pharmacokinetics 2 Flashcards
what are the 5 steps in the pathway of drugs?
- Liberation
- absorption
- distribution
- metabolism
- excretion
metabolism:
- what kind of process in metabolism?
- where does drug metabolism occur?
- what is the main purpose of metablism?
- metabolism is a multi-stage process, in which one drug can turn into many different metabolites
- drug metabolism mainly occurs in the liver in 2 phases
- the main purpose of metabolism is to make drugs which are much easier to get rid of in water (predominantly via kidney in urine or via faeces)
metabolism:
- what kind of process in metabolism?
- where does drug metabolism occur?
- what is the main purpose of metablism?
- metabolism is a multi-stage process, in which one drug can turn into many different metabolites
- drug metabolism mainly occurs in the liver in 2 phases
- the main purpose of metabolism is to make drugs which are much easier to get rid of in water (predominantly via kidney in urine or via faeces)
- what reactions can phase 1 metabolism involve?
- what are the products of phase 1 metabolism?
- what are phase 2 metabolism types of reactions?
- what are the products of phase 1 metabolism?
phase 1 metabolism:
1. it can involve reduction or hydrolysis of the drug, but the most common biochemical process that occurs is oxidation
- “functionalisation” ^ introduces or adds/reveals a reactive chemical group on a structure
- products are often more reactive
phase 2 metabolism:
3. synthetic, conjugative reactions
- creates hydrophilic (soluble in water), inactive compounds generated by adding bulky chemical structures to reactive chemical groups
what is the difference between hydrophilic and hydrophobic drugs?
- if the drug is more hydrophilic, then it can be easily be excreted through kidney and urine (does not need to be metabolised)
- if the drug is hydrophobic, then is must be metabolised (bigger hydrophobic structures are conjugated again and sicarded through bile, however bile enter intestines and is reabsorbed meaning these drugs continue to remain the body’s system)
metabolism through cytochrome P450 enzymes:
- what are cytochrome P450 enzymes?
- where does metabolism occur?
- how many human genes code for cytochrome P450 enzymes
- what are the 2 functions of cytochrome P450 enzymes?
- they are mixed mono-oxygenases
- metabolism which occurs throughout the body, but extensively in the liver
- there are 7 human genes coding for CYP P450 enzymes, the expression of these enzymes varies by sex, age, many more factors
-
functions:
- biosynthesis of steroids, fatty acids and bile acids- also responsible for (particularly phase 1 ) metabolism of endogenous and exogenous substrates
describe the metabolism of paracetamol:
paracetamol can either go through sulphate conjugation, glucoronide conjugation (conjugation being a phase 2 reaction of detoxifying a drug to make it more excretable)
- however a small percentage is metabolised by cytochrome P450 enzymes which produces a toxic metabolite
- this toxic metabolite is quickly detoxified by glutathione conjugation (this is a 3rd conjugation reaction that can only occur once paracetamol has gone through cytochrome P450 metabolism)
- however, if glutathione is depleted, the metabolites formed by cytochrome P450 metabolism is irreversibly combined with liver proteins which inhibit their function and leads to the necrosis of the liver
- acetyl cysteine can be given to improve glutathione levels
warfarin and phenobarbital:
- what is phenobarbital?
- what is warfarin metabolised by?
- what does this mean?
- phenobarbital is an inducer of cytochrome P450 enzymes meaning it increases expression of these enzymes, therefore patients taking phenobarbital present with an increased enzyme activity in the liver
- warfarin is metabolised by cytochrome P450
- therefore, there is a decreased effectiveness of warfarin in patients taking phenobarbital since it increases metabolism/elimination of warfarin by increasing enzyme activity of the liver by increasing expression of cytochrome P450 enzymes
grapefruit juice and statins:
- what is simvastatin?
- what does grapefruit juice do?
- what does this mean?
- simvastatin (a cholesterol lowering drug) is metabolised by CYP3A4 (a cytochrome P450 enzymes) in the gut wall and liver
- grapefruit juice blocks CYP3A4
- therefore prevents the metabolism of simvastatin and so there is a greater concentration of simvastatin in the blood plasma than normal when grapefruit juice is drank by patient while on simvastatin
what are 3 drug examples which are non-depolarising neuromuscular junction blockers?
what are their onsets and durations?
how are they each metabolised/eliminated?
elimination:
- what are the 2 states drugs can be eliminated as?
- how is the elimination of hydrophilic drugs different to lipophilic drugs?
- what are the 8 possible sources of excretion?
- what is the most important organ in elimination of drugs?
- drugs are eliminated either unchanged or as metabolites
- hydrophilic drugs are eliminated more readily than lipophilic drugs
- except by the lungs
- possible sources of excretion include:
- breath
- urine
- saliva
- perspiration
- faeces
- milk
- bile
- hair - the kidneys are the most important organs involved in the elimination of drugs and their metabolites
kinetic parameters:
- what is the therapeutic window?
- what is the minimum effective concentration?
- what is the minimum toxic concentration?
- therapeutic window: The gap between the minimum effective concentration and the minimum concentration that has unwanted side effects (toxicity).
- minimum effective concentration: the minimum plasma concentration that needs to be achieved before evidence of a therapeutic effect could be observed
- minimum toxic concentration: The minimum plasma concentration required to observe unwanted or toxic effects of the drug
kinetic parameters:
what is the onset of action?
onset of action: How long it takes your drug plasma concentrations to reach the “minimum effective concentration” following administration.
Most IV drugs will have quicker onset of action than orally administered drugs, because you don’t have to undergo the same processes of dissolution and absorption before the drug can get in to the blood stream
kinetic parameters:
what is the duration of action?
Duration of action – How long evidence of a drug’s pharmacological action remains evident.
For some drugs, this can be pure ages (technical term), especially if it’s effect is to induce cellular changes
kinetic parameters:
what is the Cmax?
what is the Tmax
- Cmax – The peak plasma concentration achieved after administration of a drug
Sometimes achieving a peak plasma concentration is more desirable than how long the drug stays above a certain threshold (i.e. “duration of action”) - Tmax – The time taken to reach Cmax
kinetic parameters:
what is the plasma clearance half-life/elimination half-life?
Plasma clearance half life/elimination half-life - It describes how quickly the dose of drug is removed from the body and is a function of the rate of elimination
- (i.e. predominately your kidney and liver function)
plus how well distributed a drug is around your body (how long from peak plasma concentration to half of the peak of the plasma concentration)
what occurs in repeated doses of a drug?
Repeated doses - when a patient takes doses outside of effective intervals, this builds a summation type effect in which can lead to a toxic concentration range: (with oral intake of drugs)
plasma drug concentration during IV infusion:
- what happens to plasma concentration during infusion?
- what is used instead of Cmax? (peak plasma concentration)
- plasma concentration increases during infusion until rate of input equals rate of output
- Css - steady state concentration (used instead of Cmax)
