Transcript Changes in renal physiology

Pharmacokinetics, Pregnancyinduced Physiologic Alterations
and Predicaments in Practice
Ruston S. Taylor, Pharm.D., BCPS, BCNSP
Clinical Pharmacy Specialist
Texas Children’s Hospital—The Center
Objectives

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Discuss clinical implications during pregnancy
caused by limitations of currently available
pharmacokinetic data
Identify physiologic changes along the continuum of
pregnancy in specific organ systems
Relate alterations in various organ systems to
influence on pharmacokinetic principles
??Pharmacokinetics??
First, what do we
know about
pharmacokinetics in
the pregnant
patient??
Pharmacokinetics:
Limitations to current knowledge
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Specific data for Vd and Cls in pregnancy for individual
drugs is limited due to ethical and practical considerations
Pharmacokinetic clinical trials exclude pregnant women,
due to FDA moratorium
Pharmacokinetic data that does exist in pregnancy comes
from small sample size studies and incorporates different
gestation ages
Comparator groups are often composed of non-pregnant
women, adult males, and same subject 6-8 weeks postpartum as controls
Pharmacokinetics:
Limitations to current knowledge

Limited pharmacokinetic data available for the
following:
 Anticonvulsants
 Antihypertensives
 Antibacterials
 Analgesics

All pharmacologic classes listed have lack of
consistency between studies and individuals
Pharmacokinetics:
Limited data for anticonvulsants
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Anti-epileptic drugs (AED) are the most studied
therapeutic category of agents in pregnancy
Plasma concentrations
across studied AEDs,
especially in the later stages of gestation
Decrease in plasma concentrations due to
clearance and lower concentrations of binding
proteins affect the following:
 Carbamazepine
 Phenytoin
 Phenobarbital
Pharmacokinetics: Decreased
anticonvulsant plasma concentrations

Most anticonvulsants exhibit high albumin binding
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However, the unbound concentration of “free drug” is
pharmacologically active
Special attention should be given when interpreting the
results of plasma concentrations to guide therapeutic
efficacy as most labs report total plasma concentration
(bound and unbound)
A fall in plasma concentrations does not reflect a fall in
free drug
Ideally, free drug concentrations should be monitored
Pharmacokinetics: Limited
data with antihypertensives

Beta-blockers (e.g. labetalol):
 Exhibit
a shorter t1/2 in pregnant women, suggesting the
need for more frequent doses

Calcium channel blockers (e.g. nifedipine):
 Exhibit

faster elimination
However, administration frequencies will continue to
be ultimately based on patient response
Pharmacokinetics:
Limited data with antibacterials
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Plasma concentrations of β-lactam antibiotics are
well known to correlate with response of bacterial
infections and are unaltered during pregnancy
Ampicillin exhibits increased clearance and
reduction in plasma concentrations during
pregnancy
Pharmacokinetics: Extremely
limited data with analgesics
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There is no consistent evidence detailing the
pharmacokinetics of analgesics in pregnancy (even
studies of the same drug)
No management guidance can be formed
concerning dosing schedule
However, management of pain will continue to be
based on pain score trends which may necessitate
increases in medication administration
Pharmacokinetic DISCLAIMER
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Vast and complex physiologic changes during
pregnancy have significant effects on drug
disposition
Understanding physiologic changes during the
continuum of pregnancy can help guide drug dosing
in various stages
Wide interpatient and intrapatient variability
necessitate monitoring serum drug levels when
indicated
??Physiologic changes??
• Identify physiologic changes
along the continuum of pregnancy
in specific organ systems
Why is
pregnancy
so
HARD?
Cardiovascular system:
Pregnancy-associated changes

Changes in maternal hemodynamic variables:
 Blood
volume
 Blood pressure (BP)
 Heart rate (HR)
 Stroke volume (SV)
 Cardiac output (CO)
 Systemic vascular resistance (SVR)
Cardiovascular system:
Complicating variables

Factors complicating management may include:
 Maternal
age
 Multifetal pregnancy
 Gestational age
 Body build
 Labor (length and method of delivery)
 Regional anesthesia
 Blood loss
Cardiovascular system:
Blood volume changes
McLennon CE, Thouin LG. Blood volume in pregnancy. Am J Obstet Gynecol 1948; 55:1189.
Cardiovascular system:
Pharmacokinetic changes due to blood volume
Physiologic change
Pharmacokinetic impact
Volume expansion
Decreased Cmax of drugs
Enhanced clearance
Decreased steady-state concentration
Protein binding
Decreased drug elimination occurs as drug
is inhibited from hepatic and renal
elimination
Hypoalbuminemia
Decreased sites for steroids, hormones,
and drugs to bind
Decreased binding
capacity
Larger unbound fraction
of drug (free drug)
More pharmacologic
activity
Cardiovascular system:
Changes in blood pressure
Progesterone effects
Blood Pressure (BP) = Cardiac output (CO) x systemic vascular resistance (SVR)
BP normally decreases by about 10% by the 7th week of
pregnancy
Cardiac output (CO) = heart rate (HR) x stroke volume (SV)
Increases by 10 weeks’ gestation  30-50% increases seen by
latter part of 2nd trimester
Blood pressure is a reflection of the cardiovascular system’s ability to
maintain perfusion to various organs (i.e. fetoplacental unit)
Cardiovascular system:
Increased cardiac output causes
Renal blood
flow
Pulmonary
blood flow
Uterus
• Increases by 30%
• GFR increases by 30-50%
• Increases by 30%
• 50 ml/min at 10 weeks
• 500 ml/min at term
Genitourinary system:
Changes in renal tract anatomy
As blood volume increases, the kidney
increases in length
 Dilation of collecting system occurs
secondary to muscle relaxant effects of
progesterone
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Obstruction to the
collecting system
can occur due to
enlarging uterus
Compressing the
ureters causes
urinary stasis
Increased risk of
pyelonephritis
Genitourinary system:
Changes in renal physiology
Elevated
estrogen levels
early in
pregnancy result
in renin
production
Conversion of
angiotensinogen
to angiotensin I
and II
Causes increase
in aldosterone
Results in renal
tubular sodium
retention
Genitourinary system:
Changes in renal physiology
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Glomerular filtration rate (GFR)
by 50% to a
peak around 180 mL/min by end of 1st trimester
Results in:
blood urea nitrogen (BUN) and serum creatinine
(SCr) levels > 0.8 mg/dL are indicators of abnormal
function

protein excretion considered normal
 Loss of glucose in the urine (glycosuria) is normal
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 Predisposing
factor for UTI
Genitourinary system: Pharmacokinetic
change in renal drug elimination
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As GFR
by 50%, drugs excreted primarily
unchanged in the urine are of concern:
Penicillin
 Digoxin
 Lithium
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These drugs exhibit lower steady-state serum
concentrations; however, dose alterations are
generally not prescribed as data is lacking or
conflicting
Gastrointestinal (GI) system:
Changes in GI physiology
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Progesterone-mediated smooth muscle relaxant effects
during pregnancy may
the following:
Lower esophageal sphincter tone = GERD and heartburn
 Gastric and small bowel motility
 Prolonged gastric emptying and extended intestinal transit
times

Decreased
gastric motility
Increased time in
large intestine
Increased water
absorption
Gastrointestinal (GI) system:
Pharmacokinetic changes in GI
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The following factors affect the gastrointestinal
absorption of drugs:
 Drug
formulation
 Food composition
 Chemical composition
 pH of the intestinal secretions
 Gastric emptying time
 Intestinal motility
 Blood flow
Gastrointestinal (GI) system:
Changes in metabolic activity
Enzyme
Pathway
Change in Activity
Drugs of interest
Comments
CYP1A2
Decreased
Theophylline, clozapine,
ondansetron, propranolol,
cyclobenzaprine
Caffeine half-life also
prolonged
CYP2A6
Increased
Nicotine, cotinine
Cotinine is active
metabolite of nicotine; may
have decreased effect of
nicotine gum
CYP2C9
Increased
Phenytoin, glyburide
Monitoring of phenytoin
concentration indicated
CYP2D6
Increased
Many β-blockers, including
metoprolol; many TCAs and
SSRI, codeine
Decreased concentration of
SSRI documented and may
be associated with
recurring symptoms of
depression
Gastrointestinal (GI) system:
Changes in drug metabolism in pregnancy
Enzyme
Pathway
Change in
Activity
Drugs of interest
Comments
CYP3A4
Increased
Most calcium channel blockers, including
nifedipine; most benzodiazepines; most HIV
protease inhibitors; most non-sedating
antihistamines; methadone
May have withdrawal symptoms in
patients on methadone
maintenance
UGT1A1
Increased
Acetaminophen
Unknown significance
UGT1A4
Increased
Lamotrigine
Significant decrease in serum
lamotrigine concentrations;
increase in seizure activity unless
monitoring and dose adjustment
occurs
UGT2B7
Increased
Lorazepam
Unknown significance
Gastrointestinal (GI) system:
Pharmacokinetic changes in hepatic elimination
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The cholestatic effects of progesterone on the gall
bladder interfere with the clearance of biliary
secreted drugs (e.g. rifampin)
As illustrated previously, almost all pharmacokinetic
elimination mechanisms via the CYP and UGT
systems increase during pregnancy
However, hepatic elimination cannot be quantified
as phenotypic expressions depend on the genetic
make-up which varies greatly between individuals
Endocrine system:
Changes in the pancreas
β-cells undergo
hyperplasia
during pregnancy
This results in
increased insulin
secretion
Insulin hypersecretion
results in hypoglycemia
seen in early
pregnancy
Peripheral resistance to
insulin is a result of
production of insulin
antagonists, human
placental lactogen
Placental insulin
antagonists result in
normal postprandial
hyperglycemia
Placental-Fetal
Compartment
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Placenta acts as a permeable barrier between the
maternal and fetal blood circulations
Functions to transport oxygen and nutrients from the
mother to fetus, while also providing waste
exchange from the fetus to the mother
Drugs cross mainly via passive diffusion
Factors that determine the ability of a compound to
cross the placenta include:
 pKa,
lipid solubility, and molecular size
Physiologic conclusions:
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Physiologic adaptations occur at different times and
to different degrees depending on the organ
system and individual
Maternal ability to adapt may depend on preexisting variables:
 Maternal
age
 Multiple gestation
 Ethnicity
 Genetic factors
Physiologic conclusions:
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Maternal ability to adapt may depend on
pregnancy-associated factors:
 Gestational
age
 Labor
 Intrapartum

blood loss
A better understanding of normal physiologic
adaptations of pregnancy gives practitioners the
ability to manage pregnancy-associated
complications
References:
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Belfort Michael, comp. Critical Care Obstetrics. 5th ed. Chichester:
Blackwell, 2010.
Briggs GG, Nageotte, M. Diseases, Complications, and Drug Therapy in
Obstetrics. Bethesda: ASHP, 2009.
Dawes M, Chowienczyk P. Pharmacokinetics in Pregnancy. Best Practice &
Research Clinical Obstetrics and Gynaecology. 2001; 15(6): 819-826.
Koren G. Pharmacokinetics in Pregnancy; Clinical significance. J Popul Ther
Clin Pharmacol. 2011; 18(3): e523-e527.
Little, B. Pharmacokinetics During Pregnancy: Evidence-Based Maternal
Dose Formulation. Obstetrics and Gynecology. 1999 May;90(5): 858-868.
Review.
Loebstein R, Lalkin A, and Koren G. Pharmacokinetic Changes During
Pregnancy and Their Clinical Relevance. Clin Pharmacokinet. 1997; 33(5):
328-343.