6. Kinetics Flashcards
Dynamics is … whereas kinetics is …
- what the drug does to the body
- what the body does to the drug
4 stages of pharmacokinetics
- absorption
- distribution
- metabolism
- excretion
Why do we need to calculate pharmacokinetics parameters?
- to ensure dosage regimen results in correct plasma concentration in all patients
- irrespective of disease state, capacity to eliminate, route of administration, age and other drug therapy
Order of ADME process and where they occur
- site of administration
- absorption to plasma
- distribution from plasma to tissues and back
- from plasma to urine and faeces is metabolism and excretion
Define ‘absorption’
transfer of an exogenous compound e.g the drug from site of administration into systemic circulation
Processes in absorption
- crossing cell membranes by -
- passive diffusion down conc gradient
- active transport (esp. GI tract)
In general, … compounds cross cell membranes easier
Explain
- lipid-soluble
- more rapidly absorbed
- but must be in solution and degree of ionisation is important
- the more unionised, the more is absorbed
The more unionised lipid-soluble drug, the more …
absorbed
Explain absoption in stomach for oral route of drugs action
- not important site of absorption - most orally administered drugs not absorbed here
- mainly weak acids and small amounts of aspirin, NSAIDS and alcohol that are
- very low pH (1-2)
- role of gastric empyting controls delivery of compounds to small intestine and higher rate of absorption here
What orally administered drugs are absorbed in the stomach?
- not much
- weak acids
- small amounts of aspirin, NSAIDS and alcohol
Why is not much absorbed in the stomach?
- high acidity
- drug ionisation state is changed and not in a position to be absorbed
Does stomach acid destroy drugs?
- no
- just prevents stomach from absorbing it
- weak acids can be ionised and absorbed
How often does gastric emptying occur?
What’s the basic process?
- every 2hrs
- sphincter muscle changes and relaxes
What happens to orally administered drugs in the small intestine?
- absorption site of most exogenous compounds
- preferally weak bases - like most drugs
- large, highly permeable, vascularized surface area
- pH ranges from 6 in the duodenum and 7.4 in the terminal ileum
- enterocytes in the epithelium contain drug-metabolising enzymes and transporters
List factors that affect gaatrointestinal absorption
- gut motility
- gut pH
- physico-chemical interactions
- particle size and formulation
How does gut motility affect gastrointestinal absorption?
- major effect
- generally decreased motility leads to decreased absorption
- also, excessively rapid movement reduces absorption
How does gut pH affect gastrointestinal absorption?
- poor absorption of strong acids and bases
How does physico-chemical interactions affect gastrointestinal absorption?
- tetracycline binds to Ca rich foods
- bile-acid-binding resins may bind to other drugs
How does particle size and formulation affect gastrointestinal absorption?
- pharmaceutical preparations are formulated to produce desired absorption characteristics
- slow or fast release particles
- resistant coating
Gastrointestinal absorption factors also impact …
bioavailability
- the proportion of administered dose which enters systemic circulation
Can you change gut pH?
yes
with diet
Define ‘bioavailability’
- fraction of administered dose which enters systemic circulation
Define ‘first pass metabolism’
- metabolism which occurs in the intestine and liver before drug reaches systemic circulation
What is the parameter for absorption?
- area under the curve
- used to estimate bioavailability
- use trapezoidal rule and equation
conc 0 + conc 1divided by 2 times time1-0
If a time concentration graph starts with a high concentration at 0 time, what does this show?
- IV administration
- no increase as drug absorbs into systemic circulation
For an IV dose, bioavailability is …
Compare to an extra-vascular dose
- 1
- less than 1
Limitations of bioavailability
- doesn’t consider inter and intra individual variations in enzyme activity, gastric pH and intestinal motility
- doesn’t consider rate of absorption
2 other parameters of absorption that aren’t bioavailability
- Cmax
- Tmax
Cmax and Tmax are good because…
they’re the easiest PK parameters to calculate
- just look at the time by Cp graph
How to work out Cmax and Tmax?
- at the peak of the graph
- Tmax is where it is on the X-axis
- Cmax is where it is on the Y-axis
Define ‘Tmax’
- time at which Cmax is reached
- usually in hours
Define ‘Cmax’
- maximum conc of compound after administration
- in mg/ml or ng/ml
Explain reasons for sublingual administration
- required for fast/rapid response
- utilises venous drainage from mouth into superior vena cava and top of the heart
- avoids first pass metabolism
- e.g glycerine trinitrate in diabetes
Explain rectal/vaginal route
- bypasses GI/hepatic first pass effects
- rich blood supply
- absorption may be rapid/extensive but depends on drug formulation
- pH 7-8
- drainage in rectum 2/3 systemic (middle and inferior rectal vein) and one third portal (superior rectal vein)
Main advantages of rectal/vaginal route
- useful when drug causes vomiting and nausea
- or if patient is already vomiting and GI system is compromised post op
Advantages of injection administration
- predictable, rapid action
- altenative for drugs that are irritant by other methods
- iv infusion for ill, hospitalised patients
Disadvantages of injection administration
- difficult/painful
- risk of infection
- cost and safety
- immediate adverse effects
What are subcutaenous/intramuscular injection?
- faster systemic effect than oral or local
- like local anaesthetics
List enteral routes of drug administration
- oral
- sublingual
- rectal
- vaginal