Opioids CP Module 2022-2023 PDF

University of Baghdad College of Medicine 2022-2023 Title: opioid Grade:4th Stage Module: CP Module Speaker: ASS. Prof. Dr. Mohammed Qasim Al Atrakji Date:20/2/2023 University of Baghdad/ College of Medicine 2022-2023 Learning Objectives Upon completion of this chapter, you will be able to: 1. Outli...

University of Baghdad College of Medicine 2022-2023 Title: opioid Grade:4th Stage Module: CP Module Speaker: ASS. Prof. Dr. Mohammed Qasim Al Atrakji Date:20/2/2023 University of Baghdad/ College of Medicine 2022-2023 Learning Objectives Upon completion of this chapter, you will be able to: 1. Outline the understanding of pain transmission and types of pain and explain therapeutic ways to block pain. 2. Describe the therapeutic actions, indications, pharmacokinetics, contraindications, most common adverse reactions, and important drug–drug interactions associated with narcotics 3. Discuss the use of the different classes of narcotics, narcotic antagonists,. 4. Compare and contrast the prototype drugs morphine, pentazocine, naloxone, with other drugs in their respective classes. University of Baghdad/ College of Medicine 2022-2023 Opioid Analgesics 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 semisynthetic Opiates: Drugs derived from opium – Natural or semisynthetic 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. I University of Baghdad/ College of Medicine 2022-2023 Types of Pain University of Baghdad/ College of Medicine 2022-2023 Types of Pain – contd. University of Baghdad/ College of Medicine 2022-2023 Types of Pain – contd. University of Baghdad/ College of Medicine 2022-2023 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% University of Baghdad/ College of Medicine 2022-2023 Poppy Plant - image I It opiu University of Baghdad/ College of Medicine 2022-2023 Poppy to Opioids University of Baghdad/ College of Medicine 2022-2023 Opium - History Friedrich Wilhelm Serturner – A German Pharmacist – Isolated Morphine in 1803 and named it after the Greek god of Dreams “MORPHEUS” University of Baghdad/ College of Medicine 2022-2023 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 Neurotic pain Associated reactions to pain are also relieved – apprehension, fear and autonomic effects Tolerance to pain is better University of Baghdad/ College of Medicine 2022-2023 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, midbrain and medulla - alter processing and interpretation and send inhibitory impulses through descending pthway University of Baghdad/ College of Medicine 2022-2023 D E University of Baghdad/ College of Medicine 2022-2023 Pharmacological actions of Morphine (CNS) – contd. C not is uphin no 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 DYSPHORIA – But in persons with pain & addicts sense of wellbeing, pleasurable floating feelings – kick – EUPHORIA Pharmacological actions of Morphine (CNS) –. Ssb Depression: 1. Respiratory centre depression – Both rate and depth of respiration are diminished Dangerous in Head injury and asthmatics 2. Cough Centre – Depressed 3. Temperature regulating centre – depressed 4. Vasomotor centre – high doses cause fall in BP contraindicated inshore 91 University of Baghdad/ College of Medicine 2022-2023 Stimulation: 1. CTZ – sensitize CTZ to vestibular and other impulses 2. Edinger Westphal Nucleus – miosis 3. Vagal centre – Bradycardia 4. Hippocampal cells – convulsions (inhibition of GABA release) pinpoint comay Kparid i p University of Baghdad/ College of Medicine 2022-2023 Pharmacological actions of Morphine 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 Prolactin: increased secretion due to loss of inhibitory control of dopamine my CVS: NO DIRECT EFFECT ON HEART Pay P mn Vasodilatation – histamine release, depression of vasomotor centre and directly on blood vessels decreasing the tone Cardiac work reduction due to consistent vasodilatation University of Baghdad/ College of Medicine 2022-2023 Pharmacological actions of Morphine GIT: CONSTIPATION Due to direct action on intestine reducing propulsive movement, spasm of sphincters, ntraction 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 my University of Baghdad/ College of Medicine 2022-2023 Absorption and Distribution: Variable orally (usually not given orally – 1st 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 t1/2 = 2-3 Hrs Action lasts for 4-6 Hrs Completely eliminated in 24 Hrs University of Baghdad/ College of Medicine 2022-2023 Morphine – Adverse Effects 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 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 KMNO4(POTASSIUM PERMANGNAT), Specific antidote: Naloxone: 0.4 to 0.8 mg IV repeatedly in 2-3 minutes till respiration picks up Tolerance and dependence (except miosis and constipation) University of Baghdad/ College of Medicine 2022-2023 Morphine – Therapeutic uses Analgesic: 1. 2. 3. 4. 5. 6. 7. 8. 9. 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 University of Baghdad/ College of Medicine 2022-2023 Morphine – Other Therapeutic uses Preanaesthetic Medication Balanced anaesthesia and surgical analgesia Acute Left ventricular failure – Cardiac asthma(vasodilatio and sedation) Cough – not used but Codeine is used Diarrhoea – colostomy - Loperamide, Diphenoxylate orphin Morphine Contraindications 1. 2. 3. 4. 5. 6. 7. 8. University of Baghdad/ College of Medicine 2022-2023 Two Extremes of Age e Bronchial asthma Respiratory insufficiency - emphysema Head Injury (INCREASE ICP due to CO2 retention, dilation of cerebral vessels, and increase the CSF pressure) Shock – Hypotension BPH Renal Failure, Liver diseases and hypothyrodism Unstable personalities University of Baghdad/ College of Medicine 2022-2023 Opioids - Classification a 3 1. Natural Opium Alkaloids: Morphine and Codeine 2. Semi-synthetic: Diacetylmorphine (Heroin) and Pholcodeine 3. 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 University of Baghdad/ College of Medicine 2022-2023 morphine I Pethidine 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 t.is 60 39 Morphine is pethidine I University of Baghdad/ College of Medicine 2022-2023 Pethidine 1 Binding toµ receptor Binding to Kappa receptors 2 Suppress cough usefully Doesn't suppress cough usefully 3 Cause constipation Causes less intense & less frequent constipation 4 Delay labor Less likely to prolong child-birth so is used in 1st stage of labor 5 Cause sedation and prolonged analgesia Little hypnotic effect & analgesic effect are shorter than morphine 6 No atropine –like effect (miosis) Atropine like effects: dry mouth, blurred vision & sometimes mydriasis though usually miosis 7 Profound dependence Dependence is less marked than morphine 8 More histamine release Less histamine release ME t University of Baghdad/ College of Medicine 2022-2023 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 labour – less fetal respiratory depression Dose 50-100 mg IM/SC, oral – 50-100 mg tabs. University of Baghdad/ College of Medicine 2022-2023 Opioid Receptors α Mainly 3 (three) types of receptors – μ (mu), κ (kappa) and δ (delta) Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2 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: University of Baghdad/ College of Medicine 2022-2023 μ receptor κ receptor Location μ1 – supraspinal μ2 - spinal κ1 – spinal κ3 -supraspinal Spinal supraspinal Effects Analgesia Respiratory depression Sedation Euphoria Miosis Physical dependence Loss of GI motility Spinal analgesia Dysphoria Sedation Psychomimetic Spinal analgesia Affective behaviour (Supraspinal) Respiratory depression Reduced GI motility Morphine, Codeine, Fentanyl and pentazocine weakly Pentazocine Agonists Physical dependence (nalorphine type) δ receptor Opioid Receptors – Intracellular mechanism University of Baghdad/ College of Medicine 2022-2023 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 University of Baghdad/ College of Medicine 2022-2023 Endogenous Opioid Peptides 613 Endorphins: Enkephalins: Dynorphins: University of Baghdad/ College of Medicine 2022-2023 Opioid Antagonists 1. Nalmefene 2. f Pure antagonists: Naloxone, Naltrexone and Affinity for all receptors (μ, δ and κ) Can displace opioids bound to receptors No action on Normal person but reverses poisoning Mixed Agonist-antagonists: Nalorphine, Pentazocine, Partial/weak μ agonist and κ antagonist: Buprenorphine I morphine posing Methadone: University of Baghdad/ College of Medicine 2022-2023 It is a synthetic drug structurally related or similar to morphine & acts mainly on µ receptors. The analgesic activity is equal to that of morphine & very effective orally. Dependence occurs, but is less severe & causes less severe withdrawal syndrome M because of long tl/2, therefore the addicts on morphine & heroin are transported to methadone as one step of treatment. University of Baghdad/ College of Medicine 2022-2023 Diamorphine (heroin): Semi synthetic drug made by acetylation of morphine. It is the most powerful of all dependence producing drugs (very imp.), because it's more lipophilic & enters the CNS readily & causes more euphoria than morphine Fentanyl: used in anesthesia University of Baghdad/ College of Medicine 2022-2023 Low to moderate efficacy group Codeine: its action is 1/10 that of morphine It is used in cough suppression & for short term systemic control of the acute diarrhea. biliary Partial agonists (mixed): University of Baghdad/ College of Medicine 2022-2023 Pentazocine: is a partial agonist at Kappa receptors & weak antagonists at µ receptors & delta receptors. Phenazocine: The main use is in biliary colic because; it causes less spasm of sphincter of Oddi. Buprenorphine: also it's used in biliary colic treatment. Disadvantages: although less likely to cause respiratory depression, but in overdose this depression is "only partially antagonized" by the action of naloxone. University of Baghdad/ College of Medicine 2022-2023 Tramadol: tl/2 is 6hrs. It binds to µ receptors causing analgesia. It inhibits neuronal nor-adrenaline uptake & serotonin release. It is effective orally & as effective as pethidine for postoperative pain & less likely to cause constipation & less addiction & respiratory depression. Tolerance & physical dependence: University of Baghdad/ College of Medicine 2022-2023 Tolerance occurs mainly to the agonist effects which are respiratory depression, analgesia, euphoria & sedative effects, but not to the stimulatory actions as miosis & constipations & convulsions Cross tolerance between opioids & with other CNS depressants as barbiturates & alcohol Change in no. of receptors or change in sensitivity. University of Baghdad/ College of Medicine 2022-2023 The abrupt withdrawal of the administration of the opioid would be expected to produce rebound or withdrawal syndrome. Withdrawal syndrome consists largely from the opposite actions of opioids , also associated with noradrenergic storm. Treatment of addicts: University of Baghdad/ College of Medicine 2022-2023 Withdraw morphine gradually. Substitute methadone which produces mild withdrawal syndrome, since it has long t1/2 (48hrs), perhaps supplements with chlorpromazine or benzodiazepine as valium. Clonidine decreases the severity of withdrawal syndrome by decreasing the effects of noradrenalin hyperactivity. (Clonidine stimulates presynaptic α2 – R --> inhibition of the sympathetic over activity). * Lofexidine is clonidine analogue that may also aid opioid detoxification. * Sometimes, we also use atropine or Beta blockers as propranolol that decreases emotional compulsions after stopping opioid. Morphine Poisoning: University of Baghdad/ College of Medicine 2022-2023 Coma, slow & shallow respiration, pinpoint pupil, circulation is maintained till hypoxia is advanced & cyanosis occurs. The main signs of morphine poisoning are: Bradypnea. Patient coma in an unconscious state & pupils are constricted (miosis), while in most other cases of coma the pupil is dilated. University of Baghdad/ College of Medicine 2022-2023 Treatment of morphine poisoning: Support of respiration & circulation till antagonize the effect of opioids. We give naloxone I.V. it's a pure opioid antagonist, also it is used as a test (therapeutic test) whether the coma is due morphine or not, by giving naloxone. University of Baghdad/ College of Medicine 2022-2023 thanks