THE PHENOMENON OF AGING

• Theories of aging• Physiological changes attributed

to aging• Altered Pharmacokinetics and

Pharmacodynamics

“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

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

THEORIES OF AGING1] 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.

THEORIES OF AGINGHYPOTHESIS 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.

Theories of aging (contd.)

HYPOTHESIS HOW IT MAY WORKTelomere 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.

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).

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.

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.

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

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).

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).

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).

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).

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)

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.

ORGAN SYSTEM MANIFESTATIONBody 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 brainAlterations in several aspects of cognition

Endocrine Thyroid gland atrophies with age↑ed incidence of DM, thyroid diseaseMenopause

GI ↑ Gastric pH; ↓ GI blood flow;Delayed gastric emptying;Slowed intestinal transit

ORGAN SYSTEM MANIFESTATIONGenitourinary 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/ bitternessPulmonary ↓ 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

ORGAN SYSTEM MANIFESTATIONSensory ↓ 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

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]

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].

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].

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.

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).

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.

P’cokinetic Phase P’cokinetic ParametersGI 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)

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.

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