4. Pharmacokinetics: Transport mechanism of drugs, absorption, distribution Flashcards
Pharmacokinetics
What the body does to the drug
Give the types of transcellular transport
- Diffusion
- Filtration
- Facilitated diffusion
- Active transport
Filtration
Bulk flow of solvent & solute through pores in the membrane
- Concentration gradient affects the rate
Intracellular transport
Across gaps between endothelial & epithelial cells
- Filtration
Degree of ionisation of a weak acid/base is determined by…
- The pK of the drug
- pH of its environment
When pK of a drug = pH of surroundings
50% ionisation occurs
Lower pK = stronger acid; Higher pK =
Stronger base
Rate of passage accross a semipermeable membrane is dependent on…
- Pressure
- Concentrations
- Temperature
Permeability accross a semipermeable membrane is dependent on…
- Solute size
- Solubility properties
- Chemistry
Drug absorption
Movement of drug into the bloodstream
- Usually done via mucous surface
Reasons for ↓ absorption of drugs
- Poor compound solubility
- Chemical instability in stomach
- Inability to permeate intestinal wall
Relation of small molecule absorption and blood flow
- Absorption of small, very lipid-soluble molecules is “blood flow limited”
- Higher polar molecules are “blood flow independent”
Bioavailability (F)
Fraction of drug that reaches the bloodstream unaltered
Absolute bioavailability
Measures the availability of the active drug in systemic circulation after non-IV administration
How is absolute bioavailability determined?
Pharmacokinetic study
- Plasma drug conc. vs Time plot
- Area under curve (AUC) for IV divided by that of non-IV administration
Bioavailability ≠
Bioequivalence
Relative bioavailability
Measure of the bioavailability of a drug when compared with another formulation of the same drug or delivered via a different route
Formula to calculate relative bioavailability
List the factors affecting bioavailability
- Poor absorption
- Degradation
- Intestinal motility
- Disease
- First pass effect
First pass effect
Concentration of a drug is greatly reduced before it reaches the systemic circulation
Topical/external administration sites
- Skin
- Mucous membrane
- Nose
- Mouth
- Rectum
Enteral administration sites
- Oral
- Rectal
- Oro-/nasogastric
- Intra-ruminal
Parenteral administration sites
- IV
- SC
- IM
What is key for controlling the duration of drugs effect?
Rate of dissolution of tablets
- If not readily dissolved, may be released more gradually over time with longer duration of action
Distribution
Reversible transfer of drug from one location to another
- Blood leaves bloodstream → EC fluids + Tissues
Distribution is dependent on…
- Permeability bewtween tissues
- Blood flow
- Perfusion rate
- Ability of drug to bind plasma proteins & tissue
For intracellular action drug must be…
Lipid soluble
Volume of distribution (VD)
The volume of total body fluid into which drug “appears” to distribute
- Quantifies the extent of distribution
Volume of distribution is determined by…
Administrating a known dose of drug IV & measuring initial plasma conc.
- Expressed in units of mass/volume
Binding of plasma proteins
- Only free drug diffuses through capillary walls
- Extensive binding retards rate at which drug reaches its site of action
- May prolong the duration of action
- Generally reversible
Drug redistribution
- Relative distribution of drug changes with time
- Usually highly lipophilic drugs that initially enter tissues with high blood-flow
- Quickly redistribute to tissues with lower blood flow
Blood brain barrier
- Ionised/polar drugs distribute poorly to CNS + chemotherapeutic agents & toxic compounds
- → Must pass through endothelial cells
Placental barrier
Lipid-soluble drugs cross more easily than polar drugs
Most drugs are absorbed by…
Small intestine
Rate of dissolution is described by the…
Noyes-Whitney equation
List the factors that may alter absorption from the GI tract
- Gastric emptying time → Intestinal motility
- GI blood flow
- Stomach acid → Inactivating enzymes
- Interactions with food & other drugs
Absorption of small, very lipid-soluble molecules is…
- “Blood flow limited”
- Higher polar molecules are “blood flow independent”
Distribution
Reversible transfer of drug from one location to another
- Where drug leaves bloodstream & enters EC fluids & tissue
Distribution is dependent on…
- Permeability between tissues
- Blood flow
- Perfusion rate
- The ability of a drug to bind plasma proteins & tissue
For intracellular action, a drug must be…
Lipid soluble
Volume of distribution (VD)
The volume of total body fluid into which drug “appears” to distribute
- Quantifies the extent of distribution
How is the volume of distribution determined?
- By administrating a known dose of drug IV (mass)
- Measuring initial plasma conc (mass/volume)
Binding of plasma proteins
Generally reversible
- The only free drug diffuses through capillary walls
- Extensive binding retards rate at which drug reaches its site of action & may prolong duration of action.
