IC 2 (PK) Flashcards
what causes PK and PD changes
- Aging process
- Effect of Illness, comorbidities, medications
absorption changes (PO)
- mucosal atrophy
- Gastric acid reduced
* Does not reduce by age alone - usually due to gastric acid supp (PPI/H2RA)
* Reduce vit B12, Ca, Fe absorption
* Reduce absorption and drug conc of
□ itraconazole, ketoconzaole: overcome with IV/ oral susp
□ -tinib (cancer) dasatinib, erlotinib
absorption changes (PO
Gastrointestinal transit time prolonged in old age (STOMACH –> SI)
□ Effects of disease (gastroparesis)
□ Effect of drugs (anticoag, antispasmodics, opioids)
- Same PO bioavailability, extent of absorption but incr time to peak conc
concerns for drugs that may cause esophageal injury eg
Alendronate, 30mins may not be enough for older pts to wait for bfast/ other meds (theoretically if transit time is prolonged).
□ Monitor SE and drug efficacy
□ Weigh pros and cons of drug
PO absorption and first pass metabolicm (walls of intestine and liver)
(Not much changes by age) in efflux transport/ P-glycoprotein
but DDI may affect:
- Phenytoin induce pgp: reduce dexamethasone PO bioavail (84 –>33%)
- Clarithromycin inhibit pgp: incr cmax digoxin by 84%, level of drugs incr by 64%
absorption changes (TD)
epidermis, blood supply, heat
Effect of age on TD absorption of drugs hard to characterise
- Epidermis and dermis thins with age: incr TD absorption
- Cutaneous blood supply drops: decr TD absorption
Heat incr drug deliver TD (more SE) Incr passive diffusion and blood supply
absorption (IM, SC inj)
decr absorption: muscle mass sig decr + poor blood defusion to muscle or sc tissues
distribution changes
- Total body and lean muscle mass drop
- Fat increases
Effect on distribution depends on physical property of drugs (likely reduce dose)
- Total body and lean muscle mass drop (Vd decr for water soluble med)
○ Higher serum conc, less distribute to muscles: Digoxin, ethanol, lithium, theophylline, morphine - Fat increases (Vd incr for lipid soluble med)
○ Remain in body longer: Phenytoin, VA, diazepam, lidocaine, oxazepam
distribution changes
- Meds bind to serum proteins (albumin, GP)
Age does not sig affect so not clinically impt:
- Serum albumin decr (10-15% with age) – more unbound drug (affect PT, SV)
* Albumin decr more if sick, malnourished, frail
* A1 acid glycoprotein incr with age: sick
PT and hypoalbuminuremia
- albumin <40g/L
- Adults: 90-95% PT bound to albumin. Only free PT is active.
- Aging, frail, malnourish: albumin DECR
- More free PT conc
- Require PT albumin correction as PT levels need to be interpreted in conjunction with serum albumin
SV and hypoalbuminuremia
- Adults: 90-95% highly bound to albumin
- Older adults, hypoalbuminemia: associated with falsely suppressed total VA conc
- But no establish formula for correction
changes in distribution to brain
BBB, PGP with age
Barriers to distribution of drugs into CNS with age
- Blood brain barrier = LEAKY
□ Porous with dementia - P-glycoprotein = decr activity
Risk of ADR, elderly sensitive to CNS SE of anticholinergic agents
changes in metabolism
liver function
- Inactivate and facilitate elimination
- Activate prodrugs
- May form toxic metabolite (Paracetamol – CYP2E1–> NAPQI)
Especially with alcoholics, induced more CYP2E1, more toxic metabolites accumulate
Depletes glutathione(can worsen liver damage)
changes in metabolism
phase 1 (CYP450 enzymes)
- metabolism
- inflammation
- Metabolism lower with age: due to reduced liver mass, hepatic blood flow, thickening of sinusoidal endothelium
- Frailty, incr inflammation: reduce activity
- Drug-induced inhibition and induction important
* Inhibitor: azole agent, clarithromycin, cimetidine
* Inducer: phenytoin, carbamazepine, rifampicin — DDI other drug decr conc
metabolism changes
Phase 2: conjugation (glucuronidation, acetylation, sulfation. Major enzyme: UGT)
- Largely unchanged with age. Enzyme itself not affected by age alone
- Qty of UGT may decr
* smaller liver.
* Frailty
excretion changes
kidney function decline
- Decline in kidney functions occurs with age (less reserve in kidney function)
○ Many disease/ drugs prevalent in old age that contributes to decline in kidney function
○ May be irreversible damage
○ many meds dosed based on SCr or CrCl
incr risk of kidney damage by
Chronic dehydration + AKI inducing drugs
NSAIDs/ Coxibs/ ACEi/ diuretic
* inhibition of Prostaglandin/ Ang II which are impt to maintain GFR
PD Changes
- Change in receptor affinity, post-receptor signaling system and/or homeostatic mechanism (hormone imbalance)
○ Reduced baroreflex sensitivity in aorta (unable to sense drop in BP when postural changes = orthostatic hypotension) - Elderly more sensitive to CNS suppressant (BZP/ Z-drugs, APS, narcotic analgesics)
- Dementia reduced cholinergic reserves and incr CNS SE of anticholinergics
○ vs when PK: is due to BBB more leaky, porous - Pts with DLB/ PDD (dementia with lewy body/ parkinson disease dementia) prone to Neuroleptics (antipsychotic) sensitivity reaction
○ Sedation, confusion, incr parkinsonism, cognitive decline, mortality
○ avoid DOPAMINE ANTAGONIST/ APS (except quetiapine, Pimavanserin)
(DDI) Pts with DLB/ PDD (dementia with lewy body/ parkinson disease dementia) prone to Neuroleptics (antipsychotic) sensitivity reaction
avoid DOPAMINE ANTAGONIST/ APS (except Quetiapine, Pimavanserin, clozapine…agranulocytosis)
- metoclopramide, promethazine, prochlorperazine, most antipsychotics
clozapine
quetiapine
pimavanserin
clozapine - little affinity to D2 receptors
quetiapine - little affinity to D2 receptors
pimavanserin - acts through 5HT2 RA
(APS worsen motor and neuropsychiatric sx: cognition and psychosis for pt with DLB: confusion, loss of memory)
parkinsonism: include conditions like PD, drug-induced, DLB
drug-induced parkinsonism: Dopaminergic deficiences (gait, tremor, even psychosis)
