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Maintenance Barbiturates - Thiopental, Methohexital Provides sustained anesthesia - Replaced by propofol...

Maintenance Barbiturates - Thiopental, Methohexital Provides sustained anesthesia - Replaced by propofol BZDs - Commonly used in the perioperative period include midazolam, lorazepam, and less Recovery frequently diazepam Time from discontinuation of anesthetic until consciousness - Produce minimal depression of ventilation, and protective reflexes return although transient apnea may follow rapid IV administration of Midazolam for Anesthesia Protocols induction of anesthesia Etomidate - GABA-mimetic - An IV anesthetic with hypnotic but not For minor procedures analgesic effects and is often chosen for Conscious sedation techniques (IV agents with local its minimal hemodynamic effects anesthetics) Ketamine - NMDA receptor inhibitor For more extensive surgical procedures - Partially water-soluble; highly lipid-soluble IV drugs to induce the anesthetic state, inhaled anesthetics phencyclidine derivative (with or without IV agents) to maintain an anesthetic state, - Produces significant analgesia and neuromuscular blocking agents to effect muscle - “dissociative” anesthesia” – cataleptic state relaxation - S(+) form is more potent than R (-) isomer Dexmedetimidine - Highly selective α2-adrenegic agonist Assessment of depth of anesthesia during surgery - Principally used for the short-term sedation Vital sign monitoring of intubated & ventilated Cerebral monitoring (EEG) Opioid Analgesics - Strong opioids (morphine, fentanyl, sulfentanyl) Mechanism of Action in General Anesthetics - Analgesic agents and are distinct from Anesthetics = CNS depressant general anesthetics and hypnotics Increase inhibitory (GABA) synaptic activity - Routinely used to achieve postoperative Inhaled anesthetics, Barbiturates, BZDs, Etomidate, analgesia and intraoperatively as part of a balanced anesthesia regimen and Propofol Decrease excitatory (glutamate or ACh) synaptic activity Local Anesthetics Inhaled anesthetics (Nicotinic receptor antagonists) Ester Type: 1i - Cocaine Ketamine (NMDA receptor antagonist) - Procaine - Chloroprocaine Inhaled Anesthetics Amide Type: 2i - Lidocaine Nitrous Oxide - Non-volatile gas - Bupivacaine - Weakest anesthetic; potent analgesic - Prilocaine Desflurane - Popular anesthetic for out-patient procedures MOA: blockade of voltage-gated sodium channels Sevoflurane - AOC: children (less pungent) Isoflurane Factors that determine systemic absorption of local anesthetics: Enflurane - AOC: for asthmatic patient Halothane - AOC: children (less pungent) Dosage - Most hepatotoxic Site of injection Methoxyflurane - Potent anesthetic; weakest analgesic Drug-tissue binding - AOC: during labor Local tissue blood flow The rest is volatile liquids Use of a vasoconstrictor (e.g. epinephrine) - downward direction (N to M): increasing potency Physicochemical properties - upward direction (M to N): increasing MAC Note: MAC – is the median effective dose (ED50) of the anesthetic, Toxicities: expressed as the percentage of gas in a mixture required to achieve that effect Systemic toxicity Toxicities: CNS toxicity Acute Toxicity sedation, light-headedness, visual and auditory - Nephrotoxicity disturbances and restlessness metabolism of enflurane and sevoflurane may generate Cardiotoxicity compounds that are potentially nephrotoxic Bupivacaine – most cardiotoxic enflurane with prolonged exposure – significant renal injury Local toxicity - Hematoxicity nitrous oxide – megaloblastic anemia Neural injury - Hepatotoxicity local anesthetic agents were potentially neurotoxic Halothane hepatitis durocaine – a spinal anesthetic formulation - Malignant hyperthermia containing procaine important cause of anesthetic morbidity and mortality Transient Neurologic Symptoms (TNS) Chronic Toxicity Syndrome of transient pain or dysesthesia has - Mutagenicity, teratogenicity, carcinogenicity been linked to use of lidocaine for spinal anesthesia Intravenous Anesthetics Propofol - Most frequently administered for induction DRUGS USED TO TREAT DISEASES OF THE BLOOD, of anesthesia INFLAMMATION, & GOUT - Also used for maintenance of anesthesia (continuous infusions) - Milky white appearance; slightly viscous; COAGULATION DISORDER pH ~7 - Formulated as an emulsion containing: Hemostasis 10% soybean oil Balance 2.25% glycerol Vascular event: vasoconstriction 1.2% lecithin Cellular event: platelet migration and aggregation susceptible px may experience allergic reactions Protein event: coagulation factor cascade - Act as hypnotic but does not have analgesic properties Stimuli - Has antiemetic action Endothelial injury Fospropofol - A water-soluble prodrug of propofol Presence of Foreign bodies rapidly metabolized by alkaline Stasis of blood phosphatase, producing propofol, Arterial clots: platelet-rich “white thrombi” phosphate, and formaldehyde - Licensed by the FDA in 2008 as a sedating Venous clots: fibrin-rich “red thrombi” agent for use in adult patients during monitored anesthesia care Coagulation Cascade Module 4 – Pharmacology Page 17 of 33 RJAV 2022  - Given as IV infusion for post angioplasty to prevent acute thrombosis Adenosine and Dipyridamole Phosphodiesterase - MOA: inhibits adenosine uptake, inhibitor CGMP phosphodiesterase and CAMP phosphodiesterase - Use: Primary and Secondary prevention of acute myocardial infarction (only effective if given with other antiplatelet or anticoagulant drugs) - Adverse effects: “coronary steal” phenomenon Cilostazol - Effect: vasodilator - Use: intermittent claudication Anticoagulant Direct thrombin inhibitor MOA: - Interfere the coagulation cascade - Inactivate of inhibit factor II-a directly Parenteral Hirudin Intrinsic pathway: XII, XI, IX, X - natural product from Leeches Extrinsic Pathway: III, VII X Lepirudin - recombinant form; clinically used; DOC for HIT or Heparin induced Dissolution thrombocytopenia Bivalirudin - small molecule that inactivates factor II-a; used as a antithrombotic post angioplasty Argatroban - alternative in the management of HIT Oral Dabigatran - Oral factor II-a inhibitor - Prophylaxis against VTE - Substitute or Alternative for warfarin - Adverse effects: bleeding - Drug interaction: CYP3A4 inhibitor Indirect Thrombin MOA: inhibits factor synthesis or formation of inhibitors active clotting factors (factor II-a) Parenteral Heparin - Sulfated mucopolysaccharide; released by platelets Anti-thrombotics - 2 forms: Anti-platelet Aggregants - High molecular heparin/ Regular/ Thromboxane synthesis Aspirin Unfractionated inhibitor - Low molecular heparin/ Fractionated MOA: Heparin - inhibits COX of platelets, therefore Regular/ HMWH/ Unfractionated Heparin decreasing levels of TXA2; (UFH) Irreversibly acetylates COX of - MOA : binds and forms an active platelets complex with anti thrombin or anti - For primary and secondary thrombin III prevention of acute myocardial - Monitoring parameters : aPTT / PTT infarction LMWH/ Fractionated Heparin and Analogues - Secondary prevention of stroke - MOA : forms active complex with antithrombin III Adverse effects: bleeding, GI intolerance, - Enoxaparin, Dalteparin, Tinzaparin ulcer, bronchospasm, hypersensitivity, - Fondaparinux (synthetic salicylism polysaccharide ADP inhibitor Thienopyridines - Ticlopidine, Clopidogrel, Prasugrel Uses: (HMWH and LMWH) - Given in for primary and secondary - When coagulation is needed for prevention of acute myocardial pregnancy (LMWH – choice for infarction (given at least 9 months pregnant women) after ACS) - When initiating anticoagulant therapy - Given post- angioplasty - Management of ACS (DOC: LMWH) - MOA: irreversible inhibitor of P2Y12 - Management of VTE (venous receptor thromboembolism) - Adverse effects: Adverse Effects: Ticlopidine : causes - Bleeding (antidote: Protamine thrombocytopenia, neutropenia, risk sulfate) of thrombotic thrombocytopenic - HIT purpurea - Osteoprosis Oral Non-Thienopyridines Oral anti-factor Xa - Ticagrelor – Given for post- - Direct factor Xa inhibitor angioplasty (to prevent acute - Rivaroxaban, Apixaban thrombosis) - Used in the management of venous GIIb / IIIa inhibitors MOA: blocks the G II b / III a receptor to thromboembolism prevent platelet cross-linking or aggregation - Less adverse effects Older agents - Abciximab, Eptifibatide, Tirofiban - VKORC (vitamin K epoxide reductase) inhibitor Module 4 – Pharmacology Page 18 of 33 RJAV 2022  - MOA: inhibits Vitamin K epoxide - Evolocumab, Alirocumab reductase resulting to inhibition of - MOA: inhibits PCSK9 resulting to increase in LDL receptors formation of active Vitamin K allowing increase in hepatic and tissue uptake or utilization of - Examples : Dicumarol, cholesterol Phenprocoumon, Indanedione - Evolocumab – used in the management of hypercholesterolemia (Phenindione, Anisindiones), that is refractory to other drug Warfarin - Adverse effects : Bleeding, RHEUMATOLOGIC DISORDERS Intracerebral hemorrhage, Abnormal bone development, Cutaneous necrosis Inflammatory Warfarin Autoimmune - Monitoring parameter: PT-INR Affects the muculoskeletal system - PT INR: < 2 : underdose | >3 Joints overdose Muscles Fibrinolytic Bones MOA: Activate the fibrinolytic system by conversion of the inactive Tendons and Ligaments proenzyme, plasminogen into the active enzyme plasmin, that degrades fibrin Streptokinase Source: Beta hemolytic streptococci INFLAMMATION Adverse effects : bleeding, hypersensitivity A non-sprecific immune reponse against an adverse Note: stimulus. - give premeds before running Microbial invasion infusion: antihistamine, Physical injury glucocorticoids Purpose: For protection and a part of healing process - avoid subsequent exposures APSAC Aminosylated plasminogen streptokinase activator complex Cardinal Signs of Inflammation Recombinant t-PA Alterplase, Teneclepase, Reteplase Used in the management of acute venous thromboembolism Within 3 hours of an acute ischemic stroke Within 30 mins of an acute myocardial infarction that is ST segment elevated Pro Coagulant Vitamin K - 3 forms : Vitamin K1 (phylloquinone or phytonadione); Vitamin K2 ( menaquinone); Vitamin K3 (menadione) - Used in the management of bleeding secondary to Vitamin K deficiency - Prevent hemorrhagic disorder in the newborn Epsilon Tranexamic acid (analogue) Calor Tumor Functio laesa aminocaproic acid MOA: inhibits the action of tPA and uPA Aprotein MOA: directly inhibits plasmin Rubor Dolor Used in the management of t-PA-associated bleeding Autoimmune Diseases DYSLIPIDEMIA Arise from overreactive immune response Abnormal lipid profile T cells Hypercholesterolemia: ↑ LDL ± ↓ HDL B cells Hypertriglyceridemia: ↑ Serum triglyceride Adversely target substances and tissues normally present in the body Drugs for Dyslipidemia HMG-COA reductase Inhibitor Rheumatologic Diseases: - MOA: inhibit the first committed step in cholesterol biosynthesis - Cholesterol synthesis: peaks at height of sleep Rheumatoid Arthritis – affects the synovium - Examples: (-statin) Arthritis – multiple, symmetrical Long acting (anytime) : Atorvastatin, Rosuvastatin Morning joint stiffness – (~1 hour) Short acting (at bedtime) : Simvastatin, Pravastatin Hand involvement - Adverse effects: Myalgia, Muscle pain (Myositis) , Rhabdomyolysis Fibric acid derivative Osteoarthritis – most common - MOA: increase activity of the enzyme lipoprotein lipase (LPL) Non-inflammatory - LPL: takes up and breaks down triglyceride into fatty acid and Not an autoimmune disease glycerides or glycerol = lowers serum triglyceride - Examples: Fenofibrate, Gemfibrozil Systemic Lupus Erythematosus - Use: Drug of choice in the management of hypertriglyceridemia “Lupus” - Adverse effects: Myositis, Myalgia, Rhabdomyolysis Butterfly-shaped rash Nicotinic acid Photosensitivity - A form of niacin - MOA: inhibits synthesis and release of VLDL from the liver Renal complications: Nephritis - Use: alternative to fibrates for hypertriglyceridemia - Adverse effects: hepatotoxicity at high doses, flushing Ankylosing Spondylitis Bile acid binding resins or Bile acid sequestrant Bamboo spine - Cholestyramine, Colestipol Enthesitis - MOA: inhibits recycling of bile acids Sacrolitis - Use: add-ons of statins Cholesterol transport inhibitor Drugs/ Agents - MOA : inhibits intestinal cholesterol uptake is mediated by NPC1L1-like transporter (Niemann Pick C1-Like-1) - Ezetemibe ANALGESICS - Used as an add-on for statins PCSK9 inhibitors Analgesia – loss of pain perception - Proprotein convertase subtilisin/kexin 9 (PCSK9) Module 4 – Pharmacology Page 19 of 33 RJAV 2022  NON-NARCOTICS Anti-inflammatory: 3.2-4 g/day - MOA : COX inhibition P-aminophenol Derivatives Anti-pyretic: 0.3-1.2 g/day - MOA : inhibits response to IL-1 and Acetaminophen or Paracetamol (Tylenol ®) cutaneous vasodilation Weak prostaglandin synthesis inhibitor in the periphery Anti-platelet: NMT 325 mg/day (COX inhibitor) - MOA : COX inhibition in the platelets → TXA2 Antipyretic activity (Potent aggregant) synthesis inhibition Lacks anti-inflammtory activity even at higher doses - ↓dose :↑ antiplatelet 1st line for OA - anti-aggregation = bleeding substitute for Aspirin Anticancer: potential use - Chronic inflammation (overexpression of Advantage: safe in pregnant and lactating women and COX-2) → Cancer among children Hepatotoxicity Toxicities: Risk factors: Gastric effects: dose > 5 mg/kg/day - gastritis, gastrointestinal bleeding (COX-1 pre-existing liver disease inhibition) concomitant use of CYP1A2 inducers - Treatments: PPI’s – 1st line NSAIDs Misoprostol – alternative Weak organic acids EXCEPT Nabumetone which is Reversible Decrease in GFR: metabolized into acetic acid derivatives - renal vasoconstriction → low GFR COX inhibitors → inhibits Hypersensitivity reaction: Prostaglandin - NSAID-induced Bronchial Asthma synthesis - Treatment: Zileuton, Montelukast, Zafirlukast Cyclooxygenase (COX) Enzymes - ASA Hypersensitivity Syndrome – Nasal polyposis, Chronic sinusitis Effects in Serum Uric Acid Levels - Aspirin, Tolmetin, Salicylates - < 2g/day: decreased renal excretion of urate → Antagonize uricosuric effect of uricosurics - C/I in Gout patients taking uricosurics CNS effects (ASA, Salicylates) - Mild: salicylism – hyperthermia, tinnitus, hyperventilation - Severe: acid-base imbalances, hallucination Cyclooxygenase (COX) Enzymes - Fatal: Respiratory depression Reye’s syndrome (ASA) NSAIDS – reduced prostanoid - Children: with Fever, Viral infection + ASA production and thus PGE2 for - Hepatic Failure instance will be lower - Encephalopathy (brain damage) Pyrazolones Phenylbutazone Dipyrone Sulfinpyrazone – Not an NSAID, Uricosuric Powerful analgesia and inflammatory Toxicities: Hemtologic: Isoforms of COX: - Thrombocytopenia (low platelet), Aplastic 1. COX-1 anemia (↓platelet, ↓RBC, ↓WBC), Agranulocytosis (↓granulocytes: BEN) Constitutive Enzymes Nephrotoxicities: PGs for homeostatic functions (e.g., gastroprotection) - Acute Tubular Necrosis, Anasarca (massive edema), Nephrotic Syndrome 2. COX-2 Indole Indomethacin Inducible Enzymes PGs for inflammation (PGE2) - Blocks COX-1 > COX-2 - High risk of GI effects Uses: NSAIDs - To enhance closure of Patent Ductus Arteriosus) Non-Selective COX inhibitors - Management of Bartters Syndrome (defect in Aspirin the reabsorption of electrolyte by the kidney) Pyrazolones - Treatment of pain in acute gout Indole Pyrrole Alkanoic Tolmetin Acid - C/I: Gout Pyrrole Alkanoic Acid Phenylacetic True phenylacetates: Phenylacetic Acid Acids - Sulindac Fenamates - Alclofenac Oxicam - Diclofenac Propionic Acids Acetic acid derivatives: - Ketorolac Specific COX-2 Inhibitors - Etodolac - Nabumetone Celecoxib Etoricoxib Sulindac – SJS/TEN Valdecoxib Ketorolac – treatment of pain after surgery Rofecoxib Fenamates Mefenamic acid - Advantage: less associated to gastric effects Meclofenamate - Increased risk of acute thrombotic events Flufenamic acid - Analgesia only Non-selective COX Inhibitors: - Used for NMT 5 days (acute pain) - Never given in children Aspirin Prototype; Irreversible COX inhibitor - Safest for children: Ibuprofen Oxicam Piroxicam Pharmacodynamics : - Bleeding and ulceration are more likely to Analgesic: >> COX-2 sites of the brain (central) and COX inhibition - highest risk of GI effect (peripheral) Module 4 – Pharmacology Page 20 of 33 RJAV 2022  Propionic Acids Ibuprofen Hyperventilation Naproxen Mydriasis Ketoprofen RhinorrheaHostility Flurbiprofen Contraindications Head trauma Pregnancy - Analgesic and anti-inflammatory D/I with full & partial agonists → - Ibuprofen and Naproxen: additional Antagonistic antipyretic - Naproxen: used for fever of malignancy Classifications: NARCOTICS Opiates Opioids Narcosis Based on Sources Synthetic Insensibility Stupor Opioid Agonists Strong Full Agonists Based on Mild to Moderate Full Agonist Papaver somniferum Pharmacodynamics Partial Agonist Brown gum → crude opium Opioid Antagonist Morphine (10%) Mechanism of Actions: Based on sources Opiates – Natural opium alkaloids 1. Opioid Peptides – endogenous Morphine - Standard comparison as analgesic Opioid-like pharmacologic properties: - Undergoes extensive first-pass effect Endorphins Enkephalins Codeine Met-enkephalin - Standard of comparison as antitussive Leu-enkephalin - Less effective than Morphine Dynorphins Thebaine - Precursor in the synthesis of Naloxone 2. Opioid Receptors Opioids Majority of opioid-mediated effects Semisynthetic: Mu: Heroin Analgesia - Diacetylmorphine/diamorphine Euphoria - common drug of abuse Miosis Constipation Apomorphine Respiratory depression - not an analgesic Kappa: - Dopaminergic: DA reuptake inhibitor; D2 agonist - Emetic Additional analgesia in women - Management of Parkinsonism Delta: Spinal analgesia Semisynthetic Morphine Derivatives Modulation of hormone and neurotransmitter release - Hydroxymorphone, Oxymorphone - 8-12x more potent than Morphine Opioid Agonists Mechanism of Action Stimulate the release and mimic the action of Semisynthetic Codeine Derivatives endogenous opiod peptides - Hydroxycodone, Oxycodone Actions Central - 8-12x more potent than Codeine Analgesia Synthetic: Euphoria Methadone Miosis - similar efficacy with Morphine Cough suppression - longer DOA Respiratory depression - less rapid development of tolerance Emesis - to wean off patients addicted to Morphine or Heroin Peripheral Meperidine (aka Pethidine) Constipation - no cardia or biliary effect Hypotension - converted to Normeperidine Bradycardia - used for acute pain only Histamine release - A/E: seizures Tocolysis Biliary contraction Levorphanol Clinical Uses Analgesics - 5-7x potent than Morphine Mild – Tramadol - D-isomer: Dextrometorphan Moderate – Codeine - Antitussive Severe – Morphine Management of acute pulmonary Loperamide & Diphenoxylate edema – Morphine - antidiarrheals Ability to reduce anxiety effect Diphenoxylate Can lower afterload and preload - causes addiction Anesthetic adjuncts - co-administer with Atropine Antidiarrheals Diphenoxylate Tramadol Loperamide - mild pain Antitussives - derivative of codeine Dextromethorphan Fentanyl & related drugs Toxicities Respiratory depression - Alfentanyl & Sufentanyl greatest threat - 100x more potent than Morphine Increase in Intracranial Pressure C/I: head trauma Pentazocine Tolerance: - partial kappa agonist 2-3 weeks of chronic use Physical dependence withdrawal symptoms: Frequent yawning Module 4 – Pharmacology Page 21 of 33 RJAV 2022  Based on Pharmacodynamics - Management of severe hyperuricemia; Strong Full Agonists Morphine and related drugs reduce risk of urate stone formation Fentanyl - Prevent or Management of Tumor Lysis Heroin syndrome Methadone - Adverse effect: Rash or SJS-TEN); Oxymorphone Aplastic anemia; Hepatitis; Renal failure Hydromorphone Febuxostat - Indication: the same as allopurinol Meperidine - Used if patient cannot tolerate allopurinol Levorphanol - Advantage: not associated with SJS-TEN Mild to Moderate Full Agonist Codeine and related drugs - Adverse effects: increase cardiovascular Hydrocodone mortality, myocardial infarction Oxycodone - Contraindication: CAD Tramadol Xanthine oxidase MOA : facilitate conversion of urate to a more Partial Agonist Nalbuphine inhibitors soluble product, allantoin. Butorphanol Recombinant Urate Oxidase Pentazocine Buprenorphine Pegloticase Opioid Antagonist - Treatment of Narcotic - For patient with refractory poisoning - CI: presence of G6PD deficiency Rasburicase Naloxone - Used in patients who are at risk of Naltrexone developing tumor lysis syndrome Nalorphine - Management of elevated uric acid levels Nalmefene - Adverse effects: hemolytic anemi Levallorphan DMARDs GOUT Disease-modifying antirheumatic drugs Metabolic disorder Chemically diverse agents Increase deposition of monosodium urate crystals in the Alter or reverse disease progression tissue + hyperuricemia (increase of total uric acid in the body Aka SAARDs (Slow – acting ARDs) Signs and symptoms : Full effect: 6–12 months Acute arthritis : Cardinal features of inflammation ( rubort, tumor, Classifications: calor, function laesa) Small molecule drugs usually monoarticular ( one joint | 1st Nonbiologic Agents Metarsophalangeal joint) In elderly women : polyarticular usually arthritic Large molecule drugs joint Biologic Agents Recombinant DNA technology Chronic gout : (+) tophus – subcutaneous deposit of MSU crystal Nonbiologic Agents (+) gouty nephropathy – form of chronic kidney Methotrexate - 1st line DMARD disease - MOA: blockade of AICAR transformylase (+) uric acid stone formation and Thymidylate synthetase → ↑ AMP → enhance release of Adenosine Drugs for Gout - Hence: inhibition of inflammation Acute Gout - blocks chemotaxis Pain control - NSAIDs (except aspirin and salicylates) - low dose; higher doses = anticancer - Drug of choice: short acting and lipid effect soluble Antimalarials - 2nd line DMARDs - Indomethacin - Hydroxychloroquine, Chloroquine - Ibuprofen - MOA: blocks T lymphocyte responses to - Diclofenac mitogens; inhibits chemotaxis and inhibits Anti-inflammatory Colchicine DNA & RNA synthesis - MOA: inhibits microtubule synthesis - T/E: Optic neuritis, cinchonism (tinnitus, - Adverse effects: hematologic (aplastic headache, dizziness) anemia, hemolytic anemia, Gold Compounds - Parenteral: Aurothiomalate, thrombocytopenia); acute hepatitis; renal Aurothioglucose failure; bloody diarrhea - Oral: Auranofin - Contraindication: elderly, presence of renal Sulfasalazine - Metabolized to: Sulfapyridine (active for failure DMARD), 5-aminosalicylate - Note: Diarrhea is the first indication of (Meselamine: IBD) toxicity - A/E: Nausea and vomiting, skin rashes Oral glucocorticoids and discoloration, hematotoxicities - Prednisone Leflunomide - metabolized to: A77-1726 - For polyarticular arthritis in elderly patients - inhibits dihydroorotate dehydrogenase Adrenocorticotropic hormone (IM ACTH) - inhibits ribonucleotide synthesis - For refractory polyarticular acute gout for elderly patients with renal failure Biologic Agents Chronic Gout Abatacept - T cell modulating biologic Hypouricemic therapy - inhibits activation of T cells - Goal : decrease serum uric acid;