Lecture 2: Clinical pharmacokinetics and pharmacodynamics Flashcards
What is elimination of a drug?
Metabolism and excretion
What is the importance of pharmacokinetics?
- population and patient specific tailoring
- predicting toxicity, review all medications (the addition of one new agent could be significant)
What pharmacokinetic properties need to be considered by the MRHRA (medicines and healthcare products regulatory agency)?
- bioavailability
- half-life
- drug elimination
- inter-subject variability
- drug-drug reactions
What factors influence some pharmacokinetic principles?
- renal function
- stress
- pyrexia
- alcohol/smoking
- age/sex
- exercise/diet/occupational exposure
- infection
- lactation
- liver/CVS/GI function
- pregnancy
- immunisation
- circadian and seasonal variations
What is bioavailability (F)?
Measure of drug absorption where it can be used
- drug administered via IV has 100% bioavailability
- for other routes it is referenced as a fraction of IV
What is bioavailability affected by?
Absorption
- formulation (composition of the drug)
- age (luminal changes)
- food (with or without food)
- vomiting/malabsorption
- previous surgery (bariatric)
First pass metabolism
-metabolism before reaching systemic circulation (gut lumen/gut wall/liver/lungs)
What can plasma concentration-time graphs show us?
Y axis: plasma conc of drug
X axis: time
- can show distinct phases e.g. absorption-rise in plasma conc, distribution- small pronounced drop, elimination- run off phase
- if absorption is slow, the absorption and distribution phases are resolved separately
- initial gradient of line- rate of absorption
What are modified release preparations (e.g. tablet capsule/type)?
Used to prevent rapid large fluctuations in plasma drug concentration due to rapid elimination
- more gradual absorption (plasma conc becomes more dependant on rate of absorption rather than rate of elimination)
- increases adherence
What is distribution of a drug?
We need adequate plasma levels to reach the target organs
What factors affect the distribution of a drug/theraputic agent?
- blood flow/capillary structure
- lipophilicity/hydrophilicity
- protein binding (albumin: acidic drugs, causing sequestering/glycoproteins: basic drugs/globulins/lipoproteins)
How do you interpret a concentration time graph for distribution?
In plasma:
- first drop is due to movement of drug in plasma to the well perfused tissue
- second drop due to perfusion of poorly perfused tissues
Well perfused tissues:
- first increase due to conc in well perfused tissue increasing from plasma
- drop in initial conc in well perfused tissues as the poorly perfused tissues are increasing in conc
Poorly perfused tissues:
-slow increase due to conc increasing in these tissues from plasma (distribution catching up in poorly perfused tissues)
=reach equilibrium: matching conc with plasma conc, well-perfused tissues and poorly perfused tissues
What model does rate of distribution and equilibration follow?
Multiple compartment model
How does drug protein binding affect distribution of a drug?
Only a free drug will be able to afford response at target receptor site and/or be eliminated
Why is drug-protein binding clinically important?
- high protein bound
- narrow theraputic index (toxic)
- low Vd
What could happend if a second drug was administered which binds to proteins more readily in comparison to the first drug?
Increased free first drug
- second drug dsiplaces first drug from binding proteins
- more free first drug to elicit a response
- could potentially cause harm (important in pregnancy, renal failure, hypoalbuminaemia)
What is volume of distribution?
-we can’t measure whole body drug concentration (only plasma)
Vd= dose/plasma conc of drug
e.g. 100mg divided by plasma conc of 20 mg/L= 5L (Vd= 5L)
How would you describe concentration?
Amount per volume
e.g. 100 mg/L
When would you get a very high Vd?
If the drug is very lipophilic (drug sequestered by body tissue)
What does the Vd tell you about the drug?
- smaller apparent Vd: suggests drug is confined to plasma and ECF
- larger apparent Vd: suggests drug is distributed throughout tissues
What is the clinical relevance of Vd?
Dose= Vd x drug plasma conc (allows us to know what dose to give to achieve a particular plasma concentration)
What affects metabolism of a drug?
Several sites of activity, liver having the most numerous and diverse metabolic enzymes
- phase 1 and phase 2 enzymes/metabolism
- size, lipophilicity, hydrophilicity, structural complexity affect route and mechanism
- more hydrophilic species needed to enable elimination via the kidneys (lipophilic species would be reabsorbed and stay in the system-forms a cyclical nature where drug remains in body)
What are CYPs?
Cytochrome P450
-majority of phase 1 catalysed reactions utilise the P450 system
-oxidation reactions are the most important
-found abundantly in SER in hepatocytes
(9 superfamilies of CYPs, 1-4 being really important in drug metabolism)
What do CYP’s do to drugs?
- active > inactive (most drugs)
- inactive > active (perindopril > perindoprilat: ACEI)
- active > active (codeine > morphine) (diazepam > oxazepam)
CYPs can be induced or inhibited by endogenous/exogenous compounds affecting phase 1 metabolism
What can affect the activity of CYP’s?
- age reduces activity
- hepatic disease reduces activity
- blood flow (increased/decreased activity depending on flow)
- chronic alcohol increases activity
- cigarette smoking increases activity
What inhibits CYP3A4?
Grapefruit juice
-this CYP is important in the breakdown of statins
Why is CYP2D6 important?
(absent in roughly 7% of Caucasians: likely to get drug toxicity)
(hyperactive in 30% of East Africans)
-substrates include beta blockers, some opioids, many SSRIs (selective serotonin reuptake inhibitors)
-inhibited by some other SSRI’s, other anti-arrhythmic agents, other antidepressants
What are the clinical importance of CYPs?
- important for drug prescribing and complexity of polypharmacy
- over the counter/herbal preparations have influences on CYPs
- other factors e.g. race/sex: women slower ethanol metabolisers/species: trials)
- self induced metabolism (carbamazepine): induces CYP3A4
What are some routes of drug excretion?
Fluids:
-primarily by the kidney (typically low molecular weight, polar metabolites)
-sweat/tears/genital secretions/saliva/breast milk
Solids:
-faeces/hair
Gases:
-volatile compounds
How is renal excretion of drugs affected?
- GFR and protein binding
- competition for transporters e.g. organic anion transporters
- lipid soluability (tubular reabsorption), pH, flow rate
How are high molecular weight metabolites excreted?
Hepatic (conjugated with glucoronic acid)
-bile important route for conjugates (increases molecular weight)
-excreted in faeces or reabsorbed
(Abx drug interactions: can disrupt ability of drugs to be excreted due to disruption of flora e.g. warfarin/morphine, so dose may need adjusting)
How do you recycle drugs?
Enterohepatic circulation
