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
Outline Phase II of drug metabolism
- Carried out by hepatic enzymes
- Exhibit more rapid kinetics than CYP450s
- Catalyse: sulphation, glucorinadation, glutathione conjugation, methylation, N-acetylation
- Increases ionic charge of drugs
- Enhances renal elimination
How can drugs be eliminated after being metabolised?
- Kidney - excreted in urine
- Gallbladder - excreted in bile
Outline the properties of the Cytochrome P450 enzymes
- Catalyse majority of phase I reactions
- Equally important for endogenous substances
- Oxidation reactions most important
- Found abundantly in smooth ER in hepatocytes and in most other tissues
- Encoded for by numerous genes
What do CYPs do to drugs?
- Change most drugs from active form to inactive form (after drug has had its intended effect)
- Activate perindopril to perindoprilat (inactive-active)
- Activate codeine to morphine (active-active)
- Can be induced or inhibited by endogenous/exogenous compounds - prevents other drugs from being metabolised
What factors affect the number of CYPs in the body?
- Age - leads to reduction in activity
- Hepatic disease - leads to reduction in activity
- Blood flow - can increase or decrease activity
- Chronic alcohol - increases activity
- Cigarette smoking - increases activity
- Ethnicity can affect activity of some CYPs
What is the clinical importance of CYPs?
- Due to complexity of polypharmacy (lots of drugs)
- Over the counter/herbal preparations can interact with CYPs
- Race affects metabolism
- Sex affects metabolism
- Some drugs induce CYPs after they’ve been metabolised
How are drugs excreted from the body?
- Fluids excreted primarily via kidneys
- Other possible routes: sweat, tears, genital secretions, saliva, breast milk
- Solids: faeces, hair
- Gases: volatile compounds
Outline renal clearance of drugs from the body
- Typically low molecular weight polar metabolites
Affected by:
- GFR and protein binding (gentamicin)
- Competition for transporters such as OATs (penicillin)
- Lipid solubility, pH, flow rate (aspirin)
Outline hepatic clearance of drugs from the body
- Typically high weight metabolites - conjugated with glucuronic acid
- Bile important route for conjugates
- Excreted in faeces or reabsorbed
- Enterohepatic circulation allows drugs to be recycled
What can disrupt hepatic elimination of drugs?
- Antibiotic drug interactions
- E.g. with warfarin, morphine
- Need to consider hepatic disease when prescribing due to changes in CYPs or hepatic excretion
Outline zero order kinetics
- Same amount of drug is eliminated in any given time
Outline first order kinetics
- Same proportion of drug is eliminated in any given time
- Larger amount of drug is eliminated initially because overall concentration of drug in body is highest
What is half-life like in first order kinetics?
- Independent of concentration - up to saturation point
- For a particular drug AND a pharmacokinetic process
- Elimination half-lives range from seconds to days (and weeks)
- Most of initial drug is eliminated in first half life
What is clearance?
- Constant proportion
- Independent of plasma drug concentration until saturation is reached
- Refers to volume of blood cleared per unit time
What is the equation for clearance?
- CL = rate of elimination from body/drug concentration in plasma
What happens to elimination when drug concentration is high?
- More drug in the same volume is cleared
- Elimination rate is increased which is an amount/time
What is elimination rate proportional to?
- Reciprocal of volume distribution
What is the equation to work out the elimination rate constant?
- k = CL/Vd
- k = 0.693/half life of drug
What is the equation to work out half life?
- t1/2 = 0.693 x Vd/ CL
What might influence a long half life?
- Large volume distribution
- Low clearance
What is the clinical significance of half life and how does it affect dosing decisions?
- Vd is the theoretical volume needing to be cleared - small Vd means that less volume needs to be cleared
- Clearance determines elimination
- Elimination determines half life
- This determines how much drug needs to be taken
- Influences chronic treatment - how often drugs need to be taken and how much needs to be taken at a time
What kinetics do most drugs exhibit? What is the significance of this?
- First order kinetics at therapeutic doses
- Very high doses of many drugs exhibit zero order kinetics (incl. alcohol, salicylic acid, phenytoin)
- Important consideration for toxicity and dosing
How does zero order kinetics affect elimination?
- Set amount of drug is eliminated in any given time
- Body cannot eliminate any more than set amount at each time, even if a very high dose of drug is taken initially
- Dose change can produce an unpredictable change in plasma
- Half life not calculable
What is the clinical importance of drug monitoring?
- Zero order kinetics - unpredictability
- Long half-life - dosing and accumulation
- Narrow therapeutic window
- Drug-drug interactions
- Look out for reported or expected toxic effects
What is the therapeutic effect of a drug?
- Response from a drug that is expected/desired
What is meant by the steady state of a drug?
- Therapeutic benefit of a drug is optimal at a steady state
- When concentration of drug is kept at a continuous level
- Amount of drug going into body amount of drug eliminated from body
- Steady state is effectively reached in 4-5 half lives
What happens after administration of a drug is terminated?
- 4-5 half lives pass before negligible drug remains
- Some is still left but is likely to be insufficient to elicit a therapeutic response
How is the value for steady state of a drug in plasma calculated?
- Css = Rate of infusion/CL
- At Css infusion = elimination
What is the equation used to calculate the rate of oral administration of a drug?
- Dose x bioavailability correction/time
- Need to correct bioavailability for bioavailability because not all drug gets into system
What is the curve on a graph demonstrating plasma concentration of an orally administered drug over time like?
- Lots of peaks and troughs
- Indicated intervals between doses
- Rate and absorption indicated by peak size
How do we calculate oral maintenance dose?
- clearance x plasma / bioavailability x dose interval
Define loading dose
- Single dose taken to achieve desired concentration taking into account apparent Vd
Why do we need a loading dose?
- Rapid onset required
- Drug has a long half life
- Therapeutic response needed sooner rather than later
- Larger first dose taken to achieve steady state a little bit sooner
How is loading dose calculated?
- Loading dose = Css x Vd
Which drugs have long half life and may require a loading dose?
- Digoxin
- Phenytoin
- Amiodarone
What is the clinical significance of long elimination?
- Long half life will result in a long period before drug is fully eliminated from body
- Need to consider this when terminating medication
- Increase plasma concentration of other relevant drugs
- Good example of potential medication error - e.g. in case of repeat prescriptions, discharge dose vs long-term dosing, giving other drugs that may interact
Why are dosing schedules so important?
- Maintain a dose within therapeutic range
- To be safe
- Achieve adherence
- Initiating and terminating treatment - allows us to increase or decrease dose over time
How can we tell if we’ve prescribed successfully?
- Physiological measurements e.g. BP, WBC, cholesterol
- Feeling - MSK, mood, energy
- Appearance - a rash, infection, wound, scan
- Reduced frequency of seizures/migraines
- Primary and secondary prevention
Define selectivity
- Drugs often act or elicit a response at more than one receptor subtype
- Size of response differs between receptor subtypes
- Selectivity can be quantified as the ratio of [drug] that achieves a given level of response at one receptor subtype vs [drug] needed at another receptor subtype
Define affinity
- Strength of interaction between a drug and its receptor governs binding-dissociation rate
- Higher affinity means lower [drug] needed to occupy given proportion of receptors and elicit a different response
Define potency
- In part determined by affinity and what drug-receptor complex is able to do through its signalling
- [Drug] needed to elicit a given response, influenced by receptor number and pharmacokinetics
Define efficacy
- Ability to produce maximal response of a particular system
- Clinically more important than potency in most instances
