Pharmacotherapy of Nervous System Disorders RPB40302 CNS Depressant PDF

Pharmacotherapy of Nervous System Disorders RPB40302 Dr. Omar AH Topic 2: CNS Depressant 2.1 General Anesthetic 2.2 Local Anesthetic 2.3 Hypnotic Sedative 2.4 Opiate & Opioid Analgesics (Narcotics) 2.5 Non-narcotic Analgesic 2.6 Alcohol But first... A neurophysiology memory review! Peripheral N...

Pharmacotherapy of Nervous System Disorders RPB40302 Dr. Omar AH Topic 2: CNS Depressant 2.1 General Anesthetic 2.2 Local Anesthetic 2.3 Hypnotic Sedative 2.4 Opiate & Opioid Analgesics (Narcotics) 2.5 Non-narcotic Analgesic 2.6 Alcohol But first... A neurophysiology memory review! Peripheral Nervous System Action Potential (Nerve impulse) Ca+ entry Na+ influx K+ efflux An action potential, also called (nerve impulse), is an electrical charge that travels along the membrane of a neuron. It can be generated when a neuron's membrane potential is changed by chemical signals from a nearby cell. Excitatory post synaptic potential, (EPSP) Excitatory impulse When an excitatory transmitter binds and interacts with specific receptors on postjunctional membrane, the membrane permeability to (Na+/Ca+) cations increases. + 𝑲 𝑲+ influx efflux 𝑲+ 𝑲+ Inhibitory post synaptic potential, (IPSP) Inhibitory impulse Effector cell When an inhibitory transmitter binds and interacts with specific receptors on postjunctional membrane, the membrane permeability to 𝑲+ or 𝑪𝒍− increases. ` Continuum of CNS excitability Seizure Anxiety Excitation Activation Homeostasis (Resting state) Relaxation Sedation Sleep Anaesthesia Coma  What are CNS Depressant? The are drugs that slow down the central nervous system (CNS) activity, used to treat anxiety and insomnia. MOA: CNS depressants work by 1. Increasing the levels of a neurotransmitter, gamma-aminobutyric acid (GABA). GABA is an inhibitory neurotransmitter, which means it slows down the transmission of nerve signals. 2. Block N-methyl-D-aspartate (NMDA) receptors in the spinal cord. 3. Activate 2-Pore-Domain K+ Cannel. 4. Activate μ receptors causes closing of the voltage gated Ca2+ channel on the presynaptic nerve. CNS depressants causes: Relaxation Reduced anxiety Reduced pain Impaired coordination Impaired judgment, poor concentration Slurred speech, dry mouth Sedation, sleep induction & slow breathing Loss of consciousness & confusion What are CNS Depressant used for? 1. Anxiety disorders (generalized anxiety disorder (GAD), panic disorder, specific phobias, agoraphobia, social anxiety disorder, separation anxiety disorder). 2. Insomnia 3. Pain 4. Seizures 5. Muscle spasms 6. Alcohol withdrawal However, CNS depressants have been misused as recreational drugs. When misused, CNS depressants can lead to addiction, slow breathing, lower oxygen levels, permanent brain damage, overdose and death. Hypnotic Sedative (Anxiolytics) For Anxiety disorder, Insomnia, some seizures NOT Analgesics ! Anxiety: Is an excessive mental feature of worry, fear, difficulty concentration and sleep problems Physical symptoms: Tachycardia: muscle aches, nausea, shortness of breath, trembling, pacing Hypnotic Sedative classes: 1. Benzodiazepines 2. Barbiturates 3. Non-benzodiazepine hypnotics -Benzodiazepines are idea drugs for oral sedation in dental settings, safer, less addiction potential, larger therapeutic index, less respiratory depression as compared to Barbiturates, has antiemetic effect. -Barbiturates are contraindicated in intermittent porphyria Gamma-aminobutyric acid (GABA) MOA Sleep Anxiety 5 subunits  Pre-Synaptic Post Synaptic Increased negative charge Cl- ion influx Hyperpolarization, or stabilization of resting potential making it difficult for excitatory neurotransmitters to depolarise the neuron and generate an action potential hyperpolarization Anxiolytic/Sedative/Hypnotic drugs, facilitate the actions of GABA- (A & B) A. Activation of GABAA receptor leads to increased post-synaptic Cl- ion influx; B. Activation of GABAB receptor leads to inhibition of pre-synaptic Ca+ entry and increased post-synaptic K+ permeability. Both mechanisms result in membrane Hyperpolarization. Excitatory neurons Inhibitory interneurons 1. Benzodiazepines 2. Barbiturates 3. Non-benzodiazepine hypnotics Binding site between Binding site Binding site to α-ɣ subunit between α1 subunit GABA α or β subunit Binding site ↑ frequency ↑ duration influx Sleepiness, but no anti-anxiety effect Alprazolam (Xanax®), Lorazepam (Ativan®), Diazepam (Valium®), Zolpidem, Zaleplon and Chlordiazepoxide, Oxazepam, Eszopiclone Triazolam (Halcion®),Clobazam Pentobarbital, thiopental Phenobarbital, Secobarbital Drowsiness, dizziness, impaired Drowsiness, sedation, dizziness, impaired attention, respiratory Cognitive impairment, memory loss, motor coordination depression, coma & death sedation, impaired motor coordination  Barbiturates at α&β subunits (affect channel open duration) BZD @ ɣ subunit (affect channel open frequency) Benzodiazepines: Alprazolam (Xanax®), Lorazepam (Ativan®), Diazepam (Valium®), Chlordiazepoxide, Oxazepam, Triazolam (Halcion®) Anti seizures, GAD Tranquilizer, insomnia, jet lag For alcohol withdrawal Mother's Little Helper Barbiturates: Pentobarbital, Phenobarbital, Secobarbital Non-benzodiazepine hypnotics: Zolpidem, Zaleplon and Eszopiclone  Why has benzodiazepines replaced barbiturates? Benzodiazepines Barbiturates They do not produce anesthesia in high doses & Produce loss of consciousness and have low margin of patient can be aroused. safety They can be used as day-time anxiolytic. Unacceptable drowsiness is seen. Do not affect respiratory or cardiovascular system. Causes respiratory depression & hypotension. There is a specific BZS antagonist (Flumazenil) No specific antagonist. (selective GABA-A receptor antagonist). Duration of Action of Benzodiazepines Duration of Action of Barbiturates Long acting (1-3 days): Chlordiazepoxide, diazepam, Long acting (1-2 days) Anticonvulsant flurazepam, clonazepam, chlorazepate Phenobarbital Intermediate (10-20 hrs): temazepam, lorazepam, Short (3-8hrs) Sedative & Hypnotic alprazolam, oxazepam, nitrazepam, estrazolam Pentobarbital, secobarbital & amobarbital Short acting (2-8 hrs): midazolam triazolam Ultrashort (20 min) I.V. Induction of anesthesia Thiopental 20 Anxiolytic drugs and their mechanisms of action Anxiolytic drugs are medications that are used to treat anxiety disorders. These drugs work by altering the levels of neurotransmitters in the brain that regulate mood and anxiety. Here are the different types of anxiolytic drugs and their mechanisms of action: 1. Benzodiazepines: Benzodiazepines are a class of anxiolytic drugs that work by increasing the activity of a neurotransmitter in the brain called gamma-aminobutyric acid (GABA). GABA helps to reduce the activity of the neurons in the brain, leading to a calming effect. Examples of benzodiazepines include alprazolam (Xanax®), lorazepam (Ativan®), and diazepam (Valium®), Benzodiazepines binds to ɣ subunit (and affect channel open frequency). 2. Barbiturates are a class of drugs that act as central nervous system depressants, they act on the gamma-aminobutyric acid (GABA) receptor in the brain, Barbiturates binds at α&β subunits (and affect channel open duration) Examples, Pentobarbital, Phenobarbital. 3. Miscellaneous: Carbamates, Zolpidem, Alcohol. General & Local Anaesthetics Anaesthesia is a reversable condition induced by anaesthetic drugs that cause reduction or complete loss of response to pain or other sensations, such as consciousness and muscle movement during surgery or other invasive procedures that can be painful! Anaesthesia General Local General anaesthetic X3 Groups Local anaesthetic  Stages of general anaesthesia since 1930s 1. Induction 2. Excitement 3. Surgical Anaesthesia 4. Medullary Paralysis Analgesia: Depression of inhibitory Loss of muscle tone and Respiratory and From consciousness to neurons at the CNS leads to reflexes, fully cardiovascular failure unconsciousness. ↑ excitement of involuntary unconsciousness, ideal for occurs leading to death muscle movements, ↑HR, surgery, careful monitoring BP & respiration. How general anaesthetics work? Macroscopic level Reversable loss of consciousness Amnesia Immobility and analgesia 1st Group IV agents Etomidate, Propofol, Barbiturates Inhibitory Pre-Synaptic neuron Potent at producing unconsciousness, rather than immobility or analgesia Commonly used in the induction phase They prolong opening of the channel Hyperpolarization, or stabilization of resting potential making it difficult for excitatory neurotransmitters to depolarise the neuron and generate an action potential Post Synaptic Etomidate Barbiturates Propofol Cause adrenal Suppression and myoclonus Hypotension & Apnoea, cough respiratory Bronchospasms depression respiratory depression 2nd Group efflux 2-Pore-Domain potassium K+ Cannel IV: Ketamine. And Inhaled: Nitrous Oxide, Xenon, Cyclopropane They produce significant analgesia in contrast to group 1 & 3, But weaker ability to produce unconsciousness & immobility. Used in the maintenance phase of anaesthesia Have little to no effect on GABA receptor They are mediated by N-methyl-D-aspartate NMDA receptor (NMDA) receptors in the spinal cord Calcium @ Spinal Cord And they effect 2-Pore-Domain K+ Cannel Ketamine Nitrous Oxide Xenon Cyclopropane Hypertension Tachycardia, Dizziness nausea Dizziness nausea delirium and vomiting and vomiting Hypersalivation 3rd Group, Halogenated volatile anaesthetics Halothane, Enflurane, Isoflurane, Sevoflurane, Desflurane Potent at producing immobility Neuronal Nicotinic Ach receptors Serotonin type 3 receptors Sodium channels Mitochondrial ATP sensitive potassium channels Hyperpolarization activated cyclic nucleotide gated channels  ↓BP & CO Halothane, Enflurane, Isoflurane, Sevoflurane, Desflurane Renal toxicity Arrythmia Hepatotoxicity Bradycardia & Dexmedetomidine Hypotension Sedation and analgesia without respiratory depression Binds to presynaptic alpha2 receptors (subtype 2A) in the brain and spinal cord, therefore inhibit the release of NE, terminating pain signals and inducing sedation NE Local anaesthetics Bupivacaine, Mepivacaine, Ropivacaine, Lidocaine, Procaine, Tetracaine Loss of sensory perception without unconsciousness Affect on area around application no Na+ influx Block voltage gated sodium channel Bupivacaine Ropivacaine Lidocaine Procaine Tetracaine Analgesics (Pain-killers) To alleviate pain sensation 7. Opioid Analgesics Non-opioids (Narcotics) Non-narcotics Agonist Acetaminophen Antagonist NSAIDs Agonist- Adjuncts antagonist Opiate and Opioid Analgesic / Narcotics / Morphine-like calcitonin gene related peptide Pain neurotransmitters Neurokinin 1 Protein kinase c  3 Opioid Receptors 3 Endogenous opioids μδκ 1. Enkephalins 2. Endorphins 3. Dynorphins μ κ δ Activation of μ receptors causes 1. closing of the voltage gated 𝐂𝐚𝟐+ channel on the presynaptic nerve & 2. ↓ the release of neurotransmitters into the synaptic space, also it 3. open 𝐊 + channel allowing efflux of potassium ions resulting in hyperpolarisation Synthetic Opioid Agonists Potent μ opioid receptor agonists Tramadol (SNRI effect) Fentanyl Hydrocodone Hydromorphone Methadone used to treat heroin dependency Methadone (can block NMDA 𝑪𝒂𝟐+ and SNRI receptor) Meperidine / Pethidine (Demerol®) SE: Oxycodone Nausea, vomiting, Respiratory depression Antitussive effect, suppressed immune system, Oxymorphone Constipation, Depressed renal function, Antidiuretic effect, Addiction Loperamide (non-infective diarrhea) Codeine (antitussive, cough suppression) Other opioid uses Codeine antitussive, cough suppression Loperamide (Imodium): for non infective diarrhea Fentanyl + Droperidol: laboratory animal anesthesia, cancer pain Actions of opioid receptors Response Mu Kappa Opioid Classes Mu Kappa Analgesia   Pure Agonists Agonist Agonist Respiratory Depression  Morphine, Codeine, Meperidine Sedation   (Demerol®), Fentanyl (Sublimaze®), Remifentanil (Ultiva®), propoxyphene Euphoria  (Darvon®), hydrocodone (Vicodin®), Physical Dependence  oxycodone (Percocet®)  GI motility   Agonist / Antagonist Partial- Agonist Nalbuphine (Nubaine®), Butorphanol Antagonist (Stadol®) Buprenorphine Pure Antagonist Antagonist Antagonist Naloxone (Narcan®) Naloxone (Narcan®) Naloxone is a medicine that rapidly reverses an opioid overdose. It is an opioid antagonist used to reverse or reduce or counter the effects of opioid overdose. Work by knock off the receptors attached in the brain, stopping the opioid effect, and restore normal breathing Opioid Side Effects 1. Nausea due to the stimulation of the chemoreceptors triggers on the medulla. 2. Dose dependant Respiratory depression, by reducing brain stem respiratory centre responsiveness to carbon dioxide. 3. Antitussive effect by depressing cough centre in the medulla. 4. Immune system suppression. 5. Meperidine & Morphine provoke the release of histamine causing hypotension 6. Decrease gastric motility and prolong gastric emptying time causing constipation 7. Depress renal function and produce antidiuretic effects, increase sphincter tone and thus cause urinary retention 8. Addiction by physical and psychological dependence. 9. Withdrawal symptoms (due to desensitization of opioid receptors) Opioid addiction & euphoric effect Desensitization & addiction - Activation of GABA inhibitory interneurons on the ventral tegmental area of the brain - Normally GABA reduce dopamine release in the nucleus accumbens (Pleasure & Reward System) - When opioids attach and activate Mu receptor, it suppress GABA release, - Leading to increased dopamine activity, - Leading to euphoria, pleasure & addiction Non-opioid Analgesics Often effective for mild to moderate pain: 1. Acetaminophen (Paracetamol®Panadol) 2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Salicylates Aspirin (Bayer®) Acetylsalicylic acid (ASA) Ibuprofen (Motrin®, Advil®) Propionic Acid derivative (ketoprofen®) Naproxen (Naprosyn®) Naproxen sodium (Aleve®) Ketorolac (Toradol®) Celecoxib (Celebrex®) Acetaminophen (Paracetamol®) (Panadol®) Paracetamol is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. Inhibit the synthesis of cyclooxygenase (COX-1 and COX-2), inhibits prostaglandin synthesis, only in CNS Only inhibits synthesis of CNS prostaglandins. Does not have peripheral side effects of NSAIDs like ASA: ↓ Gastric ulceration ↓ Platelet aggregation ↓ Renal flow ↓ Uterine contractions Aspirin Is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic (reduces the formation of blood clots). Inhibit synthesis of cyclooxygenase (COX-1 and COX-2) Enzyme responsible for synthesis of: Prostaglandins (PGs) Thromboxane A2 –Pain response –Involved in platelet aggregation –Suppression of gastric acid secretion –Promote secretion of gastric mucus and bicarbonate –Mediation of inflammatory response –Production of fever –Promote renal vasodilation ( blood flow) –Promote uterine contraction NSAIDs work in the brain and throughout the body Aspirin effects Advantage Disadvantages Pain relief GI ulceration: ↑ Gastric acidity & ↓GI protection Blood thinning (for CVD patients) ↑ Bleeding ↓ Fever ↓ Renal elimination ↓ Inflammation ↓ Uterine contractions during labor Acetaminophen vs NSAIDs properties Drug Fever Pain Inflammation Aspirin    Ibuprofen    Acetaminophen = Paracetamol   Alcohol Ethanol CH3-CH2-OH (↑ GABA & ↓NMDA Glutamate) = impaired body movement, Addiction due to ↓coordination, slurred speech, slow responses ↓body temp Desensitization & ↓breathing, ↑sexual arousal, ↓ability to engage in sex. @BAC 0.05% Down regulation ↑Dopamine & Serotonin = Pleasurable feeling & euphoria Eth loop Inhibitory Exctetory in the amygdala & nucleus accumbens ↑ ↓ Short term Body Overdrinking Withdrawal drinking adaptation to overcome syndrome ↑ duration response tolerance GABA/Glut Time Hypnotic Sedative (Anxiolytics) Example MOA Anticonvulsants 1. Benzodiazepines Alprazolam (Xanax®), Bind to GABA = ↑ frequency = ↑CL- influx Lorazepam (Ativan®)=(Anti seizures), Flumazenil (selective GABA-A receptor antagonist) Diazepam (Valium®), Chlordiazepoxide, Oxazepam, Triazolam (Halcion®) 2. Barbiturates Pentobarbital, Bind to GABA = ↑ duration = ↑CL- influx Phenobarbital, Secobarbital 3. Non-benzodiazepine hypnotics Zolpidem, GABA Zaleplon, Eszopiclone General Anaesthetics Group 1 (IV agents) Etomidate, Propofol, Barbiturates ↑ GABA = ↑CL- influx 2nd Group IV: Ketamine ↓ NMDA = ↓ glutamate Inhaled: Nitrous Oxide, Xenon, Cyclopropane ↑ 2-Pore-Domain potassium K+ Cannel (efflux) 3rd Group, Halogenated volatile anaesthetics Halothane, Enflurane, Isoflurane, Sevoflurane, Desflurane ↑GABA/ ↓NMDA /↑2-PDPCannel. Dexmedetomidine Dexmedetomidine ↑ presynaptic alpha2 receptors = ↓ NE Local anaesthetics Bupivacaine, Mepivacaine, Ropivacaine, Lidocaine, Procaine, Tetracaine ↓ Block voltage gated sodium Na+ channel Opioids Analgesics Tramadol (SNRI effect) Mu (μ) opioid receptor agonists 1. Endogenous opioids = Fentanyl, Hydrocodone, Hydromorphone Naloxone (selective opioid antagonist) Enkephalins Methadone (block NMDA Ca𝟐+ & SNRI receptor) [for addiction] Endorphins Meperidine / Pethidine (Demerol®) Dynorphins Oxycodone, Oxymorphone Loperamide (Imodium): for diarrhea 2. Synthetic Opioid = Codeine antitussive, cough suppression Non - Opioids Analgesics 1. Acetaminophen (Paracetamol, Panadol) ↓ COX-1 and COX-2 = ↓PG (only in CNS) 2. NSAIDs (Ibuprofen, Naproxen, Celecoxib) ↓ COX-1 and COX-2 = ↓PG (in brain& throughout body) Ethanol ↑ GABA & ↓NMDA ↑Dopamine & Serotonin "Education is not preparation for life; education is life itself."