Pharmacokinetics and pharmacodynamics Flashcards
What is the clinical importance of pharmacokinetics?
- Allows us to target and develop drugs not only at population level but also at a patient-specific level
- Predicting toxicity
- Addition of one new agent could be significant
What are the pharmacokinetic requirements to consider when producing a new drug?
- Bioavailability
- Half-life
- Drug elimination
- Inter-subject variability (differences in how drug affects different groups of people)
- Drug-drug interactions
How can we produce new drugs much faster?
- Repurpose old drugs e.g. add a compound to make it absorb better or improve side effect
- Already have lots of data about bioavailability, half-life etc.
Why do we need to obtain lots of information about pharmacokinetics when producing a new drug?
- Allows us to find a safe dose
- Gets into systemic circulation
- Find optimal plasma concentration that gets into right tissues
- Ultimately leads to effect that we want
What are some things to consider when thinking about pharmacokinetics?
- Renal function
- Smoking
- Age
- Sex
- Liver function
- Pregnancy
- Infection
- GI function
What can happen to free drugs after they’ve been absorbed?
- Enter systemic circulation
- Can be bound to proteins for distribution
- Or bound at tissue reservoirs
- Can be bound at receptors (prevents them from being distributed)
- Can be metabolised and then excreted
What is bioavailability?
- Measure of drug absorption where it can be used
- Drug administered via intravenous bolus is said to have 100% bioavailability
- For other routes, referenced as a fraction of IV
Compare oral bioavailability to IV bioavailability
- Most drugs have low oral bioavailability
- Need a large oral dose because most won’t get into systemic circulation e.g. due to metabolism and activity of liver/gut
What affects bioavailability?
Absorption:
- Formulation (can be changed to affect bioavailability)
- Age (luminal changes)
- Food (chelation, gastric emptying)
- Vomiting/malabsorption (Crohn’s)
- Previous surgery
First pass metabolism (metabolism before reaching systemic circulation)
What can happen to drug plasma concentration if elimination is rapid?
- Large fluctuations in drug plasma concentration will be seen
How do modified release preparations help prevent large fluctuations in plasma concentration?
- Allow drug to be absorbed slower or faster
- Either reduces or increases number of doses required
- Plasma concentration becomes more dependant on rate of absorption vs rate of elimination
- Can help with adherence - patient taking their medication
What is needed to allow drugs to reach their target organs?
- Need adequate plasma levels
What factors affect therapeutic agent distribution?
- Blood flow
- Capillary structure
- Poorly vs well perfused tissues
- Lipophilicity vs hydrophilicity
- If drug is bound to something else
- Chemical formula of drug
Which drugs are protein binding?
- Acidic drugs bind to albumin (common)
- Hormones bind to globulins
- Basic drugs bind to lipoproteins and glycoproteins
- Drug distribution associated with volume distribution function of these factors
What model does distribution and equilibration of of IV drugs follow?
- Multiple compartment model
- Different compartments may receive different concentrations of drug
- Takes a while for drug concentration to equilibrate between compartments
- Elimination can help speed equilibration up
What type of drug is able to have therapeutic effect?
- Free drug - travels through systemic circulation and bind with target receptors
- Drug bound to protein is unable to do anything
Outline drug-protein binding
- There is equilibrium between bound and unbound drug in different compartments
- Free drug goes onto to target receptors
What is the clinical importance of drug-protein binding?
- Some drugs bind more readily to proteins so stay outside of plasma
- If drug B is introduced that binds more preferentially to a protein, drug A gets displaced
- More drug A is free and can act at its therapeutic site
When can it be dangerous for the amount of a free drug to increase in the body?
- Pregnancy (protein levels may be lower)
- Hypoalbuminaemia
- Renal failure
Outline volume of distribution
- Proportionality factor
- Association between drug concentration we can measure in the blood and the amount that’s actually in the body (dose)
How would you describe drug concentration?
- Amount of drug per unit volume
- E.g. 100 mg/L
What is the equation for volume of distribution?
- Vd = Dose/[Drug] plasma
Why is volume of distribution often referred to as apparent?
- Protein binding
- Drug can be sequestered by other body compartments e.g. fat
- Very little drug actually stays in blood plasma
What do different values for Vd suggest?
- Smaller apparent Vd suggests drug is confined to plasma and ECF
- Larger apparent Vd suggests drug is distributed throughout tissues (eventually as drug is metabolised, more will become free and shift to plasma)
What is the equation to work out dose?
- Vd x [Drug] plasma = dose
What affects the route and mechanism of drug metabolism?
- Size
- Lipophilicity
- Hydrophobicity
- Structural complexity
Where are the sites of drug metabolism?
- Liver
- Has most numerous and diverse metabolic enzymes
- Phase I and phase II metabolism occurs here
Outline phase I of metabolism
- Phase I enzymes collectively referred to as CYP450s
- Catalyse oxidation, reduction, hydrolysis reactions
- Metabolise a wide range of molecules
- Metabolised drugs are eliminated or go onto Phase II
- Some pro-drugs are activated by Phase I metabolism
