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Primary FRCA > Pharmacology 4 > Flashcards

Pharmacology 4 Flashcards

1
Q

Outline pharmacokinetic considerations relating to neonates

A

A:

  • Slower rate of absorption po due to prolonged gastric emptying time and increased intestinal transit time
  • Less acidic gastric pH
  • Increased total drug absorption due to increased gastrointestinal transit time
  • Transdermal absorption may be rapid due to thin stratum corneum

D:

  • TBW increased (80% of body weight in preterm infant)
  • Lower body fat and increased permeability of BBB can lead to increased CNS concentrations of lipid soluble drugs
  • Reduced plasma protein binding

M:

  • Immature enzyme activity
  • Phase I metabolism increases during first 6 months, may exceed adult levels during childhood and slows again during adolescence
  • Significant variation between metabolism of specific drugs
  • Phase II metabolism varies widely

E:
-Neonatal GFR is 20-40% of adult values, slowing renal excretion

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2
Q

Outline pharmacokinetic considerations relating to the elderly

A

A:

  • Slower gastric emptying
  • Decreased absorption
  • Variable between drugs/preparations

D:

  • Decrease in total body water -> Reduced Vd
  • Increase in body fat
  • Reduced protein binding due to lower albumin levels

M:
-Reduced hepatic blood flow and enzyme activity -> increased bioavailability for hepatically cleared drugs

E:
-Reduced GFR -> reduced renal excretion

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3
Q

What are the percentages of protein, fat and water in adults, neonates and the elderly?

A

Adult:

  • 60% water
  • 18% fat
  • 16.5% protein

Neonate:

  • 70% water
  • 6% fat
  • 12% protein

Elderly:

  • 45% water
  • 35% fat
  • 12% protein
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4
Q

Outline pharmacokinetic considerations relating to pregnant women

A

A:
-Delayed gastric emptying -> increased gastric absorption and decreased small bowel absorption

D:

  • Increased CO + hepatic blood flow -> Increased clearance (or production of active metabolites)
  • Placental enzymes metabolise several compounds, including neurotransmitters
  • hPL degrades insulin -> insulin resistance

E:

  • Increased Vd + t1/2s
  • Clearance unchanged
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5
Q

Outline pharmacokinetic considerations relating to obese patients

A

A:

  • Increased BSA, CO and gut perfusion
  • No demonstrable difference in absorption despite the above

D:

  • Increased Vd for lipophilic drugs
  • Increased organ mass, LBM and blood volume

M:

  • Phase I: Unchanged / increased
  • Phase II: Increased
  • Liver function: Unchanged

E:
-Inaccuracy of estimated GFRs using body weight measures

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6
Q

Outline methods of describing body mass

A

BMI: Weight / height^2

BSA:

  • DuBois - 0.007184 x height^0.725 x weight^0.42
  • Mosteller - root ((height x weight) / 3600)

IBW:

  • Male - height - 100
  • Female - height - 105

LBM:

  • Male - (1.1 x weight) - (128 x (W/H)^2)
  • Female - (1.07 x weight) - (148 x (W/H)^2)
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7
Q

Outline pharmacokinetic considerations relating to critically ill patients

A

A:

  • Decreased GI and peripheral perfusion
  • Starvation -> intenstinal atrophy
  • Reduced gut enzyme activity
  • Gut dysmotility

D:

  • pH changes alter ionisation
  • Increased ECF/oedema can increase Vd for hydrophilic drugs
  • Reduced protein binding

M:

  • Early sepsis increases hepatic blood flow (and clearance of high extraction ratio drugs)
  • Low extraction ratio drugs are metabolised more slowly due to cytokine and acute phase protein activity
  • Increased protein diet increases enzyme activity and thus clearance

E:
-Renal dysfunction common

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8
Q

Why are TCI systems referred to as ‘open-loop systems’?

A

No measurement of actual concentration is made during infusion

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9
Q

What are the basic components of a TCI system?

A
  1. User interface
  2. Computer / microprocessor
  3. Infusion device
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10
Q

What TCI models exist for propofol in children?

A

Paedfusor

Short

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11
Q

What model and body weight is used for remifentanil TCI?

A

Minto, LBW

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12
Q

What model exists for alfentanil TCI?

A

Maitre

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13
Q

What model exists for fentanyl TCI? What are its covariates?

A

Shafer

No covariates, assumes similarity to average, non-obese patient

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14
Q

What model exists for ketamine TCI?

A

Domino

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15
Q

What are some typical remifentanil effect site concentrations used in TIVA?

A

Laryngoscopy/intubation: 4-6 ng/ml

Analgesia for laparotomy: 6-8 ng/ml

Cardiac surgery: 10-12 ng/ml

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16
Q

How common is sux apnoea?

A

1:2500 for commonest variant

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17
Q

What enzyme is affected by sux apnoea and where is the gene located?

A

Plasma cholinesterase, or butyrylcholinesterase (BChE)

Coded for by BCHE gene on long arm of chromosome 3

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18
Q

What are the most common BCHE alleles?

Outline their activities, frequencies and apnoea times

A

Eu - normal (98%) - 6 mins apnoea [100% activity]

Ea - atypical (2%) - 2h apnoea [30% activity]

Ef - fluoride resistant (0.3%) - 1-2h apnoea [40% activity]

Es - silent (0.03%) - 3-4h apnoea [0% activity]

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19
Q

How is BChE activity measured?

What are some relevant results?

A

In vitro testing for inhibition using dibucaine and fluoride

EuEu:

  • Dibucaine number: 80
  • Fluoride number: 60

EuEa:

  • Dibucaine 60
  • Fluoride 50

EaEa:

  • Dibucaine 20
  • Fluoride 20
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20
Q

What are the CYP450 enzymes most prone to genetic variation?

Name some drugs which may be affected by altered function

A

CYP2 family

CYP2C9:

  • S-warfarin
  • Phenytoin
  • Losartan
  • Diclofenac

CYP2C19:

  • Omeprazole
  • Clopidogrel
  • Diazepam
  • Propranolol

CYP2D6:

  • Codeine
  • Tramadol
  • Oxycodone
  • SSRIs
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21
Q

Outline the metabolism of codeine

A

Codeine [inactivated, 80-90%) -> Norcodeine + Codeine-6-glucuronide

Codeine [activated, 10-20%] -> Morphine (CYP2D6)

Morphine is metabolised to Normorphine, Morphine-3-glucuronide and Morphine-6-glucuronide

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22
Q

What are the phenotypes for CYP2D6?

What are possible clinical consequences?

A

Poor (PM) / Expected (EM) / Ultrafast metaboliser (UM)

Poor metabolisers will have a poor analgesic response to relevant opioid medications

Ultrafast metabolisers will have an exaggerated response, including increased risk of side-effects and overdose. Due to morphine being excreted in breast milk, there is a risk of opioid toxicity in infants breastfed by ultrafast codeine metabolisers

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23
Q

Outline clopidogrel metabolism, summarising any relevant interindividual variation

A

Clopidogrel is a prodrug, converted to its active metabolite by several CYP450 enzymes of which CYP2C19 is of most relevance

CYP2C19*17 has increased activity and *2 / *3 have reduced activity (and alternative antiplatelet agents are recommended in these cases eg. prasugrel, ticagrelor)

Phenotypes of clopidogrel metabolism are:
Ultrafast - Normal dose
Extensive (wild type) - normal dose
Intermediate (heterozygous *1 with 2/3) - alternative recommended
Poor (combinations of 2/3) - alternative recommended

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24
Q

What are arylamine N-acetyltransferases (NATs)?

Why are they important?

A

NATs are responsible for phase 2 acetylation of several drugs. There are 2 subtypes, NAT-1 and NAT-2.

NAT-1 substrates:

  • Para-aminobenzoic acid
  • Paracetamol
  • Sulfamethoxazole

NAT-2 substrates:

  • Isoniazid
  • Hydralazine
  • Dapsone

NAT-1/2 genes are found on chromosome 8 and there are several SNPs which are associated with slow acetylation - increasing risk of drug-related adverse events. Slow acetylator status can be found in up to 50% of Caucasians.

Fast- and slow-acetylator status can have an impact on cancer risk due to metabolism of carcinogens

25
Q

Which cytochrome is responsible for S-warfarin metabolism?

A

CYP2C9

26
Q

How does S-warfarin affect the coagulation cascade?

A

Inhibition of subunit 1 of Vit K epoxide reductase (VKOR) prevents recycling of Vit K which is essential for post-transcriptional carboxylation of factors II, VII, IX, X and protein C/S

27
Q

How is genetic variation relevant to warfarin metabolism?

A

VKOR and CYP2C9 both exhibit genetic variation

If genotypes are known, an algorithm can be used to suggest recommended daily doses. This takes into account:

  • Age
  • Height
  • Weight
  • VKORC1 genotype
  • CYP2C9 genotype
  • Race
  • Co-administered drugs (inducers, amiodarone)
28
Q

What are transport proteins?

How are genetic variants relevant to them?

A

Two types of transport proteins:

ATP binding cassette (ABC) group:

  • product of ABCB1 gene
  • Known as P-glycoprotein (PGP)
  • Present in intestinal epithelium, hepatocytes, proximal tubular cells and BBB endothelium
  • Substrates to wild type PGP have low oral bioavailability
  • PGP inhibited by amiodarone, verapamil and ciclosporin
  • Genetic variants of ABCB1 gene have been identified but importance is unclear

Solute carrier (SLC) group:

  • Secondary active transport proteins particularly important in reuptake of neurotransmitters
  • Relevant for GABA (SLC6A1), NA (SLC6A2), Dopamine (SLC6A3) and serotonin (SLC6A4)
  • Genetic variation may be implicated in personality disorders and response to antidepressants
29
Q

Which receptors are prone to interindividual genetic variation?

A

GPCRs

  • β1-adrenoceptor
  • μ-opioid receptor

RyR - MH

30
Q

Summarise the relevance of genetic variation to the β1-adrenoceptor

A

Relevant to response to β-blockers. Variation is in ADRB1 gene

Normal response to homozygous wild-type and heterozygous individuals

Poor response is seen where there is a glycine substitution in both alleles. This is associated with increased incidence of hypertension, CM and CCF

31
Q

Summarise the relevance of genetic variation to the μ-opioid receptor

A

The μ-opioid gene (OPRM / MOR) has two promoter regions which control which part of the gene is translated and thus which splice variant is produced. Thus the CNS is able to produce different μ-receptors from the same gene.

SNPs in OPRM1 gene in 11% of people result in an arginine->guanine substitution and a doubling of the EC50 for morphine and morphine-6-glucuronide

32
Q

Summarise the relevance of genetic variation to the Ryanodine receptor

A

RyR is a ligand gated ion channel associated with L-type voltage gated Ca2+ channels and IP3 in the SR

It is responsible for excitation-contraction coupling

25% of individuals with MH susceptibility have RyR gene mutations. >60 SNPs in the RYR1 gene on chromosome 19 have been identified

33
Q

What body provides guidance for pharmacogenetic testing?

What recommendations have they made for testing?

A

Clinical Pharmacogenetics Implementation Consortium (CPIC)

Recommendations have been issued for testing prior to drug therapy for:

  • Azathioprine / mercaptopurine / thioguanine: TPMT
  • Codeine: CYP2D6
  • Warfarin: CYP2C9
  • Clopidogrel: CYP2C19
  • Simvastatin: SLCO1B1
34
Q

How is N2O produced?

A

Heating ammonium nitrate to 250°C (NH4NO3)

Byproducts include NO, NO2, NH3, N2, HNO3 and H2O

The process of cooling and acid and alkaline gas washes removes these impurities

35
Q

How is N2O stored?

A

In French blue cylinders as a liquid

36
Q

What is the SVP of N2O at 20°C?

A

52 bar

37
Q

What is the critical temperature of N2O?

A

36.5°C

38
Q

What is filling ratio? Why is it important for N2O storage?

A

Filling ratio is the ratio of the mass of liquid in a cylinder compared to the mass of water that the cylinder could hold.

In temperate regions this should be max 0.75, in the tropics it should be max 0.67.

This is because >36.5°C the liquid N2O will change to the gaseous phase, increasing the pressure in the cylinder. The cylinders can withstand this with a filling ratio of 0.67 but not higher.

39
Q

List the physiochemical properties of N2O

A 
MAC 103%
B:GSC 0.47
Critical temperature 36.5°C
Boiling point -88.5°C
SVP (20°C) 5200 kPa
40
Q

What is N2O’s mechanism of action?

A

Inhibition of the NMDA receptor, producing analgesia and sedation

41
Q

What are the potential side effects of N2O use?

A

Inhibition of B12 activity:

  • Via oxidation of cobalt ion
  • Stops production of methionine and thus DNA replication
  • Causes megaloblastic changes in the bone marrow within hours of continuous exposure
  • Can cause SCDC with prolonged exposure

Increased cerebral blood flow and metabolic rate
-Avoided in neurosurgery

CVS depressant
-Mild effect partly offset by increase in sympathetic activity

Small decrease in tidal volumes and increase in respiratory rate

Potential for enlarging pathological gas spaces eg. PTX

Recognised risk of PONV

42
Q

What is the Poynting Effect?

A

The Poynting effect allows N2O and O2 to be produced and coexist as a mixture with properties distinct from its constituents

43
Q

What is the pseudocritical temperature of Entonox?

Why is it important?

A

PCT is the temperature below which Entonox will separate into its constituents (N2O, O2)

It is -6°C

If Entonox is allowed to separate, the N2O forms a liquid and the gaseous O2 will be delivered first, resulting in a progressively hypoxic mixture

44
Q

What are the limitations of the concentration effect model?

A
  • Gas exchange is not complete
  • No representation for re-circulating anaesthetic
  • FRC not considered
45
Q

How is xenon produced?

A

Fractional distillation of liquid air - a byproduct of oxygen manufacture

2000x more expensive than N2O

46
Q

Does N2O support combustion?

A

Yes

47
Q

What are the physiochemical properties of Xenon?

A

MAC 67.5%
B:GSC 0.114
BP -108.1°C
Critical temperature 16.6°C

48
Q

What is the mechanism of action of Xenon as an anaesthetic agent?

A

Inhibition of glutamate binding at the NMDA receptor

Incidentally also blocks 5-HT3 receptor, but does not produce PONV

49
Q

What are the systemic effects of Xenon used as an anaesthetic?

A

CVS:

  • Vagotonic
  • No effect on CO or SVR
  • Ischaemic pre-conditioning effect

RS:

  • Decreased RR and increased TV
  • Apnoea with high conc.
  • Does not produce the concentration effect

NS:
-Neuroprotective

No known toxic, allergic or carcinogenic effects

50
Q

What are some historical theories for general anaesthetic agents?

Why are they historical?

A

Meyer-Overton Hypothesis:
-Anaesthetic potency related to lipid solubility due to ability of drug to reach the CNS

Lipid bilayer expansion theory [aka Critical Volume Hypothesis]:

  • Bulky, hydrophobic anaesthetic drugs occupy space in lipid bilayer, disrupting membrane function and producing anaesthetic effect
  • Potency thought to be related to molecular size

Lateral phase separation theory:
-Suggests that anaesthetic agents act by fluidising nerve membranes to the point where lipid regions no longer have phase separations, impairing membrane protein function

Weaknesses:

  1. increases in body temperature increase membrane fluidity but do not induce anaesthesia
  2. Beyond a certain point, increasing lipid solubility decreases anaesthetic effect
  3. Stereoisomers of anaesthetic drugs have similar O:GSCs but different anaesthetic potencies
  4. Some highly lipid soluble drugs exert a convulsive effect
51
Q

What is the current working model of anaesthetic drug action?

A

Multisite hypothesis:

  • Multiple specific target sites
  • eg. Membrane proteins, receptors and channels
  • Globally results in impaired neuronal activity, particularly of thalamus and fronto-parietal cortices

Targets may be cellular or subcellular

  • CNS cells, muscle cells, glial cells, endocrine, immune cells
  • Axons, dendrites, synapses, second-messenger pathways
  • Local microcircuits throughout CNS
52
Q

Which receptors are thought to be associated with anaesthetic agent action?

A

Inhibitory:

  • GABA-A
  • Glycine

Excitatory:

  • nACh
  • 5-HT3
  • Glutamate
53
Q

Describe the GABA-A receptor

A
  • Ionotropic, post-synaptic receptor
  • Pentameric subunit structure surrounding a central Cl- channel
  • 18 possible subunits
  • Cortical receptors are predominantly 2α:2β:γ
  • Is the target for propofol, volatile agents, BDZs and ethanol
  • Activation allows influx of Cl-, causing membrane hyperpolarisation
54
Q

Describe the NMDA receptor

A
  • Ionotropic, post-synaptic receptor
  • 4 subunits (2xN1, 2xN2) surrounding a central Ca channel
  • Activation by endogenous glutamate (N1) + glycine (N2) causes Ca2+ influx, modulaing post-synaptic actions
  • Is the target for ketamine, N2O and Xenon (non-competitive antagonists)
55
Q

Describe the nACh receptor

A
  • Ionotropic, post-synaptic receptor
  • Pentameric structure (2α:β:δ:γ) surrounding central Na channel
  • ACh binding to α-subunit activates the channel, allowing Na+ influx and thus depolarisation
  • Is the target for propofol, isoflurane and ether through varying inhibition of nAChR activity
56
Q

List the predominant MOAs of the common anaesthetic agents

A

Propofol:
-GABA-A potentiation

Thio:
-GABA-A potentiation

Etomidate:
-GABA-A potentiation

Ketamine:
-NMDA antagonism

Volatiles:

  • GABA-A potentiation
  • NMDA inhibition
  • Modulation of two-pore domain K+ channels
57
Q

How may the MOAs of inhaled agents be classified?

A

Macroscopic:

  • Decreased noxious afferent activity
  • Decreased spinal efferent activity
  • Reduced cerebral blood flow and metabolism, contributing to hypnosis and amnesia

Microscopic:
-Reduced neuronal transmission through inhibitory enhancement and activatory inhibition

Molecular:
-Effects on ion channels

58
Q

How do MOAs differ between gaseous and volatile agents?

A

Volatiles:

  • Presynaptic enhanced GABA release, reduced glutamate release
  • Postsynaptic GABAR activation and mild NMDA inhibition
  • Extrasynaptic GABAR enhancement

Gaseous:
-Mainly postsynaptic NMDA inhibition

59
Q

What agents affect MAC?

A

Opioids:

  • Acute: decrease MAC
  • Chronic: increase MAC

α2-agonists:
-Decrease MAC

Alcohol:

  • Acute: decrease MAC
  • Chronic: increase MAC

Sedatives eg. BDZs
-Decrease MAC

Amphetamine:

  • Acute: increase MAC
  • Chronic: decrease MAC

Catecholamines:
-Increase MAC

Primary FRCA (34 decks)

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