Pharmokinetics

Question 1

The journey of a drug through the body stages

Answer 1

ADME 
administration
absorption 
distribution 
metabolism 
excretion

Question 2

Routes of administration

Answer 2

dermal
intramuscular 
subcutaneous 
intraperitoneal
intravenous 
inhalation 
ingestion

Question 3

routes of administration can be local or systemic- explain what this means

Answer 3

systemic = the entire organism is getting exposed to the drug

local = restricted to one area of the organism

Question 4

routes of administration can also be divided into enteral or parenteral- what does this mean?

Answer 4

enteral = via the GI tract
(usually easier)

Parenteral = everything but the GI tract

Question 5

Explain how absorption works

Answer 5

Drug goes to the GI tract and gets absorbed and taken to the liver
Travels to the liver via the hepatic portal system and then enters the systemic circulation
(Inhalation is also a good route )
Systemic exposure very quickly = intravenous

Question 6

What are the two ways in which drug molecules move around the body

Answer 6

bulk flow transfer = in the bloodstream it will move in bulk to the tissues

diffusional transfer = molecule by molecule over short distances

Question 7

what is the main problem with drugs being absorbed?

Answer 7

drugs have to transverse both lipid and aqueous environments

Question 8

give examples of compartments

Answer 8

Compartments = Aqueous e.g. Blood, lymph, extra-cellular fluid, intra-cellular fluid

Question 9

give examples of barriers

Answer 9

Barriers = Lipid i.e. cell membranes (epithelium/endothelium)

Question 10

how can drugs cross these barriers?

Answer 10

NB: non-polar substances can freely dissolve in non-polar solvents ie can penetrate lipid membranes easily

• simple diffusion
• diffusion across aqueous pores (if they are polar - least relevant mode of transport as its v small)
• carrier mediated transport
• pinocytosis

Question 11

Most drugs are either

Answer 11

weak acids or weak bases/

therefore, drugs exist in ionised (polar) and non-ionised (non-polar) forms- the ratio depends on the pH

Question 12

the ratio of ionised and non-ionised depends on?

Answer 12

the pH of the environment and the pKa of the molecules

Question 13

which one is more lipid soluble- ionised or unionised?

Answer 13

the unionised form

The unionized forms of aspirin and morphine are going to be more lipid soluble than the ionized (charged) forms of the drugs. Charged molecules are more polar and thus less lipid soluble and will find it difficult to cross membranes.
pH will be a huge determinant of absorption of drugs across lipid membranes. Weak acids will be more unionized in acidic environments and weak bases will be more unionized in alkaline environments.

Question 14

what would happen to aspirin and morphin at physiological pH 7.4?

Answer 14

aspirin would be more likely to donate protons and morphine to accept protons

Question 15

is aspirin acidic or basic?

what is the pKa of aspirin

Answer 15

acidic

3.4

Question 16

what happens when aspirin enters the stomach

Answer 16

stomach has a pH of 1, which is less than the pKa of aspirin so it is persuaded to be non-ionised

Question 17

Henderson-hasselbach equation

Answer 17

If we rearrange the equation for the weak base above - then pKa-pH is the power of the exponent that 10 is raised to in order to get [BH+]/[B] i.e. 10^[pKa-pH] = [BH+]/[B]. 10^x is also often referred to as the antilog of x. In this case x = pKa-pH.

**pKa of drug does not change pH of different body compartments

Question 18

Morphine has a pKa of 8.0
pH in the stomach is 3

Does B or BH+
predominate?

Answer 18

Ionised (BH+) dominates

100000

Question 19

Aspirin has a pKa of 3.5
The pH in stomach is 3

Does AH or A-
predominate ?

Answer 19

Unionised dominates (AH) 
3.16

Question 20

Describe the passage of aspirin through the stomach and the small intestine

Answer 20

So aspirin exists mainly in the non
-
ionised form in the stomach meaning that it 
can readily diffuse across the lipid bilayer (a
s it is non
-
polar) 
•
Eventually the aspirin will make it into the small intestine where the pH is much 
more basic
•
As the pH of the small intestine is greater than the pKa of aspirin, the aspirin 
becomes 
ionised
•
Once it is ionised it is much more difficult t
o get through the membrane 
•
So in the small intestine a much greater proportion of aspirin is 
ionised
than 
non
-
ionised so there is much 
slower absorption in the small intestine
than in 
the stomach
•
The ratio of ionised: non
-
ionised is all dictated by the pH
of the environment 
relative to the pKa of the drug
•
Once it goes through the liver and into the systemic circulation, the aspirin is in 
an 
aqueous
environment so you find a proportion of aspirin in an ionised form 
-
it is effectively 
TRAPPED
-THIS IS CALLED ION TRAPPING

Question 21

Exercise 5: Why might treatment with intravenous sodium bicarbonate increase aspirin excretion?

Answer 21

Acids in higher pH = more ionised, less lipid soluble and therefore excreted.

Question 22

Factors influencing drug distribution

Answer 22

Regional blood flow
Extracellular binding (Plasma-protein binding)
Capillary permeability (tissue alterations – renal, hepatic, brain/CNS, placental)
Localisation in tissues

Question 23

How does regional blood flow work?

Answer 23

Tissues that are well perfused are likely to be exposed to higher concentrations of the drug.

Some tissues may increase in perfusion when their activity increases eg skeletal muscle

Highly metabolically active tissues tend to have a greater blood flow and denser network of capillaries.

Question 24

How does extracellular binding (plasma protein binding work?

Answer 24

If a plasma protein is bound to the drug then it is no longer available for absorption

50-80% tend to be bound to plasma proteins

Albumin can bind both the unionised and ionised type of drugs

There are small gaps between endothelial cells that are water filled (aqueous) and so
ionised aspirin
can pass through these gaps

Question 25

How does Capillary permeability work?

Answer 25

Lipid soluble drugs have good access to all tissues (even the brain) and will be well distributed across body tissues.
Water soluble drugs have poor access to tissues and are dependant on saturable carrier proteins for access to tissues. As a result, they tend to be less well distributed across body tissues.

•Distribution also depends quite heavily on capillary architecture 
oFenestrated
-more permeable to drugs
oContinuous
-found in normal vessels, has water
-filled gap junctions 
oDiscontinuous
-large gaps between endothelial cell

Question 26

How does localisation in tissues work?

Answer 26

** fat isn’t usually highly perfused, so it is a very lipophilic environment, so drugs that are lipophilic tend to localise in fatty tissue. Fat soluble drugs highly partition into fatty tissues eg brain and testes

Blood flow to the body fat is very low – approximately 2% of the cardiac output. As a result, at any given moment in time, only small amounts of the non-ionised drug is being delivered to the body fat.
The lipid solubility of the drug. We mentioned morphine above. Morphine can access the brain, which suggests it is fairly lipid soluble. However, its oil/water partition coefficient (i.e how well it dissolves in fat versus how well it dissolves in water) is 1. If 98% of the drug is being distributed to body water (i.e. other tissues) and only 2% of it to body fat, then very little will distribute to body fat. However, some drugs have high oil/water partition coefficients. For example some general anaesthetics can have an oil/water partition coefficient of 5000. As a result, the 2% that reaches the body fat will accumulate in this tissue very effectively. The drug that resides in the body fat will then slowly leak back into the bloodstream (due to the poor blood flow to this tissue and the preference of the drug for the body fat versus the aqueous blood)

Question 27

What are the two major routes of excretion?

Answer 27

Liver- some drugs are concentrated in the bile

Kidney- ultimately responsible for the elimination of most drugs

Question 28

How are drugs eliminated from the kidney?

Answer 28

1. glomerular filtration (size dependent) -glomerulus
2. active secretion (dependent on available transporters) -proximal tubule
3. passive reabsorption- dependent on urine pH and extent of drug metabolism (for lipid soluble drugs)

Question 29

How does liver work in drug excretion?

Answer 29

Biliary excretion allows the concentration of large molecular weight molecules that are very lipophilic

there are also active transport systems that secrete drugs into bile. The active transport systems are geared for the transport of bile acids
and glucuronides
into the bile-drugs hitch a ride on this because they
are non-polar and have a large molecular weight

Question 30

what is enterohepatic cycling?

Answer 30

drug/metabolite excreted into gut (via bile) then reabsorbed, taken to liver
and excreted again

Question 31

what are the problems with enterohepatic cycling?

Answer 31

Biliary excretion can cause problems because of enterohepatic cycling
oThe drug or metabolite gets excreted into the gut but then it can get
reabsorbed and returned to the liver via the enterohepatic circulation
oThis leads to
drug persistence

Question 32

What are the other routes of drug excretion?

Answer 32

lungs, skin, gastrointestinal secretions, saliva, sweat

Question 33

Define bioavailability

Answer 33

Bioavailability (linked to absorption)

Proportion of the administered drug that is available within the body to exert its pharmacological effect

Question 34

Define apparent volume of distribution

Answer 34

Apparent volume of distribution (linked to distribution)
The volume in which a drug appears to be distributed
- an indicator of the pattern of distribution

Question 35

Define biological half-life

Answer 35

Biological half-life (linked to metabolism/excretion)

Time taken for the concentration of drug (in blood/plasma) to fall to half its original value

Question 36

Define clearance

Answer 36

Clearance (linked to excretion)
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time

(Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes.)