphine causing more euphoria. It has no accepted medical use in USA, but it is used in other countries in severe cancer pain.

• Heroin users experience more severe withdrawal symptoms than morphine

Pakistani heroin addict

Moderate agonist: Codeine

• The analgesic potency of codeine is much less than the morphine, however it shows good anti-tussive activity at doses that do not causes analgesia. Codeine is often used in combinations with aspirin and acetaminophen

Mixed agonist-antagonist & partial agonist

• Mixed agonist-antagonist: shows agonistic activity and are used to relieve pain.

• Pentazocine: it acts as agonist on К receptors and weak agonist at µ and δ receptors. Pentazocine promotes analgesia activating receptors in spinal cord. It can precipitate withdrawal symptoms in morphine users. Tolerance and dependence develops with repeated use.

Buprenorphine

• A partial agonist acting on the µ receptors, its major usage is in opiate detoxification, because it has less severe and shorter duration of withdrawal symptoms compared to methadone. It causes little sedation, respiratory depression and hypotension even at higher doses. Adverse effects are respiratory depression which do not easily reverse with NALOXONE .

Antagonists

• Opioid antagonists bind with high affinity to opioid receptors but fail to activate response

• Naloxone: naloxone antagonise µ, К, and δ receptors. It has 10 fold higher affinity to µ than for К receptors. It reverses the coma and respiratory overdose of opioids within 30 seconds of i.v injection of naloxone .

Naltrexone

• It has similar action like naloxone but longer duration of action than naloxone. A single oral dose of naltrexone blocks the effect of injected heroin up to 48 hrs. Naltrexone may cause hepatotoxicity.