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
what is Functionalisation
Introduction of a reactive group
Products more reactive, and sometimes more toxic.
what are cytochrome P450
Large family of related but distinct enzymes
- may act on same substrate but at different rates
- Embedded in smooth endoplasmic reticulum
- Require oxygen, NAPDH (nicotinamide adenine dinucleotide phosphate) and NAPDH-P450 reductase
different types of P450 metabolise different drugs
give variations in P450
- between species
- genetic polymorphisms
- CYP2C9 genetic variants are common = Low metabolic activity - environment factors
- consume, things you are exposed to, other drugs- could induce or reduce metabolism of drug- affects plasma concentrations of drug it is metabolising
give 3 examples of other phase 1 enzymes
- Butrylcholinesterase
- structurally similar to acetylcholine – overactivates cholinergic receptors on muscles to cause paralysis = neuromuscular blocker
- hydrolyses suxamethonium - Aspirin esterase
- In plasma
- Hydrolyses aspirin to salicylate - Alcohol dehydrogenase
- In liver cell (hepatocyte) cytoplasm
- Oxidises ethanol to acetaldehyde
- Requires NAD+
what is the aim of phase 1 and 2 reactions
decrease lipid solubility and thus increase renal excretion
what do phase 2 reactions need to occur
donors
- compounds which donate their group
what is conjugation
where does it occur
attachment of a substituent group
liver
what happens during phase 2 reactions and what are their products normally like
Another chemical or group is added to exposed group making them more water souble so more likely to be excreted
If not enough donor, cause more reactive group= toxic
products are norammly inactive
what are the chemicals that can be conjugated and what are their donors
Glucuronyl - UDP-α-glucuronide
Sulfate - Glutathione
Methyl - S-adenosyl methionine
Acetyl - acetyl CoA
what enzyme is used in phase 2 reactions
UDP – glucuronyl transferase
what are pro-drugs
a drug that is inactive and becomes active once it is metabolised
how are drugs eliminated
Depends on physicochemical properties of drug & metabolites
how can drugs be eliminated
- faeces
- mass transport in gut - urine
- water soluble, filtered out by kidneys- penicillin - exhaled
- volatile gases - breast milk
- secreted into glands - sweat
- secreted into glands
how do we quantify elimination
total clearance (ClTot)
what is total clearance (ClTot)
Volume of plasma (or blood) cleared of the drug per unit of time (usually l/hr) to achieve overall elimination of drug from the body
what is the equation of total clearance (CLTot)
Total body CL = sum of all organ CL processes
- CLTot = CLmet + CLren + Clall the other ones
what equation is used to estimate clearance from graph
Divide the dose given (Q) by
the total systemic exposure to the drug (Area under curve)
what is the equation for clearance (L) of a drug administered by IV or orally
IV dose (mg/L) / IV area under the curve (mg/L/hr)
oral dose X bioavailability (F) / oral area under the curve
what is first order kinetics
rate of elimination directly proportional to drug concentration
= Exponential decay
- 25%↓ in concentration dependent of concentration
what is zero order kinetics
25%↓ in concentration independent of concentration
= linear decay
what is elimination rate constant (Kel)
fraction of drug eliminated per unit time at any time point
Expressed as (time)-1 so if 0.1 hr-1 = 10% of drug at that point is eliminated per hour
what is the equation for elimination rate constant
total clearance/ volume of distribution
what is the equation for elimination rate constant slope when using plasma concentration
Slope = a/b h-1
Example
Kel = ln (10/2)
5.8-3.4 hours
Kel = 1.61 = 0.67 hr-1
2.4 hrs
~ 67% of drug remaining eliminated / hr
at that time point
- use PP
what is elimination half life (t ½)
Time taken for plasma drug concentration to reduce by 1/2
what is the equation for half life
ln2/Kel
after about 6 halfs life, very little drug left in body
