Pharmacokinetics & Pharmacodynamics Flashcards
What is the difference between pharmacokinetics and pharmacodynamics?
PKs are the effects of the drug on the body
PDs are the effects of the body on the drug
What are the 4 broad ways in which drugs work?
Depression
Stimulation
Destruction
Replacement
Name some unconventional mechanisms of action.
Disruption of structural proteins
Enzymes
Covant linkage
Chemical reactions
What is the difference between an agonist and a partial agonist?
draw a dose response curve to show the difference?
An agonist will bind to a receptor fully whereas a partial agonist will only partially bind to a receptor to ellict a smaller response.
What is a competitive antagonist?
Draw the dose-response curve from competitive antagonists
Competitive antagonists bind to receptors at the same binding site as the endogenous ligand or agonist, but without activating the receptor.
What is the definition of bioavailabilty?
The fraction of a dose which finds its way into a body compartment, usuaully the circulation
What is the bioavaliability of an IV bolus?
100%
How would you measure bioavaliabilty for all routes apart from IV bolus?
Bioavaliability = Area under curve for route
Area under curve for IV
What does the area of the curve (AUC) represent?
The total drug exposure
Which factors effect bioavaliability?
- *A**bsorption of drug
- First pass metabolism
- *D**istribution
- Protein binding
- Volume of distribution (Vd)
Metabolism
Excretion
“ADME”
Give examples of some things that may effect absorption of a specific drug?
Drug formulation - intermediate vs modified release
Age of patient
Food intake
Vomiting, malabsorption
What is meant by the term “first pass metabolism”?
At what sites might this occur?
Metabolism occuring before the drug enters the systemic circulation
The gut lumen
The gut wall
The liver
Give some examples of drugs that are metabolised before they enter the systemic circulation i.e. at first pass metabolism
Insulin
Ciclosporin
Propanolol
The distribution of a drug refers to its ability to ________ in the body
‘dissolve’
Drug distribution can be divided into which two categories?
Protein binding
&
Volume of distribution (Vd)
In order to have a pharmalogical effect, most drugs must be bound or unbound?
Unbound (free)
Give some examples of circulating proteins that drugs might be bound to?
Albumin
Globulins
Lipoproteins
Acid glycoproteins
The amount of ______ drug determines its action at receptor
free
What does displacement of drugs from binding sites cause?
Protein Binding Drug Interactions
Changes in protein binding that cause changes in drug distribution are only important if which 3 criteria are met?
- high protein binding
- low Vd
- has narrow therapeutic ratio
Which factors may affect protein binding?
Hypoalbuminaemia
Pregnancy
Renal failure
Displacement by other drugs
Why does the risk of toxic effects of protein bound drug “A” increase when adding a highly protein bound drug?
The highly protein bound drug is going to take up the binding sites on protein and mean that amount of free drug A increases- the risk of toxic effects from drug A also increases
How do you work out volume of distribution?
Dose
Concentration of drug at time 0
The half life of a drug is ________ to Vd (and clearance)
Proportional
What are the amounts (in litres) of fluids in the major body compartments of a 70kg man?
Intracellular: 23l
Interstitial space: 14l
Intravascular space: 5l
What are the differences between phase I and phase II liver enzymes in relation to drug metabolism?
Phase I- oxidation & reduction by CYP enzymes
Phase II- conjugating enzymes: facilitate the addition of endogenous molecules such as glucuronic acid and glutathione
The end products of conjugation are ________ enabling rapid elimination from the body
water-soluble
True of Flase: The end products of conjugation are usually pharmacologically active
FALSE
They are usually inactive
CYP450 isoenzymes are present mainly where?
Where else can they be found?
Liver
Gut and lung
Give some examples of the major isoforms of cytochrome P450
CYP2D6
CYP3A4
CYP2C9
Give an example of a drug interaction that causes changes in plasma levels of the drug due to enzyme inhibition
State what the clinical consequence of such could be
Warfarin
+Cimetidine
Increase in plasma concentration of warfarin
Patient becomes increasingly anti-coagulated
Increased risk of bleeding for that patient
List some important factors that should be considered when prescribing drugs, in relation to their metalbolism
OTC drugs
Drug-drug interactions
Food-drug interactions
Race
Age
Sex
Species (drug development)
Clinical/physiological condition
The main route of drug elimination is via what?
Give examples of some other, less common, routes.
The kidneys
Lungs, breast milk, sweat, tears, genital secretions, bile, saliva
Which 3 processes determine the renal excretion of drugs
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
What is drug clearance?
The ability of the body to excrete drug
Clearance mostly = _______
If _______ is reduced, then clearance is reduced
GFR
______ is inversely proportional to clearance
Drug half-life
A reduction in clearance (GFR) increases ________
drug half-life
What is meant by 1st order kinetics in relation to drug elimination?
What is another term for this kind of drug elimination?
The rate of elimination is proportional to drug level
Linear drug elimination
What is the meaning of the term “Zero order kinetics”?
How else can this be described?
The rate of elimination is constant- it is FIXED per unit time
Non-linear kinetics
What can we obtain from drugs displaying 1st order kinetics compared to those with 0 order kinetics?
Can determine the HALF-LIFE of the drug and predict the dose increment with 1st order
Cannot do these with 0 order
Why are zero order drugs more likely to result in toxicity?
The half life is not calculable
Dose increments not predictable
Small dose changes may produce:
- Large increments in plasma concentration
- Therefore lead to toxicity
Because of the unpredictability of drugs showing zero order kinetics, what must we do to ensure they are safe to use?
Drug monitoring
Apart from zero order kinetics, why else might we use drug monitoring?
Long half-life
Narrow therapeutic window
Greater risk of drug-drug interactions
Known toxic effects
Monitoring of therapeutic effect
During repeated drug administration, a new steady state is achieved in ________ half-lives, irrespective of _________
3-5
Dose or frequency of administration
Once the steady state (CpSS) is reached, how may half lives does it usually take to eliminate the drug?
Same as to reach steady state from initial dose
(3-5)
Due to the number of half-lives required to get to steady state, what can we do clinically to ensure the patient is benefitting from the drug from the initial dose and not having to wait for therapeutic levels to be reached?
Give a loading dose (much higher dose than maintenance dose) to get to therapeutic levels
Give an example of a drug that requires a loading dose, and explain why
Digoxin
It has a high volume of distribution due to its long half-life
It would take over a week to reach a steady state but patient needs the benefit of the drug asap- therefore we use loading dose to get to this therapeutic level
How does renal failure effect the ability to use a loading dose?
It doesn’t usually, unless the patient has very severe renal failure
But the maintenance dose should be reduced if the renal failure leads to reduced clearance of the drug
In a patient with renal failure it is going to take ________ to eliminate the drug
Longer
How do we work out the loading dose of a drug?
Loading dose = Vd x [Drug]target
Work out the loading dose for this patient:
100kg man
Phenytoin Vd= 0.7L per kg body weight
CpSS Phenytoin= 20mg/L
Phenytoin is administered as salt w. 92% Phenytoin
Phenytoin Vd= 100 x 0.7 = 70L
LD= 70 x 20 = 1400 mg
True LD= 1.4g ÷ 0.92 = 1.5g
How do we calculate the half-life of a drug?
Drug half-life = Vd ÷ Clearance
Example of working out half life ??????
?????
Explain what is meant by the multi compartment model of the rate drug elimination
Takes into account that most drugs do not remain solely in the plasma
Distribution occurs in multiple compartments and equilibrium between these is not equal
Therefore rate of elimination varies
How does the addition of a competitive antagonist to agonist change Emax and EC50 in a dose-response curve?
What does this mean in terms of the dose of agonist required?
Emax = not changed
EC50= increased
Higher dose of agonist needed to eliicit the same response
How does the addition of a non-competitive antagonist to agonist change Emax and EC50 in a dose-response curve?
What does this mean in terms of the dose of agonist required?
Emax is reduced
EC50 stays the same
No matter how the dose of agonist is changed, the response stays the same and will be less than it would have been with agonist alone
Describe the term “drug selectivity” and how this relates to side effects in patients.
The more “selective” a drug is for its target, the less chance that it will interact with different targets and have less undesirable side effects
Describe the term “drug specificity” and give some examples
How well targeted drugs are against a specific receptot subtypes which enables them to be targeted against a specific organ
Less actions on non-target organs
e.g. heart beta1 adrenergic receptors
lungs beta2 adrenergic receptors
What is “affinity”?
The tendency of a drug to bind to a specific receptor type
What is “efficacy”?
The ability of a drug to produce a response as a result of the receptors being occupied
The maxmum effect of a drug
What is “potency”?
The dose required to produce the desired biologic response
What is the therapeutic index?
The relationship between concentrations causing adverse effects and concentrations causing desirable effects
= EC50(adverse effect)
EC50(disired effect)
What is a therapeutic window?
A range of dosages that can effectively treat a condition whilst still remaining safe
give some examples of drugs with narrow therapeutic windows
Warfarin
Digoxin
How does altered P-glycoprotein activity change the absorption of a drug?
It changes the active transporter
Large amount of free drug leads to increased rate of ____________
Excretion
Protein binding interactions are important for what kinds of drugs?
IV drugs
Drugs with hort-half life
Drugs with narrow therapeutic index
Give some examples of drug-renal disease interactions and the consequences that make these important to bear in mind when prescribing
Falling GFR - either chronic or acute:
(digoxin, aminoglycoside abx)
- Reduced clearance of renally excreted drugs
- Disturbances of electrolytes may lead to toxicity
- Nephrotoxins may cause further kidney damage
Give some examples of drug-hepatic disease interactions and the consequences that make these important to bear in mind when prescribing
Reduced clearance of drugs metabolised by the liver
Reduced CYP450 activity
= Longer half lives = Increased toxicity
e.g. Opiates in cirrhosis–> accumulation–> coma
Give some examples of drug-cardiac disease interactions and the consequences that make these important to bear in mind when prescribing
Falling cardiac output:
-Excessive response to hypotensives
-Reduced organ perfusion
reduced hepatic blood flow & clearance, reduced renal blood flow & clearance
Give some examples of drug-food interactions and the consequences that make these important to bear in mind when prescribing
Grapefruit juice
Inhibits several CYP450 isoenzymes, reduced clearance of simvastatin, amiodarone, terfenadine = increased exposure of drug
Cranberry juice
Inhibits CYP2C9 isoform, reduced clearance of warfarin= enhanced anticoagulant effect, increased risk of haemorrhage
What is an adverse drug reaction?
An unwanted or harmful reaction which occurs after administration of a drug(s) and is suspected or known to be due to the drug(s)
Explain the differences between major, moderate and mild ADRs
Major: permanent/life threatening
Moderate: requires additional treatment
Mild: trivial/unnoticable
Give some examples of situations that would be high risk for ADRs
- Ignorant, inappropriate and reckless prescribing (salty+++)
- Polypharmacy
- Patients at the extremes of age
- Multipple medical problems
- Use of drugs with narrow therapeutic windows
