Lifespan Pharmacology

Question 1

Describe penetration of drugs through placental barrier:

Answer 1

1. Placenta is the membrane separating foetal blood from maternal blood
2. During pregnancy, the thickness of placenta diminishes
   a) i.e. during 1st trimester, mean thickness is about 25 microns whereas during 3rd trimester it is approximately 2 microns

Question 2

Describe drug therapy in pregnancy:

Answer 2

1. Most drugs can cross the placenta and expose the baby to their effects
2. Factors affecting placental drug transfer and drug effects on foetus include:
   a) Drug physiochemical properties
   b) Rate which drug crosses placenta and amount reaching the foetus
   c) Duration of drug exposure
   d) Distribution in different foetal tissues
   e) Stage of placental and foetal development
   f) Effects of drugs used in combination

Question 3

Describe the altered pharmacokinetics in pregnancy; Absorption

Answer 3

1. Gastrointestinal absorption
   a) Decreased GI motility - drug stays in GIT longer
   b) Decrease in gastric acid secretion - increase in gastric pH therefore negatively affecting drugs that require acidic pH for absorption
   c) Increase in gastric mucus secretion
   d) Nausea and vomiting - nausea leading to decrease in drug compliance and vomiting decrease in drug absorption
2. Lung absorption
   a) Increase in cardiac output and tidal volumes by about 50% - may lead to hyperventilation and increased pulmonary blood flow
3. Transdermal absorption
   a) Increase in peripheral vasodilation
   b) Increase in blood flow to the skin
   c) Leads to enhanced transdermal absorption

Question 4

Describe the altered pharmacokinetics in pregnancy; Distribution

Answer 4

1. Increase in plasma volume which results in decrease of plasma proteins appearing (more plasma volume = more diluted plasma protein content - less concentrated)
   a) Blood volume thus increased by 30-50%
2. Increase of volume of interstitial fluid
3. Increase in volume of distribution

Question 5

Describe the altered pharmacokinetics in pregnancy; Metabolism

Answer 5

1. Oestrogen/Progesterone increases induce hepatic P-450 pathway
   a) Results in increase rate of metabolism and hence elimination of drug more quickly
2. Other isoenzymes are inhibited by progesterone leading to impaired clearance
3. Other extra-hepatic enzymes such as cholinesterase have diminished activity during pregnancy

Question 6

Describe the altered pharmacokinetics in pregnancy; Excretion

Answer 6

1. Glomerular filtrate rate in pregnancy increases by 50% in first trimester
   a) By 2nd trimester, this increase is up to 80%
2. This means that water soluble drugs such as beta-lactam antibiotics have much more rapid clearance occurring
3. Changes in tubular excretion or reabsorption however are unknown

Question 7

What is the regulation of placental passage?

Answer 7

1. Lipid solubility
   a) Drugs that are lipid soluble are likely to get across placenta as long as they have a low molecular weight
2. Molecular weight
   a) Drugs with large molecular weight (e.g. Heparin) are too large to get across the placenta
3. Degree of ionisation
   a) The more ionised they are (more polarised) the less likely it will be to get across the placenta
4. Placental transporters
   a) There is some placental transporters which pump drug back into maternal circulation to protect foetus from toxic effects (e.g. P-glycoprotein transporter)

Question 8

What are the pharmacodynamic factors influencing drug therapy?

Answer 8

1. Maternal drug actions:
   a) Physiology of some organs may be altered by pregnancy - hence some drugs may be required when the woman is pregnant that were not necessary when she was not pregnant
   b) Some drugs have predictable toxic drug actions in foetus so should not be used
   i) Neonatal withdrawal syndrome - caused by chronic use of opioids by the mother
   ii) Use of teratogenic drugs during pregnancy - ACE inhibitor causing renal damage to the foetus
2. Foetal therapeutics:
   a) Involves drug administration to pregnant woman with foetus being the drug target e.g. corticosteroids to stimulate lung maturation when pre-term birth is expected

Question 9

How do we define what is teratogenic to foetus?

Answer 9

1. Mechanisms:
   a) Direct drug effects on maternal tissues with indirect effects on foetal tissue
   b) Direct effects on processes for tissue differentiation
   c) Deficiency in a critic substance
2. To be considered teratogenic a substance it should:
   a) Result in a characteristic set of malformations
   b) Exert its effects at a particular stage of foetal development
   c) Show a dose dependent incidence

Question 10

What is the drug absorption in neonates?

Answer 10

1. Absorption after IM or SC injections in neonates depends on blood flow to the area and gastrointestinal function
2. Blood flow is decreased by:
   a) Cardiovascular shock
   b) Vasoconstriction
   c) Very little muscle mass
   d) Diminished perfusion of area
3. GI function in neonate changes significantly after birth
   a) Full term: GI secretion begin soon after birth
   b) Pre-term: GI secretion begin more slowly
   c) Gastric emptying time is increased by 6-8 hours
   d) Peristalsis is irregular and may be slow
   e) Gastrointestinal enzymes tend to be lower

Question 11

Drug use during lactation:

Answer 11

1. Most drugs are detectable in breast milk
   a) However, concentrations are usually low which prevents infants from receiving therapeutic amounts
   b) Some drugs do carry serious toxicities (e.g. radioactive iodine or cancer chemotherapy) and must be avoided
2. Recommendations for feeding mothers:
   a) Safe drug: take it 30-60 minutes after nursing and 3-4 hours before the next feeding
   b) No safety data: avoid drug use or discontinue breast feeding

Question 12

How does age affect therapeutic window?

Answer 12

1. As we age, therapeutic window becomes much more narrow

2. Progression to toxicity also increases as we age

Question 13

What is the difference in gastrointestinal system in paediatric patients than adults?

Answer 13

1. Gastrointestinal pH changes
   a) In children it is more alkaline than in adults
2. Gastric emptying is much slower in children
3. Gastric enzymes involved in metabolism of drugs are still immature
4. Bile acids and biliary function is also immature
5. Gastrointestinal flora hasn’t fully established in children
6. Differences in diet (e.g. formula or breast milk in neonates)

Question 14

Describe the altered pharmacokinetics in children; Absorption

Answer 14

1. Prolonged gastric emptying time and irregular gut motility which interferes with achievement of peak plasma concentration of drug
2. Decreased transit times in upper intestine which affects absorption
3. Presence of food will decrease absorption of certain drugs such as paracetamol, penicillin, and ampicillin
   a) This is due to having much smaller stomachs
4. Increase in protein diet and decrease in carbohydrates (such as heavy milk diets in infants) increases the rate of clearance of some medications (e.g. theophylline)
5. Absorption of lipid soluble drugs decreases in infants as they have a low concentration of lipase and bile acid

Question 15

Describe parenteral route in paediatric patients:

Answer 15

1. Absorption from IM and SC routes is erratic due to low proportion of skeletal mass to adipose tissue
2. Perfusion is decreased to muscles in premature infants
3. IV route should be preferred in serious conditions
4. Absorption from rectum is adequate

Question 16

Describe percutaneous route in paediatric patients:

Answer 16

1. Drugs are readily absorbed from intact skin as stratum corneum is thin and skin is well hydrated
   a) This leads to decreased dose of drug being required when administered through this route
   b) Excessive percutaneous absorption has resulted in significant toxicities

Question 17

Describe the altered pharmacokinetics in children; Distribution

Answer 17

Factors to consider:

1. Size of body water compartments
   a) Total water content is high in children - 65% in older children and 80% in neonates
   b) Therefore, increase or decrease in extracellular fluid spaces (due to diarrhoea and nephrotic syndrome) can result in increase or decrease in plasma concentration of medications - dose must be monitored and adjusted accordingly
2. Plasma protein binding
   a) Due to immature systems, there is less plasma binding proteins in children = more free drug
3. Degree of development of blood brain barrier hasnt matured yet
4. pH changes and composition of body fluids and tissues
5. Blood flow and tissue specificity for tissue receptor sites

Question 18

Describe the altered pharmacokinetics in children; Metabolism

Answer 18

1. Drug metabolising enzymes are immature in neonates, so drug metabolising capacity is limited
2. Oxidation reactions are immature at birth leading to increase toxicity
3. Plasma esterases are decreased in infants leading to possible prolonged apnoea
4. Sulfation reaction is more active in infants and children leading to more toxic metabolites of paracetamol
5. Drug metabolism is faster for certain drugs after 1st year of life leading to decrease in drug half-life

Question 19

What is the paediatric elimination of medications?

Answer 19

1. Glomerular filtration matures in relation to age, adult values reached by 3 years of age
   a) Therefore, neonates have decreased renal blood flow, glomerular filtration, and tubular function yields prolonged elimination of medications
2. Longer dosing intervals are thus necessary to prevent toxicity
3. Dosage of drugs eliminated by kidney should be reduced in infants

Question 20

Describe pharmacodynamic alterations in children:

Answer 20

1. Drug responses may be different in paediatric age and adults though mechanism is same
   a) Possibly due to immature receptors or neurotransmitters system
2. Antihistamines and barbiturates cause paradoxical excitement while amphetamine decreases abnormal hyperactivity
3. Premature infants are less sensitive to vasoconstrictive action of adrenaline and mydriatic action of phenylephrine

Question 21

Describe pharmacokinetics in the elderly:

Answer 21

1. Decrease in speed of absorption
2. Decrease in cardiac function - may affect distributino
3. Decrease in rate of liver metabolism - higher drug levels
4. Decrease in kidney function - longer half-lifes and higher levels of drugs)
5. Decrease in muscle mass and water content

Question 22

Describe the altered pharmacokinetics in elderly; Absorption

Answer 22

1. Factors affecting GIT absorption:
   a) Altered nutritional habits - possibly eating less and dehydrated
   b) Greater consumption of non-prescription drugs
   c) Slower gastric emptying time - drugs are in stomach longer and take longer to absorb

Question 23

Describe the altered pharmacokinetics in elderly; Distribution

Answer 23

1. Decrease in lean body mass
2. Decrease in body water content
3. Increase in fat
4. Decrease in serum albumin levels
5. Increase in alpha-acid glycoprotein
   These changes alter the loading dose of drugs

Question 24

Describe the altered pharmacokinetics in elderly; Metabolism

Answer 24

1. Metabolising capacity decreases in liver due to normal ageing
   a) Conjugation reactions are not significantly affected
2. Decrease in hepatic blood flow which causes;
   a) Slower metabolic inactivation of drug
   b) Decrease in first pass metabolism of drugs
3. Decrease in the induction of hepatic enzymes with drugs
4. Decrease in liver’s ability to recover from injuries that occur
5. Malnutrition and diseases that affect hepatic function are also common in elderly that would promote these changes

Question 25

Describe the altered pharmacokinetics in elderly; Elimination

Answer 25

1. Renal parameters that decrease with normal ageing are;
   a) Renal blood flow
   b) Glomerular filtration
   c) Tubular secretion
2. Serum creatinine level may still be in normal range
3. Lungs are important for excretion of volatile drugs
   a) Decrease in respiratory capacity and increase in incidence of active pulmonary disease in elderly so parenteral anaesthetic agents are preferred over inhalation
4. In patients with renal insufficiency, dosing schedule based on serum creatinine level and creatinine clearance level

Question 26

Describe the altered pharmacodynamics in elderly:

Answer 26

1. Decrease in neurotransmitter synthesis (Ach, dopamine, and serotonin levels)
2. Decrease in baroreceptor response
3. Decrease in responsiveness to beta-receptor stimulation
4. Decrease in receptor protein synthesis
5. Most reaction to drugs is increased = danger of toxicity
6. Presence of disease states common = exacerbates problems