IC2 PK & PD Changes in Elderly

Question 1

What is the key rule to follow when starting drug therapy for elderly?

Answer 1

start low and go slow

Question 2

For PK absorption, what are the causes of lowered gastric acid secretion?

Answer 2

1. Mucosal atrophy

• Gastric acid secretion not reduced by age alone
• When patients get older, we think that gastric acid secretion drops. Studies show that it is not due to aging process but due to muscle atrophy in the stomach
• Older adults without such problems have the same gastric acid secretion as younger patients

2. Gastric acid suppression therapy

• Reduced Vitamin B12, Calcium, iron
• Use of gastric acid suppression therapy e.g. PPI and H2RA, esp long term, will reduce the absorption of all these vitamins from dietary sources e.g. vit B12, Ca, Fe
• Will lead to a lot of problems e.g. vit b12 deficiency
• Itraconazole capsules (↓85%), ketoconazole (↓64-66%)
• Ketoconazole hardly used nowadays unless used by endocrinologist for hormonal indications
• IV or oral suspensions for itraconazole to avoid the reduced absorption of them when using gastric acid suppression therapy
• Cancer therapy involving certain thyroid kinase inhibitors, –tinib such as dasatinib (Sprycel), erlotinib (Tarceva)1,2,3,4,5 and nylotinib (serum concentrations will be decreased)
• Erlotinib out of fashion, mainly used to treat certain leukemias, now superceded by other more advanced tinibs
• If realised that patients have these types of tinibs and have gastric supression tx then need to discuss with the dr

Question 3

For PK absorption, what affects gastrointestinal transit time?
How does this affect certain medications?

Answer 3

• Gastrointestinal transit time prolonged in old age
• Unable to separate the effects of diseases and/or drugs on this parameter
  Same oral bioavailability²
• Theoretical risk that ½ hours of wait may not be enough for alendronate / risedronate

Stomach to long intestine (gastric emptying) will take longer in

• Not just due to older age
• certain diseases E.g. diabetes, gastroparesis
• Drugs e.g. anticholinergic, opioids, antispasmatic

Prolonging gastric emptying rate is not such a problem in terms of oral bioavailabiltiy

• It increases the time to peak conc. but will not affect extent of absorption (most likely because they are absorbed in the stomach)
• Theoretically affect use of certain meds e.g. alendronate and risedronate
• Because they have the sit up for 30mins-1hr, before taking breakfast so that give the meds time to go into the SI
• Thus if patient have gastric emptying prolongation problems, the 30-mins-1hr may not be enough. Make meds less effective or increase risk of esophagus ulceration / esophagitis → damage to lining of esophagus

If really want to give, need to monitor patient for efficacy and ADR

Question 4

What to look out for for first pass metabolism under absorption?

Answer 4

From small intestines to systemic circulation (First pass metabolism)

• metabolism in the intestines and liver
• Efflux transporter: p-glycoprotein (p-gp) > reduced absorption
• Besides metabolizing enzymes e.g. CYP cytochrome, have pgp which reduces absorption. By kicking out the drugs into the lumen
• Some drugs can affect the pgp activity
• No change for most drugs on the account of age alone
• Drug-Drug interactions may affect
• Phenytoin reduces dexamethasone’s oral bioavailability from 84% to 33%
• Clarithromycin increases Cmax of digoxin by 84% and levels of the drug by 64%2,6,7
• Clarithromycin inhibiting p-glycoprotein, cause more digoxin to be absorbed and increase the level of the drug, increasing the risk of ADR and toxicity

Question 5

For transdermal route, what factors affect the absorption?

Answer 5

1. Epidermis and dermis thin when ones age
2. Cutaneous blood supply drops → Cause Absorption to reduce

• Former increases transdermal absorption, latter decreases transdermal absorption
• Effect of age on transdermal absorption of drugs hard to characterise
• While the thinning skin will cause absorption to increase but then the blood supply will drop which cause absorption to be reduced, so can’t really determine the changes of the overall bioavailability of the drugs when given as transdermal patch

3. More importantly, heat increases drug delivery. Serious harm, even death may result

• Increase passive diffusion and blood supply
• Fentanyl patch
• Exelon patch
• Nitroglycerin patch
• Rate of drug delivery is reliant on the heat

If heat comes from fever, but elderly rarely mount high fever (so it’s a blessing in disguise but that means the immune system is not great

If younger patients, fever is high, the drug delivery will be high and cause toxicities

Some elderly like to put hot water bag over the buprenorphine patch will cause increase in absorption of the meds → cause long deep sleep but good thing never stop breathing

Counsel properly that the patch can be placed anywhere on the body not necessarily at the site of pain, otherwise they put there and they put heat pad on it… ded they patient might stop breathing :<
This applies to the other patches but the effect will be different due to the diff pharmacological effects but can cause great harm if not careful with it

Question 6

What are some factors that affect distribution?

Answer 6

• Total body water and lean muscle mass drop
• Fat increases
• Effect on distribution depends on physical/physiochemical property of drugs
• Serum albumin and α1-acid glycoprotein (carrier proteins)
• Aging associated with 10-15% decrease in serum albumin; more if sick → When sick, drug will be more due to increase in inflammation
• α1-acid glycoprotein increases with age but mainly because of illness

The above changes not clinically important1,2,3 → Pharmacological actions of the drugs, the above changes are not clinically important

Question 7

How to interpret Phenytoin levels? What to consider when interpreting phenytoin levels?

Answer 7

Interpretation of Phenytoin Level

• In adults 90-95% of phenytoin is bound to albumin
• Only free phenytoin is pharmacologically active
• When serum albumin drops, free concentration increases transiently
• All factors being constant, free concentration drops to the same level before the serum albumin decreases
• Result: same free concentration but total concentration drops
• Conclusion: phenytoin levels need to be interpreted in conjunction with serum albumin
  Google: phenytoin albumin correction
  e.g. https://www.mdcalc.com/phenytoin-dilantin-correction-albumin-renal-failure

Question 8

How to you interpret sodium valproate levels?

Answer 8

• Hypoalbuminemia also associated with falsely suppressed total valproic acid concentration
• But no established formula for correction
• Better to measure the free concentration of Na valproate rather than taking the total conc and use the formula to correct for the hypoalbuminemia

But a lot of hospital the labs do not have the capacity to measure free levels of the Na valproate, so see albumin is low and dr wants to increase further, prof will consult the neurology specialist

Question 9

What are some factors that affect drug distribution into the brain?

Answer 9

Barriers to the distribution of drugs into the Central Nervous System

1. Blood Brain Barrier

• Meta-analysis shows more leaky and porous BBB in old age
• Meta-analysis by same researchers also suggests dementia associated (cause even more porous) with more porous BBB than aging alone

2. P-glycoprotein (P-gp; efflux proteins)

• Small study suggests that P-gp activity lower in elderly → Thus can use this to explain why elderly experience more CNS side effects from drugs e.g. anticholinergics
• Clinical studies support the notion that leaky BBB in old age increases the risk of adverse drug reactions
• Elderly more sensitive to CNS side effects of anticholinergic agents1,12

Question 10

Which organ is the most involved in metabolism? And what does it do?

Answer 10

Metabolism mainly in liver

1. Inactivate and facilitate elimination
2. Activate
3. Toxic metabolite

Question 11

What are the 2 types of metabolism?

Answer 11

Metabolism: two types

1. Phase I: Cytochrome P450 (CYP) enzymes

• 15 CYP isozymes, 3A4 most abundant

2. Phase II: Conjugation such as glucuronidation, acetylation, sulfation

• Major enzyme is Uridine 5’-diphospho glucoronyltransferase (UGT)1,5
• Adds glucuronic acid (make it more water soluble)

Question 12

Why do we need to avoid overdose of paracetamol (beyond 4g/24hrs)?
Which type of metabolism is involved in this?
What enzyme is involved in producing toxic metabolite?
What are the risk factors?
What is the name of the toxic metabolite?
What can help to reverse paracetamol overdose?
What prevents the reversing of paracetmol overdose?

Answer 12

Paracetamol can become a toxic metabolite, through phase 2 glucuronidation

• CYP2E1
• Alcohol induces it, so in heavy alcohol users have more active CYP2E1 so likely to produce more toxic metabolite
• NAPQI (toxic metabolite)
• Can be neutralized by glutathione but depleted in someone who is malnutrition like an alcoholic (double whammy)

If patient has cirrhosis, they will have more liver damage when take paracetamol :(

Question 13

What factors affect phase I metabolism?

Answer 13

1. Age
2. Frailty
3. CYP enzyme inducers or inhibitors

• Phase I metabolism lower with age
  Mainly due to reduced liver mass, hepatic blood flow, and thickening of sinusoidal endothelium (lower ability to maintain metabolic and immune homeostasis)
  CYP enzyme may not be affected by aging alone
• Frailty may reduce activity through increased inflammation → Presence of frailty can affect the levels of CYP enzyme
• Drug-induced inhibition and induction important → Of CYP cytochrome which in turn inhibit or induce the meds
  Inhibitor: Azole agents, clarithromycin, cimetidine
  Inducers: phenytoin, carbamazepine, rifampicin

Question 14

What affects phase II metabolism?

Answer 14

1. Smaller liver
2. Frailty

• Phase II metabolism largely unchanged with age
  Enzyme itself may not be affected by age alone
• But quantity dropped with smaller liver
• Frailty caused more drop as it affects enzyme activity1,2,5 (UGT) → presence of frailty might cause activities of UGT to be lower

Question 15

What happens when amlodipine/nifedipine is taken together with rifampicin?

Answer 15

Rifampicin is a CYP3A4 inducer, thus this increases the metabolism of Amlodipine / Nifedipine, thus serum concentration decreases and in turn reduces effectiveness

Question 16

Which organ is the most involved in excretion?
What factors worsen excretion?
What are some drugs to avoid to prevent worsening of excretion?

Answer 16

Kidney most important organ in drug/metabolites elimination

1. Age
2. Disease/drug
3. dehydration

• Decline in kidney functions occurs with age
• Many diseases/drugs prevalent in old age contribute to the decline
• Even robust elderly with good kidney functions less likely to recover after an insult1,2 e.g. AKI → This is becos when older, have less physical reserves in kidney compared to younger patients. - Risk factor of increasing risk of AKI is dehydration.
• High prevalence (48%) of chronic dehydration among community dwelling patients who sought help at an Emergency Department¹⁴
• Prostaglandin/Angiotensin II important to maintain GFR
• Caution with NSAIDs/Coxib/ACEI/Diuretics → all worsens AKI
• Thus if give ACEi, coxibs, NSAIDs anything that can block the prostaglandins or angiotensin II, patient is more likely to develop AKI
• Once remove the offending drugs, they might not be able to recover back to normal kidney state

Question 17

Which medicine(s) for nausea and vomiting can be used for someone who is dehydrated/have BLD/PDD and why?
However, what is one thing you need to consider before giving this medicine(s)?
What would you want to do to tackle the issue of using the medicine(s)?

Answer 17

Domperidone

• Domperidone is better since the patient has BLD and parkinsonism
  becos it does not cross BBB
• But in practice don’t use a lot of domperidone in elderly as not safe in patient with prolonged QTc (can cause torsades de pointe)
• Polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and lead to code blue / collapse

Ondansetron
If the nausea and vomiting is not very troubling to the patient then will go without medicines

• If patient really need sth then give ondansetron but can increase risk of torsades de pointes if patient has QTc prolongation, thus try to avoid IV administration, try to use lowest dose possible becos torsade de pointed induced by these kind of things are dose dependent and more likely to happen when receive as parenteral compared to oral

Want to look at modifiable risk factors for prolonged QTc normally see electrolyte imbalance, low K and low Mg for patient with diarrhea / vomiting, want to correct these things

• This helps to reduce cardiotoxicity risk from these agents if symptomatic relief of emesis is impt
• If want to use this kind of meds that can cause torsades de pointe, need to do it cautiously → means correct all the possible reversible causes and start with the lowest dose and then monitor

Question 18

What happens when PD is altered?
Examples of how altered PD is affecting elderly?

Answer 18

Change in receptor sensitivity, post-receptor signaling system, and/or homeostatic mechanism

E.g. Reduced sensitivity of baroreflexes in aorta → Less likely to respond well to postural changes thus more likely to experience postural hypotension

• Elderly more sensitive to CNS suppressant e.g. benzodiazepine
• Dementia reduces cholinergic reserves and increases CNS side effects of anticholinergic
• Neuroleptics (Antipsychotic) Sensitivity Reaction in patients with DLB/PDD. Thus, Avoid these group of meds as they increase sedation, confusion, increase in Parkinsonism, cognitive decline, higher death rate
• NO metoclopramide, promethazine (found in procodine), prochloperazine, antipsychotics (except low-dose quetiapine)
• Dementia with lewy bodies / Parkinson disease dementia may only affect 30-50% of patients with these conditions
• When it happens, they will become very sedated and confused. Their parkinsonism will increase and become more permanent and associated with cognitive decline and mortality rate will be higher