4. Variability in response to drugs

Question 1

What factors cause variability in physiological response?

Answer 1

-age
-genetics
-obesity
-ethnicity
-psychology
-pregnancy
-pathophysiology
-nutrition

Question 2

How does genetic variation alter drug response?

Answer 2

Some ethnicities can have different responses to the same drug, for e.g

-in 8% of caucasians, their CYP2D6 gene are poor metabolisers, therefore this means increased activity of tramadol, and has a reduced codeine clinical effect

However

-in 28% of North Africans, their CYP2D6 gene is an ultra-rapid metaboliser, therefore has a lack of therapeutic effect of tramadol, and an increased codeine clinical effect

Question 3

What is pharmacogenomics?
Give an example

Answer 3

-studies to identify the genes that are involved in determining the responsiveness to a given drug
-e.g breast cancer tumour genomics can help predict which women will most likely benefit from chemotherapy after breast surgery

Question 4

In neonates, how does their absorption, distribution, metabolism and excretion differ?

Answer 4

Absorption= higher gastric pH and delayed gastric emptying

Distribution= increased membrane permeability and reduced plasma albumin

Metabolism= different metabolites and enzyme system still developing until age 10

Excretion= reduced GFR

Question 5

For the drug midazolam, how will this have a different effect in neonates based on the below information?

Midazolam – a benzodiazepine used in neonates
-Rapid onset, short acting
-Highly protein bound (97% to albumin)
-Metabolised by liver enzymes (CYP3A4)
-Excreted renally

Answer 5

1. albumin levels are reduced= more midazolam free in the circulation
2. reduced GFR= could lead to decreased excretion
3. Enzymes systems still developing= slower metabolism

Question 6

In the older person, how does their absorption, distribution, metabolism and excretion differ?

Answer 6

Absorption= reduced gastric acid secretion and intestinal epithelium

Distribution= reduced body water and increased adipose tissue

Metabolism= reduced liver size and blood flow

Excretion= reduced kidney GFR and size

Question 7

For the drug morphine, how will this have a different effect in the older person based on the below information?

Morphine – opioid analgesic
-Well absorbed orally
-Low protein binding (~35%)
-Has an active metabolite with similar actions (and side effects) as morphine
-Parent drug and metabolites excreted predominantly in urine

Answer 7

Active metabolites of morphine could prolong the effects of the drug

Renal drug excretion is slower in the older person= increased risk of side effects

GI side effects= Worse constipation in the older person

Question 8

In pregnancy, how does their absorption, distribution, metabolism and excretion differ?

Answer 8

Absorption= Slowed GI motility and morning sickness

Distribution= extracellular fluid increase by up to 50% and decreased albumin concentration

Metabolism= Activity of hepatic enzymes are induced, so drug metabolism may be increased

Excretion= GFR increased and renal blood flow, and some drugs excreted in breast milk

Question 9

In obesity, how does their absorption, distribution, metabolism and excretion differ?

Answer 9

Absorption= absorption via IM or SC injection variable due to impaired tissue blood flow to peripheries

Distribution= obesity increases the body fat/ water ratio and increases volume of distribution

Metabolism= associated with diabetes, potential for fatty degeneration within the liver

Excretion= increased blood pressure and altered kidney function

Question 10

For the drug diazepam, how will this have a different effect in obesity based on the below information?

Diazepam – a benzodiazepine many uses
-Well absorbed from gut, reduced with high fat meal
-Highly protein bound (99% to albumin)
-Highly lipophilic and distributes widely into brain and fatty tissue
-Metabolised by liver enzymes to active metabolites
-Excreted renally as metabolites and parent drug

Answer 10

1. Body fat is increased in obesity therefore a lipophilic drug like diazepam will remain in the body for longer
2. Due to liver impairment= metabolism and plasma binding protein could be reduced, therefore more free drug and side effects

Question 11

What are the key pathophysiology to be aware of?

Answer 11

-malnutrition
-shock
-gastric stasis
-hepatic impairment
-renal impairment

Question 12

What are the key lifestyle impacts to be aware of?

Answer 12

-chronic alcohol use
-disordered eating
-abrupt cessation of smoking
-illicit substance misuse