¥ 2. Ionisation and isomers

Question 1

What properties allow a molecule to be hydrophilic?

Answer 1

Needs polarity to be able to disrupt waters polar hydrogen bonds.

Hydrocarbons therefore need polar functional groups to dissolve (particularly nitrogen and oxygen).

Solubility is affected by the size of the hydrocarbon

Question 2

What is the difference between a strong and weak electrolytes?

Answer 2

Strong electrolytes fully dissociate into ions in solution (e.g. in a liquid such as water)

Weak electrolytes only partially dissociate. The proportions are dependent on the pH.

Question 3

What are the two most important functional groups that allow partial dissociation of electrolytes into ions in water?

Answer 3

Carboxyl (R - COOH) and amine (R - NH2)

Question 4

What is the basic formula for partial dissociation of an electrolyte in solution?

Answer 4

Proton donor <=> proton acceptor + H

Question 5

What is pKa?

Answer 5

The pH at which 50% dissociation of an electrolyte is maintained

Proton donor <=> proton acceptor + H+

Therefore at pKa the forward reaction K1 (forward rate constant) = the backward reaction K2 (backward rate constant).

Question 6

What is Ka?

How is Ka related to:

K1 and K2?
pKa?

Answer 6

Ka is the acid dissociation constant

At equilibrium: K1 [proton donor] = K2 [proton acceptor] [H+]
[H+] = (K1/K2) ([proton donor] / [proton acceptor])

K1/K2 = Ka

pKa = negative log of Ka

Question 7

What is a logarithm?

Negative logarithm?

Answer 7

Logarithms are the inverse of exponents. A logarithm (or log) is the mathematical expression used to answer the question: How many times must one “base” number be multiplied by itself to get some other particular number?

For instance, how many times must a base of 10 be multiplied by itself to get 1,000? The answer is 3 (1,000 = 10 × 10 × 10). So the logarithm base 10 of 1,000 is 3. It’s written using a subscript (small number) to the lower right of the base number. So the statement would be log10(1,000) = 3

Negative = Calculating the negative log is as simple as performing the normal log function on 1/x instead of x. The base stays the same. For example, the negative log of -log(10) = log(1/10) =

Question 8

Is a volatile a weak acid or a weak base?

Answer 8

Neither

Question 9

How do we derive the Henderson hasselbalch equation?

Answer 9

Do on paper and check derivations/formula sheet 1

HH

Question 10

What is the pKa of the carbonic acid and bicarbonate system?

Answer 10

6.1

Question 11

What equation do we use to calculate the ratios of ionised to unionised components of the carbonic acid and bicarbonate system?

What is the ratio of ionised:unionised for pH: 7.1, 8.1, 9.1?

Answer 11

pH = pKa + log ([HCO3-]/[H2CO3])

pH 7.1 = 10:1
8.1 = 100:1
9.1 = 1000:1

Question 12

What is a buffer?

Answer 12

Chemical that tries to maintain a steady pH in a system if acid or alkali is added.

Question 13

When are bases and acids ionised compared to their pKa?

Answer 13

Bases are ionised below their pKa and acids are ionised above their pKa

Question 14

What properties of drugs effect the ability of an agent to reach the brain?

Answer 14

The lipid solubility and the pKa

Question 15

What issues might there be with ionisable drugs that are being injected and how might we combat this?

Use propofol and thio as an example

Answer 15

To be injected drugs need to be dissolved in solution i.e. ionised

Some drugs will need a very low or high pH to be ionised which can be irritant. So there needs to be other ways to make them soluble e.g.

Propofol into lipid emulsion with egg phosphatide
Thio stored under nitrogen which makes it alkali if mixed with water

Question 16

How does pKa affect onset of action?

Use morphine (7.9) and alfentanil (6.4) as examples

Answer 16

pKa defines the amount of ionisation in relation to pH and therefore lipid solubility

Morphine (weak base) = pH of 7.9
Alfentanil (weak base) = pH of 6.4

Bases are ionised below their pKa, therefore at physiological pH of 7.4, over 50% of the morphine is ionised, whereas under 50% of the alfentanil (100x less ionised than morphine) is. Meaning alfentanil has a faster onset of action

Question 17

How does ionisation effect duration of action?

Use propofol (11) and fentanyl (8.5) as an example

Answer 17

More ionised = less lipid soluble = longer duration as less of the drug stays in the plasma, away from the fat stores, stopping is being redistributed.

Propofol is a weak acid with a pKa of 11, so at physiological pH hardly any is ionised and so is quickly redistributed.

Fentanyl has a pKa of 8.5 and is a weak base, so is more ionised at physiological pH and is not redistributed to fat stores and so has a longer duration of action.

Question 18

What is an isomer?

Answer 18

A molecular with the same molecular formula, but a different arrangement

Question 19

What are structural isomers?

Example?

Answer 19

Have different chemical structures so have different pharmacological and physical properties

E.g. iso and enflurane

Question 20

How is tautomerization related to isomers?

Example?

Answer 20

Is a form of dynamic structural isomerisation. Where 2 isomers exist in equilibrium with each other.

Thiopental where the -SH (thiol) group displaces the -Sna (sodium) in an acidic environment. The thiol then undergoes tautomerization to thione

Question 21

What is steroisomerism?

What are the two different types?

What are the features of these?

Answer 21

Same chemical structure, but different spatial configurations. 2 types:

Geometric: occurs in compounds with an alkene group (c=c) as there is no free rotation around a double bond. (Look at diagram on page 18 of pharma 2). Cis = both on same vertical plane of the c=c and trans = on different vertical sides of the double bond. Mivacurium is an example.

Optical: where 4 different groups are attached to the same atom. Makes non superimposable mirror images. A pair is called enantiomers and they rotate plane polarised light in opposite directions. DextRoratory = right. Levorotatory = left.

Question 22

What is a racaemic mix?

Answer 22

An equal mixture of optical isomers. Has no overall effect on the plane of polarised light

Question 23

How do we name optical isomers?

Answer 23

We have the chiral centre (the carbon atom)

Then we order the others according to atomic number. We place the lowest at the top and then the other 3 around the chiral centre.

If the descending order of the other 3 is clockwise this is called R. Anti-clockwise is called s.

Question 24

What are diasteroisomers?

Examples?

Answer 24

When a drug has more than 1 chiral centre and so don’t form mirror images.

Atracurium, tramadol and methohexital

Question 25

Are both isomer entantiomers going to have the same effect?

Answer 25

No they can have different activity, responses or potencies

Question 26

What are the differences between ketamine entantiomers?

Answer 26

S+= useful IV agent
R- = agitation, post op pain and emergence reactions

Question 27

What are the differences between bupivicaine entantiomers?

Answer 27

S+ = prolonged local anaesthesia
R- = convulsant and cardiotoxic effects

Question 28

How many atracurium isomers are there in a mix and which is available individually?

What benefit does this have?

Answer 28

10

Cisatracurium: x3 potent, minimal autonomic and histamine release and reduced laudanosine levels.

Question 29

What LA’s exist as optical isomer pairs?

Which are best and why?

Answer 29

Mepivicaine, prilocaine, bupivicaine and ropivicaine.

S-isomers better as: increased vasoconstriction and less cardiotoxocity and motor block.

Question 30

How much of a drug will be ionised if a pKa value is over 2 units away from 7.4?

Answer 30

Either 99% or 1% will be ionised depending on whether the drug is an acid base and what it’s pKa is

Question 31

Look at YouTube if required

Answer 31

Prof Dave Henderson hasselbalch
Ted ex logarithms

Question 32

What are entantiomers?

Answer 32

A pair of optical isomers