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Drugs Used in Pregnancy

Drugs Used in Pregnancy

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Published by anaeshkl

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Published by: anaeshkl on Apr 07, 2012
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PHARMACOKINETIC CONSIDERATIONS
most drugs can cross the placenta
risk of pharmacologic and teratogenic effects
critical factors affecting placental drug transfer and drugeffects on the foetus include
the physicochemical properties of the drug
the rate at which the drug crosses the placentaand the amount of drug reaching the foetus
the duration of exposure to the drug
distribution characteristics in different foetaltissues
the stage of placental and foetal development atthe time of exposure to the drug
the effects of drug interaction
lipid solubility
lipophilic drugs diffuse readily and rapidly across the placenta and enter the foetal circulation
intravenous anaesthetic agents cross the placenta almost immediately and can producesedation or apnoea in newborn
small amounts of unionised salicylate is highlylipid soluble and crosses placenta rapidly
ionization
highly ionised drugs crosses the placenta slowly andachieve very low concentrations in the foetus
muscle relaxants -succinylcholine,tubocurarine
impermeability of the placenta to polar compounds isrelative rather than absolute
can be influenced by high enoughconcentration gradients
molecular size
molecular weights
250-500 D : cross placenta easily dependingon their lipid solubility and degree of ionization
500-1000 D: cross the placenta with moredifficulty
>1000 D : cross the placenta very poorly
applications
choice of anticoagulant in pregnant women
heparin (large molecular weight, polar)
warfarin is contraindicated
exceptions to the size rule
maternal antibody globulins and certain polypeptides cross the placenta by unidentifiedselective mechanisms
protein binding
degree of binding to plasma proteins affects the rate of transfer and the amount transferred across placenta
transfer of poorly lipid soluble and ionised drug will beslow if also highly bound to maternal plasma proteins
very lipid soluble compounds will not be greatlyaffected by protein binding
transfer of such drugs dependent on and proportionate to placental blood flow
foetal proteins have lower binding affinity for 
sulphonamides, barbiturates, phenytoin, andlocal anaesthetic agents
drugs which are least protein bound cross the placentamore readily resulting in a higher UV/MV ratio
UV/MV ratio (pKa)
lignocaine 0.52-0.69 (pKa 7.85)
mepivacaine 0.69-0.71 (pKa 7.65)
 bupivacaine 0.31-0.44 (pKa 8.05)
low foetal
α
1-acid glycoprotein concentrations lead tolow plasma binding of drugs
placental drug metabolism
 placenta has monoamine oxidase, cholinesterase,microsomal drug-metabolising enzyme systems
metabolic activities include oxidation,reduction, hydroxylation, N-dealkylation,demethylation (pentobarbitone is metabolisedhere), hydrolysis, and conjugation
toxic metabolites may result (ethanol, benzpyrenes)
foetal drug metabolism
40-60% of umbilical venous blood enters foetal liver, adrug that enters the liver may be partially metabolised before reaching the circulation
active metabolites may adversely affect thefoetus
foetal hepatic extraction of drugs protects the brain andmyocardium of the foetus to some extent against highcirculating drug concentrations
at third month of gestation, cytochrome P450 is present in foetal liver 
glucuronyl transferase activity extremely low
drug uptake and distribution in mother
 biochemical and physiological changes
gastrointestinal motility is decreased, gastricemptying time may increase by 30-50%
will alter the rate of drug absorptionfrom GIT
during later stage in labour, drugabsorption from GIT is greatly delayedafter receiving opioids (pethidine,heroin, pentazocine, but not by epiduralanalgesia
hypoproteinaemia, modifying drug bindingduring pregnancy
 blood volume increases by 30-40% during pregnancy
 proliferation of smooth endoplasmic reticulum
indicating an increase in hepaticmicrosomal enzyme activity
renal plasma flow and glomerular filtrationrates increase
renal clearance of drugs may bemodified.
Drugs Used In Pregnancy
 NC Hwang 2008
 
FDA PREGNANCY CATEGORY LABELING OFDRUGSCategoryA
Description:
Controlled studies show no risk-Adequate,well-controlled studies in pregnant women have failed todemonstrate a risk to the foetus in any trimester of  pregnancy.
Category B
Description:
 No evidence of risk in humans-Adequate,well controlled studies in pregnant women have notshown increased risk of foetal abnormalities despiteadverse findings in animals,
or
In the absence of adequate human studies, animal studiesshow no foetal risk. The chance of foetal harm is remote, but remains a possibility.
Category C
Description:
Risk can not be ruled out-Adequate, well-controlled human studies are lacking, and animal studieshave shown a risk to the foetus or are lacking as well.There is a chance of foetal harm if the drug isadministered during pregnancy; but the potential benefitsmay outweigh the potential risk.
Category D
Description:
Positive evidence of Risk-Studies inhumans, or investigational or post marketing data, havedemonstrated foetal risk. Nevertheless, potential benefitsfrom the use of the drug may outweigh the potential risk.For example, the drug may be acceptable if needed in alife threatening situation or serious disease for whichsafer drugs cannot be used or are ineffective.
Category X
Description:
Contraindicated in Pregnancy-Studies inanimals or humans, or investigational or post-marketingreports, have demonstrated positive evidence of foetalabnormalities or risk which clearly outweighs any possible benefit to the patient
EFFECTS OF DRUGS IN THE FOETUS
therapeutic drug actions
corticosteroids are used to stimulate foetal lungmaturation when premature birth is expected
 phenobarbitone when administered to the mother near term,
can induce foetal hepatic enzymes responsiblefor the glucuronidation of bilirubin
has been shown to decrease the risk of intracranial bleeding in preterm infants
antiarrhythmic agents have been given to mothers for treatment of foetal arrhythmias
toxic drug actions
chronic use of opioids
may produce dependence in the foetus andnewborn
may manifest after delivery as neonatalwithdrawal syndrome
high doses of ethanol (especially during 1st and 2ndtrimesters)
foetal alcohol syndrome, central nervoussystem, growth and facial development may beaffected
angiotensin-converting enzyme inhibitor 
can result in irreversible renal damage in thefoetus (contraindicated in pregnant women)
diethylstilbestrol
at risk for adenocarcinoma of vagina after puberty
teratogenic drug actions
teratogen
causes a characteristic set of malformations,indicating a selectivity for certain target organs
exerts its effects during organogenesis
shows a dose-dependent incidence
mechanisms
a direct effect on maternal tissues withsecondary or indirect effects on foetal tissues
interfere with the passage of oxygen or nutrients through the placenta and thereforehave effects on the most rapidly metabolisingtissues of the foetus
direct actions on the processes of differentiation in developing tissues
a single intrauterine exposure to a drug can affect thefoetal structures undergoing rapid development at thetime of exposure
thalidomide phocomelia risk occurs during the4th to the 7th week of gestation because it isduring this time that the arms and legs develop
neural tube defects occur with carbamazepineuse (T1)
warfarin causes hypoplastic nasal bridge andchondrodysplasia (T1), central nervous systemmalformations (T2), risk of bleeding (T3)
AGENTS ALTERING UTERINE TONE ANDCONTRACTION
uterine tone increased by
α
-adrenoceptor agonists
oxytocin
ergometrine
PGE
2
PGF
2
(acetylcholine, bradykinin, histamine, serotonin)
uterine tone decreased by
β
2
-adrenoceptor agonists
volatile anaesthetics
nitroglycerin
magnesium sulphate
Ca
++
channel blockers
 prostaglandin synthase inhibitors
alcohol (by suppressing oxytocin secretion)
Drugs Used In Pregnancy
 NC Hwang 2008
 
DRUGS THAT INCREASE UTERINECONTRACTIONOxytocin
the oxytocin receptor is a G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-
β
increases intracellular Ca
++
 by release of intracellular Ca
++
 by inositol-1,4,5-triphosphate as well as direct or depolarization-induced activation of voltage-sensitive Ca
++
channels
pharmacokinetics
absorption
administered intravenously for stimulation of labour 
administered as nasal spray to induce postpartum lactation
inactive via oral route as it is destroyed in thestomach and intestines
not bound to plasma proteins
metabolised in liver and kidney
β
of 5 minutes
effects on the uterus
stimulates both the frequency and force of contraction
at higher concentrations, produces sustained uterinecontraction
sensitivity of uterus to oxytocin increases during pregnancy
exogenous oxytocin can increase or enhance rhythmiccontractions at any time, but in early pregnancy onlyvery high doses elicit a response
other effects
causes contraction of myoepithelial cells surroundingmammary alveoli, leads to milk ejection
has weak antidiuretic and pressor activity
indications
induction of labour 
Rh incompatability
maternal diabetes
 preeclampsia
augmentation of dysfunction labour in the presence of uterine inertia
incomplete abortion
control of postpartum haemorrhage
augment postpartum lactation
oxytocin challenge test
 provides information about placentalcirculatory reserve
adverse effects
maternal death due to hypertensive episodes
water retention
uterine rupture
foetal death
contraindications
foetal distress
 prematurity
abnormal foetal presentation
cephalopelvic disproportion
 predispositions for uterine rupture
Ergotamine
a fungal by-product belonging to a family of lysergicacid derivatives
effects on the uterus
causes strong uterine contractions via partial agonisteffect on
α
adrenoceptor (also antagonist effect)
serotonin receptor 
dose-dependent effects
small dosages, rhythmic contraction andrelaxation of uterus
large dosages, powerful sustained uterinecontraction
increasing dominance of 
α
1 receptors as pregnancy progresses
increases the sensitivity of uterus to thestimulant effects of ergot
ergonovine is more selective in uterine actions
agent of choice for obstetric application
adverse effects
gastrointestinal disturbances
diarrhoea, nausea, vomiting
activation of medullary vomiting centre and of gastrointestinal serotonin receptors
 prolonged vasospasm resulting in limb gangrene, bowelinfarction
contraindications
obstructive vascular diseasescollagen diseases
DRUGS THAT INHIBIT UTERINECONTRACTION
indicated to delay or prevent premature parturition, andto delay delivery for brief periods in order to undertakeother therapeutic measures
tocolytic agents currently in use include
β
2 adrenergic agonists (ritodrine, terbutaline,fenoterol, albuterol)
magnesium sulphate
Ca
++
channel blockers
 prostaglandin synthase inhibitors
nitroglycerin
Ritodrine
administration
available for both oral and intravenous administration
initial rate of 0.1 mg/min, gradually increasing to 0.35mg/min or until labour is controlled, infusion maintainedfor 12 hours
conversion to oral therapy maximum dose 120 mg per day
other effects
 produces dose related tachycardia, increase in systolic pressure, pulse pressure, stroke volume, and cardiacoutput and decrease in diastolic pressure and peripheralvascular resistance
secretion of renin is enhanced, resulting in decreasedrenal excretion of Na
+
, K 
+
and water 
over hydration during therapy may result in pulmonary oedema (5%)
Drugs Used In Pregnancy
 NC Hwang 2008

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