Drugs Used in Management of pain DR: Asmaa Fady. MD., MSC, M.B, B.Ch اسم ورقم المقرر – Course Name and No. 7/14/2019

Learning objectives: Objectives of the lecture: At the end of this lecture the student should: Revise how pain is perceived and modulated, emphasizing on neurotransmitters, receptors, channels involved. Classify drugs used in management of pain. Expand on pharmacology of opiates, patterns of classification, mechanism of action, indications, ADR,…etc. detailing on morphine as an example. Compare in brief actions and indications of other opiate agonists and antagonists اسم ورقم المقرر – Course Name and No. 7/14/2019

Pain An unpleasant sensory or emotional experience initiated by a harmful (tissue damaging or noxious) stimulus. The sensory nervous system perception of such stimuli is termed “Nociception”. اسم ورقم المقرر – Course Name and No. 7/14/2019

اسم ورقم المقرر – Course Name and No. 7/14/2019

Periaqueductal Grey Matter Substantia Gelatinosa Somatosensory Cortex  Perception of Pain Cingulate Cortex  Affective component of Pain Enkephalines, NE, GABA Thalamus PAIN Transmission & Processing Periaqueductal Grey Matter Dorsal Root Ganglion Pain signals Substantia Gelatinosa Substance P- glutamate Spinal Cord Noniceptors Prostaglandins, Bradykinins, 5HT, Histamine Stimulus

Key mediators of nociception: Mediators that activate nociceptors (ascending pathway) are: Bradykinin Prostaglandins Substance P Glutamate Mediators that act to reduce the perception of and response to pain (descending pathway): Endorphins (e.g. Enkephalin) Monoamines (e.g. serotonin, norepinephrine). اسم ورقم المقرر – Course Name and No. 7/14/2019

Drugs used in management of pain (Analgesics): Drugs used to treat mild or moderate pain (non opioids)include: Paracetamol NSAIDs (e.g. Aspirin, Ibuprofen, naproxen) Drugs used to treat severe pain are opioids (e.g. morphine) اسم ورقم المقرر – Course Name and No. 7/14/2019

Drugs used in management of pain: اسم ورقم المقرر – Course Name and No. 7/14/2019

Pharmacological classification of analgesics Analgesics :These are drugs that relieve pain without loss of consciousness or other sensations by CNS Effect. Classification of Analgesics: A) Central Analgesics = Proper Analgesics: 1- Narcotic (opioid) Analgesics e.g. Morphine. 2- Anti-Pyretic Analgesics (non-steroidal anti- inflammatory drugs = NSAIDs.) e. g. Aspirin. B) Peripheral Analgesics = Not Proper Analgesics: a- Nitroglycerine in Anginal pain. c- Antacids in Peptic ulcer. d- Antispasmodics e.g. Atropine in colic. اسم ورقم المقرر – Course Name and No. 7/14/2019

Narcotic (Opioid) Analgesics These are drugs that relieve pain centrally, but in large dose they cause stupor & drowsiness, & on long use they produce tolerance & dependence. Classification of Narcotic Analgesics Opioid Agonists (morphine) Opioid Antagonists (naloxone) mixed Opioid Agonists antagonist (Buprenorphine): agonist on kappa & delta , antagonist om mu اسم ورقم المقرر – Course Name and No. 7/14/2019

Classification of Narcotic Analgesics A- Opioid Agonists: I- Natural (Phenanthrene Opium Alkaloids) : a- Morphine b- Codeine = methyl morphine. II- Semisynthetic Morphine (phenanthrene) Derivatives: a- Di-acetyl-morphine (Heroin). b- Di-hydro-morphinone c- Di-hydro-codeinone III- Synthetic Morphine Substitutes: a- Meperidine b- Fentanyl c- Methadone d- tramadol B- Mixed Agonist-Antagonist Narcotic Analgesics: a- Pentazocine b- Buprenorphine c- Nalbuphine d- Butorphanol اسم ورقم المقرر – Course Name and No. 7/14/2019

opioids Derived from the dried milky juice  exuded by incised seed capsules of a species of poppy, Papaver somniferum, Mimic action of endogenous opioids; Endorphins. Act on endogenous opioid receptors mu, delta, kappa, sigma اسم ورقم المقرر – Course Name and No. 7/14/2019

Morphine -pharmacokinetics 1- Absorption: a- well absorbed Orally, But 1st pass hepatic metabolism. b- Better absorbed after S.C. & I.M. injections. c- In shock (Slow Diluted I.V. injection). 2- Distribution: All over the body & passes B.B.B.& Placental Barrier: a- During pregnancy (Addiction of Fetus). b- During labor Neonatal asphyxia اسم ورقم المقرر – Course Name and No. 7/14/2019

Morphine -pharmacokinetics 3- Metabolism: a- Extensive Hepatic First Pass Metabolism. b- Conjugated with Glucuronic acid (Deficient in extremities of age) and converted into: - Morphine-6-Glucuronide More Active than Morphine. - Morphine-3-Glucuronide Inactive. 4- Excretion: a- Saliva. b- Stomach Stomach wash in all cases of poisoning. c- Bile Enterohepatic circulation. d- Milk Affect suckling baby. e- Urine Major route of excretion. 5- t ½ : (2 – 3 hours) & Duration of action (6 – 8 hours). اسم ورقم المقرر – Course Name and No. 7/14/2019

Morphine –pharmacodynamics mechanism of action Morphine stimulates specific Opioid = Opiate receptors in CNS & Periphery. Types of Opiate (Opioid) Receptors: (CNS_ Smooth ms) 1- Mu (1 & 2): Analgesia (Spinal & Supra-spinal), Euphoria, Sedation, Dependence, inhibition of R.C., Miosis & Constipation. 2-Kappa (1, 2 & 3): بس أضعفAnalgesia (Spinal & Supra-spinal), Dysphoria, Less inhibition of R.C. & Less Miosis. 3- Delta (1 & 2): Analgesia (Spinal mainly) & Constipation. 4- Sigma: Dysphoria & Hallucination.  اسم ورقم المقرر – Course Name and No. 7/14/2019

Morphine –pharmacodynamics mechanism of action Mechanism of Opiate (Opioid) Receptors: 1- They are membrane receptors coupled to Gi-protein: 2- Inhibit Adenylate cyclase Decrease cAMP. 3- Open K+-Channel (postsynaptic) Hyperpolarization. 4- Block Ca2+-Channel (presynaptic) Decrease Release of transmitters & mediators. اسم ورقم المقرر – Course Name and No. 7/14/2019

Pharmacological Actions of Morphine 1- CNS: depression & stimulation of certain parts: - - - - - - - - - - - - - - - - - - - - + + + + + + + + + + + + + 1-Analgesia all types of pain except itching 1-Euphoria 2-Narcosis 2-Excitation in some females & Animals 3- R.C. : Hypoventilation & Hypoxia 3- 3rd Cranial nerve Miosis (PPP) 4- Cough center : Antitussive 4- Vagal center (CIC) Bradycardia 5- V.M.C. : Hypotension 5- C.T.Z. (Small dose) Nausea & vomiting 6- H.R.C. : Hypothermia 6- A.D.H. 7- Hormones: ACTH, FSH & LH. 8- Lowers seizure threshold Epilepsy اسم ورقم المقرر – Course Name and No. 7/14/2019

Analgesic effect of Morphine: a- Effective in all types of pain especially Deep visceral pain. b- Not effective in itching. Morphine is a Histamine- releaser. c- Morphine affects pain perception & integration: - Inhibits Release of Substance-P & Glutamate in Substantia gelatenosa Inhibits pain transmission. - Sensory cortex Inhibits Pain perception. - Frontal cortex Alters psychological reaction to pain Indifference. اسم ورقم المقرر – Course Name and No. 7/14/2019

Pharmacological Actions of Morphine 2- A. N. S.: Sympathetic (inhibit VMC) & Parasympathetic (stimulate CIC). 3- Eye Miosis Pin Point Pupil (PPP) 4-C. V. S. Bradycardia & Hypotension a- Inhibit VMC & Stimulate Vagal center (CIC) b- Direct Venodilator effect. c- Release of Histamine V.D. اسم ورقم المقرر – Course Name and No. 7/14/2019

Pharmacological Actions of Morphine 5- Respiratory System: - Depresses R.C. - Depresses Cough center Central Antitussive. - Histamine release Bronchospasm especially in susceptible asthmatic patients. 6- Smooth muscle Spasmogenic effect (except Bv). 7- G. I. T. : contract circular muscle and relax longitudinal ms. a- Spasmogenic decreases Propulsive peristalsis & increases Segmental contraction Constipation b- Decrease All secretions (except salivary). اسم ورقم المقرر – Course Name and No. 7/14/2019

Pharmacological Actions of Morphine 8- Biliary Tract Spasmogenic Spasm of biliary duct &Sphincter of Oddi Increase Intrabiliary pressure. - Avoid after cholecystectomy. - In biliary colic Add Atropine to Morphine 9- Urinary Tract Spasmogenic Spasm of Ureter In renal colic Add Atropine to Morphine. Spasm of sphincters Retention of Urine Oliguria Increased A.D.H. 10- Uterus: No effect but Morphine passes placental barrier Neonatal asphyxia. 11- Skin: Histamine release Itching اسم ورقم المقرر – Course Name and No. 7/14/2019

Therapeutic Uses of Morphine 1- Pain : Analgesic in Severe Visceral Pain except itching. a- Cardiac pain e.g. Myocardial infarction b- Cancer pain especially in terminal stages c- Colic: Add Atropine in Biliary & Renal colic. d- Bone Fractures (Except Skull, Morphine is contraindicated in Head injury). e- Postoperative: Except Biliary. 2- pulmonary Edema due to Acute Left Ventricular Failure: a- Venodilator. b- Sedation c- Slow respiration. 3- Primary Neurogenic shock. 4- Preanesthetic medication. اسم ورقم المقرر – Course Name and No. 7/14/2019

Contraindications of Morphine: 1- Head injury: a- Miosis Interfere with proper diagnosis. 2- Increased Intra-cranial tension. 3- Epilepsy. 4- Respiratory diseases e.g. Asthma & C.O.P.D. 5- Acute abdomen: Morphine Interfere with proper diagnosis. 6- Pregnancy & Labor. 7- Liver disease (Deficient metabolism) 8- Extremities of age (Deficient metabolism) 10- Alone in biliary & renal colic. 11- Allergy to morphine. اسم ورقم المقرر – Course Name and No. 7/14/2019

Adverse Effects of Morphine: 1- Interfere with proper diagnosis of Head injury & Acute abdomen. 2- Inhibition of Respiration 3- P.P.P. (pin point pupil) 4- Nausea & Vomiting 5- Bronchospasm 6- Constipation 7- Retention of urine 8- Neonatal asphyxia 9- Itching 10- Tolerance (all effects except miosis & constipation) 11- Acute Morphine Poisoning. 12- chronic Toxicity (addiction) اسم ورقم المقرر – Course Name and No. 7/14/2019

Acute Morphine Poisoning a- Manifestations: Coma + PPP + Hypoventilation, Hypoxia, Hypotension & Hypothermia. b- Cause of Death : Respiratory Failure. c- Treatment: - Artificial respiration. - Stomach wash in Every case even after parenteral poisoning. Use K-Permanganate + Charcoal + MgSO4. Specific Morphine Antagonists e.g. Naloxone (0.4 mg I.V.). اسم ورقم المقرر – Course Name and No. 7/14/2019

Opioid antidote (antagonist): naloxone Pure antagonist. More selective on mu receptors. Therapeutic uses: a- Acute Morphine poisoning ( 0.4 mg I.V.) to be repeated due to Short t ½ = 1 hour b- Opioid-induced Neonatal asphyxia Mother (IM) or Neonate (Intraumbilical). c- Diagnosis of Opioid addiction S.C. Withdrawal manifestations e.g. Mydriasis اسم ورقم المقرر – Course Name and No. 7/14/2019

Other Opioids: Methadone 1- As potent as Morphine. 2- Longer t ½ = 1 – 2 days Less withdrawal manifestations. 3- Local anesthetic effect. 4- Uses: a- Analgesic in Severe visceral pain e.g. Terminal cancer. b- To substitute Morphine & Heroin during their withdrawaL. اسم ورقم المقرر – Course Name and No. 7/14/2019

Other opiods: Meperidine ( Pethidine) Synthetic Strong agonist : Morphine-Like + Atropine- Like ( No P.P.P. may cause Mydriasis, No Constipation, No Narcosis (No Hypnosis). Uses: 1- Severe Visceral pain e.g. Myocardial infarction. 2- Alone in Biliary & Renal colic. (single use is allowed) 3- Pre-anesthetic medication (Better than Morphine). 4- Obstetric Analgesia. اسم ورقم المقرر – Course Name and No. 7/14/2019

Other Opioids: Fentanyl 1-Synthetic drug Derivative of Meperidine. 2- Strong Mu receptor Agonist Strong Analgesic 80 Times > Morphine 3- High Lipid solubility: I.V. Rapid Onset + Short duration 4- Used as I.V. Anesthesia: but induce vomiting if used alone. 5- Used In cancer pain as transdermal patches. 6- Adverse Effects (Vomiting, Marked inhibition of R.C. & increase Muscle tone & Truncal rigidity) اسم ورقم المقرر – Course Name and No. 7/14/2019

Other Opioids: Codeine (Methyl-Morphine) Phenanthrene Opium Alkaloid. Therapeutic Uses: a- Antitussive (15-30 mg at bed time) in Dry useless cough & Dangerous cough e.g. Postoperative. b- Analgesic (10 mg) in Mild & Moderate visceral pain + Aspirin & Paracetamol. اسم ورقم المقرر – Course Name and No. 7/14/2019

اسم ورقم المقرر – Course Name and No. 7/14/2019