Population Specific Pharmacotherapy Flashcards
Two membranes of the placental barrier
ST (syncytiotrophoblastic layer)
CT (cytotrophoblastic layer)
Which placental barrier layer is outside?
ST
Which placental barrier layer is on the inside?
CT
What is the purpose of the placental barrier?
to serve as a barrier preventing drug transport across the placenta
What are 3 characteristics that make a substance cross the placental barrier easier?
low molecular weight, un ionized, higher lipophilicity
in terms of placental permeability, lipid permeability is directly proportional to ______ and permeability is inversely proportional to _______
lipophilicity; molecular size
medications sized <500 Da
cross placental barrier easily
medications sized 500-1000 Da
cross with difficulty
medications sized >1000 Da
cross very poorly
Medications with high lipophilicity and low molecular weight will
cross the placenta easily
Protein bound drugs and placenta
Free form may cross but anything bound to protein would have difficulty
Drug movement across the placental membrane is reduced by
efflux transporters
What are the transporters that exist on the membrane of the placenta? (4)
P-glycoprotein
BCRP
MRP1
MRP2
In what layer of the placental barrier are phase I and phase II enzymes located?
ST
the amount of enzymes in the placental barrier are much ___ than in the liver
less
amount of enzymes in the placental barrier change with _____
gestational age
Metabolism of meds that pass through the placental barrier
small amount of metabolism takes place. if they do pass through and are not effluxed out, they can pose potential harm to the fetus.
4 different types of drugs that reach the fetus
- drugs which have favorable effects on the fetus
- drugs which have no effect on the fetus
- drugs that have adverse effects on the fetus
- teratogens which are drugs that effect embryonic of fetal development.
Always check ____ when prescribing meds to pregnant women
teratogenicity
If toxicities occur in the placenta between weeks 3 and 8, what can you expect?
abnormalities in development of the fetus
What needs to be considered if a mother really requires a medication during fetal development?
how severe is the potential effect? is it temporary or permanent?
teratogens
medications that will cause malformation of an embryo
Teratogenic effects most often occur during
organogenesis
Expression of teratogenic effects depend on
drug
fetal variability
Phenytoin as a teratogen (and its effects)
It is a highly protein bound drug. The protein bound phenytoin will not cross the placenta but all of the free phenytoin can cause harm such as growth retardation, microcephaly, mental retardation, and a broad depressed nasal bridge
Lithium as a teratogen
causes cardiac malformation
Methotrexate as a teratogen
will cause skeletal malformation
tetracycline as a teratogen
stained teeth and hypoplasia of enamel
alcohol as a teratogen
intrauterine growth retardation, mental retardation, microcephaly, and joint abnormalities
Teratogenic risk category A
Possibility of fetal harm appears remote
FDA teratogenic risk category A and B
okay to administer
Teratogenic risk category B
Either animal reproduction studies have not demonstrated fetal risk
or
controlled studies did not demonstrate adverse effects and there is no evidence of risk in later trimesters
FDA teratogenic risk C
Should only be given is benefit > risk
Teratogenic risk D
Pharmacy will typically intervene
Teratogenic risk category X
risk clearly outweighs any possible benefit
Women who are pregnant or planning to become pregnant and are on ACE inhibitors
will likely be changed to labetolol or methyldopa
Unbound medications and lactation
Unbound form will easily pass from plasma to milk, and can pass back.
Because babies (assuming they are breast fed) do not metabolize drugs at an adult level,
we need to know if drugs passing into breastmilk will harm the baby
5 factors that promote drug transfer into milk
small volume of distribution low protein binding high lipophilicity un ionized low molecular weight
Highly protein bound medications can still effect fetus/breast milk because
the free form may still be able to circulate, and even small concentrations can have a profound effect on a neonate.
Chloramphenicol causes what in babies
Gray Baby Syndrome.
Mechanism of Gray Baby Syndrome
Immature liver enzyme, UDP-glucuronosyltransferase, results in an accumulation of toxic metabolites. Can be fatal.
Symptoms of gray baby syndrome (6)
cyanosis ash gray color of skin lethargic eyes limp body tone hypotension death
Benzyl alcohol causes what in babies?
Gasping syndrome
Symptoms of gasping syndrome (4)
gasping respirations
severe metabolic acidosis
hypotension
death
mechanism of gasping syndrome
immature ability to conjugate benzoic acid with glycine, resulting in an accumulation of benzoic acid.
total body water % in adults vs neonates and its implications
adults: 65%
neonates: 80%
more water and less albumin means less protein for protein bound drugs to bind to.
Acid secretion in adults vs neonates and its implications
Neonates have much less gastric acid secretion. There will be less breakdown in the stomach and more drug available in circulation, necessitating lowest doses of medications.
At what age is adult renal function achieved?
age 2
GFR in neonates as compared to adults and its implications
Neonatal GFR is much lower than adult level, necessitating lower doses because medications will not be cleared as quickly.
Integumentary differences in neonates and adults
neonates have much thinner stratum corneum and an increased perfusion to cutaneous tissue. This implies an increased absorption of topical medications. Neonates have a higher body surface:weight ratio.
3 Factors affecting absorption of PO meds to neonates
- lower gastric acid secretion
- reduced gastric emptying
- reduced intestinal motility
3 Factors affecting absorption of IM meds to babies
- inefficient muscular contractions
- reduced perfusion to skeletal muscles
- greater density of capillary beds in skeletal muscle
Factor affecting rectally administered meds to babies
increased frequency of pulsatile contractions in the rectum (babies poop more) which may decrease the absorption of rectally administered drugs.
BBB in babies
immature and unable to effectively resist flow of meds across the barrier the way an adult BBB can.
Lower body fat % in infants compared to adults and its implications re: lipophillic drugs
The meds will stay in the blood stream rather than sequestering in the fat.
Ceftriaxone and neonates
Contraindicated because bilirubin competes with medications for protein binding. CFX can give babies hyperbilirubinemia
bilirubin and protein bound drugs for babies
babies have less protein. bilirubin will compete with medications for protein binding, resulting in higher freedrug concentrations of certain drugs.
Phase 1 Enzymes in babies
They are not fully developed until childhood but most of the development takes place in 1st year of life
Phase 2 enzymes in babies
Phase 2 activities can take several years to fully develop
A baby will have a decreased expression of CYP3A4. You give an APC medication that is a substrate for this enzyme. What do you expect?
An increased effect because the parent compound will not be efficiently metabolized into an inactive metabolite.
may require dose changes/adjustments
A baby will have a decreased expression of CYP3A4. You give a prodrug that is a substrate for this enzyme. What do you expect?
Decreased clinical effect because drug will not be readily metabolized into its active metabolite.
When does a baby’s Creatinine clearance and tubular secretion reaxh adult values
Reaches adult values in 1-2 years.
When considering medications for small children, what are two indicators to consider re:clearance?
creatinine clearance and tubular secretion
Renal dosing considerations for small children
As renal function changes with age, it is important to stay on top of if your dosing is adequate while also avoiding accumulation.
Absorption in pregnancy is effected by (2)
- reduced gastric acidity/increased pH
2. reduced GI tract motility
Implications for absorption of meds in pregnant women
Bioavailability of medications may or may not be altered because of reduced gastric acidity and motility.
reduced motility may be somewhat counteracted by reduced acidity.
Reduced GI motility in pregnancy may lead to
delayed onset of action of PO meds
3 factors that alter distribution in pregnancy and implication
- increase in plasma volume by up to 50%
- increase in total body water by ~20%
- decrease in plasma albumin
Change in dosing is not always required but should be monitored on a patient to patient basis, especially when giving highly protein bound medications.
Why might a pregnant patient be over responding to a medication with a narrow therapeutic index and high protein binding?
Less albumin to bind too, more free drug, more chance for AEs.
Increased expression of what CYP enzymes in pregnancy? and implication
CYP2D6, CYP3A4
increased metabolic capacity of these enzymes
decreased expression of what CYP enzyme in pregnancy and implication
CYP1A2
decreased metabolic capacity of this enzyme
expression of phase II enzymes in pregnancy
is decreased
drug elimination in pregnancy is altered because
renal blood flow increases by 50% in the beginning of the second trimester, dose adjustments typically are needed at this point for renally eliminated drugs.
Drugs eliminated renally for pregnant patients
will almost certainly need to be dose adjusted to maintain therapeutic concentrations.
What might you expect when giving atorvastatin, a pro drug metabolized by CYP3A4, to a pregnant patient?
amplified effect of the drug and increased potential side effects like muscle pain.
factors of pharmacokinetic changes in the elderly (6)
- less total body water %
- less lean mass %
- higher body fat %
- Lower serum albumin
- lower hepatic blood flow
- lower renal blood flow
implications of more body fat in elderly re: pharmacokinetics
changes in drug distribution. lipophilic meds can accumulate in fat, which may present a danger to the elderly patient.
implications of decreased hepatic blood flow in the elderly (apc and prodrugs)
less medication is traveling through the liver and thus less metabolism is occurring in the liver - leading to higher concentration and potential toxicity of APCs / lower clinical effect of pro drugs.
Cardiovascular changes in elderly (4) affecting pharmacokinetics
- susceptible to orthostatic hypotension
- decreased beta adrenergic receptor function
- increased hypotension from CCBs
- increased risk of long QT/torsades
Changes in BBB in the eldery
BBB becomes more permeable and there is overall greater sensitivity to the effects of drugs that gain access to the CNS.
Anticholinergic medications in the eldery
have a greater impact on cognitive function/decline.
resource for assessment of inappropriate prescribing for the elderly
beers criteria
Absorption is altered in critically ill patients because
shock state reduces blood flow to stomach, resulting in delayed gastric emptying.
Effect of vasopressors on absorption of PO meds / recommendation
Can increase response of PO meds because more blood is going to vital organs. Switch to IV.
Effect of vasopressors on absorption of topical medications
Meds like fentanyl patch won’t be as effective bc blood is being shunted to vital organs. Beware of OD when vasopressors are decreased.
Volume of distribution (Vd) in critically ill patients
increased because of presence of edema/administration of fluids. Particularly with abx.
Protein binding in critically ill patients
critically ill patients typically have low albumin, increasing free/unbound drug in circulation.
Hydrophilic and lipophilic medications in patient with edema
hydrophilic meds will stay in edema, lipophilic meds will be less effected.
Phenytoin in critically ill patients
narrow therapeutic doses potentially requiring decreased dose if albumin is low. more free phenytoin -> greater CNS depression.
Vanco trough in critically ill/septic patient
May be very different than what you’d expect in healthy patients because there is a different response to distribution in septic patients.
Elimination in critically ill patients
Increased excretion of certain metabolites and toxins due to possible glomerular hyperfiltration
Hepatic injury and metabolization in critically ill patients
hepatic injury/infection/ischemia will cause liver to metabolize slower.
If you are treating a patient with an APC that is metabolized by CYP3A4 and you have a hepatocellular injury reducing the capacity of CYP3A4…
You will have an increased clinical effect and potential toxicities
If you are treating a patient with a pro drug that is metabolized by CYP3A4 and you have a hepatocellular injury reducing the capacity of CYP3A4
You will have almost no conversion to active form and thus minimal effects on target sites.
Presence of uremia relating to med absorption
less GI acid and less GI motility. These two reductions may balance each other but medication onset will be delayed. Switch to IV if possible.
How does renal failure affect distribution?
displacement of uremic toxins = decreased albumin concentration -> decreased albumin binding
This leads to increased concentrations of free/unbound drug leading to toxicity for meds with narrow therapeutic indexes.
In severe renal disease, you should…
adjust doses to prevent accumulation
renal failure and drug elimination
there is a decrease in GFR, and, thus a decrease ins ecretion
drugs that are not fully metabolized by the liver
will often be eliminated renally
drugs and their metabolites may do what in the setting of renal failure?
accumulate and result in toxicity
If a med is not fully metabolized by liver and not fully eliminated renally due to dysfunction or disease state, what happens?
the remaining med will go back to the liver to be metabolized again and then back into systemic circulation. this can happen multiple times before complete elimination. If this is not achieved, dialysis is necessary.
diazepam has active metabolites that are cleared renally. What might you expect from a patient in renal failure who is on diazepam?
Increased effect of diazepam because the active metabolite will recirculate. This will cause a greater activation of gaba, leading to inhibitory effects in the CNS.
APCs vs active parent and active metabolite drugs in renal failure
APCs are okay
active metabolite drugs are dangerous
decrease in GFR and dosing
check renal dose adjustments
what renal conditions have specific dosing parameters?
decreased GFR, ESRD requiring dialysis, or Aki requiring dialysis
Pharmacokinetic changes in the malnourished patient are related to (4)
- reduction in albumin
- liver dysfunction affecting metabolism
- changes in fat/muscle content
- potential dehydration
lower fat content in malnutrition means what for pharmacokinetics?
lipophilic drugs will be less likely to accumulate and more likely to circulate
How does obesity alter medication absorption? (3)
- increased gastric emptying
- decreased subcutaneous absorption (more adipose but less blood supply per adipose tissue)
- physical difficulties with IM and IV
How does obesity affect distribution of lipid soluble drugs
There is increased Vd of lipid soluble drugs in obese patients. there will be a greater accumulation of those drugs in the tissues which results in a longer lasting clinical effect. Dosing may need to be increased in order to get initial desired effect because meds are settling in fat. Have to be careful not to OD the patient.
If dosing a water soluble drug to an obese patient…
dose based on ideal or lean body weight instead of actual because the fat tissue does not need to be accounted for.
if dosing a lipid soluble drug for an obese patient…
use actual body weight for dosing
when is it appropriate to use ideal/lean body weight dosing on an obese patient?
- when the medication is water soluble
- when calculating GFR (if pt is >120% ideal weight)
CYP2E1 activity in the obese patient
is increased
Phase II conjugation activity in the obese patient
is increased
Hepatic blood flow in the obese patient
is decreased
the half life of lipid soluble drugs in the obese patient
is increased
dosing obese patients with normal renal function
increased doses may be necessary because there is likely an increased GFR
Calculated/measured creatinine clearance in obese or critically ill patients
is not accurately correlated
if patients are greater than 120% of ideal body weight, what weight should be used for creatinine clearance? actual or ideal?
ideal. if done off of actual, there is risk for overestimation of dose.
If patient beings to respond differently to treatment regimen
consult drug information resources and pay attention to your individual patient.
protein bound meds in lactation
If it becomes protein bound to the protein in the milk, it won’t cross back over. it will partition to that area and would be ingested by the baby
Cp(t)
drug concentration in placma
Cm(t)
drug concentration in milk
Cm(t)
drug concentration in milk
Vm
milk volume
CLsec
secretion clearance
CLre
reuptake clearance
