G5 ADME in the older patient

Question 1

what can age-mediated alterations in physiology influence? what is key with these alterations?

Answer 1

• the absorption, distribution, metabolism and elimination of many drugs
• key is understanding these changes to ensure the desired therapeutic outcomes are achieved in individuals at all stages in the HLC

Question 2

for a drug to be bioavailable following oral administration, we need:

Answer 2

• release of the drug from the formulation
• dissolution in the biological fluids
• passage through the gut wall
• passage through the liver
• entry into the systemic circulation

Question 3

physiological changes that occur in the older patient that may affect ADME of drug include:

Answer 3

• delayed gastric emptying
• decreased GI motility and transit
• reduced splanchnic blood flow
• changes in the GI mucosa
• changes in fluid volumes
• changes in the GI pH
• alteration in body fat / water composition

Question 4

describe which fluid volumes change in the older patient and what these result in

Answer 4

• reduced saliva
• reduced gastric and intestinal fluid
• results in reduction of drug dissolution

Question 5

what are changes in fluid volumes of the older patient relevant to in terms of routes of administration? give an example

Answer 5

• the buccal and sublingual route

example:
- glyceryl trinitrate (to treat angina) displays a slower rate of absorption in older patients
- this is attributed to reduced saliva production
- dosage forms for glyceryl trinitrate include sprays and tablets for under the tongue

Question 6

what changes do older patients exhibit regarding transit time?

Answer 6

• delayed gastric emptying
• decreasing GI motility and transit

Question 7

ideal oral drug characteristics compared to realistic characteristics

Answer 7

ideal:
- high solubility in GI fluids
- high permeability
- high stability in GIT

reality:
- changing solubility and stability in different regions of the GIT
- results in regional-specific absorption
- weak acid drugs absorbed more in small intestine than stomach despite theoretical assumption

Question 8

what does the delayed gastric emptying in older patients change?

Answer 8

• the period of time that the dosage form resides in the region of the GIT where the greatest extent of absorption occurs

Question 9

describe delayed gastric emptying in patients with Parkinson’s. give examples of molecules / drugs

Answer 9

• results in levodopa displaying greater bioavailability
• delayed gastric emptying might affect different drugs in different ways
• acid-labile drugs like penicillin would have reduced bioavailability

Question 10

what can dysphagia result in? use paracetamol as an example

Answer 10

• delayed oesophageal transit time which may lead to premature drug release and reduced bioavailability
• dosage form may get stuck somewhere in the upper GIT so drug may be released further up GIT than normal
• plasma concentrations of paracetamol in the first hour after taking have been shown to be lower in subjects where tablets have become stuck in the oesophagus

Question 11

what is dysphagia?

Answer 11

difficulty swallowing

Question 12

describe the changes in the intestinal mucosa of older patients

Answer 12

• reduction in surface area of the jejunum (second part of small intestine) results in a slower rate of absorption via passive diffusion
• reduced blood supply and reduced surface area so less absorption despite longer transit time

Question 13

state the effect of reduced splanchnic blood flow in the older patient

Answer 13

prolongs the time required for absorption

Question 14

describe the effect of age on the secretion of gastric acid

Answer 14

• somewhat unclear
• some studies show an age-related reduction and others show no significant change

Question 15

what is achlorhydria?

Answer 15

when the stomach doesn’t produce enough stomach acid

Question 16

describe achlorhydria in older patients

Answer 16

• there is a greater prevalence of achlorhydria in older people than younger people
• therefore, drugs which suppress gastric acid secretion (eg. PPIs) are often prescribed in the older patient

Question 17

what can PPIs do when prescribed in the older patient?

Answer 17

• reduce the absorption of drugs that are best absorbed in acidic environments (eg. ketoconazole, dipyridamole)
• can affect the activation of pH dependent prodrugs (less acid affects activation)
• can alter solubility of drugs
• prevent production of as much gastric acid so pH increases

Question 18

what is ketoconazole?

Answer 18

antifungal

Question 19

what is dipyridamole?

Answer 19

anti-platelet

Question 20

give an example of a pH dependent prodrug whose activation can be affected by PPI prescription (increased gastric pH)

Answer 20

• eg. clorazepate (a benzodiazepine)
• it is hydrolysed in the stomach

Question 21

what dosage form modifications can dysphagia lead to?

Answer 21

• tablet splitting / crushing
• extemporaneous formulation of a suspension from a tablet

Question 22

what kinds of tablets should patients with dysphagia NOT crush?

Answer 22

• modified release
• those with an enteric coating
• can affect efficacy and result in adverse effects

Question 23

what can crushing of modified release tablets lead to?

Answer 23

• increased risk of fluctuations between toxic and sub-therapeutic plasma concentration
• network that controls the release (polymer) is broken
• this causes drug dumping at the start (overdose) and no drug being released later on (underdose)
• very dangerous if condition is serious when not on meds

Question 24

what is meant by modified release tablets?

Answer 24

• over time the tablet is slowly releasing the drug as it travels through the GIT
• polymer is used as a network for which drug is gradually released through

Question 25

what can happen if tablets with an enteric coating are crushed?

Answer 25

- can increase the extent of drug degradation in the stomach, resulting in sub-therapeutic plasma levels - likelihood of adverse effects such as gastric irritation increases - enteric coating protects acid-labile drugs from gastric acid and can also protect stomach from drugs that harm stomach lining (eg. aspirin)

Question 26

state some other issues regarding tablets crushing regardless of enteric coatings and modified-releases

Answer 26

- inaccurate dosing due to transfer losses (they are likely to crush on their countertops) - cross contamination if crushing devices are shared

Question 27

what does topical drug delivery involve and what is this route used to treat?

Answer 27

- involves the application of a formulation to the skin with the intention of the active pharmaceutical ingredient being retained in the skin - used to treat local disorders (eg. psoriasis or eczema)

Question 28

what does transdermal drug delivery involve?

Answer 28

the entry of the active into the systemic circulation

Question 29

what must happen for delivery into the systemic circulation by the transdermal route to occur?

Answer 29

- drug must surpass the stratum corneum which presents a primarily lipophilic route to absorption

Question 30

after a transdermal drug has surpassed the stratum corneum, what must happen?

Answer 30

- drug must then partition into and diffuse through the more aqueous viable epidermis and dermis layers

Question 31

in order for transdermal drugs to surpass the lipophilic stratum corneum and aqueous epidermis and dermis, what properties must the drugs have?

Answer 31

- must possess a balance of lipid and aqueous solubility

Question 32

what are 'shunt routes'?

Answer 32

- routes through stratum corneum, viable epidermis and dermis via eccrine sweat ducts and hair follicles - these appendages occupy a small surface area of the skin so absorption via these routes is often considered negligible

Question 33

advantages of transdermal route of drug delivery

Answer 33

- less frequent dosing - a reduction in adverse effects - avoidance of first-pass effect and therefore avoidance of any changes associated with ageing on the first-pass effect

Question 34

describe HRT given by transdermal route

Answer 34

- HRT can be used to treat menopause symptoms - a 40-80 fold lower dose of estradiol can be used in transdermal route compared to the oral route - can also be used to treat hypogonadism for which there is a high prevalence in the middle-aged to older male population

Question 35

what is hypogonadism?

Answer 35

diminished function of the sex glands

Question 36

physiological changes to the skin which occur with ageing

Answer 36

- drying of the stratum corneum and decrease in lipids - a reduction in sebaceous gland activity - atrophy (wasting away) of the skin capillary network

Question 37

what can age-related physiological changes to the skin result in?

Answer 37

- changes in the barrier function of the stratum corneum - reduced blood supply to the epidermis resulting in alterations in plasma levels of drugs from transdermal route

Question 38

which transdermal drugs' absorption is most affected by age?

Answer 38

- extent of absorption of lipophilic drugs is less likely affected by ageing compared with hydrophilic drugs - hydrophilic are more affected due to decrease of lipids in stratum corneum

Question 39

regarding inhalers, what is often observed in the older patient? what does this result in?

Answer 39

- poor inhaler technique - can be caused by the onset of muscle weakness in the hands, cognitive decline or lack of coordination results in: - symptoms being unmanaged - increased reliance on rescue therapies (as opposed to control managements) - hospital admission

Question 40

in the case of drug powder inhalers, how can reduced inspiratory effort impact the patient?

Answer 40

- impacts fraction of dose within the correct particle size to be deposited in the lungs - larger particles are produced which are deposited in the mouth and oropharynx which doesn't adequately control asthma symptoms

Question 41

describe age-related changes in body fat / water composition

Answer 41

- body water and muscle mass decrease with age - body fat often increases (males 18-36%, females 33-45%)

Question 42

what do age-related changes in water / fat composition affect? describe the different effects on different drugs

Answer 42

- volume of distribution (affects different drugs differently dependent on physicochemical properties) - hydrophilic drugs have decreased Vd (due to less volume of water) and increased plasma concentration due to same mass of drug in smaller volume of water - lipophilic drugs have increased Vd (due to more fat) and decreased plasma concentration due to more fat for drug to go to

Question 43

describe age-related changes in plasma protein concentrations and explain what these changes affect

Answer 43

- total serum albumin concentrations decrease by 12% during ageing - this affects the fraction of free drug in the systemic circulation due to less opportunity for binding - this may lead to toxicity

Question 44

what drugs could changes in plasma protein concentrations cause toxicity for?

Answer 44

- drugs which are highly protein bound and have a narrow therapeutic window - eg. warfarin - there is very little scope between lowest effective ad maximum safe dose

Question 45

what happens to unbound drug in the plasma in terms of elimination?

Answer 45

- passively transverses the glomerular membrane into the renal tubule

Question 46

what is glomerular filtration responsible for?

Answer 46

the elimination of a large number of water-soluble drugs and metabolites

Question 47

describe the changes in renal function and GFR with age

Answer 47

- renal function and GFR frequently decrease with age - typical GFR decrease is 20-50% - this means drugs with a narrow therapeutic index may require dose adjustment (eg. digoxin and lithium)