Drugs in Pregnancy

Maternal Kinetics
 Vd

increases by up to 20% for water and lipid soluble drugs. Total body water can increase up to 8L. May need to LD.  Serum albumin decreases up to 10g/L NB interpretation of drug concentrations (revise therapeutic range downward)  Liver metabolism increases (clearance can double)  Renal plasma flow increases (more rapid elimination if high fu)
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Teratogenic drugs in humans

 Alcohol: Alcohol:

fetal alcohol syndrome  Androgenic agents: masculinisation of female fetus  Carbamazepine: neural tube defects Carbamazepine: in 1%  Lithium: Ebsteins anomaly (tricuspid Lithium: valve and RV)  Methotrexate:congenital anomalies Methotrexate:congenital
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 Retinoic

acid derivatives: malformations in up to 50%  SSRIs: ? Cardiac abnormalities (5HT2B

agonists)
 Thalidomide: Thalidomide:

phocomelia  Valproic acid: neural tube defects (1-2%) acid: (1 Warfarin: nasal hypoplasia, chondroplasia punctata (6th-9th week)

Fetal adverse effects

 ACE

inhibitors: inhibitors: renal failure, oligohydramnios  Alcohol: withdrawal syndrome Alcohol:  Antithyroid drugs: goitre, hypothyroidism drugs:  Barbiturates: withdrawal Barbiturates:  Benzodiazepines: hypotonia, apnoea, Benzodiazepines: wihdrawal

      

Chloramphenicol: Chloramphenicol: Gray syndrome NSAIDs: NSAIDs: pulmonary hypertension (premature ductus closure); delayed onset of labour Opiates: Opiates: withdrawal Quinolones: Quinolones: cartilage/joint damage in animals Sulphonamides: Sulphonamides: kernicterus SSRIs: SSRIs: withdrawal Tetracyclines: Tetracyclines: impaired tooth enamel mineralisation (2nd half of pregnancy)

 QUESTION


A 24-year-old woman is on doxycycline 100 mg/day for 24-yearmoderately severe acne. She wants to become pregnant. In terms of foetal outcome, at what stage of pregnancy (measured from last menstrual period) is the risk to the foetus greatest from exposure to doxycycline?
    

A. Pre-conception. PreB. 0-4 weeks. 0C. 4-8 weeks. 4D. 8-12 weeks. 8E. 12-40 weeks. 12-

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Therapeutic drug monitoring (TDM)

 The

individualisation of dosage by maintaining plasma concs within a target range  Drug concs used as surrogates of therapeutic/adverse effects  Clinical effects more closely related to drug concentration than dose  At steady state plasma conc usually proportional to receptor conc
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TDM which drugs?

 Narrow

therapeutic range  Significant pharmacokinetic variability  Relationship between plasma concentration and clinical effects  Established target conc range  Cost effective drug assay
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Sources of PK variability
 Compliance  Age

(NB elderly)  Physiology (gender, pregnancy)  Disease (hepatic, renal, cardiac failure)  Drug interactions  Genetic polymorphisms
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Indications for TDM

 Toxicity: Toxicity:

diagnosis or avoidance  Dosing: 1.After dose adjustment (wait for Dosing: steady state); 2. Assessment of adequate loading dose (eg phenytoin); 3. Dose forecasting (eg aminoglycosides)  Monitoring: 1. Compliance; 2.Diagnosing Monitoring: underunder- treatment (anticonv, immunosupp); 3.Diagnosing failed Rx
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When to sample?
    

Unless TDM forecasting or toxicity concerns, sample at steady state For perhexiline, monitor before steady state to detect poor metabolisers With phenytoin loading, can check if adequate loading, dosing PrePre-dose trough for most drugs (least variable time point in dosing interval) Occasionally, sample at time of symptoms to detect toxicity (eg carbamazepine)
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Interpretation
?

Correct sample timing  ?steady state  ? Other considerations (eg serum K with digoxin, albumin, renal failure with phenytoin)  Most assays measure total drug conc (but only free drug exerts effect)  Treat the patient, not the level (target range is relatively arbitrary)
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PERHEXILINE

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Perhexiline
A

CYP2D6 substrate  Beware poor metabolisers  T 2-6 days (normal metabolisers) 2 Time to steady state 2-4 weeks 2 Usual dose 100 - 200 mg daily (100 mg bd)  Therapeutic range 150-600 mcg/L 15018

When to check levels

1

week after commencement (to detect poor metabolisers)  Check OH-perhexiline:perhexiline OHratio  Normal metaboliser: ratio 310. 3 Rx 100 mg bd  Poor metaboliser: ratio <0.3 (or concomitant CYP2D6 inhibitor). Rx 100 mg weekly
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 Limited

metabolic capacity: ratio 0.30.33.0. May saturate easily Rx 100 mg daily  Ultra-rapid metaboliser: ratio >10. UltraRx 300 -500mg daily

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Mr JU
 100

mg bd x 1 week  Perhexiline plasma conc 230 mcg/L  OH-perhexiline conc 1145 mcg/L OH Ratio 5.0 (= normal metaboliser)  Continue 100 mg bd.  Repeat levels after 2 weeks

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Mr BN
 Perhexiline

100 mg bd x 7 days  Perhexiline plasma conc 244 mcg/L  OH-perhexiline conc <20 mcg/L OH Ratio <0.1 (=PM)  Reduce dose to 100 mg WEEKLY and repeat levels after 2 weeks
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Mr AN
 Perhexiline

100 mg bd x 7 days  Perhexiline conc after 1 week 1298 mcg/L  OH-perhexiline <25 mcg/L OH Ratio <0.02 (=PM)  Withhold perhexiline. Recheck levels after 1 week.  Commence 100 mg WEEKLY when back in therapeutic range
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Mr PL
 Perhexiline

100 mg bd x 7 days  Perhexiline conc 121 mcg/L  OH-perhexiline 926 mcg/L OH Ratio = 7.65 (normal metaboliser)  Continue 100 mg bd (not at steady state)  Repeat level after 2-4 weeks and if 2still sub-therapeutic, increase dose to sub150 mg bd
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