L66: Drug Absorption And Distribution Flashcards
Where can drug distribute to
- Circulation
- Site of action
- Tissue reservoirs
- Biotransformation / Metabolism
- Excretion
Carry of drug to bodies tissues
- Bulk flow of water with drug dissolved (free drugs, small molecules: 100-300 Dalton)
- Protein-bound drug (paracellular transport, large molecules)
Transport of drugs across cell membrane
Drug factor
- Size
- Shape
- Charge / Ionisation
- Lipid solubility
- Binding to protein
- Lipid:water partition coefficient
Environmental factors
- Concentration gradient
- Cell surface area
- Temperature
- Distance
Oral absorption
Physicochemical interaction
- GI pH
- Chelation
- Exchange resin binding
- Adsorption
- Dissolution
GI motility
- Gastric emptying
- Intestinal motility
Equilibrium of non-electrolyte vs Ionic compound
Non-electrolyte: equilibrium achieved when equal concentration on both sides
Ionic compound: depends on pH (degree on ionisation —> charges)
Electrolyte drug distribution depend on
- pH gradient across the membrane
2. pKa
Ion trapping
Result of pH difference across cell membrane
—> basic drugs trapped in acidic fluid (gastric juice)
—> acidic drugs trapped in basic fluid (plasma)
Bioavailability definition
Fraction of a dose of drug reaching site of action (0-1) —> determine therapeutic efficacy
Measuring plasma / urine drug level is an indirect estimate of drug at site of action: assuming that drug is in equilibrium between site of action and blood/urine
F = AUCev/AUCiv F= (unchanged drugs excreted in urine)ev/(unchanged drugs excreted in urine)iv
Factors affecting bioavailability
- Disintegration
- Dissolution
- Transfer across membrane from GIT into systemic circulation
First-pass effect
Drug is metabolised between administration site (GI) and site of sampling (blood)
2 superfamilies of drug transporters
- ABC: ATP binding cassette (active transport, efflux only)
2. SLC: solute carrier transporter (facilitated transporter, influx + efflux)
Factors affecting distribution of drugs
First phase of distribution (plasma and interstital)
- Cardiac output
- Regional blood flow (well-perfused organ receive more drugs)
- Tissue volume
Second phase of distribution (interstitial and intracellular)
1. Lipid solubility (BBB: endothelial tight junctions, entry depend on transcellular)
2. Plasma Protein binding (acidic: albumins, basic: alpha1-acid glycoprotein)
3. Tissue binding
(pH usually not a problem due to only slight difference)
Drug interaction at distribution
- Competition for plasma protein binding, esp important for drugs that are
- highly protein bound
- narrow therapeutic index
- low volume of distribution
- low potency - Drugs affect size of compartment e.g. diuretics decrease plasma volume —> increase concentration of other drugs
Plasma protein binding
- limit concentration in tissue
- only unbound drug can transport across membrane
- may displace other protein bound to albumin —> potential toxicity
—> Class I (dose given < available binding site)
—> Class II (dose given»_space; available binding site)
—> Class II will displace Class I —> increase in Class I drug effect and decrease in duration of action - depends on:
1. drug concentration
2. affinity
3. dissociation constant
Tissue binding
- most drug accumulate in tissues due to active transport and tissue binding
- bind to:
1. Organelles
2. Fat (lipid-soluble drugs)
3. Bone (tetracycline)
