Absorption and Distribution Flashcards
What is pharmacokinetics?
ADME. what the body does to the drug
does ADME occur simultaneously or in isolation
These processes happen in isolation, but the summation of these is the pharmacokinetic profile of the drug:
what does absorption depend on?
administration route
what 2 factors does distribution depend on?
-how lipid-soluble the drug molecule is (to pass through membranes)
-how the drug binds to blood plasma proteins (albumin). If drug binds to blood proteins → doesn’t really have biological efficacy.
what does elimination involve?
excretion into urine and/or by inactivation by liver enzymes.
PD factors
differing physiological responses to the same drug conc
PK factors
differing drug conc at the target area.
ED50
effective dose in 50% people
TD50
toxic dose in 50% of people
LD50
lethal dose in 50% of people
Margin of safety
= ED50 -TD50
Therapeutic Index
Therapeutic Index: ratio of median lethal or toxic dose to the median effective dose
define bioavailability
% of drug reaching the systemic circulation and available for bioactivity.
define bioequivalence
similarity between drugs/formulations. At the same conc., is one drug bioequivalent to another?
administration routes
- Oral
- Rectal
- Inhalation
- Topical
- Parenteral (beyond the intestines): Intravenous, Intramuscular, Subcutaneous & Intraperitoneal
main site of absorption
small intestines
oral administration
& BUT
Needs to be:
- Soluble in gastric fluid otherwise won’t be absorbed
- Stable in gastric fluid otherwise will be broken down
- Enter the intestine and penetrate gut epithelium
- Enter the bloodstream
BUT, how much actually gets to the blood?
Parenteral administration
& BUT
Beyond the intestines
- Fast acting
- Traverses fewer body compartments
- Delivers accurate dose
BUT, more likely to overdose, and once injected it cannot be recalled.
Topical
- Good for skin as easily absorbed
- Stable controlled release
- Minimises side effects
min effective vs max tolerated
When a drug is administered, a peak is produced, which falls over time as its eliminated. Achieve highest level of drug within window of minimum effective concentration and maximum tolerated concentration for as long as possible.
steady state
When drug concentration in the plasma is constant. Occurs within 3-5 half lives. Ideally, looking for steady state to fall within the therapeutic window.
absorption vs distribution
- Absorption: Passage of drug from site of administration → blood.
- Distribution: Delivery of the drug from blood → tissue.
what fraction of total body water does intracellular fluid make
2/3
what fraction of total body water does extracellular fluid make
1/3
what fraction of extracellular fluid does plasma fluid form
1/4
what fraction of extracellular fluid does interstitial fluid form
3/4
4 Ideal characteristics for maximal drug absorption
- Low molecular size
- Non-polar (made by amino acid side chains)
- Charged (made by amino acid side chains)
- High lipid solubility. BUT, this might mean its poorly dissolved in aqueous solutions.
Ways to regulate the release of drugs
- Dosage form = solution, capsule/tablet, cream
- Excipients = added onto drugs to change properties (e.g., binders, disintegrants, diluents)
- Delayed release (e.g., Enteric coating). The coating of oral tablets is broken down by the gut to ensure drug is delivered to the right place.
- Sustained release (e.g., Matrix diffusion). Matrices can be implanted into body so drug is released over months.
pKa
= acid dissociation constant = the pH value at which a species will accept or donate a proton i.e., in ionic form.
- Aspirin is a weak acid with a pKa of 3.5. At pH 3.5, 50% of it is in ionised form, and 50% is in unionised form.
- If the pH changes, these percentages also change.
- The unionised fraction is lipid soluble.
7 factors determining the rate of permeability across lipid membranes
-permeability coefficient
-concentration difference
-Solubility of drug in the membrane (Lipophilicity is essential)
-Carrier-mediated transport through pH partition (Ionisation)
-Binding to plasma protein
-Blood flow at site of absorption
-Surface area in contact with the drug
passive diffusion & what law it follows
- Simplest way of transport.
- High conc/pH → low conc/pH.
- Variable rate.
- Follows Ficks law of diffusion: rate of diffusion of a substance across unit area (such as a surface or membrane) is proportional to the concentration gradient.
Carrier mediated transport/facilitated diffusion & what law it follows
- Carrier proteins identify, bind and transport drugs across membranes.
- Usually bind endogenous proteins.
- Rate is much less variable than passive diffusion.
- Follows Michaelis-Menten equation: used for enzyme kinetics.
Active transport
- Membrane channels actively move drug against conc. gradient
- Low → high conc.
- Requires energy in the form of ATP.
Pinocytosis
- Fluid endocytosis.
- Extracellular fluid is taken up in a vesicle → invagination → budding of vesicle → which then releases the drug
- Used for large and complex drugs (such as insulin being injected peritoneally).
the compartment model
Within the body are interconnected compartments. The conc. of drug within a single compartment remains constant, however movement between compartments determines PK and PD of the drug (e.g., where and for how long a drug remains active in the body).
factors affecting drug distribution (rate-2 and extent-5)
Affecting rate:
Membrane Permeability
Blood Perfusion
Affecting extent:
Plasma protein binding
Intracellular binding
pH differences
Lipid solubility
Available transport mechanisms.
what plasma proteins do acidic drugs bind to
albumin
what plasma proteins do basic drugs bind to
globulins (alpha and beta)
what does binding of plasma proteins do to the drug?
makes drug inactive.
Quantifying bioavailability
- To quantify bioavailability, dose response curves are plotted.
- One curve here gives dose response for IV and one for oral administration.
- Area under curve (AUC) gives total bioavailability! Log conc/time.
