Med design Flashcards
define soft-drugs
active drug that are deactivated by metabolism
opposite of prodrug
3 reason why use soft drugs?
- reduce duration of action
- reduce toxicity/ se (limit distribution)
- avoid multiple active metabolites with diff PD
process of soft drug metab in body
- active drug administered
- metabolism
maybe hydrolysis - into inactive, NON-toxic metab
we introduce metabolically sensitive group to soft drugs, which does not overly change physical, steric, electronic property of the lead. these group are called?
isostere
metabolisable isosteres that are often used are?
esters! metab into inactive metab w carbo acid gp, carbamates (ester+amide), and less often quaternary nitrogens
what are isostere?
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)
an example of soft drug (hint: analgesic)
there is no build up of the drug
fentanyl- aromatic ring
remifentanil- ester mimics the ring and is readily hydrolysed
one word describes the method used for drug design of soft drug
RETROmetabolic
- study the structure of inactive metab from normal drug
- want inactive metab as major one
- turn it into active drug but easily metabolisable
the R group to the ester in soft drug can increase…therefore
increase lipophilic of the drug and therefore the half life, make it longer acting
describe the MOA of local anaesthetics?
- high affinity for open state of
- Na channel
- resersiblly bind and inactivate Na channel
- block AP
describe the structure of local anaesthetics eg. lidocaine
basic N separated from aromatic ring by short chain containing ester or amide (2 C away)
describe how the pka (acidity) of amine group important in MOA?
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+
local anaesthetics containing amide (lidocaine) or ester groups (cocaine)- which one is more prone to metabolism?
ester group (cocaine) will get hydrolysed more easily than amide (lidocaine) amide group is longer lasting
what is the problem with Propofol: “milk of amnesia” in term of PK?
- high log p= 4
- poor water solubulity
- oil in water emulsion as injection (pain)
(Long duration of action?)
What are the ways to improve solubility of propofol? What approach did they use?
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)
What’s the final product of this drug design for propofol?
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)
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?
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
What’s the BZ derivative that has even faster metabolism than midazolam?
When is it used?
Remimazolam (used remifentanil approach) is even shorter acting
Add Ester on side chain
Used in hepatic or renal impairemenr
What is the sub that people use to hunt games?
What does the sub do?
Curare
Paralysis of skeletal muscle. By compete with Ach binding to neuromuscular receptor
What is the API in curare
D-tubocurarine
What is the active part in d- tubocurarine (SAR)
What is the problem?
Quaternary Nitrogen
Prob: big molecule so long duration of action- can cause resp depression
What’s the prob with other bisquaternary salts?
- selectivity to neuromuscular Rec
- extensive renal/ biliary excretion so cant be used in renal impaired pt due to accumulation
What approach/ steps did we take to ensure a more rapid metabolism of d-tubocurarine?
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)
What’s the final product of d-tubocurarine derivative that has a shorter duration of action (soft drug) What are the differences
Atracurium besylate
A symmetrical structure, a soft drug
It undergoes Hofmanns élimination (break c-n+ bond like petaline)
Its Ester get hydrolysed
