3. Pharmacokinetics 1 Flashcards
What is the difference between Pharmacodynamics and Pharmacokinetics?
- Pharmacodynamics is what the drug does to the body
- Pharmacokinetics is what the body does to the drug
Define the terms absorption, distribution, metabolism and excretion as they apply to drugs?
(ADME)
Absorption, Distribution, Metabolism and Excretion
- A - Absorption (movement of a drug from its site of administration into the blood)
- D - Distribution (movement of drug out of the blood into the tissues and site of action)
- M - Metabolism or breakdown of drug (mainly in the liver, but also in other tissues)
- E - Excretion of drug and metabolites (mainly via the kidney, but also through other routes)
What is the structure of a Cell Membrane?
Cell Membrane - The cell membrane is a barrier which drugs must pass through in order to exert their therapeutic effect e.g. absorption from the stomach into the blood and distribution to the tissues
- The cell membrane basically consists of a phospholipid bilayer
- A phospholipid is a lipid (fat) molecule which contains a phosphate group
- It has a hydrophilic “head” and a hydrophobic (lipophilic) “tail”
- Phospholipid bilayer which also contains
- cholesterol (strength and consistency of membrane)
- proteins (enzymes and transport)
- carbohydrates
- aqueous pores
- proteins which can act as transporter molecules
What are 3 ways drugs may cross the cell membrane?
Movement of Drugs Across The Cell Membrane
Drugs may cross the cell membrane in a number of different ways including:
- Diffusion directly through the lipid (fatty) membrane
- Diffusion through aqueous pores in the membrane
- Combination with a protein transporter in the membrane
What is Passive (Simple) Diffusion?
What is Facilitated Diffusion?
Passive (Simple) Diffusion
- Movement of drugs across the cell membrane without the need for energy expenditure
- Dependent on the concentration gradient and the permeability of the membrane (Fick’s Law of Diffusion)
- Cannot move against a concentration gradient
- Most drugs move across the cell membrane by passive (simple) diffusion
What are 3 examples of drug types that enter the cell by simple (passive) or facilitated diffusion?
Passive (Simple) Diffusion
- Lipid soluble drugs dissolve in the cell membrane and diffuse across the membrane
- Water soluble drugs cross the cell membrane through aqueous channels in the membrane (small molecules)
- Some drugs move across the cell membrane by combining with solute carrier (SLC) transporter proteins (facilitated diffusion)
What is Active Transport?
Which molecules can be transported into the cell in this way?
Active Transport
- Active transport is movement of drugs across the cell membrane which involves the expenditure of energy
- Active transport can move drugs against a concentration gradient
- ATP binding cassette (ABC) transporters are active pumps which source their energy from ATP
- They can transport sugars, neurotransmitters, amino acids and metal ions e.g. iron and levodopa
What is Drug Absorption?
What are 6 routes of drug administration?
Drug Absorption
- Drug absorption = the movement of a drug from its site of administration into the blood (plasma)
- To move from the site of administration into the blood (be absorbed) drugs must pass through cell membranes
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Routes of administration:
- Oral
- Sublingual
- Rectal
- Inhalation
- Transdermal
- Injection - e.g. subcutaneous, IM and IV
- Intravenous administration, by definition, bypasses absorption as the drug is injected directly into the blood – works quickly
What is Oral Absorption?
Oral Absorption
- Oral administration is where the drug is taken by mouth and swallowed
- Convenient and relatively safe
- While some of the drug can be absorbed in the stomach, the majority of drug absorption following oral administration takes place in the small intestine
- In order to be absorbed following oral administration a drug must pass through cell membranes of the stomach/small intestine and blood vessels
- Following oral administration most drugs are absorbed by passive (simple) diffusion
What are 7 factors which may affect the absorption of a drug following oral administration?
Factors Affecting Oral Absorption
- Lipid solubility of the drug
- Molecular size of water soluble drugs (need to be smaller as pass through pores)
- Whether the stomach is full or empty (gastric emptying time)
- Whether the drug is taken with or without food e.g. aledronate
- Stability of the drug in the gastrointestinal tract e.g. insulin
- Type and properties of the form of administration e.g. liquid, tablet, sustained release, rate of dissolution (you cant absorb a tablet!)
- First pass metabolism
What impact does gastric emptying have on the rate of drug absorption and why?
Rate of Drug Absorption - Gastric Emptying
As a general rule, anything which delays gastric emptying reduces the rate of drug absorption, and anything which increases gastric emptying increases the rate of drug absorption
- The duodenum/small intestine has a far greater surface area than the stomach (also thick mucus), and the epithelium is more permeable than in the stomach
- Because of this, the rate of drug absorption is far greater once a drug has entered the duodenum/small intestine (some drug will always be in the unionised form)
What is First Pass Metabolism?
First Pass Metabolism
- When a drug is swallowed it is absorbed from the stomach/small intestine
- It enters the portal circulation and is carried by the portal vein to the liver
- The liver is the major organ for drug metabolism and if the drug is extensively metabolised only a small amount of non-metabolised drug may leave the liver, go to the heart and enter the systemic circulation
- Some drugs may also undergo metabolism in the gastrointestinal tract wall
What is the issue with administration of drugs that have a high first pass metabolism?
What are 4 examples of drugs that have a high first pass metabolism?
High First Pass Metabolism
- If a drug has a high first pass metabolism larger doses are needed if it is administered orally
- In some cases the drug is inactive if administered orally e.g. glyceryl trinitrate
- Examples:
- Glyceryl trinitrate
- Amitriptyline
- Metoprolol
- Morphine
What are 4 routes of administration which avoid first pass metabolism?
Where do they go in the body
First Pass Metabolism
- Routes of administration which avoid first pass metabolism include:
- Sublingual
- Rectal
- Transdermal
- Subcutaneous & IM injections
- Drugs from these sites are absorbed into veins which drain to the heart without entering the portal system and liver
What is Oral Bioavailability of a drug?
How bioavailable is a drug that has been adminstered intravenously?
How is it calculated?
Oral Bioavailability of a Drug = the fraction (F) of the unchanged drug which reaches the systemic circulation following oral administration
- By definition, a drug is 100% bioavailable when administered intravenously
- Oral bioavailability is calculated by comparing the areas under the plasma concentration versus time curves for intravenous and oral administration of the same dose
What is the Bioavailability of a drug?
Bioavailability of a drug = the fraction (F) of the unchanged drug which reaches the systemic circulation following administration
- By definition, a drug is 100% bioavailable when administered intravenously - compare AUCs
What is Drug Bioequivalence?
Bioequivalence
Two products are considered to be bioequivalent if they produce such similar plasma concentrations of the same active ingredient (rate and extent of absorption) that their effects should be identical
