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

PARACELSUS (1493-1541)

“All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.”

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

• 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 α2 adrenergic agonist

MECHANISM OF ACTION

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

• 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

PHARMACOKINETIC PRINCIPLES

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 effect-site(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

• Patient’s 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

• 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

Barbiturates

• Systemic effectsCardiovascular: transient reductions in systemic arterial

Pressure and cardiac output, inc HR, minimal change in SVR

Thiopental and thiamylal – induce histamine release.• RespiratoryPotent central respiratory depressantsDose dependent minute volume and TVDepressed 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 δ 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

• Induction dose: 1.5 to 2.5 mg/kg IV• Recommended IV infusion rate 100-200

µg/kg/min for hypnosis and 25 to 75µg/kg/min for sedation

Propofol

2,6-diisopropylphenol

Propofol

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 11-

βhydroxylase, 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.

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).

BenzodiazepinesMECHANISM OF ACTION

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

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 THE DIFFERENCES BETWEEN THEM

5- Pain on injection and subsequent thrombophlebitis is less likely with midazolam (an emulsion of diazepam)

6- Midazolam is more costly than diazepam).

7- Midazolam’s duration of action is less than diazepam but almost 3 times that of thiopental.

8- Elimination half time for midazolam range from 1-4 hours, and for diazepam from 21-37 hours.

9- Midazolam is supplied as a clear liquid in concentrations of 1-5 mg/ml.

Benzodiazepines

Benzodiazepine antagonists (Flumazenil)

• It’s an imidazobenzodiazepine.

• It specifically antagonizes benzodiazepine’s

central effects by competitive inhibition.

• It’s 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

• 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

Benzodiazepine antagonists (Flumazenil)

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

• 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 (75-200µg/kg/min IV) produces opioid-sparing effects when administered as an adjuvant during GA

• Induction of anesthesia can be accomplished w/ 1-2mg/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 (4µg/kg/min IV) is equivalent to morphine (2mg/hr IV) for production of postoperative analgesia

Ketamine

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 α-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

Summary

• 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