G5 ADME in the older patient Flashcards
what can age-mediated alterations in physiology influence? what is key with these alterations?
- 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
for a drug to be bioavailable following oral administration, we need:
- 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
physiological changes that occur in the older patient that may affect ADME of drug include:
- 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
describe which fluid volumes change in the older patient and what these result in
- reduced saliva
- reduced gastric and intestinal fluid
- results in reduction of drug dissolution
what are changes in fluid volumes of the older patient relevant to in terms of routes of administration? give an example
- 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
what changes do older patients exhibit regarding transit time?
- delayed gastric emptying
- decreasing GI motility and transit
ideal oral drug characteristics compared to realistic characteristics
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
what does the delayed gastric emptying in older patients change?
- the period of time that the dosage form resides in the region of the GIT where the greatest extent of absorption occurs
describe delayed gastric emptying in patients with Parkinson’s. give examples of molecules / drugs
- 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
what can dysphagia result in? use paracetamol as an example
- 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
what is dysphagia?
difficulty swallowing
describe the changes in the intestinal mucosa of older patients
- 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
state the effect of reduced splanchnic blood flow in the older patient
prolongs the time required for absorption
describe the effect of age on the secretion of gastric acid
- somewhat unclear
- some studies show an age-related reduction and others show no significant change
what is achlorhydria?
when the stomach doesn’t produce enough stomach acid
describe achlorhydria in older patients
- 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
what can PPIs do when prescribed in the older patient?
- 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
what is ketoconazole?
antifungal
what is dipyridamole?
anti-platelet
give an example of a pH dependent prodrug whose activation can be affected by PPI prescription (increased gastric pH)
- eg. clorazepate (a benzodiazepine)
- it is hydrolysed in the stomach
what dosage form modifications can dysphagia lead to?
- tablet splitting / crushing
- extemporaneous formulation of a suspension from a tablet
what kinds of tablets should patients with dysphagia NOT crush?
- modified release
- those with an enteric coating
- can affect efficacy and result in adverse effects
what can crushing of modified release tablets lead to?
- 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
what is meant by modified release tablets?
- 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
what can happen if tablets with an enteric coating are crushed?
- 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)
state some other issues regarding tablets crushing regardless of enteric coatings and modified-releases
- inaccurate dosing due to transfer losses (they are likely to crush on their countertops)
- cross contamination if crushing devices are shared
what does topical drug delivery involve and what is this route used to treat?
- 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)
what does transdermal drug delivery involve?
the entry of the active into the systemic circulation
what must happen for delivery into the systemic circulation by the transdermal route to occur?
- drug must surpass the stratum corneum which presents a primarily lipophilic route to absorption
after a transdermal drug has surpassed the stratum corneum, what must happen?
- drug must then partition into and diffuse through the more aqueous viable epidermis and dermis layers
in order for transdermal drugs to surpass the lipophilic stratum corneum and aqueous epidermis and dermis, what properties must the drugs have?
- must possess a balance of lipid and aqueous solubility
what are ‘shunt routes’?
- 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
advantages of transdermal route of drug delivery
- 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
describe HRT given by transdermal route
- 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
what is hypogonadism?
diminished function of the sex glands
physiological changes to the skin which occur with ageing
- drying of the stratum corneum and decrease in lipids
- a reduction in sebaceous gland activity
- atrophy (wasting away) of the skin capillary network
what can age-related physiological changes to the skin result in?
- 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
which transdermal drugs’ absorption is most affected by age?
- 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
regarding inhalers, what is often observed in the older patient? what does this result in?
- 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
in the case of drug powder inhalers, how can reduced inspiratory effort impact the patient?
- 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
describe age-related changes in body fat / water composition
- body water and muscle mass decrease with age
- body fat often increases (males 18-36%, females 33-45%)
what do age-related changes in water / fat composition affect? describe the different effects on different drugs
- 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
describe age-related changes in plasma protein concentrations and explain what these changes affect
- 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
what drugs could changes in plasma protein concentrations cause toxicity for?
- 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
what happens to unbound drug in the plasma in terms of elimination?
- passively transverses the glomerular membrane into the renal tubule
what is glomerular filtration responsible for?
the elimination of a large number of water-soluble drugs and metabolites
describe the changes in renal function and GFR with age
- 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)
