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Primary FRCA > Pharmacology 5 > Flashcards

Pharmacology 5 Flashcards

1
Q

List the potentially useful properties of benzodiazepines

A 
Sedation
Anxiolysis
Anticonvulsant
Muscle relaxation
Amnesia
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2
Q

Where do benzodiazepine drugs act?

A

GABA-A receptor

Positive allosteric modulation through binding to BDZ site, increasing response to GABA activation.

This increases postsynaptic Cl- influx and hyperpolarisation, exerting a neuroinhibitory effect

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3
Q

How are benzodiazepines classified?

A

Short / medium / long acting

Short:

  • Midazolam
  • Triazolam
  • Oxazepam

Medium:

  • Lorazepam
  • Temazepam

Long:

  • Diazepam
  • Clonazepam
  • Flurazepam
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4
Q

What is a typical BDZ infusion regimen used for sedation in ICU?

A

Midazolam

  1. 02-0.08 mg/kg loading
  2. 04-0.2 mg/kg/h infusion
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5
Q

What are the IV BDZ regimens for use in status epilepticus?

A

Lorazepam:

  • 4mg, repeated x1 for adult
  • 100 μg/kg, max 4mg for child

Clonazepam:

  • 1mg, repeated x1 for adult
  • 500μg for child (all ages)

Diazepam (Diazemuls):
-5-10mg every 10 min

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6
Q

How long do the anticonvulsant effects of lorazepam last?

A

6-12h

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7
Q

How does baclofen exert its therapeutic effect?

A

Agonist at GABA-B receptor

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8
Q

What effect do BDZs have on memory?

A

Anterograde amnesia

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9
Q

What are the chemical features of the BDZs?

A

6-membered phenolic ring abutting a 7-membered ring, which has an attached phenolic group

Highly lipid soluble, mostly oral preparations

IV preparations are in lipid emulsion (diazemuls), propylene glycol (lorazepam, clonazepam) or in an acidic solution making use of tautomeric properties (midazolam)

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10
Q

How does an acidic solution render midazolam water soluble?

A

Tautomerism

Amine group of 7-membered ring becomes protonated, ‘opening’ the ring and conferring water-solubility.

At body pH, the ring closes and the functional BDZ group is active and very lipid soluble

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11
Q

Outline the pharmacokinetic properties of midazolam

A
  • Short acting, t1/2: 2-4h
  • Hydroxylated then glucuronidated
  • Hydroxylation produces the active metabolite alpha-1-hydroxymidazolam but only produced at 1/10 the concentration of midazolam
  • Duration prolonged in hepatic failure
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12
Q

Outline the pharmacokinetic properties of diazepam

A
  • Long acting, t1/2: 43h
  • Metabolised to several active compounds before excretion
Major pathway (>60%):
-Diazepam -- [CYP3A4] -> Nordiazepam -- [CYP2C19] -> Oxazepam

Minor pathway:
-Diazepam – [CYP2C19] -> Temazepam – [CYP3A4] -> Oxazepam

Oxazepam is then glucuronidated for renal elimination

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13
Q

Outline the pharmacokinetic properties of lorazepam

A
  • t1/2: 14h

- 75% hepatically conjugated with little metabolism

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14
Q

What are the common side effects of BDZ use?

A

Sedation
Cognitive impairment
Memory impairment
Excitation and aggression

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15
Q

Do BDZs cross the placenta?

A

Yes, readily

Also present in breast milk

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16
Q

What are the unwanted effects of long-term BDZ use?

A
  • Impaired co-ordination + increased falls risk
  • Drowsiness, dizziness, tremor
  • Nausea
  • Impaired operation of equipment/driving etc.
  • Tolerance and physical dependence
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17
Q

Outline the features of the BDZ withdrawal syndrome

A
  • Insomnia
  • Anxiety/restlessness
  • Impaired concentration
  • Muscle cramps
  • Headache
  • Nausea
  • Mood swings
  • Seizures with abrupt withdrawal

Withdrawal from short acting BDZs will occur in 24-48h. Long acting withdrawal may not present until up to 3 weeks after cessation

The withdrawal syndrome may last several months

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18
Q

Outline the features of BDZ overdose

A
  • Intoxication / impaired cognition
  • Somnolence
  • Impaired co-ordination
  • Ataxia
  • Anterograde amnesia
  • Respiratory depression
  • Hypotension
  • Bradycardia
  • Hypothermia
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19
Q

How is BDZ overdose managed?

A

Supportive treatment

Flumazenil is usually used only if respiratory depression is a significant feature

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20
Q

Outline the features of the non-BDZ sedative drugs

A

‘Z’ drugs:

  • Eg. zopiclone, zolpidem
  • Also acts at BDZ site on GABA-A receptor
  • Mainly used for hypnosis
  • Dose of all is 10mg nocte or 5mg in elderly

Chloral hydrate:

  • Used historically for short-term treatment of insomnia
  • MOA unknown
  • SEs include D&V, drowsiness, pruritus, rash, dyspnoea, bradycardia
  • May precipitate acute porphyria

Clomethiazole:

  • Sedative used in treatment of alcohol withdrawal
  • Structurally related to thiamine
  • Acts at GABA-A receptor as a positive allosteric modulator but at different site to BDZs

Promethazine:
-Sedative H1 antagonist

Melatonin:

  • Pineal hormone involved in sleep wake cycle
  • Licensed for short term insomnia treatment >55 years
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21
Q

Which sedative agents are commonly used in ICU?

A

Midazolam

Propofol:
Pros - anxiolysis, anticonvulsant, amnesia, antiemetic, reduces ICP, rapid on/offset
Cons - Reduces CO + SVR + BP

Opioids:
Pros - Sedative, analgesic, anxiolytic
Cons - Venodilator, sympatholysis, bradycardia, hypotension

Morphine
Pros - Cheap
Cons - Accumulation, prolonged offset

Fentanyl
Pros - Short distribution t1/2, no active metabolites
Cons - Significant duration effect on CSHT

Remifentanil
Pros - Rapid on/offset, may shorten mechanical ventilation time, constant CSHT
Cons - Relatively expensive

Clonidine:
1-2 mcg/kg/h
Pros - Sedation, analgesia, no respiratory depression
Cons - Haemodynamic changes (initial 🠙MAP then 🠛), bradycardia, rebound hypertension

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22
Q

Summarise the pharmacology of propofol

A
  • 2,6-diisopropylphenol is a phenol derivative
  • MW 178.28, pKa 11
  • Used for 1. Induction and maintenance of general anaesthesia 2. Sedation 3. Treatment of refractory N&V 4. Treatment of status epilepticus
  • Presented in an isotonic lipid emulsion of pH 7-8.5 which is light and room temperature stable. Most commonly as a lipuro formulation of medium and long chain triglycerides. Some preparations contain EDTA, glycerol, egg phosphatide, soya bean oil and sodium hydroxide
  • Can be mixed with 5% glucose, lidocaine or alfentanil
  • Main action is hypnotic (?through GABA-A, ACh, α2R, D2)
  • Administered intravenously at a dose of 1-2.5mg/kg for induction and as an infusion of rate 4-12mg/kg/h for maintenance of anaesthesia. Plasma concs of 0.5-1.5 and 2-6mcg/ml are associated with sedation and hypnosis respectively.
  • Hypnosis produced 30-40 seconds from induction dosing and lasting up to 10 mins
  • Causes up to 25% 🠛 MAP + SVR; 20% 🠛 CO; risk of bradycardia / asystole; apnoea; reduced laryngeal reflexes; 🠛TV 🠙RR; 🠛CO2/O2 response; bronchodilation; 🠛ICP/CPP/CMRO2; dystonic movements; anticonvulsant; 🠛IOP; antiemetic
  • Causes pain on injection, green urine and risk of propofol infusion syndrome with prolonged use
  • Contraindicated in peanut/soya allergy
  • 98% protein bound, Vd 4L/kg
  • Rapid glucuronidation and sulphation in the liver and lungs. No active metabolites known. Inhibits CYP450
  • 98% eliminated in urine (1% unchanged); 2% in faeces; clearance 20-30ml/kg/min; CSHT (<8h) 40 mins
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23
Q

What are putative risk factors for propofol infusion syndrome?

A
  • High dose (>4mg/kg/h) for >48h
  • Concomitant vasopressor/glucocorticoid use
  • Age <18 years
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24
Q

What are the possible clinical features of propofol infusion syndrome?

A
  • Metabolic acidosis
  • Rhabdomyolysis
  • Multi-organ failure
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25
Q

What is the Bristol regimen for propofol infusion?

A

A commonly known manual controlled infusion

  1. 1 mg/kg loading dose
  2. 10mg/kg/h for 10 mins
  3. 8mg/kg/h for 10 mins
  4. 6mg/kg/h thereafter
26
Q

What are some commonly used methods for determining depth of anaesthesia?

A
  1. Bispectral index
  2. Entropy
  3. Auditory evoked potentials
27
Q

Define the concept of closed-loop anaesthesia

A

A computerised feedback loop including depth of anaesthesia monitoring which accordingly adjusts infusion rates for TCI

28
Q

What are the most common barbiturates in anaesthesia and their primary uses?

A

Thiopental
-RSI + status epilepticus

Methohexital
-ECT + prehospital

Phenobarbital
-Anticonvulsant

29
Q

Summarise the common production process for the barbiturates

A

Malonic acid + Urea -> Barbituric acid + water

Substituting a hydrogen ion on the barbituric acid ring with an alkyl or aryl group confers hypnotic activity

30
Q

How are barbiturates classified?

A

Thiobarbiturates:

  • eg. thiopental
  • highly lipid soluble and protein bound
  • Completely liver-metabolised

Oxybarbiturates:

  • eg. phenobarbital
  • Less lipid soluble / protein bound
31
Q

How do barbiturates exert their pharmacodynamic effects?

A
  1. Facilitation of inhibitory synaptic transmission through enhanced GABA-A mediated Cl- influx
  2. Blocking of:
    - non-NMDA glutamate receptors
    - voltage-gated Na+ and Ca2+ channels
    - K+ channels
    - nAChRs
32
Q

How is thiopental presented?

A

Pale yellow powder containing racemic thiopental with 6% Na2CO3
Dissolved in water to produce a 25mg/ml solution with pH 10.5 promoting formation of the soluble enol isomer

33
Q

What is the pKa of thiopental?

A

7.6

34
Q

What happens to thio after injection?

A

physiological pH promotes formation of lipid soluble keto-form

35
Q

Summarise the pharmacokinetics of thiopentone

A

Rapid emergence following induction due to redistribution. Vd 2.2L/kg; 80% protein bound.
On emergence, only 18% of thio will have been metabolised
Metabolised by CYP450 to inactive metabolites but early saturation and reversion to zero-order kinetics

36
Q

How is thiopental used in status epilepticus

A

Repeated 250mg boluses up to 5g

May be followed by infusion of 4-10mg/kg/h

37
Q

Summarise the systemic effects of thiopental

A

CVS:

  • 🠛MAP + CO
  • Venodilatation but no change in SVR
  • Reflex tachycardia
  • Myocardial depression with rapid high doses

RS:

  • Transient apnoea followed by 🠛RR + TV
  • 🠛CO2/O2 response
  • Laryngospasm / bronchospasm may occur as reflexes not depressed

CNS:

  • 🠛ICP/CPP/CBF/CMRO2
  • 🠛IOP
  • Anticonvulsant
  • Antanalgesic at low dose
  • Myoclonus

IS:
-Anaphylaxis 1:20,000

Other:

  • P450 inducer
  • Crystals may precipitate if injected into joints
  • May cause thrombosis if injected arterially
38
Q

How is methohexital presented?

A

White powder containing racemic mixture of two (of four) optical methohexital isomers with 6% Na2CO3
Dissolved in water to produce 10mg/ml solution with pH 11 and shelf-life of 6 weeks

39
Q

What is the pKa of methohexital?

A

7.9

40
Q

What happens to methohexital after injection?

A

physiological pH increases unionised fraction, allowing methohexital to cross the BBB

41
Q

Summarise the pharmacokinetics of methohexital

A 
Vd 2L/kg
50-65% protein bound
Main metabolite is hydroxymethohexitone, which has minimal hypnotic activity
Lower accumulation than thiopental
Elimination t1/2: 3-5h
42
Q

Summarise the systemic effects of methohexital

A

CVS:

  • 🠛MAP + CO (less than thio)
  • Venodilatation but no change in SVR
  • Reflex tachycardia (more than thio)

RS:

  • Transient apnoea followed by 🠛RR + TV (more than thio)
  • 🠛CO2/O2 response
  • Laryngospasm / bronchospasm more common than thio

CNS:

  • Rapid hypnosis lasting 3-4 mins from single dose
  • Occasional excitatory phase
  • Can precipitate seizures in epilepsy

Other:

  • Pain on injection
  • Precipitation on intraarticular injection
  • Thrombosis on intraarterial injection (less than thio)
  • Increased ADH secretion
43
Q

How is phenobarbital presented?

A

Odourless white crystalline powder or in a 20% solution to be diluted to 2% before IV injection

44
Q

Outline the pharmacokinetics of phenobarbital

A

Vd 0.7L/kg
50% protein-bound
25% excreted unchanged renally; 75% hepatically metabolised
Powerful P450 inducer

45
Q

What are the uses of phenobarbital?

A

Anticonvulsant that can be used in all types of seizures except absence
Rarely used to treat status epilepticus

46
Q

Summarise the systemic effects of phenobarbital

A
  • Cardiovascular and respiratory depression
  • Sedation and cognitive impairment, coma in overdose, hyperkinesia
  • Megaloblastic anaemia, mild hypersensitivity and osteomalacia
47
Q

Summarise the physiochemical properties of etomidate

A 
Imidazole derivative
MW 342
Two optical isomers, R(+) is active
Highly lipid soluble
Water soluble at low pH
48
Q

How is etomidate formulated?

A

In solution with ethylene glycol

49
Q

Summarise the pharmacokinetic features of etomidate

A 
Hepatic metabolism with extraction ratio of 0.5
85% renally cleared, 13% in bile
Vd 2.5-4.5L/kg
75% protein bound
Et1/2 3-5h
50
Q

Summarise the systemic effects of etomidate

A

CNS:

  • Hypnosis through GABA-B2/3 receptors
  • 🠛CBF/CMRO2
  • 🠛IOP
  • Lowers seizure threshold
  • Myoclonus

CVS:
-No effect on MAP/HR/PAP/CO/SVR/coronary perfusion

RS:

  • Minimal effects
  • CO2 response reduced
  • Hiccups on induction

Endo:

  • Dose-dependent reversible inhibition of 11β-hydroxylase and minor inhibition of 17α-hydroxylase
  • This causes accumulation of cortisol precursors and secondary inhibition of ascorbic acid re-synthesis (required for steroid production) and mineralocorticoid production
  • Despite this, a single induction dose has not yet been associated with adverse endocrine outcomes
51
Q

What are the adverse effects associated with etomidate?

A
  • Pain on injection
  • Haemolysis
  • N&V
  • Superficial thrombophlebitis
52
Q

What is the induction dose of etomidate?

A

0.2-0.6 mg/kg

53
Q

Summarise the physiochemical properties of ketamine

A

Phencyclidine derivative
MW 238
pKa 7.5
Two optical isomers - S(+) more potent
Highly lipid soluble
Racemic mixture contains benzethonium chloride which is potentially neurotoxic
S(+) enantiomer is preservative-free and thus can be used neuraxially

54
Q

Summarise the pharmacokinetic characteristics of ketamine

A

Vd 3L/kg
Et1/2 2-3h
Clearance of 1L/min
Dependent on hepatic flow

55
Q

Where does ketamine exert its pharmacodynamic action?

A
  1. NMDA receptor
  2. Thalamoneocortical projection system
  3. Opioid receptors
  4. AChRs and monoamine receptors
  5. Neuronal sodium channels
56
Q

Outline ketamine’s action at the NMDA receptor

A

-Negative allosteric modulation of NMDAR activity, reducing Na+/Ca2+ influx

57
Q

What is the mechanism for the ‘dissociative anaesthesia’ seen with ketamine?

A

-Functional and electrophysiological dissociation between the limbic and thalamoneocortical systems

58
Q

What are the effects of ketamine on the CVS?

A

Stable patient:
-🠙HR / MAP / CO / MO2 / PVR

Shocked patient:
-🠛HR / MAP / CO / MO2 / PVR

59
Q

What are the respiratory effects of ketamine?

A
  • Respiratory depression with high dose
  • Reflexes remain in tact
  • Bronchodilatation
60
Q

What are the CNS effects of ketamine?

A
  • 🠙 CBF / CMRO2 / ICP
  • Theta activity and abolition of alpha activity on EEG
  • Purposeful movements and hypertonus can occur
61
Q

What are the features of the emergence reactions seen with ketamine?

A
  • Hallucinations, illusions, vivid dreaming
  • Less prominent in children
  • Occurence may be reduced with BDZs
62
Q

What is known about the neuroprotective effects of ketamine?

A
  • Rat studies suggest an anti-apoptotic effect following ischaemia
  • No proven effect in humans yet

Primary FRCA (34 decks)

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