NONVOLATILEANESTHETICSPRESENTED BY JACOB HUMMEL, M.D.TULANE ANESTHESIOLOGY

OBJECTIVESAn overview of the nonvolatile anesthetics

- Kinetics/Dynamics- Organ system effects

• -Effects of Propofol on the cardiovascular system• -Pharmacological differences between fospropofol &• propofol• -Effects of Barbiturates on CBF and CMRO2• -How Benzodiazepines affect ventilation• -Ketamine effects on CBF and CMRO2• -Dexmedetomidine, effects of bolus vs. infusion

GOALS-It is my desire to have you walking away from this lecture feeling well versed in all topics related to nonvolatile anesthetics -It is also my desire for everyone to find this lecture enjoyable and entertaining and serve as a catalyst to our collective PLD session this afternoon

DISCLOSURESAll opinions expressed today are those of a licensed physician, however, some CRNAs still claim that CA-1s, like myself, are still only students

GENERAL OVERVIEWNonvolatile anesthetics have several uses, but primarily are used for 1. INDUCTION2. MAC/ICU SEDATION

Several of these drugs can be administered via various routes, but their use in anesthesiology is primarily via the intravenous route

Most of the anesthetics described are lipophilic in nature which means RAPID ONSET and RAPID TERMINATION of their anesthetic effects

PHARMACOKINETICSWhat the body does to the drug…-The drugs in this class are primarily administered intravenously and therefore bypass absorption

-The initial termination of their effects leading to waking up from anesthesia is the result of re-distribution into less perfused tissues

-Biotransformation is primarily completed by the liverPhase I: oxidation (P450), reduction, hydrolysisPhase II: conjugation with glucuronides

KINETICS (CONT.)-Kidneys are the prinicipal organ of excretion

-The kinetics for most drugs can be described by a two-comparment model, central and peripheral

-The kinetics for some drugs are better explained by a three-compartment model, central and 2 peripherals

PHARMACODYNAMICSWhat the drug does to the body…-The mechanism of action of most drugs depends on the interaction with a receptor

-The receptors are likely tied to either the function of ion channel or the production of a second messenger

-Most of our anesthetics act at the synapse of neurons and affect GABAa chloride channels or NMDA cation channels

PROPOFOLMost frequently administered drug for induction of anesthesia and also used for ICU sedation, procedure sedation, rapid sequence induction and PONV

Formulations support bacterial growth and there are cases of SEPSIS and DEATH related to propofol contaminationEgg allergy not necessarily a contraindication to its use

PROPOFOL-KINETICSInitial distribution half-life of 2-8 minutes, typically 8-10 minute wake-up from induction doseClearance of propofol exceeds hepatic blood flow, suggesting extrahepatic metabolismModerate cirrhosis and chronic renal failure do not affect clearance

…however, being a pop icon does affect how your body clears the drug…

PROPOFOL (CONT.)Decrease in arterial blood pressure due to drop in SVRHypotension is more pronounced than thiopental and more likely to occur with:

Large doses!, Rapid Injection!, Old Age!

Also impairs normal baroreflex response (no inc. HR)

PROPOFOL (CONT.)Profound respiratory depressant as many patients will become apneic after induction doseInhibits response to hypoxia and hypercarbiaPositives include depression of upper airway reflexes and less incidence of wheezing

According to the 2009 autopsy report, "the cause of death is acute propofol intoxication," which caused the singer to stop breathing

PROPOFOL (CONT.)Decreases cerebral blood flow and intracranial pressure

Provides neuroprotection against focal ischemia (not global)

Induction accompanied by twitching/spontaneous movement easy to be confused as seizure activity but appears to have anticonvulsant properties

And when it comes to antiemetic effects, you can’t BEAT IT!

FOSPROPOFOLThe water-based prodrug of propofol and was approved by the FDA for use as a sedation agent for MAC procedures

Metabolized by alk phos in a reaction that produces propofol, phosphate and formaldehyde

Kinetics have been difficult to establish

Dynamics similar to propofol but onset and recovery are prolonged

FOSPROPOFOL-SAFETYASPF newsletter:http://www.apsf.org/newsletters/html/2010/summer/07_Fospropofol.htm

Fospropofol has the advantage of less pain on injection, less risk of hyperlipidemia and less bacterial contamination

High incidence of perineal paresthesias and pruritus…awkward

Frustrating pharmacokinetics but serves as an alternative during propofol shortages

Substitutions at Carbon #5 determines hypnotic potency and anticonvulsant effectSubstitutions at Carbon #2 alter the lipid solubility

Derived from barbituric acid, this class has varying degrees of hypnotic, sedative and anticonvulsive effects

BARBITURATES

BARBITURATES (CONT.)Even though they are derived from acid, the ultimate formulations are alkaline with a pH of 10 therefore they cannot mix with acids (NMBDs) or it will precipitate

Precipitates will block IV lines and cause tissue necrosis if accidentally injected into an artery

The formulations are also racemic mixtures and the potencies reflect the ratio of the different isomers

BARBITURATES-KINETICSDuration of action determined by re-distribution, not metabolism

All of the barbiturates, except for phenobarbital are metabolized by oxidation in the liver and excreted into the urine after conjugation

Chronic administration of barbiturates or other drugs that induce oxidative enzymes (P450) enhance its metabolism

BARBITURATES (CONT.)Thiopental is highly protein bound (80%), but its great lipid solubility and high nonionized fraction (60%) account for maximal brain uptake within 30 sec.

Induction dose affected by: AGE, SERUM ALBUMIN, BLOOD ACIDITY and VOLUME STATUS

Methohexital and thiopental have similar distribution patterns, but methohexital is cleared quicker than thiopental which accounts for the slightly faster recovery after anesthesia

QUESTIONWhich of the patients described below will require the smallest induction dose of thiopental?

A. 45 year-old hyperventilating and anxious with questionable drug abuse history

B. 65 year-old with hx of liver disease who was involved in a trauma with lots of blood loss

C. 65 year-old with hx of CAD currently on a high protein diet

D. 22 year-old sickle cell patient who has crackles on exam after transfusion of 2 units of PRBCs

ANSWERA. 45 year-old hyperventilating and anxious with questionable drug abuse historyB. 65 year-old with hx of liver disease who was involved in a trauma with lots of blood lossC. 65 year-old with hx of CAD currently on a high protein dietD. 22 year-old sickle cell patient who has crackles on exam after transfusion of 2 units of PRBCs

Increased age, Decreased albumin, Hypovolemic and Acidotic

BARBITURATES -PHARMACODYNAMICSThe sedation for anesthesia is achieved through the action at the reticular activating system

Suppress transmission of excitatory neurotransmitters and enhance transmission of inhibitory transmitters

They work at the synapse by either limiting neurotransmitter release or stereoselectively interacting with postsynaptic receptors

BARBITURATES (CONT.)CARDIAC – smaller depressant effects than propofol, depress the medullary vasomotor center and decrease sympathetic outflowNegative ionotropic effects are usually masked by baroreceptor-mediated reflexes like increased heart rate

RESP – decrease tidal volumes and decrease rateBlunt response to hypercarbia and hypoxiaInduction doses will cause apneaNot as good as propofol for facilitating airway instrumentation

BARBITURATES (CONT.)CEREBRAL – A good choice for neurosurgical cases because they are potent cerebral vasoconstrictors and decrease CBF, CMRO2 and ICPProvide neuroprotection from focal cerebral ischemia (not global)Increasing doses decrease CMRO2 to a point where there is a flat line on the EEGMethohexital does not have this isoelectric effect, in fact, it activates epileptic foci and is used in surgery aimed to ablate epileptic fociNO ANALGESIC PROPERTIES! In fact, it may lower the pain threshold

QUESTIONIn which scenario would a barbiturate not offer neuroprotection for the patient?

Cerebral Ischemia resulting from…A. Acute cerebellar strokeB. Clips used during aneurysmal surgeryC. Cardiac arrestD. Surgical retraction

ANSWERCerebral Ischemia resulting from…A. Acute cerebellar strokeB. Clips used during aneurysmal surgeryC. Cardiac arrestD. Surgical retraction

This is an example of global ischemia

THIOPENTAL VS PROPOFOL

“(Propofol)… resulted in a significantly quicker recovery and an earlier return of psychomotor function as compared with thiopentone and midazolam irrespective of the agent used for maintenance of anaesthesia.”

BENZODIAZEPINESBenzodiazepines are used for premedication, IV sedation, induction of anesthesia and suppression of seizure activity

The structures of commonly used benzodiazepines and their antagonist flumazenil share a seven-member diazepine ringThe benzene ring adds to the lipophilicity

BENZODIAZEPINES-KINETICSDiazepam is quite lipid soluble and rapidly penetrates the blood-brain barrier

Midazolam is water-soluble, but its imidazole ring closes at a physiological pH making it highly lipophilic

Lorazepam is only moderately lipophilic, why it has slower onset and recovery

Collectively they are slower in onset and recovery than thiopental

BENZODIAZEPINES-KINETICSBenzodiazepines are metabolized in the liver into water-soluble glucuronides that are excreted by the kidneys

Midazolam and diazepam have similar distribution patterns, but midazolam has a significantly shorter half-life (2 hrs) than diazepam (30 hrs) because of its high hepatic extraction ratio

But the same holds true for the benzodiazepines as with the other anesthetics, the termination of their action is dependent on re-distribution and not metabolism

BENZODIAZEPINES-DYNAMICSLike barbiturates, benzodiazepines also activate GABAa receptor complexes and enhance Cl- current to hyperpolarize neurons and effectively reduce their excitability

Benzodiazepines have their own specific binding site on GABA receptors and midazolam has a twice greater affinity for these receptors than diazepam

GABA receptors responsive to benzodiazepines are almost exclusively located on post-synaptic nerve endings in the cerebral cortex minimal depressant effects on ventilation and blood pressure

BENZODIAZEPINES (CONT.)CARDIAC – minimal depressant effects, HR occasionally rises

RESP – usually minimal depressant, but can cause apnea but usually in the presence of opiatesProduces decreased response to carbon dioxide

CEREBRAL – like barbiturates, they decrease CBF and CMRO2, but to a smaller extent

Midazolam unable to produce isoelectric EEG, suggesting a ceiling effect to their decreases in CMRO2

Minimal effect on ICP, no neuroprotective qualities

AS AN INDUCTION AGENT?Rarely used for induction, but you can use a dose of 0.1-0.3 mg/kg

Onset of induction is slower than other induction agents

Appears on paper to have a better organ system profile with less cardiac and respiratory affects, but it is unlikely it offers any advantage over the other induction agents

OPIODSClass of drugs known for their analgesic effects

Classified as anesthetics because of their sedative qualities

OPIODS - KINETICSFentanyl and Sufentanil have the highest lipid solubility leading to quick onsets and quick recoveries (5-20 minutes)

Even though it has less lipid solubility, alfentanil is quicker in onset than fentanyl and sufentanil

Redistribution terminates the action of all opiods, however large doses must depend on biotransformation to adequately lower plasma levels

Biotransformation takes place in the liver and since they all have a high extraction ratio, clearance depends on hepatic blood flow

OPIODS (CONT.)Remifentanil has a unique ester structure makes it susceptible to ester hydrolysis in the blood

This extrahepatic metabolism is so rapid and complete that the duration of remifentanil infusion infusion has little effect on wake-up times

Its context sensitive half time (time required for the plasma concentration to decline by 50% after termination of infusion) is 3 minutes regardless of the duration of infusion

Remifentanil is therefore an excellent choice as a continuous infusion

OPIODSCARDIAC – minimal direct effects, but the release of histamine leads to decreses in SVR and blood pressuresMeperidine is similar in structure to atropine and can cause increased heart rate

RESP – decrease ventilation, particularly respiratory rateElevated apneic threshold (CO2 level at which they breathe)Fentanyl, sufentanil and alfentanil increase chest wall rigidity that is responsive to neuromuscular blocking agentsHistamine can also cause bronchospasm

OPIODSCEREBRAL – variable effects on ICP and CPP, reduce CMRO2 and ICP in general, but to a lesser extent than barbiturates or benzodiazepinesStimulation of the CTZ is responsible for the high incidence of nausea/vomitting

G.I. – slows gastric emptying and sounds a lot like an internal medicine problem

ENDOCRINE – block the hormones associated with the stress response, may be beneficial to patients with heart disease

QUESTION Propofol:

a.Has a faster onset-time for hypnosis than thiopental.

b.Has a longer context-sensitive half-time than fentanyl after a 1 h infusion.

c.Has a higher clearance than alfentanil.

d.Is suitable for infusions of long duration because it has a large volume of distribution at steady state.

e.Has a clearance that is greater than hepatic plasma flow.

QUESTION. Alfentanil:

a.Reaches steady-state more rapidly than fentanyl using a constant infusion rate.

b.Is less lipid soluble than fentanyl.

c.Has a faster onset-time than propofol because it has a lower pKa.

d.Has the same context-sensitive half-time after an infusion of 2 h as after an infusion of 6 h.

e.Administration can be through a commercially available target-controlled delivery device.

KETAMINEA derivative of PCP and 10 times less potent, it differs from other anesthetics in it stimulating effects on the organ systems and the analgesia it provides

The R-(-) isomer is the most potent stereoisomer and all formulations in the U.S. are only available as racemic mixtures

KETAMINE-KINETICSHigh lipid solubility ensures rapid onset

Termination of effects occur first as the result of redistribution to other inactive tissues and then metabolized in the liver by P450

Ketamine has very low protein binding (12%)

KETAMINE-DYNAMICSMajor effect of ketamine is through the inhibition of the NMDA receptor complex

After induction of ketamine, patients go into a cataleptic state where their eyes are open and a slow, nystagmic gaze is present

Frequently increases lacrimation and salivation, should pre-treat with an anticholinergic like glycopyrrolate

No amnestic qualities, will need to supplement with midazolam if used as sole anesthetic

KETAMINE-DYNAMICSSignificant analgesic properties

Emergence from ketamine may include vivid dreams, hallucinations, out of body experiences along with an array of distorted senses (visual, auditory, tactile)

Patients can either experience fear or euphoria

Children have a decreased incidence of these emergent reactions

KETAMINE (CONT.)CARDIAC – produces transient increases in systemic blood pressure and heart rate through sympathetic stimulationHowever, it also is a direct myocardial depressant…only shows in a critically ill patient

RESP – does not produce respiratory depressionResponse to hypercarbia remains intactProtective airway reflexes remain intactRelaxes bronchial smooth muscleBeware, kids can still get laryngospasm on ketamine

KETAMINE (CONT.)CEREBRAL – Ketamine is not to be used for someone with intracranial pathology as it increases CBF, increases CMRO2 and increases ICPHowever, it can be used as an anticonvulsant

…Ultimately, ketamine is an important alternative because of its desirable cardio and respiratory effects while also providing analgesia by different routes, but its regular use is prohibited by emergence reactions

ETOMIDATEEtomidate is a hypnotic with no analgesic properties and minimal hemodynamic effects

Structurally unrelated to other anesthetics, but behaves very similar to barbituratesEtomidate contains a carboxylated imidazole ringPrepared in propylene glycol, causes pain on injection

ETOMIDATE-KINETICSOnly available as IV, bypasses absorption

Highly protein-bound, but still characterized as a very rapid onset of action due to its high lipid solubility and large nonionized fraction at physiological pH

Redistribution is responsible for decreasing the plasma concentration to awakening levels

Shorter half-life than thiopental because of its clearance

ETOMIDATE-DYNAMICSDepresses the reticular activating system and mimics the inhibitory effects of GABA

Unlike barbiturates, it has disinhibitory effects in the extrapyramidal motor area leading to myoclonus at a rate of 30-60%

PONV more than common than seen with a barbiturate induction

ETOMIDATE (CONT.)CARDIAC – Produces minimal, if any, changes in heart rate and cardiac output with a slight decrease in systemic blood pressureContractility remains the sameNo histamine release

ETOMIDATE (CONT.)RESP – ventilation is affected less with etomidate than with barbiturates or benzodiazepinesInduction doses do not result in apnea unless given with opiods

CEREBRAL – decreases CBF, CMRO2 and ICP to SAME EXTENT as thiopentalCPP remains constant because cardiac function is well perservedChanges on EEG resemble those of barbiturates, however, the one difference is their enhancement of SSEPs

SO WHY IS IT NOT USED…?First off, we never have it…

Second off, and probably more relevant, it causes adrenocortical suppression

Induction doses transiently inhibit enzymes involved in cortisol and aldosterone synthesis (11-beta hydroxylase)

The suppression only lasts 4-8 hours, difference in opinion as to whether there is an increased mortality rate

DEXMEDETOMIDINESelective alpha-2 agonist and primarily used for ICU sedation or as an adjunct during general anesthesia or for sedation during awake fiberoptics

Observations of patients who took clonidine revealed the decreased amounts of anesthetic that were required, so now it is part of our anesthetic arsenal

DEXMEDETOMIDINE-KINETICSVery water soluble

Rapid hepatic metabolism

A relatively high context sensitive half time, surprisingly

DEXMEDETOMIDINE-DYNAMICSHypnosis presumably results from stimulation of alpha-2 receptors located in the locus ceruleus

Analgesic effect results from alpha-2 stimulation in the spinal cord

The sedation created by dexmedetomidine is a different quality as it more resembles sleeping as it activates endogenous sleep pathways

Tolerance and dependence develop as seen with clonidine

DEXMEDETOMIDINE (CONT).CARDIAC – infusion produces moderate decreases in heart rate and SVR with a subsequent decrease in blood pressureHowever, when given as a bolus it will produce transient increases in blood pressure and pronounced decreases in heart rateBradycardia can be significant enough to require treatment

RESP – moderate decrease in tidal volumes

CEREBRAL – decrease CBF, no significant effects on CMRO2 or ICP

DROPERIDOLA dopamine receptor antagonist, affecting the caudate nucleus and chemoreceptor trigger zone (similar to haldol)

Commonly used for PONV, it garners classification as an anesthetic for its activity in the CNS and its tranquilizing effects

DROPERIDOL (CONT.)CARDIAC – mild alpha adrenergic blocking effects lead to vasodilationAssociated with prolongation of QT, must have an EKG before administering (>440ms is contraindication)Can induce catecholamine release, DO NOT USE WITH PHEOCHROMOCYTOMA

CEREBRAL EFFECTS - -Extrapyramidal reactions-Makes them apprehensive and fearful-Decrease CBF and ICP, but not CMRO2

Propofol 1-2.5 3-8 2-10 2-4 97 20-30 4-23

Thiopental 3-5 5-10 2.5 2-4 83 3.4 11

Methohexital 1-1.5 4-7 2.2 5-6 73 11 4

Midazolam 0.1-0.3 15-20 1.1-1.7 7-15 94 6.4-11 1.7-2.6

Diazepam 0.3-0.6 15-30 0.7-1.7 10-15 98 0.2-0.5 20-50

Lorazepam 0.03-0.1 60-120 0.8-1.3 3-10 98 0.8-1.8 11-22

Ketamine 1-2 5-10 3.1 11-16 12 12-17 2-4

Etomidate 0.2-0.3 3-8 2.5-4.5 2-4 77 18-25 2.9-5.3

Dexmedetomidine N/A N/A 2-3 6 94 10-30 2-3

Dose Duration Vd Distribution Protein Clearance Elimination

COMPARISON OF PROFILES

CONCLUSIONQuickest onset and recovery?

GABA? NMDA? Alpha 2? Opiod?

Biggest cardiac depressent?

Biggest respiratory depressant?

Most neuroprotective?

REFERENCESComparative Study Between Three Intravenous Drugs:Thiopentone Sodium, Propofol and Midazolam:Study of 100 Cases and Critical Review. S K Mondol1, M A Rahim 2, TAJ June 2007; Volume 20 Number 1

Ronald D. Miller 2000 5th edition Anaesthesia

Clinical Anesthesiology - G. Edward Morgan; Maged S. Mikhail; Michael J Murray. 2005-08-26