Pharm Flashcards
What are some substances that cross the BBB with ease?
water, CO2, O2, lipid-soluble free steroid hormones
P-gp’s role
excludes substances/drugs from CNS via efflux from endothelial cells
Conditions that compromise BBB integrity
- progressive loss via age and disease
- temporary loss via MI/cerebral edema, marked rise in BP, injection of hypotonic solutions
- also recently noted: repeated sub-concussive collisions; may release S100B into blood, make Abs, and get degenerative changes evident only years later
How do drugs get into the CNS past BBB?
- receptor-mediated transcytosis (i.e., receptors for insulin, LDL, iron transferrin, leptin)
- non-specific adsorptive-mediated transcytosis
Features of the BBB
- tight junctions and adherens junctions between endothelial cells
- closely apposed basal lamina
- astrocytic end feet
- metabolic enzymes within the endothelial cells
- transport mechanisms, for transcytosis, etc.
- P-glycoprotein for efflux
Energy-dependent pumps of the BBB
- SLC
- ABC family: P-gp, BSEP, MRP, BCRP
Properties of drugs that access the CNS
- lipophilicity
- free-drug (not protein bound)
- non-ionized
- in general, all proteins/polypeptides are excluded
- pro-drugs are good formulations for action limited to CNS
Highly lipid drugs
- have long elimination half-lives (take a while to get out of the body)
- have short duration of clinical action: act but then are quickly distributed elsewhere; this is particularly important when re-distribution takes them out of the CNS
- the BBB is a 2-way street; goes in via concentration gradient, then when it’s all in CNS it’s gonna leave via concentration gradient (phenobarbital)
General drug classes that are significant P-gp substrates/inhibitors
- *Substrates: (can’t really be overcome with higher dose of the drug, like dealing with CYPs can)
- anti-cancer agents (a real problem for treating brain tumors)
- antidiarrheals
- antidepressants
- antihistamines
- antipsychotics
- antiretrovirals
- cardioactive drugs
- antiemetics
- H2 antagonists
- GLUCOCORTICOIDS
- *P-gp inhibitors:
- amiodarone, cyclosporin, nifedipine, quinidine, verapamil
Antidepressant activity on P-gp?
- in depressed patients, there may be a lack of feedback inhibition to the hypothalamus because P-gp is kicking out the GCs/cortisol that would otherwise feedback inhibit
- antidepressants have been shown to enhance GC receptor activity in vitro, but not if P-gp is also present
- thought is that antidepressants may occupy P-gp, meaning the GCs can get in all the way to hypothalamus and have their effect
How do peripheral autonomic drugs impact CNS function via effects on adrenergic and cholinergic pathways?
by getting into the CNS and binding to the same receptors (which exist in both places) but having different effects
Major side effects of adrenergic antagonist therapy
• Alpha-1 blockade from antidepressants: postural HOTN and dizziness; potentiation of anti-hypertensive effects of other drugs; reflex tachycardia
Major [CNS] side effects of cholinergic antagonist therapy
• muscarinic receptor blockade from antidepressants: blurred vision; CNS = memory/cognition, impairment, delirium;
• peripheral effects:
dry mouth, dec. peristalsis, constipation; precipitate narrow-angle glaucoma, sinus tachycardia, urinary hesitancy/retention
Locus ceruleus
- regulates sleep and arousal
- contains the majority of noradrenergic neurons in the brain
Nicotinic receptors coupled to:
multimeric ion channel; opening allows influx of Na/Ca; cell depolarizes
