pharma jangi

• Dr. Jangi Shawkat Salai


  MBChB, MD, MSc. PhD., Consultant Oncologist and Internist, Rizgary Teaching Hospital
• Drugs Used in the Treatment of Pain

  2024
• Pain


  An unpleasant sensory and emotional experience arising from actual or potential tissue damage
• Nociception


  A physiological response by which pain is perceived, it started first in the nociceptors
• Sensory Nervous System: Pain Pathways

  1. Peripheral Receptors (Nociceptors)

  2. C-fibers (unmyelinated)

  3. Aδ-fibers (thinly myelinated)

  4. Spinothalamic Tracts (Dorsal Root Ganglion)

  5. Cortical Neurons

  6. Thalamus

  7. Brainstem

  8. Trigeminal Ganglia
• Noxious Stimuli


  Voltage gated sodium channels, Glutamate, Substance P
• The management of pain is a multidisciplinary team effort involving physicians, psychologists, nurses, and physical therapists
• TREATMENT OF PAIN OPTIONS


  • Physical therapy
  • Medications
  • Acetaminophine (Paracetamol)
  • Nonsteroidal anti-inflammatory medications (NSAID)
  • Narcotic medications
  • Steroid medications
  • Antidepressant and anticonvulsant medications
  • Nerve blocks
  • Implantable devices
  • Aneasthesia
  • Surgery

  
• WHO Analgesic step ladder

  • Step 1: Non opioid (+ or-) adjuvant
  • Step 2: Weak opioid (+) Non opioid (+ or-) adjuvant
  • Step 3: Strong opioid(adjuvant
  • Step 4: Anesthetic/Neurosurgical Interventions

  
• Acetaminophen (PARACETAMOL)


  • Common in OTC (Over The Counter) products because of its relative lack of unwanted side effects
  • One of the most common ingestions
  • It has analgesic, antipyretic and very weak anti-inflammatory

  
• Mechanism of action of Acetaminophen


  • Inhibition of prostaglandin synthesis in the brain by inhibition of a recently discovered isoform COX-3
  • It also acts partially by activation of descending serotogenic pain-inhibiting pathways
  • It does not affect platelet function
• Uses of Paracetamol


  • To treat mild to moderate pain such as headache and dysmenorrhoea particularly in patients who should avoid aspirine because of gastric intolerance, bleeding tendency or allergy, or because the age of the patient is less than 12 years
  • The usual dose is 0.5-1 gm every 4-6 h
• Pharmacokinetics of Acetaminophen


  • Rapidly absorbed from GI tract
  • Peak concentrations 1-2 hrs (tabs)
  • 10% bound to plasma proteins
  • Half-life is 2-3 hrs, in overdose can be 12 hours
  • Inactivated in the liver by conjugation as Glucoronide and Sulfate (sulphate)
  • N-acetyl-p-benzoquinone imine (NABQI) is a highly reactive minor metabolite that produce from paracetamol. It is inactivated by Glutathione. But the level of glutathione is limited in the liver so in overdose situation the amount of NABQI is increased and leads to cell death in the liver and kidney
• Acetaminophen Overdose


  • Taking 150mg/kg body weight (10-20 tab of 500mg) induces sever hepato-cellular damage and renal tubular necrosis
  • Those who are at risk: Who takes other drugs and alcohol that induces liver enzymes, so more NABQI will be formed, Malnourished patients (glutathione depletion)
• NSAIDs


  They have three major actions (anti-inflammatory, antipyretic and analgesic), all of which are due mainly to the inhibition of arachidonic acid cyclo-oxygenase in inflammatory cells (the COX-2 isoenzyme), and the resultant decrease in prostanoid synthesis
• Mode of Action of NSAIDs

  1. They block Prostaglandin (PG) synthesis through inhibition of the Enzyme CYCLO-OXYGENASE (COX)

  2. COX catalyses the synthesis of PG and Thromboxane (TBX) from arachidonic acid
• COX-1


  Constantly expressed in most cell types and has a maintenance role in the body, being concerned with tissue homeostasis
• COX-2


  Induced (increased in amount and activity) when inflammatory cells are activated (by cytokines like IL-1 and TNF-α) and it produces PG
• The useful anti-inflammatory action of NSAID is owed to inhibition of COX-2
• Many adverse effects are related to inhibition of COX-1, particularly on the GIT (due to loss of cytoprotective mucosal PGI2 and PGF2α)
• The development of selective COX-2 inhibitors assumed importance
• Non selective COX Inhibitors

  • Salicylic acids
  • Acetic acids
  • Fenamic acid
  • Propionic acids
  • Enolic acids
  • Oxicams
• Non selective COX Inhibitors

  • Aspirin
  • Indomethacin, Diclofenac, Etodolac, Sulindac, Ketorolac
  • Mefenamic acid
  • Naproxen, Ibuprofen,, Fenbufen
  • Ketoprofen, Tiaprofenic acid
  • Phenylbutazone, Azapropazone
  • Piroxicam, Meloxicam, Tenoxicam
• Selective COX-2 Inhibitors


  • Celecoxib
  • Rofecoxib
  • Etoricoxib
• Clinical uses of the NSAIDs

  • For anti-inflammatory effects in chronic or acute inflammatory conditions (e.g. rheumatoid arthritis and related connective tissue disorders, gout and soft tissue diseases)
  • To lower temperature. Paracetamol is preferred because it lacks gastrointestinal side-effects and, unlike aspirin, has not been associated with Reye's syndrome in children
  • There is substantial individual variation in clinical response to NSAIDs and considerable unpredictable patient preference for one drug rather than another

  
• Pharmacokinetics of NSAIDs


  • Absorbed almost completely from the GIT
  • Tend no to undergo first-pass elimination
  • Highly bound to plasma albumin
  • Have small volume of distribution
  • Their t1\2 values in plasma are either short (1-5 h) or long (10-60 h)
  • The vast majority are weak acidic drugs that localize pereferentially in the synovial tissue of inflammed joints
• Drug Interactions of NSAIDs

  • ACE inhibitors and receptor blockers: risk of renal impairment and hyperkalemia
  • Anticoagulant and antiplatelets (clopidogrel and ticlopidine) agents: increased risk of GIT bleeding, inhibiting the metabolism of warfarin and increase its effect
  • Oral hypoglycemic agents: inhibit the metabolism and increase intensity and duration of action
  • Antihypertensives: their effect is lessened due to sodium retention by inhibition of renal prostaglandin formation
  • Diuretics: NSAIDs cause sodium retention and reduce diuretic and antihypertensive efficacy; risk of hyperkalemia with potasium-sparing diuretics; increased nephrotoxicity risk with indomethacin and ketorolac
• Compound preparations of NSAIDs are not better than single drug in therapeutic effect, maybe more adverse reactions, preferable to use single drug
• Narcotic Analgesics (Opioids)


  Opium is extracted from poppy seeds (Paper somniforum) and has been used for thousands of years to produce euphoria, analgesia, sedation, relief from diarrhea, and cough suppression
• Mechanism of action of Opioids

  1. Activation of peripheral nociceptive fibers causes release of substance P and other pain-signaling neurotransmitters from nerve terminals in the dorsal horn of the spinal cord

  2. Release of pain-signaling neurotransmitters is regulated by endogenous endorphins or by exogenous opioide agonists by acting presynaptically to inhibit substance P release, causing analgesia
• Short-acting opioids


  • codeine
  • Tramadol
  • hydromorphone
  • Immediate-release morphine
  • Immediate-release oxycodone
  • Immediate-release tramadol
• Long-acting opioids


  • Modifies release tramadol
  • Methadone
  • Modified-release hydromorphone
  • Modified-release morphine
  • Modified-release oxycodone
  • Transdermal buprenorphine
  • Transdermal fentanyl
• Strong Agonists


  • Morphine
  • Meperidine
  • Methadone
  • Fentanyl
  • Sufentanyl
  • Heroin
  • Oxycodone and Oxymorphone
• Mixed Agonist Antagonist and Partial Agonists

  • Pentazocine
  • Buprenorphine
  • Nalbphine and Butorphanol
• Other Analgesics


  • Tramadol
  • Tapentadol

  
• Pharmacological Effects of Opioids

  • Sedation and anxiolysis: Drowsiness and lethargy, Apathy, Cognitive impairment, Sense of tranquility
  • Depression of respiration: Main cause of death from opioid overdose, Combination of opioids and alcohol is especially dangerous
  • Cough suppression: Opioids suppress the "cough center" in the brain
  • Pupillary constriction: Pupillary constriction in the presence of analgesics is characteristic of opioid use
  • Nausea and vomiting: Stimulation of receptors in an area of the medulla called the chemoreceptor trigger zone causes nausea and vomiting, Unpleasant side effect, but not life threatening
  • Gastrointestinal symptoms: Opioids relieve diarrhea as a result of their direct actions on the intestines
  • Other effects: Opioids can release histamines causing itching or more severe allergic reactions including bronchoconstriction, Opioids can affect white blood cell function and immune function

  
• Opioids Antagonists


  • Naloxone
  • Naltrexone
• Opiate Withdrawal Syndrome


  • Stage I up to 8 Hrs: Anxiety, Drg craving
  • Stage II 8-24Hrs: Anxiety, Insomnia, GI disturbance, Rhinorrhea, Mydriasis, Diaphoresis
  • Stage III up to 72 Hrs: Tachycardia, Nasea and vomiting, Hypertension, Diarrhea, Fever and Chills, Tremors, Seizure and Muscle spasms