Unit4_Pharm

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Pain and Inflammation:

Pain and Inflammation

Categorizing Pain:

Categorizing Pain Duration: Acute- < 6 months Chronic- > 6 months – not just an extension of acute Origination: Nociceptive- tissue injury, arthritis, etc Neuropathic – diabetic neuropathy, RSD, phantom limb, etc

Pain and Inflammation:

Pain and Inflammation Peripheral Pain Pathways Injured tissue (and ischemia) releases several chemicals that trigger pain 1. bradykinin (most potent) 2. prostaglandins 3. histamine 4. capsaicin These bind nociceptors (pain neurons) that relay information to the spinal cord

CNS Pain Neurotransmitters:

CNS Pain Neurotransmitters Excitatory Neurotransmitters: 1. Glutamate 2. Substance P 3. Neurokinin (A and B) Inhibitory Neurotransmitters Serotonin Norepinephrine GABA Opiates- endorphins, enkephalins , dynorphins

Pain Pathways:

Pain Pathways

Analgesic Pathways:

Analgesic Pathways

Analgesic Pathways: Midbrain and Brainstem :

Analgesic Pathways: Midbrain and Brainstem Opiate neurons: Inhibit GABA Inhibition of GABA releases: 1. NE neurons 2. Serotonin neurons Opiate neurons stimulated by: 1. Ascending fibers ( spinothalamic tract) 2. Descending fibers from other nucleii

Central Pain Receptors:

Central Pain Receptors

Opioid Analgesics :

Opioid Analgesics Receptor Types in brain and spinal cord: mu ( μ ) – analgesia, euphoria, respiratory depression, sedation, constipation delta ( δ ) – analgesia, euphoria, respiratory depression kappa ( κ ) – analgesia without euphoria, sedation, constipation

Opioid Analgesics :

Opioid Analgesics Classification of Drugs: Strong Agonists: morphine, meperidine (Demerol) , methadone ( Dolophine ) fentanyl ( Duragesic ), hydromorphone ( Dilaudid ) - mostly Mu receptor 2. Mild to Moderate Agonists: Codeine, hydrocodone ( Hycodan ), oxycodone ( Oxycontin ), Percocet ( oxycodone + acetominophen ) Vicodin ( hydrocodone + acetominophen ) Percodan ( hydrocodone + aspirin) - not as efficacious as strong agonists

Opioid Analgesics :

Opioid Analgesics Classification of Drugs: Mixed Agonists/Antagonists: butorphanol ( Stadol ) , pentazocine ( Talwin ), nalbuphine ( Nubain ) - full agonist at Kappa, partial agonist at Mu. Antagonists: naloxone ( Narcan ) , nalmefene ( Revex ), naltrexone ( ReVia ) Miscellaneous: Tramadol ( Ultram ) - mu, blocks reuptake NE, 5-HT

Opioid Analgesics :

Opioid Analgesics Mechanism of Action: Presynaptic - G protein-block Ca++ Postsynaptic - G protein-open K+

Opioid Analgesics :

Opioid Analgesics Generalized Effects: CNS - analgesia, sedation - cough suppression - respiratory depression - nausea, vomiting - meiosis - convulsions Mixed agonists/antagonists do not produce respiratory depression or euphoria but may cause hallucinations, nightmares, and anxiety

Opioid Analgesics :

Opioid Analgesics Generalized Effects: Peripheral - constipation - hypotension Tolerance: GI, Meiosis not affected Narcotic Withdrawal - fever, sweating, shivering - muscle aches, weakness, fatigue - nausea, vomiting, anorexia, tachycardia

Case Study:

Case Study The patient is a 45 year old female with a 2 yr history of pain over the left anterior pelvic region. She had previously had multiple surgeries in that area including radiation for cervical cancer, hysterectomy, appendectomy, a hernia, and an infected lymph node. She rated her pain level at 6, with episodes at level 10. She was also being treated for hypertension, bipolar disorder, and smoking cessation. Her medications included Vasotec (for hypertension), Seroquel for bipolar disorder, Ultraam for pain, and Welbutrin for smoking cessation. The therapist wrote down the side effects of the patients medications and altered her therapy to include 1. therapy two hours after administration of Ultraam, 2. noting behavior and mood, 3. assistance during positional changes, and 4. monitoring of vital signs. Side effects of the drugs included: Vasotec – orthostatic hypotension, tachycardia, dry cough, angioedema of the face and extremities Wellbutrin – agitation, dry mouth, constipation, tremor, tachycardia, seizure (especially when undergoing withdrawel of alcohol and/or sedatives Seroquel – orthostatic hypotension, seizure, tardive dyskinesia, impairment of motor activities, sedation Ultraam – constipation, orthostatic hypotension, sedation, seizures, especially in pts taking SSRI’s, MAO inhibitors, tricyclic antidepressants, other opioids, neuroleptics, or other drugs that reduce the seizure threshold.

Treatment of Pain:

Treatment of Pain 2. Atypical Analgesics Anti-Seizure Medications ( Neurontin , Tegretol , etc) Interfere with nerve transmission A. Gabapentin ( Neurontin ) – initially designed as GABA agonist - latest research shows binds Ca++ channel to block Ca++ entry - Side effects: - dizziness, fatigue, ataxia - impotence, blurred vision, dry mouth ( anticholinergic ) - in children: agression , emotional lability , hyperkinesia Also used in MS tremors, bipolar, diabetic neropathy and other investigational conditions

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation Atypical Analgesics B. Pregabalin ( Lyrica ) - binds Ca++ channel to block Ca++ entry - side effects similar to gabapentin C. Carbamazepine ( Tegretol ) - blocks polysynaptic reflexes via Na channel mechanism Side effects: - dizziness, drowsiness, Water retention - Anticholinergic - nausea, constipation, vomiting Also used in bipolar and schizophrenia, restless leg syndrome, diabetic neuropathy, and other investigational conditions

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation Atypical Analgesics: C. Tricyclic Antidepressants Amitriptyline ( Elavil ) , etc - prevent reuptake of NE, probably serotonin Side effects: - transient sedation - orthostatic hypotension - arrhythmias - anticholinergic D. SSRI – Paroxetine (Paxil)

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation 3. Non-Opioid Analgesics NSAID’s Salicylates: - Aspirin, Salicylic Acid Inhibit COX I and COX II enzymes Applications as: 1. analgesic 2. anti-inflammatory 3. antipyretic 4. anticoagulant

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation Side Effects: GI (pain, peptic ulcer?) Low doses increase uric acid (gout?) Reye’s syndrome in children with viral infection (leads to lethargy, coma, death) May exacerbate renal and/or hepatic disease Reduced tissue healing High doses cause tinnitus, hearing deficits, vertigo, increased ventilation – resp. alkalosis followed by acidosis at higher levels Sensitivity in asthmatics, allergies

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation NSAID’s Non- Salicylates Diclofenac Voltaren more potent than Naproxen Diflunisal Dolobid 3-4 times more potent than aspirin but lacks antipyretic Ibuprofen Motrin, others fewer GI than aspirin Indomethacin Indocin relatively high incidence of side effects Ketorolac Toradol IM injxn provides post surgical analgesia equivalent to opiates Meclofenamate Meclomen no advantage or disadvantage compared to others Naproxen Anaprox, Naprosyn similar to Ibuprofen Nabumetone Relafen fewer side effects than most NSAIDs Piroxicam Feldene long half life (45 hours). better tolerated than aspririn Tolmetin Tolectin short half-life (1 hr)

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation B. COX II Inhibitors Celecoxib (Celebrex) , Bextra , Rofecoxib ( Vioxx ) - reduce pain and inflammation - fewer side effects than other NSAIDs - may increase the risk of upper respiratory infection - some GI problems (diarrhea, heartburn, stomach cramps, bleeding) but fewer incidence than others COX II thought to be important in production of Omega-3 fatty acids, which are cardioprotective against the formation of blood clots and atherosclerosis.

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation C. Acetominophen : Antipyretic, analgesic No anti-inflammatory or anticoagulant effects May work primarily on central prostaglandins Side effects - liver toxicity - do not exceed dosage

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation 4. Steroids ( glucocorticoids ): Generic Name Trade Name Clinical Applications Short acting Cortisone Hydrocortisone Cortone Cortel anti-inflammatory anti-inflammatory Intermediate acting Prednisone Prednisolone Triamcinolone Deltasone Delta-Cortel Aristocort more potent than hydrocortisone, used in muscle inflamm, asthma more potent than hydrocortisone, used in asthma, MS much more potent than hydrocortisone Long acting Dexamethasone Decadron anit -inflammatory also used to control cerebral edema and intercranial pressure

Treatment of Pain and Inflammation:

Treatment of Pain and Inflammation Steroids: Side effects: skin breakdown muscle breakdown osteoporosis cataracts elevated blood glucose mood swings and psychosis hypertension adrenal insufficiency Stages of Tissue Healing Inflammatory/clotting Organization Regeneration

Rheumatoid Arthritis:

Rheumatoid Arthritis Chronic, Systemic Disorder- synovitis and destruction of Articular tissue- Autoimmune Basis of joint destruction Pain, Stiffness, inflammation of small synovial joints Progressive, often intermittent Criteria: 1. Morning stiffness >1 hr 2. Involvement of 3 or more joints 3. Arthritis of hand joints 4. Symmetric arthritis 5. Subcutaneous nodules over joints 6. Serum rheumatoid factor 7. Radiographic changes

Treatment of Rheumatoid Arthritis:

Treatment of Rheumatoid Arthritis NSAIDs CorticoSteroids (4x /yr inection/joint) or oral DMARDs (disease modifiying antirheumatic drugs) - Inhibit immune system (t and B lymphocytes, cytokines, etc) - retard or stop progression

Treatment of Rheumatoid Arthritis:

Treatment of Rheumatoid Arthritis DMARDs (disease modifiying antirheumatic drugs) Antimalarials - inhibit T cell function - Azathioprine ( Imuran ) Side Effects: retinal toxicity renal toxicity 2. Gold compounds - inhibit T cell growth and proliferation - inhibit macrophages Side effects: - GI distress - proteinurea , conjuctivitis

Treatment of Rheumatoid Arthritis:

Treatment of Rheumatoid Arthritis DMARDs (disease modifiying antirheumatic drugs) 3. Tumor Necrosis Factor (TNF) inhibitors - inhbit TNF (which promotes inflammation) - Enterecept ( Enbrel ), Ifliximab ( Remicade ), Adalimumab ( Humira ) - I.v . - 2/wk, biweekly, slow infusion/8wks, respectively Side Effects: upper respiratory tract infections sepsis lymphoma demylenating disorders mimic MS Others; - multiple effects on immune system- some antineoplastic - Methotrexate ( Rheumatrex , etc) - inhibit DNA/RNA- blocks proliferation of immune cells Side effects: GI pulmonary, hematologic disorders liver dysfunction hair loss

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