Intro Biopharmaceutics Flashcards
What does Bioavailability refer to?
Amount of drug that goes into the
-BLOOD
-TISSUES
Steps required for Absorption:
Disintegration -> Dissolution -> only when in solution it can be absorbed
How can bioavailability be measured?
-Pharmacokinetic profile: periodically take blood samples and measure the concentration of the blood -> curve
-Metric: Cmax, Tmax (time associated with Cmax),
AUC (area under the curve)
MEC (minimum effective concentration), MTC (maximal tolerance concentration) -> gap between MEC and MTC = therapeutic window
-time above MEC: Duration of effect: how much time the drug spends being therapeutically active
What does the fall of the concentration in the pharmacokinetic curve indicate?
-Metabolization of the drug
-Distribution into the tissues
-Elimination
What is happening at the top of the pharmacokinetic curve?
Absorption and Elimination is approximately equal
Recognize the rate process in the curve:
First order: the rate of absorption or elimination changes with the amount of concentration (high concentration -> high rate, decrease in concentration leads to decrease in the rate)
Zero order: constant decrease in rate, regardless of concentration
What is the rate process in the absorption and elimination phase of an orally administered drug?
First order: bc the rate is proportional to the concentration of the drug present in the body -> and the concentration is changing over time (for absorption and elimination)
How is Bioavailability designated?
-determined by AUC
-designated as F
-IV has 100% -> F=1
-IV used to compare -> other routes expressed as a fraction of 100% -> f.e. 0.8 = 80%
What does Biopharmaceutics deal with?
What is the effect of:
-Dosage form (tablet, solution, disintegration step involved?)
-Physico-chemical properties (solubility, lipophilicity, ionization)
-route of administration (IV, oral)
-Physiological function (taken after a heavy meal, drug transport across the membrane, first-pass metabolism for oral route)
–> effect on BIOAVAILABILITY
ADME: Absorption, Dissolution, Metabolism, Elimination
Which administration routes have the fastest onset?
- IV
- Inhaler: lung has a large surface area compared to the drug -> fast absorption
- Solution -> no disintegration
- capsule -> only the shell has to disintegrate
- tablet -> disintegration needed
- topical creams, and ointments -> have to cross dead skin (stratum cornea)
If the pharmacokinetics of the same drug is so different, why are there different dosage forms available?
-f.e. capsule form of Albendazole has low absorption
-absorption is not needed bc it works in the gut and interferes with the glucose absorption of the worms
-neuromuscular junction blocker for worms -> worms paralyzed
What are rate-limiting steps in oral drug absorption?
The slowest process prior to Absorption is the rate-limiting one (Bottlenecks)
-vary with the drug
-f.e. a compressed tablet will take a long to disintegrate (bottleneck)
f.e. insoluble drugs -> Dissolution is the bottleneck
What is the function of a diluent?
-It bulks up the volume, f.e. you have 10mg of the drug and you want 100;
-works as a binder
-in the stomach, it adsorbs the water and breaks up the tablet = DISINTEGRANT
Ka (up), Tmax (down), AUC (up)
-Lactose
Dibasic calcium phosphate
Starch
Microcrystalline cellulose
What is the function of Lubricant?
-Lubricants prevent the granules to get stuck in the hopper or puncher and ensure uniform granules
-they are lipophilic and delay wetting and disintegration
Ka (down), Tmax (up), AUC (down)
-Magnesium stearate
Stearic acid
Hydrogenated vegetable oil
Talc
The function of coating agents:
-delays the disintegration of the dosage form and dissolution of the drug -> to pass the stomach
Ka (down), Tmax (up), AUC (down)
-Methylcellulose
Cellulose acetate phthalate (CAP)
How does Starch improve the dissolution of a hydrophobic drug?
-Hydrophilic diluent (Starch) dissolves in gastric fluid, leading to a porous mass of drug -> fluid will penetrate the mass of drug -> increase in dissolution
How is the effect of Lubricants shown in a PK
-Lower Cmax, Tmax shifted to the right, lower AUC
How much solubility is required for Absorption?
-Just a bit is sufficient
Dissolution -> Particles in solution bump into the tissue (villi) of jejunum through Brownian Motion and pass through the membrane -> Absorption
How does Absorption occur even with small Solubility?
-Equilibrium between the insoluble and soluble form of the drug
-once some of the soluble particles get absorbed, some of the insoluble particles will turn soluble to establish the equilibrium
Is the Solubility of rock salt (big chunks) and table salt (fine) different?
No, the solubility is the same, bc the chemical structure is equal
-but the particle size is different -> DISSOLUTION is different
table salt dissolves quicker -> so the RATE of dissolving different = DISSOLUTION
Parameters of Noyes-Whitney Equation: of Dissolution:
dC/dT = D * A/h * (Cs - C)
dC/dT = rate constant
D = dissolution coefficient
A = particle surface area
h = layer thickness
(Cs - C) = concentration gradient (between layer and bulk phase)
when dissolving the particles diffuse to the layer phase, then into the bulk phase -> we want the layer to be thin (stirring), to facilitate the diffusion of particles into the bulk phase
How do physiological factors (functions of the body) affect dissolution in vivo?
-size reduction in stomach
-mixing and motility (a full stomach will have more motility)
-viscosity (a full stomach has more viscosity)
What are strategies to improve drug solubility?
-Size reduction
-amorphic drugs
-Co-solvents
Why are amorphous forms more water soluble?
Because the structure of an amorphous form is unorganized, unstable, and has high free energy -> making it easy for water to disrupt the structure compared to the organized structure of the crystalline form
-BUT bc of instability the amorphous form might spontaneously change its formulation
How do Co-solvents increase Solubility?
Why is it a better Co-solvent than water?
-Co-solvents like alcohol are miscible with water and built pockets in which the drug can dissolve more freely
-less polar than water and therefore better for less polar drugs
The 4 most common Co-solvents: Glycerol, Ethanol, Polyethylene glycol, Propylene glycol
(polarity is measured by dielectric constant - how well solvents deal with ionized species; water has a high dielectric constant, benzene, and chloroform have low dielectric constant (organic and not used in oral drugs), alcohol is intermediate)
Why do salt forms increase solubility?
-the anionic part (f.e. Na) will more readily leave in leave behind the charged part, which can interact with water
-there are chances that H in the acid will leave, but chances are way less
Difference in organic and inorganic counterions?
organic counterions often have multiple hydroxyl groups and thereby increase dipole-dipole interaction with water
Improvement of Solubility with prodrugs:
-f.e. Steroids are poor water soluble, so it can be combined with an aminoacid -> PRODRUG by an ester bond -> in the plasma the ester prodrug will be cleaved by esterase, releasing the drug
When does a decrease in Solubility increase Bioavailability?
Penicillin G is very water soluble -> works quickly -> eliminated quickly -> so it would have to be injected more often
-replace K+ with benzathine (lipophilic molecule) to prolong the duration of action
-Erythromycin is water soluble but very bitter
-> ester prodrug between stearate acid and erythromycin (OH group) -> doesnt dissolve on the taste buds
Improving Solubility by Complexation
-Cyclodextrin are cyclized polar molecules (hydroxyl groups at the outside -> water soluble outside), the cavity inside is non-polar, whereby an insoluble drug can be packed into
Where does Complexation reduce Bioavailability?
Chelation: Complexation between Ca or Mg with charged molecules -> chelated or complexed drugs will not get absorbed
-Tetracyclin should not be taken with milk or Antacids (containing Ca or Mg)
