Pharmacokinetics 1 Flashcards
what does ADME stand for ?
absorption - is the administration of the drug into the systemic circulation
distribution- is the movement of the drug from the systemic circulation to the target tissue
metabolism - breaking down the drug down
excretion - removal of the drug from the body
define pharmacokinetics :
it is how the body affects a drug
what is pharmacokinetics important for ?
important for constructing dosage and administration regimes
- many drugs fail due to poor kinetics in man
what does an effective drug require a balance between ?
between its ADMET properties
- adsorption
- distribution
- metabolism
- excretion
- toxicity
what is the Cmax?
it is the maximum concentration that a drug achieves in tested area after administration and before second dose
what is Cmin ?
it is the minimum concentration achieved in a tested area after administration
what is Tmax ?
it is the time at which C max is achieved
what does disposition equal ?
absorption, distribution, metabolism and excretion
what is T0.5?
it is the time at which half the Cmax is achieved
what are Cmax, Tmax and T0.5 dependent upon after oral administration ?
dependent on drug absorption rates and disposition profile of the drug
what does AUC stand for ?
area under the curve
the are under the curve of a plot of concentration of drug in plasma against time
what does the AUC show us ?
shows the total exposure that the body gets from a single dose
also shows the maximum drug concentration that the body receives and shows the speed of drug metabolism
what is the therapeutic index?
= toxicity in 50% of population/ minimum effective dose 50%
also known as therapeutic window
= TD50/ED50
if a drug x can regress cancer cells by binding to R1 receptor and its KD is 2nM and it also binds to R2 causing cell death of healthy cells with a KD of 800nM, what is drug x’s therapeutic index?
= 800/2 = 400
this ratio allows us to see at what point a highly beneficial therapeutic becomes a lethal toxin
what does a narrower therapeutic index mean ?
the narrower range means it is more likely to cause toxicity/overdose
what is absorption ?
it is the movement of drug from the site of administration to systemic circulation - NOT THE SITE OF ACTION
what is bioavailability a measure of ?
it is a measurement of the rate and extent to which a drug reaches the systemic circulation(expressed as F) and applies to all routes of administration
- it is defined by the rate it appears in the blood and the relative amount of drug from the administration dosage which enters the systemic circulation
what is the ROA ?
route of administration- it is very important and the most appropriate route must be considered
describe the different speeds of absorption for different methods of administration :
from fasted to slowest
- intravenous
- pulmonary
- intramuscular
- subcutaneous
- oral
how is bioavailability determined and what is the bioavailability of intravenous drugs ?
= AUC(oral)/AUC(i.v)
bioavailability of i.v is 100% beccause 100% is placed in the circulation
what information does the Cmax and Tmax provide?
gives the rate of absorption
what does i.v admin avoid ?
it avoids first pass metabolism
what are the advantages/disadvantages of i.v. admin ?
advantages
- very rapidly acting- 5-10seconds, very useful for pain relief
disadvantages
- not useful for drug compliance
- increased chance of infection, overdose, arterial damage
how does oral admin work ?
it is the most common and onset is about 10-20mins but it needs to be absorbed
- absorbed by small intestine, which has a large surface area and a rich blood supply
what can affect oral avalability ?
- weak acids, the ionized form HA is readily absorbed in the stomach but weakly basic drugs are poorly absorbed
- problems with empty/full stomach - drug has to be able to survive the gastric enzymes, stomach acid and not bind to calcium ions in food and also cope with gut bacteria
what are most oral drugs ?
most are weak acids or weak bases
- only the unionised form will be absorbed
for acid- HA- A- + H+ = HA is unionised
for base- B + H+ - BH+ = B is unionised
what is good for oral bioavailability?
low metabolic clearance
what can cause a low bioavailability ?
poor absorption or high metabolism
what is an indicator of absorption speed?
time to reach Cmax
what is sublingual admin and what are some examples ?
drug is placed under the tongue
- rapid absorption
- no first pass metabolism
- but small surface area
e.g GTN- it cant be taken orally because it will not survive first pass metabolism
buprenorphone- a post operative pain killer
what are the problems with sublingual admin ?
incorrect usage - patient may swallow it
taste
availability
more expensive to manufacture
what are the benefits of rectal admin ?
no pH problems
no issues with stomach acid
no damage to stomach lining
good if patients keeps vomiting
what are i.m and s.c admin ?
i. m.= inrtamuscular admin and s.c.= subcutaneous admin
- drug is placed into the connective tissue matrix and absorbed into local vessels
- they have low impedence (fenestrations) so it allows for paracellular diffusion
- useful for absorption of hydrophilic drugs and large drugs
- generally a low level of fluid is administered- <5ml
what are the benefit of aerosol admin ?
very rapid
avoids first pass metabolism
large absorption area - inhalation surface area is about 100m2 and it is permeable with low metabolism
- anaesthetics often given this way
what is topical admin ?
it is targetted to the site of injury
must be lipid soluble to pass through skin
has localised actions
- benefits= avoids first pass metabolism but not always effective at targeting areas distant from application
why is distribution important ?
it detects tissue sequestration
it determines the loading dose
provide info for adjusting dose
what are the 4 compartments of the body which are all linked together and enable drug to distribute between ?
blood extracellular fluid intracellular fluid fat others= synovial fluid, fetus
what does the volume of drug distribution show us and how is Vd calculated ?
shows how well a drug is distributed
Vd= plasma clearance(Cl)/elimination rate constant(K) or amount of drug in body/plasma drug concentration
how does lipophilicity affect the volume of distribution of a drug ?
the higher lipophilicity of a drug the higher the volume of distribution
- desired volumes of distribution change for different drugs
how do you calculate volume ?
volume= amount/concentration
how is the % bound drug to plasma proteins determined?
= bound drug/ bound drug + free drug * 100
what factors affect distribution of a drug ?
intracellular tissue binding lipid solubility ph vs pKa intervention of BBB placental/mamary transfer of drugs
what can volume of distribution in a patient also depend on ?
depends on body size and can be quoted as L/Kg
an analgesic (75mg) is administered by i.v and a blood sample shows the initial concentration in the blood is 0.9 micrograms/ml. what is the Vd of the analgesic ?
VD= amount / concentration
= 75000micrograms / 0.9 = 83 litres
