Lecture 3- Pharmacokinetics and pharmacodynamics Flashcards
some things to consider when thinking about pharmakinetics (patient factors)
after a drug has entered systemic circulation (absorbed)
- it can stay free
- it can bind and unbind to its target receptor
- it can enter tissue reservoirs (where is can bind to proteins or adipose)
- it can bind to protein in the blood (albumin)
- it can be metabolised (to become active or inactive)
- it can be excreted
Clinical consideration of PK influences MHRA (medicines and healthcare products regulatory agency) and FDA approval and standard dosing. Key factors
- Bioavailability
- Half-life
- Drug elimination
- Inter-subject variability
- Drug-drug interactions
Absorption
Used to describe the journey of a drug travelling from the site of administration to site of action.
Bioavailability (F)
- Measure of drug absorption where is can be used
- Drugs administered via intravenous bolus is said to have 100% bioavailability
- Oral dose will not be 100%
- Therefore : other routes references a fraction of IV
bioavailability is affected by
absorption and first pass metabolism
absorption and bioavailability
- Formulation i.e. oral or IV
- Age
- Food (chelation, gastric emptying)
- Vomiting/malabsorption
- Previous surgery (bariatric)
First pass metabolism
- Metabolism before reaching systemic circulation
- E.g. drugs absorbed in GI, goes straight to the liver via the hepatic portal vein and is metabolised before reaching systemic circulation
- E.g. metabolised in the lungs
Rate of absorption
- Plasma conc-time graphs show distinct phases
- Rate of absorption dictates the visibility of distribution and elimination phases
- Look at the initial gradient of [plasma/ time curve]
if absorption is very quick
(steep gradient)
distinct phase between the absorption and distribution (circled part on graph)
- Rise in plasma conc very quickly
- Then distribution as the drug distributes through the tissue (pronounced drop on the graph- coving)
- Run off phase with elimination
If absorption is slow
then the absorption and distribution phase will be occurring at the same time – no coving on the graph seen- slightly less steep accumulation of drug in the plasma.
Manipulating absorption of drugs using modified release preparation
we want to keep drug concentration within the therapeutic range as long as possible
- If elimination is rapid large fluctuations in [plasma] will be seen
- Large periods of time below minimum effective concentration
- Periods of time above the maximum safe conc- side effects
how do modified preparations work
- Plasma conc becomes more dependent on the rate of absorption vs rate of elimination
-
Can help with adherence
- E.g. if fast onset release medication is causing bad side effect
Some factors affecting therapeutic agent distribution- Volume of distribution (Vd)= function of these factors
-
Blood flow
- Better distribution in highly vascularised tissue
- Capillary structure
-
Lipophilicity
- Drugs can pass through plasma membrane
-
Hydrophilicity
- Drugs pass through aqueous channels
-
Protein binding (sequesters drug, changing PK in terms of distribution)
- Albumin- acidic drugs (most common)
- Globulins- hormones
- Lipoproteins- basic drugs
- Glycoproteins- basic drugs
distribution and multiple compartments
Rate of distribution and equilibration from IV admin typically follows a multiple compartment model
Drug protein binding and distribution
- *
- Typically only free drugs will afford response at target receptor site and/ or be eliminated
- Displacement of a drug from binding site can result in protein binding drug interaction
- If highly protein bound
- Narrow therapeutic index
- Low Vd
Increased free drug will be able to afford increased response or be eliminated
- E.g. if a second drug is given that displaces first drug from binding protein
- More free drug to elicit a response
- Potentially causing harm e.g. pregnancy (fluid balance), renal failure, hypoalbuminemia (amount of protein in diet will change the amount of albumin in plasma- effect amount of free drug)
(apparent) Volume of distribution
- It is a proportionality factor
- Dose/[drug]plasma
- We can’t easily measure whole body drug concentration- only blood plasma
- Concentration = the amount of solute in given volume
calculate this Vd (1)
100mg/ 20 mg/L= 5l (Vd)
calculate this Vd (2)
- High proportion of adipose in compartment increases amount dissolved, limiting amount dissolved in the plasma
- Vd = 100/5 ug/mL = 20L
- 5ug/mL = 5 mg/L
calculate Vd of (3)
always remmeber units
- High protein binding. Plasma conc slightly higher than in high adipose example. Vd= 100/10= 10L
- 10 ug/mL= 10mg/L
calculate presuming dose is 100mg/L
- Lipophilic drug.
- Plasma conc 500 ng/mL = 0.5 mg/L.
- Vd= 100/0.5= 200L
what does a Vd of 200L mean
200L of fluid would be required to have a drug conc of 0.5mg/L in the plasma–> very high Vd (not much found in the plasma)
a smaller Vd suggest
drug is confied to plasma and ECF
–> may need to use a lower conc of the drug since more stays in the plasma where the drug can be active
a larger apparent Vd suggest
drug is distributed throughout tissue
2 women are both 5’7 but one weighs 58kg and the other 70kg. Who will have the lower Vd of a drug if
58kg women
- lower body mass, therefore less adipose for drug to distribute into
- higher conc of drug stays in the plasma
- may need a lower dose
clinical relavance of Vd
can help determine dose to be givenn
Vd= Dose/ [Drug] plasma
therefore
Dose=Vd x [Drug] plasma
outline drug metabolism
Several sites of activity, liver having the most numerous and diverse metabolic enzymes
Size, lipophilicity, hydrophobicity, structural complexity affects route and mechanism
- Some drugs only go through phase I
- Some just go through phase II
- Some go through phase I or phase I
why do drugs need to be metabolised
- to turn them on i.e. pro drug –> drug
- Hydrophobic species need to be made more ionic (molar)- hydrophilic to enable elimination via the kidneys
- Lipophilic species would be reabsorbed and stay in the systems
which enzyme catalyse the majority of phase 1 reactions
Cytochrome P450 (CYPs)
Cytochrome P450 (CYPs)
- Oxidation reaction most important
- Found abundantly in smooth ER in hepatocytes
- Numerous genes that encode these enzymes, CYP families 1-4 deals with most reaction
What do CYPs do to drugs
CYPs can be induced or inhibited by endogenous/exogenous compounds affecting phase I metabolism
- Age increase = reduced activity of CYPs
- Hepatic disease = reduced activity of CYPs
- Blood flow = increased flow (decreased effect of CYPs), decreased flow (increased effect of CYPs)
- Cigarette smoking= increased activity of CYPs
- If someone stops smoking may need to think about dose of drug
Clinical importance of CYPS
Important for drug prescribing and complexity of polypharmy
example of counter/herbal preparations which can induce/inhibit CYPs
- St Johns Wort (P450)
- Taken as a mood stabiliser
- Valerian
- Grapefruit juice
- Alcohol
other factors which effect activity of CYPs
- Race
- Sex- women slower ethanol metabolisers
- Species (need to think about this with drug development)
example of self induced metabolism
- E.g. carbamazepine induces CYP3A4 and is also a substrate for CYP3A4
CYP inhibition example
e.g. Grapefruit juice inhibits CYP3A4, which is an important enzyme in the breakdown and elimination of statins
genetic factors and CYPs
CYP 2D6 (substrates inc B-blockers, many SSRs and some opioids)
- Missing in 7% of Caucasians
- Drug toxicity
- Cant metabolise drug
- Hyperactive in 30% east Africans
- Hard to get to therapeutic level of drugs
- E.g. wont feel effect of opioids
- CYP 2D6 also inhibited by SSRIs, other antiarrhythmic agents and other antidepressants
drug excretion via
- Fluids
- Primarily via the kidneys (20% of systemic blood flow)
- Other routes: sweat, tears, genital secretions, saliva, breast milk
- Solids- faeces and hair (e.g. drug testing)
- Gases- volatile compounds
renal excretion
- Typically low molecular weight (small) polar metabolites
- Affected by
- GFR (clearance) and protein binding (gentamicin)
- Competition for transporters such as organic anion transporters (OATs) (penicillin)
- Lipid solubility, pH, flow rate (aspirin)
- Manipulation of pH e.g. alkalinising can help treat poisoning and gout à drive excretion e.g. salicylates
- Think weak acids and bases from ESA1
Hepatic
- Typically high molecular weight metabolites- conjugated with glucuronic acid
- Bile important for conjugates- increased mwt-larger compounds
- Excreted in faeces or reabsorbed
- Enterohepatic circulation- environment for recycling of drugs
- Endogenous examples e.g. bilirubin and steroid hormones
- Enterohepatic circulation- environment for recycling of drugs
- Antibiotics may change gut flora which allows conjugates to be disruptedà enterohepatic reabsorption
- E.g. warfarin, morphine- dose may need adjusting
- Hepatic disease is of importance when prescribing
- Changes in CYPs or hepatic excretion
First order kinetics (Linear elimination kinetics)
- Elimination of a constant percentage (or fraction) of the drug per unit time (if a large functional reserve of enzymes)
- That is - if there is Large Functional Reserve and Plenty of Phase I/II Enzyme sites
- Plenty of OAT/OCT Transporters
- For most drugs, the elimination occurs at a rate directly proportional to the concentration of the drug—i.e., the higher the drug concentration, the higher its elimination rate (e.g., 50% per unit time, as shown in the figure).
- Rate of metabolism /transport will be proportional to the number of molecules occupying a catalytic/ carrier site per unit time
Zero-order kinetics (Nonlinear kinetics)
- Elimination of a constant quantity of the drug per unit time independent of the concentration of the drugs
- With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large.
- Therefore, the plasma drug concentration is much greater than the Michaelis constant Km, and drug metabolism is constant and independent of the dose
which order’s half life can you predict
only first order
- Independent of conc- up to saturation point
- Half-life is particular for different drug and pharmacokinetic process
- Elimination half-lives can range from minutes to days (and weeks)
Clearance (CL)
- Volume of blood cleared per unit time (mL/min)
- Constant proportion not amount
- Independent of [plasma] drug
e.g. if 10% of 1000mL are cleared in 1 min- clearance = 100mL/min
celarance and higher drug concentration
If a drug concentration is high- more drug in the same volume can be cleared- elimination rate is increased.
if plasma levels of drug is low
elimination is going to be low
elimination rate constant (K) equation
therefore we can calculate half life if we know volume of distribution and clearance
clinical significance of elimination rate constant
Elimination kinetics and toxicity
- Most drugs exhibit first order kinetics at therapeutic doses (half life is constant)
- High doses and alcohol, salicylic acid and phenytoin- zero order
- Important consideration for toxicity and dosing
zero order drugs and toxicity
- Dose change can produce unpredictable change in [plasma]
- T1/2 not calculable
clinical importance of drug monitoring
- Zero order kinetics – the unpredictability
- Long half-life – dosing and accumulation
- Narrow therapeutic window – the “goldilocks” zone
- Drug-drug interactions (metabolic/genetic), measure [plasma] for some drugs (phenytoin…)
Looking out for:
- Reported or expected toxic effects
- Therapeutic effect – response that is expected/desired?
Steady-state concentration (Css)
occurs when the amount of a drug being absorbed is the same amount that’s being cleared from the body when the drug is given continuously or repeatedly- time during which the concentration of the drug in the body stays consistent.
‘The input rate is the same as the elimination rate’
For most drugs, the time to reach steady state is
four to five half-lives if the drug is given at regular intervals—no matter the number of doses, the dose size, or the dosing interval.
A half-life is how long it takes for half of the drug to be eliminated from the body.
why do we measure time to get Css in half lifes
let’s assume we administer a dose every half-life. If a single dose is given every half-life, half of the first dose will be cleared from the body before the next dose.
therapeutic benefit optimal at
steady state (Css/Cpss)
after termination of the drug how long does it take for neglible drug to remain
4-5 hlaf life’s
- some drug will still remain (however insuffieicent to elict therapeutic response
(think about traces of recreational drugs)
[plasma] at steady state
can use the clearance equation to calculate Css. Why?
- clearance = / rate of elimination from body/ drug concentration in plasma
therefore
….
- rate of elimination = CL x [plasma]
- at Css infusion= elimination
- rate of infusion = CL x Css
therefore. ..
Css= rate of infusion/Cl
dosing can be
single (headache) vs multipe (hypertension
rate of administration =
D= dose
F= bioavailability
t= time
rate of elimination=
CL x Css
at steady state administration =
elimination
because at steady state adminstation = elimination we can combine the equations to work out Css
loading dose
- when rapid onset required or a drug with a long half-life
- is a higher dose administered on treatment initiation.
- will still take the usual four to five half-lives to reach steady state, but the initial concentration will be closer to the eventual steady-state concentration—which means the therapeutic effect will happen faster.
examples of drugs with a loading dose
- E.g. Digoxin, phenytoin, amiodarone (antiarrhythmic drugs)
loading dose equation
Clinical example of loading dose use- Amiodarone
- Large apparent Volume of distribution – very large ~ 66L/kg
- Lipophilic so gets into lots of compartments
- Predominantly hepatic metabolism and biliary excretion
- Long half life – very long 50 – 60 days
- Css (steady state plasma conc) will be reached in………..
- If amiodarone is to be used for SVT (not typically first line) then a loading dose is going to be required
- Give large bolus to start to getting in therapeutic range quickly
Amiodarone elimination
- Long t1/2 will result in long period before drug is fully (almost) eliminated from the body - months
- Important consideration if terminating medication
- i.e. may increase [plasma] of other cardiac drugs
- Good example of potential medication error – repeat prescriptions, discharge dose vs. long term dosing
Aims of dosing schedules
- Maintain a dose within the therapeutic range
- Safe
- Achieve adherence
- Initiating and terminating treatment- titrating up and down (increase and decreasing dose)
therapeutic index/ratio
=median toxic/median therapeutics
- most therapeutic level
how do you known you have prescribed successfully
Response to drug therapy- knowing you have prescribed successfully!
- 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
define selectivity
- drugs often act at or can elciit a response at mor ethan one receptor subtype (alpha, beta, LTCC etc)
- the size of the response always differs between receptor subtypce
- selectivity can be quantified as the ratio of [drug] that achieves a given level of response at one receptor subtrype vs [drug] needed at the other receptor type
problems with selectivity
Would ideally like to give Salmeterol- binds really well to B2 and not well to B1 (less side effects). However it is insoluble.
affinity
stregnth of itneraction between drug and its receptor, governs the recpetor binding dissocaition rate
higher affinity means lower [drug] needed to occupy given proportion of receptors and elicit a given response
effciacy
ability to produce the maximal response of a particualr system (vasodilation, block calcium channel etc).
efficacy clinically more important than potency- a potent drug may never achieve the response required
potency
in part determined by affinity and what drug-receptor complex is able to do through its signalling.
in real terms- humans are not expiremnts, [drug] to elicit a given response is influenced by receptor number and PK (EC50 or ED50)
example of drug action- PD
