1. A 43-year-old man with a long history of chronic renal
insufficiency comes to the ED with a 5-day history of
productive cough and shortness of breath. Physical exam
reveals rales in the middle lobe of his right lung. X-ray of
the chest shows consolidation in the same area. He begins
therapy with levofloxacin.
Which of the following indicates how the dosing of
levofloxacin would differ in this patient compared with a
patient with no underlying health problems?
A.
B.
C.
D.
E.
F.
G.
Higher LD, higher MD
Higher LD, same MD
Lower LD, lower MD
Lower LD, same MD
Same LD, higher MD
Same LD, lower MD
Same LD, same MD
1. A 43-year-old man with a long history of chronic renal
insufficiency comes to the ED with a 5-day history of
productive cough and shortness of breath. Physical exam
reveals rales in the middle lobe of his right lung. X-ray of
the chest shows consolidation in the same area. He begins
therapy with levofloxacin.
Which of the following indicates how the dosing of
levofloxacin would differ in this patient compared with a
patient with no underlying health problems?
A.
B.
C.
D.
E.
F.
G.
Higher LD, higher MD
Higher LD, same MD
Lower LD, lower MD
Lower LD, same MD
Same LD, higher MD
Same LD, lower MD
Same LD, same MD
2. A 43-year-old man with a long history of chronic renal
insufficiency comes to the ED with a 5-day history of
productive cough and shortness of breath. Physical exam
reveals rales in the middle lobe of his right lung. X-ray of
the chest shows consolidation in the same area. He begins
therapy with azithromycin, a macrolide antibiotic.
Which of the following indicates how the dosing of
azithromycin would differ in this patient compared with a
patient with no underlying health problems?
A.
B.
C.
D.
E.
F.
G.
Higher LD, higher MD
Higher LD, same MD
Lower LD, lower MD
Lower LD, same MD
Same LD, higher MD
Same LD, lower MD
Same LD, same MD
2. A 43-year-old man with a long history of chronic renal
insufficiency comes to the ED with a 5-day history of
productive cough and shortness of breath. Physical exam
reveals rales in the middle lobe of his right lung. X-ray of
the chest shows consolidation in the same area. He begins
therapy with azithromycin, a macrolide antibiotic.
Which of the following indicates how the dosing of
azithromycin would differ in this patient compared with a
patient with no underlying health problems?
A.
B.
C.
D.
E.
F.
G.
Higher LD, higher MD
Higher LD, same MD
Lower LD, lower MD
Lower LD, same MD
Same LD, higher MD
Same LD, lower MD
Same LD, same MD
Age Range Definitions
Premature: born before 37 weeks gestational age
Neonatal: 1 day-1 month
Infants: 1 month-1 year
Pediatric - children 1-11 years
Adolescent: 12-16 years
Adult
Geriatric: > 65 years
MD / tau [mg/hr] = Cpss (avg) [mg/L] x CL [L/hr]
Pharmacokinetic Disposition of Drugs
Physiological factors relevant to hepatic metabolism and
renal excretion change substantially with development
and aging
Drug clearance [CL] will change substantially
Dosage regimens [MD (maintenance dose) and tau
(dosage interval)] must be adjusted to avoid underdosage
or overdosage
MD / tau [mg/hr] = Cpss (avg) [mg/L] x CL [L/hr]
Pharmacodynamic Actions of Drugs
Receptor interactions are NOT substantially different across
age groups: pediatric - adult - geriatric
Target plasma levels [Cpss (avg)] are generally equivalent
Dosage adjustments are based on age-related differences in
size (mg/kg)
BUT - some important exceptions exist [see Robbins lecture 3-2]
Pediatric Pharmacology
SUMMARY - Pharmacokinetic Considerations
Absorption
By 1 year of age, adult-child differences NOT substantial
Volume of Distribution
Body proportions and fat distribution change with age, but
effect on Vd for most drugs is relatively minor
Loading doses of drugs change little for children
Cp [mg/L] = DOSE [mg]
Vd [L]
Pharmacokinetic Considerations
Hepatic Metabolism
Matures as function of postnatal age - highly variable in
neonates
• Dosage for drugs metabolized by liver may need
individual adjustment
• Example: inefficient chloramphenicol glucuronidation
leads to accumulation  shock (Grey Baby syndrome)
Multiple hepatic detoxification systems (CYP450) exist, each
with variable patterns of maturation
REVIEW
Pharmacokinetics - Metabolism
Liver is primary organ of drug metabolism
Oxidation (CYP450 enzymes) most common pathway
Lipid-soluble compounds are generally converted to more
water-soluble (more polar) compounds that are more
readily excreted
Source of
Drug-drug interactions
REVIEW
Contribution of CYP450s to Drug Metabolism
1A2
3%
2C
18%
2A6
1%
3A
52%
2D6
25%
2E
1%
Pharmacokinetic Considerations
Hepatic Metabolism
Phase I Pathways
CYP1A2  reach adult levels by 4-5 months
Substrates: Caffeine, theophylline
CYP2C9  > adult levels at teens (< 30% at birth)
Substrates: NSAIDs, warfarin
CYP2D6  adult levels by 10 years (no activity at birth)
Substrates: Antidepressants, opioid analgesics
CYP3A4  > adult levels by 1 year (30-75% at birth)
Substrates: Cisapride, “statins”, calcium channel blockers
REVIEW
Pharmacokinetic Considerations
Clinically Relevant Inducers and Inhibitors
Inducers
Inhibitors
Phenobarbital [1A2, 2C9, 2C19, 3A4]
Cimetidine [2D6, 3A4, 1A2]
Phenytoin [2C9, 2C19, 3A4]
Erythromycin / Clarithromycin [3A4]
Carbamazepine [2C9, 2C19, 3A4]
Azole antifungals [3A4]
Rifampin [1A2, 2C9, 2C18, 3A4]
Fluoxetine (other SSRIs) [2D6,3A4]
Ethanol [2E1]
Grapefruit juice [3A4]
St. John’s Wort [3A4]
HIV protease inhibitors [3A4]
Tobacco smoke (not nicotine) [1A2]
Omeprazole [2C19]
Available without prescription
Pharmacokinetic Considerations
Hepatic Metabolism
Phase II Pathways
Sulfate and Glycine conjugation 
adult levels at birth
Acetylation

adult levels by 2 yrs
Glucuronide conjugation*

0-25% at birth
adult levels by 2-3 y/o
*Grey baby syndrome
with chloramphenicol
Pharmacokinetic Considerations
Renal Excretion
Renal clearance matures as a function of postgestational age
Clearance of renally excreted drugs is more predictable
outside the neonatal period
Timeline of Hepatic and Renal Function Maturation
Acetylation and
Glucuronidation
Glycine Conjugation
Phase I (CYP450)
Sulfation
0
10
20
Age in: Days
30
2
3
4
5
Months
6
1
2
3
Years
Tubular Sec
Renal Blood Flow
GFR
SUMMARY - Pharmacokinetic Considerations
Drug Clearance
Hepatically eliminated drugs have clearances that vary
more widely in children than in adults
Multiple enzyme systems – variable rates of maturation
Poor at birth, then rates of development are variable and
unpredictable
The need to monitor drug levels is greatest for hepatically
eliminated drugs
Renal clearance of drugs is more predictable in children
Renally excreted drugs can be cleared more rapidly in
children
SUMMARY - Pharmacokinetic Considerations
Drug Clearance
Maintenance doses may change dramatically with age
Drugs are cleared more rapidly in children (in general),
whether eliminated via renal or hepatic processes
Maintenance doses (calculated on a mg/kg/day basis)
can be higher than encountered in adults
Acetaminophen analgesic dose = 10-15 mg/kg
Ibuprofen antipyretic dose = 5-10 mg/kg
SUMMARY - Pharmacokinetic Considerations
Drug Dosing
Therapeutic levels of drugs (Cp) in children same as adults
Dosage regimens reflect size and age-related changes in Vd
(L/kg) and CL (ml/min/kg)
Drug doses commonly per unit weight (most often mg / kg)
If greater accuracy required (cancer chemotherapy), dosing
can be based on body surface areas:
 mg / m2 (considers weight and height)
3. Select the true statement regarding pharmacotherapy in
children:
A. Most drugs will be effective at a lower Cp in children
than adults
B. CYP450 isozymes show similar developmental patterns
and reach adult levels by age 3-4 years of age
C. Hepatically eliminated drugs show little variation in
clearances in children compared to the variations seen
in adults
D. Renal clearance of drugs is more predictable in children
than hepatic clearance
E. Cancer chemotherapeutic agents are more safely dosed
in children on a mg/kg basis
3. Select the true statement regarding pharmacotherapy in
children:
A. Most drugs will be effective at a lower Cp in children
than adults
B. CYP450 isozymes show similar developmental patterns
and reach adult levels by age 3-4 years of age
C. Hepatically eliminated drugs show little variation in
clearances in children compared to the variations seen
in adults
D. Renal clearance of drugs is more predictable in children
than hepatic clearance
E. Cancer chemotherapeutic agents are more safely dosed
in children on a mg/kg basis
4. All of the following medications can have adverse
reactions specific to the pediatric population EXCEPT:
A.
B.
C.
D.
E.
F.
G.
H.
CNS stimulants
Prednisone
Fluticasone
Ciprofloxacin (fluoroquinolone)
Acetaminophen
Aspirin
Doxycycline
Azithromycin
4. All of the following medications can have adverse
reactions specific to the pediatric population EXCEPT:
A.
B.
C.
D.
E.
F.
G.
H.
CNS stimulants
Prednisone
Fluticasone
Ciprofloxacin (fluoroquinolone)
Acetaminophen
Aspirin
Doxycycline
Azithromycin
Pharmacodynamic Considerations
Drug Reactions Specific to Children
Growth is an important pharmacological endpoint in children
and can be affected by drugs.
Most psychoactive agents can have modest effects on
growth, esp. CNS stimulants
Anti-inflammatory corticosteroids (including topical
agents) are potent inhibitors of growth
Intellectual development can be impaired by barbiturates
Pharmacodynamic Considerations
Drug Reactions Specific to Children
Tetracyclines are incorporated into growing bone and
teeth and are contraindicated in children and in pregnancy
Aspirin (salicylates) not recommended for use in children
prior to puberty because of risk for hepatic dysfunction
• Increased incidence of Reyes syndrome
 Fatty liver with acute encephalopathy
 Salicylate interaction with chicken pox and influenza
Geriatric Pharmacology
Medications and the Elderly (≥ 65 yrs)
13% of population
30% of all Rx drugs
40% drug-related hosp.
50% of OTCs
50% of drug-related deaths
Medication Review
[from Wallace 3-2-16]
• Major cause of illness, hospitalization, mortality
• High risk for Adverse Drug Reactions (ADR)
 Polypharmacy
 Comorbid conditions
 Impaired renal function not evident in serum Cr
• Compliance/adherence is often problematic
• Includes OTC, herbals, and alcohol use
Sample Recommendations (2)
[from Wallace 3-2-16]
• Medication adjustments

New medication

Dose change

Discontinue medication

Switch medication

Monitor medication

Pharmacist referral
Drug Interactions
100
% Probability
of Interaction
90%
Age
Half of patients > 75
are on > 5 medications
75
50%
50
25
Predictors of Drug
Interactions
Severity of Disease
18%
Chronic Disease
0
2
4
8
Number of Medications
Summary of Age-Related Pharmacokinetic Changes
Absorption
 gastric pH
 absorptive surface
 splanchnic blood blow
 GI motility
 gastric emptying rate
Distribution
 cardiac output
 TBW & LBW  Δ Vd
 hepatic/ renal blood flow  relative tissue perfusion
 body fat  Δ Vd
 albumin
Metabolism
 liver mass
 hepatic blood flow
 enzyme activity Δ CL
Excretion
 renal blood flow
 GFR (CrCl)  Δ CL
 tubular secretion
 renal mass
Pharmacokinetics - Absorption
Possible Age-Related Physiological Changes
Decrease in gastric acid production (increased pH) for:
Decrease in absorption of weak acid drugs (e.g.,
warfarin, penicillin)
Increase in absorption of weak base drugs (e.g., TCADs,
benzodiazepines, opioid analgesics, anticonvulsants)
Inappropriate (early) release of enteric-coated drugs
(e.g., aspirin)
Decreased gastric emptying and GI motility
Pharmacokinetics - Absorption
Possible Effects of Disease
Congestive heart failure: slowed or reduced absorption
Gastroparesis:  gastric emptying and GI motility
Pharmacokinetics - Absorption
Drug Effects
Decrease gastric emptying and GI motility
• Drugs with anticholinergic actions - diphenhydramine,
TCADs
Increase gastric emptying and GI motility
• Metoclopramide, cisapride, stimulant laxatives
Decrease absorption
• Physiochemical interactions in gut with concomitant
administration of drugs (cholestyramine binding warfarin)
Pharmacokinetics - Absorption
SUMMARY
Rate of absorption (time to peak Cp) may be changed slightly
with aging
Extent of absorption (bioavailability) usually unchanged for
most medications with aging
Changes in absorption
rarely of clinical significance
Pharmacokinetics – Distribution
Cp [mg/L] = DOSE [mg]
Vd [L]
[t1/2  Vd / CL]
Body composition changes with aging
• Relative decrease in TBW and lean body mass
• Relative increase in adipose tissue
Changes in Vd for a given drug can occur as a result of
these changes and necessitate dosage changes
Pharmacokinetics – Distribution
Cp [mg/L] = DOSE [mg]
Vd [L]
[t1/2  Vd / CL]
Decrease in Vd for relatively water soluble drugs  higher
plasma concentrations (Cp) with normal adult doses
• Digoxin
• Aminoglycoside antibiotics
• Lithium
NOTE: May require lower Loading Dose
Pharmacokinetics – Distribution
Cp [mg/L] = DOSE [mg] [t1/2  Vd]
Vd [L]
[t1/2  1 /CL]
Increase in Vd for relatively lipid soluble drugs  slower
elimination - increased t1/2 and drug accumulation possible
• Chlordiazepoxide
• Diazepam
NOTE: May require higher Loading Dose
NOTE: May require lower Maintenance Dose ( Vd   t1/2)
• BUT changes in clearance are more likely to influence t1/2
and necessitate changes in MD ( CL   t1/2)
Pharmacokinetic Disposition of Drugs
MD / tau [mg/hr] = Cpss (avg) [mg/L] x CL [L/hr]
Physiological factors relevant to hepatic metabolism
and renal excretion change substantially with aging
Drug clearance [CL] will change substantially and will
almost always decrease
Dosage regimens [MD and tau (dosage interval)] must
be adjusted to avoid underdosage or overdosage
REVIEW
Pharmacokinetics - Metabolism
Liver is primary organ of drug metabolism
Oxidation (CYP450 enzymes) most common pathway
Lipid-soluble compounds are generally converted to more
water-soluble (more polar) compounds that are more
readily excreted
Source of
Drug-drug interactions
5. Which of the following metabolic transformations would
you most expect to occur at a slower rate in the elderly
patient?
A.
B.
C.
D.
E.
F.
N-demethylation of diazepam by CYP3A4
Acetylation of isoniazid by N-acetyltransferase
Aliphatic hydroxylation of flurazepam by CYP2C19
Sulfation of acetaminophen by sulfotransferase
O-demethylation of tramadol by CYP2D6
Glucuronidation of oxazepam by glucuronyl transferase
5. Which of the following metabolic transformations would
you most expect to occur at a slower rate in the elderly
patient?
A.
B.
C.
D.
E.
F.
N-demethylation of diazepam by CYP3A4
Acetylation of isoniazid by N-acetyltransferase
Aliphatic hydroxylation of flurazepam by CYP2C19
Sulfation of acetaminophen by sulfotransferase
O-demethylation of tramadol by CYP2D6
Glucuronidation of oxazepam by glucuronyl transferase
Pharmacokinetics - Metabolism
Decrease in hepatic mass and blood flow - 1% per year
after age 40
Can decrease first pass metabolism of drugs with high
extraction ratio (i.e., blood flow dependent)
• Nitrates, propranolol, lidocaine, phenobarbital, nifedipine
Phase I reactions (oxidation, reduction, hydrolysis)
decrease with age in 30-35% of elderly patients
• Chlordiazepoxide, diazepam
Phase II reactions (conjugation, glucuronidation) are
minimally affected by aging
• Lorazepam, oxazepam, temazepam
Increasing Plasma Half-life for Diazepam with Age
Pharmacokinetics - Metabolism
SUMMARY
No adequate marker exists to determine hepatic drug
metabolizing capacity in an individual patient
Titration of doses to achieve desired response is important
If choice exists among agents in a therapeutic class:
Drugs undergoing phase II metabolism will be more reliably
eliminated in the elderly
Lorazepam / oxazepam are preferred over diazepam /
chlordiazepoxide in elderly patients
Selected Physiologic Changes Associated
with “Normal” Aging
[from Wallace 3-2-16]
Renal Volume Regulation
•  GFR (variable but averages 10ml  / decade)
•  ADH/renal response to hypovolemia
•  sodium excretion response to hypervolemia
•  renal excretion of drugs
•  ability to compensate for volume depletion and
volume overload states
Pharmacokinetics – Renal Excretion
RBF
Pharmacokinetics – Renal Excretion
Renal function declines consistently with age (~ 10% /
decade from age 20)  decreased functioning nephrons
• Decreased GFR, renal plasma flow, and tubular secretion
RECALL the age variable in equation for estimation of GFR:
CrCl (ml/min) = (140  age) x (wt. Kg) x 0.85 females
(SCr x 72)
NOTE: GFR may be impaired despite normal SCr values
Pharmacokinetics – Renal Excretion
Drugs eliminated primarily by the kidneys will accumulate
in the presence of renal impairment
SUMMARY
Consider renal dosing (adjustments based on CrCl) in
elderly patients receiving drugs eliminated by the kidney to
prevent toxic accumulations
Relationship between Renal Function (creatinine clearance)
and Digoxin Clearance in Young and Old Subjects
Summary of Age-Related Pharmacokinetic Changes
Absorption
 gastric pH
 absorptive surface
 splanchnic blood blow
 GI motility
 gastric emptying rate
Distribution
 cardiac output
 TBW & LBW  Δ Vd
 hepatic/ renal blood flow  relative tissue perfusion
 body fat  Δ Vd
 albumin
Metabolism
 liver mass
 hepatic blood flow
 enzyme activity Δ CL
Excretion
 renal blood flow
 GFR (CrCl)  Δ CL
 tubular secretion
 renal mass
Age - Related Pharmacodynamic Changes
Changes in response to drug at the level of drug-receptor
interaction
MD / tau [mg/hr] = Cpss (avg) [mg/L] x CL [L/hr]
6. Which of the following statements is TRUE regarding the
pharmacology of diazepam in the adult vs geriatric patient?
A. Diazepam-related motor incoordination and falls are more
likely in the elderly
B. The Vd of diazepam increases in the elderly
C. The bioavailability of diazepam decreases in the elderly
D. Higher LDs may be required in the elderly
E. Higher MDs may be required in the elderly
F. The half-life of diazepam increases in the elderly
G. Time to reach steady state with a given MD will decrease
6. Which of the following statements is TRUE regarding the
pharmacology of diazepam in the adult vs geriatric patient?
A. Diazepam-related motor incoordination and falls are more
likely in the elderly
B. The Vd of diazepam increases in the elderly
C. The bioavailability of diazepam decreases in the elderly
D. Higher LDs may be required in the elderly
E. Higher MDs may be required in the elderly
F. The half-life of diazepam increases in the elderly
G. Time to reach steady state with a given MD will decrease
Drug-Related Problems in Elderly
• Polypharmacy
• Drug Interactions
• Adverse Events
• Non-Adherence
• Inappropriate Medications
• Drug-Induced Disease
*** Stay Tuned for Dr. Robbins Cases ***
Any time left?
The Beer’s Criteria
Expert consensus criteria for safe medication use in elderly
patients (> 65 years old)
Originally published in 1991 – updates 1997-2002-2011
Addresses inappropriate drugs regardless of diagnosisconditions OR drug use in certain diagnosis-condition
48 medications or classes of medications to avoid
• Worst offenders: amitriptyline, diazepam, doxepin
20 diseases or conditions and medications to be avoided in
older adults with these conditions. Examples:
• Hypertension: pseudoephedrine, methylphenidate
• Syncope or falls: benzodiazepines, TCADs
STOPP and START Criteria
Lists used to identify red flags that might require intervention,
not as the final word on medication inappropriateness
STOPP (Screening Tool of Older Person’s potentially
inappropriate Prescriptions)
• Within a therapeutic classification, drugs are designated as
potentially inappropriate, the clinical concern is identified,
and therapeutic alternatives are suggested
START (Screening Tool to Alert doctors to Right Treatment)
• Begin with recommendations for appropriate drug use
• Look for therapeutic duplication
• Optimize monotherapy
• Then add drug from different class
Drug-Induced Functional Impairments
Mobility
Supporting structure (arthralgias, myopathies, osteoporosis)
Worsened by corticosteroids, phenytoin, heparin-warfarin,
decreased vitamin D intake
Movement disorders (extrapyramidal disorders)
Worsened by dopamine receptor blockers 
antipsychotic agents, metoclopramide
Drug-Induced Functional Impairments
Mobility
Balance
Tinnitus, vertigo:
Worsened by aspirin, aminoglycosides, ethacrynic
acid
Hypotension:
Worsened by beta-blockers, calcium channel
blockers, diuretics, vasodilators, antidepressants
Psychomotor retardation:
Worsened by benzodiazepines, antihistamines,
antipsychotic agents, antidepressants
Urinary Bladder and its Innervation - REVIEW
Pharmacology of Urination
GO: Stimulate M – block α1
STOP: Block M or stimulate α1 - β2-3
β2-3
M
α1
M
Drug-Induced Functional Impairments
Incontinence
Overflow (from urinary retention)
Worsened by anticholinergic agents, agents with
anticholinergic side effects (tricyclic antidepressants,
antihistamines, typical antipsychotic agents), smooth
muscle relaxants,  -adrenergic agonists
Treated with: -adrenergic antagonists [tamsulosin
(Flomax®)]
Stress (from urethral sphincter insufficiency unmasked by
coughing sneezing, lifting, sneezing)
Worsened by -adrenergic antagonists (prazosin,
doxazosin)
Urinary Bladder and its Innervation - REVIEW
Pharmacology of Urination
GO: Stimulate M – block α1
STOP: Block M or stimulate α1 - β2-3
β2-3
M
+ Bethanechol
Tamsulosin
α1
M
Drug-Induced Functional Impairments
Incontinence
Urge (from detrusor hyperreflexia with sphincter
dysfunction – Overactive Bladder)
Worsened by cholinergic drugs for dementia (AChEIs),
diuretics
Treated with: antimuscarinic agents [tolterodine]
Secondary from oversedation with sedatives or hypnotics
Urinary Bladder and its Innervation - REVIEW
Pharmacology of Urination
GO: Stimulate M – block α1
STOP: Block M or stimulate α1 - β2-3
Mirabegron
+
β2-3
Tolterodine
M
α1
M
Drug-Induced Functional Impairments
Constipation
Worsened by opioid analgesics, antimuscarinic agents, 1st
gen antihistamines (esp. diphenhydramine), CCBs- verapamil
Mental State
Metabolic alterations with beta-blockers, corticosteroids,
diuretics, sulfonylureas
Cognitive impairment with opioid analgesics, cimetidine,
propranolol, antipsychotic agents, anticonvulsants, BDZs
Behavioral toxicity with anticholinergics, cimetidine, l-dopa,
digoxin, opioid analgesics, β-blockers, corticosteroids