pharmacokinetics Flashcards
Define absorption..
the movement of drug from site of administration into plasma
what determines the absorption of a drug?
route - blood flow to that region, 1st pass metabolism, local affects only?
drug - its chemistry (acid, base, Pka, lipid solubility, size, partition coefficients)
method of absorption - ions channels, active transport, simple diffusion, pinocytosis.
factors affecting diffusion - ficks and grahams law
- size, lipid solubiltiy including proportion of ionisation (PKA), conc gradient, thickness of membrane, S.A.
how does subcut or IM absorption compare to oral?
faster
however rate is variable depending on blood flow to that site
also more painful
which routes of administration are subject to 1st pas metabolism?
oral
rectal
(nasal, sublingual, dermal, sub cut, IM and IV all bypass)
what factors determine transdermal absorption?
patient factors
* age - poor blood supply in elderly
* gender - men have thicker skin
* ethnicity
* type of skin e.g. thick callus , different blood supply via region.
* diseased skin - inflammed
device factors
* the type of drug - small, lipid soluble e.g. fentanyl patch.
* more potent, the less needed so quicker absorption to effect
* good contact or cream rubbed in well
what are the pros and cons of giving a drug IM?
pros
* bypass 1st pass
* quicker acting
* can be used for patients that are non-compliant without capacity
cons
* painful
* can result in swelling / haematoma/ abscess
* less predictable as different blood supply to different regions/ individuals
* risk of accidental IV
define bioavailabilty?
Refers to the fraction of drug that enters the systemic circulation after non-IV administration compared to that in IV administration.
calculated by AUC in oral / AUC IV when drug conc vs time is plotted
what factors influence bioavailability?
- drug chemisty - acid/base, pKA etc
- type of preparation - enteric coated tablets prevent stomach acid breaking down
- the route of administration - where its affected by 1st pass metabolism, its blood supply etc
- 1st pass metabolism - degree the drug is affected, liver blood flow, efficiency of enzyme systems.
- metabolism - e.g. broken down by esters before fully reaching systemic circulation
- co-administered drugs - may inhibit 1st pass metabolism, may change GI absorption e.g. prokinetics
can you think of examples where 0 bioavailability is useful?
vancomycin in c.diff
antacids in stomach
anytime you want local actions only
what is the difference between absolute and relative Bioavailability?
absolute bioavailability = AUC oral/IV
Relative is for those that cant be given IV . Relative bioavailability compares the bioavailability of a drug from a particular formulation or route of administration to that of a reference formulation or route. It does not require an intravenous reference dose.
what factors impact amount of drug absorbed by the inhalation route?
Drug
* blood:gas partition coefficient
* size - MW
* conc gradient
carrier gas:
* e.g. for inhalers like salbutamol - can influence where the drug reaches.
* 1-3um will reach alveolus.
* may not need to reach this far e.g. bronchodilators and can be bigger
Patient
* minute ventilation
* surface area, thickness
* deadspace
which drugs can be given by epidural route?
analgesic .. local anaesthetic, opioids, ketamine, clondine
steroids
adrenaline and bicarb as adjuncts - bicarb improves onset of local anaesthetics, adrenaline causes vasoconstiction to prevent systemic uptake of drugs.
what factors affect absorption via oral route?
drug
- Pka, acid / base
- formula (enteric coating, modified release)
- size
patient
* GI motility
* vomitting
* villous atrophy in elderly/ underdeveloped in kids
* microbiome
* other drugs - acidity, motility
* first pass metabolism
what determines where in GIT a drug is absorbed?
S.A of small intestine means most drugs absorbed here.
some drugs are more unionised at stomach pH e.g. weak acids - aspirin however still mostly by duodenum due to S.A
weak bases more unionised in duodenum
stomach emptying time
can you give examples of drugs that undergo high first pass metabolism and low?
high first pass
- morphine , nitrites
variable - propanolol
low - paracetamol, aspirin
define volume of distribution…
the theoretical volume a drug distrubutes into in the body to produce the concentration of drug found in the plasma
calculated by based on formula
conc = amount of drug / volume
determined by drug properties - molecular size, lipid solubility, tissue binding, plasma binding, ionisation.
define distribution..
the transfer of a drug into different body compartments
depends on drug properties and barriers present between compartments and protein binding.
what factors affect distribution of drugs..
drug properites
* ability to cross membranes - size, unionisation, pka.
* e.g. small lipid soluble generally have high Vd, lo
* tissue vs plasma protein binding - plasma protein binding reduces Vd, tissue binding increases it.
patient factors
* regional blood flow - i.e. initially distributes to areas of high blood flow, then medium, then low.
* fat content
* body pH
* hepatic / renal disease
what assumptions can be made based on Vd of a drug?
high Vd - absorbed into all compartments e.g. lipid compartments too and thus very lipid soluble - can go into all 3 compartments - intracellular, interstial and plasma
small Vd - absorbed only into water soluble compartments e.g. plasma.
is 14L a small or large Volume of distribution?
small
per Kg this would be 0.2L/kg
e.g. NMBA
which drugs require a loading dose?
those with a large Vd
this will help them reach their effective plasma concentration quicker
e.g. digoxin , amiodarone
equation for loading dose..
Vd x plasma target conc
how do hepatic and renal disease effect volume of distribution?
hepatic
* affects protein binding- less proteins, more free drug to distribute to lipid rich areas
* ascites - increased Vd of water soluble drugs due to extra fluid areas
renal disease
* fluid retension
* acidosis can also protein binding, ionised/unionised
explain the effects of plasma protein binding…
WHAT IS PPB…
drugs can bind plasma proteins through ionic bonds, hydrogen bonds or weak van deer waals.
the 2 main plasma proteins that bind drugs are albumin and alpha 2 acid glycoprotein. albumin binds acidic drugs e.g. aspirin and ACG bind basic drugs e.g. lidocaine.
Due to the weak interactions, the process is usually reversible and exists in equilibrium
plasma protein + free drug <=> plasma protein-D
thus the drug will exist as partly free form and partly bound form in the blood. it is the free form that is able to cross barrier to other compartments and exert effects and be excreted.
hence PPB effects
* drug distribution
* onset of action
* duration - metabolism & excretion effected
* Drugs can also displace one another resulting in DDIs.
* risk of drugs with narrow therapeutic index - PPB is acting as a reservoir, if plasma protiens reduced or displacement can result in quick increase in free drug portion and toxicity. usually only significant if PPB is 90% or more