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Pharmacology for Anaesthetists > Intravenous anaesthetic agents > Flashcards

Intravenous anaesthetic agents Flashcards

1
Q

What is the mechanism of action of general anaesthetic agents. Draw a GABA receptor to illustrate this and the differential binding sites.

A

Allosteric modulation of inhibitory and excitatory neurotransmitter receptors.

Inhibitory neurotransmitters

  1. GABA
  2. Glycine

Excitatory neurotransmitters

  1. NMDA
  2. Neuronal acetylcholinesterase

Drawing:
Central Cl pore
5 subunits: beta - alpha - beta - alpha - gamma (clockwise from 12 o clock)
Benzo’s bind alpha-gamma interface
Volatiles bind 1st alpha subunit
GABA itself binds at the two alpha-beta interfaces.

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2
Q

With regard to allosteric modulation of neurotransmitters, describe the effect of the following agents on the inhibitory and excitatory neurotransmitter receptors:

Propofol
Thiopental
R-etomidate
S-etomidate
Ketamine 
Isoflurane
N2O
Xenon
A

Propofol, Thiopental and Isoflurane

Potentiate GABA and Glycine: ​++++
Inhibit Ach: -

Ketamine, N2O and Xenon
Inhibit NMDA receptor (glutamate ntmtr): -

R-etomidate: potentiates GABA: ++++
S-etomidate: does nothing

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3
Q

Which general anaesthetic agent supports the protein based mechanism of action of anaesthetics (rather than the lipid solubility or molecular theory mechanisms)?

A

R-etomidate: potentiates GABA: ++++
S-etomidate: does nothing

Both equally lipid soluble

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4
Q

Do inhaled or intravenous GA agents produce more immobility and why

A

Volatile agents –> spinal cord is a more important binding site for volatile agents versus IV agents –> more immobility

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5
Q

What is the name of the neurotransmitter that stimulates the NMDA receptor and what is this receptor predominantly involved with? Are there other substances that modulate and inhibit it?

A

Glutamate

NMDA receptor: learning and memory

Magnesium modulates
Ketamine/N2O/Xenon inhibit it

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6
Q

Describe the Meyer-Overton principle. Draw and label the graph.

A

Early 20th century Meyer and Overton independently described a linear correlation between lipid solubility and potency of anaesthetic agents.

At the time this suggested a non-specific mechanism of action based on this physico-chemical property.

Graph:
X - axis is LOG Oil: Gas (index of lipid solubility)
Y - axis is MAC: MAC = ± 1/Potency

Inverse relationship straight line graph
Left to right and top to bottom:
Agent (Oil gas : MAC)
1. N20 (1.4 ; 105)
2. Xenon (1.9 ; 71)
3. Desflurane (29 ; 6.6)
4. Sevoflurane (80; 2.0)
5. Enflurane (98 ;1.68)
6. Isoflurane (98 ; 1.17)
7. Halothane (224 ; 0.75)
8. Methoxyflurane (950 ; 0.16)
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7
Q

Define intravenous anaesthetic

A

Agents that will induce loss of consciousness in one arm - brain circulation time.

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8
Q

List the 15 most important factors for an ideal anaesthetic agent

A
  1. Rapid on (unionized @ phys. pH)
  2. Rapid off with no accumulation during long infusion
  3. Potent (High O:G - low dose rqrd.)
  4. Analgaesic @ subanaesthetic doses

Think of all the adverse effects of induction agents:

  1. Minimal CVS/RSP depression (Prop/Thio)
  2. No emesis (Etomidate)
  3. No pain on injection (Prop)
  4. No excitation or emergence phenomena
  5. No toxic effects or hypersensitivity reactions
  6. No drug interactions
  7. No histamine release
  8. Inexpensive
  9. Water soluble
  10. Long shelf life at room temperature
    15.
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9
Q

Classify the currently used IV induction agents

A

Barbiturates: Thiopental

Non-barbiturates: Propofol, Ketamine, Etomidate

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10
Q

Describe and substantiate the preparation of thiopental

A

SODIUM THIOPENTAL

  1. 2.5% solution
  2. Bright yellow powder
  3. Required in water soluble ‘enol’ form for storage and administration. Therefore pH as high as possible for this. Vial contains:
  4. Sodium carbonate –> pH 10.5 favouring H2O soluble ‘enol’ form which is more desirable as a preparation
  5. Nitrogen instead of air. Air contains CO2 –> reaction with water to reduce pH –> less alkaline and negate above effect.
  6. After injection into physiological pH the lipid solubility ‘keto’ form of the drug increases –> permitting rapid access to the target site.
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11
Q

Describe Thiopental: P1 DODSS P2 MMVI TBC

Preparation
Dose
Onset
Duration
Specifics
Systems
Protein bound and percent unionized (pKa)
Metabolism
Metabolites
Volume distribution
Interactions

Telimination
Bioavailability
Clearance

A

Preparation: Weak acid. Yellow powder + Na2CO3 + N2 (not air)
Dose: 3 - 7 mg/kg
Onset: 30 - 60 seconds
Duration: 5 - 10 minutes
Specifics:
1. TAUTOMERISM: stored pH 10.5 - ‘enol’ tautomer which is water soluble –> into plasma pH 7.4 becomes lipid soluble to enter effect site.
2. PORPHYRIA
3. INTRA-ARTERIAL INJXN –> to pH 7.4 –> keto form –> no longer water soluble crystals accumulate arterioles/capillaries –> ischaemia (in veins continuous arrival of new venous blood). Rx: immediate intra-arterial of PAPAVERINE, Analgaesia, SNS block of limb and anticoagulation.
4. Low doses: antalgaesic
Systems:
CNS - GA. Reduced: CMRO2, CBF, ICP.
CVS - Reduced: CO, SV, SVR. Increased HR (reflex)
RSP - Depression. Laryngospasm. Bronchospasm. RR down.
RENAL - CNS depression –> increased ADH. Reduced cardiac output –> reduced UO.
EYES - Decreased IOP
Pain injection: No
GIT: No N/V

Plasma binding: 80%
Percent unionized 60% (pKa = 7.6)
Mechanism: Allosteric modulation and potentiation of GABA and Glycine receptors; inhibition of neuronal ACh receptors.
Metabolism: Hepatic oxidation. As infusion may go from first order to zero order. CYP450 induced.
Metabolites: Active.
Vd: 2.5 ml/kg
Interactions: NSAIDS - reduce vailable protein binding sites

Telimination: ±10 hrs
Bioavailability: -
Clearance: 3.5 ml/kg/min

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12
Q

Define Tautomerism

A

The dynamic interchange between 2 different forms of molecular structure depending on the environmental conditions

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13
Q

How much thiopental is free to work at the target site? How does it bring about its effect despite this?

A

Protein bound 80%
Free drug = 20%

Thiopental is a weak acid
pKa = 7.6 SO 60% of FREE drug is unionized

Of 20% free drug 60% is unionized and can move to target site. 60% of 20% = 12%

So 12 % of administered dose is available to enter target site.

Despite this, high lipid solubility + high CO to brain –> rapid onset.

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14
Q

Weak acids ionize at pH ______ their pKa

Weak bases ionize at pH ______ their pKa

A

Above

Below

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15
Q

How should the dose of thiopental be altered in critically ill patients and why?

A

Critically ill –> acidosis + reduced plasma protein binding (hypoalbuminaemia)–> more unionized unbound drug present –> LESS thiopental required.

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16
Q

Describe Propofol

Presentation
Dose
Onset
Duration
Specifics
Systems
Protein bound (%)
Percent unionized (pKa)
Metabolism
Metabolites
Interactions

Telimination
Bioavailability
Clearance

A

Propofol = phenolic derivative

Presentation: 
1% or 2% lipid-water emulsion (soya bean oil, egg licithin, glycerol) due to poor solubility in water 
Dose: 
1 - 2.5mg/kg induction
4 - 8ug/ml maintains anaesthesia

Onset: 15 - 45 seconds
Duration: 2 - 8 minutes

Specifics:
ADVANTAGES
1. Rapid onset / recovery
2. Antiemetic / Antipruritic / Anticonvulsant
3. Potent relaxation airway reflexes
4. Bronchodilator
5. Suitable renal / hepatic insufficiency

DISADVANTAGES
1. Pain on injection
2. Contamination risk (lipid emulsion)
3. CVS and RSP effects
4. PRIS
(Propofol Related Infusion Syndrome)
- Fat overload with: refractory bradycardia and CVS collapse with metabolic acidosis + Rhabdomyolysis + Renal Failure + Hyperlipidaemia + Hepatomegaly.
- 33 --> 66% mortality
- Propofol C/I sedation in children < 16 years.

Systems
CNS: Decreased CMRO2, CBF, ICP. Rx: Status. Neuroexcitatory in 10%: Dystonia ± choreiform movements ± opisthotonus
CVS: Reduced SVR, BP, CO, HR
RSP: Reduced RR, Vt, hypoxic / hypercapnic CNS response. Apnoea (1/3 healthy pts.)
GIT: Antiemetic (? Dopamine antagonism)
Renal: May turn urine and hair green
Metabolic: PRIS - >4mg/kg per hour for > 48 hours

Protein bound: 98%
Mechanism: Allosteric modulation and potentiation GABA a and glycine receptors; Inhibition of neuronal Ach receptors.
Metabolism: Liver: Glucoronidation + Hydroxylation. Some extrahepatic metabolism (Clearance>HBF)
Metabolites: Inactive quinol conjugated + excreted in urine.
Vol distribution: 4.0 L/kg
Interactions: opioids/benzos/volatiles (synergism)

Telimination: 5 - 12 hours
Bioavailability: /
Clearance: 30 - 60 ml/kg/min

17
Q

What is egg lecithin

A

Purified mixture of phospholipids that does not contain proteins or cholesterol. Can be fully metabolized.

18
Q

Define the propofol infusion syndrome and list 6 proposed risk factors.

A

PRIS is a rare, life-threatening condition characterised by bradycardia progression to asystole and one or more of:

  1. Metabolic acidosis (BE < -10)
  2. Rhabdomyolysis (myoglobinuria / CK)
  3. Hyperlipidemia
  4. Hepatomegaly (fatty)

Rare complication propofol infusion associated with doses >4mg/kg for > 48 hours.

Risk factors

  1. Concomitant catecholamine infusion
  2. Concomitant steroid therapy
  3. Young age
  4. Critical illness
  5. Low CHO intake
  6. Inborn errors metabolism
19
Q

Describe the pathophysiology and clinical characteristics of the propofol related infusion syndrome

A

Pathophysiology:
Triggering factors: Propofol > 4mg/kg per hour for > 48 hours + catecholamine infusion + steroid therapy.

Impaired mitochondrial fatty acid metabolism –> imbalance between. energy demand and utilization –> cardiac / muscle necrosis.

20
Q

How can early warning signs be detected with regard to the Propofol infusion syndrome

A
  1. ECG - Brugada-like pattern (Convex STE in V1 - V3) . RBBB. arhythmia. Heart block
  2. Unexplained lactic acidosis. hyperK (renal failure/rhabdo)
  3. Labs: Lipaemia. Renal failure. CK. Propofol levels
21
Q

What is the management of PRIS

A

Discontinue propofol
Supportive (Consider pacing)
CHO adequate

22
Q

Describe ketamine P1 DODSS P2MMMVI TBC

Presentation
Dose
Onset
Duration
Specifics
Systems
Protein bound
pKa percent ionized
Mechanism
Metabolism
Metabolites
Interactions

Telimination
Bioavailability
Clearance

A

Phencyclidine derivative

Presentation:
Water soluble. Racemic or S(+) anantioner. 10 mg/ml or 50 mg/ml or 100 mg/ml. pH: 3.5 - 5.5. Brown glass (poor photostability).

Dose: 
IV Induction: 1 - 2 mg/kg 
IM induction: 5 - 10 mg/kg
IV analgaesia: 0.2 - 0.5 mg/kg
PO procedural sedation (paeds): 5 - 10mg/kg

Onset:
IV: 60 - 90 seconds
IM: 5 - 15 minutes
PO: 20 - 30 minutes

Duration:
IV: 20 - 60 minutes
IM: 30 - 120 minutes
PO: 60 - 90 minutes

Specifics:

  1. Dissociative anaesthesia = conscious. brainstem reflexes intact + spontaneous breathing
  2. Analgaesic
  3. Bronchodilator
  4. Hypersalivation
  5. Stimulation SNS: less CVS depression
  6. Psychoactive effects: hallucinations / delirium / dreams

Systems:
CNS - Dissociative state. Dissociation of thalamocortical and limbic systems on EEG. Analgaesia. Amnesia. Increased CBF, CMRO2, ICP.
CVS
1. SNS +: increased circulating catecholamines –> Increased: BP, HR, CO, myocardial O2 demand. Masks
2. Direct myocardial depression.
RSP
1. RR increased
2. Laryngeal reflexes preserved (jaw muscle tone –> airway obstruction.
3. Bronchodilation
GIT
Nausea and vomiting (more common vs prop and thio)
Hypersalivation
URO
- high dose ketamine associated with severe interstitial cystitis

Protein bound: 25%

pKa + percent ionized: pKa = 7.5 (weak base). 44% Unionized.

Mechanism:

  1. Noncompetitive (allosteric) block of glutamate NMDA receptors within sensory nerve endings
  2. Opioid (MOP and DOP) agonist activity

Metabolism: Liver. P450. N-demethylation + hydroxylation
Metabolites: norketamine (weakly active = 30% as potent as ket) - cleared by kidneys.
Interactions: Multiple. Inducers and other CNS depressants.

Telimination: 2 - 4 hours
Bioavailabity: largely depends on the route of administration (e.g. 20% oral; 90% intramuscular; 25% rectal; 50% intranasal; 77% epidural) [32,40,41].
Clearance: 17 ml/kg/min.

23
Q

Is there evidence that ketamine causes dysrhythmias

A

No. despite SNS +.

24
Q

Differentiate the clinical effects of the ketamine enantiomers

A

S +
1. More potent x 2 - 3
2. Advantageous in ischaemic heart disease
Less direct myocardial suppression (does not block ATP dependent K+ channels)
3. Produces less intense emergence phenomena

25
Q

Describe Etomidate P1DODS P2MMMVI TBC

Presentation
Dose
Onset
Duration
Specifics
Systems
Protein bound
pKa + percent ionized at physiological pH
Mechanism
Metabolism
Metabolites
Vol. distribution
Interactions

Telimination
Bioavailability
Clearance

A

Imidazole derivative and an ester

Presentation
0.2% solution with pH 4.1.
Propylene glycol (improve stability + reduce irritant properties) (Lipid formulation also now available –> Etomidate Lipuro)

Dose
0.3 mg/kg

Onset
Onset: 20 - 45 seconds

Duration: 3 - 10 minutes

Specifics
ADVANTAGES
1. Superior haemodynamic stability
2. Rapid onset/offest
3. Anticonvulsant (reduced CMRO2, CBF, ICP)

DISADVANTAGES

  1. Inhibits adrenal cortisol biosynthesis: inhibits 11 beta-hydroxylase and 17 alpha hydroxylase –> reduced 11-deoxycortisol to cortisol.
    - Lasts < 24 hours
    - Plasma cortisol do not appropriately rise but do not fall.
    - Septic shock - etomidate increases chance of adrenal insufficiency.
    - NO multiple doses or infusion
    - NO evidence for prophylactic steroid co-administration
  2. PORPHYRIA
  3. PONV ++ (‘evomidate’)
  4. Pain on injection
  5. Myoclonus
  6. No analgaesia
  7. Mild increase airway resistance

Systems
CNS - general anaesthesia. amnesia. Reduced CMRO2, CBF, ICP.
CVS - Minimal reduction SVR
RSP - Mild increase airway pressure
Metabolic - Inhibition 11B and 17a hydroxylase –> inhibition of cortisol and aldosterone synthesis.
GIT - Nausea and vomiting

26
Q

What is normal intra-ocular pressure and what factors determine the intra-ocular pressure

A

Normally: 16 ± 5 mmHg

Factors:

  1. Equilibrium between production and drainage of aqueous humour
  2. IO blood volume (CVP)
  3. Scleral rigidity and capacity
27
Q

What is the effect of metoclopramide on IOP

A

Mild elevation for 30 minutes

28
Q

What is plasma half life

A

The time it takes for the initial plasma concentration to fall by 50%

Pharmacology for Anaesthetists (37 decks)

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