Aletered states of physiology

Question 1

Changes in paeds

Answer 1

• Pregnancy also yeilds changes

Question 2

Routes of administration paeds- Oral

Answer 2

Most common route
 Majority of drugs pass through GI system
 Some absorbed almost immediately through oral mucosa
 Excellent for emergency drugs e.g. buccal midazolam

Question 3

Routes of administration paeds- Nasal

Answer 3

Also absorbed quickly
 Avoids first pass metabolism
 e.g. nasal diamorphine for pain relief

Question 4

Routes of administration paeds- Skin

Answer 4

Absorption is increased in children:
 Larger surface area: body weight ratio
 Greater perfusion and hydration
 Neonates/infants very thin, permeable skin
Caution:
 Increased systemic absorption
 Increased potential for side effect
 E.g. alcohol gel can be absorbed causing skin reactions

Question 5

Routes of administration paeds- Rectal

Answer 5

 Avoids first pass metabolism
 Rich blood supply
 Increases absorption
 Variable in children
 Expulsion may be enhanced in young children:  Frequent and larger muscle contractions
 Appropriate formulations
 Appropriate route in some circumstances:
 diazepam for epileptic seizures
 analgesics/antipyretics e.g. paracetamol if the child is vomiting/NBM

Question 6

Routes of administration paeds- Lungs

Answer 6

 Structure and capacity
developmental changes may alter the pattern of inhaled drug absorption in young patients
 Correct developmental administration advice is key
 example the use of a mask and spacer in infants

Answer 7

-Depends on skeletal muscle blood flow
 Changes occur in blood flow during childhood
-Ideally should be avoided in children  Painful
 Compliance/concordance
-Neonates have very low muscle bulk  muscle damage may occur
 Inadequate perfusion
 Inadequate absorption
 Unpredictable
- Can be useful in emergency situation
 examples of drugs given via this route are vitamin K and naloxone

Question 8

Absorption in the elderly- changes to GIT

Answer 8

• Reduced gastric acid secretion
• Impaired mobility
• reduced gastric emptying

Question 9

Absorption in pregnancy

Answer 9

 Nausea = difficulties re adherence (administration)
 Vomiting = Unsure of quantity of drug absorbed.
 Reduced gastric emptying = reduced motility (probably due to increased progesterone production) and reduced intestinal absorption means maximal drug concentration falls
 Increased gastric pH (less acidic) = reduced absorption of weak acid and alkali molecules
 Peripheral vasodilation results in more absorption of parenterally administered drugs.

Question 10

What is volume of distribution and why is it useful

Answer 10

 The Vd indicates the extent to which a drug distributes beyond the plasma into various tissues and body compartments. A high Vd suggests extensive tissue distribution, while a low Vd indicates limited distribution predominantly within the plasma.
- Knowing this is useful because it aids:
 Dosage calculations
 Drug clearance
 Therapeutic monitoring
 Pharmacokinetic modeling

Question 11

Distribution in paeds

Answer 11

• Increased total body water:
   Total body water and extracellular fluid volume decrease with increasing age
   Neonates require higher doses of water-soluble drugs, on an mg/kg basis, than adults.
• Decreased plasma protein binding:
   Neonates have lower levels of albumin & globulins
   Plasma protein binding is therefore reduced in neonates
   Neonatal high circulating bilirubin levels may also displace drugs from albumin

Question 12

Distribution in the elderly

Answer 12

• Reduction in lean body mass
• Increased adipose tissue
• Reduced water in the body
• Changes in volume of distribution Vd
• Hydrophilic drugs: lower Vd
• Lipophilic drugs: higher Vd
• Decrease in plasma protein = higher percentage of drug that is unbound (active)

Question 13

Distribution in pregnancy

Answer 13

 More total body water and expanded plasma volume, thus, greater volume of distribution (Vd) of water soluble drugs
 More body fat, thus, greater Vd of fat soluble drugs
 Less albumin production and available albumin could be already occupied by hormones. Thus, greater proportion of free drug molecules.

Question 14

Metabolism in paeds

Answer 14

 Metabolic rate dramatically increased in children, often greater than adults
 Enzyme (Cytochrome P450) systems mature at different times
 May be absent at birth, or present in reduced amounts.
 Altered metabolic pathways may exist for some drugs
 Compared with adults, children may require more frequent dosing or higher doses (mg/kg) to achieve adult equivalent plasma
concentrations including:
 carbamazepine  phenytoin
 theophylline

Question 15

Metabolism in the elderly

Answer 15

• Liver size and mass declines with age
• Reduced hepatic blood flow
• Reduced hepatocyte activity

Question 16

Metabolism in pregnancy

Answer 16

 Increased levels of hormones (oestrogen and progesterone) may cause enzymatic inhibition or induction, depending on which enzymes are involved.
 Inhibited enzymes= CYP1A2, CYP2C19
 Induced enzymes= CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4, UGT

Question 17

Excretion in paeds

Answer 17

 Kidneys are primary organ responsible for the excretion of drugs and their metabolites
 Maturation of renal function is a dynamic process
- begins early during fetal organogenesis and is complete by early childhood
- can dramatically alter the plasma clearance of compounds with extensive
renal elimination.
 Renal excretion is dependent on glomerular filtration, tubular secretion and reabsorption.
 Renal blood reaches adult levels by 3-5 months
 Renal function 1-3 years
 Tubular function develops more slowly
 The half-life of drugs eliminated by the immature kidneys may be prolonged.

Question 18

Excretion in the elderly

Answer 18

• Renal function declines with age due to decreased kidney size, renal bloods flow, No’ of functioning nephrons
• Use cockcroft/gault
• Accumulation= risk of toxicity

Question 19

Excretion in pregnancy

Answer 19

 Greater hepatic blood flow, thus, greater excretion of high hepatic extraction drugs
 Greater renal blood flow, thus, higher glomerular filtration rate. Therefore, water soluble drugs / metabolites excreted faster than normal.

Question 20

Genetics

Answer 20

 Genetic make-up also plays a role in our drug response
- Example – the failure to produce CYPD26 enzyme which converts codeine to morphine
 Codeine is metabolised to morphine by the CYPD26 enzyme
 Genetic differences make people respond to codeine in different ways
- 7-10% Caucasians and 1-2% of Asians are described as poor metabolisers of codeine
- ‘Poor metabolisers’ have no expression of the genes to produce CYPD26 enzyme
- cannot convert codeine to morphine and have no response to codeine as an analgesic
- ‘ultra metabolisers’ have duplications of the gene for CYPD26
- convert codeine to morphine more quickly than others and are at increased risk of toxic effects such as respiratory depression.
- On average 1-7/100 population are ultra metabolisers however there are significant ethnic differences

Question 21

Codeine in paeds

Answer 21

 There are a number of cases in the literature of serious morbidity, even fatalities after the use of codeine post tonsillectomy in children
- more at risk of respiratory depression post operatively due to previous history of sleep apnoea
- In most of the cases, children were found to be ‘ultra metabolisers’ of codeine
 Adverse effects of codeine have also been reported in breastfeeding neonates whose mothers are taking codeine
- reports have shown that the mothers were ‘ultra metabolisers’ of codeine
 Codeine should only be used to relieve acute moderate pain in children >12yrs only if other medications have failed (MHRA, 2013)