Lev_wk5_ CNS L11 Analgesics PDF Lecture Notes

DRUGS Acting on the Central Nervous System (CNS) Date: 09/23/2024 Lecture 11: Analgesics Anait S. Levenson, M.D., Ph.D. Office Hours: By Appointment (send me an email) Email: [email protected] Learning Objectives: ▪ CNS Drugs ✓ CNS Pharmacology and Drug Development ✓ CNS...

DRUGS Acting on the Central Nervous System (CNS) Date: 09/23/2024 Lecture 11: Analgesics Anait S. Levenson, M.D., Ph.D. Office Hours: By Appointment (send me an email) Email: [email protected] Learning Objectives: ▪ CNS Drugs ✓ CNS Pharmacology and Drug Development ✓ CNS Drugs: Therapeutic Importance ✓ Drug Action in CNS ✓ Sites and Mechanisms of Drug Action ✓ Agonists and Antagonists ✓ The Blood-Brain Barrier (BBB) ▪ Analgesics ✓ Types of Pain and Pain Processing System ✓ Sites of Pharmacological Intervention ✓ Opioids: Classification and Uses ✓ Opioids: Mechanisms of Action (Receptors) ✓ Opioids: Pharmacological Effects (Agonists and Antagonists) ✓ Opioids: Adverse Effects ✓ NMDA-Receptor Antagonists as Analgesics ✓ Non-Opioid Analgesic Agents  Drugs Action in CNS CNS Pharmacology: how drugs alter brain activity and offset pathology NeuroPharmacology: how drugs act on neurons at cellular/molecular level PsychoPharmacology: how drugs modify behavior, perception and affect a thought  Developments of CNS Drugs In the last three decades, dramatic advances have been made in the CNS pharmacology Regrettably, recent developments are not that good: large pharm companies severely restricting neuropsychiatric drug development efforts citing ▪ Low chances of successful CNS drug applications CNS drugs Other drugs Clinical use 8.2% 15% Regulatory approval 1.9 years 1.2 years Phase II & III development 8.1 years < 6 years Phase III success of candidate drugs 46% 66%  CNS Drugs Drug: A substance used to prevent or treat conditions associated with stimulation or depression of the brain associated with both mental and physical processes Therapeutic Importance: Relieve pain and fever Suppress disorders of movement or seizures Induce sleep or arousal Reduce desire to eat Inhibit motion sickness Treat anxiety, mania, depression Prescription Drug: A drug that is limited to use under the supervision of a veterinarian because of potential danger, difficulty of administration, or other indications Controlled Drug: A drug that has a potential for abuse or dependence; classified into schedules according to its level of abuse potential  Drug Action in CNS Drugs act like neurotransmitters, transferring electro-chemical messages between neurons in the brain and spinal cord Drugs can speed - up the transfer: CNS stimulants Drugs can slow - down the transfer: CNS depressants CNS drugs act on specific receptors that modulate synaptic transmission Some nonspecific agents (alcohol, anesthetics) have non-receptor-mediated actions that result in alterations in synaptic transmission  Effects of CNS Drugs Drugs can alter the function of CNS to provide: Analgesia: narcotic (opioids) and non-narcotic (NSAIDs & NMDA receptor antagonists) Tranquilization (sedation) effects Anticonvulsant effects Antiemetic effects Anxiolytic, sedative, and hypnotic General anesthetic effects Behavior changes: CNS stimulants CNS Depressants (antidepressants, anxiolytic drugs)  CNS Drugs Actions: Pharmacokinetics Pharmacodynamics Drug distribution Target tissues and stimulation (CNS: depression or stimulation) Agonists & Antagonists Agonists: Bind to and stimulate target tissue (CNS) Antagonists: Bind to target tissue but don’t stimulate  Sites for Drug Action 1 1. Action potential in presynaptic fiber 2. Synthesis of neurotransmitter (NT) 3. Storage 4. Metabolism 5. Release 2 4 3 6. Reuptake into the presynaptic neuron or glial cell 6 7. Degradation 5 6 8. Receptor for the NT 7 9. Receptor-induced increase/decrease in ionic conductance 10 10. Retrograde signaling 8 9  Targets for Drug Action Main targets for neuroactive drugs: ❖ Ion channels ❖ Receptors ❖ Enzymes ❖ Transport proteins Most of the targets occur in several different molecular isoforms, giving rise to subtle differences in function and pharmacology Slowly developing secondary responses to the primary interaction of the drug with its target are often important (delayed efficacy of antidepressants, tolerance and dependency with opioids)  The Blood-Brain Barrier (BBB) The term BBB denotes the highly-selective barrier separating the brain tissue from the blood circulation The main function is the protection of CNS against toxins, pathogens and even NTs (glutamate) The barrier consists of a continuous layer of endothelial cells joined by tight junctions and surrounded by astrocytes Canine Brain  Drugs and BBB Circulating drugs must cross BBB in order to gain access to the neurons of the brain DRUGS: ❖ Small in molecular size (CO2, caffeine, nicotine, heroin) ❖ Lipid-soluble (lipophilic) ❖ Poorly bound to protein ❖ Non-ionized at the pH of cerebrospinal fluid (CSF) ❖ Diffusion or carrier-mediated transfer (L-DOPA) The BBB tends to increase in permeability in the presence of inflammation or at the site of tumor The BBB is poorly developed in neonates; hence, chemicals can easily gain access to the neonatal brain  Analgesics Pain: is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain has been recognized for its contribution to morbidity and mortality Analgesic drugs are used to inhibit pain processing at different levels Goal of therapy: reduction of transduction, transmission, modulation, and perception of pain  Classes of Pain DURATION LOCATION Acute: sudden in onset, resolves in 1-3 days. Visceral: abdominal or thoracic cavity initiates from traumatic insult well controlled with an analgesic Somatic: musculoskeletal damage Chronic: slow in onset, persists for weeks/months Neuropathic: damage affecting the somatosensory altered homeostasis, long-term distress nervous system combination of potent analgesics  Pain Processing System 4 3 2 1 Pharmacological Intervention of Pain Processing 4 3 Tricyclic antidepressants Cholinesterase inhibitors Phenothiazines Anticonvulsants 2 1 2 major classes: ▪ Opioids ▪ Non-opioids (NSAIDs)  Opioids Derivatives of opium from poppy plant Opium: extract from the white milky sap of unripe bulbs of the poppy plant contains morphine and codeine Active chemical compounds in opium are Morphine and Codeine Analgesic, anesthetic, and sedative Hypnotic, analgesic, cough suppressant  Opioids and Opiates Opiates: narcotic drugs derived from opium poppy or semi-synthetic derivatives with narcotic properties. Natural or not natural. Representatives: opium, morphine, codeine, heroin (3x > potent) Opioids: fully-synthetic or semi-synthetic narcotic drugs that mimic the natural opiate. Not found in nature. Representatives: hydrocodone, oxycodone (oxymorphone), fentanyl, tramadol Endogenous opioid neuropeptides: endorphins, enkephalins, dynorphins are release by the neuroendocrine cells to activate receptors  Opioids ▪ Controlled substances except for antagonists and certain partial agonists ▪ Administration: IV, IM, SC, oral, rectal, transdermal, subarachnoid, and epidural ▪ PK: Metabolized in the liver and excreted in the urine ❖ Cats are deficient in the metabolic pathway, the t1/2 of most opioids in cats may be prolonged ❖ The elimination t1/2 is 1 hr in dogs, 3 hr in cats, and 1.5 hr in horses ▪ Wide margin of safety (animals don’t ask for prescription or go to black market)  Opioids ▪ Produce analgesia and sedation ▪ Anesthetic induction when combined with other drugs ▪ Classified as full agonists, partial agonists, mixed agonist-antagonist Uses: Analgesia ▪ Prevent and treat postoperative pain ▪ Used with tranquilizers to produce neuroleptanalgesia Pre-anesthetic ▪ agonists, partial agonists, or mix agonist-antagonists ▪ May be used alone or in combination with - Tranquilizers - Anticholinergics  Opioids Mimic endogenous opioid peptides, such as endorphins, dynorphins, encephalins, which are naturally made in our bodies Pharmacological effects: Analgesia and sedation but they depend on many factors Dogs: sedation narcosis Cats, horses, and ruminants: may cause CNS stimulation bizarre behavior patterns or dysphoria  Opioids Mechanism of action (MOA): ▪ Bind to the receptors in the brain and spinal cord and mediate the inhibition of neurotransmission and endocrine secretion ▪ Stimulate opioid receptors [mu (µ), kappa (κ), and delta (Δ)] ▪ Each opioid has a different action at each receptor ▪ Receptors are present in numerous cells/ tissues (brain, spinal cord, on peripheral neurons, and digestive tract )  Opioid Receptors All opioid receptors are G-coupled receptors that mediate the inhibition of neurotransmission and endocrine secretion The receptors are present in numerous cells/tissues including brain, spinal cord, GI tract, urinary tract, and vas deferens (sperm duct) in male reproductive system Three- receptor subtypes: µ-receptors: brain, spinal cord Spinal and supraspinal analgesia, euphoria, mild sedation, miosis, respiratory depression, chemical dependence, inhibition of Ach and dopamine release, and a decrease in GI motility κ-receptors: cerebral cortex, spinal cord and other brain regions Spinal and supraspinal analgesia, sedation, dysphoria, diuresis, and miosis Δ-receptors: limbic system, cerebral cortex, and spinal cord Spinal and supraspinal analgesia, inhibition of dopamine release, and cardiovascular depression  Classification of Commonly Used Opioids Agonists Morphine, hydromorphone, oxymorphone (10 times >), fentanyl (75-125 times > potent), tramadol ( potent vs fentanyl) (elephants) Butorphanol P +++ 0 Dogs, cats, horses Keep analgesia, reversal of sedation & respiratory depression Buprenorphine P -- 0 Small animals Analgesic Nalbuphine -- ++ 0 Dogs, cats Mild, moderate pain, tropical Naloxone --- -- - Small animals Reversal: CNS sedation, respiratory depression, shock Naltrexone --- -- - Wildlife & large animals Reversal of carfentanil P: partial; 0: no affinity; + or – degree of affinity  Non-Opioid Analgesic Drugs Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Acetaminophen (Paracetamol, Tylenol) Ibuprofen Aspirin (limited amount of time) MOA: Inhibition of the pro-inflammatory enzyme cyclooxygenase (COX) Nonselective Selective COX1, COX2 COX2 Uses: to reduce swelling, stiffness, joint pain caused by inflammation ❖ Carprofen (dogs, cats, reptiles, and birds) Rare side effects: Kidney ❖ Deracoxib (only dogs, after surgery) Liver ❖ Firocoxib (dogs, horses, osteoarthritis & surgery) GI problems ❖ Meloxicam (dogs and cats, osteoarthritis) Drug-drug interaction Non-Opioid Analgesic Drugs NMDA Receptor Antagonists as Analgesics ▪ N-methyl-D-aspartate (NMDA) Receptor is a Glutamate receptor and Ca++ ion channel ▪ Ligands: Glutamate and Glycine ▪ Mediating learning and memory functions NMDAR Antagonists: ❖ Amantadine (anti-dyskinetic; dogs, cats: acute and chronic pain) ❖ Ketamine (anesthetic; hospital use) ❖ Gabapentin (GABA analogue, anticonvulsant; neuropathic pain, cancer-related pain) ❖ Amitriptyline (antidepressant; arthritis, neuropathic and chronic pain) ❖ Lidocaine patch (local anesthetic, veterinary pain management) ❖ Methadone ( analgesic and pre-anesthetic in dogs and cats)