Ionisation

Question 1

What factors determine how hydrophillic (water soluble) a molecule is?

Answer 1

Polarity: a molecule with polarity is needed to disrupt the
hydrogen bonds of water. (As something becomes ionised it becomes more water soluble)

Size (smaller molecules will be more water soluble than a larger molecule of similar polarity)

Hydrocarbons require functional groups (particularly nitrogen and oxygen) to dissolve.

Question 2

Which are the 2 most important functional groups which allow partial dissociation (i.e form weak acids/bases)?

Answer 2

Carboxyl groups (weak acids)
Amine groups (weak base)

Question 3

Define pKa?

Answer 3

pKa is the dissociation constant for a weak acid or base, and describes the pH at which there will be 50% dissociation.

Question 4

What is the Henderson Hasselbach equation?

Answer 4

pH= pKa + log (Base/Acid)

Question 5

Which anaesthetic drugs are weak acids/bases?

Answer 5

All induction agents, analgesics and local anaesthetics and most NMB’s are weak acids are bases.

Note: except for the volatiles.

Question 6

What is the significance of a weak acid/bases’s pKa being more than 2 pH units away from 7.4?

Answer 6

Then the drug will either be 99% or 1% ionised (depending on the pKa value and whether the drug is an acid or a base)

Question 7

With regards to pKa when are acids ionised and when are baces ionised?

Answer 7

Acids Above: Acids become ionised at pH’s above their pKa

Bases below: Bases become ionised at pH’s below their pKa

Question 8

Are the following induction agents acids or bases and what are their pKa’s: Propofol, Thiopental, Ketamine, Etomidate?

Answer 8

Propofol: weak acid 11.0 (therefore >99% unionised at physiological pH)

Thiopental: weak acid 7.6

Ketamine: weak base 7.5

Etomidate: weak base 4.2 (therefore >99% unionised at physiological pH)

Question 9

Are the following induction agents acids or bases and what are their pKa’s: Paracetamol, ibuprofen, fentanyl, alfentanyl and morphine?

Answer 9

Paracetamol: weak acid 9.4
Ibuprofen: weak acid 5.9
Fentanyl: weak base 8.4
Alfentanyl: weak base 6.4
Morphine: weak base 7.9

All NSAIDs are weak acids. All opiates are weak bases.

Question 10

The pKa of the carbonic acid/bicarbonate buffering system is 6.1. Calculate the ratio of ionised to unionised products at the following pH:
1. 7.1
2. 7.6
3. 8.2

Answer 10

Need to use henderson hasselbach equation.

pH=pKa + log (base/acid)

Rearrange to log (base/acid) =pH-pKa

1. 7.1-6.1 = log (base/acid)
1= log (base/acid)
10 to the power of 1 = 10 Therefore ration is 10:1

**2. **7.6-6.1= log (base/acid)
1.5 = log (base/acid)
10 to the power of 1.5 = 31.6

**3. ** 8.2 - 6.1 = log (base/acid)
2.1= log (base/acid)
10 to the power of 2.1 = 125

Question 11

At what pH would the carbonic acid/bicarbonate buffering system be at its most efficient?

Answer 11

At is pKa which is 6.1

This is an open system as the products can be excreted i.e. H+ by
the kidney and CO2 by the lungs. 80% of HCO3- is reabsorbed by the proximal tubule.

Question 12

Which 2 properties are impotant for an anaesthetic agent to reach the brain?

Answer 12

Lipid solubilty

pKa of the drug (as this will determine degree of ionisation and therefore greatly influence lipid/water solubility)

Ionised = more water soluble Unionised = more lipid soluble

Question 13

How are the following induction agents made water soluble (so that they can be given as intravenous agents) Propofol, Etomidate, Thiopental?

Answer 13

1. Propofol – lipid emulsion through egg phosphatide
2. Etomidate – solubilised with polyethylene glycol or intralipid
3. Na Thiopental – Powder held under nitrogen dissolves into alkaline form with water.

Question 14

Which factors influence the onset of action of anaesthetic drugs?

Answer 14

They need to cross the blood brain barrier. Crossing in greater amounts means a faster onset of action and this is dependent on:

1. pKa
2. Lipid solubility
3. Proportion of unbound drug (>protein binding means unfavourable conc. gradient)

Question 15

Morphine has a pKa of 7.9 40% protein bound
Alfentanil has a pKa of 6.4. 90% protein bound

Which has a faster onset of action and why?

Answer 15

Remember all opiates are weak bases.

At physiological pH of 7.4:

Morphine will be more ionised than unionised (as its the pH
is below its pKa)

Alfentanyl will be very unionised as (the pH is above its pKa)

Therefore despite alfentanyl being more protein bound due to it be 100x less ionised it has a much faster onset.

Question 16

How does ionisation effect duration of action?

Answer 16

The **more ionised a drug is the greater the plasma concetration will be. **

If a drug is very unionised it will be poorly water soluble and more lipid soluble, it will therefore redistribute to lipid stores around the body.

Therefore more ionised drugs tend to have longer durations of action.

Example:
Propofol is >99% unionised and has a very short duration of action as it redistributes very quickly.