Lilly White Peter Radley

Clinical Pharmacology
PHCY432
Topics Learning outcomes
Applied Pharmacotherapy and • Overview of relevant systems relevant to falls • L3.4
Patient Care • Overview of drug-target interactions in the
system • L3.5
Lecture 20 – Falls • Effects of the drugs on the system/patient • L3.6
(beneficial and harm)
Dan Wright • Variability in dose-response (PK, PD,
• L3.7
variability)

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Assessable tasks Lilly White

• Identify pharmacological pathways that increase the risk of falls
• 82 year old frail woman, 161 cm, 51 kg
• Understand how changes in pharmacokinetics and pharmacodynamic
• Fell 1 year ago and fractured R distal radius
with increased age/ frailty impact the risk of falls
• Hypertension, osteoporosis, osteoarthritis, depression, insomnia, fear
• Describe the influence of homeostatic change on the risk of falls
of falling, sarcopaenia
• Understand how drugs increase the risk from falls.
• Bilateral muscle weakness
• Currently takes 12 medicines (≈15 doses) per day

Falls are multifactorial – brings together material from PHCY220, 310 and 320

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 First some stats…
• 1 in 3 > 65years of age fall each year
• Half of falls result in injury
• 10% are serious
Pharmacological pathways
• Fear of falling develops in ~30% of people who fall & the risk of falls…
• So fear of falling is one of the bigger risk of fall (the ‘falls cycle’)

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Body systems
Symptom example: dizziness …
cerebral
involved in falls risk
vestibular

visual basal ganglia

• “Woozy”, “weak”, “unsteady”, “light headed”, “feeling faint”…etc
cardiovascular
e.g. blurred vision e.g. Parkinson’s
e.g. dizziness, hypotension, etc
cerebellar Origin could be;
neuromuscular • Cardiovascular/respiratory: low blood pressure, hypoxia
Peripheral nervous system
e.g. neuropathy, reduced muscular • Vestibular: vertigo
reflexes e.g. weakness, cramping,
muscle pains • Cerebellum: ataxia
Drugs that impact more than
Or other systems;
one system are particularly • Endocrine: hypoglycaemia
problematic for falls risk

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 Drug example: tricyclic antidepressants (TCAs) Drugs are often
cerebral lumped
vestibular
together in
visual basal ganglia
scoring tools
cardiovascular

cerebellar

neuromuscular
Peripheral nervous system
muscular

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Key messages
• Older people take more drugs (polypharmacy)
• More drugs don’t necessarily mean an increased falls risk
• Not all drugs are the same with regards to falls risk
• Lumping drugs together in scoring tools makes it difficult to identify
and mitigate problems from high-risk drugs

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What we don’t know from this is whether 2 drugs of
this list are more or less than additive in risk.
Falls risk and polypharmacy
• Fall risk is associated with the use of polypharmacy, but only when at
least one established fall risk-increasing drug was part of the daily
regimen

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Absorption
• Slower absorption, and increased time
to peak concentration
• The extent of drug absorption is
seldom affected by increasing age

KEY MESSAGE
• Age per se does not affect drug

Pharmacokinetic changes absorption to a large extent unless

gastrointestinal pathology is present

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Distribution
• Older people have a different body composition to younger folks
• Increased fat mass (for a given body weight) and reduced lean mass
• May impact the distribution of some drugs
KEY MESSAGE
• Possible increased duration of effect from lipophilic drugs
• e.g. longer duration of sedation from benzodiazepines due to
prolonged redistribution from fat sites.
Elimination
• Both renal and hepatic clearance are affected by age
• Kidney function, based on GFR, is reduced by about 1% per year after the age of 40
• Hepatic clearance changes with increase age are poorly quantified – about a 15-
60% reduction in clearance in the elderly
• Since clearance is prolonged half-life is increased.

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Key messages – elimination changes in the elderly

• Both renal and hepatic clearance are affected by age
• Drug clearance in the elderly is reduced
• Drug half-life is generally longer
• A dose reduction may be required to ensure safety
• Start low and go slow
Pharmacodynamic changes

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Receptor sensitivity or changes in Receptor sensitivity in the elderly has been
homeostatic function? shown for these examples
• Apparent changes in receptor function with age are often based on physiological • Vit K dependent clotting factors more sensitive to warfarin
system responses
• 𝐶𝑎 − 𝑐ℎ𝑎𝑛𝑛𝑒𝑙 antagonists: ↑ sensitivity to heart rate and BP changes
• Receptor function is therefore confounded with homeostatic mechanisms (see
next slides) • 𝛽 − 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟: generally less sensitive
• It is not always possible to determine whether changed receptor pharmacology • e.g. salbutamol has a reduced bronchodilator response
actually exists • 𝛼 − 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟 function is maintained with age
• The examples in the next slides have been evaluated at the receptor or their
messenger systems • 𝑀 − 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟 function in CNS is ↓ so increased effects of antimuscarinics
• 𝐺𝐴𝐵𝐴𝐴 - increased sedation with benzodiazepines
Importantly homeostatic changes are most likely going to dominate (next section)

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Stimulus
Homeostasis
Homeostatic
• A regulatory process that maintains body systems set point
in a stable condition
• Usually this is controlled in a feedback loop:
Sensor
• Stimulus (e.g. standing up) (or receptor)
• Homeostatic set point (usual BP)
• Sensor (e.g. baroreceptors)
Homeostatic changes •
•
Control centre (e.g. ANS)
Effector (e.g. increased vascular tone)
(-) Control Centre

• Homeostasis can be affected by pathology, age,

etc
Effector
(physiological response)

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Components of a homeostatic system
• Set point (the point that the body tries to return to)
• Sensor/ receptor (a mechanism that detects when the system no
longer at the usual set point)
• Control centre – the bit that determines what will happen…
• Effector (physiological systems that can react to maintain
homeostasis)
How can age impact homeostasis?
• Set point – not usually affected by age but by an underlying pathology
(e.g. hypertension, obesity, diabetes)
• Sensor – this becomes less sensitive
• Control centre – depending whether under conscious (more impacted
by age) or subconscious control (less impacted)
• An effector – usually affected by an underlying pathology

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Standing up
Age can affect Postural hypotension
• Standing up causes a sudden pooling of blood Usual BP
• Temperature  in the lower extremities due to gravity
• Pressure change detected by baroreceptors
• Glucose 
• The brain increases sympathetic response
• Most electrolytes / water (most renal systems)  Baroreceptor
• Increased HR and vascular tone which
• Blood gases / pH ? maintains BP.
• Neurotransmission  • If BP overshoots - baroreceptors will detect
(-) ↑ sympathetic
and reduce the ANS response
• Neuroendocrine (e.g. gonadal, adrenal, thyroid axes) 
• The system dampens itself so the oscillations
• Haemodynamics  in BP are reduced and stable
↑ HR and vascular
tone

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 Standing up
With increased age… Vasodilators and postural hypotension
• Baroreceptors become less sensitive Usual BP
• Probably due to ↓ arterial flexibility (i.e. • Any drug that reduces vascular tone will reduce the body’s ability to respond to
hardening of the arteries, plaque etc) positional change  Falls risk ++
with age Baroreceptor • Examples (vasodilators):
• Less able to detect changes in artery becomes less • 𝛼 −blockers, ACEI, Ca – antagonists, nitrates
stretch sensitive

• If one part of the cycle is impaired then the

whole cycle impaired ↑ sympathetic
(-)
• BP is not maintained on standing and the
hypotensive person can fall
↑ HR and vascular
tone

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System Impact of drugs

Cerebral CNS depressants – e.g. alcohol, sedatives
Take home messages Cognition – e.g. anticholinergics
Vestibular (causing vertigo) alcohol
8th cranial nerve toxicity – e.g. gentamicin
basal ganglia Suppression of dopamine – e.g. dopamine antagonists,
• Homeostasis is a critical part of physiological function psychotropics, tricyclic antidepressants
Cerebellar CNS depression - High dose benzodiazepines
Neuronal toxicity – lithium, chemotherapy, antiepileptics
• In older people homeostatic mechanisms are impaired Neuropathy – some antimicrobials
Visual Changes in visual accommodation – e.g. anticholinergics
• Some drugs work by altering homeostatic function and have Cardiovascular Reduction in BP – e.g. antihypertensives, drugs acting to decrease
increased effect in older people sympathetic tone or increase muscarinic tone
Muscular Reduction in muscle mass or strength – e.g. corticosteroids reduce
muscle mass
Neuromuscular Rare (outside of anaesthetics)
Peripheral nervous system Neuropathies –some chemotherapy treatments, some anti-TB drugs

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 Anticoagulants
• Anticoagulants are associated with an increased risk of major bleed
• normalised yearly incidence of 0.3-0.5% for Afib and 1.3% for VTE
• Intracranial haemorrhage has higher mortality than other bleeds
• The stroke risk from untreated atrial fibrillation in patients > 70 y is up
to 10%
Risk from falls • Risk:benefit therefore favours anticoagulants

Risk from fall: increased risk of harm from bleeding risk

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Osteoporosis and falls Drug-induced osteoporosis

Clear association
• Osteoporosis may increase the risk of falls due to fear of falling
• Glucocorticoids (long term)
• The presence of osteoporosis increases the risk of fracture (a risk • PPIs (20-60% increased risk)
from a fall). • Medroxyprogesterone
• It is estimated that 70% of all fractures are osteoporotic • GnRH agonists (gonadotropin-releasing hormone agonist)

Unclear
• antiepileptic drugs
• SSRIs

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Concluding remarks
• Guidelines tend to lump drugs together (good or bad) but not
consider their differences
• Clinical pharmacology allows you to un-lump drugs as individual
classes can be considered good or bad
• The Clinical Pharmacology of Falls is complicated but important for
decision making in patients who are at risk

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