General Anesthetics (Week 3, Mod 9)

REMINDER:

What are the two main targets of general anesthetics?

GABA receptors - inhibitory neurotransmitter - enhanced

NMDA receptors - stimulatory receptor -

What are the 4 different '“stages” of anesthesia?

• Stage 1 - Voluntary movement

• Stage 2 - Involuntary movement or excitement

• Stage 3 - Surgical Anaesthesia

• Stage 4 - Medullary Paralysis - IRREVERSIBLE, want to avoid

What are intravenous anesthetic agents mainly used for? Describe the advantages and disadvantages of this.

Typically used to INDUCE anesthesia… rapid onset

• sometimes used for maintenance; needs to have suitable pharmacokinetics for this

Advantages

• Rapid smooth induction (minimal excitement)

* Rapid protection of the airway

• Important in dyspnoeic patients & those at risk of regurgitation / aspiration

• No environmental pollution

Disadvantages

• IV access required

What are inhalational anesthetic agents mainly used for? Describe the advantages and disadvantages of this.

Typically used for MAINTENANCE of anesthesia

• occasionally used for induction

Advantages

• Delivery / elimination depends on ventilation

• Rapid adjustment of anaesthetic depth

Disadvantages

• Equipment required

• Endotracheal tube, carrier gas (oxygen), vaporiser, breathing system etc.

• Environmental pollution

What are the advantages and disadvantages of using inhaled anesthetics to induce anesthesia?

Advantages

• IV access can be secured after induction

• Make them sleepy so IV access can be easier (typical in pocket pets)

Disadvantages

• Environmental pollution

• Takes longer & delay in securing airway may be a problem in some cases

Describe the pharmacokinetics of intravenous agents in anesthesia… what are the two main factors that can affect its duration in the body?

Duration of action influenced by both redistribution of the drug through the body and metabolism of the drug

• Relative contribution depends on agent

• Determines suitability for TIVA (total intravenous anesthesia)

Redistribution:

• Concentration of drug determined by lipid solubility, composition of tissue, and blood flow

• Will have an initial loss of consciousness, but the drug will eventually redistribute through the body (see image)

  • Animal will slowly regain consciousness as the drug redistributes from the central nervous system to other areas of the body

  • DRUG STILL IN BODY UNTIL METABOLIZED

Metabolism:

• Metabolized by liver or elsewhere in the body

Describe the pharmacodynamic effects of GAs on the nervous system in general…

• inhibit conduction of action potentials 

• inhibit transmission at synapses

  • ↓ transmitter release

  • ↓ action of transmitter

  • ↓ excitability of post-synaptic cell

• brain regions

  • reticular formation

  • hippocampus

Describe the pharmacodynamic effects of GAs on the CVS and respiration in general…

• ↓ contractility of isolated heart preparations

Whole animal:

• effects on cardiac output and blood pressure vary

• potentially arrhythmogenic

• ↓ respiration

• ↑ arterial P CO₂

What are the three most common IV anesthetics?

• Propofol

• Steroid anaesthetics

eg Alfaxalone

• Dissociative agents

eg Ketamine

Describe propofol and its mechanism of action… know the general pharmacokinetic features of the drug.

Chemically unrelated to others (hindered phenol)

• oil at room temp. (emulsion)

• enhanced GABA transmission

• short acting, smooth and rapid recovery

Pharmacokinetics:

• highly plasma protein bound 

• large volume of distribution (>3 L/kg)

• redistribution and metabolism

• phase II metabolism - conjugated in the liver and “another site” (sulphate and glucuronide)   prior to excretion in urine

• rapidly cleared (> 40 ml/kg/min) 

• suitable for TIVA

What are some cases in which the pharmacological effect of propofol may be enhanced or prolonged?

Can be prolonged in CATS

May also be enhanced in patients with hypoproteinemia

In what cases is the pharmacological effect of propofol NOT prolonged?

Pharmacological effect is not prolonged:

• if repeated IV doses are administered (i.e. it is suitable for maintenance in dogs)

• in dogs with hepatic dysfunction 

Describe alfaxalone and its mechanism of action… know the general pharmacokinetic features of the drug.

• insoluble in water, presented in cyclodextrin vehicle

• ➢enhances inhibitory action of GABA 

            ? inhibits nicotinic acetylcholine receptors

            ? inhibits noradrenaline uptake

• high therapeutic index - very popular for this reason

• rapid induction

• rapid metabolism

• suitable for total intravenous anaesthesia (TIVA)

Describe ketamine and its mechanism of action… know the general pharmacokinetic features of the drug.

Interrupts the association between limbic and cortical regions

• inhibits NMDA receptors

• Dissociative agents produce a different “quality” of anaesthesia

  • Sensory loss with analgesia; a plus for this drug

• Increased muscle tone

• Eyes open ± slow nystagmus

• Active reflexes incl. laryngeal/pharyngeal reflexes

• Less profound CVS & respiratory depression

• Hallucinations / emergence delirium

What are some of the benefits of using TIVA?

• Easy to administer (minimal equipment)

• Pharmacokinetics are known / predictable

• Inhalational anaesthetics may be unsuitable in some individuals

• Avoids risk to people administering drugs, i.e. no environmental pollution 

What is the most widely used inhalation agent for anesthesia, and why?

ISOFLURANE

• Licensed in non-food producing animals

  • Good speed of induction / recovery / change of depth

  • Pungent odour (not ideal for induction)

  • Minimal metabolism

  • Cardiac output better maintained

  • Less arrhythmogenic

What are the two other most commonly used inhalation agents for anesthesia?

Sevoflurane and nitrous oxide

Describe the general features of sevoflurane…

• •Licensed in dogs

  • Rapid induction / recovery / change of anaesthetic depth 

  • Pleasant odour & minimal airway irritation so suitable for induction

  • Low rate of metabolism

Gaining popularity in veterinary anaesthesia
despite higher cost

Describe the general features of nitrous oxide…

Colourless gas, without taste or odour 

• Stored under pressure in cylinders

MAC (%) >100

• not very good potency

Oil:gas partition coefficient 1.4

Blood:gas partition coefficient 0.47

% metabolised <0.01

VERY good analgesic properties… will need to be used in conjunction with iso or sevo

• actually helps with the absorption of the other two inhalation agents