PK PD Pharacokimetics And Pharmacodynamics Flashcards
What’s the difference between pharmacokinetics, pharmacogentics and pharmacodynamics?
Pharmacokinetics - what the body does to a drug
Pharmacogenetics - how individuals differences affect metabolism
Pharmacodynamics - what the drug is doing at receptor level
What can happen to a free drug in the body?
Protein- bound drug
Metabolised -> active/ inactive
Excreted
Distributed to tissues reservoirs
Interact with receptors -> (therapeutic) effect
Key factors affecting pharmacokinetics?
Bioavailability Half-life Drug elimination Inter-subject variability (clinical trials) Drug- drug interactions
Renal function Stress Pyrexia Alcohol Smoking Occupational exposure Lactation Albumin level Circadian/ seasonal variations
What is oral bioavailability? What affects it?
Measure of the amount of drug that gets into systemic circulation relative to IV route (=100%/ 1)
Measure of drug absorption where it can be used
<1 = lower bioavailability
Absorption Formulation Age Food Vomiting/ malabsorption First pass metabolism (gut lumen, gut wall, liver)
How to calculate bioavailability from a time, plasma concentration of drug graph
(Area under curve oral/ AUC IV) X 100%
How does the rate of absorption dictate visibility of distribution and elimination phases?
Fast absorption means a more obvious distribution phase
Whereas slow absorption means gradual plasma conc increase
Give an example of an extended release modified release preparation
Meteor in can be altered through tweeted preparation to change the pharmacokinetic parameters -> slower absorption so can be taken once a days rather than 3 but more expensive, less Gi discomfort, increased adherence
What affects distribution of a drug?
Blood flow Capillary structure Lipophilicity Hydrophilicity Protein binding
Which type drugs tend to bind to which proteins?
Albumin - acidic drugs
Globulins - hormones
Lipoproteins - basic drugs
Glycoproteins - basic drugs
When is displacement of a drug from binding sites resulting in protein binding drug interactions important?
- highly protein bound
- narrow therapeutic index
- low Vd
When is a sceond drug displacing a first drug from binding proteins important?
Results in more free first drug to elicit a response, potentially causing harm
- pregnancy (fluid balance)
- renal failure
- hypoalbuminaemia
How to calculate Vd?
Dose/ drug plasma conc
If you give a dose of 100mg, the plasma concentration is measured as 20mg/ L and the Vd as 5L what does this mean?
To achieve a plasma conc of 20mg with 100mg dose you need 5L for it to be dissolved into
What does the Vd tell you about where the drug is in the body?
In general
A smaller apparent Vd suggests a drug confined to plasma and extracellular fluid
A larger apparent Vd suggests drug is distributed throughout tissues
Compare where drugs are found if there Vd is <12L compared to >200L
<12L - found mostly in plasma
> 200L majority distributed, sequestered into other tissues
Describe the stages of metabolism
Drug
Phase 1 enzymes
Oxidation/ dealkylation/ reduction/ hydrolysis
Phase 2 enzymes
Glucoronide/ sulphate/ glutathione/ N-acetyl
Conjugates
-> gall bladder -> bile
OR
-> kidney -> urine
Explain how cytochrome P450 isoenzymes are affected by exogenous substances
CYP1A - induced by smoking CYP2C - many inhibitors CYP2D - metabolises many drugs CYP2E - alcohol metabolism CYP3A - 50% therapeutics
Majority of phase 1 catalysed reactions utilise the P450 system
How do CYP450 enzymes work on most drugs and how else can they work?
Active -> inactive (most)
Inactive -> active (perindorpril -> perindoprilat/ levodopa -> dopamine)
Active -> active (codeine-> morphine/ diazepam -> oxazepam)
Induced/ inhibited by endogenous/ exogenous compounds affecting phase 1 metabolism e.g. age, hepatic disease, blood flow, alcohol (antibiotics), cigarette smoking
What effect does grapefruit juice have on statin therapy?
CYP3A4 inhibition -> increased statin (simvastatin/ lovastatin) plasma concentration -> more likely time get side effects
How is CYP 2D6 affected by genetic variations, substrates and other drugs?
CYP 2D6
- Absent in 7% Caucasians
- Hyperactive/ increased induction in 30% East Africans
- substrates include beta blockers, many SSRIs, some opioids
- inhibited by some SSRIs, other antiarrhythmic agents and other antidepressants
How are drugs eliminated?
Primarily via kidney
Fluids (sweat, tears, genital secretions, saliva, breast milk)
Solids (faeces, hair)
Gases (volatile compounds e.g. alcohol)
What Drugs are normally renally metabolised? What affects this?
Typically low molecular weight polar metabolites
Affected by: GFR, protein binding (gentamicin), competition for transporters (penicillin), lipid solubility/ PH/ flow rate (aspirin)
What is clearance? How do you calculate it?
Clearance of drug from the body - clearance from all routes, both metabolism and excretion taken together (mL/ min), mostly GFR
- volume of blood cleared per unit time (mL/ min)
Rate of elimination from body (mg/min) / drug concentration in plasma (mg/ mL)
What drugs are normally hepatically metabolised? What affects this?
Typically high molecular weight - conjugated with glucuronic acid (phase 2)
Bile -> faeces or reabsorbed -> enterohepatic circulation
Antibiotic drug interactions (manipulate gut biome, change rate of reabsorption)
How does elimination rate constant relate to Vd and clearance? Therefore how can that be displayed in an equation?
Elimination is inversely proportional to Vd (1/Vd)
Elimination is directly proportional to clearance
K (rate constant) = CL/ Vd
K = 0.693/t1/2
Substitute K for CL/ Vd
t1/2 = (0.693 X Vd) / CL
What type of elimination kinetics do most drugs exhibit? What about alcohol, salicylic acid and phenytoin? What does this mean needs considering?
Most drugs first order kinetics at therapeutic doses (t1/2 constant)
High doses, alcohol, salicylic acid and phenytoin - zero order so dose change can produce unpredictable change in plasma concentration as t1/2 not calculable - important consideration for toxicity and dosing
What is the steady state? When is it normally reached?
The steady state concentration (CSS) is when the amount going into the body equals the amount leaving the body and it’s used as the maintenance dose for patients
It’s reached about 5t1/2
Reaches new steady state after another 5t1/2
After 5t1/2 almost complete elimination (negligible drug concentration)
Therapeutic benefit optimal at steady state
What equations are true once steady state is reached?
Normally : rate of elimination = CL X [plasma]
At Steady state: [plasma] = CSS
So rate of elimination = CL X Css
At steady state: Rate of elimination = rate of infusion so
Rate of infusion = CL X Css
Css = rate of infusion/ CL CL = rate of infusion/ Css
What do the symbols in this equation mean: rate of administration = (DXF)/ t ? What about this one: rate of elimination = CL X Css? How can these be combined at steady state? From that equation what can you do to change the Css?
D = maintenance dose F = bioavailability correction t = dose interval (how often drug is given)
CL = clearance Css = steady state concentration
At steady state rate of administration = rate of elimination so:
(DXF)/ t = CL X Css
OR
Css = (DXF)/ (tXCL)
Can only change t (dose interval) and D (maintenance dose) as F (bioavailability) and CL (clearance) are constant
What is the loading dose? When is it used? How can we calculate loading dose?
Accelerates getting to steady state (large initial dose) single dose to achieve desired concentration apparent Vd
Used if rapid onset required or drug with long t1/2 (e.g. Digoxin large Vd and large t1/2)
If Vd = dose/ [plasma] then
[plasma] = dose/ Vd
At steady state:
Css = loading dose/ Vd
Loading dose = Css X Vd
If a drug has a long t1/2 what’s important to consider?
Long period before drug is fully eliminated from body - may be months so consider interactions with other drugs
E.g. amiodarone t1/2 50-60 days and increased [plasma] of other cardiac drugs
What’s important to consider for dosing schedules?
Maintain dose within therapeutic range
Safe
Achieve adherence
Initiating and terminating treatment - titrations up and down
How can we measure response to drug therapy?
Physiological measurements
Feeling
Appearance
Primary and secondary prevention
Examples of drug actions and examples for those
Agonist (binds to receptor and causes response) e.g. adrenaline
Partial agonist (partial response) sub- maximal e.g. formoterol
Inverse agonist (prevents response happening, some receptors have basal activity in R state) e.g. propranolol
Competitive antagonist e.g. naloxone on opioid receptors
Non- competitive antagonist (causes functional changes to receptor) e.g. some alpha blockers
Functional antagonist (agent acts at different receptor but causes opposite response)
