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Parenteral Agents

Parenteral Agents. Ideal Intravenous Agent. Rapid Onset, No Excitatory Side Effects Non-irritating, Water Soluble Analgesic @ Subanesthetic doses Rapid Emergence & Biodisposition No Respiratory & Cardiovascular Side Effects Cerebral Protectant, Non – Toxic Cheap!!!. Intravenous Drugs.

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Parenteral Agents

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  1. Parenteral Agents

  2. Ideal Intravenous Agent • Rapid Onset, No Excitatory Side Effects • Non-irritating, Water Soluble • Analgesic @ Subanesthetic doses • Rapid Emergence & Biodisposition • No Respiratory & Cardiovascular Side Effects • Cerebral Protectant, Non – Toxic • Cheap!!!

  3. Intravenous Drugs • Comparison to Inhalational Drugs • Controllability depends on: • Hyperventilaton • Inspired Concentration • Uptake Factors • Solubility, Cardiac Output, Gradient

  4. Intravenous Drugs • Easy To Overdose • Dissipation of Effects Depends on: • Distribution • Plasma volume to vessel rich group • Redistribution • VRG to muscle, skin, fat • Elimination • Biotransformation in Liver • Excretion by Kidney

  5. Distribution of Cardiac Output

  6. Opiods • A chemical substance that has a morphine like action in the body • The main use is for pain relief • These agents work by binding to opiod receptors, which are principally found in the CNS & GI tract

  7. Opiod Classification • Classified by either their chemical structure or their action on opiod receptors. • Classification by structure (semi-synthetic or synthetic) may be helpful in determining cross-allergy potential • Classification by action (agonist, agonist-antagonist, antagonist) provides insight into the result of an individual opiod

  8. Opioid Classification

  9. Opioid Classification

  10. Opioid Receptors

  11. Opioid Pharmacokinetics • Weak bases • Free base is more lipid soluble than ionized • High lipid solubility improves onset • Ionized form is needed for receptor binding • All bound to plasma protein • Albumin • Alpha-1 acid glycoprotein

  12. Opioid Pharmacokinetics • BIOTRANSFORMATION • Primarily in the liver • Morphine also in kidney • Remifentanil: plasma and tissue esterase • All have high first pass effect (hepatic extraction ratio) • Large oral:parenteral difference • Codeine least • Morphine, Meperidine high • Fentanyl approaches 1.0

  13. Opioid Effects • Analgesia • Sedation • Mood alteration • Respiratory depression • Anti-tussive • Nausea and Vomiting • Gastrointestinal • Biliary tract spasm • Miosis • Pruritis • Cardiovascular • Tolerance • Physical dependence • Addiction • Neuroendocrine • Thermoregulatory • Chest wall rigidity • Peripheral • Histamine release

  14. Opioid Effects • RESPIRATORY DEPRESSION • All opioids depress respiration • Caused by a dose-dependent decrease in the response of the respiratory center to carbon dioxide • The slopes of the alveolar ventilatory reponse to carbon dioxide are reduced and shifted to the right (there is less ventilation per amount of carbon dioxide)

  15. Opioid Effects • NAUSEA AND VOMITING • Common adverse side effect of any opioid, with no documented differences among the difference agents • High-dose opioids appear to inhibit the vomiting center • Naloxone will not reverse nausea and vomiting (can trigger it)

  16. Opioid Effects • SEDATION • Opioids can induce drowsiness and mental clouding (mu-2 and kappa receptor stimulation) • Profound sedation can occur when used with other CNS depressants (Benzodiazepines) • Addition of an opioid will likely reduce the amount of BNZ required

  17. Remifentanil (Ultiva)

  18. REMIFENTANIL (ULTIVA®) • Onset 30 seconds • Maintenance 0.05-2 mcg/kg/min • Ultrashort acting • Ester linkages result in rapid hydrolysis by non-specific plasma esterases • Allows for: • Lower dosage of Propofol • Shorter Recovery Time • Decreased Respiratory Depression during Recovery

  19. Context Specific Half-Life • Context Specific Half-Life Time required for drug concentration in the central compartment to decrease 50% after continuous infusion is stopped

  20. Propofol/Opiod Recovery

  21. Propofol (Diprivan)

  22. Propofol (Diprivan®) • 2,6-diisopropylphenol • Non-barbiturate anesthetic, chemically unrelated to other anesthetics (hypnotic) • Rapid IV induction 2-2.5 mg/kg • Loss of consciousness within 40 seconds • Recovery 10x more rapid than thiopental • Minimal post op confusion • Antiemetic properties • Undergoes Extensive Distribution & Rapid Elimination

  23. Propofol (Diprivan) • Pharmacokinetics • Onset: within 40 seconds • Peak effect: 1 minute • Duration: 5 – 10 minutes • Interaction/Toxicity: Potentiates CNS & Circulatory depressant effects of narcotics, sedative hypnotics and volatile agents

  24. PROPOFOL • Formulated in an oil in water emulsion • Soybean oil • Glycerol • Egg lecithin (egg yolks) • Potential culture medium • Propofol by Zeneca contains EDTA which slows microorganism growth • One generic contains sodium metabisulfite • Another generic contains benzyl alcohol

  25. PROPOFOL • Inhibits NMDA subtype of glutamate receptors • Agonistic activity at the β1 subunit of GABAA receptor • Rapid redistribution • Distribution half-life 2-4 minutes • Elimination half-life 3-12 hours • Metabolized in the liver • Clearance of propofol exceeds liver blood flow suggesting extrahepatic metabolism

  26. PROPOFOL Cardiovascular Effects • 30% reduction in systemic blood pressure with induction and/or maintenance doses • Decreased cardiac output secondary to decrease in stroke volume • Peripheral vasodilation • No change in heart rate • Significant hypotension in the elderly, hypovolemic, & patients with limited cardiac reserve

  27. PROPOFOL Respiratory Effects • Decreased tidal volume • Apnea with induction dose (30%) • No histamine release

  28. PROPOFOL Other Effects • Amnesia • Antiemetic • Pain on injection • Irritates venous intima and activates kallikrein-kinin system to increase bradykinin production • Large vein, rapid infusion and slow administration, lidocaine may help

  29. PROPOFOL Other Effects • Propofol infusion syndrome • MI, hyperkalemia, metabolic acidosis, rhabdomyolysis, heart failure • Most often associated with prolonged, high-dose infusions ( >5 mg/kg/h for more than 48h) • May occur with high dose, short-term infusion during surgery • Most often in children

  30. PROPOFOL • “Diprivan® Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products” • Egg allergy? • Egg yolks contain lecithin • Egg whites do not • Sulfite Allergy • Benzyl alcohol hypersensitivity

  31. Ketamine

  32. KETAMINE (KETALAR®) • Dissociative Anesthetic • Phencyclidine derivative (1963) • Water soluble • Lipid soluble • Dissociation • Analgesia • Amnesia • Catalepsy

  33. “Nothing in my wildest dreams of minimal equipment ever approached the simplicity and the safety of the ketamine technique under these true test conditions.” Dr. Roy Wilson, aftermath of 1976 Guatemala Earthquake

  34. KETAMINE • Pharmacokinetics • Peak plasma concentration • 1 minute IV • 5 minutes IM • 30 minutes oral • Redistribution • 15 minutes IV • 30-120 minutes IM • Sedation/Analgesia (Deep) • IV, 0.5 – 1 mg/kg • IM, 2.5 – 5 mg/kg • PO, 5-6 mg/kg • Induction (GA) • IV, 1-2.5 mg/kg • IM, 5-10 mg/kg • In the Dental Clinic, we often use 2.2 mg/kg IM ( to allow for IV )

  35. KETAMINE • Respiratory Effects • Upper airway reflexes intact • Spontaneous ventilation • Bronchodilation • Salivary & Tracheobronchial Secretions • increased risk of laryngospasm • (Use Anticholinergic for Antisialogogue Effect) • IM onset of action for IM Glycopyrrolate is 15-30 minutes while IV onset is < 1 minute so rapid IV insertion is ideal

  36. KETAMINE • Cardiovascular effects • Increases BP, HR, CO • Weak antidysrhythmic • Increases coronary perfusion • Increases myocardial oxygen consumption

  37. KETAMINE • Emergence phenomena • Psychic reactions • 0-50% in adults • 0-10% in children • Risk factors • Suppression by benzodiazepines • Incidence related to dose and rate of administration • Nausea and Vomiting • 0-43% • Late occurrence

  38. BENZODIAZEPINES • Benzodiazepine Receptor • facilitates GABA-mediated chloride ion influx • Favorable therapeutic index • Anxiolysis • Sedation • Amnesia • Anti-convulsant • Muscle relaxation

  39. Midazolam (Versed)

  40. MIDAZOLAM • Water soluble • No venous irritation or phlebitis • Improves IM uptake • High lipid solubility when injected • Closure of benzodiazepine ring at physiologic pH • No active metabolites • Elimination half-life 2.5 hours • CYP 3A4 inhibitors intensify and prolong the effects of benzodiazepines

  41. Diazepam (Valium)

  42. Diazepam (Valium) • Dosing: • Premedication & Sedation • IV / IM / PO / Rectal, 2-10 mg (0.1 – 0.2 mg/kg) • Anticonvulsant • IV, 0.05 – 0.2 mg/kg q 10-15 minutes, (max 30 mg) • Elimination: Hepatic

  43. Diazepam (Valium) • Pharmacokinetics • Onset • IV, < 2 minutes • PO, 15 minutes to 1 hour • Peak Effect • IV, 3 – 4 minutes • PO, 1 hour • Duration • IV, 15 min – 1 hour • PO, 2 – 6 hours

  44. Diazepam (Valium) • Caution: • Inject slowly through large veins to reduce thrombophlebitis • (aka we are not going to use it IV) • Return of drowsiness may occur 6-8 hours after dose because of enterohepatic recirculation • Sedative & Circulatory depressant effect potentiated by opiods & other CNS depressants

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