List some special populations
- Infants and children
- Elderly people
- Pregnant & breastfeeding women
- Obese/underfed
- Patients with clinical issues:
- Liver failure
- Kidney failure and dialysis
- Extracorporate membrane oxygenation (ECMO)
- Therapeutic cooling
Why are these populations special?
- Different PK/PD
- Use different drugs
- High potential of damaging self or other (pregnant/breastfeeding)
Why teach us about special populations?
- Higher risks of adverse drug events
- Higher risk of ineffective therapy
- More complicated prescribing and dispensing
Describe the paradox of modern drug development
1) Clinical trials provide evidence of efficacy and safety at usual doses in NORMAL populations
2) Physicians treat individual patients who can vary widely in their response to drug therapy (no response, efficacious and safe, adverse drug reaction)
Drug prescriptions in pediatrics are often drugs used ____-______
off-label
Why is pediatric prescribing much more complicated than prescribing for adults?
- the specific and general aspects of paediatric patients (size, immaturity)
- the limitations of commercially available dosage formulations
- the challenges of administering drugs
- the dearth of information about drug use in children
- the general inadequacy of clinical pharmacology training
For the reasons we just discussed about pediatric prescribing being more complicated than adult, how should practitioners handle pediatric prescribing?
- prescribe judiciously
- select carefully the safest dosage regimen available
- educate their patients, caregivers and staff about their choices and expected positive and negative effects
- have available and use written, electronic, as well as human sources of expert advice
- document their therapeutic decisions and plans
- carefully monitor their patients’ responses to therapy
Prescriptions may be off-label when given for a different: ??
- age group
- dosage
- indication
- dosage form
- route of administration
___% of drugs prescribed in paediatrics are off-label
30-80
List some novel drug devices for drug administration to children
- Modified teat/pacifier with drug-loaded reservoir
- Dosing spoon filled with liquid medicine
- Coated particles on dosage spoon (pulp-spoon)
- Dropper tube
- Dose-sipping technology (straw with medicine and beverage)
- Solid dosing pen
List the divisions of childhood
- Infancy
- Toddler
- Pre-School
- School age
- Adolescent
- Early
- Middle
- Late
____ ______ may increase with weight, height, age, BSA and CLcr (creatinine clearance)
drug clearance
Ontogeny
the branch of biology that deals with the development of an individual organism or anatomical or behavioral feature from the earliest stage to maturity
What is involved in pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
Gastric pH is ____ in infants
lower
Infants have an _____ absorption of drugs degraded by acid (ex. penicillin)
increased
Biliary function is _____ in infants
reduced
Infants have a _______ absorption of some drugs such as Pleconaril
decreased
Infants have _____ gastric emptying which will cause an increased half-life of some drugs (ex. cisapride)
decreased
Infants have altered GI tract absorption of some drugs: ______ very poorly absorbed by infants
Phenytoin
Infants have ____ GI motility which can cause potentially greater absorption (ex. ahminoglycosides)
lower
Infants have a marked _______ in gut wall activity of Phase 1 and Phase 2 enzymes
reduction
Infants have ___ transporter function which can lead to reduced absorption
reduced
What factors influence extra oral drug absorption?
- barrier thickness
- regional blood flow
- diffusional surface area
- hydration
Distribution of drug through VoD effected by ??
- Water-fat ratio
- Plasma protein binding
- Acid-base balance
- Regional blood flow
- Cardiac output
Do infants have more or less water than adults?
Infants have much more water (80%) than adults (60%)
Infants therefore have an ______ VD for water-soluble agents
increased
The BBB of infants is ___ functional
less
*this allows possibility for drug molecules that normally cannot access the brain to cross the BBB
Plasma protein binding is ____ efficient in infants
less
*this causes an increased clearance of highly bound drugs
Metabolic routes ____ at different rates
mature
____% of mothers initiate breastfeeding
80
___% of mothers take drugs
80
What is the MP ratio?
Milk-to-plasma ratio
pH of milk?
7.0
pH of maternal plasma?
7.4
Most drugs are safe if:
??
- They are commonly prescribed for infants
- They are considered safe in pregnancy
- They are not absorbed from the stomach or intestines
- They are not excreted into the milk
List some challenges of geriatric pharmacotherapy
- New drugs available each year
- HC approved and off-label indications are expanding
- Changing managed-care formularies
- Advanced understanding of drug-drug interactions
- Increasing popularity of nutraceuticals
- Multiple co-morbid states
- Poly pharmacy
- Medication compliance
- Effects of aging physiology of drug therapy
- Medication cost
Elderly:
Rate of absorption may be ___
delayed
- lower peak concentration
- delayed time to peak concentration
Elderly:
Overall amount absorbed (bioavailability) is _____
unchanged
Elderly:
For drugs with extensive first-pass metabolism, bioavailability may _____ because less drug is extracted by the liver:
-Decreased liver mass
-Decreased liver blood flow
increase
List some factors that affect absorption
- Route of administration
- What is taken with the drug
- Divalent cations (Ca, Mg, Fe)
- Food, enteral feedings
- Drugs that influence gastric pH
- Drugs that promote or delay GI motility
- Comorbid conditions
- Increased GI pH
- Decreased gastric emptying
- Dysphagia
Elderly:
Have decreased body water which means decreased Vd for ______ drugs
hydrophilic
Elderly:
Have decreased lead body mass so they have decreased Vd for drugs that bind to ____
muscle
Elderly:
Increased fat stores which means _____ Vd for lipophilic drugs
increased
Elderly:
Have _____ plasma protein (albumin) which means there is an increased percentage of unbound or free drug (active)
decreased
Elderly:
Metabolic clearance of drugs by the liver may be reduced due to
- decreased hepatic blood flow
- decreased liver size and mass
Examples:
- morphine
- meperidine
- metoprolol
- propranolol
- verapamil
- amitryptyline
- nortriptyline
Phase 1 metabolism pathways
oxidation
hydroxylation
dealkylation
reduction
Phase 2 metabolism pathways
glucuronidation
conjugation
acetylation
Effect of phase 1 metabolic pathways
conversion to metabolites of lesser, equal or greater
Effect of phase 2 metabolic pathways
conversion to inactive metabolites
Medications undergoing Phase ___ hepatic metabolism are generally preferred in the elderly due to inactive metabolites (no accumulation)
2
Other factors affecting drug metabolism?
Gender Comorbid conditions Smoking Diet Drug interactions Race Frailty
List some effects of aging on the kidney
-decreased kidney size
-decreased renal blood flow
-decreased number of functional nephrons
-decreased tubular secretion
Results in: decreased glomerular filtrate rate (GFR)
Elderly:
Aged kidneys results in decreased drug clearance of which drugs?
- atenolol
- gabapentin
- H2 blockers
- digoxin
- allopurinol
- quinolones
Elderly:
_____ ______ is used to estimate glomerular rate
creatinine clearance (CrCl)
Elderly:
Serum creatinine alone not accurate in the elderly due to ???
- lower lean body mass
- lower creatinine production
- lower glomerular filtration rate
Elderly:
Serum creatinine stays in _____ range, masking change in creatinine clearance
normal
Measuring Creatinine clearance is ??
- time consuming
- requires 24 hr urine collect
How do we estimate Creatinine clearance?
Cockroft Gault Equation:
(IBW in kg) x (140-age) / 72 x (Scr in mg/dL)
x 0.85 for females
Pharmacodynamics
the time course and intensity of pharmacologic effect of a drug
Age-related changes in pharmacodynamics:
Increased sensitivity to sedation and psychomotor impairment with ________
benzodiazepines
Age-related changes in pharmacodynamics:
Increased level and duration of pain relief with _____ _____
narcotic agents
Age-related changes in pharmacodynamics:
Increased drowsiness and lateral sway with _____
alcohol
Age-related changes in pharmacodynamics:
Decreased HR response to ____ ______
beta blockers
Age-related changes in pharmacodynamics:
Increased sensitivity to _______ _____
anticholinergic agents
Age-related changes in pharmacodynamics:
Increased cardiac sensitivity to _______
digoxin
PK and PD changes generally result in ______ clearance and ______ sensitive to medications in older adults
decreased clearance
increased sensitivity
Elderly:
How do we decrease the risk of drug intolerance and toxicity?
use of lower doses, longer intervals, slower titration
careful monitoring is necessary to ensure successful outcomes
What are some consequences of overprescribing?
- Adverse drug events
- Drug interactions
- Duplication of drug therapy
- Decreased quality of life
- Unnecessary cost
- Medication non-adherence
List some most common medications associated with ADEs in the elderly
- opioid analgesics
- NSAIDs
- anticholinergics
- benzodiazepines
- CV agents
- CNS agents
- musculoskeletal agents
Patient risk factors for ADEs
- polypharmacy
- multiple co-morbid conditions
- prior adverse drug event
- low body weight or body mass index
- age >85
- estimated CrCl < 50 mL/min
Most common DDIs?
- CV drugs
- psychotropic drugs
Most common drug interaction effects?
- confusion
- cognitive impairment
- hypotension
- acute renal failure
Concepts in Drug-Drug Interactions?
- Absorption may be increased or decreased
- Drugs with similar effects can result additive effects
- Drugs with opposite effects can antagonize each other
- Drug metabolism may be inhibited or induced
_____ alters Vd of lipophilic drugs
obesity
______ alters Vd of hydrophilic drugs
ascites
____ may increase sensitivity, induce paradoxical reactions to drugs with CNS or anticholinergic activity
dementia
____ or _____ impairment may impair metabolism and excretions of drugs
renal or hepatic
drugs may exacerbate a _____ ______
medical condition
Principles of prescribing in the elderly
- avoid prescribing prior to diagnosis
- start with a low dose and titrate slowsly
- avoid starting 2 agents at the same time
- reach therapeutic dose before switching or adding agents
- consider non-pharmacologic agents
Elderly:
Factors in non-adherence?
Financial, cognitive or functional status
Beliefs and understanding about disease and medications