ADME in the older patient Flashcards
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 which may affect the absorption, distribution, metabolism and elimination of drugs include:
-Delayed gastric emptying
-Decreased gastrointestinal motility and transit
-Reduced splanchnic blood flow
-Changes in the gastrointestinal mucosa
-Changes in fluid volumes
-Changes in the gastrointestinal pH
-Alteration in body fat/water composition
how do changes in fluid volumes affect oral drug delivery?
Reduced saliva, gastric, and intestinal fluids results in a reduction in drug dissolution. This is also relevant to the buccal and sublingual route. For example, glyceryl trinitrate (used to treat angina) displays a slower rate of absorption in the elderly attributed to reduced saliva production. Dosage forms for glyceryl trinitrate include sprays and tablets for under the tongue.
how do changes in transit time affect oral drug delivery?
-Older patients exhibit delayed gastric emptying and decreased gastrointestinal motility and transit.
-Ideal drug characteristics: high solubility in GI fluids, high permeability, high stability in GI tract.
-Reality: changing solubility and stability in different regions of the GI tract result in regional-specific absorption
Describe how changes in transit time affects bioavailability?
Delayed gastric emptying therefore changes the period of time that the dosage form resides in the region of the gastro-intestinal tract that the greatest extent of absorption occurs. This increases bioavailability.
Describe Dysphagia (difficulty swallowing)
-greater prevalence in older patients
-can result in delayed oesophageal transit time, which may lead to premature drug release and reduced bioavailability.
describe how changes in intestinal mucosa affects oral drug delivery?
A reduction in surface area of the jejunum (the second part of the small intestine) results in a slower rate of absorption via passive diffusion.
Describe how reduced splanchnic blood flow affects oral drug delivery
Prolongs the time required for absorption
Describe how changes in gastrointestinal pH affects oral drug delivery
The effect of age on the secretion of gastric acid is somewhat unclear, with some studies showing an age-related reduction in secretion, and others showing no significant change. There is, however, a greater prevalence of achlorhydria (when the stomach does not produce enough stomach acid) in the older population (up to 10%) than in the younger population (< 1 %). Further, drugs which suppress gastric acid, such as proton pump inhibitors, are often prescribed in the older population.
drugs which suppress gastric acid, such as proton pump inhibitors, are often prescribed in the older population2. This can:
-Reduce the absorption of drugs which are best absorbed in acidic environments, such as ketoconazole (antifungal) and dipyridamole (antiplatelet).
-Can affect the activation of pH dependant prodrugs e.g. clorazepate (a benzodiazepine) which is hydrolysed in the stomach.
-Can alter the solubility of drugs
dosage form modification for dysphagia?
Dysphagia can lead to dosage form modification, such as tablet splitting/crushing, or extemporaneous formulation of a suspension from a tablet.
what care must be taken for patients with dysphagia?
do not crush tablets that are modified-release or possess an enteric coating. Crushing tablets can affect efficacy and result in adverse effects.
crushing modified release tablets?
crushing results in an increased risk of fluctuations between toxic and sub-therapeutic plasma concentrations.
crushing tablets with an enteric coating?
can increase the extent of drug degradation in the stomach, resulting in sub-therapeutic plasma levels. The likelihood of adverse events such as gastric irritation increases.
other problems with tablet crushing?
-Other problems associated with tablet crushing include inaccurate dosing due to transfer losses, and cross-contamination when crushing devices are shared.
-Crushing tablets can change pharmacokinetic parameters
what does topical drug delivery involve?
Topical drug delivery involves the application of a formulation to the skin, with the intention of the active pharmaceutical ingredient (API) being retained in the skin. This route is used to treat local disorders e.g. psoriasis or eczema.
what does transdermal drug delivery involve?
Transdermal drug delivery involves the entry of the active into the systemic circulation.
Describe how transdermal drug delivery must occur
For delivery into the systemic circulation via this route, drug must surpass the stratum corneum, which presents a primarily lipophilic route to absorption. Drug must then partition into and diffuse through the more aqueous viable epidermis and dermis layers. Drugs for transdermal delivery must therefore possess a balance of lipid and aqueous solubility
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Describe ‘shunt routes’
There are ‘shunt routes’ through via eccrine sweat ducts and hair follicles, but these appendages occupy a small surface area of the skin, and so absorption via these routes is often considered to be negligible.
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Advantages of using transdermal drug delivery?
-Less frequent dosing
-A reduction in adverse effects
-Avoidance of first-pass effect, and therefore avoidance of any changes associated with aging on the first-pass effect.
What is a common therapy delivered via transdermal route?
-HRT can be used to treat the symptoms associated with menopause. A 40 – 80-fold lower dose of estradiol can be used when delivering via the transdermal route compared with the oral route.
-Transdermal HRT can also be used to treat hypogonadism (diminished function of the sex glands), for which there is a high prevalence in the middle-aged to older male population.
Physiological changes to the skin which occur with ageing include:
-Drying of the stratum corneum and decrease in lipids.
-A reduction in sebaceous gland activity.
-Atrophy of the skin capillary network.
How do these physiological changes to the skin with aging impact drug absorption?
-These changes may result in changes in the barrier function of the stratum corneum, and reduced blood supply to the epidermis, resulting in alterations in plasma levels of drugs administered via the transdermal route with ageing.
-Studies have shown that changes in the appendages or ‘shunt routes’ that occur with age do not appear to influence percutaneous absorption, postulated to be as a result of these occupying such a small area of the skin.
-The extent of absorption of lipophilic drugs has been shown to be less likely affected by ageing compared with hydrophilic drugs.
Poor inhaler technique is often observed in the older population which is caused by?
This can be caused by the onset of muscle weakness in the hands, cognitive decline, or lack of co-ordination. Poor inhaler technique results in symptoms becoming unmanaged, increased reliance on rescue therapies (as opposed to controlling asthma effectively), and hospital admission.
In the case of dry powder inhalers, reduced inspiratory effort can cause?
negatively impact the fraction of the dose within the correct particle size to be deposited in the lungs. Larger particles are produced, which are deposited in the mouth and oropharynx
how do changes in body fat/water composition affect distribution?
-Body water and muscle mass decrease with age, and body fat often increases (males 18 – 36 %, females 33 – 45 %). This will affect the volume of distribution (Vd) of drugs differently dependant on physicochemical properties.
-Polar drugs ↓ Vd and ↑ in plasma concentration
-Lipophilic ↑ Vd and ↓ in plasma concentration
How do changes in plasma protein concentrations affect distribution?
Total serum albumin concentrations decrease by 12 % during aging, affecting the fraction of free drug in the systemic circulation. This may lead to toxicity, in particular for drugs which are highly protein bound and have a narrow therapeutic windows such as warfarin.
Describe glomerular filteration
Unbound drug in the plasma passively transverses the glomerular membrane into the renal tubule. Glomerular filtration is responsible for the elimination of a large number of water-soluble drugs and metabolites
Describe how the changes in glomerular filtration rate affect elimination
Renal function and glomerular filtration rate frequently decrease with age (typical decreases in GFR are 20 – 50 %), meaning drugs with a narrow therapeutic index, such as digoxin and lithium, may require a dose adjustment.
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