Anesthetics (Pharm 125) PDF

ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 iii. DRUG INTERACTIONS OUTLINE I. INTRODUCTION TO ANESTHETICS...

ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 iii. DRUG INTERACTIONS OUTLINE I. INTRODUCTION TO ANESTHETICS LEGEND II. ANESTHESIA TECHNIQUES Bold + highlight - DOH medicine access A. GOALS TO ANESTHESIA program III. ANESTHETICS Bold - included in PNF-EML A. GENERAL ANESTHETICS Orange - Registered with the Philippine FDA, i. MECHANISM OF ACTION but Non-PNF ii. GENERAL ANESTHETICS - INHALED Brown - Highlighted during the lecture 1. PHARMACOKINETICS 2. EFFECTS II. ANESTHESIA TECHNIQUES 3. FACTORS IN SELECTION 4. INDICATIONS 5. SUMMARY iii. GENERAL ANESTHETICS - INTRAVENOUS 1. KINETICS 2. PROPOFOL (2,6-DIISOPROPYLPHENOL) 3. ETOMIDATE 4. KETAMINE A. GOALS TO ANESTHESIA 5. THIOPENTAL 6. SUMMARY III. ANESTHETICS 7. INDICATION: GENERAL General Anesthetics ANESTHESIA ○ Inhaled anesthetics 8. INDICATION: MONITORED Volatile Agents (liquid turned to gas) ANESTHESIA CARE Sevoflurane - Available 9. INDICATION: SEDATION Desflurane 10. INDICATION: PAIN Halothane* (Not FDA registered) MANAGEMENT Isoflurane - Available 11. OTHER INDICATIONS Gaseous Agents (already gas by nature) 12. DEXMEDETOMIDINE Nitrous Oxide (N2O) - Available, 13. OTHER MEDS: Laughing Gas BENZODIAZEPINES ○ Intravenous Anesthetics B. ADJUVANTS AND ADJUNCTS Propofol i. OTHER MEDS: OPIOIDS Ketamine ii. OTHER MEDS: NEUROMUSCULAR Etomidate BLOCKERS Barbiturates - Thiopental C. LOCAL ANESTHETICS Not that used anymore i. NERVE ANATOMY Dexmedetomidine ii. NERVE PHYSIOLOGY iii. ESTERS AND AMIDES Benzodiazepines 1. MECHANISM OF ACTION ○ Practice: cocktail, multimodal therapy (many 2. KINETICS agents with smol dose -> synergistic w/o too much 3. INDICATIONS side effects 4. INDICATIONS: INTRAVENOUS Local anesthetics ANESTHESIA ○ Aminoesters IV. NEUROMUSCULAR BLOCKERS Tetracaine A. BLOCKADE Benzocaine i. NONDEPOLARIZING ○ Aminoamides ii. DEPOLARIZING Lidocaine PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 1 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Bupivacaine ○ Anterograde amnesia Ropivacaine ○ avoid the peripheral conduction of pain - Prilocaine connections stronger = post op problems Articaine ○ No pain not mean no manage possibility Levobupivacaine Still give anes agenda - opioids Mepivacaine Detecting excitation caused by the Dibucaine transmission of pain: opioids help the calm ○ Etc: Diphenhydramine??? down severe pain stimuli (higher BP and HR) Adjuvants and/or adjuncts ○ Sedation ○ Opioid analgesicsS2 (except Butorphanol) α1 subunit of GABAA @ CNS (cortical, ○ Neuromuscular blockers thalamus) ○ Epinephrine ii. GENERAL ANESTHETICS - INHALED A. GENERAL ANESTHETICS 1. PHARMACOKINETICS alveoli for absorption i. MECHANISM OF ACTION Complex! No single mechanism actual mechanism is not known, the following are just proposed: Molecular (volatile anesthetics) ○ Ligand-gated (GABA, NN, ACh, NMDA, etc.) ○ voltage-gated (Na+, K+, Ca2+, etc) Molecular (N2O) MAC (Minimum Alveolar Concentration): ○ Ligand-gated (NMDA, NN, ACh) ○ ED50 : anesthetic producing immobility ○ voltage-gated (K+, Ca2+) concentration of anesthetic gas in the lungs ○ μ opioid receptor agonism (alveoli) that prevents movement in 50% of ○ Others patients Cellular 1 MAC - ED50 level is achieved (0.5 MAC = half ○ Neuronal excitability - hyperpolarized or of ED50) depolarized Administration: mixture of gas decreased conduction of action potentials ○ Mixture: anesthetics, oxygen, and medical air especially if depolarization is sustained (nitrogen mixed with oxygen) Overall ○ anesthesia machine: mechanical ventilator and a ○ “Immobility” substrate vaporizing machine Na+ and K+ channels @ spinal cord ○ continuous ○ “Unconsciousness”/Hypnosis ○ Volatile Anesthetics - volatile liquids PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 2 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Factors affecting uptake: When anesthetic is stopped + less conc in the ○ Partial pressure air needed to inhale, the anesthetic gas still in gas -> add pressure to air -> patient inhale the blood diffuses to the alveoli -> breathed concentration of anesthetic in the alveoli (FA) out. = the concentration inhaled (FI) -> Faster process speeds up when there's high blood equilibrium is reached (FA/F1 = 1) -> faster flow to the lungs. onset ○ Tissue solubility ○ Alveolar ventilation Anesthetics can dissolve in different body Higher alveolar ventilation means increased tissues, not just in blood like fat -> patient uptake of the gas. takes longer to wake up -> needs to go back to Alveoli present there for gas exchange. lung so -> blood -> brain and CNS depress -> ○ Solubility lung for excretion Blood-gas partition coefficient: >1 means ○ Duration of exposure more soluble in blood Longer -> build in tissue -> slow recovery How much the anesthetic gas tends to (wake up) partition in the blood from a liquid state to a gaseous state To speed up recovery during emergence: ↑ solubility: slower time to equilibrium hyperventilation - remove gas fast from alveoli Medyo makulit yung gas, dissolves most ○ introduce a state of alkalosis coz CO2 is being of it in the blood exhaled out too ↓ solubility: faster time to reach equilibrium Eventually it reaches equilibrium due to lower presence of gas soluble in blood ○ Cardiac Output ↑Pulmonary blood flow ⟶ ↑Uptake ⟶ slower increase of FA/F1 to 1 Pulmonary blood flow: How much blood goes to the lungs - how much blood will take up the anesthetic agents from the alveoli ○ Alveolar-venous partial pressure Distribution 2. EFFECTS ○ Dependent on relative solubility of the drug General anesthesia state (reversible) lipid soluble = deposit or distribute to the ○ Hypnosis (unconsciousness) - GABAA (NMDA for fatty areas of the body -> when stop = patient N2O) is still anesthetized coz slow to go back to ○ Amnesia - GABAA α5 subunit, neuronal nAChRs lung for excretion ○ Analgesia - NMDA and μ opioid for N2O Metabolism ○ Akinesia (immobility) ○ CYP2E1 ○ Autonomic and sensory block ○ Halothane*: 50% hepatic (liver) metabolism - drug ↓ sympathetic tone = cardiovascular metab by liver depression (brady, hypotension) Elimination Remedy: Decrease the dose or conc ○ Blood-gas partition coefficient High = The anesthetics prefer the blood -> Skeletal & smooth muscle relaxation - voltage-gated stay in body longer Ca2+ channel block Low = The anesthetics prefer the gas -> ○ Halogenated: potent uterine muscle relaxants diffuse out fast Foley Catheter - lose control ○ Pulmonary blood flow ○ monitor the fluid balance coz baka no make urie Some of the anesthetic can be eliminated = hypovolemic state directly through the lungs. PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 3 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Respiratory ○ Volatiles + NaOH/KOH adsorbents = CO formation ○ Airway irritation (from laryngospasm) (none w/ N2O) ○ Bronchodilation (Ca2+ channel block, RyR Ca2+ ○ Sevoflurane + NaOH/KOH adsorbents = channel leak, increased CO2 tone) compound A (nephrotoxic in rats) ○ Respiratory depression (stage III, IV) Forms nephrotoxic (dmg to kidney) Need ventilator or else frequency of breathing compounds would become very low and shallow = patient death. Malignant hyperthermia – activation of mutated RyR1 receptors Cardiovascular ○ Uncontrolled Ca2+ release ○ Myocardial depression (variable MOAs) ○ Muscle contraction (shiver, etc.) and Hypotension (Low BP) or Bradycardia (Low hypermetabolic activity heart rate) ○ For volatile anesthetics, but esp. w/ Halothane* Blocking Na+ channels (Nav1.5), K+ channels, ○ ask if may history of anes complics Ca2+ channels Mild with N2O Environmental ○ N2O: megaloblastic anemia ○ Global Warming Irreversible oxidation of cobalt in vitamin B12 Volatile anesthetics (Co+ → Co3+) N2O = greenhouse gasses and ozone MOA: (-) methionine synthase, -> (-) folate depleters cycle -> no precursors to RBC -> size increase + ○ Occupational Exposure hemoglobin levels are low Toxicity Cerebral ○ Transient Renal Changes ○ Reduced cerebral metabolic rate (CMR) + Prolonged exposure to Enflurane (liberated F- cerebral vasodilation ions) vasodilation = ↓ cerebral Others: low solubility, rapid elimination blood flow ○ Transient LFT Increase Konti req for blood coz decrease metab LFT = Liver Function rate. Toxicity rare except w/ Halothane >1 MAC: vasodilation > ↓CMR = ↑ cerebral Halothane hepatitis – reactive blood flow Trifluoroacetylchloride + hepatic proteins, + Importance: Less ATP demand, theoretically autoimmune response better chances to survive lack of blood flow ○ Hematotoxicity ○ Transition to stage II (induction/emergence) N2O prolonged exposure → decrease Laryngospasm, emesis, aspiration of stomach methionine synthase → megaloblastic contents – 5-HT3 potentiation (N2O: gas anemia expansion) Vomiting is bad coz wala na protective 3. FACTORS IN SELECTION reflex (cough, gag) = aspiration pneumonia kaya no eat before surgery Volatile N2O gas expansion and postoperative N/V ○ Bronchodilation duration-dependent ○ Skeletal, smooth muscle relaxation Excitability, exaggerated response to stimuli (dose-dependent) ○ Postoperative N/V (CTZ) - nastimulate ○ ↓ cerebral metabolic rate (CMR), ↑ cerebral blood flow (CBF) Reactions with CO2 adsorbents ○ Laryngospasm ○ imp part of the anesthesia machine - collect CO2 ○ Respiratory depression from the patient or else rebreathe the CO2, -> ↓ ○ Myocardial depression and vasodilation oxygen + Anes gas in body (hypotension) PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 4 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Emergence delirium ○ Sevoflurane and Isoflurane have little effect on ○ Postoperative nausea and vomiting (vs IV) cerebral autoregulation - allow stable blood flow ○ Malignant hyperthermia even if blood pressure changes ○ Induction time takes longer Isoflurane ○ Longer duration due to high-fat solubility. 4. INDICATIONS Nitrous Oxide INDICATION FOR ALL INHALANT ANESTHETICS IS ○ 2nd Gas Effect coz absorb fast in alveoli GENERAL ANESTHESIA ○ Not metabolized - its excretion is in the lungs. Induction - IV ○ IV - if need start fast iii. GENERAL ANESTHETICS - INTRAVENOUS ○ Gas - longer start - Pedia and adults needing spontaneous breathing 1. INTRAVENOUS KINETICS ○ N2O – adjuvant (no prod gas by itself) Speeds up ADME of others via “2nd gas 3-Compartment Model effect” ○ Vascular/Central Compartment Maintenance (Stage III) - Inhalation Metab drug by going to heart ○ total IV, or combination (balanced anesthesia) ○ Target Compartment Induction with IV and maintained with inhaled Effect Site ○ Sevoflurane – procedures synergy = myocardial ​ depression Thiopental is AVOIDED in long procedures PH ○ Sevoflurane, Isoflurane, and Nitrous Oxide 2. PROPOFOL (2,6-DIISOPROPYLPHENOL) PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 5 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Most common general anesthetic May Injection site pain, so use smoll White dose of lidocaine, local anesthetic, before giving propofol. MOA GABAA receptor activation (β1-, β2-, and β3-subunit) KINETICS Rapid hepatic metabolism to ○ Intrinsic CNS depressant H2O-soluble components effects ○ Extrahepatic metabolism: NMDA receptor antagonism renal (main) and lungs Vasodilation → reduced hepatic FORMULATION Emulsion containing soybean oil, blood flow → slower metabolism of glycerol, and lecithin from egg yolk certain drugs ○ poor water solubility → rapid *Fospropofol: H2O-soluble onset prodrug broken down into Avoid in patients with soy, egg Propofol, Formaldehyde (oxidized allergies to Formate), phosphate Microbial contamination risk ○ Use aseptic techniques 3. ETOMIDATE ○ AVOID multidose use from 1 vial in >1 patient ○ Dispose opened vial after 6 MOA GABAa PAM (A1β2Y2) hours ○ Like BZD a2B receptor agonism EFFECT COMMON 11β-hydroxylase inhibition ○ Hypnotic (no analgesia), ○ production of cortisol, respiratory depressant – GABAa corticosterone, aldosterone Fast to sleep w/ pain pa rin (water and sodium retention) Cannot be given alone ○ Low Aldosterone = ○ ↓ cerebral blood flow, metabolic hyponatremic rate ○ Vasodilation EFFECT CNS At start dose may ○ Activate seizure foci hypotension ○ ↓ cerebral blood flow, Manage with adj. Such as intracranial pressure phenylephrine and Better hemodynamic stability ephedrine ○ α2B receptor agonism RARE Adrenal insufficiency – ○ Propofol Infusion Syndrome ○ 11β-hydroxylase inhibition (PRIS) Injection site pain, phlebitis: low pH Metabolic acidosis (propylene glycol) Hyperkalemia, Hyperlipidemia KINETICS Rapid onset and recovery Rhabdomyolysis Ester hydrolysis → inactive Hepatomegaly metabolites Renal failure Highly protein bound ECG changes, arrhythmias, -> cardiac failure 4. KETAMINE Green Urine ○ PRIS = multi-organ conditions Dissociative Anesthesia Important IV Anesthetic PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 6 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 MOA MAIN (biphasic) ○ NMDA receptor antagonism ○ Preferred with patients who OTHERS have cardiovascular diseases ○ μ opioid receptor agonism ○ Stimulant in heart (binds κ, σ too) ○ 1st: myocardial depression, ○ SERT, NET blocker; negative inotropy antimuscarinic ○ 2nd: indirect stimulant effect (activation of sympathetic NS) EFFECT NO PARALYSIS NET blockade, vagal Dissociative anesthesia: profound blockade (M2) analgesia + disconnect from Tachycardia, HTN, surroundings increased CO and ○ Dissociation myocardial O2 consumption Depersonalization: detachment from body KINETICS Are important to the MOA Derealization: dreamy Ketamine = R- + S-ketamine Feel high ○ Esketamine - more ○ Analgesia – NMDA antagonism, psychotomimetic; more μ agonism potent NMDA antagonist preventing opioid-induced ○ Arketamine - more potent hyperalgesia antidepressant Interferes pain modulation Metabolites ○ Nystagmus ○ 2R,6R-HNK – binds other ○ Lacrimation, salivation glutamate receptors Risk for aspiration ○ S-NK – NMDA antagonism atropine, and independent of AMPAR antimuscarinic, to Not protein bound decrease secretions. ○ Increased skeletal muscle tone 5. THIOPENTAL ○ Coordinated, seemingly purposeless movements (limbs, Barbiturates: Thiopental trunk, head) Not commonly used; not an important IV anesthetic Cerebral vasodilation (skip) ○ Increased cerebral brain flow, metabolism, intracranial MOA GABA A positive allosteric pressure modulator, BUT at higher doses: ○ Avoid people with tumor or ○ Ion channel open longer suffer from high intracranial ○ Does not require GABA to work pressure ○ Consequence: lower Psychotomimetic effects (on therapeutic index vs benzos emergence) – NMDA antagonism ○ Block NT ○ Basta high Stability (in alkaline) Prevents bronchospasm ○ Thiopental: 2 weeks Risk of addiction, tolerance, withdrawal ○ Long-term: “Ketamine 6. SUMMARY bladder”/ulcerative cystitis (pain, nocturia) Cardiovascular: sympathomimetic PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 7 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Dexmedetomidine, Lidocaine) *Precaution: hypnotic effects synergistic When all IV is used it is called TIVA Propofol - incomplete anesthetic coz no analgesia so need opioid Adj used give hypnotic effects 8. INDICATION: MONITORED ANESTHESIA CARE No complete loss of consciousness, + total recall Continuous monitoring of vitals by anesthesia provider; ready to add meds or switch to general anesthesia if needed Ketamine Propofol Etomidate 9. INDICATION: SEDATION Propofol – during procedures, mechanical ventilation Propofol Ketamine – for procedures (e.g. in burn wound care ○ Antiemetic and antipruritic ○ Combination may be used Agent is good to use with opioids to lessen 10. INDICATION: PAIN MANAGEMENT the vomiting effect Perioperative pain: Ketamine (in combination) – may AE: hypotension also reduce opioid requirements Etomidate ○ ONLY KETAMINE for pain management ○ Better hemodynamic stability ○ Cocktail used by sir: Ketamine + propofol + ○ Post-op N/V opioid (very small dose) ○ Dose dependent involuntary myoclonic Migraine headache: Propofol movements ○ Transient adrenal insufficiency 11. OTHER INDICATIONS ○ Activates seizure foci Cushing’s, hypercortisolemia: Etomidate Ketamine ○ Produces adrenal suppression ○ Sympathomimetic effects (increased BP, HR, CO) Treatment-refractory unipolar depression: Ketamine ○ Psychomimetic effects on emergence (intermittent IV infusion, 0.5 mg/kg) 7. INDICATION: GENERAL ANESTHESIA 12. DEXMEDETOMIDINE Induction – adults with IV access Favorite sedative in neuroanesthesia/ neurologic ○ Preferred: Propofol procedures but least effects on cerebral circulation ○ Ketamine, Etomidate: patients with hemodynamic instability Ketamine (S2 regulated) but still MOA α2 agonist (↑affinity vs Clonidine) preferred over Etomidate coz in PNF α2A ○ Thiopental ○ CNS – postsynaptic regulation Not rly used and need S2 of inattention, hyperactivity, ○ To reduce aspiration risk: Rapid Sequence impulsivity Induction and Intubation (RSII) (Spinal cord: analgesia) Maintenance (maintain stage III) – inhalation, total IV, ○ ANS – presynaptic brakes on or combination (balanced anesthesia) NE release ○ Total intravenous anesthesia (TIVA): IV α2B anesthetic (Propofol) + analgesic (Opioid) + ○ CNS – sedation adjuncts/adjuvants (Ketamine, ○ ANS – vasoconstriction (blood PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 8 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 vessels) leads to hypertension Amnesic - anterograde amnesia α2C ○ CNS – sedation, hypotension; INDICATIONS Preoperative sedation (avoid spinal cord: analgesia routine use) ○ ANS – presynaptic brakes on Adjuvant during induction adrenaline release (adrenal gland) leads to hypotension B. ADJUVANTS AND ADJUNCTS i. OTHER MEDS: OPIOIDS EFFECT Sedation (non-REM sleep) Fentanyl, Remifentanil Analgesia (spinal cord α2A/2C ○ mng pain in post-op wounds receptors) ○ Remifentanil - short half-life + rapid-acting = ○ Reduced opioid need continuous infusion and faster wake-up time Anxiolysis (downregulation of ○ Opioids has sedative and analgesic effects noradrenergic receptors) Hypo/hypertension and bradycardia ○ Can go both ways INDICATIONS Balanced anesthesia Dry mouth Opioid-based anesthesia for cardiac surgery KINETICS Highly protein bound ○ Opioids have min CV effect Metabolism: CYP2A6/direct glucuronidation ii. OTHER MEDS: NEUROMUSCULAR BLOCKERS Context-sensitive t1/2 : 4 min (after Pancuronium*, Rocuronium, Vecuronium, 10-min infusion), 250 min (after Cisatracurium, Atracurium, Mivacurium, Gantacurium 8-hour infusion) Longer exposure = longer half-life so calc proper dose and adjusting MOA Non-depolarizing neuromuscular time to avoid deposits blockers/NMBS Target Controlled Infusion (Infusion Pump) INDICATIONS Anesthesia adjunct for endotracheal intubation INDICATIONS Sedation (short-term) patients who Anesthesia adjunct for surgery and are mechanically ventilated mechanical ventilation Procedural sedation (longer onset vs Propofol) Succinylcholine/Suxamethonium Adjunct for postoperative acute and chronic pain MOA depolarizing neuromuscular blockers/NMBS 13. OTHER MEDS: BENZODIAZEPINES Midazolam INDICATIONS Anesthesia adjunct for ○ only one useful in anes ○ Ayaw mo the longer-acting one. endotracheal intubation Others: ○ Diazepam C. LOCAL ANESTHETICS i. NERVE ANATOMY MOA Sedative-Hypnotic Anxiolytic Anticonvulsant PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 9 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 iii. ESTERS AND AMIDES Esters – Tetracaine*, Benzocaine Amides – Lidocaine, Bupivacaine, Ropivacaine, Prilocaine, Articaine, Levobupivacaine, Mepivacaine, Dibucaine Ester vs. Amide (count the number of “i” in the name) ○ Ester = 1 ex. Tetracaine ○ Amide = 2 ex. Lidocaine 1. MECHANISM OF ACTION Reversible blockade of Na+ channels (intracellular) ○ Local Anes - weak bases acting on nerves and must traverse through layers so may anes effect ○ Tonic blockade – reduced ion channels present in open state w/ infrequent stimuli ○ Use-dependent/ phasic blockade – when ion channels repetitively stimulate ○ Block the propagation of action potentials on Tissue layers the nerves ○ Afferent & efferent nerve fibers surrounded Decremental decay by endoneurium ○ Enough volume to block nerve impulse ○ Bundled nerve fibers = fascicle generation across a long-enough length of nerve ○ Each fascicle is surrounded by perineurium fiber ○ Groups of fascicles surrounded by epineurium ○ Conduct of action potential decreases Myelination Duration of action - Influenced by effects on blood ○ Lipid sheath around the nerves vessels ○ CNS: myelin sheath puro oligodendrocytes ○ Low concentration → vasoconstriction = localized ○ PNS: myelin sheath puro Schwann cells ○ High concentration → vasodilation = blood circulat ○ Interrupted by nodes of Ranvier ○ Other factors: concentration, time, site of Make fast the action potentials (saltatory application conduction) 2. KINETICS Nerve fiber types Only 1-2% penetrate nerve ○ A – small to large diameter, myelinated ○ Higher concentration = faster onset ○ B – small diameter, myelinated ○ Higher volume = wider scope ○ C – small diameter, non-myelinated Distribution (2-compartment model: blood & Susceptibility to nerve block: highly-perfused tissue) ○ Aγ motor, Aδ sensory fibers (small myelinated) ○ Influenced by pH (Anesthetic = weak base) ○ > Aα and Aβ fibers (large, myelinated) Ex. Lower pH (ex. Inflamed tissue) → ○ > C fibers (nonmyelinated) protonated → poor penetration thru membrane (less lipid soluble) = slow onset ii. NERVE PHYSIOLOGY Alkalinization (+HCO3-) → unprotonated → Signal transduction thru electrical impulses faster onset ○ Conducted via action potentials Effects of Epinephrine ○ APs triggered by membrane depolarization ○ Vasoconstriction for localized effect (Na+ influx) ○ Prolonged local anesthetic action ○ Peak followed by repolarization (K+ efflux) ○ Increased intensity of action ○ Refractory period ○ Decreased local anesthetic systemic absorption Sodium channels (don’t memorize) Metabolism ○ Aminoesters: cholinesterase (blood) ○ Aminoamides: carboxylesterases (liver) PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 10 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ Prolonged elimination of Bupivacaine, Usually usually Bupivacaine (duration 2-8 h vs Lidocaine, Ropivacaine in infants Lidocaine’s 0.5-1 h), Ropivacaine, Lipophilicity → potency Tetracaine* ○ Degree to which it can reach the nerves / travel Topical anesthesia through the lipid barriers ○ Lidocaine, Benzocaine, Tetracaine*, EMLA (Lidocaine+Prilocaine) 3. INDICATIONS ○ Mucous membranes Lidocaine + Prilocaine: pain associated with needle e.g. Lidocaine or Tetracaine* sprays in insertion, IV catheter placement endotracheal anesthesia Lidocaine (IV): reduce pain w/ Propofol administration Diphenhydramine oral solution - canker sores ○ transiently cause pain itself coz (+) transient ○ Abraded skin (e.g. for suturing) – Lidocaine-Epi receptor potential vanilloid-1 (TRPV-1) and Tetracaine (LET) transient receptor potential ankyrin-1 (TRPA-1) ○ Intact skin (EMLA for venipuncture, intravenous Regional anesthesia cannulation, skin grafting, etc.) ○ Infiltration anesthesia – subcutaneous Tumescent anesthesia (liposuction) Minor skin procedures ○ SQ injection of large volumes of dilute local ○ Intravenous regional anesthesia (IVRA) / Bier’s anesthetics + adjuvants block Alt. to peripheral nerve block for short procedures on hand & forearm 4. ADR: INTRAVENOUS ANESTHESIA IV admin to limb occluded with torniquet (will Lidocaine - anti-inflammatory and analgesic in visceral not go into systemic circulation) surgery Usually Lidocaine, Prilocaine LAST - Local Anesthetic Systemic Toxicity (CNS + CV) ○ Peripheral nerve block – minor (single nerve) and ○ Anesthetics are neurotoxic - Can kill neurons major (≥2 distinct nerves/plexus); = avoid general BBB penetration causes CNS toxicity anes complics and minimize use of opioids ○ Low doses - Mild distrubances (lightheadedness, Surgical anesthesia and/or postoperative tinnitus, tongue numbeness analgesia in: ○ High doses - Seizures, Unconsciousness Upper & lower extremity blocks – Lidocaine, ○ Higher doses - CNS Depression, Coma, Respiratory Bupivacaine, Ropivacaine, Mepivacaine Depression Digital nerve blocks CV toxicity Nerve blocks of the trunk, neck, scalp – ○ Higher doses compared to CNS toxicity Bupivacaine, Ropivacaine ○ Likelier with Bupivacaine Regional anesthesia – Neuraxial anesthesia ○ Mechanisms: ○ Epidural anesthesia and analgesia Heart: blocks conduction system via Na+ Abdominal, pelvic, lower extremity surgeries channels can cause arrhythmia Any; usually Bupivacaine (duration 2-8 h vs Outside heart: vasodilation (high doses) + Lidocaine’s 1-2 h) Ropivacaine, pulmonary arterial hypertension Levobupivacaine (but rarely Tetracaine*) ○ Effects Bupivacaine: selective sensory blockade Hypotension, Dysrhythmias, Myocardial (analgesia), limited motor blockade/muscle depression weakness at lower doses At worst: complete heart block (electrical insert a needle and pass through a catheter activity is de-synced), CV collapse and placed just outside the epidural space; Potentiated by acidosis, hypoxia inject and space bathed with local anesthetic Local anesthetics are also classified as anti-arrythmic and will still pass the dura = slow absorption agents, but when abused/inappropriately used can and low potency (mostly for analgesia) cause anemia ○ Spinal anesthesia (subarachnoid space) Transient Neurologic Symptoms Lower extremity, lower abdominal, pelvic, ○ Pain, sensory abnormalities perineal procedures ○ Especially with Lidocaine PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 11 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Myotoxicity Pipercuronium ○ Muscle pain, dysfunction Depolarizing: NM agonist excess ○ Intracellular Ca2+ dysregulation ○ Succinylcholine/Suxamethonium ○ Most risk: Bupivacaine ○ Least risk: Tetracaine, Procaine i. NONDEPOLARIZING RARE MOA: competitive antagonist at NM receptors at the Hypersensitivity (very rare) NMJ/motor end plate ○ IgE-mediated (less common; leads to anaphylaxis) ○ Large doses: enter ion channel pore or cellular (delayed, via T-lymphocytes ○ Competetive → block reversibly by ○ Contact dermatitis acetylcholinesterase inhibitors ○ Usually aminoesters → metabolism to Indications p-aminobenzoic acid ○ Anesthesia adjunct: Endotracheal intubation → Nerve toxicity (extremely rare) Paralysis: prevent injury, hoarseness ○ Radioculopathy - 0.03% ○ Surgery or mechanical ventilation ○ Parapelegia - 0.0008% Abdominal surgery - muscle relax tense = not Methemoglobinemia with Prilocaine, Benzocaine good view = safer In ○ Hepatically metabolized with O-toluidine ○ Prohibits any motion or response, while anesthesia ○ Clinically significant at 600 mg IV. NEUROMUSCULAR BLOCKERS Technically AntiACh agents, but not rly Drugs that inhibit the nicotinic receptors (NM) @ neuromuscular junction - nerve to muscle or motor end plate Nicotinic receptors - ionotropic receptors. Normal ○ 1 ACh -> conformational change -> high affinity for 2nd Ach w/-> Na+ ions enter -> depolarization -> AP Atracurium and Rocurium is the most commonly -> muscle contract used. Order of muscle paralysis ○ Face, eyes, fingers (small) ii. DEPOLARIZING ○ Limbs, neck, trunk (large) Succinylcholine/Suxamethonium ○ Intercostals, diaphragm (respi.) MOA Blockade Phase 1 Block: Depolarization ○ Nondepolarizing: NM blockade ○ Binds to NM -> Depolarization -> Transient ○ Depolarizing: NM agonist excess contractions (fasciculation) ○ Not metabolized at junction → no repolarization A. BLOCKADE ○ Flaccid Paralysis Nondepolarizing: NM blockade (antagonist) Phaes 2 Block: Desensitization ○ Tubocurarine: Prototype drug ○ Prolonged binding For poison arrow ○ Repolarized, yet desensitized ○ Short acting ○ long sustained depolarization = no refractory Mivacurium period (kahit repolar = no contract) Gantacurium Indications ○ Intermediate-acting ○ Anesthesia adjunct: Endotracheal intubation → Benzylisoquinolium: Atracurium, Paralysis: prevent injury, hoarseness Cisatracurium ○ Rapid sequence intubation due to quick Aminosteroid: Vercuronium, Rocuronium paralysis ○ Long Acting ○ Used in emergencies where the patient has not Pancuronium achieved fasting before the surgical procedure PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 12 of 13 ANESTHETICS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) James Louie D. Tronco, RPh, MD | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Side Effects ○ Life Threathening hyperkalemia From muscle twitches ○ Malignant Hyperthermia ??? → Ca2+ → muscle hypermetabolsim Tx Dantrolene ○ Muscle Pain/Myalgia - Common ○ Increased intragastric, intraocular and intracranial pressure ○ Cardiac Dysrhythmia iii. DRUG INTERACTIONS Enhanced effect ○ NMBA combos Non-depolarizing given *after* depolarizing Non-depo + Non-depo (same class = additive, different class = synergistic) ○ Inhaled anesthetics: plus malignant hyperthermia (rare) ○ Local anesthetics (large doses) ○ Antibiotics (aminoglycosides, tetracyclines, clindamycin) ○ Li – resembles cations → activates K + channels → blocks NMJ transmission ○ Antidepressants Decreased effect ○ NMBA combos: non-depolarizing given *before* depolarizing ○ Antiepileptics Disease interaction ○ Myasthenia Gravis: enhanced block ○ Burns: less block; higher doses needed (receptors increase) Residual block (Non-depolarizing) ○ Morbidity Respi. difficulty, complications, recovery delay ○ Spontaneous recovery ○ Pharmacologic recovery Neostigmine > edrophonium: Blocked AChEI→ more ACh → muscarinic receptors also bound → + atropine/glycopyrrolate Given for atracurium (reversible NMDA) Sugammadex: modified γ-cyclodextrin Binds rocuronium 1:1 NM bound rocuronium diffuses from receptor Free sugammadex binds rocuronium Very expensive PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Magalued, Mendoza Page 13 of 13