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CPT > Pharmacokinetics and pharmacodynamics > Flashcards

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
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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
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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.
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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
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5
Q

What are some things to consider when thinking about pharmacokinetics?

A
  • Renal function
  • Smoking
  • Age
  • Sex
  • Liver function
  • Pregnancy
  • Infection
  • GI function
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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
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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
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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
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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)

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10
Q

What can happen to drug plasma concentration if elimination is rapid?

A
  • Large fluctuations in drug plasma concentration will be seen
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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
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12
Q

What is needed to allow drugs to reach their target organs?

A
  • Need adequate plasma levels
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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
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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
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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
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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
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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
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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
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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
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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)
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21
Q

How would you describe drug concentration?

A
  • Amount of drug per unit volume
  • E.g. 100 mg/L
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22
Q

What is the equation for volume of distribution?

A
  • Vd = Dose/[Drug] plasma
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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
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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)
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25
Q

What is the equation to work out dose?

A
  • Vd x [Drug] plasma = dose
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26
Q

What affects the route and mechanism of drug metabolism?

A
  • Size
  • Lipophilicity
  • Hydrophobicity
  • Structural complexity
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27
Q

Where are the sites of drug metabolism?

A
  • Liver
  • Has most numerous and diverse metabolic enzymes
  • Phase I and phase II metabolism occurs here
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28
Q

Outline phase I of metabolism

A
  • 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
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29
Q

Outline Phase II of drug metabolism

A
  • 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
Q

How can drugs be eliminated after being metabolised?

A
  • Kidney - excreted in urine
  • Gallbladder - excreted in bile
31
Q

Outline the properties of the Cytochrome P450 enzymes

A
  • 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
Q

What do CYPs do to drugs?

A
  • 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
Q

What factors affect the number of CYPs in the body?

A
  • 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
Q

What is the clinical importance of CYPs?

A
  • 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
Q

How are drugs excreted from the body?

A
  • Fluids excreted primarily via kidneys
  • Other possible routes: sweat, tears, genital secretions, saliva, breast milk
  • Solids: faeces, hair
  • Gases: volatile compounds
36
Q

Outline renal clearance of drugs from the body

A
  • 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
Q

Outline hepatic clearance of drugs from the body

A
  • 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
Q

What can disrupt hepatic elimination of drugs?

A
  • Antibiotic drug interactions
  • E.g. with warfarin, morphine
  • Need to consider hepatic disease when prescribing due to changes in CYPs or hepatic excretion
39
Q

Outline zero order kinetics

A
  • Same amount of drug is eliminated in any given time
40
Q

Outline first order kinetics

A
  • 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
Q

What is half-life like in first order kinetics?

A
  • 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
Q

What is clearance?

A
  • Constant proportion
  • Independent of plasma drug concentration until saturation is reached
  • Refers to volume of blood cleared per unit time
43
Q

What is the equation for clearance?

A
  • CL = rate of elimination from body/drug concentration in plasma
44
Q

What happens to elimination when drug concentration is high?

A
  • More drug in the same volume is cleared
  • Elimination rate is increased which is an amount/time
45
Q

What is elimination rate proportional to?

A
  • Reciprocal of volume distribution
46
Q

What is the equation to work out the elimination rate constant?

A
  • k = CL/Vd
  • k = 0.693/half life of drug
47
Q

What is the equation to work out half life?

A
  • t1/2 = 0.693 x Vd/ CL
48
Q

What might influence a long half life?

A
  • Large volume distribution
  • Low clearance
49
Q

What is the clinical significance of half life and how does it affect dosing decisions?

A
  • 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
Q

What kinetics do most drugs exhibit? What is the significance of this?

A
  • 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
Q

How does zero order kinetics affect elimination?

A
  • 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
Q

What is the clinical importance of drug monitoring?

A
  • 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
Q

What is the therapeutic effect of a drug?

A
  • Response from a drug that is expected/desired
54
Q

What is meant by the steady state of a drug?

A
  • 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
Q

What happens after administration of a drug is terminated?

A
  • 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
Q

How is the value for steady state of a drug in plasma calculated?

A
  • Css = Rate of infusion/CL
  • At Css infusion = elimination
57
Q

What is the equation used to calculate the rate of oral administration of a drug?

A
  • Dose x bioavailability correction/time
  • Need to correct bioavailability for bioavailability because not all drug gets into system
58
Q

What is the curve on a graph demonstrating plasma concentration of an orally administered drug over time like?

A
  • Lots of peaks and troughs
  • Indicated intervals between doses
  • Rate and absorption indicated by peak size
59
Q

How do we calculate oral maintenance dose?

A
  • clearance x plasma / bioavailability x dose interval
60
Q

Define loading dose

A
  • Single dose taken to achieve desired concentration taking into account apparent Vd
61
Q

Why do we need a loading dose?

A
  • 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
Q

How is loading dose calculated?

A
  • Loading dose = Css x Vd
63
Q

Which drugs have long half life and may require a loading dose?

A
  • Digoxin
  • Phenytoin
  • Amiodarone
64
Q

What is the clinical significance of long elimination?

A
  • 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
Q

Why are dosing schedules so important?

A
  • 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
Q

How can we tell if we’ve prescribed successfully?

A
  • 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
Q

Define selectivity

A
  • 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
Q

Define affinity

A
  • 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
Q

Define potency

A
  • 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
Q

Define efficacy

A
  • Ability to produce maximal response of a particular system
  • Clinically more important than potency in most instances

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