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Opioid analgesic
 

Opioid analgesic

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Undergraduate MBBS level theory class power point presentation

Undergraduate MBBS level theory class power point presentation

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  • Narcotic is a greek term meanig stupor(deficiency of mental and physical alertness) pethidine, fentanyl, sufentanyl and alfentanyl are synthetic.
  • Phenanthrene is a  polycyclic aromatic hydrocarbon  composed of three fused  benzene  rings--as the above formula shows. Phenanthrene has five  resonance structures , given below. Reactions of phenanthrene typically occur at the 9 and 10 positions. Many benzylisoquinolines have a  methylated  nitrogen atom as well as functional groups containing oxygen ( -OH ,  -OCH3 , -OCH2O-) in positions 6, 7, 3' and 4'
  • Dorsal gray horn – substancia gelattinosa
  • Tolerance and dependence is the most comon problem with morphine. Tolerance is exhibited in most action except constipation and miotic action. It produces psychological and physical dependence Because of this abuse potential increases. Mostly medical and paramedical persons go for morphine abuse. This is the major drawback of morphine. Withdrawal may lead to Drug seeking behaviour and may turn to Morphine withdrawal syndrome. It is characterized by anxiety, fear, restlesness, diarrhoea, abdominal coli, delirium and convulsion - treatment is methadone.
  • Different tissues in human body produces substances which behave like opium Pharmacologically but chemically peptides. Remember opium is alkaloid. These re called endogenous opioid peptides. They are located in Brain, Pituitary, Spinal Chord which can modulate pain.

Opioid analgesic Opioid analgesic Presentation Transcript

  • Opioid Analgesics Department of Pharmacology, NEIGRIHMS
  • Opioid Analgesics (against algesia) – some important terms
    • Analgesics: Are the Drugs which selectively relieves pain by acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness – Opioids and NSAIDS
    • Opioids: Any drug which binds to the opioid receptors (Pharmacologically related) in the CNS and antagonized by Naloxone . They may be – Natural, Synthetic and semi-synthetic
    • Opiates: Drugs derived from opium – Natural or semi-synthetic
    • Narcotics: Drugs derived from opium or opium like compounds, with potent analgesic effects associated with significant alteration of mood and behavior, and with the potential for dependence and tolerance following repeated administration.
  • Types of Pain
  • Types of Pain – contd.
  • Types of Pain – contd.
  • Opioids - Opium
    • A dark brown, resinous material obtained from poppy ( Papaver somniferum ) Capsules.
    • OPIUM
    • PHENANTHRENE
    • Morphine 9-14%
    • Codeine 0.5-2%
    • Thebaine 0.2-1%
    • BENZYLISOQUINOLINE
    • Papaverine 0.8-1%
    • Noscapine 3-10%
    • Narcine 0.2-0.4%
  • Poppy Plant - image
  • Poppy to Opioids
  • Opium - History
    • Friedrich Wilhelm Serturner
      • A German Pharmacist
      • Isolated Morphine in 1803 and named it after the Greek god of Dreams “MORPHEUS”
  • MORPHINE (Pharmacological actions) - CNS
    • Analgesia:
      • Strong analgesic
      • Visceral pain is relieved better than somatic pain
      • Degree of analgesia increases with dose
      • Nociceptive pain is better relieved than Neuretic pain
      • Associated reactions to pain are also relieved – apprehension, fear and autonomic effects
      • Tolerance to pain is better
  • MORPHINE – Analgesia action
      • Two components – spinal and supraspinal
      • Inhibits release of excitatory transmitters from primary afferents – at Substantia gelatinosa of dorsal horn
      • Exerted through Interneurones – gating of pain
      • At supraspinal level in cortex, meidbrain and medulla - alter processing and interpretation and send inhibitory impulses through descending pthway
  • D E
  • Morphine - The Gate Theory
  • Pharmacological actions of Morphine (CNS) – contd.
    • Sedation:
      • Drowsiness and indifference to surroundings
      • Inability to concentrate and extravagant imagination – colorful day dream
      • Apparent excitement
      • Larger doses produce sleep – EEG resembles normal sleep
    • Mood effects:
      • In Normal persons calming effect, mental clouding, feeling of detachment, lack of initiative etc. - unpleasant in absence of pain
      • Sometimes DYSHORIA
      • But in persons with pain & addicts sense of wellbeing, pleasurable floating feelings – kick
      • EUPHORIA
  • Pharmacological actions of Morphine (CNS) – contd.
    • Depression:
      • Respiratory centre depression – Both rate and depth of respiration are diminished
        • Dangerous in Head injury and asthmatics
      • Cough Centre – Depressed
      • Temperature regulating centre – depressed
      • Vasomotor centre – high doses cause fall in BP
    • Stimulation:
    • CTZ – sensitize CTZ to vestibular and other impulses
    • Edinger Westphal Nucleus – miosis
    • Vagal centre – Bradycardia
    • Hippocampal cells – convulsions (inhibition of GABA release)
  • Morphine - Effects
  • Pharmacological actions of Morphine – contd.
    • Neuro-endocrine:
        • GnRH and CRH are inhibited – FSH, LH and ACTH levels are lowered – only short term – tolerance develops
        • Decrease in levels of Sex hormone and corticosteroids, but no infertility
        • Increases ADH release – oliguria
    • CVS: NO DIRECT EFFECT ON HEART
        • Vasodilatation – histamine release, depression of vasomotor centre and directly on blood vessels decreasing the tone
        • Cardiac work reduction due to consistent vasodilatation
  • Pharmacological actions of Morphine – contd.
    • GIT: CONSTIPATION
        • Due to direct action on intestine reducing propulsive movement, spasm of sphincters, decrease in all GIT secretions
    • Smooth Muscles:
        • Billiary Tract: Billiary colic – closure of sph. Of Oddi
        • Bladder: Urinary urgency but difficulty
        • Bronchi - Bronchospasm
  • Morphine - Pharmacokinetics
    • Absorption and Distribution:
        • Variable orally (usually not given orally – 1 st pass metabolism, given IM or IV)
        • Widely distributed – liver, spleen, kidney etc.
        • Enters Brain slowly
        • Readily crosses placental barrier – dependence in fetus
    • Metaboloism:
        • In Liver by glucoronidation – water soluble metabolites
        • Morphine-6- Glucoronide – analgesic – in renal failure prolong analgesia
        • Morphine-3-glucoronide – No analgesia – neuroexcitatory
    • Excretion:
        • Via Urine, Plasma t 1/2 = 2-3 Hrs
        • Action lasts for 4-6 Hrs
        • Completely eliminated in 24 Hrs
    • Preparation: 10, 15, and 20 mg. (IV: 2 – 10 mg)
  • Morphine - Pharmacokinetics
  • Morphine – Adverse Effects
    • Respiratory Depression: Infant and Old
    • Vomiting
    • Sedation, Mental Clouding – sometimes dysphoria
    • Hypotensive effect
    • Rise in Intracranial Pressure
    • Apnoea: Newborn
    • Urinary retention
    • Idiosyncrasy and allergy
    • Acute Morphine Poisoning: occurs if >50 mg (Lethal dose – 250 mg), Gastric lavage with KMNO 4 , Specific antidote: Naloxone: 0.4 to 0.8 mg IV repeatedly in 2-3 minutes till respiration picks up
    • Tolerance and dependence
  • Morphine – Therapeutic uses
    • Analgesic:
      • Long Bone Fracture
      • Myocardial Infarction
      • Terminal stages of cancer
      • Burn patients
      • Postoperative patients
      • Visceral pains – pulmonary embolism, pleurisy, acute pericarditis
      • Biliary colic and renal colic
      • Obstetric analgesia
      • Segmental analgesia
  • Morphine – Other Therapeutic uses
    • Preanaesthetic Medication
    • Balanced anaesthesia and surgical analgesia
    • Acute Left ventricular failure – Cardiac asthma
    • Cough – not used but Codeine is used
    • Diarrhoea – colostomy - Loperamide, Diphenoxylate
  • Morphine - Contraindications
    • Two Extremes of Age
    • Bronchial asthma
    • Respiratory insufficiency - empysema
    • Head Injury
    • Shock – Hypotension
    • Undiagnosed acute abdomen
    • BHP
    • Renal Failure, Liver diseases and hypothyrodism
    • Unstable personalities
  • Opioids - Classification
    • Natural Opium Alkaloids: Morphine and Codeine
    • Semi-synthetic: Diacetylmorphine (Heroin) and Pholcodeine
    • Synthetic Opioids:
      • Phenylpiperidines:
        • Pethidine (Mepiridine) and its congeners – Diphenoxylate and Loperamide
        • Fentanyl and its congeners – sufentanil, remifentanil and alfentanil
      • Phenyl-heptylmines: Methadone and congeners like Propoxyphene and Dextropropoxyphene
      • Benzomorphans: Pentazocine
      • Morphinan compounds and congeners: Levorphanol and Butorphanol
  • Pethidine
    • Morphine Vs Pethidine:
      • 1/10th as potent as Morphine, but Efficacy is similar
      • Produces as much sedation, euphoria and respiratory depression in equianalgesic dose and similar abuse potential
      • Less spasmodic action in smooth muscles – less miosis, constipation and urinary retention
      • Rapid but short duration of action (2-3 Hrs)
      • Vagolytic effect - Tachycardia
      • Devoid of antitussive action
      • Less histamine release – safer in asthmatics
      • Better oral absorption
  • Pethidine – contd.
    • Pharmacokinetics
      • Well absorbed orally, bioavailability 50%
      • Effects appear in 10-15 min. after oral absorption
      • On parenteral administration action lasts for 2-3 Hrs
      • Metabolized in liver – mepiridinic acid and norpethidine
      • Norpethidine accumulates on chronic use
      • Excreted in urine
  • Pethidine – contd.
    • Adverse Effects:
        • Similar to Morphine
        • Atropine like effects – dry mouth, blurred vision, tachycardia
        • Overdose – tremors, mydriasis, delirium and convulsion due to norpethidine accumulation
    • Uses:
        • Analgesic as substitute of Morphine
        • Preanaesthetic medication
        • As analgesic during labor – less fetal respiratory depression
        • Dose 50-100 mg IM/SC, oral – 50-100 mg tabs.
  • Methadone
    • Chemically dissimilar but similar in most of pharmacological actions – analgesic, respiratory depression etc.
    • High action orally as well as parenterally
    • Single dose effect is – same with Morphine including duration of action
    • Cumulation – on repeated administration (t 1/2 24-36 Hrs)
    • Highly bound to plasma protein 80 to 90%
    • Metabolized in liver by – demethylation and cyclization
    • Excreted in urine
    • Slow action and less subjective effect – abuse potential is low
    • Used as substitution therapy as opioid dependence: 1:4mg and 1:20 mg of Morphine and Pethidine respectively
    • Codeine is used as substitution in Methadone addiction
  • Tramadol
    • Centrally acting analgesic
    • Very low action on opioid receptors
    • Other mechanisms involved in analgesic action – 5-HT and NA reuptake inhibition – spinal inhibition of pain
    • Effective both orally and IV (100mg = 10 mg Morphine)
    • Side effects are similar to Morphine but less prominent
    • Well tolerated and low abuse potential
    • Only Partially reversed by Naloxone
    • Used in chronic neuropathic pain and short diagnostic procedures
    • Dose: 50-100 mg IM/IV/Oral
    • (Contramol)
  • Opioid Receptors
    • Mainly 3 (three) types of receptors – μ (mu), κ (kappa) and δ (delta)
    • Subtypes: μ 1, μ 2, κ 1, κ 2, κ 3, δ 1 and δ 2
    • Location: Peripheral Nerve endings, SG in spinal chord, Periaqueductal gray (PAG) in midbrain and Brain stem (medulla, hypothalumus and also amygdala
    • Opioids are – agonists, partial agonist or competitive antagonists of these receptors
    • Overall effect depends on nature of interaction and affinity to these
    • Morphine is agonist of all but affinity is higher for mu
  • Effects of Different Opioid Receptor Stimulation: μ receptor κ receptor δ receptor Location μ 1 – supraspinal μ 2 - spinal κ 1 – spinal κ 3 -supraspinal Spinal supraspinal Effects Analgesia Respiratory depression Sedation Euphoria Miosis Physical dependence Loss of GI motility Spinal analgesia Dysphoria Sedation Psychomimetic Physical dependence (nalorphine type) Spinal analgesia Affective behaviour (Supraspinal) Respiratory depression Reduced GI motility Agonists Morphine, Codeine, Fentanyl and pentazocine weakly Pentazocine
  • Effects of Opioid Receptor Stimulation
  • Effects of Opioid Receptor Stimulation – contd.
  • Opioid Receptors – Intracellular mechanism
    • All are G-protein coupled receptors
    • Located on prejunctional neurones
    • Inhibits release of transmitters – NA, DA, 5-HT, GABA and Glutamate
    • Activation reduces intracellular cAMP formation - Opening of K+ channel via μ and δ . and supression of N type of Ca++ channels
    • Ultimately Hyperpolarization and reduced intracellular Ca++ Reduced Neurotransmitter release
  • Endogenous Opioid Peptides
    • Endorphins:
        • Derived from POMC
        • ß-endorphins: 2 Types - ß-endorphin1 and ß-endorphin-2
        • Primarilty μ agonist and also has δ action
    • Enkephalins:
        • Derive from Proenkephalin
        • Met-ENK and leu-ENK
        • Met-ENK - Primarily μ and δ agonist and leu-ENK – δ agonist
    • Dynorphins:
        • Derive from Prodynorphin: DYN-A and DYN-B
        • Potent κ agonist and also have μ and δ action
  • Opioid Antagonists
    • Pure antagonists: Naloxone, Naltrexone and Nalmefene
      • Affinity for all receptors ( μ , δ and κ )
      • Can displace opioids bound to α -receptors
      • No action on Normal person but reverses poisoning and withdrawal symptoms in addicts
    • Mixed Agonist-antagonists: Nalorphine, Pentazocine, Butorphanol and Nalbuphine
    • Partial/weak μ agonist and κ antagonist: Buprenorphine
  • Nalorphine
    • Not used anymore
    • Previously used as Opioid antagonist
    • But, antagonism is restricted to μ -receptor only and agonist of κ -receptor
    • Drawbacks - dysphoria and psychomimetic effects
  • Pentazocine
    • Weak μ -receptor antagonist, but agonist of κ -receptor
    • One of the commonly used agents, given orally and IM
    • Low abuse liability
    • Pharmacokinetics:
      • High 1 st pass metabolism but effective orally
      • Half life = 3-4 Hrs
      • Metabolized in liver by glucoronide conjugation
      • Dose: orally 50-100 mg and parenterally 30-60 mg IM
    • Uses:Moderately severe pain in Injury, Burns, Fracture Trauma, Cancer and Orthopaedic manuevers
    • (Fortwin, Fortagesic)
  • Pentazocine Vs Morphine
    • Spinal analgesia via kappa receptor
    • Dose is 30 mg Vs 10 mg and low ceiling effect
    • Sedation and Respiratory depression at lower doses
    • Tachycardia and rise in BP – dangerous in MI
    • Lesser smooth muscle spasms
    • Vomiting and other side effects are less
    • Subjective effects – lower ceiling (psycomimetic effects)
    • Tolerance develops on repeated use, but lesser than Morphine
    • Withdrawal symptoms – both Morphine and Nalorphine like
    • Good analgesic in subjects not exposed to Morphine
    • Precipitate withdrawal – in Morphine addicts
  • Buprenorphine
    • Synthetic thebaine congener and highly lipid soluble
    • Given Sublingually or parenterally but not oral – high 1 st pass metabolism
    • Selective μ -agonist analgesic
    • 20-30 times more potent than Morphine
    • Slow but longer duration of action upto 24 Hrs
    • Pharmacological effects are similar to Morphine
    • Has ceiling effect in analgesic and respiratory depression
    • Good analgesic for naive patients but addicts – precipitates withdrawal syndrome
    • Lower tolerance and physical dependence than Morphine and abuse liability
    • Withdrawal syndromes are similar to Morphine
  • Buprenorphine – contd.
    • Adverse Effects:
      • Hypotension (Postural)
      • Respiratory depression (fatal in neonates) and cannot be reversed by Naloxone
    • Uses:
      • Long lasting painful conditions – cancer
      • Postoperative pain
      • Myocardial infarction
    • Preparations: Norphine, Tidigesic
        • 0.3 mg/ml injections and 0.2 mg sublingual tablets
  • Naloxone
    • Competitive antagonist of all types of opioid receptors
    • But, blocks μ -receptors at much lower dose
    • Always injected IV (0.4 t0 0.8 mg) - All symptoms of Morphine action are antagonized – respiratory stimulation
    • At higher doses 4-10 mg: antagonizes actions of Nalorphine and Pentazocine – dysmorphic and psychomimetic effects are not suppressed ( δ )
    • Withdrawal symptoms: 0.4 mg doses – Morphine and 4-5 mg doses – Nalorphine and Pentazocine
  • Naloxone – contd.
    • Buprenorphine actions are prevented but not reversed fully – tight bond with receptors
    • Also acts on endogenous opioids
    • Antagonizes respiratory depression of Diazepam and N 2 O
    • Uses:
        • Acute Morphine Poisoning (0.4 – 0.8 mg IV 2-3 min, maximum 10 mg.
        • New Born – opioid poisoning
        • Reverse respiratory depression intr-aoperatively
        • Diagnosis of Morphine addiction
        • Alcohol intoxication
  • Opioids – other uses
    • Antidiarrhoeal agents: Diphenoxylate and Loperamide
    • Antitussives: Codeine, Dextromethorphan, Noscapine, Pholcodeine, Levopropoxyphene
  • Important
    • Classification of opioids
    • Remember - Pharmacological actions, adverse effects, indications and contraindications of Morphine, Pethidine, Pentazocine
    • Remember in short – Methadone, Tramadol, Buprenorphine and Naloxone
    • Opioid receptors
  • THANK YOU