Placental transfer is a concern
because certain drugs may induce congenital
abnormalities.
If administered immediately prior to
delivery, drugs may directly adversely affect the
infant.
Characteristics of drug-placental
transfer:
Mechanism: typically simple
diffusion
lipid-soluble,non-ionized
drugs are more likely to pass from the
maternal blood into the fetal
circulation.
By
contrast, ionized drugs with low
lipid-solubility are less likely
to pass through the placental
"barrier".
The fetus is
exposed to some extent to all
drugs taken by the mother.
Anesthesia correlation:
Placental transfer
of basic drugs
Placental transfer of
basic drugs from mother to fetus: local
anesthetics
Fetal pH is lower than
maternal pH
Lipid-soluble, nonionized
local anesthetic crosses the placenta converted
to poorly lipid-soluble ionized drug
Gradient is
maintained for continual transfer
of local
anesthetic from
maternal circulation to fetal
circulation
In fetal
distress, acidosis contributes to
local anesthetic accumulation
Benet, Leslie Z, Kroetz, Deanna
L. and Sheiner, Lewis B "The Dynamics of Drug
Absorption, Distribution and Elimination". In,
Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman,
J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill
Companies, Inc.,1996, pp. 3-27
Stoelting, R.K.,
"Pharmacokinetics and Pharmacodynamics of Injected
and Inhaled Drugs", in Pharmacology and Physiology
in Anesthetic Practice, Lippincott-Raven Publishers,
1999, 1-17
Drug effects may also
be terminated by redistribution -- from
its site of action to other tissues or
sites
A highly lipophilic-drug
may:
Rapidly partition
into the brain
Act for a short period of
time
and then
redistribute into other tissues
-- often ultimately concentrating
in adipose tissue.
Redistribution
is the mechanism responsible for
termination of action of
thiopental (pentothal),an
anesthetic inducing agent.
Benet, Leslie Z, Kroetz, Deanna
L. and Sheiner, Lewis B The Dynamics of Drug Absorption,
Distribution and Elimination. In, Goodman and Gillman's
The Pharmacologial Basis of Therapeutics,(Hardman, J.G,
Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman,
A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 3-27
Most drugs: bound to some
extent to plasma proteins
Major plasma proteins
important for drug binding include:
albumin
lipoproteins
alpha1
-acidic glycoprotein
Extent of protein binding
important for drug distribution since
only unbound fraction may diffuse across
biological membranes
Volume of distribution
(Vd): inversely proportional to protein
binding
Drug clearance: influenced by
protein binding since only the unbound
drug fraction may reach and serve as
substrate for drug metabolizing enzymes
Small changes in fraction of
drug bound significantly influences free
plasma concentration for highly plasma
protein bound drugs, e.g. warfarin, propranolol,
phenytoin, diazepam
For example: a
drug that is 98% protein-bound
--following a decrease to 96%
protein-bound results then a
twofold increase in plasma drug
concentration
Characteristics of drug-protein
binding
Extent of protein binding:
parallels drug lipid solubility
Drug-plasma albumin binding
-- often nonselective
many drugs with
similar chemical/physical
properties may compete for the
same protein-binding sites
Examples:
sulfonamides -- displace
unconjugated bilirubin
from albumin binding
sites (may lead to
neonatal bilirubin encephalopathy)
Renal failure:
may
decrease drug bound fraction (may
not require changes in plasma
albumin or other plasma protein
concentration; suggesting
elaboration of a metabolic factor
from the kidney that competes
with drug-plasma protein binding
sites)
Example:
phenytoin (free fraction
increased in renal
failure patients)
alpha1
-acidic glycoprotein concentration increases
following surgery, myocardial infarction
and in response to chronic pain:
In
rheumatoid arthritis patients
increased a1
-acidic glycoprotein
concentration resulting increased lidocaine
(Xylocaine) and propranolol (Inderal) protein
binding.
Stoelting, R.K.,
"Pharmacokinetics and Pharmacodynamics of Injected
and Inhaled Drugs", in Pharmacology and Physiology
in Anesthetic Practice, Lippincott-Raven Publishers,
1999, 1-17.
unbound drug
concentration in plasma (plasma
protein-bound drug is not filtered)
Drug secretion rates:
extent of
drug-plasma protein binding
carrier saturation
drug transfer
rates across tubular membranes
rate of drug
delivery to secretory sites
Changes in plasma protein
concentration
Blood flow
Number of functional nephrons
Special concerns: Renal disease in elderly
The kidney loses about 20% of its mass between
ages 40 and 80 with most of the difference reflected in a decrease
in renal cortical vasculature, tubular atrophy and dilatation
along with interstitial scarring. The kidney has the ability
to compensate to some extent by hyperfiltration and hyperfunction
of remaining nephron units; however, despite these changes
GFR declines beginning at about age 35 to 40 -- yearly decline =
about 1 ml/per minute
Creatinine clearance is a measure of renal
function. The Cockcroft-Gault equation for creatinine
clearance takes into account age:
(140-age) x body weight (kg) / 72 x serum
creatinine (mg per dl)
For women, the results above should be
multiplied by 0.85
Accordingly, for a serum creatinine of
1.5 mg/dL for two men who weigh 81 kg, an 80 year-old
man's creatinine clearance would be 45 ml per minute
compared with 90 ml per minute for a 20 year-old.
Pharmacokinetic factors that change
with age include:
Summary
creatinine clearance (reduced)
hepatic blood flow (reduced)
lean muscle mass (reduced)
renal blood flow (reduced)
serum albumin level (reduced)
total body water (reduced)
total body fat (increased)
Generally the rate and extended drug
absorption are not significantly altered by age; however, prescribed
drugs such as anticholinergic agents, laxatives, calcium channel
blockers influence gastrointestinal motility
Reduced hepatic function associated
with aging decreases the rate at which active metabolites are
produced.
Since total body water decreases and
total body fat increases with age, volume of distribution will be
altered.
For example, the more
water-soluble drugs will exhibit a reduced apparent volume of
distribution, causing an increased plasma concentration.
Examples include digoxin (Lanoxin, Lanoxicaps), cimetidine (Tagamet),
and ethanol.
For more fat-soluble drugs, the
opposite result is observed. Therefore drugs such as
diazepam (Valium) and chlordiazepoxide (Librium) will exhibit
extended half lives.
With age-dependent reduction in serum
albumin, drugs that are typically extensively protein-bound, such as
propranolol (Inderal), will be more likely found as free drug,
accounting for a prolonged and enhanced drug action.
In conclusion, age related reduction
in hepatic function and renal clearance will tend to prolong drug
half-life. It may be necessary therefore to adjust dosages to
account for these physiological changes.
Ref: Hassan Ali, Renal Disease in the
Elderly in Postgraduate Medicine, 100, 6 December (1996).
above to
begin the lecture