Pharmokinetics 2 Flashcards
How is SA maximised in SI?
Plicae circularis
Villi
Microvilli
(30-35m2)
What is bioavailibility?
Fraction of defined dose which reaches specific body compartment
(circulation cost common ref compartment)
What is IV reference value bioavailabilty CVS?
100% - all reaches CVS
How are other routes of bioavailability compared?
Reference intravenous bioavailability (eg oral/IV)
Factors affecting drug absorption
Physiochemical
GI Physiology
First pass metabolism - GI and Liver
determine proportion of drug entering systemic circulation
How do measure bioavailability?
Plot plasma conc against time post dose
Calculate area under curve
for oral - area under oral curve/area under IV curve
Oral availability equation
F = amount reaching systemic/drug given IV
AUC
Where does F (bioavailability) lie?
Between 0 and 1
1 = all to systemic 0 = none to systemic
Drug distribution
How drugs travel through the body
- therapeutic/non therapeutic (side effects) interactions
- Interactions with other molecules
First stage - 3 parts distribution
Bulk flow: large distance via arteries –> capillaries
Diffusion: capillaries –> interstitial fluid –> cell membrane targets
Barriers to diffusion: Interactions/permeability/non target binding
Diffusion across capillaries affected by
Level of permeability
Expression of endogenous transporter/OAT, OCT
3 types capillaries
Continuous (closed, tight gap junctions, tight intercellular cleft)
Fenestrated (less tight cleft. fenestrations)
Sinusoid (leaky sinuses. big fenestrations)
Continuous found
BBB CNS Muscle Skin Fat
Fenestrated found
Intestinal
Endocrine/exocrine glands
Kidney glomeruli
Sinusoidal found
Bone marrow
Lymph
Liver
Spleen
(allow cells out)
Large effect on pharmacokinetics is…
Heterogenous structures/tissues of body
Different body types
Major factors affecting drug distribution
Lipophilicity/Hydrophilicity
Degree of drug binding to plasma/tissue proteins
Lipophilicity/Hydrophilicity
If lipophilic - easily move across membrane
if hydrophilic - barriers are related to absorption barriers (capillary permeabilty, drug pKa, pH, OAT/OCT density)
Degree of drug binding to plasma/tissue proteins
Drugs bind to proteins in circulation
eg. Albumin (globulin)
Lipoproteins (acid glycoproteins)
Example albumin
If drug bound to albumin acts as ‘dynamic reservoir’ of drug
ONLY FREE DRUG can bind to targets
If drug binds to protein = decreased free drug available
Binding to albumin
Binding not strong (equilibrium)
Multiple drugs can bind - competition for binding sites (affects pharmacokinetics)
3 body fluid compartments
Plasma water (3L) Extracellular water (plasma (3) + interstitial (11) 14L) Total body water (extracellular + intracellular 42L)
Barriers at compartments
Capillary membrane barriers (between plasma and interstitial)
Target tissue membrane barriers (between interstitial and intracellular)
What does increasing penetration of drug do?
Drug moves more readily from plasma –> interstitial –> intracellular
= decreased plasma drug concentration Increased Vd (volume distribution)
Where are most drug targets located?
Membrane of intracellular cells
Only need to penetrate to interstitial to have effect
Why is volume distribution (Vd) apparent?
Group all main fluid compartments as ONE compartment
= summary of drug through plasma, interstitial and intracellular
Pretend concept
What is Vd usually referenced to?
Plasma concentration
dependent on push/pull factors
What do values of Vd mean?
small Vd: less penetration of interstitial/intracellular compartment
large Vd: greater penetration of interstitial/intracellular compartment
Vd units
litres (70kg standard assumed)
Litres/kg (affected by weight)
Vd equation
Drug dose/plasma drug (at time =0)
What can Vd be affected by?
Blood flow Hypoalbuminemia Body weight changes (increased lipid, more to pass through) Other drugs Renal failure - drug excreted slower Pregnancy Paeds Geriatrics Cancer
