10. Different groups

Question 1

How is ADME altered in a neonate?

Answer 1

A:
Enteral = lower gastric pH and slower gastric emptying and intestinal transit time = slower rate but increased proportion
Rectal = variable blood supply, so absorption placement dependent
Transdermal= thin stratum corneum = rapid

D: higher TBW, lower fat and increased BBB permeability. Decreased protein binding.

M: immature enzymes = reduced phase 1 (normal by first few years and slows again in puberty). Phase 2 varies.

E: lower egfr

Question 2

How is ADME altered in the elderly?

Answer 2

A: slower gastric emptying (insignificant)

D: smaller TBW and higher body fat ratio. Decreased albumin and decreased muscle bulk (reduction in muscle blood flow making remi etc. longer to metabolise).

M: reduced hepatic blood flow and enzyme activity = lower first pass metabolism.

E: decreased EGFR and tubular secretion

Question 3

How is ADME altered in pregnancy?

Answer 3

A: delayed gastric emptying =increased stomach uptake and reduced intestinal

D: increased TBW and fat. Dilution of albumin concentration and increased fatty acids compete for protein binding increasing free drug (alkaline still bing to alpha glycoprotein, so unchanged).

M: increased CO, hepatic blood flow and enterohepatic blood circulation. placental enzymes metabolise various neurotransmitters and drugs e.g. placental lactogen degrades insulin.

E: same

Question 4

How does obesity alter ADME?

Answer 4

A: no significant change

D: increased body fat = difficult calculations, larger organs, increased blood volume

M: increased phase 2

E: difficult to calculate

Question 5

What is ideal body weight?

How do we calculate it?

Answer 5

Estimate of lean body mass.

Men = height in cm - 100 and women = - 105.

Question 6

How do we calculate lean body mass?

Answer 6

Male = (1.1 x weight) - (128 x (weight/height squared))

Female = (1.07 x weight) - (148 x (weight/height squared))

Question 7

What are the names of the two formulae to calculate body surface area?

Answer 7

Dubois and mosteller

Question 8

How is ADME altered in the critically ill?

Answer 8

IV preferred due to decreased BA.

A: blood diverted to vital organs away from gut, intestinal atrophy following starvation, reduced motility from hypoperfusion and opioids.

D: ph changes, fluid shifts to increase interstitial and reduced proteins.

M: hepatic flow increases in early sepsis and then reduces (reduces HER > 0.7 as dependent on CO). Low HER dependent on enzyme activity which is decreased by cytokines and acute phase proteins. Enteral feeding increases enzyme activity.

E: renal dysfunction

Question 9

What is splicing and alternative splicing for mRNA?

Answer 9

Splicing: Pre-mRNA formed from introns and exons. Introns spliced out and exons form mRNA.

Alternative splicing: genes have different promoter regions which can cause different formation of exons being spliced from the same gene.

Question 10

What are pharacogenomics and pharmacogenetics?

Answer 10

Genome = study of how whole genome alters drug response

Genetics = 1 gene alters response

Question 11

What will result from SNP substitution?
Deletion?
Additions?

Answer 11

SNP = same amino acid from different codon, different amino acid or stop codon made.

Deletions and additions cause frameshift mutations.

Question 12

What is the mutation in sux apnoea?

What are the different alleles involved?

Answer 12

Autosomal recessive Pseudocholinesterase mutation
Heterozygous = mildly prolonged

EU = normal
EA = atypical
Ef = fluoride resistant
Es = silent

Ea Ea = most common
Es Es = longest duration

Question 13

How do we test for abnormal pseudocholinesterase genes?

Answer 13

Benzoylcholine is mixed with plasma cholinesterase producing a light emitting reaction.
Dibucaine (LA) binds to PCs reducing reaction

Abnormal genes reduce light
EuEu = 80% light inhibited = dibucaine number of 80
EaEa = DN of 20

Fluoride can also inhibit reaction and detects Ef gene.

No inhibition occurs in EsEs

Question 14

What gene is responsible for codeine and tramadol metabolism?

What are the products?

What are the different issues with mutations of this?

Answer 14

CYP2D6

C = morphine
T = o methyl metabolite (1000x more potent at u receptors)

Get ultrafast metabolisers
Expected
Poor e.g. codeine resistant

Question 15

What gene mutations can affect clopidogrel and what actions should we take?

Answer 15

Clopidogrel is a prodrug which is metabolised to active by CYP2C19

Ultrafast and extensive metabolisers = normal dose
Intermediate and poor need an alternative antiplatelet.

Question 16

What enzyme is responsible for S warfarin metabolism and what does warfarin inhibit?

Answer 16

CTYP2C9

2, 7, 9, 10 and protein C and S

Question 17

What are acetyltransferases involved in and what does mutations of this enzyme cause?

What are the alleles involved?

Answer 17

Hepatic phase 2 acetylation. NAT1 and NAT2.

Slow acetylators have Nat 2*5 which effects 50% of white people

Fast acetylators are high risk for colon cancer
Slow for bladder cancer

Question 18

What is an example of a gene which will reduce oral bioavailability?

What are some inhibitors of this?

Answer 18

P-glycoprotein (PGP)

On kidney, liver and brain endothelium so dictates drug movement.

Wild type increases its activity and reduces BA.

PGP inhibitors = amiodarone, verapamil and ciclosporin

Question 19

What mutation is linked to personality disorders and response to SSRI’s?

Answer 19

SLC6A4 solute carrier for 5HT (serotonin)

Question 20

What are the two important G protein receptors that can mutate that can affect important anaesthetic drug binding?

What problems can this cause for patients/drugs?

Answer 20

B1 adrenoreceptors: increased risk of HTN, cardiomyopathy and HF, most common in black people.

U opioids: MORE 1 increased the EC50 of morphine

Question 21

What does trastuzimab target?

Answer 21

HER2

Question 22

What does imatinib do?

Answer 22

Inhibits tyrosine kinase in CML (Philadelphia chromosome)