A brief look into the inevitable process of aging, the various theories attempting to explain the aging phenomenon; normal physiological aging changes that play a role in pharmacokinetics and pharmacodynamics w.r.t. drugs.

1. THE PHENOMENON OF
AGING
• Theories of aging
• Physiological changes attributed to
aging
• Altered Pharmacokinetics and
Pharmacodynamics

2. “For age is opportunity no less than youth
itself, though in another dress.
And, as the evening twilight fades away the
sky is filled with stars, invisible by day.”
- Henry Wadsworth Longfellow

3.  Phenomenon of aging is unavoidable [Universal process].
Aging Disease
Intrinsic Intrinsic and extrinsic
Depends on genetic
factors
Depends on genetic and
environmental factors
Always progressive Discontinuous; may progress,
regress or be arrested entirely
Irreversible Treatable; usually has a
known cause

4. THEORIES OF AGING
1] Stochastic theories:
 ‘Changes result from damage due to environmental hazards
or accumulation of random events.’
 Egs.:
• Free radicals theory – free radicals cause cellular damage;
the cumulative effects cause cellular dysfunction, and result in
aging.
• ‘Wear and tear’ theory – accumulated damage to vital parts
of the cell lead to aging and death.
2] Programmed change theories:
 ‘Changes that occur with aging are genetically programmed.’
 Eg.:
• Involution of the thymus gland gradually impairs the immune
system.

5. THEORIES OF AGING
HYPOTHESIS HOW IT MAY WORK
Genetic • Aging is a genetic program.
• Activated in post-reproductive life when an
individual's evolutionary mission is
accomplished.
• Eg.: Involution of thymus gland
Oxidative
Stress
• Accumulation of oxidative damage to DNA,
proteins and lipids.
• Interferes w/ normal function.
Mitochondrial
Dysfunction
• Common deletion in mitochondrial DNA w/ age.
• Compromises mitochondrial function.
• Alters cell metabolic processes and adaptability
to environmental change.
Hormonal
changes
• The decline and loss of circadian rhythm in
hormones secretion.
• Produces a functional hormone deficiency state.

6. Theories of aging (contd.)
HYPOTHESIS HOW IT MAY WORK
Telomere
Shortening
• Aging is related to a decline in cells’ ability to
replicate.
Defective Host
Defences
• The failure of the immune system to respond
to infectious agents.
• Overactivity of natural immunity (auto
immune status).
• Creates vulnerability to environmental
stresses.
Accumulation
of Senescent
cells
• Renewing tissues become dysfunctional
through loss of ability to renew.

7. PHYSIOLOGICAL AGING
 Difficult to differentiate b/n 1° age changes (physiological);
2° age changes (pathophysiological); and 3° age changes
(sociogenic and behavioural).
 Age-related changes vary greatly.
 Severe change in one organ does not mean severe changes
in other organs.
 All functions and parameters in the human body DON’T show
age-related changes (eg.: HCV remains the same).
 Balanced decline in both production and breakdown
(eg.: testosterone, cortisol, thyroxine, aldosterone and insulin).
 Normal aging: ed DA conc. in brain↓ Influences→ onset and
severity of Parkinson’s disease.
 Menopause (related to in osteoporosis↑ & atherosclerosis).
 Arteriosclerosis → age-related in diastolic B↑ .P. (major CVA
risk factor).

8. IMMUNE SYSTEM
 Decreased cell-mediated and humoral immunity w/ age.
 Prominent effect is seen on the Thymus gland (site where
stem cells differentiate into T-lymphocytes).
 At age 50 functional impairments due to→ thymus
involution
Reduced thymic output of T-cells
 Compensatory mechanism: spleen and lymph nodes help to
differentiate the stem cells.
 B-cells don’t function and respond normally.
 Increase in various autoantibodies (Rh factor) increases the
risk of autoimmune disorders.
 UTIs, RTIs, Nosocomial infections and wound infections are
common.

9. CV SYSTEM
 Increase in heart weight.
 In myocardium: in fat↑ , collagen and elastin levels.
 Fibrous plaques deposition; vascular calcification and
reduced arterial compliance.
URINARY SYSTEM
 Anatomical and functional changes.
 Anatomic changes:
• Loss of glomeruli; ed kidney size↓ ; renal tubular and
vascular changes.
• In lower UT men more susceptible to→ Prostatic
Hypertrophy.
• Women become prone to urinary incontinence; UTIs; uterine
and cervical cancers.
 ↓ed renal function (from 5th
decade); ed GFR↓ (by 1ml/min
per year);
[More rapid in men (even in absence of CV, renal or acute
diseases)].
 ↓ed renal blood flow and plasma flow.

10. ENDOCRINE SYSTEM
 Age-related changes occur in extrahepatic hormonal
regulatory mechanisms.
 ↓ed hormones reduced endocrine→ regulatory functions;
deficiencies in hormonal feedback mechanisms;
reduced binding affinities;
 Altered composition of hormones [pancreatic and adrenal]
decreased glucose tolerance w/ age
 Insulin release is impaired; reduced nos. of insulin receptors.
 Decreased production of sex hormones.
 In Post-menopausal women: reduced levels of estrogen
increased risk of osteoporosis and CV diseases

11. RESPIRATORY SYSTEM
 Upper respiratory tract (respiratory organs outside chest
cavity; eg.: nose, nasal cavities, pharynx, larynx and upper
trachea).
 Lower respiratory tract (organs within the chest cavity;
lower trachea, bronchi, bronchioles, alveoli and lungs).
 increased diameter of trachea and central airways;
increased volm. of alveolar ducts;
membranous bronchioles narrow
↑ed dead end space
 Lung weight loss > 20% ; decreased chest wall compliance.
 RESULT :
• decreased elastic recoil of lungs.
• decrease in maximal expiratory flow.
 increased risk for RF (aspiration / inhalation of foreign
material into tracheobronchial tree major respiratory→
illnesses).

12. GASTROINTESTINAL SYSTEM
 Oral disorders are common amongst the elderly.
 Oral cavity:
• Poor oral health (due to poor hygiene, disease or disease
treatment rather than from dysfunction).
 Traumatic lesions in oral cavity (ulcerative / atrophic /
hyperplastic)
increased susceptibility of oral mucosa to diseases.
[Corticosteroids, antibiotics, cytotoxics and immunosuppressive Tx
exacerbate the susceptibility of oral mucosa].
 High risk of local ADRs [fixed eruptions (reddened blisters);
swelling; glossitis and stomatitis].
 Gastric muscular atrophy and gastric mucosa thinning (in
80% of people > 50 yrs of age).
 Reduced gastric secretion ( ed gastric pH);↑ reduced gastric
cell function.
 Gastric emptying is 2.5x slower in older people (b’coz it is
controlled by CNS, which loses it’s efficiency w/ advancing
age).

13. GI system (contd.)
 Causes of ed gastric emptying↓ :
• Stress; lack of ambulation; fatty meals
• Intestinal obstruction, GU, MI, DM.
 Reduced Vit. D absorption and intestinal absorption of Ca.
 Constipation is common (altered motility in the
intestines).
 Relatively, the liver is least affected (liver weight
correlates w/ body weight. Both start decreasing by 5th
and 6th
decade).
 Decreased hepatic blood flow (affects metabolic clearance
of drugs).
(Hepatic CLcannot exceed hepatic blood flow).

14. THE NERVOUS SYSTEM
 Decreased cellular brain mass and cerebral blood flow.
 Longer time for sensory conduction.
 Increased permeability of BBB.
 RESULT: decreased coordination; prolonged reaction time;
impaired short-term memory (learning and info
retrieval).
 MANIFESTATIONS: More falls (mainly among elderly women);
Urinary incontinence; confusion;
Homeostatic balance declines.
 Nerve cells are lost (but, nerve cells controlling eye
movement aren’t affected).
 Cerebral blood flow is affected by dementia, atherosclerosis,,
DM, HTN, stroke and vice-versa.
 Altered serotonin levels (cognition, pain, feeding, sleep,
sexual behaviour are affected).

15. INTEGUMENTARY SYSTEM
 Consists of epidermis, dermis, subcutaneous layers +
accessory structures (hair, nails, sebaceous glands and sweat
glands).
 Epidermal cells (contain melanocytes) must be continuously
replaced w/ new cells that divide.
• decreased production rate of the new cells (by 30 - 50%).
• decreased melanocytes no. (reduced melanin; more prone to
UV light effects).
 Dermis:
• Decreased collagen and elastin (thinning and wrinkling of skin)
• Collagen loss (skin is more prone to wear and tear)
• Elastin loss (skin loses it’s resilience)
 Hairs (graying; thinning and loss)

16. GENERAL VIEW
 Body composition ( in lean body mass↓ , skeletal mass and
total body water).
 Ears (loss of high-frequency hearing).
 Endocrine system (menopause; testosterone↓ ).
 Bone mineral loss.
 ↑ed incidence of DM; ed ADH secretion↑ (in response to
osmolar stimuli).
 ↓ed functional reserve capacity (i.e. ability to respond to
physiologic challenges or stresses);
 Impaired homeostasis
 Most affected – CV, musculoskeletal and CNS.
 Examples of impaired homeostatic mechanisms :
• postural or gait stability, orthostatic blood pressure
responses,
• thermoregulation, cognitive reserve, bowel and bladder
function.
 Relatively small stresses → major morbidity and mortality.

17. ORGAN SYSTEM MANIFESTATION
Body Composition ↓ed Total body water; ↓ed Lean body mass;
↑ed Body fat; or ↓ed Serum albumin
↑ed alpha-1-Acid glycoprotein ( or by several
disease states).
CV ↓ Myocardial sensitivity to beta-adrenergic
stimulation
↓ Baroreceptor activity ; ↓ C.O.; ↑ TPR
CNS ↓ Weight and volume of the brain
Alterations in several aspects of cognition
Endocrine Thyroid gland atrophies with age
↑ed incidence of DM, thyroid disease
Menopause
GI ↑ Gastric pH; ↓ GI blood flow;
Delayed gastric emptying;
Slowed intestinal transit

18. ORGAN SYSTEM MANIFESTATION
Genitourinary Vaginal Atrophy (↓ed estrogen);
Prostatic hypertrophy ( androgenic hormonal
changes);
Age-related changes → incontinence
Immune ↓ Cell-Mediated Immunity
Liver ↓ Hepatic size and blood flow
Oral Altered dentition;
↓ed ability to taste sweet /sour/ bitterness
Pulmonary ↓ Pulm. respiratory muscle strength
↓ Chest wall compliance;
↓ Total alveolar surface; ↓ VC
↓ Maximal breathing capacity
Renal ↓ GFR; ↓ Renal blood flow; ↓ Renal mass
↑ Filtration fraction; ↓ Tubular secretory function

19. ORGAN SYSTEM MANIFESTATION
Sensory ↓ Lens accommodation → farsightedness
Presbycusis (loss of auditory acuity);
↓ Conduction velocity
Skeletal Loss of skeletal bone mass (osteopenia)
Skin Skin dryness, wrinkling, changes in pigmentation,
epithelial thinning, loss of dermal thickness;
↓ed hair follicles;
↓ed melanocyte nos. in hair bulbs

20. ALTERED ABSORPTION
 Age-related 2° changes in GI physiology affect medications’
absorption (since most drugs are taken orally).
 Age-related physiologic changes have little influence on drug’s BA
(Most drugs are absorbed via passive diffusion).
 Few drugs require active transport for absorption → ↓ed BA
 ↓ed first-pass effect on hepatic and/or gut wall metabolism
↑ed BA and higher plasma drugs concs. (propranolol and morphine).
 Concurrent ingestion of grapefruit juice → ↑ed BA
[ Grapefruit juice constituents inhibit CYP450 isoenzyme
↓ed first-pass metabolism exaggerated p’cologic
effects]

21. ALTERED DISTRIBUTION
 Drug distribution depends on:
• blood flow, PP binding and body composition
[each of these are altered with age].
 Vd changes have a direct impact on the amount of medication that
must be given as a loading dose.
 ↓ed Vd (hydrophilic drugs); ↑ed Vd (lipophilic drugs).
 ↓ed P-gp activity in the blood–brain barrier w/ aging
↓
brain of aged individuals is exposed to higher levels of drugs and
toxins.
[ P-gp is a member of the multidrug resistance (MDR)-associated protein family of efflux
transporters that regulates drug transport across blood–brain barrier].

22. Distribution (contd.)
Plasma Proteins & binding
 Major PPs to which medications bind : albumin, globulin (α 1-acid gp).
 Concs. of these proteins may change w/ concurrent pathologies seen
w/ increasing age.
 ↓ed serum albumin → ↑ed free fraction of acidic drugs (naproxen,
phenytoin, tolbutamide, and warfarin).
 Burns, cancer, inflammatory disease, trauma → ↑ed α 1-acid gp
↓
↓ed free fraction of basic drugs
(lidocaine, propranolol, quinidine, and imipramine)
 Consider these changes when interpreting serum drug concs.
[b’coz only total drug concentrations (sum of free and protein-bound
drug) are reported].

23. ALTERED METABOLISM
 Liver is the major organ responsible for drug metabolism.
 Phase I (oxidative) and Phase II (conjugative) reactions.
 In older adults, there is an increased interindividual variability vs
other age groups (obscures true age-related changes).
 Age-related declines in Phase I metabolism are mostly due to ↓ed
hepatic volume than reduced hepatic enzymatic activity.
 ↓ed Phase I metabolism (e.g., hydroxylation, dealkylation)
↓ed drug CL and ↑ed t1/2 (diazepam, piroxicam, theophylline &
quinidine).
 Phase II metabolism (e.g., glucuronidation, acetylation) of
medications such as lorazepam and oxazepam is relatively
unaffected by advancing age.

24.  Hepatic enzymes are relatively unaffected by advancing age
• induction (e.g., by rifampin, phenytoin);
• inhibition (e.g., by fluoroquinolone and macrolide antimicrobials,
cimetidine)
 ↓ed hepatic blood flow → ↓ed drugs’ metabolism (imipramine,
lidocaine, morphine, and propranolol).

25. ALTERED ELIMINATION
 Renal excretion
• primary route of elimination for many drugs.
• ↓ing GFR.
• renal tubular secretion may not decline in proportion to other renal
processes.
• creatinine clearance estimation – not entirely accurate in individual
patients, but useful screening approximation.
• Cockcroft and Gault equation
• age (years); actual body weight (kgs.);
• serum creatinine conc. (mgs/dl);
• For women, multiply this result by 0.85.

26. P’cokinetic Phase P’cokinetic Parameters
GI Absorption Unchanged passive diffusion (No change in BA
for most drugs).
↓ Active transport and BA for some drugs
↓ First-pass extraction (↑ BA for some drugs)
Distribution ↓ Vd of water-soluble drugs
↑ Vd for fat-soluble drugs
↑ or ↓ free fraction of highly PP-bound drugs
Hepatic
Metabolism
↓ CL and ↑ t1/2 for some oxidatively metabolized
drugs, and drugs w/ high hep. extraction ratios
Excretion ↓ CL and ↑ t1/2 for renally eliminated drugs and
active metabolites
ALTERED P’COKINETICS (in a nut shell)

27. ALTERED P’CODYNAMICS
 Altered drug response or ‘sensitivity’ is observed in older adults.
 4 possible mechanisms :
(a) changes in receptor numbers
(b) changes in receptor affinity
(c) post-receptor alterations (binding)
(d) age-related impairment of homeostatic mechanisms.
 ↓ed density of parathyroid hormone, muscarinic, β-adrenergic, α 1-
adrenergic & μ- opioid receptors w/ ↑ing age.
 Older adults
• more sensitive to the CNS effects of benzodiazepines.
• ↑ed analgesic responsiveness to opioids vs younger counterparts
(even in cases of similar p’cokinetic parameters).
• enhanced anticoagulants responsiveness (warfarin, heparin,
thrombolytics).
• ↓ed responsiveness to β -agonists/antagonists.

29. THANK YOU!!!