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Pharmacology for Anaesthetists > Propofol > Flashcards

Propofol Flashcards

1
Q

Describe the pharmaceutical presentation of propofol

A

1% emulsion of fat droplets in water –> milky white

The vial contains 6 things:

1% propofol
1.2 % Egg phospholipid
2.25% Glycerol
10% Soybean oil

EDTA
NaHCO3

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2
Q

Why is propofol a lipid emulsion

A

It is not water soluble and requires a vehicle to carry it into the patient

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3
Q

Why is Glycerol added into the propofol vial

A

To adjust tonicity

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4
Q

Why is NaHCO3 added to the propofol vial. What is the pKa of the emulsion and what is the implication of this.

A

To adjust pH –> 6.5 - 8.0
pKa = 11
It is a weak acid and as acids ionize at physological pH above their pKa, at physiological pH (7.4 which is below pKa of 11) –> most of the drug is unionized and able to cross BBB

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5
Q

Why is EDTA added to propofol vial

A

Antimicrobial

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6
Q

Why can patients with egg allergies get propofol

A

The 1.2% Egg phospholipid is a yolk component rather than an egg white component –> The usual egg allergy is to egg white albumin.

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7
Q

What is fospropofol. What are its advantages and disadvantages

A

It is a prodrug of propofol which is more water soluble leading to reduced pain on injection.

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8
Q

Summarise the relevant pharmacokinetics of propofol

A

Adminstration
- IV only –> 100% bioavailability

Distribution

  • Onset: 1 arm brain circulation (10 - 20 s)
  • Bolus Vd = 4.1 L/kg
  • Protein bind = 98%
  • Bolus t1/2 = 2 minutes
  • Steady State t 1/2 = 5 - 12 hours

Metabolism

  • Liver: glucoronide and sulphate conjugation
  • ?? Extrahepatic metabolism too (cirrhotic patients metabolize normal quantities of propofol)
  • inactive metabolites:
  • CYP450: 60% into quinol –> a glucoronide and sulfate. 40% straight into a glucoronide
  • Unaffected by renal and hepatic disease

Excretion

  • Clearance: 30 - 60 ml/kg/min (10 x faster than thiopentone)
  • Clearance decreased in neonates and elderly
  • Terminal elimination half life: 5 - 12 hours
  • 0.3 % excreted unchanged
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9
Q

What is the context sensitive half time for propofol at 3 hours and also at 8 hours

A

3 hours = context sensitive half time is 10 mins

8 hours = context sensitive half time of 30 minutes

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10
Q

Define volume of distribution

A

Volume of distribution is the apparent volume into which a specific dose of a drug distributes to give the measured drug concentration in plasma. It is calculated by dividing the dose administered by the plasma concentration and is measured in L/Kg.

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11
Q

Compare the volumes of distribution and plasma protein binding of the IV induction agents

A

Propofol Thiopentone Ketamine Etomidate

Vd 4.0 2.5 3.0 3.0
Protein 98% 80% 25% 75%

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12
Q

Define clearance

A

The volume of blood cleared of a drug per unit time

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13
Q

What is the mechanism of action of propofol

A

Propofol potentiates GABA A receptors which are Chloride channels. More chloride channels open allowing increased Cl- into the cell. This causes hyperpolarization of the resting membrane potential and reduced threshold breach and AP generation in CNS neurons.

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14
Q

List the effects of propofol

A

CNS

  1. Anaesthesia / sedation
  2. Choreiform movements ± opisthotonus
  3. Anti-epileptic
  4. Reduced CBF + reduced CMRO2

CVS
Sympathetic Nervous System Inhibition (indirect effects)
1. Reduced preload (venodilatation)
2. Reduced afterload (vasodilatation)
3. Minimal direct effect on contractility
4. Net effect on cardiac output in a patient not in compensated shock is minimal.

RSP

  1. Decreased tidal volume
  2. Increased RR
  3. Abolished response to hypoxia and hypercapnoea
  4. Bronchodilatation
  5. Depressed laryngeal reflex

GIT

  1. Antiemetic (D2 antagonism)
  2. Antihistamine

MSK
1. Muscle relaxation (higher doses)

Renal
1. Green urine (and hair) –> from phenols

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15
Q

List the contra-indications to propofol

A
  1. Extreme Haemodynamic fragility
  2. Allergy to one of the ampuole contents
  3. Ridiculously high serum triglycerides
  4. Very high intracranial pressure
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16
Q

When does the Propofol Infusion Syndrome (PRIS) occur

A

4 mg/kg/hr for 48 hours

70 kg male
28 ml/hour of propofol for 48 hours

17
Q

What are the clinical features of Propofol Infusion Syndrome (PRIS)

A

HEART

  1. Acute bradycardia –> asystole
  2. Cardiogenic shock / Heart Failure

ACIDOSIS
3. HAGMA

FAT

  1. Hyperlipidaemia
  2. Fatty Liver

MUSCLE and KIDNEY
6. Rhabdomyolysis

18
Q

Describe the mechanism of the propofol infusion syndrome

A

Prolonged high doses of propofol –> inhibition of co-enzyme Q and cytochrome C in the ETC. i.e electrons cannot be transported between protein complexes on the mitochondrial membrane –> breakdown of oxidative phosphorylation –> reduced ATP synthesis –> anaerobic respiration –> hyperlactataemia HAGMA

Also: Impaired fatty acid metabolism: FFAs are not converted to acteyl-CoA –> thus no ATP via lipolysis + FFA accumulation in blood stream –> contributes toward acidosis

19
Q

What is the treatment of PRIS

A
  1. Supportive
  2. STOP propofol
  3. Charcoal haemoperfusion can reduce FFAs
20
Q

What are the early ECG changes in PRIS

A

Sudden onset RBBB with STE in V1 to V3

21
Q

What are the properties of an ideal intravenous anaesthetic agent

A

PHARMACEUTICAL/PHYSICAL

Soluble in water
Chemically Stable:
- no reconstitution required
- no additives/preservatives required
- prolonged shelf life at room temperature
- Stable in presence of air and light
Not support of bacterial growth
Chemically inert
- Non-reactive: rubber/metal/glass/plastic

PHARMACOKINETICS

Administration/Availability
- multiple routes

Distribution

  • Rapid onset
  • No accumulation with infusion
  • Rapid and predictable offset
  • Safe in Renal or Liver impairment

PHARMACODYNAMICs

Pain on injection - NO
Intra-arterial/extravasation - SAFE
Anaesthesia within one arm brain circulation time
Analgaesic
Antiemetic
Antiepileptic
Muscle relaxation
No emergence
No change in CBF or ICP
Minimal CVS or RSP depression
No histamine release or bronchospasm
Safe in Obs and paeds
Not teratogenic
22
Q

Why is propofol the ideal agent for TIVA

A
  1. Short acting
  2. Short half life
    Reduced risk of accumulation and recovery
  3. Smooth and rapid induction
  4. high metabolic clearance and elimination
23
Q

What is the context sensitive half life at 2 hours, 6 hours and 9 hours for a propofol infusion

A

2 hours infusion - 20 minutes
6 hours - 30 minutes
9 hours - 50 minutes

24
Q

Why is propofol TIVA particularly suited to neuroanaesthesia

A

Smooth and rapid induction
Predictable pharmacokinetics and recovery
Reduced risk of accumulation

Does not impair cerebral autoregulation
Does not increase CBF/CMRO2/ICP

25
Q

What is the dose of propofol

A

Induction: 2 - 3 mg/kg
Maintenance: 4 - 12 mg/kg/hour maintenance

Pharmacology for Anaesthetists (37 decks)

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