Intravenous Sedatives and Hypnotics - Part I PDF

INTRAVENOUS SEDATIVES AND HYPNOTICS University of Puerto Rico – Medical Sciences Campus School of Nursing – Nurse Anesthesia Program E N F E 7 1 3 1 – A d va n c e d Pharmacology I J o r g e H e r n a n d e z , D N A P, C R N A Hypnotics Sedatives Sedatives: drug that induces a state of calm or s...

INTRAVENOUS SEDATIVES AND HYPNOTICS University of Puerto Rico – Medical Sciences Campus School of Nursing – Nurse Anesthesia Program E N F E 7 1 3 1 – A d va n c e d Pharmacology I J o r g e H e r n a n d e z , D N A P, C R N A Hypnotics Sedatives Sedatives: drug that induces a state of calm or sleep. Anxiolytics Hypnotic: drug that induces hypnosis or sleep. Anxiolytic: drug that reduces anxiety. Rapid drug induced uncounscioussness GENERAL ANESTHESIA Sedative-hypnotics Chemical Structures 50% erythrocytes + 48% Albumin Propofol (1.5 – 2.5 mg/Kg Induction) Ø 2,6-diisopropyl phenol Ø IV as a 1% solution 10% soybean oil 2.25% glycerol 1.2% purified egg Discard 6 hrs. afer opening medium maintains isotonic with blood emulsifier Ø Formulation supports bacterial growth and increases triglyerides with prolonged infussion 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Propofol § Mixing of propofol with other drugs is not recommended § Lidocaine + propofol could result in droplets that pose risk of pulmonary embolism Propofol Alternatives § Ampofol: low-lipid emulsion that does not require preservative but has higer pain on injection § Aquavan & fospropofol: prodrug has risk of infection, pain on injection, hypertryglyceridemia and pulmonary embolism. • Formulations with cyclodextrins: non-lipid formulation 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Propofol Mechanism of Action § Selective modulator of GABAA receptors. Evidence of potentiation at glycine receptors. § Immobility not caused by drug-induced spinal cord depression (as opposed to volatile anethetics). 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Propofol Pharmacokinetics • Clearance of propofol from plasma exceeds hepatic blood flow. Tissue uptake (first-pass into lung) Hepatic oxidative metabolism P450 Rapid and extensive Water soluble sulfate and glucuronic acid Drug Distribution 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Propofol Clinical Uses “Drug of Choice” § Induction of Anesthesia (1.5 to 2.5 mg/kg IV or blood levels of 2 to 6 𝜇/mL ü Children Higher dose on a mg/kg basis Larger central distribution & clearance rate ü Elderly Require a lower induction dose 25% - 50% Smaller distribution & clearance rate, & pharmacodynamic activity Awakening without residual CNS effects occurs at plasma concentrations of 1.0 to 1.5 𝜇/mL 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Propofol Clinical Uses Intravenous Sedation Short context-sensitive half-time & short site equilibrium (ideal) Typical conscuouss sedation 25 to 100 𝜇𝑔/kg/min Low incidence of nause and vomiting and residual sedation Mechanical Ventilation & Cardiac Surgery Modulates postop. hemodynamic response (decreased incidence of HTN & Tachycardia) 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Propofol Clinical Uses • Maintenance of Anesthesia: 100 tp 300 mcg/kg/min (often in combination with an opioid). • Nonhypnotic Therapeutic Applications 1. Antiemetic Effects – subhypnotic dose of propofol (10 – 15 mg IV) 2. Anticonvulsant Activity – possesses antiepileptic properties and GABA-mediated presynaptic and postsynaptic inhibition of chloride ion channels. 3. Attenuation of Bronchoconstriction – decreases prevalence of wheezing after induction & intubation in healthy & asthmatic patients. Formulation with metabisulfite can caus bronchoconstriction in asthmatic patients. 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Solid squares = wheezing Respiratory resistance after tracheal intubation is less after induction of anethesia with thiopental or etomidate. 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 • • Interaction with Opioids (Pharmacokinetics) 1. Alfentanil and propofol have effect on each others plasma concentration through changes in elimination and distribution clearance. 2. Coadministration increases remifentanil concentration (decrease in central Vd and distribution clearance of remifentanil by 40% & elimination clearance by 15%) Interaction with Opioids (Pharmacodynamics) 1. Coadministration with any of phenylpiperidines (fentanyl and cogeners) show synergism. 2. The higher the opioid dose, the less propofol is needed. 3. Short acting opioid = use low dose propofol / Long acting opioid = use higher propofol dose Effects on Organ Systems Effects on Organ Systems 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Effects on Organ Systems/Central Nervous System 1. Decreases cerebral metabolic rate for oxygen (CMRO2). 2. Decreases cerebral blood flow (CBF). 3. Decreases intracranial pressure (ICP). 4. Large doses can decrease blood pressure significantly and consequently, cerebral perfussion pressure (CPP). 5. CPP = MAP – (MAP or ICP) whichever one is greater. 6. Propofol does not affect cerebral autoregulation 7. Produces EEG changes similar to thiopental (including burst suprrresion). 8. SSEPʼs are not signigicantly modified (unless addtion of N2O or volatile) 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Effects on Organ Systems/Cardiovascular System • Decreases systemic blood pressure often accompanied by decrease in SVR and CO. • Inhibition of sympathetic vasoconstrictor nerve activity. • Negative inotropic effect • Blood pressure effects of propofol may be exaggerated in hypovolemic patients, elderly and compromised left ventricle. • Addition of N2O does not alter CV effects & pressor response to ephedrine is augmented. • HR typically remains unchanged • Acceptable in patient with Wolff-Parkinson-White syndrom and does not prolong QT. decrease in intracellular calcium availability. 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Effects on Organ Systems/Cardiovascular System Thiopental l l Propofol 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Effects on Organ Systems Bradycardia Related Death v Profound bradycardia and asystole have been described in healthy adult patients even with anticholinergic prophylaxis (1.4:100,000). 5 mg/kg/hr v Increases risk of oculocardiac reflex during pediatric strabismus surgery repair. v Decreased responsiveness to atropined may be observed. v May require treatment with Isoproterenol 10 mg/kg/hr 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Effects on Organ Systems Hepatic and Renal Function Lungs • Does not affect hepatic or renal function • Dose-dependent depression of ventilation (apnea occurring in 25 – 35% of patients after induction. • Uric acid excretion may manifest as cloudy urine but does not signify renal damage. Propofol Infusion Syndrome • Opioids potentiate respiratory depression. “Can occur with prolonged infusions” • Ventilatory response to arterial hypoxemia is decreased. • Maintenance infusion will decrease frequency and tidal volume. 1. 2. 3. 4. Hepatocellular injury Lactic acidosis Bradydysrhythmias Rhabdomyollysis 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Effects on Organ Systems Intraocular Pressure • Propofol is associated with significant decrease in intraocular pressure. Coagulation • Does not alter test of coagulation or platelet function. • Inhibit platelet aggregation that is induced by proinflammatory lipid mediators including thromboxane A2 & platelet activating factor. Other Side Effects (oil-in-water emulsion formulation related) • Bradycardia, risk of infection, pain on injection and hypertiglyceridemia Allergic Reactions • Allergenic components: phenyl nucleus and diisopropyl side chain. • Diisopropyl radical present in many cosmetic formulations. • Anaphylaxis on first exposure has been observed, especially if Hx of other allergiesl, often NMBDʼs 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Effects on Organ Systems Lactic Acidosis Proconvulsant Activity • Prolonged high-dose (>75 mcg/kg/min) for longer than 24 hours. • Seizure like movement reflect a subcortical origin. • Unexpected tachycardia should prompt lab. evaluation for metabolic acidosis. • Prolonged myoclonus can be observed. • Metabolic acidosis (reversible when early and discontinued). • Reflect poisoning (cytopathic hypoxia) of the electron transport chain & impaire oxidation of fatty acids. • Differential diagnosis with anion-gap • No reason to avoid propofol in patients with history of seizures. Abuse Potential • 2009 - Michael Jackson 𝜸 − 𝑨𝒎𝒊𝒏𝒐𝒃𝒖𝒕𝒚𝒓𝒊𝒄 𝑨𝒄𝒊𝒅 𝑨𝒈𝒐𝒊𝒔𝒕𝒔 Effects on Organ Systems Antioxidant Properties • • • Potent antioxidant properties (resemble Vitamin E). Neuroprotective effect of propofol related to antioxidant properties of phenol ring. Inhibits lipid peroxidation (benficial in acute lung injury and coronary artery bypass graft surger). Pain on Injection • Most commonly reported adverse event. • Minimized by injecting in large vein. • Lidocaine 1% preceding injection or use of potent short-acting opiod helps. Airway Protection • Altered pharyngeal function with risk of aspiration due to loss of protective airway reflexes. 𝑬𝒕𝒐𝒎𝒊𝒅𝒂𝒕𝒆 “Carboxylated imidazole-containing compound that is chemically unrelated to any other drug used for IV induction” v Imidazole nucleus renders etomidate (like midazolam), water soluble at acidic pH and lipid-soluble at physiologic pH. Commercial Preparation • Original formulation contained 35% propylene glycol High Incidence of Pain on Injection • Has been changed to a fat emulsion which has eliminated pain on injection but retained myoclonus. • Oral formulation for transmucosal delivery is available and avoids firs-pass hepatic metabolism. 𝑬𝒕𝒐𝒎𝒊𝒅𝒂𝒕𝒆 Mechanism of Action 1. Administerd as a single isomer R(+) which is 5x more potent tha S(-) isomer. 2. Selective modulator of GABAA receptors. Pharmacokinetics 1. Large Vd which suggests large tissue uptake. 2. Weak base (pK 4.2, pH 8.2) 99% unionized at physiologic pH (penetrates bain rapidly with peak concentrations at 1 minute. 3. 76% proteing bound to albumin. 4. Prompt awakening after a single dose of etomidate reflects redistribution from brain to inactive tissue sites. 𝑬𝒕𝒐𝒎𝒊𝒅𝒂𝒕𝒆 Metabolism v Rapidly metabolized by hydrolysis of the ethyl ester side chain to its carboxylic acid ester Water-soluble, pharmacologically inactive compound v Hepatic microsomal enzymes and plasma esterases are responsible for this hydrolysis. v 85% of a single dose of etomidate is accounted as carboxylic acid in urine and 10 to 13% in bile. v Clearance is somewhat slower than propofol 18-25 mL/Kg vs 20 – 30 mL/Kg (contributes to slower elimination). v Vd is half that of propofol 2.5 – 4.5 L/kg vs. 2-10 L/kg (contributes to faster elimination). v Vd dominates with a shorter terminal elimination half-life (3-5 hrs) vs. propofol (4-7 hrs.). v Context sensitive half-life less likely to increase with continous infusion when compared to propofol. 𝑬𝒕𝒐𝒎𝒊𝒅𝒂𝒕𝒆 Cardiopulmonary Bypass 1. Alternative to propofol or barbiturates for IV induction (0.2 – 0.4 mg/kg), especially in the presence of an unstable CV system. 2. Onset = arm to brain circulation. 3. Common myoclonus after induction (imbalance of inhibitory & excitatory influences in the thalamicocortical tract). Attenuated by prior administration of opioid. 4. Awakening occurs 5 to 15 minutes after administration (similar to propofol). 5. Phsychomotor function recovery is somewhat slower than propofol. 6. Analgesia is not produced by etomidate (as with propofol and barbiturates). 7. Prinicipal limitin aspec is ability of drug to suppress adrenocortical function. 8. Increased PONV after etomidate administration. Side Effects – CNS • Potent direct cerebral vasoconstrictor that decreases CBF & CMRO2 35% to 45%. • Decreases ICP. • Adrenocortical suppression limits clinical usefulness (not viable for long term care). • May activate seizure foci (similar to methohexital) • Augments amplitude of SSEPʼs which makes monitoring reliable. Adrenocortical Suppression 𝑬𝒕𝒐𝒎𝒊𝒅𝒂𝒕𝒆 Side Effects – Cardiovascular System v Cardiovascular stability is characteristic of induction with etomidate v Minimal changes in HR, SV and CO. MAP may decrease 15% due to decreases in SVR (watch out for hypovolemic patients). v Doses greater than the recommended (>0.4 mg/kg) can significantly decrease BP and CO v Within the established dose ranges there is none to negligible negative inotropic effects on the heart. Others v Hepatic and renal function tests are not altered by etomidate v Intraocular pressure is decreased with etomidate (similar degree to propofol). v Does not result in detrimental effects when accidentally injected into an artery. 𝑬𝒕𝒐𝒎𝒊𝒅𝒂𝒕𝒆 Side Effects – Ventilation v Depressant effects of etomidate on ventilation seem to be less than barbiturates and propofol. v Decreases in TV are offset by compensatory increases in the frequency of breathing. v Etomidate may stimulate ventilation independent of medullary centers. Pain on Injection • Eliminated with the use of etomidate in lipid emulsion rather than propylene glycol. Useful when of maintenance spontaneous ventilation is desired. 𝑬𝒕𝒐𝒎𝒊𝒅𝒂𝒕𝒆 Side Effects – Adrenocortical Suppression v 11-𝛽 hydroxylase inhibition lasts 4 to 8 hours after an induction dose. v Patients experiencing sepsis or hemorrhage might be at a disadvantage due to cortical suppression. v Asses risk vs. benefits when using etomidate. Allergic Reactions v Incidence is low. 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Principal Pharmacologic Effects: q Although effective for acute insomnia not used (cognitive problems & mortality) 1. Anxiolysis 2. Sedation 3. Anticonvulsant 4. Spinal cord-mediated skeletal muscle relaxation (not adequate itself for surgery nor it potentiates NMBDʼs) 5. q Fewer tendencie to produce tolerance, less potential for abuse & greater margin of safety vs. barbiturates & opioids. q Do not induce micrsomal enzymes vs. barbiturates. Anterograde amnesia (greater potency than sedative effects) Midazolam is the most commonly used benzodiazepine. 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Mechanism of Action • Produces pharmacologic effect by facilitating action of GABA (enhance affinity rather than activate directly). • Postsynaptic neurons are rendered resistant to excitation. • Benzodiazepines have built-in ceiling effect that prevents them from exceeding physiologic maximum of GABA inhibition (low toxicity). • Differences in onset and duration among benzodiazepines reflect differences in: ü Potency (receptor binding affinity) ü Lipid solubility (ability to cross the BBB) ü Pharmacokinetics (uptake, distribution, metabolism and elimination). § All benzodiazepines are highly lipid soluble and highly protein bound (albumin). 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Nucleoside Transporter Systems Side Effects – Chronic Administration • Benzos decrease adenosine degradation by inhibiting the nucloside transporter. • • Adenosine = reduces cardiac O2 demand (lowers HR) and causes coronary vasodilation. • Does not adveresly affect BP, HR, cardiac rhythm. Electroencephalogram • Resemble effects of barbiturates • Midazolam incapable of producing isoelectric EEG Fatigue and drowsiness in patients treated chronically (sedation could last up to 2 weeks). • Careful administration should ensue if patient has respiratory disease or poor oxygenation. • Anterograde amnesia is accentuated by alcohol consumption. 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Side Effects – Drug Interactions • Benzodiazepines exert synergistic sedative effects with: ü ü ü ü Alcohol Inhaled anesthetics Opioids 𝛼2 agonists • Anesthetic requirements are decreased. • Potentiate ventilatory depressant effects of opioids. • Analgesic action of opioids is reduced. Hypothalamic-Pituitary-Adrenal Axis • Alprazolam – Inhibition of ACTH & Cortisol Dependence • Signs – onset of physical or psychologic symptoms after dose adjustment or DC. • Symptoms – can occur after > 6 months of use of low-potency benzos. ü Irritability ü Insomnia ü Tremulousness 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Side Effects – Aging Platelet Aggregation • Aging and liver disease affect glucuronidation < oxidation. • May inhibit platelet aggregating factor resulting in drug-induced inhibition of platelet aggregation. • Lorazepam, oxazepam and temazepam preferred given metabolism by glucuronidation. • Not clinically significant. • Can accelerate cognitive decline in elderly patients. • Intrinsically sensitive to benzos. • Avoid Diazepam 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Midazolam • Water-soluble bzdp. with imidazole ring that provides stability in aqueous solution and rapid metabolism. • pKa of 6.15 buffered to 3.5 pH for water solubility purposes. • Has no need for propylene glycol & does not cause discomfort durin IV or IM injection. Open ring = water soluble Closed ring = lipid soluble 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Midazolam - Pharmacokinetics • Prompt passage into brain but slow effectsite equilibrium time (0.9 – 5.6 min.) • 50% first-pass hepatic metabolism for orally administered midazolam. • • Rapidly metabolized by hepatic and small intestine P450 (CYP3A4) to active & inactive metabolites. Short duration due to redistribution (lipid soluble) and rapid hepatic clearance. Metabolism • Slowed in the presence of: ü Cimetidine ü Erythromycin ü Calcium channel blockers ü Antifungal drugs Active metabolite with Non-detectable concentrations in plasma Inhibit P450 Metabolite with half the activity of parent drug Conjugated to be cleared by kidneys Consider critcally ill patients with renal insufficiency on continuous infusion. 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Midazolam – Renal Clearance • Elimination half-time, Vd, and clearance of midazolam are not altered by renal failure. Extensive hepatic metabolism. Effects on Organ Systems – CNS Ventilation • Can produce dose dependent depression of ventilation. • Depression potentiated with concomitant administration of opiods. • Decreases CMRO2 and CBF. • Depress swallowing and decreases upper airway reactivity. • CO2 vasomotor responsiveness is maintained. Cardiovascular System • Have not shown to be neuroprotective in humans. May improve neurologic outcomes. • Potent anticonvulsant (in status epilepticus) • Hemodynamic response to endotracheal intubation is not reliably blunted. • Large doses for induction (0.2 mg/kg) can produce a decrease in BP & increase in HR. 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Midazolam – Clinical Uses (Pre-Op) Induction of Anesthesia • Most common preop. medication used in children (PO). Know pediatric dosing! • Seldomly used for this purpos but itʼs doable. • Recommended 20 mins. before surgery but can be given up to 10 mins. • Crosses placenta, but fetal-to-maternal ratio is significantly less than that for other benzos. Intravenous Sedation • 1 – 2.5 mg IV (onset 30 – 60 sec.) with peak effect at 3 – 5 min. • Effective for sedation during regional as well as brief therapeutic proc. Maintenance of Anesthesia • Used to supplement opioids, propofol and/or inhaled anesthetics. • Anesthetic requirements are decreased in a dose-dependent manner. • Context-sensitive half-time increases modestly with increased duration of administration. Postoperative Sedation • Observed with long duration infusion or administration (tissues saturate). 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Diazepam Protein Binding • Highly lipid-soluble benzodiazepine with a longer duration of action. • High degree of protein binding • Seldomly used as part of the anesthesia care plan. Commercial Preparation • Dissolved in organic solvents (propylene glyco, sodium benzoate) because it is insoluble in water. • Rapidly absorbed from the GI tract with near 100% bioavailability & peak concentrations in 1 hour (adults) 15-30 min. (children). • Readily crosses placenta & has high Vd Metabolism • Metabolized by hepatic microsomal enzymes by oxidative N-demethylation. 48 - 96 hrs. elimination half-time Active metabolite that can contribute to the return of drowsiness (after 6-8 hrs.) 𝑩𝒆𝒏𝒛𝒐𝒅𝒊𝒂𝒛𝒆𝒑𝒊𝒏𝒆𝒔 Diazepam – Elimination Half-time • Ranges from 21 to 37 hrs. in health volunteers. • Cirrhosis of the liver can cause fivefold increase in half-time (decreased protein binding & hepatic clearance). • Half-time also increases with age. • Longer elimination half-time that lorazepam but shorter duration of action (dissociates from GABAA faster)