Pharmacokinetics II Flashcards
What are the 4 major water compartments in the body?
What percentages of the body weight do these conribute to?
1) Extracellular fluid
2) Intracellular fluid (20-40%)
3) Transcellular fluid (2.5%)
4) Fat (20%)
How does the volume of a compartment affect a drug?
Concentration of a drug in that compartment at equilibrium
What percentage do the water compartments contribute to the body weight?
50-70%
What are the 3 components of extracellular fluid and how much body weight percentage?
1) Plasma (4.5%)
2) Interstitial fluid (30-40%)
3) Lymph (1-2%)
What is interstitial fluid?
Extracellular fluid which bathes cells and tissues
How are drugs distributed to different parts of the body?
In the plasma
Where is the bioavailability of a drug measured?
In the plasma
How does fat impact the pharmacokinetics of a drug? (4)
- Made of lipids
- Non- polar drugs can easily enter and accumulate here
- Poorly perfused
- Varies between different people
Examples of the compartments of the body which are tightly regulated and why(2)
The foetus
- Protected by the placenta
The CNS
- Protected by the BBB
What is the distribution of the drug based upon?
- Permeability
- Lipid solubility
What is the BBB impermeable to and why?
Water soluble molecules, they have poor lipid solubility
Examples of drugs which can’t cross the BBB?
- Antibiotics
- Chemotherapy drugs
(poor lipid solubility)
Examples of which molecules easily cross the BBB?
Lipid soluble
- Ethanol
- Caffeine
What happens to tight junctions during inflammation?
Become ‘leaky’
Where is the chemoreceptor zone in the body and what does this do?
- Outside of the BBB
- Induces vomiting - can happen during drug treatments
How does the protein albumin affect the free concentration of drugs in the plasma?
- Binds to acidic drugs
- Reduces the concentration of drug in the plasma
What are the 3 considerations of drug dose, regarding albumin?
When low doses of free drug are needed- need to increase dose to overcome binding to albumin
When high doses of free drug are needed - already taking a high dose
- Binding to and from albumin can decrease/increase the concentration of drug in the plasma - dangerous
Taking another drug can displace the original drug from albumin - increasing free concentration of the original drug
How does the partition into body fat effect the free concentration of drug in compartments why is this a disadvantage?
- Drug accumulates in the body fat
- Changes the amount and duration of drug in the body
- Difficult to predict the concentration of drug where you want it to act
What drugs are more likely to partition into the body fat?
Lipid soluble drugs
What affects drug concentration in the body?
Absorption (permeability, lipid solubility, into fats)
Distribution
Metabolisation
Excretion
Where does drug metabolism mostly occur?
In the liver
What are the 2 biochemical reactions in the liver?
Phase 1 - catabolic reaction
Phase 2 - synthetic (anabolic) reactions
What happens in phase 1 in the liver?
- Produce more reactive compound
- By oxidation, reduction or hydrolysis
- Adds a reactive group (-OH) which serves as a point of attack for phase 2 reaction
What happens in phase 2 in the liver?
- Conjugation to produce an inactive product
-
What is conjugation?
Attachment of a substituent group
What are the microsomal enzymes present in the liver?(3)
- Cytochrome P450
- Alcohol dehydrogenase
- MAO
Where is cytochrome P450 found?
Embedded in the membrane of the smooth muscle endoplasmic reticulum of the liver
Which enzyme can cause drug concentration to increase and why?
Alcohol dehydrogenase as it is easily saturated
What does enzyme induction cause?
- Increase metabolic enzyme in the body
- Cause drug to have a less effect as concentration decrease
What does drug metabolism depend upon?
The ability of the drug to cross the membrane into the liver
What are pro-drugs?
Drugs which only become active after undergoing phase 1 of metabolism
Drugs which concentrations rise slower in the body
How do drugs get into the liver? (2)
Through the portal system
Through the plasma
How may the metabolism of drugs decreased as they go through the portal system?
They join up with bile
How do drugs escape metabolism? What happens instead?
They bind with food in the gut - go straight out of the body through excretion
How is aspirin eliminated from the body?
Phase 1
- Gain OH group
- Make salicylic acid
Phase 2
- Large sugar molecule added to the free -OH group
- Forms glucuronide
- Drug can no longer bind to target - drug action stopped
- Facilitate excretion out of the body
What is important about the intermediate of paracetamol when it is being metabolised?
It it poisonous
Why is there differences between how individuals metabolise drugs?
- Polymorphisms between individuals in P450 enzyme
- Different isoforms of P45 react with different drugs
What are inducers of P450 drug metabolism?
Certain food activate/ inhibit P450
What are the 3 routes of drug excretion from the body?
1) Renal excretion
2) GI excretion
3) Lung excretion
When are drugs excreted in the urine?
After undergoing phase 2 of metabolism and after glomerular filtration etc. into the urine
Which drugs go through urine excretion and which drugs don’t?
Small drugs do
Drugs bound to albumin don’t
What happens if a person has kidney disease?
Concentration of drug in the blood may be higher
What % of drugs are excreted through the kidneys?
80%
What does the time course of clearance of a drug from the body follow and what is this?
Mono-exponential decay
What does exponential decay depend upon?
Rate of metabolism and rate of excretion
What is the half-life of a drug dependant on?
- The concentration of drug taken
- The drug taken
Describe saturation kinetics of a drug
- Enzyme cannot keep up with the metabolism of the drug
- When exceed the rate of which drug can be administered (set by the metabolism of the drug)
- Linear increase in concentration of the drug in the plasma
- Unexpected increase of the drug concentration causing toxicity
What are some advantages of prodrugs? (4)
- Prevent damage to the GI tract
- Selective toxicity (eg. only cleaved in HIV cells)
- Cross BBB quicker than active form
- Greater bioavailability than active from
What determines the rate of which a drug can be administered?
The metabolism of the drug
Are strong bases absorbed well in the GI tract? Why?
NO
Favours dissociation of the drug - poor absorption
What is sublingual administration?
What does this avoid?
Placing a tablet underneath the tongue
Avoids first pass metabolism in the liver
