Pharmacokinetics and pharmacodynamics Flashcards
1
Q
What is the clinical importance of pharmacokinetics?
A
- 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
2
Q
What are the pharmacokinetic requirements to consider when producing a new drug?
A
- Bioavailability
- Half-life
- Drug elimination
- Inter-subject variability (differences in how drug affects different groups of people)
- Drug-drug interactions
3
Q
How can we produce new drugs much faster?
A
- 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.
4
Q
Why do we need to obtain lots of information about pharmacokinetics when producing a new drug?
A
- 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
5
Q
What are some things to consider when thinking about pharmacokinetics?
A
- Renal function
- Smoking
- Age
- Sex
- Liver function
- Pregnancy
- Infection
- GI function
6
Q
What can happen to free drugs after they’ve been absorbed?
A
- 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
7
Q
What is bioavailability?
A
- 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
8
Q
Compare oral bioavailability to IV bioavailability
A
- 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
9
Q
What affects bioavailability?
A
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)
10
Q
What can happen to drug plasma concentration if elimination is rapid?
A
- Large fluctuations in drug plasma concentration will be seen
11
Q
How do modified release preparations help prevent large fluctuations in plasma concentration?
A
- 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
12
Q
What is needed to allow drugs to reach their target organs?
A
- Need adequate plasma levels
13
Q
What factors affect therapeutic agent distribution?
A
- Blood flow
- Capillary structure
- Poorly vs well perfused tissues
- Lipophilicity vs hydrophilicity
- If drug is bound to something else
- Chemical formula of drug
14
Q
Which drugs are protein binding?
A
- 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
15
Q
What model does distribution and equilibration of of IV drugs follow?
A
- 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
16
Q
What type of drug is able to have therapeutic effect?
A
- Free drug - travels through systemic circulation and bind with target receptors
- Drug bound to protein is unable to do anything
17
Q
Outline drug-protein binding
A
- There is equilibrium between bound and unbound drug in different compartments
- Free drug goes onto to target receptors
18
Q
What is the clinical importance of drug-protein binding?
A
- 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
19
Q
When can it be dangerous for the amount of a free drug to increase in the body?
A
- Pregnancy (protein levels may be lower)
- Hypoalbuminaemia
- Renal failure
20
Q
Outline volume of distribution
A
- Proportionality factor
- Association between drug concentration we can measure in the blood and the amount that’s actually in the body (dose)
21
Q
How would you describe drug concentration?
A
- Amount of drug per unit volume
- E.g. 100 mg/L
22
Q
What is the equation for volume of distribution?
A
- Vd = Dose/[Drug] plasma
23
Q
Why is volume of distribution often referred to as apparent?
A
- Protein binding
- Drug can be sequestered by other body compartments e.g. fat
- Very little drug actually stays in blood plasma
24
Q
What do different values for Vd suggest?
A
- 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)
25
What is the equation to work out dose?
- Vd x [Drug] plasma = dose
26
What affects the route and mechanism of drug metabolism?
- Size
- Lipophilicity
- Hydrophobicity
- Structural complexity
27
Where are the sites of drug metabolism?
- Liver
- Has most numerous and diverse metabolic enzymes
- Phase I and phase II metabolism occurs here
28
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
29
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
30
How can drugs be eliminated after being metabolised?
- Kidney - excreted in urine
- Gallbladder - excreted in bile
31
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
32
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
33
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
34
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
35
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
36
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)
37
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
38
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
39
Outline zero order kinetics
- Same amount of drug is eliminated in any given time
40
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
41
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
42
What is clearance?
- Constant proportion
- Independent of plasma drug concentration until saturation is reached
- Refers to volume of blood cleared per unit time
43
What is the equation for clearance?
- CL = rate of elimination from body/drug concentration in plasma
44
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
45
What is elimination rate proportional to?
- Reciprocal of volume distribution
46
What is the equation to work out the elimination rate constant?
- k = CL/Vd
- k = 0.693/half life of drug
47
What is the equation to work out half life?
- t1/2 = 0.693 x Vd/ CL
48
What might influence a long half life?
- Large volume distribution
- Low clearance
49
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
50
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
51
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
52
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
53
What is the therapeutic effect of a drug?
- Response from a drug that is expected/desired
54
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
55
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
56
How is the value for steady state of a drug in plasma calculated?
- Css = Rate of infusion/CL
- At Css infusion = elimination
57
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
58
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
59
How do we calculate oral maintenance dose?
- clearance x [plasma](that we want) / bioavailability x dose interval
60
Define loading dose
- Single dose taken to achieve desired concentration taking into account apparent Vd
61
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
62
How is loading dose calculated?
- Loading dose = Css x Vd
63
Which drugs have long half life and may require a loading dose?
- Digoxin
- Phenytoin
- Amiodarone
64
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
65
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
66
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
67
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
68
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
69
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
70
Define efficacy
- Ability to produce maximal response of a particular system
- Clinically more important than potency in most instances
