Drug elimination I (distribution, metabolism, elimination) L5 Flashcards
What happens to drug once it has been absorbed into plasma
it gets distributed to other body compartments
this distribution is not equal
what factors affect distribution
- blood perfusion of the tissue or organ
- ability to cross the membrane
- plasma protein binding ability
give percentage of free drug in different compartments
intracellular water: 35%
fat: 20%
interstitial water: 16%
plasma water: 5%
transcellular water: 2%
-( CSF digestive secretions peritoneal fluid )
what are 3 different ways drug can cross membrane
- lipophilic, unionised: lipid bilayer
- small, water soluble: aqueous pores
- hydrophilic, ionised: carrier proteins
what are two important membranes
- GI tract
- blood brain barrier
what is the blood brain barrier
Continuous layer of epithelial cells around brain and spinal cord
means brain inaccessible to many drugs
Can become leaky with inflammation
Benefits of BBB preventing CNS effects of certain drugs e.g. antihistamines and sedation
Psychoactive drugs need to be able to penetrate BBB
what did the mice experiment show about blood brain barrier
mouse injected with histamine labelled with C13
- shows up black
parts of the mouse was black/grey
brain was completely white
- shows impermeable nature
what are the two main plasma proteins and what do they bind to
- albumin
- Binds mostly acidic drugs (e.g. warfarin, NSAIDs) and a small number of basic drugs (e.g. TCA’s) - α1 acid glycoprotein (AAG)
- Binds mostly basic and neutral drugs
↑ inflammatory disease
what factors does the amount of drug bound to plasma proteins depend on
- Concentration of free drug in plasma
- Affinity for the binding site on proteins (2 sites per albumin molecule)
- Concentration of protein
what is the purpose of plasma proteins
bound drugs can not cross membranes
Small differences in binding e.g. 99.5 vs 99% can have large effects on free drug concentration and therefore drug effect
how do we quantify distribution
using Apparent volume of distribution (Vd)
what is volume of distribution (Vd)
volume of fluid that would be required to contain the total amount of drug in the body (Q) at the same concentration as that present in the plasma Cp
what is the equation for volume of distribution (Vd)
total amount of drug administered (Q)/ plasma concentration (Cp) at time 0
units of volume i.e. l or ml
what does volume distribution not tell us
what compartment the drug is in
if a drug has a high volume distribution, what does it mean interms of composition in plasma
higher the Vd, less bound to plasma proteins so leaves blood quicker into tissue
how are drugs eliminated from the body
via metabolism and excretion
what is the main route of excretion
and what are the two other routes
in urine via kidneys
intestine, skin, lungs
what happens to lipophilic drugs before they are excreted
need to be metabolised to more polar products making them water soluble
Polar = positive charge on one area of molecule and negative charge on other e.g. water
describe the two pahses of metabolsim
phase 1:
- catabolic mostly mediated by cytochrome P450
phase 2:
- Anabolic conjugation reactions
what is the aim of phase 1 reactions
Enzymatic reactions which often expose or introduce a hydroxyl (-OH), amino (-NH2), sulfhydryl (-SH), or carboxyl (-COOH) polar functional group to the lipophilic drug
what is oxidation
where does it mainly take place
addition of oxygen and/or the removal of hydrogen (really loss of electrons)
in the liver
what is hydroxylation
Conversion of a hydrogen to a hydroxyl group by adding oxygen
R-H ⇒ R-OH
what is deamination
Conversion of an amino group to a carbonyl group via addition of oxygen and removal of hydrogen
R-C-NH2⇒R-C=O
what is dehydrogenation
Conversion of a hydroxyl group to a carbonyl group via removal of hydrogen
R-C-OH ⇒ R-C=O
