Absorption and Distribution

Question 1

What is pharmacokinetics?

Answer 1

ADME. what the body does to the drug

Question 2

does ADME occur simultaneously or in isolation

Answer 2

These processes happen in isolation, but the summation of these is the pharmacokinetic profile of the drug:

Question 3

what does absorption depend on?

Answer 3

administration route

Question 4

what 2 factors does distribution depend on?

Answer 4

-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.

Question 5

what does elimination involve?

Answer 5

excretion into urine and/or by inactivation by liver enzymes.

Question 6

PD factors

Answer 6

differing physiological responses to the same drug conc

Question 7

PK factors

Answer 7

differing drug conc at the target area.

Question 8

ED50

Answer 8

effective dose in 50% people

Question 9

TD50

Answer 9

toxic dose in 50% of people

Question 10

LD50

Answer 10

lethal dose in 50% of people

Question 11

Margin of safety

Answer 11

= ED50 -TD50

Question 12

Therapeutic Index

Answer 12

Therapeutic Index: ratio of median lethal or toxic dose to the median effective dose

Question 13

define bioavailability

Answer 13

% of drug reaching the systemic circulation and available for bioactivity.

Question 14

define bioequivalence

Answer 14

similarity between drugs/formulations. At the same conc., is one drug bioequivalent to another?

Question 15

administration routes

Answer 15

• Oral
• Rectal
• Inhalation
• Topical
• Parenteral (beyond the intestines): Intravenous, Intramuscular, Subcutaneous & Intraperitoneal

Question 16

main site of absorption

Answer 16

small intestines

Question 17

oral administration

& BUT

Answer 17

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?

Question 18

Parenteral administration

& BUT

Answer 18

Beyond the intestines
- Fast acting
- Traverses fewer body compartments
- Delivers accurate dose

BUT, more likely to overdose, and once injected it cannot be recalled.

Question 19

Topical

Answer 19

• Good for skin as easily absorbed
• Stable controlled release
• Minimises side effects

Question 20

min effective vs max tolerated

Answer 20

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.

Question 21

steady state

Answer 21

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.

Question 22

absorption vs distribution

Answer 22

• Absorption: Passage of drug from site of administration → blood.
• Distribution: Delivery of the drug from blood → tissue.

Question 23

what fraction of total body water does intracellular fluid make

Answer 23

2/3

Question 24

what fraction of total body water does extracellular fluid make

Answer 24

1/3

Question 25

what fraction of extracellular fluid does plasma fluid form

Answer 25

1/4

Question 26

what fraction of extracellular fluid does interstitial fluid form

Answer 26

3/4

Question 27

4 Ideal characteristics for maximal drug absorption

Answer 27

- 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.

Question 28

Ways to regulate the release of drugs

Answer 28

- 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.

Question 29

pKa

Answer 29

= 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**.

Question 30

7 factors determining the rate of permeability across lipid membranes

Answer 30

-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

Question 31

passive diffusion & what law it follows

Answer 31

- 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.

Question 32

Carrier mediated transport/facilitated diffusion & what law it follows

Answer 32

- 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.

Question 33

Active transport

Answer 33

- Membrane channels actively move drug against conc. gradient - Low → high conc. - Requires energy in the form of **ATP**.

Question 34

Pinocytosis

Answer 34

- 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).

Question 35

the compartment model

Answer 35

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).

Question 36

factors affecting drug distribution (rate-2 and extent-5)

Answer 36

Affecting rate: **Membrane Permeability Blood Perfusion** Affecting extent: **Plasma protein** binding **Intracellular** binding **pH differences** **Lipid solubility** **Available transport mechanisms**.

Question 37

what plasma proteins do acidic drugs bind to

Answer 37

albumin

Question 38

what plasma proteins do basic drugs bind to

Answer 38

globulins (alpha and beta)

Question 39

what does binding of plasma proteins do to the drug?

Answer 39

makes drug inactive.

Question 40

Quantifying bioavailability

Answer 40

- 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.**