ADME Flashcards
(39 cards)
2 ways to avoid first pass metabolism
buccal/sublingual mucosa route (directly into bloodstream. venous return drains away from portal vein) rectal mucosa (bypasses portal vein)
4 ways soluble molecules can cross cell membranes
- diffusing directly through lipid (lipid solubility is highly important)
- diffusing through aqueous pores (more likely important for gas diffusion)
- transmembrane carrier proteins (eg. solute carriers)
- pinocytosis (mostly macromolecules, not drugs)
2 main routes for DRUGS to cross barriers/membranes
- diffusing directly through lipids: need particular chemical properties. associated with proteins (highly fat soluble, won’t want to exist in aqueous state)
OR - transmembrane protein with variety of mechanisms. Harnessing the mechanisms of normal proteins designed to carry things from diet to gut
weak bases in acidic environment
likely to be ionised.
slow rate of absorption in SI
more ionisation = less driving force to get the drug across the plasma..
BUT
once they are in the blood (pH is more neutral), the drug becomes slightly more ionised, trapping it back into the plasma sucked in.
weak acids in acidic environment
acidic: unlikely to be ionised. rapid easy absorption across SI.
still dependent on drug moving from stomach to SI though.
I am less ionised and have lipophilic properties. Will I easily get across the membrane?
Yes!
BUT then I’ll easily come back out of blood again.
What factors might influence decreased absorption of drug (re. GI motility)?
intestinal motility interactions with food (eg. bisphosphonates have high affinity for Ca. Eat food high in Ca, they are busy binding that and won't be absorbed. Absorption of bisphos decreased into blood) Interactions with acid (eg. increased exposure of acidic environment might chemically destroy the drug like penicillins can be degraded. so if take them on empty stomach, decreased absorption). presystematic metabolism (enzymes in stomach changing drug increasing FPM)
Clinical effect of delayed absorption?
Probably no effect - just different kinetics.
eg. paracetamol on an empty stomach will decrease Cmax (time taken to get peak plasma conc) over a longer time but the total paracetamol absorbed will be the same.
What factors might influence increased absorption of drug (re. GI motility)?
poorly water soluble drugs
increased solubilisation (eg betablocker taken with fatty food. will help dissolubilised highly lipophilic drugs and aid absorption)
decreased presystemic metabolism
OVERALL
factors affecting oral absorption
- particle size and formulation
- GI motility
- first pass metabolism (by gut wall or hepatic enzymes - any means of changing the drug. not just the liver!)
- physicochemical factors (direct drug interactions, dietary factors, varying pH)
- splanchnic blood flow (increased flow increases drug absorption)
- efflux pumps (become insensitive and upregulate P-glycoprotein to allow things to be hoovered out)
3 types of parenteral routes
- subcutaneous (slow absorption due to slow blood flow)
- intramuscular (lipophilic drugs rapidly. few barriers and high perfusion. capillaries are fenestrated , get through pores/leaky endothelial junctions. less dependent on transport proteins)
- inhalation
- intranasal
- topical
how will high MWT or very lipophobic drugs travel if administered intramuscular?
in lymphatics
what properties allows for such fast absorption using intramuscular route?
capillaries are fenestrated in muscles, get through pores/leaky endothelial junctions.
3 factors determining rate of onset of parenteral routes?
extent of capillary perfusion
drug vehicle (eg. v lipophilic drug injected in oily substance will SLOWLY get into blood)
affected by factors altering perfusion (eg. cold/hot compress
when do inhaled drugs become systemic?
lipid-soluble (volatile/gaseous anaesthetics)
drugs of abuse
accidental poisoning
what do inhaled drugs act on?
alveolar epithelium and bronchial mucosa
ways to ensure inhaled drugs keep local effect?
- modify structure (keep it highly ionised! eg. ipratropium)
- particulate size (eg. salbutamol)
- selectivity of Rs (high specificity for beta-2 R. expression of these limited to lungs and smooth muscle.)
- rapid breakdown in circulation (eg. fluticasone)
Advantages (2) and disadvantage of intranasal administration
+ avoids first pass metabolism
+ ease, convenience, safety
- limited drugs that are suitable (and requires very concentrated)
what keeps topical administration with local effect?
skin as a barrier:
stratified, squamous epithelium
keratinised layer
sebaceous gland secretions
3 examples of topical drugs desiring only local effects
corticosteroids for eczema (hydrocortisone)
antihistamines for insect bites (mepyramine)
local anaesthetics (EMLA)
2 examples of topical drugs desiring systemic effects
transdermal patches (HRT, GTN, nicotine) accidental poisoning (AChEsterase insecticides)
When giving topical drugs, what do you have to be careful of in children?
surface area: volume
different effects of a patch on adult vs. child
2 types of IVDs (intravascular device) providing 100% bioavailability
Peripheral venous catheters CVCs
Arterial catheters
if someone needed large volume of drug over a long period of time, which IVD
want more secure, less infection risk
centrally venous catheter
