PK, PD In Elderly

Question 1

Explain PK Changes in Elderly (Absorption - Oral Route)

Answer 1

1. Mucosal atrophy (not always associated with aging) –> Reduce gastric acid levels
2. Gastric acid suppression (PPI, H2RA)
   - Reduce B12, Fe, Ca, Itraconazole, Ketoconazole, Cancer therapy with -tinibs
3. Increase GI transit time
   - Same BA (usually no effect) but theoretically can affect absorption of some meds –> e.g: bisphosphonates)
4. FPE may be affected due to metabolism in intestines and liver
5. P-gp not much effect on age alone (no change for most drugs)
6. DDI:
   - phenytoin reduce dexamethasone BA
   - clarithro increase cmax of digoxin (due to inhibition of p-gp)

Question 2

Explain PK Changes in Elderly (Absorption - Transdermal)

Answer 2

Aging –> skin atrophy and thinning (incr absorption) but reduce blood flow (reduce absorption)

Hard to characterise effect on transdermal absorption

Key point: fever/heat –> incr drug delivery due to increase passive diffusion and blood supply (fetanyl, exelon, nitroglycerin)

Question 3

Explain PK Changes in Elderly (Distribution)

Answer 3

Total water body, lean mass drop and fat increases

Serum albumin and a-1 glycoprotein decreases with age but mainly due to illness

Brain: BBB more leaky and porous. P-gp also reduced –> incr risk of CNS side effects

Question 4

How to Interpret Phenytoin Levels in Elderly?

Answer 4

Initial: Reduce albumin –> Incr free phenytoin transiently

Subsequent: Same free conc but total conc drop (free conc will drop if all factors are constant)

Interpret phenytoin levels in conjunction with serum albumin

Sheiner-Tozer equation: Corrected total phenytoin concentration = Observed total phenytoin concentration/[(0.2 × Albumin) + 0.1]; phenytoin in µg/mL, albumin in g/dL

Question 5

How to Interpret Valproate Levels in Elderly?

Answer 5

Hypoalbuminemia but no validated formula so titrate according to free valproate levels

Inform Urology if albumin low

Note: some labs don’t count free valproate

Question 6

Explain PK Changes in Elderly (Metabolism)

Answer 6

Mainly affect Phase I instead of Phase II

Phase I reduced due to reduced liver size, hepatic blood flow and thickening of sinusoidal epithelium.
- CYP affected by frailty (incr inflammation), aging
- Inhibition: azoles, clarithro, cimetidine
- Inducer: rifampicin, CBZ, phenytoin

Phase II can be affected if liver size reduced and frailty cause more drop as it reduce enzyme activity

Question 7

Explain PK Changes in Elderly (Excretion)

Answer 7

Drop in renal function –> affects clearance

Elderly that is robust but get insult from kidneys is less likely to recover

Risk factors: dehydration, NSAIDs, coxibs, ACEI, diuretics

Question 7

Explain PD Changes in Elderly

Answer 7

Mechanism:
1. Changes in receptor sensitivity
2. Post receptor signalling system
3. Homeostatic mechanism (e.g: baroreceptor decr, less sensitive and unable to bring back BP)

Disease states:
- Dementia reduce cholinergic reserves, incr CNS effects
- DLB/PDD: Antipsychotic sensitivity reactions (sedation, confusion, parkisonism, cognitive decline, more death) –> no metoclopramide, prochlorperazine, FGA or SGA (except low dose quetiapine)