Med design

Question 1

define soft-drugs

Answer 1

active drug that are deactivated by metabolism

opposite of prodrug

Question 2

3 reason why use soft drugs?

Answer 2

1. reduce duration of action
2. reduce toxicity/ se (limit distribution)
3. avoid multiple active metabolites with diff PD

Question 3

process of soft drug metab in body

Answer 3

• active drug administered
• metabolism
  maybe hydrolysis
• into inactive, NON-toxic metab

Question 4

we introduce metabolically sensitive group to soft drugs, which does not overly change physical, steric, electronic property of the lead. these group are called?

Answer 4

isostere

Question 5

metabolisable isosteres that are often used are?

Answer 5

esters! metab into inactive metab w carbo acid gp, carbamates (ester+amide), and less often quaternary nitrogens

Question 6

what are isostere?

Answer 6

groups that mimic the another functional group (retain the pharmacology/PD of the lead) in terms of size and shape but can be metabolised easily (we have control over PK)

Question 7

an example of soft drug (hint: analgesic)

there is no build up of the drug

Answer 7

fentanyl- aromatic ring

remifentanil- ester mimics the ring and is readily hydrolysed

Question 8

one word describes the method used for drug design of soft drug

Answer 8

RETROmetabolic

• study the structure of inactive metab from normal drug
• want inactive metab as major one
• turn it into active drug but easily metabolisable

Question 9

the R group to the ester in soft drug can increase…therefore

Answer 9

increase lipophilic of the drug and therefore the half life, make it longer acting

Question 10

describe the MOA of local anaesthetics?

Answer 10

• high affinity for open state of
• Na channel
• resersiblly bind and inactivate Na channel
• block AP

Question 11

describe the structure of local anaesthetics eg. lidocaine

Answer 11

basic N separated from aromatic ring by short chain containing ester or amide (2 C away)

Question 12

describe how the pka (acidity) of amine group important in MOA?

Answer 12

rapid onset: non-protonated form of amine NH3- (not too basic -ve) is lipid soluble, get to site of action in lipid rapidly

Na channel activity: quaternary protonated form of amine NH4+

Question 13

local anaesthetics containing amide (lidocaine) or ester groups (cocaine)- which one is more prone to metabolism?

Answer 13

ester group (cocaine) will get hydrolysed more easily than amide (lidocaine)
amide group is longer lasting

Question 14

what is the problem with Propofol: “milk of amnesia” in term of PK?

Answer 14

• high log p= 4
• poor water solubulity
• oil in water emulsion as injection (pain)
  (Long duration of action?)

Question 15

What are the ways to improve solubility of propofol? What approach did they use?

Answer 15

Pro-drug approach
1. add Ester group on O from OH phenolic group
(Like heroin, mask OH with ester group. Faster metabolism)
2. Add basic N to R group of the Ester. (Basic N get protonated at pysio PH, make salt, increase solubility)
3. Replace acyl groups with ether groups ( less lipophilic, more soluble. ether has O -H Bond donor)

Question 16

What’s the final product of this drug design for propofol?

Answer 16

Fospropofol
With PO4 3- group ( 2x OH instead of O)
Rest remains same
PO4 3- group is charged (like basic NH3-), can make salt, increases water solubility (2x OH-> 2x ONa)

Question 17

2 keto BZ: diazepam has low pka, long onset of action due to many active metabolites, next day drowsiness. What can we add to increase stability and reduce onset of action?

Answer 17

Triazole: midazolam
Add imidazole ring (basic) with Me group on it.
Imidazole is more stable to hydrolysis than normal lactam (N= to ketone)
Me: benzylic type methyl, easy to oxidised to alcohol CH2OH -> glucuronide
shorter duration of action
Used pre op

Question 18

What’s the BZ derivative that has even faster metabolism than midazolam?
When is it used?

Answer 18

Remimazolam (used remifentanil approach) is even shorter acting
Add Ester on side chain
Used in hepatic or renal impairemenr

Question 19

What is the sub that people use to hunt games?

What does the sub do?

Answer 19

Curare

Paralysis of skeletal muscle. By compete with Ach binding to neuromuscular receptor

Question 20

What is the API in curare

Answer 20

D-tubocurarine

Question 21

What is the active part in d- tubocurarine (SAR)

What is the problem?

Answer 21

Quaternary Nitrogen

Prob: big molecule so long duration of action- can cause resp depression

Question 22

What’s the prob with other bisquaternary salts?

Answer 22

• selectivity to neuromuscular Rec

- extensive renal/ biliary excretion so cant be used in renal impaired pt due to accumulation

Question 23

What approach/ steps did we take to ensure a more rapid metabolism of d-tubocurarine?

Answer 23

Looked at petaline which also has quanternary N

It undergoes Hofmanns élimination (H removed from OH, leave O-, then elimination of N+ good leaving group)

Question 24

What’s the final product of d-tubocurarine derivative that has a shorter duration of action (soft drug) What are the differences

Answer 24

Atracurium besylate
A symmetrical structure, a soft drug
It undergoes Hofmanns élimination (break c-n+ bond like petaline)
Its Ester get hydrolysed

Question 25

Describe how we changed etomidate to reduce its fatal accumulation of metabolite due to fast metabolism?

Answer 25

• soft drug itself with Ester group deactivated by esterase
• add another Ester group at the R chain which is less hindered allow rapid metabolism (2 esters)
• add tertiary carbon (triangle) next to the ester carbonyls. In the middle.
• the triangle slows metabolism- hydrolysis of Ester by creating hinderance
• increase potency
• prolong half life