MR 9 Pharmacokinetics Flashcards
What is pharmacokinetics?
What the body does to a drug
What 4 questions should be asked when prescribing drugs?
Is drug getting into patient? (pharmaceutical process)
Is drug getting to site of action?(pharmacokinetic process)
Is drug producing desired effect? (pharmacodynamic process)
Is it translated to a therapeutic effect? (therapeutic process)
What formulations of drugs are there?
solid
liquid
What sites of administration can there be for a drug?
Local (eye, skin, inhalation etc)
Systemic:
Enteral (sublingual, oral, rectal)
Parenteral (subcutaneous/intramuscualar/intravenous injection, inhalation, transdermal
What is oral bioavailability?
The proportion of a dose given orally (or by any other route than intravenous) that reaches systemic circulation in an unchanged form
How is bioavailability expressed?
Amount -measured by area under curve of blood drug level vs time. depends on 1st pass metabolism and gut absorption
Rate- measured by peak height and rate of rise of drug level in blood. Depends on pharmaceutical factors, gut absorption
What is the therapeutic ratio?
Max tolerated dose/minimum effective dose
lethal dose to 50% of people) LD50/ED50 (effective dose in 50% of people
Describe the first pass effect
Substances absorbed from lumen of ileum enter venous blood which drains to hepatic portal vein and is transported directly to liver which is main site of drug metabolism as contains all necessary enzyme systems. This means the drug may be extensively metabolised during first pass through the liver.
What routes of administration can avoid first pass effect?
parenteral, sublingual, rectal
How much of an oral dose of paracetamol is usually metabolised by first pass effect?
90%
What is drug distribution?
The theoretical volume into which a drug has distributed assuming occurred instantaneously
How is drug distribution calculated?
Amount given/ Plasma concentration at time 0
Does free or total drug exert an effect?
free
When are protein binding interactions important?
When drug highly bound to albumin (>90%)
Drug has small volume of distribution
Drug has low therapeutic index
e.g warfarin, tolbutamide
What dose is an object drug (class I drug) used at?
dose much lower than number of albumin binding sites
What dose is a Precipitant Drug (class II drug) used at?
dose greater than number of available albumin binding sites
What happens when object and precipitant drugs are administered simultaneously?
Object drugs displaced at albumin binding sites by precipitant drugs, raising free levels of object drug.
This gives higher risk of toxicity
What are precipitant drugs to warfarin?
sulphonamides, aspirin, phenytoin
What are precipitant drugs to tolbutamide?
sulphonamides, aspirin
What is a precipitant drug to phenytoin?
Valproate
What is 1st order kinetics?
When drug elimination is proportional to drug level.
Constant fraction of drug eliminated in unit time
Half life can be defined
What is 0 order kinetics
When rate of elimination is a constant
Is 1st order kinetics linear?
No but when plotted log y axis against time yes
What does a graph of 0 order kinetics look like?
linear downward diagonal
During repeated drug administration how long does it take to achieve a new steady state?
5 half lives
Which rule of kinetics do most drugs follow?
1st order
Compare 1st and 0 order drugs
1st order- give predictable therapeutic response from dose increades
0 order- give therapeutic response that can suddenly escalate as elimination mechanisms saturate (rare examples e.g alcohol)
What happens in phase 1 drug metabolism?
Most drugs stable and unreactive so in phase 1 a reactive molecule is exposed on parent molecule or added to the molecule
What are the most common reaction types in phase I?
oxidation, reduction, hydrolysis
What enzyme system is used in phase I?
Cytochrome P450 (CYP) system
What qualities do the enzymes in CYP system have?
inducible
inhibitable
What high energy co-factor is used in phase I drug metabolism?
NADPH
What are some enzyme inducers of phase I and what drugs do they affect?
Phenobarbitone- warfarin
Rifampicin- oral contraceptive
Cigarettes- theophylline
What is an example of an enzyme inhibitor of phase I and what drugs does it affect
Cimetidine, diazepam
Give an example of a drug that can bypass phase 1?
morphine
What happens in phase II of drug metabolism?
The reactive intermediate from phase I is conjugated with a polar molecule to form a water soluble complex
What is the most common conjugate?What else can drugs conjugate with?
Glucoronic acid
sulphate ions, glutathione
What does phase II of drug metabolism requuire?
Specific enzymes and high energy co-factor uridine diphosphate glucuronic phosphate UDPGA
In what state is the drug when its filtered through the glomerular tuft in the kidney?
Free
When are weak acid drugs most excreted?
When urine is alkaline as this will ionise the drug and ionised drugs arent reabsorbed by the tubule
e.g aspirin
When are weak base drugs most excreted?
When urine is acidic as this will ionise drug and ionised drug stays in lumen and isnt reabsorbed by lumen
e.g amphetamine
