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Pharm Exam 1 > Population-Specific Pharmacotherapy > Flashcards

Population-Specific Pharmacotherapy Flashcards

1
Q

Describe how the placenta acts a a ‘barrier’ to drug distribution

A

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
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2
Q

Discuss passage of drugs across the placenta in relation to permeability

A
  1. Lipid permeability is proportional to lipid solubility
  2. Lipid permeability is inversely proportional to molecular size:
    <500 Da cross readily
    500-1000 Da cross with difficulty
    >1000 Da cross very poorly
  3. 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)
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3
Q

What role do transporters play in passage of drugs across the placenta?

A
  • 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)
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4
Q

What role does placental metabolism play in passage of drugs across the placenta?

A
  1. 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
  2. Drugs that can cross the syncytial layer are subject to a small amount of metabolic machinery before entering fetal circulation
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5
Q

What is the bottom line in regards to passage of drugs across the placenta?

A

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
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6
Q

What are the different ways that drugs can affect the fetus?

A
  • 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
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7
Q

How many drug classes are considered teratogenic? In what period of development do most teratogens affect development?

A
  • 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)
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8
Q

What are some examples of teratogenic medications?

A
  • ACE/ARB
  • Anticonvulsants
  • Systemic corticosteroids
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9
Q

What are the different teratogenic risk categories and what do they mean?

A

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)

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10
Q

What are the old and new labels of prescription drug labeling in specific populations?

A

OLD

  1. 1 Pregnancy
  2. 2 Labor and Delivery
  3. 3 Nursing Mothers

NEW

  1. 1 Pregnancy (includes Labor and Delivery)
  2. 2 Lactation (including Nursing Mothers)
  3. 3 Females and Males of Reproductive Potential
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11
Q

Describe how drugs partition during lactation

A
  • Maternal plasma is 7.4 and milk is 7.1 => ion trapping of bases
  • Also relates to lipophilicity and size of drugs
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12
Q

How do practitioners choose appropriate medications for nursing mothers?

A

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
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13
Q

What are the age ranges for neonates, infants, children, and adolescents?

A
  • Neonate: = 28 days
  • Infant: 29 days - 12 months
  • Child: 1 - 12 years
  • Adolescent: 13 - 17 years
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14
Q

What is the mechanism of chloramphenicol causing “gray baby syndrome,” and what are the signs?

A

Mechanism: Immature UDP-glucoronosyltransferases resulting in accumulation of toxic metabolites

Signs:

  • Cyanosis
  • Ash gray color of skin
  • Limp body tone
  • Hypotension
  • Death
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15
Q

What is the mechanism of benzyl alcohol causing “gasping syndrome,” and what are the signs?

A

Mechanism: Immature ability to conjugate benzoic acid with glycine, resulting in accumulation of benzoic acid

Signs:

  • Gasping
  • Severe metabolic acidosis
  • Hypotension
  • Death
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16
Q

With which step of metabolism do infants struggle?

A

Drugs that require phase II reactions because these mechanisms are immature for the first year

17
Q

Which pediatric age group struggles most with absorption and why?

A

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

18
Q

Which pediatric age group struggles most with distribution and why?

A

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%)

19
Q

How is hepatic clearance different in pediatrics?

A

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

20
Q

How is renal clearance different in pediatrics?

A
  • 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
21
Q

What is the bottom line regarding dosing in pediatrics?

A

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
22
Q

What are some conditions prevalent in pregnancy?

A
  • N/V
  • Constipation
  • Reflux esophagitis
  • Nasal congestion & rhinitis
  • UTIs
  • HTN
  • DM
  • Thromboembolism
23
Q

What are some factors affecting absorption in pregnancy?

A
  • 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*
24
Q

What are some factors affecting distribution in pregnancy?

A
  • 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*
25
Q

What are some factors affecting metabolism in pregnancy?

A
  • 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*
26
Q

What are some factors affecting excretion in pregnancy?

A

Renal blood flow, hence GFR, increases by 50% by beginning of second trimester
Drugs eliminated renally will need dose adjustment

27
Q

What are some age-related changes that impact pharmacokinetics?

A
  • Decrease % body water
  • Decrease % lean body weight
  • Increase % body fat (double)
  • Decrease serum albumin
  • Decrease hepatic blood flow (half)
  • Decrease renal blood flow (half)
28
Q

What are some age-related changes that impact pharmacodynamics related to the cardiovascular system?

A
  • 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
29
Q

Which special population is subject to changes in both pharmacokinetics AND pharmacodynamics?

A

The elderly

30
Q

What are some age-related changes that impact pharmacodynamics related to the CNS?

A
  • MUCH greater sensitivity to drugs that gain access to CNS (narcotics, anesthetics)
  • BBB more permeable
  • Decreased ability to compensate for imbalances in cholinergic signaling
31
Q

What are some criteria used for assessment of inappropriate prescribing to elderly?

A
  1. 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
  2. Assessing Care of Vulnerable Elders
    - Quality indicators for appropriate medication
    - Indicators specify 8 drug therapies to be avoided
32
Q

How is absorption affected in renal failure?

A

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

33
Q

How is distribution affected in renal failure?

A

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

34
Q

How is elimination affected in renal failure?

A
  • 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%
35
Q

Describe the effects of hepatic disease on pharmacokinetic actions of drugs

A

(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)
36
Q

When is dose adjustment required in hepatic disease, and when is it not?

A

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

Pharm Exam 1 (4 decks)

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