MYRA M.

PAGALING MD

History and Principles

1926
Lundy introduced the concept of Balanced anesthesia

1932
Hexobarbital, 1st ultrashort-acting barbiturate, introduced by Weese in Germany, considered to be the 1st successful and widely used IV anesthetic

1935
Thiopental by Lundy in Minnesota and Waters in Wisconsin; became widely accepted, largely because of the lack of excitatory myoclonic movements that were seen w/ hexobarbital

PROPERTIES OF THE IDEAL ANESTHETIC AGENT

Pharmacodynamic/pharmacokinetic properties
Causes hypnosis and amnesia Rapid onset (time of one arm-brain circulation) Rapid metabolism to inactive metabolites Minimal cardiovascular and respiratory depression No histamine release or hypersensitivity reactions Nontoxic, nonmutagenic, noncarcinogenic No untoward neurologic effects, such as seizures, myoclonus, antanalgesia, neurotoxicity Other beneficial effects: analgesic, antiemetic, neuroprotection, cardioprotection Pharmacokinetic based models to guide accurate dosing Ability to continuously monitor delivery

PROPERTIES OF THE IDEAL ANESTHETIC AGENT

Physicochemical properties
Water soluble Stable formulation, nonpyrogenic Nonirritating, painless on IV injection Small volume needed for induction Inexpensive to prepare and formulate Antimicrobial preparation

MECHANISM OF ACTION
Exert primary effects through interaction w/ inhibitory neurotransmitter GABA Activation of GABA-receptor complex increases transmembrane chloride conductance, resulting in hyperpolarization and functional inhibition of postsynaptic neuron
GABAA receptors conduct chloride and bicarbonate anions to hyperpolarize the membrane of mature neurons, and are the primary targets for the anesthetic effects (sedation, anxiolysis, hypnosis, amnesia) of all IV anesthetics and sedatives, except KETAMINE

MECHANISM OF ACTION

MECHANISM OF ACTION
BDZ increase the efficiency of the coupling b/w GABA and its receptor (ceiling effect) Barbiturates & Propofol decrease the dissociation of GABA from its receptor Thiopental exert effect via competitive inhibition of nicotinic Ach receptors in the CNS Ketamine noncompetitive blockade at NMDA receptor inhibits neuronal sodium channels and calcium channels responsible for the dissociative amnesia Dexmedetomidine centrally active 2 adrenergic agonist

PHARMACOKINETIC PRINCIPLES
Highly perfused (vessel-rich) tissues
Brain and spinal cord Result: LOC within the time of one arm-brain circulation (about 20 seconds depending on the cardiac output) Muscles Fat

Elimination: liver

PHARMACOKINETIC PRINCIPLES
Hepatic extraction ratio is the measure of the rate at which anesthetics are cleared from the systemic circulation by the liver 3 categories
High propofol, etomidate, ketamine Intermediate methohexital, midazolam Low thiopental, diazepam, lorazepam

Factors that contribute to interpatient variability in Pharmacokinetics

Degree of protein binding Efficiency of renal and hepatic clearance mechanisms Aging (lean body mass decreases) Pre-existing diseases (hepatic, renal, cardiac) Drug interactions Body temperature

Pharmacodynamics
Principal pharmacologic effect of IV anesthetics is to produce CNS depression manifesting as sedation and hypnosis When steady state plasma concentrations are achieved, it can be assumed that the plasma concentration is in equilibrium w/ the effectsite(receptor) concentration Most sedative hypnotic drugs (except for ketamine) cause a proportional reduction in cerebral metabolism (CMRO2) and CBF, resulting in a decrease in intracranial pressure

Pharmacodynamics
Most sedative-hypnotic drugs can cause occasional EEG seizure-like activity despite also acting as anticonvulsants. One should differentiate b/w the epileptogenic activity (methohexital) and myoclonic like phenomena (etomidate) Most sedative-hypnotics (exception is ketamine) lower intraocular pressure in parallel w/ effects on ICP and BP w/ exception of ketamine(and to a lesser extent, etomidate), IV anesthetics produce dose dependent depression of ventilation (transient apnea followed by decreased tidal volume)

Factors contributing to the hemodynamic changes

Patients preexisting cardiovascular and fluid status, Resting SNS tone Chronic CV drug use Use of preanesthetic medications Speed of drug injection Onset of unconsciousness Direct pharmacologic actions of anesthetic and analgesic drugs on the heart and peripheral vasculature

Barbiturates
Physicochemical properties
Weak acids that are poorly soluble in water at neutral pH Most commonly used: thiopental, thiamylal, and methohexital are formulated as racemic mixtures of the water soluble sodium salts and use sodium carbonate to maintain alkaline pH of 10-11 Classified as:
Thiobarbiturates (sulfur @ C2) thiopental, thiamylal Oxybarbiturates(oxygen@ C2) - methohexital

Barbiturates
Substitution of sulfur for oxygen at C2, increases lipophilicity w/c results in increased potency, more rapid onset and shorter duration of action Most popular anesthetic induction agent until 1990s induce anesthesia lasting 4-8mins Thiomylal>Methohexital 3x more potent than thiopental Pain on injection methohexital

Barbiturates
Thiopental and thiamylal
Adult induction dose: 3-5 mg/kg IV

Methohexital
Adult induction dose: 1.5 mg/kg IV Associated w/ high incidence of myoclonic like muscle tremors and other signs fo excitatory activity (e.g. Hiccoughing)

Barbiturates
Systemic effects Cardiovascular: transient reductions in systemic arterial Pressure and cardiac output, inc HR, minimal change in SVR Thiopental and thiamylal induce histamine release. Respiratory Potent central respiratory depressants Dose dependent minute volume and TV Depressed medullary center ventilatory responses to hypercapnia and hypoxia

Barbiturates
Neurologic
Potent anticonvulsant Thiopental only agent shown to produce long term cerebral protection in focal ischemia Undesireable CNS effects: paradoxical excitement in small doses and involuntary skeletal muscle movement (myoclonus)

Others
Stimulation of mitochondrial enzyme aminolevulinic acid reductase, the rate limiting enzyme in porphyrin biosynthesis, can exacerbate acute intermittent porphyria in susceptible patients Do not suppress adrenocortical stimulation Can cause neonatal depression if used for CS for doses >8mg/kg

Propofol
2,6 di-isopropylphenol Achiral, lipophilic, sterically hindered substituted phenol Very weak acid; nonionized at physiologic pH Formulated at 1% in an oil/water emulsion containing 10% soybean oil, 1.2% egg lecithin and 2.25% glycerol (as an osmotic agent) pH 6.0-8.5

Propofol
Induction dose: 1.5 to 2.5 mg/kg IV Recommended IV infusion rate 100-200 g/kg/min for hypnosis and 25 to 75g/kg/min for sedation

Propofol

2,6-diisopropylphenol

Propofol
Rapid redistribution and hepatic elimination result in rapid return to consciousness w/ no residual effects Low incidence of nausea and vomiting Useful for short procedures and ambulatory surgery Rapid clearance, short context sensitive half time, make it useful for maintenance of anesthesia by continuous infusion w/o significant cumulative effect Exhibits pharmacodynamic synergism w/ benzodiazepines and opioids (hypnotic effect) Pain on injection is a significant problem

Propofol
Systemic effects
Cardiovascular
Decreases arterial BP by 15-40% Significant reduction in SVR and cardiac filling w/ little or no direct effect on myocardial contractility Variable effect on HR, produces less tachycardia than thiopental Resets baroreceptor reflex control of HR, resulting in unchanged HR despite reduction in BP Hemodynamic effect is magnified in hypovolemic or elderly patients and in patients w/ impaired LV function Enhanced relaxation of intrinsic muscles Minimal increase in plasma histamine levels Not arrhythmogenic, does not sensitize the heart to catecholamines

Propofol
Respiratory
Potent respiratory depressant Produces apneic period of 30-60 seconds following normal induction dose Less common hiccough, cough and laryngospasm because of > depression of laryngeal reflexes Causes bronchodilation, useful for patients w/ asthma

Propofol
Neurologic
Anticonvulsant, used for treating refractory epilepsy Can be epileptogenic in pxs w/ seizure disorder Can shorten the duration of convulsions after ECT

Other
Significant antiemetic activity even at subanesthetic doses Effective antipruritic Effective in reducing IOP Does not trigger malignant hyperthermia Potentially porphyrinogenic No direct effect on neuromuscular transmission Can cause neonatal depression after prolonged infusion

Propofol
Propofol infusion syndrome
Metabolic acidosis Lipemic plasma Myocardial failure Hepatomegaly Rhabdomyolysis

Etomidate
Carboxylated imidazole derivative Weak base Poorly water soluble Hyperosmotic solution in 35% propylene glycol Prepared as the pharmacologically active R(+) stereoisomer

Etomidate

ethyl 3-[(1R)-1-phenylethyl]imidazole-4-carboxylate

Etomidate
Fewer cardiovascular and respiratory depressant actions than thiopental Useful for induction in patients with impaired ventricular function or cardiac tamponade and in cases of hypovolemia Remarkable for its relative lack of cardiovascular effects Pain on injection is common Most immunologically safe

Etomidate
Systemic effects
Cardiovascular
Hemodynamic stability results from reduced effects on the sympathetic nervous system and baroreceptor reflex responses Smaller changes in supply and demand of myocardial Oxygen Negative inotropic effect 2x lower than equianesthetic dose of thiopental Does not evoke histamine release, associated w/ low incidence of hypersensitivity reactions

Etomidate
Respiratory
Less respiratory depression than barbiturates Decreased minute ventilation and tidal volume Increased RR Transient apnea can develop esp in geriatric patients Depresses the sensitivity of the medullary respiratory center to CO2

Etomidate
Neurologic
Decreases cerebral metabolic rate of oxygen consumption (CMRO2) and cerebral blood flow and reduces elevated ICP w/o reducing arterial blood pressure or cerebral perfusion pressure; this results in an increase in supply-demand ratio for cerebral oxygen Can activate seizure foci, a property that can be used to facilitate intraoperative localization Accompanied by high incidence of excitatory phenomena, including spontaneous muscle movement, hypertonus and myoclonus

Etomidate
Other
Directly suppresses adrenal cortical function Reversibly inhibits the activity of steroid 11hydroxylase, a key enzyme in steroid biosynthesis which persists 6-8hrs after induction dose and unresponsive to ACTH Nausea and vomiting is common Potentially porphyrinogenic Inhibitor of plasma cholinesterase and can prolong the action of succinylcholine in pxs w/ cholinesterase deficiency

Benzodiazepines
Features which result in their popularity as adjuvant IV anaesthetic agents: 1 amnesia 2 minimal cardiarespiratory depressant effect. 3 anticonvulsant activity. 4 low incidence of tolerance and dependence.

Benzodiazepines
MECHANISM OF ACTION
1 They inhibit the actions of glycine (by increasing the conc. Of a glycine inhibitory neurotransmitter) which will lead to antianxiety and skeletal muscle relaxant effects. 2 They facilitate the actions of the inhibitory neurotransmitter GABA which results in the sedative and anticonvulsant effects. Benzodiazepines are highly lipid soluble. They are highly protein bound (albumin).

Benzodiazepines
They are metabolized by the liver through conjugation with glucoronic acid and excreted by the kidneys. Midazolam and Diazepam are the most commonly used benzodiazepines during operative procedures. Diazepam and lorazepam are insoluble in water, their formulation contains propylene glycol, a tissue irritant that cause pain on injection and venous irritation

Benzodiazepines
MIDAZOLAM AND DIAZEPAM They are commonly used to provide: 1- IV sedation. 2- amnesia.

3- reducing anxiety.

Benzodiazepines
THE DIFFERENCES BETWEEN THEM
1- Midazolam is 2-3 times more potent than diazepam: 2- The dose for IV conscious sedation: 0.5 3 mg up to 0.1 mg/kg for midazolam, and 1-10 mg for diazepam. 3- The dose for inducing anesthesia: 0.2 0.4 mg/kg for midazolam , and 0.15-1.5 mg/kg for diazepam. 4- Midazolam has a more rapid onset, greater amnestic effect, less postoperative sedative effects than diazepam.

Benzodiazepines
5- Pain on injection and subsequent thrombophlebitis is less likely with midazolam (an emulsion of diazepam) 6- Midazolam is more costly than diazepam). 7- Midazolams duration of action is less than diazepam but almost 3 times that of thiopental. 8- Elimination half time for midazolam range from 14 hours, and for diazepam from 21-37 hours. 9- Midazolam is supplied as a clear liquid in concentrations of 1-5 mg/ml.

Benzodiazepine antagonists (Flumazenil)

Its an imidazobenzodiazepine.

It specifically antagonizes benzodiazepines

central effects by competitive inhibition. Its elimination half-time is one hour,

considerably less than most benzodiazepines;

therefore we will need repeated administrations of flumazenil to antagonize a benzodiazepine

with a longer half-time

Benzodiazepine antagonists (Flumazenil)

Flumazenil is supplied as a colourless liquid in a concentration of 0.1 mg/ml. The usual initial dose is 0.2 mg over 15 seconds, if the desired level of consiousness is not obtained within one minute of administration we can give repeated doses of 0.1 mg every minute up to the maximum of 2 mg, and if sedation recurs we can use infusions of 0.1-0.4 mg/hour. Flumazenil is well tolerated. The most common side is nausea (4% of patients) Respiratory depression produced by BDZ is not completely reversed

Ketamine
Weak base, partially water soluble arylcyclohexylamine derivative US, formulated as a racemic mixture of 2 enantiomers in aqueous solution w/ sodium chloride and benzethonium chloride S(+)enantiomer 3x more potent than R(-) enantiomer

Ketamine

(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone

Ketamine
MOA
Antagonistic effect on N-Methyl-D-aspartate(NMDA) Inhibits neuronal sodium channels (modest local anesthetic activity) and calcium channels (cerebral vasodilation) Interacts with NMDA and opioid, muscarinic and monoaminergic receptors

Produces dose-dependent CNS depression, leading to a so-called dissociative anesthetic state

Ketamine
Low dose ketamine (75-200g/kg/min IV) produces opioid-sparing effects when administered as an adjuvant during GA Induction of anesthesia can be accomplished w/ 12mg/kg IV (4-8 mg/kg IM), producing an effect that lasts for 10-20 mins, although recovery to full orientation may require an additional 60-90mins Subanesthetic dose (0.1-0.5 mg/kg IV) produce analgesic effects Low dose infusion (4g/kg/min IV) is equivalent to morphine (2mg/hr IV) for production of postoperative analgesia

Ketamine
Sympathomimetic activity Useful in the rapid induction of anesthesia in hemodynamically unstable patients who have acute hypovolemia, hypotension, cardiomyopathy, constrictive pericarditis, or cardiac tamponade, and in patients w/ CHD or bronchospastic disease Agent of choice for rapid induction of anesthesia in patients who have acute asthma or cardiac tamponade

Ketamine
Unique advantage: versatility of administration routes, IV, IM, oral, rectal Extensively metabolized in the liver to norketamine, w/c is one third to one fifth as potent as the parent compound

Ketamine
Systemic effects
Cardiovascular
Results primarily from stimulation of the sympathetic nervous system to produce tachycardia and hypertension Increases atrioventricular conduction time and has a direct myocardial depressant effect, however is masked by the sympathomimetic effect Cardiostimulatory effect: increases in systemic and pulmonary arterial vascular resistance and pressure, HR, cardiac output, myocardial oxygen consumption, coronary blood flow and cardiac work Contraindicated in pxs w/ CAD

Ketamine
Respiratory
Transient decrease RR; apnea is rare Upper airway reflexes and muscle tone are maintained Increased salivary and tracheobronchial secretions can lead to cough and laryngospasm Bronchodilatory effect is extremely useful in pxs w/ reactive airway disease or bronchospasm Unique in its ability to maintain FRC possibly because of maintenance of skeletal muscle tone

Ketamine
Neurologic
Potent cerebral vasodilator that increases CBF and ICP in spontaneously breathing patients Contraindicated in neurosurgical procedures Direct cerebrovascular effect Increases IOP Produces mydriasis, nystagmus, and excitatory CNS effects In low doses, might control neurogenic pain and reverse the wind up Phenomenon

Ketamine
Other
Emergence reactions, including delirium, excitement, confusion, euphoria, fear, vivid dreaming, and hallucinations 1st hour of emergence Enhances the action of nondepolarizing muscular blockers possibly by blocking the nicotinic receptors Increases muscle tone but does not trigger malignant hyperthermia Can stimulate uterine contraction in the 1st trimester of pregnancy

Dexmedetomidine
Centrally active -2 adrenergic agonist that produces potent sedative and analgesic-sparing properties and reduces sympathetic outflow from the CNS Approved for sedation of mechanically ventilated patients in ICU Also used for diagnostic and therapeutic procedures (regional and local anesthesia) outside theh ICU (off-label use) Comparable to midazolam when used for premedication but incidence of intraoperative hypotension and bradycardia is increased Blunt the acute hemodynamic response to laryngoscopy and intubation

 Provide the most efficient method for the rapid induction of general anesthesia in adults Rapid uptake and redistribution into the CNS as a result of the agents high lipophilicity provides for the rapid onset and short duration of effects after bolus administration Propofol has become the IV drug of choice for outpatients undergoing ambulatory surgery

 Clinical use of midazolam (often combined w/ other injected drugs), etomidate (cardiac stability) and ketamine (hypovolemic patients) is restricted to specific situations in w/c their unique pharmacologic profiles offer advantages over other available IV anesthetics

Use of IV drugs for maintenance of anesthesia

rapid, short acting, sedative-hypnotics and opioids are better suited for continuous administration techniques