ANESTHETIC AGENTS

Jehn Mihill

Objectives

To review some commonly used anesthestic agents

To discuss briefly some definitions related to the pharmacology of these medications

To discuss some common applications of these drugs in the context of your everyday work

Some definitions

Half life (T1/2)

The time taken for the plasma concentration of a drug to fall by 50% when first order kinetics are observed

Volume of distribution (Vd)

The volume into which a drug appears to be uniformly distributed at the concentration in plasma

- Influenced by lipid solubility, binding to plasma proteins and molecular size.

- - A low Vd indicates drug mainly restricted to intravascular space. High Vd indicates significant tissue uptake

Redistribution-the process by which a drug is moved from the

vessel rich group to the vessel poor group- This is the primary method responsible for the

termination of effect of the majority of anesthestic drugs

- Pharmacokinetics- Commonly explained as what the body does to

the drug- Pharmacodynamics- - what the drug does to the body

Pharmacokinetics (simplified) Absorption : the process of a substance

entering the blood circulation

Metabolism (biotransformation) Role of metabolism is to convert active lipid

soluble drug into water soluble and often inactive drug

Phase 1 reaction: Redox reaction (addition of a polar group), that

prepares the drug for phase 2 reaction, and sometimes inactivates the drug

Phase 2 reaction:- Glucoronidation (addition of an ionized group to

the drug) that prepares the drug for excretion, and often inactivates the drug

Excretion: The elimination of substances from the body. (often done by the kidneys- but can be lungs etc)

Plasma concentration curves Drugs injected intravenously are removed

from the plasma through two primary mechanisms: (1) Distribution to body tissues and (2) metabolism + excretion of the drugs. The resulting decrease of the drug's plasma concentration follows a biphasic pattern

Types of induction agents

Propofol Barbiturates: Thiopental, Methohexital Benzodiazepines: Midazolam, Diazepam Phenylcyclidines: Ketamine Etomidate Dexmedetomidine

The ideal IV anesthestic

Physicochemical water soluble long shelf life stable on exposure to light Pharmacokinetics small volumes required short duration of effect; rapidly

inactivated

The “ideal” IV anesthetic

Physicochemical- water soluble

- long shelf life; stable on exposure to light

Pharmacokinetics - small volumes required

- short duration of effect; rapidly inactivated

Year of introduction of different IV anesthetics 1935 – Thiopental 1957 – Methohexital 1960 – Droperidol 1965 – Ketamine 1965 – Diazepam 1972 – Etomidate 1977 – Propofol 1978 – Midazolam 2000 – Dexmedetomidine

Propofol

HistoryPhysicochemical propertiesPharmacokineticsEffects on organ-systemsClinical uses

History

1st clinical trial reported by Kay and Rolly in 1977

Initial formulation with Cremophor resulted in anaphylactoid reactions

Reformulated as a lipid emulsion Today is the most frequently

used IV anesthetic

Physiochemical properties

Alkylphenol Oil at room temperature, insoluble in

aqueous solution, highly lipid soluble Present formulation: 1% propofol + 10%

soybean oil + 2.25% glycerol + 1.2% egg phosphatide + 0.005% disodium edetate

Stable at room temperature Not light sensitive

Pharmacokinetics

Two-compartment model Redistribution half-life 2-8 minutes Elimination half-life around 4 hours

- rapid liver metabolism extrahepatic metabolism (lungs) excreted by the kidneys Context-sensitive half-time < 40

minutes (for infusions up to 8 hours)

Pharmacology

Primarily a hypnotic agent Mechanism NOT fully understood –

evidence points to binding to the beta subunit of the GABAA receptors in the hippocampus and prefrontal cortex

Produces a sense of well-being by increasing dopamine levels in the nucleus accumbens

Antiemetic effect by decreasing serotonin levels in the area postrema

Pharmacology

Anticonvulsant at induction doses

Decreases ICP and reduces CMRO2 while maintaining autoregulation

Dose-dependent duration of apnea after induction

During infusions TV is preferentially decreased, while RR is maintained

Pharmacology

Most prominent CVS effect – decrease in SBP by 25-40%, mostly by reducing SVR

Atenuates the tachycardic response to hypotension (resets the baroreflex)

Preserves the global myocardial oxygen supply-demand ratio

Effective in treating pruritus induced by spinal opiates

Clinical Uses

Induction and Maintenance of anesthesia

Sedation for countless procedures OK for Neuro (ECTs) and Cardiac cases ED95 unpremedicated patients 2.5mg/kg Earlier return of psychomotor function

than thiopental or methohexital Lower incidence of PONV than any other

hypnotic agent

Side Effects

Pain on injection Myoclonus < than etomidate, but > than

thiopental Propofol Infusion Syndrome

-lethal, first described in children subsequently in critically ill adults with infusions 5mg/kg/hr for > 48 hours;

includes cardiomyopathy, skeletal myopathy, hyperkalemia, lipemia, metabolic acidosis

Barbiturates

History Thiopental, Methohexital Physicochemical properties Pharmacokinetics Effects on organ-systems Clinical uses

History

Barbital – 1st barbiturate with sedative properties described in 1903

Hexobarbital – 1st short acting barbiturate introduced clinically in 1932 in Europe

Thiopental – introduced clinically in North America by R. Waters and J. Lundy in 1935 was characterized after Pearl Harbor as “the ideal form of euthanasia in war surgery”

Physicochemical

Water soluble salts in alkaline solutions; if alkalinity is reduced barbiturates precipitate as free acids

Thiopental is stable for 1 week if refrigerated after reconstitution

Methohexital remains stable for 6 weeks The groups (aryl or alkyl) attached to

the C atom in position 5 are responsible for the hypnotic activity

Pharmacology

Mechanisms of action remain largely unknown

evidence shows that binding of a barbiturate to the GABAA receptor both enhances (at low barbiturate concentrations) and mimics (at high concentrations) the action of GABA on the GABAA receptor, thus enhancing the actions of this inhibitory neurotransmitter

Pharmacology

Dose-related decrease in CMRO2 until isoelectric point is reached; after that, cerebral metabolic rate remains at 50% of baseline

Parallel reductions in CBF (the ratio of CBF to CMRO2 is unchanged) and ICP

CPP is preserved because ICP decreases to a greater extent than MAP

Protection from incomplete cerebral ischemia

Pharmacology

Cardiovascular depression from both cardiac and vascular effects.

Peripheral vasodilation is accompanied by a decrease in contractility secondary to reduced availability of Ca to myofibrils. In addition HR is increased.

Patients without adequate compensatory mechanisms may therefore display serious hemodynamic depression

Clinical Uses

Excellent hypnotic – onset 15 seconds No analgesia Thiopetal – analgesic at low doses Methohexital is cleared more rapidly

than thiopental – recovery profile similar to propofol

Contraindications

Porphyria may be precipitated by the administration of thiopental

Garlic and onion taste in 40% of patients Allergic reactions such as facial edema,

bronchospasm and anaphylaxis have been reported

Local tissue irritation at the site of injection leading in rare cases to tissue necrosis

Benzodiazepines

History Midazolam, Diazepam, Lorazepam Physicochemical properties Pharmacokinetics Effects on organ-systems Clinical uses

History

Chlordiazepoxide(Librium) was discovered accidentally to have sedative, hypnotic and amnestic effects in the early 1960’s when a patient who was taking it fell, fractured her sacrum, yet did not remember the trauma, nor did she complain of pain

Diazepam(Valium) was first used in 1965 Lorazepam(Ativan) was synthesized in

1971 Midazolam(Versed) was introduced in

1978 1977 specific benzodiazepine receptors

were described

Physicochemical

Highly lipid soluble at physiologic pH, water soluble when formulated in a buffered acidic medium (pH 3.5)

Midazolam solution contains 0.8% NaCl, 0.01% disodium edetate and 1% benzyl alcohol

pH is adjusted to 3 with HCl

Pharmacokinetics

Biotransformation occurs in the liver, the metabolites have activity and over time can accumulate

Termination of action is the result of redistribution from the CNS to other tissues

Midazolam has greater hepatic clearance than diazepam and lorazepam

All 3 are affected by obesity

Pharmacology

Hypnotic, sedative, anxiolytic, amnesic, anticonvulsant, and centrally produced muscle relaxant activities

Mechanism of action is well understood: occupation of the BDZ receptor modulates GABA

BDZ receptors are found in the olfactory bulb, cortex, cerebellum, hippocampus, substantia nigra and inferior colliculus

Pharmacology

Log-term exposure to benzodiazepines produces tolerance

Reduce CMRO2 and CBF in a dose-related manner, while maintaining their normal ratio

Increase the seizure threshold Produce dose-related ventilatory

depression and act synergistically with opioids even though they act at different receptors

Pharmacology

Only slight reduction in MAP HR and CO are maintained – safe for use

in aortic stenosis Act synergistically with opioids in

decreasing systemic BP – probably due to reduced sympathetic tone when the drugs are given together

Clinical Uses

Preoperatively for sedation and anxiolysis

Intraoperatively during local or RA Induction of GA: 0.2mg/kg No analgesia Recent reports focused on the potential

role of IT midazolam as an adjunct to IT opioids

Phencyclidines (Ketamine) History Physicochemical properties Pharmacokinetics Effects on organ-systems Clinical uses

History

Phencyclidine was introduced in clinical use in 1958, but produced an unacceptably high rate of postanesthetic hallucinations and delirium. Still used illicitly today for recreational purposes.

Ketamine, one of 200 derivatives of phencyclidine was released for clinical use in 1970

Physicochemical

Partially water soluble Prepared as an acidic solution – pH 3.5 to

5.5 containing the preservative benzethonium chloride

Racemic mixture of 2 enantiomers in equal amounts

The isomer S(+) is also available commercially

Pharmacokinetics

Metabolized by the liver to a compound (norketamine) with significantly less activity (20%)

Two-compartment model Distribution half-life: 11-16 minutes Elimination half-life: 2-3 hours

Pharmacology

Produces dissociative anesthesia – patients appear to be in a cataleptic state – eyes are open, cough and swallow reflexes are present, yet there is no recall of surgery or anesthesia

Selectively depresses neuronal function in neocortex and thalamus, while stimulating parts of the limbic system

NMDA receptor interaction may mediate the hypnotic and analgesic effects

Some opioid mu receptor activity has been described for the S(+) enantiomer

Pharmacology

Increases CMRO2, CBF and ICP 10-30% of adult patients who receive

ketamine as a major part of the technique experience emergence reactions such as illusions, vivid dreaming and extracorporeal experiences – usually they abate within 1 hour from emergence

Benzodiazepines – most effective treatment for emergence reactions

Pharmacology

Minimal effect on the central respiratory drive

Bronchial smooth muscle relaxant Increases HR, BP, myocardial work and

oxygen consumption. This hemodynamic changes are not related to the dose used or to the baseline cardiac function of the patient

Clinical Uses

Preventive analgesia 10-20 mg IV Ideal choice for cardiac tamponade and

restrictive pericarditis Excellent choice for severe reactive

airway disease Excellent choice for anterior mediastinal

mass when spontaneous ventilation must be preserved

Good choice for sedation of uncooperative patients (pediatric, MR, etc)

Excellent additive to postop pain control

Etomidate

History Physicochemical properties Pharmacokinetics Effects on organ-systems Clinical uses

History

Synthesized in 1964 Introduced in clinical practice in 1972,

gained quickly widespread popularity due to its hemodynamic stability

Early enthusiasm was tempered by reports of inhibition of steroid synthesis as well as a relatively high incidence of PONV

Physicochemical

Imidazole derivative Exists as 2 stereoisomers, but only the

(+) isomer is active as a hypnotic Water insoluble Unstable in a neutral solution Formulated as a propylene glycol

solution (35%) with a pH of 6.9

Pharmacokinetics

Metabolized in the liver to inactive form Excreted by the kidney (85%) and bile

(13%) Initial distribution half-life of 2.7 minutes Elimination half-life around 4 hours Clearance by the liver is high

Pharmacology

Hypnosis is achieved in one arm-brain circulation after an induction dose

Mechanism of action not elucidated; appears to be similar to that of propofol, involving the GABAA receptor

0.3mg/kg reduces CBF by 34% and CMRO2 by 45% without change in MAP

Reduces ICP by up to 50% and the intraocular pressure by 30-60%

Pharmacology

Associated with grand mal seizures; has been shown to produce increased EEG activity in epileptogenic foci

High incidence of myoclonic movement thought to be associated with centers in the brainstem

Hiccups or coughing may accompany induction

40% incidence of PONV

Pharmacology

1983 report on ICU patients sedated with etomidate >5 days showed higher mortality when compared to a similar group that received high-dose steroids as part of the trauma protocol.

Dose-dependent, reversible, inhibition of ascorbic acid synthesis, which is required for steroid production in humans. Indeed vit C supplementation restores cortisol levels to normal after etomidate use

Pharmacology

Several studies throughout the 1990’s showed that after etomidate induction the nadir of cortisol levels remains in the low-normal range, that the adrenocortical suppresion lasts <20 hours, and that high-stress surgery can overcome this temporary suppresion

Clinical Uses

Ideal choice for the cardiovascularly compromised patient undergoing high-stress surgery (aortic, valve, CABG)

Ideal for rapid sequence induction in cardiac and lung transplantation

Sedation for cardioversion in CAD, MI Sedation for ECTs – can produce longer

seizures than possible with other agents Often used in trauma

Dexmedetomidine

History Pharmacokinetics Effects on organ-systems Clinical uses

History

Initial observation of the reduction of the MAC of halothane by clonidine sparked the interest in alpha2 agonists

Early 2000’s - dexmedetomidine - has 1600 fold greater selectivity for the alpha2 than the alpha1 receptor

Parmacokinetics

Rapid distribution Extensively metabolized by the liver Excreted in both urine and feces Elimination half-time: 2 hours Context sensitive half-time: 4 minutes

after a 10-minute infusion to 4 hours after an 8-hour infusion

Pharmacology

Acts on alpha2 receptors in the locus ceruleus (sedative effect) and spinal cord (analgesic effect)

The sedative effect is exerted through the endogenous sleep-promoting pathways

Amnestic in a dose-dependent manner Decreases HR, SVR and indirectly

myocardial contractility Biphasic hemodynamic response after a

bolus injection (BP up by 22% within 5 minutes then down by 15% from baseline within 1 hour)

Clinical uses

Premedicant: 0.33-0.67mcg/kg 15 minutes before surgery attenuates response to ET intubation

Sedation in mechanically ventilated ICU patients - advantages over propofol: requires significantly less opioid and HR were slower (!CAD patients) – disadvantage: more recall

Loading dose 2.5mcg/kg/hr for 10 minutes , then maintenance infusion of 0.1-1mcg/kg/hr

Droperidol

History Effects on organ-systems Clinical uses

History

Introduced in the 1960’s as a derivative of haloperidol – used in combination with fentanyl (Innovar) first by DeCastro and Mundeleer during their research into neuroleptanesthesia, the “artificial hibernation

Use today severely restricted by the black box warning regarding potential for fatal arrhythmias

Pharmacology

Acts centrally and results in a submaximal inhibition of GABA receptors and full inhibition of alpha2-acetylcholine receptors – this explains the anxiety, restlessness and dysphoria that occur despite apparent tranquility and cataleptic immobility

Action on GABA receptors in the chemoreceptor trigger zone is responsible for the antiemetic effect

Pharmacology

Extrapyramidal signs – worsens symptoms of Parkinson’s disease

Causes balance disturbances May precipitate malignant neuroleptic

syndrome May prolong the QT interval (delay

myocardial repolarization) and precipitate torsades de pointes – dose dependent

Clinical Uses

Effective antiemetic: 0.6-1.25 mg IV for a 70kg adult reduces the incisence of PONV by 60%

Equally effective to ondansetron Efficacy enhanced by combination

with ondansetron and dexamethasone

Effective in the treatment of pruritus secondary to opioid administration

Summary

Propofol – most commonly used IV anesthetic; formulated in a lipid emulsion; rapid onset & offset; antiemetic effect

Thiopental & Methohexital – formulated as Na salts in a water base at alkaline pH; rapid onset & offset; provide cerebral protection; contraindicated in porphyria

Summary

Midazolam – primarily premedicant for anxiolysis and amnesia; rapid onset & offset; lack of active metabolites

Ketamine – provides both a dissociative state of hypnosis and analgesia; sympathomimetic action preserves cardiac function; preserves autonomic reflexes; minimal effect on respiration

Summary

Etomidate – used primarily for induction in cardiovascularly compromised patients; inhibits adrenocortical synthesis

Dexmedetomidine – sedation, hypnosis and analgesia; dose-related biphasic effect on BP; minimal effect on respiration

Droperidol – produces a state of neuroleptanesthesia in large doses; effective antiemetic; prolongs QT interval