2 Clinical Pk and Pd Flashcards
what are the 4 steps involved in the pharmacokinetics?
absorption
distribution
metabolism
excretion
what 2 steps make up elimination?
metabolism
excretion
what is the clinical significance of pharmacokinetics?
allows us to tailor dosing to individuals
predicting toxicity
what are the pharmacokinetic properties considered when licensing a drug?
bioavailability half-life drug elimination inter-subject variability drug-drug ionteractions
give some examples of changeable things that affect pharmacokinetics?
Renal function Stress Pyrexia Alcohol Smoking (multiple drugs) Age Sex Exercise Infection Diet Occupational exposure Lactation Liver function Albumin Cardiovascular function Circadian and seasonal variations Immunisation Barometric pressure GI function Pregnancy
what is bioavailability?
Measure of drug absorption where it can be used. Routes of drug administration are referenced as a fraction of i.v. bolus administration bioavailability
what is the bioavailability of a drug given by intravenous bolus?
100% bioavailability
what is bioavailability affected by?
• Absorption - Formulation - Age (luminal changes) - Food (chelation, gastric emptying) - Vomiting/malabsorption (Crohn’s) - Previous surgery (bariatric) • First pass metabolism - metabolism before reaching systemic circulation (gut lumen, gut wall, liver and even lungs)
what is first pass metabolism?
- metabolism before reaching systemic circulation
gut lumen, gut wall, liver and even lungs
what is shown on a plasma concentration-time graph?
the rate of absorption which dictates the visibility of distribution and elimination phases.
if the elimination of a drug is rapid, how will this effect plasma concentration of the drug?
there will be large fluctuations in the plasma drug concentration and dosing will have to be more regular to try and keep the plasma concentration within the therapeutic range
how do modified release preparations of drugs impact the plasma concentrations of drugs?
Modified release preparations help regulate the absorption and therefore excretion of drugs. It makes the plasma concentration more dependent on the rate of absorption and therefore as this is being regulated, it is more slowed down and gradual and therefore there are less fluctuations in the plasma concentrations, with the concentration staying within the therapeutic raneg for longer
How can modified release preparations provide alternative dosing schedules?
As modified release preparations keep the plasma concentrations within the therapeutic range for longer as it reduces the amount of fluctuations by making the concentration more dependent on rate of absorption than elimination. This means that doses can be taken less frequently, and typically adherence is better
what are some of the factors affecting the therapeutic agent distribution?
blood flow capillary structure lipophilicity hydrophilicity protein binding volume of distribution
how does drug-protein binding affect the efficacy of the drug?
as typically only free drugs will be able to afford a response at target receptor site, if there is a lot of drug-protein binding, the drug will not be able to elicit a response and the dosing will have to be increased
when is drug-protein binding clinically important?
if the drug is highly protein bound
if the drug has a narrow therapeutic index
if there is a low volume of distribution
what factors can influence the amount of drug-protein binding?
pregnancy (fluid balance)
renal failure ( reduced excretion of drugs)
hypoalbuminaemia
if a second drug has a higher affinity for a protein than the first drug, how will this affect the plasma concentrations of the first drug?
the second drug will displace the first drug from binding proteins and therefore the plasma concentration of the first drug will increase
what is concentration?
the amount of drug per volume (mg/L)
what is the volume of distribution?
volume of distribution = dose / [drug]plasma
Is a proportionality factor of how much of the given drug remained in the plasma and how much is sequestered by body tissue
a smaller apparent Vd suggests drug confined to plasma and extracellular fluid a larger apparent Vd suggests drug is distributed throughout tissues
what qualities of a therapeutic agent affect its metabolism?
Size
lipophilicity
hydrophobicity
structural complexity
what enzymes are involved in the majority of phase I catalysed metabolic reactions?
CYP 450
where are cytochrome P450 enzymes predominantly found?
in the smooth ER and mitochondria of hepatocytes
what are some of the common CYP inducers?
carbamazepine phenytoin rifampicin cigarette smoke st johns wart ethanol / alcohol
what are some of the common CYP enzyme inhibitors
amiodarone grapefruit juice trimethoprim omeprazole COCP verapamil
why is grapefruit juice not advised in patients on statins?
As grapefruit juice is an inhibitor of CYP 3A4. therefore the plasma concentrations of statins would increase drastically if these patients drink grapefruit juice. This would cause statin overdose and put patients at an increased risk of rhabdomyolysis
carbamazepine has self induced metabolism. what does this mean?
carbamazepine is a substrate for CYP 3A4 and an inducer. This means that the dose of carbamazepine will have to be increased gradually as it induces its own metabolism
how are fluid drugs eliminated?
Primarily via the kidney in urine (~20% of systemic blood flow)
Other possible routes:
sweat, tears, genital secretions, saliva, breast milk
how are solid drugs eliminated?
faeces and hair
how are gaseous drugs eliminated?
as volatile compounds on exhalation
what is the structure of drugs that are excreted renally?
Typically low molecular weight (small) polar metabolites
what are some of the factors that affect renal excretion of drugs?
- GFR and protein binding (gentamicin)
- Competition for transporters such as OATs (penicillin)
- lipid solubility, pH, flow rate (aspirin)
what is the clearance of a drug?
clearance is the volume of plasma that is cleared of a substance in a unit of time. (ml/min). both metabolism and excretion taken together by definition
what is the structure of drugs that are excreted hepatically?
Typically high molecular weight metabolites - conjugated with glucuronic acid
what are some endogenous examples of drugs that are excreted hepatically?
bilirubin
steroid hormones
how do antibiotics interact with drugs such as warfarin and morphine?
by changing the baterial gut flora. this can disrupt the conjugation of these drugs with glucuronic acid and therefore their reabsorption through the enterohepatic circulation
Name some of the parameters that influence PK and suggest how or why?
renal and hepatic function - affect elimination
stress - causes changes in corticosteroids which can affect how drugs are absorbed
alcohol and smoking - CYP enzyme inducers
age - change is fat, muscle composition and CYP expression
sex - females metabolise alcohol more slowly
Why is apparent volume of distribution useful clinically and why is it described as apparent?
useful for estimating as effective and appropriate dose for drugs
apparent as cannot easily measure the whole body drug concentration so instead measure the blood plasma concentration.
From a PK perspective what is clinically significant about enterohepatic circulation?
affects the elimination of a drug. hepatically excreted drugs (in bile) can be reabsorbed through the enterohepatic circulation, maintaining the concentration of the drug for longer.
What are the three broad outcomes of drug metabolism in terms of drug activity?
most drugs are metabolised form active to inactive
prodrugs are metabolised from inactive to active ( perindopril to perindoprilat)
some change structure which affects their degree of activity
( codeine metabolised to morphine)
Describe the change in [drug] after a single dose in a well perfused vs. poorly perfused part of the body
d
what is meant by zero order kinetics?
the slope of the curve is linear. change in concentration over change in time = -k. the rate of elimination is constant
what is meant by first order kinetics?
the rate of elimination is proportional to the concentration of the drug.the change in concentration/change in time = -kC. the slope of the curve is curved
what is the half life of a drug independent of?
concentration - up to saturation point
what is saturation point?
the point at which the elimination of a drug would shift from following first order elimination to zero order elimination.
in a drug that follows first order kinetics, when is most of the initial drug eliminated?
in the first half life.
what is clearance dependent on?
the amount of drug being delivered to the kidney
- not dependent on the plasma concentration of the drug (essentially a proportionality factor)
give the equation for clearance of a drug
clearance = rate of elimination / drug concentration in plasma
what are the units for clearance?
ml/min
what is the relationship between elimination rate and volume of distribution?
elimination rate is inversely proportional to the volume of distribution.
If the volume of distribution is large, there will be more drug sequestered by the tissues of the body and less within the plasma. As the drug concentration in the plasma would be low, less drug in the same volume can be cleared and elimination rate is decreased
a drug has a long half-life. what is the clearance and volume of distribution of this drug likely to be like?
likely to have a very large volume of distribution (more sequestered drug, less in plasma, lower excretion rate)
likely to have a small clearance proportion.
what drugs exhibit zero order kinetics?
high doses of drugs above saturation point
alcohol
salicylic acid
phenytoin
why is the half life of phenytoin not calculable?
as phenytoin follows zero order kinetics. There is an elimination of an absolute amount within a given time regardless of plasma concentration. A change in dose therefore can produce an unpredictable change in plasma concentration
what criteria might make drug monitoring necessary?
if the drug has zero order kinetics
long half-life for dosing and accumulation
if the drug has a narrow therapeutic window
if there are drug-drug interactions
what do we look out for when doing drug monitoring?
reported or expected toxic effects
therapeutic effect
how long does it take to reach steady state plasma concentration?
4-5 half lives
why is it beneficial to reach steady state plasma concentration?
as therapeutic benefit is optimal at steady state
what is the equation for finding Css?
plasma steady steady state = rate of infusion / clearance
(maintenance) dose x bioavailability / dose interval x clearance = Css
what is the equation for the rate of administration?
rate of administration = dose x oral bioavailability / dose interval
why are loading doses used?
used when rapid onset is required
used when drug has a long half-life and would take a long time to reach therapeutic range
- when therapeutic response is needed sooner rather than later. Single dose to achieve desired concentration in apparent Vd
give some examples of drugs that require a loading dose?
digoxin
phenytoin
amiodarone
what equation can we use to work out the loading dose of a drug?
Css = loading dose / Vd
Loading dose = Css x Vd
why is a loading dose used with amiodarone?
as amiodarone has a very large apparent Vd - goes into lots of tissues. This gives it a very long half life and therefore would take a very long time to reach the steady state plasma concentration
what are the main aims of a dosing schedule?
- Maintain a dose within the therapeutic range
- Safe
- Achieve adherence
- Initiating and terminating treatment – titrating up and down (increasing or decreasing dose)
what can be used to measure the response to a drug therapy?
- Physiological measurements – BP, WBC, cholesterol…
- Feeling – MSK, mood, energy • Appearance – a rash, infection, wound, scan
- Primary and secondary prevention – this can be a particular challenge
what is meant by the selectivity of a drug?
A property of a drug determined by combining its affinity at various binding sites, the knowledge of which can help predict a drug’s potential for therapeutic and side effects.
what is meant by the affinity of a drug?
Strength of interaction between a drug and its receptor, governs the receptor binding-dissociation rate.
Higher affinity means lower [drug] needed to occupy given proportion of receptors and elicit a given response.
what is meant by potency?
[drug] needed to elicit a given response, influenced by receptor number and PK (EC50 or ED50 often used).
what is meant by efficacy?
Ability to produce the maximal response of a particular system (vasodilation, block a channel etc.).
Efficacy clinically more important than potency in most instances – a more potent drug may never achieve
the response required.
what is an inverse agonist?
a ligand that binds to a receptor and produces the opposite pharmacological effect that would be produced by an agonist or by the natural ligand. For example, if agonism of the receptor led to sedation, an inverse agonist might cause wakefulness.
Explain why it takes 4-5 half life’s to reach steady state [plasma]
as after 4-5 half lives, the concentration that remains from the first dose is negligible but also in the steady state plasma concentration.
Why is it particularly important to show caution when prescribing phenytoin which shows zero order elimination kinetics?
as in zero order kinetics the elimination of a drug is not dependent of its plasma concentration. therefore a change in dose can produce an unpredictable change in the plasma concentration and quickly increase it to above the therapeutic window
How do clearance and elimination rate differ?
clearance is the proportion of the body cleared from a substance in a unit of time. Elimination rate is the amount of substance that is removed from the body per unit time.
To increase or decrease the Css, what dosing parameters could you change?
increase the dose amount
increase the frequency of dosing
increase its bioavailability
reduce its clearance
Describe the relationship between t1/2, Vd and Clearance
half-life = 0.693 x Vd / clearance
