Population-Specific Pharmacotherapy Flashcards
Describe how the placenta acts a a ‘barrier’ to drug distribution
The syncytiotrophoblastic (ST) layer is essentially an epithelial layer
- The term ‘syncytio’ indicates cells that have fused to provide little in the way of intercellular access to anything
- Apical and basal membrane bilayers represent the primary barrier to the movement of drugs across the placenta
Discuss passage of drugs across the placenta in relation to permeability
- Lipid permeability is proportional to lipid solubility
- Lipid permeability is inversely proportional to molecular size:
<500 Da cross readily
500-1000 Da cross with difficulty
>1000 Da cross very poorly - Note the potential relevance of binding to albumin and ‘ion trapping’
- Passage of drugs across the placenta in hindered for those drugs that bind to (maternal) albumin
- Weak bases partition better into fetal circulation than weak acids (fetal 7.3, maternal 7.4)
What role do transporters play in passage of drugs across the placenta?
- Passage of an occasional drug into fetal circulation is facilitated by certain transporters
- Passage of more than a few drugs into fetal circulation is attenuated by efflux transporters: P-glycoprotein (MDR1), Others (BRCP, MDR3)
What role does placental metabolism play in passage of drugs across the placenta?
- The syncytial trophoblastic layer expresses many forms of cytochrome P450 and all enzymes for phase II reactions
- Amounts of the different enzymes are far less than that of the liver
- Amounts of the different enzymes may vary with gestational age - Drugs that can cross the syncytial layer are subject to a small amount of metabolic machinery before entering fetal circulation
What is the bottom line in regards to passage of drugs across the placenta?
The fetus can be exposed to many kinds of drugs administered to the mother!
- A very large number of drugs have the properties of permeability to cross the placental membrane
- The placental membrane has only a small amount of efflux transporters
- The placental membrane has only a small amount of metabolic enzymes
What are the different ways that drugs can affect the fetus?
- Drugs can have desired actions of therapeutic value to fetus
- Drugs can have neither therapeutic nor deleterious actions to fetus
- Drugs can have adverse or toxic actions to fetus for the same reason they are to adult
- Drugs can have actions that modify embryonic or fetal development: TERATOGENS
How many drug classes are considered teratogenic? In what period of development do most teratogens affect development?
- 30
- Embryonic period, weeks 3-8
- Mechanisms of teratogenesis are poorly understood
- The ‘penetrance’ of teratogenic actions varies depending on drug and genetic variability (never 100% chance of defects)
What are some examples of teratogenic medications?
- ACE/ARB
- Anticonvulsants
- Systemic corticosteroids
What are the different teratogenic risk categories and what do they mean?
A: Possibility of fetal harm remote
B: Evidence of fetal risk in animals
C: Drugs should be given only if potential benefit justifies the potential risk to fetus
D: Evidence of fetal risk in humans - benefits may be acceptable despite risk (life-threatening situations)
X: Risk of use of drug in pregnant woman clearly outweighs any possible benefit (there is a better alternative)
What are the old and new labels of prescription drug labeling in specific populations?
OLD
- 1 Pregnancy
- 2 Labor and Delivery
- 3 Nursing Mothers
NEW
- 1 Pregnancy (includes Labor and Delivery)
- 2 Lactation (including Nursing Mothers)
- 3 Females and Males of Reproductive Potential
Describe how drugs partition during lactation
- Maternal plasma is 7.4 and milk is 7.1 => ion trapping of bases
- Also relates to lipophilicity and size of drugs
How do practitioners choose appropriate medications for nursing mothers?
LACTMED
If clinical data are not available,
- Choose drugs that are highly protein bound, have a high molecular weight, have a short half-life, have no active metabolites, and are well tolerated
- Have the mother avoid nursing during times of peak drug concentration and, if possible, have her plan nursing before administration of the next dose
What are the age ranges for neonates, infants, children, and adolescents?
- Neonate: = 28 days
- Infant: 29 days - 12 months
- Child: 1 - 12 years
- Adolescent: 13 - 17 years
What is the mechanism of chloramphenicol causing “gray baby syndrome,” and what are the signs?
Mechanism: Immature UDP-glucoronosyltransferases resulting in accumulation of toxic metabolites
Signs:
- Cyanosis
- Ash gray color of skin
- Limp body tone
- Hypotension
- Death
What is the mechanism of benzyl alcohol causing “gasping syndrome,” and what are the signs?
Mechanism: Immature ability to conjugate benzoic acid with glycine, resulting in accumulation of benzoic acid
Signs:
- Gasping
- Severe metabolic acidosis
- Hypotension
- Death
With which step of metabolism do infants struggle?
Drugs that require phase II reactions because these mechanisms are immature for the first year
Which pediatric age group struggles most with absorption and why?
Neonates
1. PO drugs
- Lower gastric acid secretion
- Lower gastric emptying and intestinal motility
(Cmax low, Tmax higher => higher dosing than would expect)
- Lower biliary function
2. Topically/percutaneously administered drugs
- Thinner stratum corneum
- Increased cutaneous perfusion
- Greater body surface-to-weight ratio
3. IM drugs
- Inefficient muscular contractions
- Reduced skeletal muscle blood flow
- Higher density of skeletal muscle capillaries
4. PR drugs
- Greater number of higher-amplitude pulsatile contractions in the rectum decrease absorption of solid forms of drugs
Which pediatric age group struggles most with distribution and why?
Neonates and infants
- Extracellular fluid per kg body weight for neonates is double that of adults (total body water 125% that of adults)
(for drugs that only circulate in plasma, drug diluted to half concentration compared to adult)
- Serum albumin is lower: 2 - 4.5 g/dL in neonates vs 3.4 - 5.4 g/dL in adults
- Endogenous substances, i.e. bilirubin, can compete with drugs for binding to albumin (drug can kick out bilirubin to cause increased level bilirubin)
- Neonates have lower body fat percentage and immature BBB (only 10-15%, infants 20-25%)
How is hepatic clearance different in pediatrics?
Phase I enzymes
- Cytochrome P450 isoenzymes & other phase I enzymes, such as alcohol dehydrogenase, don’t fully develop until childhood
- Most of development is achieved in 1st year
- Individual CP450 isoenzymes develop at varying rates
Phase II enzymes
- The activities of many phase 2 enzymes take 1 - several years to develop fully
How is renal clearance different in pediatrics?
- Creatinine clearance - when normalized to BSA quite low and variable in neonates (2-40) and climbs to adult values within 1-2 years
- Development in tubular secretion follows the same timeline
- Major determinant of age-appropriate dosing for compounds with extensive renal elimination
What is the bottom line regarding dosing in pediatrics?
Dosing appears idiosyncratic relative to an adult
- Fate of any single drug can vary at multiple pharmacokinetic levels
- Sometimes pharmacokinetic events pull together in one direction, sometimes they counterbalance
Dosing info widely available for large number of drugs, i.e. Lexicomp Peds & Neo handbook
- Caution for neonates r/t variability
- Caution for drugs with narrow therapeutic indices/eliminated by renal excretion - subject oto variability
What are some conditions prevalent in pregnancy?
- N/V
- Constipation
- Reflux esophagitis
- Nasal congestion & rhinitis
- UTIs
- HTN
- DM
- Thromboembolism
What are some factors affecting absorption in pregnancy?
- Decreases in gastric acidity
- Decreases in gastric and intestinal motility
- N/V
- Changes in absorption often portrayed as variable, but changes in Cmax (decreases) and bioavailability are well worth watching*
What are some factors affecting distribution in pregnancy?
- Plasma volume increases up to 50%
- TBW expands by about 20%
- Plasma albumin concentrations decrease (relative to volume increases)
- Usually don’t have to worry about dosing except in drugs that work solely in blood plasma or those bound to plasma albumin whose therapeutic ranges are small*
What are some factors affecting metabolism in pregnancy?
- CYP2D6 and CYP3A4 increased to some extent
- CYP1A2 and certain phase II enzymes are decreased
- Extent to which changes in metabolic enzymes impact dosing will differ depending on drug*
What are some factors affecting excretion in pregnancy?
Renal blood flow, hence GFR, increases by 50% by beginning of second trimester
Drugs eliminated renally will need dose adjustment
What are some age-related changes that impact pharmacokinetics?
- Decrease % body water
- Decrease % lean body weight
- Increase % body fat (double)
- Decrease serum albumin
- Decrease hepatic blood flow (half)
- Decrease renal blood flow (half)
What are some age-related changes that impact pharmacodynamics related to the cardiovascular system?
- Susceptible to orthostatic hypotension 2/2 decrease in arterial compliance and baroreceptor reflex response (underscores inefficient homeostatic adjustments)
- Decreased B-adrenergic receptor function
- Increased hypotensive response to CCBs
- Increased risk developing drug-induced QT prolongation and torsade de pointes
Which special population is subject to changes in both pharmacokinetics AND pharmacodynamics?
The elderly
What are some age-related changes that impact pharmacodynamics related to the CNS?
- MUCH greater sensitivity to drugs that gain access to CNS (narcotics, anesthetics)
- BBB more permeable
- Decreased ability to compensate for imbalances in cholinergic signaling
What are some criteria used for assessment of inappropriate prescribing to elderly?
- Beers criteria
- Drugs that should be avoided in elderly in general due to ineffectiveness/unnecessarily high risk (antihistamines => anticholinergic activity)
- Drugs that should be avoided in elderly know to have specific medical conditions (NSAIDS in HF => magnify fluid retention)
- Drugs that should be used in elderly with caution - Assessing Care of Vulnerable Elders
- Quality indicators for appropriate medication
- Indicators specify 8 drug therapies to be avoided
How is absorption affected in renal failure?
Almost always caused by uremia
- N/V/D & gastritis
- Diminished gastric & intestinal motility
- Increased gastric pH
Occasionally, absorption apparently increased in renal failure, but unclear how
How is distribution affected in renal failure?
Decrease in binding of drugs to albumin
- Decrease in concentration of albumin (loss of glomerular integrity => dumping albumin into urine)
- Displacement by uremic toxins
Increase in unbound drug => important for drugs with narrow therapeutic windows
How is elimination affected in renal failure?
- Involves decrease in GFR & secretion (transport) - dramatic impact on drugs that don’t undergo substantive metabolism
- Dramatic impact on elimination of the vast majority of drug metabolites - watch active (or toxic) metabolites
- Change in dosing regimen can be ‘general’ in nature
~GFR >50 = 100%
~GFR 10-50 = 75%
~GFR <10 = 20-50%
Describe the effects of hepatic disease on pharmacokinetic actions of drugs
(Alcoholic liver cirrhosis, chronic infections of Hep A/B/C)
- Drug accumulation (drugs normally broken down by CYPs accumulate)
- Failure to form an active metabolite (from prodrug)
- Increased bioavailability (liver producing less albumin, less bound & more circulating)
- Decreases in plasma albumin
- Impaired renal function (hepatorenal syndrome - the 2 often go together)
When is dose adjustment required in hepatic disease, and when is it not?
Not required if:
- Drug is eliminated entirely through excretion through mechanisms apart from liver
- Drug metabolized by liver only to a small extent (<20%)
- Watch for impaired renal function!
Otherwise, dose adjustment is required, but largely empirical. Factors underlying need for adjustment include:
- Extraction ratio
- Extent to which drug binds albumin
- Disease progression-dependent decreases in select metabolic enzymes
