Fundamentals: Pharmacology - Drugs in pregnancy and the elderly

Question 1

Seven factors affecting placental drug transfer

Answer 1

1. Lipid solubility: increased lipid solubility increases placental transfer (e.g. thiopental)
2. Drug ionisation: increased ionisation decreases placental transfer (relative: increased transfer with increasing concentration and lipid solubility)
3. Molecular size: cross placenta easily if 250-500MW
4. pKa: maternal blood pH is 7.4 and foetal blood pH is 7.3 (basic drugs with pKa >7.4 will undergo ion trapping in foetus)
5. Placental transporters: may pump drugs back into maternal circulation (or vice versa)
6. Protein binding: drug transfer impeded by maternal protein binding (more important for lipid soluble drugs), foetal proteins also have lower binding affinity than maternal (e.g. sulfonamides, barbiturates, phenytoin, local anaesthetics)
7. Placental and foetal metabolism: placenta itself can metabolise drugs to produce either active or inactive metabolites (e.g. prednisolone metabolised to inactive prednisone - can be used in pregnancy without steroid exposure to foetus), 40-60% of umbilical venous blood enters liver (first pass metabolism), some drugs in umbilical artery may be shunted through placenta back to umbilical vein

Question 2

What % of umbilical venous blood enters the liver?

Answer 2

40-60%

Question 3

Three characteristics of teratogens

Answer 3

1. Results in characteristic set of malformations
2. Exerts effects at particular stage of foetal development
3. Shows dose-dependent incidence

Question 4

Describe the five teratogenic risk categories

Answer 4

Category A: possibility of harm remote
Category B: no risk in animal-reproduction studies but no studies in human pregnancy, OR adverse effect in animal-reproduction studies but not confirmed in human pregnancy
Category C: adverse effect in studies in animals, but no studies available in human pregnancy (or no studies available at all)
Category D: evidence of human foetal risk but benefits to pregnant woman may be acceptable (e.g. life-threatening or no alternatives in serious disease)
Category X: evidence of risk in human and animal studies (or in clinical experience), risk outweight benefit

Question 5

Six examples of drugs that are category A in pregnancy

Answer 5

1. Cephalexin
2. Chloromycetin ear drops
3. Nitrofurantoin
4. Metoclopramide
5. Sulfasalazine
6. Methyldopa

Question 6

Two examples of drugs that are category B in pregnancy

Answer 6

1. Dicloxacillin
2. Vancomycin

Question 7

Eight examples of drugs that are category C in pregnancy

Answer 7

1. Oxycodone
2. Morphine
3. Enoxaparin
4. Heparin
5. Promethazine
6. Metoprolol
7. Nifedipine
8. Digoxin

Question 8

Two adverse effects of ACEIs in pregnancy

Answer 8

1. Renal damage
2. Hypocalvaria

Question 9

Two antibiotics contraindicated in pregnancy and their effects

Answer 9

1. Tetracyclines (contraindicated throughout pregnancy): discolouration and defects of teeth and altered bone growth
2. Chloramphenicol (contraindicated in 3rd trimesters): “grey baby syndrome” (cyanosis, hypothermia, CV collapse)

Question 10

During what trimester of pregnancy are ACEIs contraindicated?

Answer 10

Throughout

Question 11

Seven recreational drugs contraindicated in pregnancy and their adverse effects

Answer 11

1. Amphetamines: abnormal developmental patterns, decreased school performance
2. Barbiturates: neonatal dependence with chronic use
3. Cocaine: increased risk of spontaneous abortion, placental abruption, premature labour, and neonatal cerebral infarction; abnormal development, decreased school peformance
4. Ethanol: foetal alcohol spectrum disorder
5. Diazepam: neonatal dependence with chronic use
6. Heroin, methadone: neonatal abstinence syndrome with chronic use
7. Tobacco smoking: IUGR, prematurity, SIDS, perinatal complications

Question 12

Four anticonvulsants contraindicated in pregnancy and their adverse effects

Answer 12

1. Phenytoin (contraindicated throughout pregnancy): foetal hydantoin syndrome (IUGR, microencephaly, limb defects, congenital heart defects)
2. Valproate (contraindicated throughout pregnancy): neural tube defects, cardiac and limb malformations, developmental delay, possibly autism
3. Carbamazepine (contraindicated in 1st trimester): neural tube defects
4. Topiramate (contraindicated in 1st trimester): oral cleft

Question 13

Adverse effects of warfarin in pregnancy

Answer 13

1st trimester: hypoplastic nasal bridge, chondrodysplasia punctata
2nd trimester: CNS malformations
3rd trimester: risk of bleeding (discontinue for 1 month before delivery)

Question 14

Oral hypoglycaemics contraindicated in pregnancy and their adverse effects

Answer 14

Chlorpropamide (sulfonylurea): prolonged symptomatic neonatal hypoglycaemia

Question 15

Three thyroid medications contraindicated in pregnancy and their adverse effects

Answer 15

1. Iodide: congenital goiter, hypothyroidism
2. Methylthiouracil: hypothyroidism
3. Propylthiouracil: congenital goiter

Question 16

Adverse effects of isotretinoin in pregnancy

Answer 16

Extremely high risk of CNS, face, ear and other malformations

Question 17

Adverse effects of lithium in pregnancy

Answer 17

1st trimester: Ebstein’s anomaly (congenital heart defect involving tricuspid valve)
3rd trimester: neonatal toxicity

Question 18

Adverse effects of corticosteroids in pregnancy

Answer 18

Cleft palate in 1st trimester

Question 19

Two antidepressants contraindicated in pregnancy and their adverse effects

Answer 19

In 3rd trimester:
1. Tricyclic antidepressants: neonatal withdrawal
2. SSRIs: neonatal abstinence syndrome, persistent pulmonary HTN of newborn

Question 20

Adverse effects of androgens in pregnancy

Answer 20

Masculinisation of female foetus in 3rd trimester

Question 21

How does IM drug absorption differ in infants from adults?

Answer 21

IM absorption unpredictable in sick preterm infants due to low muscle mass and decreased peripheral perfusion (high-risk drugs in this setting include cardiac glycosides, aminoglycosides, anticonvulsants)

Question 22

In what three ways does oral drug absorption differ in infants from adults?

Answer 22

1. Gastric acid secretion increases over hours after birth in full-term infants (slower in pre-terms, highest on day 4)
2. Gastric emptying prolonged (up to 6-8hrs) first day post delivery: results in increased absorption in the stomach and decreased in the small intestine
3. Decreased GI enzyme activity (including pancreatic enzymes, bile acids, lipase)

Question 23

Three drugs whose (oral) absorption is decreased in neonates

Answer 23

1. Paracetamol
2. Phenobarbital
3. Phenytoin

Question 24

Two drugs whose (oral) absorption is increased in neonates

Answer 24

1. Ampicillin
2. Benzylpenicillin

Question 25

Three drugs whose (oral) absorption is unchanged in neonates

Answer 25

1. Diazepam 2. Digoxin 3. Sulfonamides

Question 26

Describe the differences in drug distribution in infants compared with adults

Answer 26

1. Increased total body water in infants: extracellular water (up to 40%) decreases concentration of drug at receptor sites (mainly relevant for water-soluble drugs) 2. Decreased body fat in preterm infants compared with full-term 3. Decreased protein binding in neonates: results in increased concentration of free drug -> increased effect or toxicity despite normal total serum concentration (e.g. local anaesthetics, diazepam, phenytoin, ampicillin, phenobarbital)

Question 27

How is CYP450 activity different in neonates compared with adults? What does this mean for drug metabolism?

Answer 27

Decreased (50-70% lower) Results in slower clearance and prolonged elimination t1/2

Question 28

Give an example of a maternal drug which induces foetal hepatic enzymes

Answer 28

Phenobarbital

Question 29

How does drug metabolism differ in toddlers compared with adults?

Answer 29

Metabolic rate of drugs higher during toddlerhood (12-36 months) Increased dose/kg needed compared with adults

Question 30

How does drug excretion differ in neonates compared with adults? What about during toddlerhood?

Answer 30

Decreased GFR in newborns (30-40%) Reaches adult values by 6-12 months Exceeds adults during toddlerhood

Question 31

When should breastfeeding be ideally timed relative to maternal drug administration?

Answer 31

Medication should be taken 30-60mins after nursing and 3-4hrs before next feed

Question 32

Six medications which are present in breastmilk in high concentrations, and their effects in the newborn

Answer 32

1. Tetracycline: tooth staining 2. Isoniazid: pyridoxine deficiency 3. Opiates (particularly codeine if mother is a rapid metaboliser): neonatal dependence 4. Lithium: toxicity 5. Iodinated albumin and radioiodine: thyroid suppression (breast feeds should be withheld for days to weeks after small doses) 6. Amiodarone: thyroid dysfunction

Question 33

Two methods for calculating paediatric drug doses using age and weight

Answer 33

Dose = adult dose x [age/(age+12)] Dose = adult dose x (weight/70)

Question 34

How does drug absorption change with advanced age?

Answer 34

No major changes Altered nutritional habits, increased consumption of non-prescription drugs (e.g. antacids, laxatives), slowed gastric emptying

Question 35

What factors result in altered drug distribution in the elderly?

Answer 35

Decreased lean body mass Decreased body water Increased fat percentage Decreased serum albumin (binds weak acids), increased orosomucoid (binds basic drugs): decrease loading dose but no change to maintenance

Question 36

How does hepatic metabolism change with age? Is this change greatest in phase I or II reactions? What causes this change?

Answer 36

Decreased hepatic metabolism (for some drugs more than others) Greatest change in phase I reactions May be caused by decreased hepatic flow (e.g. in setting of heart failure), severe nutritional deficiencies, or decreased ability to recover from injury (e.g. alcohol or viral hepatitis)

Question 37

How does drug excretion change with advancing age?

Answer 37

Decreased CrCl (2/3 of population) -> prolonged t1/2

Question 38

What is the difference in serum creatinine in the elderly?

Answer 38

Creatinine may be normal despite decreased CrCl Due to decreased muscle mass

Question 39

Describe two drugs with altered pharmacodynamics in the elderly

Answer 39

1. Sedative-hypnotics: increased sensitivity 2. B-agonists: decreased responsiveness

Question 40

Those with Alzheimer's disease are more sensitive to which class of drugs?

Answer 40

Antimuscarinics

Question 41

Two classes of drugs used to treat Alzheimer's disease

Answer 41

1. Cholinesterase inhibitors 2. NMDA channel blockade

Question 42

Three examples of cholinesterase inhibitors used in Alzheimer's disease

Answer 42

1. Donepezil 2. Rivastigmine 3. Galantamine

Question 43

Example of an NMDA channel blocker used in Alzheimer's disease

Answer 43

Memantine

Question 44

Pharmacokinetics of cholinesterase inhibitors

Answer 44

Absorption: orally active Distribution: good CNS penetration

Question 45

Two adverse effects of cholinesterase inhibitors

Answer 45

1. Nausea, vomiting, diarrhoea 2. Peripheral cholinomimetic effects

Question 46

Do cholinesterase inhibitors alter disease progression in Alzheimer's?

Answer 46

No

Question 47

Which class of drugs can interact with cholinesterase inhibitors to cause toxicity?

Answer 47

CYP450 inhibitors

Question 48

Why should cimetidine be avoided in the elderly?

Answer 48

Increased risk of confusion and slurred speech in elderly Inhibits metabolism of other drugs including phenytoin and warfarin

Question 49

11 drugs with age-related decrease in hepatic clearance

Answer 49

1. Alprazolam 2. Barbiturates 3. Clobazem 4. Diazepam 5. Flurazepam 6. Imipramine 7. Nortriptyline 8. Propranolol 9. Quinidine 10. Theophylline 11. Tolbutamide (sulfonylurea)

Question 50

9 drugs with no age-related change in hepatic clearance

Answer 50

1. Ethanol 2. Isoniazid 3. Lidocaine 4. Lorazepam 5. Nitrazepam 6. Oxazepam 7. Prazosin 8. Salicylate 9. Warfarin