Intravenous Sedatives and Hypnotics (Part II) PDF

Intravenous Sedatives and Hypnotics (Part II) University of Puerto Rico – Medical Sciences Campus School of Nursing – Nurse Anesthesia Program ENFE 7131 – Advanced Pharmacology I Jorge Hernandez, DNAP, CRNA 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Phencyclidine derivative that produces “dissocia...

Intravenous Sedatives and Hypnotics (Part II) University of Puerto Rico – Medical Sciences Campus School of Nursing – Nurse Anesthesia Program ENFE 7131 – Advanced Pharmacology I Jorge Hernandez, DNAP, CRNA 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Phencyclidine derivative that produces “dissociative anesthesia” which is characterized by evidence on the EEG of dissociation between the thalamocortical and limbic systems. ü Resemble cataleptic state “eyes remain open with slow nystagmic gaze”. ü Patient is noncommunicative although wakefulness may appear to be present. ü Hypertonus and skeletal muscle movements can occur independent of surgical stimulation. ü The patient is amnesic, and analgesia is intense even at subanesthetic doses. ü Frequency of emergence delirium limits the clinical usefulness as a sole agent. ü Has significant risk for abuse potential (used as a recreational drug). 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Structure-Activity Relationships 1. Water soluble molecule that structurally resembles phencyclidine (angel dust). 2. Two optical isomers: S(+) ketamine & R (-) ketamine. 3. Racemic mixture is most frequently used in the US. 4. Esketamine S (+) isomer used for treatment resistant depression (Spravato). 5. Esketamine (widely used in Europe): • More intense analgesia • Faster metabolism & recovery • Less salivation • Lower incidence of emergence reactions 6. Both isomers inhibit re-uptake of catecholamines back into postganglionic sympathetic nerve endings. 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Mechanism of Action 1. Mechanism of action of ketamine-induced analgesia and dissociative anesthesia is unknown. 2. Ketamine binds to N-methyl-D-aspartate receptors 3. Ketamine exerts effects at other sites: • Opiod receptors • Monoaminergic receptors • Muscarinic receptors • Voltage-sensitiv Na+ & L-type Ca+ channels • Neuronal nicotinic acetylcholine receptors 4. Inhibits neutrophil production of inflammatory mediators (improves blood flow). 5. Inhibition of cytokines (CD131-erythropoietin) in blood may contribute to analgesic effect. 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine NMDA Receptor Antagonism 1. Member of the glutamate receptor family 2. Ligand-gated ion channel require coagonism glutamate glycine 3. Ketamine inhibits activation of NMDA by glutamate. 4. Decreases presynaptic release of glutamate. 5. S(+) isomer has greater affinity for the PCP/ketamine binding site. 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Pharmacokinetics Ø Rapid onset of action, relatively short duration of action and high lipid solubility. Ø Not significantly bound to plasma proteins. Ø High hepatic clearance (1 L/min) and large Vd (3 L/kg) = elimination of 2 to 3 hours. Metabolism Ø Extensive metabolism by cytochrome P450 (demethylation to form norketamine metabolite). Ø Norketamine is 1/5 – 1/3 as potent as ketamine. Ø Chronic administration causes enzyme induction which in turns causes tolerance. . 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Clinical Uses Analgesia (0.2 – 0.5 mg/kg IV) v Unique drug evoking intense analgesia at subanesthetic doses. Ø Lower cocentration treshold for oral administration vs IM (hepatic first-pass & production of norketamine). v Prompt induction of anesthesia when administered IV. Ø Greater for somatic than for visceral pain. v Inclusion of antisialagogue pre-op is recommended (decrease likelihood of coughing and laryngospasm). v Neuraxial use of ketamine appears to be of limited value . Ø Attributed to activity in the thalamic & limbic system. Ø Spinal cord NMDA inhibition (ketamine, magnesium, and dextromethorphan). Useful in managing postop pain. Ø Analgesia during labor without neonatal depression. 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Induction of Anesthesia (1-2 mg/kg IV or 4-8 mg/kg IM) – Malignant Hyperthermia Safe v Does not produce pain or irritation on injection. v Consciousness is lost in 30 to 60 seconds after IV and 2 to 4 after IM administration. v Normal to slightly depressed pharyngeal and laryngeal reflexes. v Return of consciousness usually occurs in 10-20 min & full orientation in 60-90 min. v Useful in burn patients (dressing changes), debridements and skin grafting. v Useful to induce pediatrics through the IM route (fast onset). v Useful in hypovolemic patients (drugs cardiovascular stimulating effect) v Can cause myocardial depression if cathecolamine depletion is present. v Care should be taken in the patient with CAD, risk of seizure, increased intracranial and/or intraocular pressure v Its bronchodilator effects make it an useful alternative in asthmatic patients. 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Other Usses v Subanesthetic doses of ketamine (0.3 mg/kg/hr) reduce the likelihood of opioid tolerance & improves analgesia. v Improvement of psychiatric disorders. v Symptomatic improvement of restless leg syndrome. 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Central Nervous System Side Effects Cardiovascular System ”Ketamine increases CBF and CMRO2” ”Effects resembles SNS stimulation” Ø ICP – potent cerebral vasodilator capable of increasing CBF by 60%. Not present with mechanically ventilated patients. Ø Neuroprotective Effects – antagonistic effect of NMDA receptors has possible neuroprotective role. Ø EEG – at high doses it can produce burst suppression. Unlikely to precipitate generalized convulsions in patients with seizure disorders. Ø Increases ampltitude of SSEP’s. Auditory and visual evoked potentials responses are decreased by ketamine. v Enhances dysrhythmogenicity of epinephrine. v In vitro, ketamine produces direct myocardial depression. 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Ventilation and Airway Bronchomotor Tone Ø Does not produce significant depression of ventilation. v Ketamine has bronchodilatory activity. Ø Ventilatory response to CO2 is maintained. Ø Apnea can occur if drug is administered rapidly or if an opioid is added. Ø Upper airway tone is well maintained and upper airway reflexes. v IV induction drug of choice if active bronchospasm. Tissue Damage v Repeated use can cause tissue damage (snorting). v Increase liver enzymes, allergic hepatitis, renal damage. Allergic Reactions v Rare 𝑵𝒐𝒏 − 𝑮𝑨𝑩𝑨 𝑺𝒆𝒅𝒂𝒕𝒊𝒗𝒆 𝒂𝒏𝒅 𝑯𝒚𝒑𝒏𝒐𝒕𝒊𝒄𝒔 Ketamine Emergence Delirium Prevention Ø Visual, auditory, proprioceptive and confusional illusions which may progress to delirium. Ø Use of a benzodiazepine preop Ø Cortical blindness may be transiently present. Ø Dreams and hallucinations can occur up to 24 hours after administraion (morbid content). Ø Incidence: 5 to 30% Ø Risk Factors: ü Age older than 15 years ü Female gender ü Dose greater than 2 mg/kg ü History of personality problems Drug Interactions Ø Ketamine administered in the presence of inhaled anesthetics may resut in hypotension. Ø Ketamine enhance action of NMBD’s Ø Beta-blockers reduce ketamine induced increase in HR and BP Ø Interferes with heart preconditioning Ø May prolong recovery from succinylcholine (possible inhibition of plasma cholinesterase activity). 𝑩𝒂𝒓𝒃𝒊𝒕𝒖𝒓𝒂𝒕𝒆𝒔 Ø Introduction of Thiopental in 1934 revolutionized the practice of anesthesia. “Gold Standard” Prevention Ø Derived from barbituric acid and the substitutions on this molecule determine physochemical properties, pharmacokinetics and relative potency. Ø Oxybarbiturates have oxygen in second position. Ø Replacement of the oxygen with a sulfur atom results in the thiobarbiturates (more lipid soluble and greater hypnotic potency). Ø A phenyl group in the fifth position (phenobarbital) increases anticonvulsant but not hypnotic potency. Ø A methyl group on the nitrogen increases hypnotic potency but lower seizure treshold. Barbiturates share the structure of barbituric acid and differ in the C2, C3, and N1 substitutions. 𝑩𝒂𝒓𝒃𝒊𝒕𝒖𝒓𝒂𝒕𝒆𝒔 Mechanism of Action Pharmacodynamics and Clinical Applications • Potentiation of GABAA channel activity. • Oral & IV barbiturates have been replaced by benzodiazepines for pre-op. medication and for treating grand mal seizures. Pharmacokinetics • Rapid onset, rapid awakening due to rapid uptake and posterior redistribution out of the brain into inactive tissues. • Context sensitive half-time is prolonged with longer infussions (highly sequestered in fat an muscle). • Thiobarbiturates are metabolized in hepatocytes & extrahepatic sites (kidneys & CNS). • Thiopental has low hepatic extraction ratio and capacity-dependent elmination. • Barbiturates have hangover type CNS effects tha may persist long after ceasing administration. • Rectal administration of methohexital has been used in pediatrics for induction in uncooperative patients. 𝑩𝒂𝒓𝒃𝒊𝒕𝒖𝒓𝒂𝒕𝒆𝒔 Treatment for Increased Intracranial Pressure & Ischemic Injury Induction of Anesthesia Thiopental (1) = 61% nonionized • Relative potency (pH of 7.4) Thiamylal (1.1) • Can be administered to decrease refractory ICP Methohexital (2.5) = 75% nonionized • Decreases CBF by vasoconstriction • Decreases CMRO2 • Dose requirements for thiopenthal vary with patient age, weight, and most importantly cardiac output. • Useful for inducing patients with increased ICP • Methohexital is useful during temporal lobe resection of seizure producing areas and electroconvulsive therapy (watch for myoclonus). • Can achieve burst suppression and isoelectric EEG • Propofol benefits from less nausea faster recovery needed for discharge. • Used to improve survival after global cerebral ischemia. 𝑩𝒂𝒓𝒃𝒊𝒕𝒖𝒓𝒂𝒕𝒆𝒔 Side Effects Somatosensory Evoked Potentials v Thiopental 5m/kg IV produces a transient 10 – to 20 – mmHg that is offset by a compensatory 15 – 20 beats per minutes increase in HR (decrease supply and increase demand of O2 within the coronary arteries). Ø Dose dependent change in SSEP’s and BAEP’s Ventilation v Dose-dependent depression of medullary and pontine ventilatory centers. v Decreased sensitivity to CO2 and apnea is especially likely in the presence of other deppresant drugs. v Laryngeal and cough reflexes not depressed until large doses have been administered. Enzyme Induction Ø Stimulate increase in liver microsomal protein content (2 – 7 days of sustained use). Ø Accelerate metabolism of oral anticoagulants, phenytoin & tryciclic antidepressants, corticosterois, vit. K Ø Productionn of Heme is accelerated and may exacerbate intermittent porphyria. 𝑩𝒂𝒓𝒃𝒊𝒕𝒖𝒓𝒂𝒕𝒆𝒔 Intra-arterial Injection v Inadvertent intra-arterial injection of thiopental. Intense Vasoconstriction & Excruciating Pain v Gangrene and permanent damage can occur. v Immediate attempts to dilute drug should occur and prevent arterial vasospasm by injecting lidocaine or papverine. 𝑩𝒂𝒓𝒃𝒊𝒕𝒖𝒓𝒂𝒕𝒆𝒔 Allergic Reactions v Both Anaphylactic and anaphylactoid reactions can occur. v Thiopental is associated with histamine release. . 𝑫𝒆𝒙𝒎𝒆𝒕𝒐𝒎𝒊𝒅𝒊𝒏𝒆 “Highly selective, specific and potent 𝜶𝟐 -adrenergic agonist (1,620:1 to 𝜶𝟏)” Ø Highest density of alpha-2 receptors is present in the pontine locus coeruleus (SNS innervation & modulator of vigilance). . Ø 7 to 10 x more selective than clonidine (220:1) for alpha-2 with a shorter duration of action. Ø Atipamezole ia a specific and selective alpha-2 receptor antagonis that rapidly reverses the sedative & CV effects of precedex Not available for human use Ø Produces sedation by decreasing SNS activity and the level of arousal. Calm patient who can be easily aroused. Amnesia is not assured. Pharmacokinetics Ø Elimination half-time – 3 hours; Highly protein bound - >90%; Has weak inhibiting effects of P450 𝑫𝒆𝒙𝒎𝒆𝒕𝒐𝒎𝒊𝒅𝒊𝒏𝒆 Clinical Use q Pretreatment with dexmetomidine attenuates : 1. Hemodynamic response to tracheal intubation. 2. Decreases plasma catecholamine concentration during anesthesia. 3. Decreases perioperative requirements of opioids and inhaled anesthetics. q Despite marked dose-dependent analgesia and sedation, there is only mild depression of ventilation. q As with clonidine, it is reported to be effective in attenuating cardiostimulatory and postop delirium effects of ketamine. q It is effective in treating pos-op shivering. q Severe bradycardia may follow rapid infusion of dexmetomidine, and even cardiac arrest. 𝑫𝒆𝒙𝒎𝒆𝒕𝒐𝒎𝒊𝒅𝒊𝒏𝒆 Postoperative Sedation q 0.2- 0.7 𝜇𝑔/𝑘𝑔/hr IV is useful for sedation postoperatively in critical care patients in the ICU (specially if intubated). q Useful to prevent withdrawal symptoms from long-term sedation with benzodiazepines. q May be accompanied with systemic hypotension and bradycardia (sympatholytic and vagomimetic actions).