Pharmacology of general anesthetics

Dr. Ashraf Arafat, MDDr. Ashraf Arafat, MDAssistant Professor Assistant Professor

Department of Anesthesia, King Saud University

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Benzodiazepines (BZ)Benzodiazepines (BZ)

The 3 main drugs used in this category are diazepam, The 3 main drugs used in this category are diazepam, lorazepam and midazolam. lorazepam and midazolam.

Primary uses:Primary uses:

Anti-anxiety agent pre-op for premedication.Anti-anxiety agent pre-op for premedication.

SedationSedation

They are inadequate for use in surgical anesthesia “on They are inadequate for use in surgical anesthesia “on their own”, and must therefore be used with another their own”, and must therefore be used with another anesthetic agent (i.e. an inhalation anesthetic). anesthetic agent (i.e. an inhalation anesthetic).

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Advantages:Advantages:Relatively rapid onsetRelatively rapid onset

Cause amnesiaCause amnesia

Relatively little cardiovascular effectRelatively little cardiovascular effect

Anti-convulsantAnti-convulsant

Disadvantages:Disadvantages:Not analgesicNot analgesic

Cause respiratory depressionCause respiratory depression

Long-acting (diazepam or repeated inj. of midazolam)Long-acting (diazepam or repeated inj. of midazolam)

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a. diazepam (Valium)a. diazepam (Valium)It is water-insoluble, so IV use requires a non-It is water-insoluble, so IV use requires a non-aqueous vehicle which can cause local irritation/pain aqueous vehicle which can cause local irritation/pain

b. midazolam (Dormicum)b. midazolam (Dormicum)- water soluble, so drug of choice for IV administration - water soluble, so drug of choice for IV administration -It has a more rapid onset and more rapid elimination It has a more rapid onset and more rapid elimination than the other BZ’s. than the other BZ’s. -The most potent amnestic The most potent amnestic

c. lorazepam (Ativan)c. lorazepam (Ativan)water-insoluble, water-insoluble, less potent amnestic than less potent amnestic than midazolam, but a more potent amnestic than midazolam, but a more potent amnestic than diazepam. diazepam.

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BarbituratesBarbiturates

The 3 main drugs used in this category are The 3 main drugs used in this category are thiopental, thiamylal, and methohexital. thiopental, thiamylal, and methohexital.

Primary Use: Primary Use: Induction of anesthesiaInduction of anesthesia

Advantages: Advantages:

Rapid onset (10 - 30 sec)Rapid onset (10 - 30 sec)

Short duration (5 – 8 min) initial dose; redistributed Short duration (5 – 8 min) initial dose; redistributed from brain to muscle; prolonged on repeated from brain to muscle; prolonged on repeated injectioninjection

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Disadvantages:Disadvantages:Not analgesicNot analgesic

Decrease blood pressureDecrease blood pressure

Decrease respiratory rate and tidal volume or Decrease respiratory rate and tidal volume or apnea.apnea.

Coughing, laryngospasm, bronchospasm.Coughing, laryngospasm, bronchospasm.

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OpioidsOpioidsOpioids produce moderate sedation and profound Opioids produce moderate sedation and profound analgesia. They exert their effects by binding with analgesia. They exert their effects by binding with opioid receptors in CNS ( 3 major opioid receptors opioid receptors in CNS ( 3 major opioid receptors μ μ (mu), (mu), κκ (kappa), and (kappa), and δδ (delta). (delta).

The opioids most commonly used are The opioids most commonly used are

fentanyl fentanyl

sufentanil citrate (Sufenta)sufentanil citrate (Sufenta)

alfentanil (Alfenta)alfentanil (Alfenta)

remifentanil (Ultiva)remifentanil (Ultiva)

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Primary uses:Primary uses:

Analgesia Analgesia

Advantages:Advantages:

Profound analgesiaProfound analgesia

Relative cardiovascular stabilityRelative cardiovascular stability

High potency, short duration (15-30 min.; High potency, short duration (15-30 min.; Remifentanil; 5 min) except morphineRemifentanil; 5 min) except morphine

Reduces emergence phenomenaReduces emergence phenomena

Reversible by opioid receptor antagonistsReversible by opioid receptor antagonists

Disadvantages:Disadvantages:

NauseaNausea

Slow gastric emptyingSlow gastric emptying

Respiratory depression at high doses (assisted Respiratory depression at high doses (assisted ventilation required).ventilation required).

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FentanylFentanyl

A potent synthetic opioid agonist with between 50-100 A potent synthetic opioid agonist with between 50-100 times the analgesic potency of morphine. times the analgesic potency of morphine.

Used to aid induction and maintenance of general Used to aid induction and maintenance of general anesthesia and to supplement regional and spinal anesthesia and to supplement regional and spinal anesthesia. anesthesia.

Ability to maintain cardiac stability. Ability to maintain cardiac stability.

Sufentanil citrate (Sufenta)Sufentanil citrate (Sufenta)Rapid induction of analgesia (similar to Fentanyl)Rapid induction of analgesia (similar to Fentanyl)Compared to fentanyl and sufentanil, alfentanil has a Compared to fentanyl and sufentanil, alfentanil has a shorter duration of action because its high protein shorter duration of action because its high protein binding and relatively low lipid solubility .binding and relatively low lipid solubility .

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Remifentanil (Ultiva)Remifentanil (Ultiva)

Ultra short acting and rapidly cleared because it’s Ultra short acting and rapidly cleared because it’s ester linkages are susceptible to hydrolysis by ester linkages are susceptible to hydrolysis by esterases in tissues and RBC’s. esterases in tissues and RBC’s.

MorphineMorphine

May produce hypotension and bronchoconstriction May produce hypotension and bronchoconstriction as a consequence of its histamine-releasing as a consequence of its histamine-releasing action.action.

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KetamineKetamineA complete i.v. anesthetic -causes “dissociative A complete i.v. anesthetic -causes “dissociative anesthesia”anesthesia”

Primary uses:Primary uses:Induction or anesthesia in at risk patients w/ Induction or anesthesia in at risk patients w/ cardiovascular problemscardiovascular problems

Sedation or general anesthesia in childrenSedation or general anesthesia in children

Advantages:Advantages:

Cardiovascular stimulantCardiovascular stimulant

BronchodilatorBronchodilator

Profound analgesia and amnesiaProfound analgesia and amnesia1212

Disadvantages:Disadvantages:

Emergence reactions (not in children <15; Emergence reactions (not in children <15; adults >65)adults >65)

Increases intracranial pressureIncreases intracranial pressure

Suppresses respiration (less severe than Suppresses respiration (less severe than other anesthetics)other anesthetics)

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Propofol (Diprivan)Propofol (Diprivan)

Primary uses:Primary uses:

A sedative/hypnotic A sedative/hypnotic

Induction or maintenance of general anesthesia. Induction or maintenance of general anesthesia.

Sedating intubated, mechanically ventilated Sedating intubated, mechanically ventilated patients. patients.

Advantages: Advantages:

Rapid induction and recovery times even after Rapid induction and recovery times even after repeated injectionsrepeated injections

Anti-emetic propertiesAnti-emetic properties

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Disadvantages:Disadvantages:

Pain on injectionPain on injection

Involuntary muscular movementInvoluntary muscular movement

Respiratory depression ,apnea Respiratory depression ,apnea

bradycardia and hypotension. bradycardia and hypotension.

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EtomidateEtomidatePrimary use: Primary use: Induction in patients w/ cardiovascular problemsInduction in patients w/ cardiovascular problems

Advantages:Advantages:Rapid inductionRapid induction

Ultra-short acting (5 min)Ultra-short acting (5 min)

No cardiovascular depressionNo cardiovascular depression

Minimal respiratory depressionMinimal respiratory depression

Disadvantages:Disadvantages:

Pain on injectionPain on injection

Involuntary muscular movementInvoluntary muscular movement

Nausea and vomitingNausea and vomiting

HiccupsHiccups

Not analgesicNot analgesic1616

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Desflurane Desflurane Advantages:Advantages:

Rapid onset and recovery of anesthesia (useful for Rapid onset and recovery of anesthesia (useful for outpatient procedures)outpatient procedures)

One of least metabolized to toxic byproductsOne of least metabolized to toxic byproducts

Disadvantages:Disadvantages:Low volatility, so requires a special vaporizerLow volatility, so requires a special vaporizer

Pungent and irritating to the airway (leading to more Pungent and irritating to the airway (leading to more coughing, laryngospasm, so it is not as useful for coughing, laryngospasm, so it is not as useful for extended surgical procedures)extended surgical procedures)

High inspired gas concentrations lead to a significant High inspired gas concentrations lead to a significant increase in the patient’s BP & HR.increase in the patient’s BP & HR.

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sevoflurane:sevoflurane:AdvantagesAdvantages::

Rapid onset and very rapid recovery of anesthesia Rapid onset and very rapid recovery of anesthesia (useful with children)(useful with children)

Not as pungent as desflurane (also useful with Not as pungent as desflurane (also useful with children) children)

Has good bronchodilating properties and is the agent Has good bronchodilating properties and is the agent of choice in patients with asthma, bronchitis, and COPD. of choice in patients with asthma, bronchitis, and COPD. It has little effect on the heart rate. It has little effect on the heart rate.

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Disadvantages:Disadvantages:

Carbon dioxide absorbents in anesthesia Carbon dioxide absorbents in anesthesia machines degrade sevoflurane to a fluorinated machines degrade sevoflurane to a fluorinated hydrocarbon, which is degraded by renal lyase hydrocarbon, which is degraded by renal lyase enzymes to a thioacylhalide.enzymes to a thioacylhalide.

This compound has been observed to cause This compound has been observed to cause necrosis of the proximal tubule in rats. necrosis of the proximal tubule in rats.

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Isoflurane:Isoflurane:

Advantages:Advantages:It causes peripheral vasodilation and increased It causes peripheral vasodilation and increased

coronary blood flow (useful in patients with ischemic coronary blood flow (useful in patients with ischemic heart disease)heart disease)

Disadvantages:Disadvantages:Moderate solubility, so recovery from anesthesia Moderate solubility, so recovery from anesthesia

may be delayedmay be delayed

Isoflurane can make the heart “more sensitive” to Isoflurane can make the heart “more sensitive” to circulating catecholamines (like epinephrine). circulating catecholamines (like epinephrine).

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Halothane Halothane Used for induction in children (sweet Used for induction in children (sweet pleasant odor); pleasant odor);

Toxicity – cardiac arrhythmias, Toxicity – cardiac arrhythmias,

““halothane hepatitis” (rare). halothane hepatitis” (rare).

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Nitrous OxideNitrous OxideNot used alone (except where full anesthesia Not used alone (except where full anesthesia not necessary; e.g. dental procedures);not necessary; e.g. dental procedures);

Causes more nausea/vomiting;Causes more nausea/vomiting; Contraindicated in patients with air filled cavities Contraindicated in patients with air filled cavities

(e.g. air embolus, pneumothorax, etc) or vitamin (e.g. air embolus, pneumothorax, etc) or vitamin B12 deficiency. B12 deficiency.

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D. Neuromuscular blocking D. Neuromuscular blocking drugsdrugs

Used to perform tracheal intubation, facilitate Used to perform tracheal intubation, facilitate ventilation and to provide optimal surgical operating ventilation and to provide optimal surgical operating conditions, for example during laparotomy. conditions, for example during laparotomy.

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Depolarizing(Succinycholine)Depolarizing(Succinycholine)Structurally similar to acetylcholine and function as Structurally similar to acetylcholine and function as competitive inhibitors. competitive inhibitors.

Very short duration of action Very short duration of action

Metabolized very quickly by an enzyme called Metabolized very quickly by an enzyme called plasma cholinesterase. plasma cholinesterase.

A useful drug in situations where muscle relaxation A useful drug in situations where muscle relaxation is needed for only a short time such as to facilitate is needed for only a short time such as to facilitate intubation. intubation.

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Side effects :Side effects :Fasciculations .Fasciculations .

Muscle painMuscle pain

Bradycardia.Bradycardia.

Increases in ocular and gastric pressure,Increases in ocular and gastric pressure,

Hyperkalemia .Hyperkalemia .

Anaphylaxis. Anaphylaxis.

Malignant hyperthermia: a dramatic increase in Malignant hyperthermia: a dramatic increase in body temperature, acidosis, electrolyte imbalance body temperature, acidosis, electrolyte imbalance and shock and shock

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Nondepolarizing blockersNondepolarizing blockersThey act by competitively blocking the binding of ACh to its receptors and inhibit muscular and inhibit muscular contraction. contraction.

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Pancuronium bromide (Pavulon)Pancuronium bromide (Pavulon)

The first steroid NMBD in clinical use has a slow The first steroid NMBD in clinical use has a slow onset and long duration of action. onset and long duration of action.

It does not cause histamine releaseIt does not cause histamine release

Weak sympathomimetic properties and causes Weak sympathomimetic properties and causes tachycardia. tachycardia.

It is partly de-acylated in the liver to a metabolite It is partly de-acylated in the liver to a metabolite with neuromuscular blocking properties, and with neuromuscular blocking properties, and partly excreted unchanged in the urine. partly excreted unchanged in the urine.

Its action is prolonged in renal and hepatic Its action is prolonged in renal and hepatic impairment. impairment.

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Atracurium besylate (Tracrium)Atracurium besylate (Tracrium)Widely used and have an intermediate onset and Widely used and have an intermediate onset and duration of action .duration of action .

It causes release of histamine but has no direct It causes release of histamine but has no direct cardiovascular effects.cardiovascular effects.

MetabolismMetabolism is by Hofmann degradation and ester is by Hofmann degradation and ester hydrolysis in the plasma, hence its duration of hydrolysis in the plasma, hence its duration of action is independent of renal and hepatic action is independent of renal and hepatic function. function.

A breakdown product of atracurium, A breakdown product of atracurium, laudanosinelaudanosine may accumulate due to very slow hepatic may accumulate due to very slow hepatic metabolism and upon crossing into the brain may metabolism and upon crossing into the brain may cause seizures cause seizures

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Cisatracurium(Nimbex)Cisatracurium(Nimbex)

Isomer of atracuriumIsomer of atracurium

Less laudanosine formed .Less laudanosine formed .

Unlike atracurium it does not release histamine. Unlike atracurium it does not release histamine.

It is It is metabolised metabolised by Hofmann degradation and by Hofmann degradation and does not accumulate in renal failure. does not accumulate in renal failure.

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Vecuronium Vecuronium bromide(Norcuron)bromide(Norcuron)

Vecuronium is structurally similar to pancuronium Vecuronium is structurally similar to pancuronium but has a slightly faster onset and shorter but has a slightly faster onset and shorter (intermediate) duration of action.(intermediate) duration of action.

It does not release histamine or have any It does not release histamine or have any cardiovascular effects. cardiovascular effects.

MetabolismMetabolism in the liver occurs active metabolites in the liver occurs active metabolites before being excreted in the bile and urine.before being excreted in the bile and urine.

Lack of dependence on good kidney function for Lack of dependence on good kidney function for elimination provide advantages over other elimination provide advantages over other neuromuscular blocking agents. neuromuscular blocking agents.

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Rocuronium.Rocuronium. The most rapid onset of the clinically available The most rapid onset of the clinically available non-depolarizing NMBDs. Intubating conditions non-depolarizing NMBDs. Intubating conditions can be achieved in 60-90 seconds after an can be achieved in 60-90 seconds after an induction dose of 0.6 mg/Kg.induction dose of 0.6 mg/Kg.

An intermediate duration of action .An intermediate duration of action .

MetabolisedMetabolised in the liver and excreted in the bile. in the liver and excreted in the bile.

Minimal cardiovascular effects .Minimal cardiovascular effects .

Does not release histamine, Does not release histamine,

Higher incidence of anaphylactic reactions Higher incidence of anaphylactic reactions

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Anticholinesterases Anticholinesterases (Neostigmine)(Neostigmine)

(acetylcholinesterase inhibitors) are agents (acetylcholinesterase inhibitors) are agents

that inhibit the action of the acetylcholinesterase that inhibit the action of the acetylcholinesterase enzyme at the neuromuscular enzyme at the neuromuscular

junction. junction. Clinical tests of adequate resolution of Clinical tests of adequate resolution of

neuromuscular block include the ability to lift the neuromuscular block include the ability to lift the head from the bed for 5 seconds, head from the bed for 5 seconds,

No role for anticholinesterases in reversing the No role for anticholinesterases in reversing the effects of suxamethonium. effects of suxamethonium.

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Side effects Side effects

Bradycardia, miosis, GI upset, Bradycardia, miosis, GI upset,

Nausea, bronchospasm, increased bronchial Nausea, bronchospasm, increased bronchial secretions, sweating and salivation. secretions, sweating and salivation.

For this reason an antimuscarinic such as For this reason an antimuscarinic such as glycopyrronium or atropine must be administered glycopyrronium or atropine must be administered along with the anticholinesterase to minimise these along with the anticholinesterase to minimise these effects. effects.

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