Slides 12 Chemistry Advanced Le Gresley

Pharmacodynamic/pharmacokinetic
With Adam Le Gresley
Mohammed sofyan Alqadsi, fas.cn11@gmail.com

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Principle phases in drug action
Classification Pharmaceutical Phase Pharmacokinetic Pharmacodynamic

Phase Phase
Process taking Disintegration of Absorption Drug-receptor

place dosage form Distribution (or enzyme) interaction
Dissolution of active Metabolism in target tissue
substance Excretion
Objective Optimization of Optimization of Optimization of

pharmaceutical biological required biological
availability availability effect
(drug available for (drug available for (induction of
absorption) action) therapeutic effect)

Pharmacokinetic phase
The compound with the best binding affinity for a target

in vitro is not necessarily the best drug (may show poor
activity in vivo)
For the drug to be useful, it must first reach

its target site, it
• must be absorbed in sufficient quantity,
• must distribute into target tissue, and
• should not be metabolised too quickly

or extensively
Need to design drugs which can satisfy the above

Absorption
Most drugs are given via oral route: why?
• If drug is given by non-intravenous (IV) route, not all of it may be absorbed into circulation
• Poor oral absorption of active drug can lead to poor bioavailability
This can be due to a number of factors

• Drug lipophilicity • Degradation
• Solubility • Metabolism
• Ionization • Physiology

Lipophilicity 1
In general, the higher the lipophilicity of a drug, the higher its membrane
permeability and the higher its metabolic clearance (first-pass effect)
Therefore, it is important to balance lipophilicity with metabolic susceptibility

Lipophilicity 1
Modification of the drug structure can alter lipophilicity of the compound:
• Molecules can be made more lipophilic by masking a polar group with an alkyl or acyl
group, e.g. convert phenol or alcohol to ether or ester; or primary amine to secondary
or tertiary amine
• This, however, may lead to reduction in activity if polar group needed for interaction
with receptor (should try to temporarily mask group prodrugs see later)
HO N Cl HO N
OH OH
NH NH
OH O OH O O OH O OH O O
tetracycline
tetracycline chlortetracycline
chloretetracycline

Lipophilicity 2
Or polar groups can be added if a molecule is too lipophilic, e.g. fluconazole
Cl OH
F
F
Clotrimazole Fluconazole
(Canesten(R)) (Diflucan(R))

Lipophilicity 3
Also, amprenavir: poor aqueous solubility therefore large number of excipients required.
This results in a dose of 8 capsules twice daily.
Incorporating a phosphate into the molecule (fosamprenavir) dramatically increased aqueous

solubility, resulting in higher drug load in tablet (decreased to 2 tablets twice daily)
Phosphate removed in brush border by phosphatases, yielding parent drug (therefore acts as a
prodrug).
O O
N N
O O
S NH S NH
HO
HO P
H H
OH
Fosamprenavir Amprenavir
Ionization
• Most drugs are weak acids or bases therefore

exist in both unionized and ionized form
• Unionized molecules cross cell membranes more

readily and thus are better absorbed
• Ionizable groups can be masked, e.g. converting

carboxylic acid into an ester, as in the case of a
number of prodrugs
• However, other factors also affect the amount

of active drug being absorbed.
• Acid sensitivity can be a major problem for some

drugs and will have a dramatic effect on the amount
of active drug absorbed

Acid sensitivity - example
Benzylpenicillin is prone to acid hydrolysis due to the influence of acyl side chain:
.
-
ring-opening

How can this be overcome?
Incorporating a side-chain R group that is electron-withdrawing, e.g. phenoxymethyl

penicillin (pen V)
Electron density on carbonyl reduced

EWG
Pen V far more stable to acid than
benzylpenicillin and is given orally

Drug distribution
Membrane Barriers: Blood Brain Barrier (BBB): Layer of tightly packed endothelial
cells that allows only small (<500Da) lipophilic drugs to cross by diffusion.

BBB penetration
Example , codeine and diamorphine
3
HO
10 x increase O
O
HO O HO
Codeine Morphine
O
3
6 100 x increase
O
O Diamorphine

Summary
Property Modification
Permeability Increase lipophilicity
Reduce polarity/ionization
Prodrug approaches
Solubility Add ionizable centre

Increase polarity/H-bonding
Decrease lipophilicity
BBB Increase lipophilicity

Prodrug approaches

Dieses Dokument gehört: Mohammed sofyan Alqadsi
Hinweis: Dieses Dokument ist urheberrechtlich geschützt. Die Vervielfältigung,

Verbreitung, Wieder- bzw. Weitergabe und sonstige Nutzung ist ohne die schriftliche
Genehmigung der Lecturio GmbH nicht gestattet.


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Pharmacodynamic/pharmacokinetic

With Adam Le Gresley

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Classification Pharmaceutical Phase Pharmacokinetic Pharmacodynamic

Process taking Disintegration of Absorption Drug-receptor

Objective Optimization of Optimization of Optimization of

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

The compound with the best binding affinity for a target

For the drug to be useful, it must first reach

• must be absorbed in sufficient quantity,

• must distribute into target tissue, and

• should not be metabolised too quickly

Need to design drugs which can satisfy the above

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Most drugs are given via oral route: why?

• Poor oral absorption of active drug can lead to poor bioavailability

This can be due to a number of factors

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Therefore, it is important to balance lipophilicity with metabolic susceptibility

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Modification of the drug structure can alter lipophilicity of the compound:

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Or polar groups can be added if a molecule is too lipophilic, e.g. fluconazole

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Incorporating a phosphate into the molecule (fosamprenavir) dramatically increased aqueous

• Most drugs are weak acids or bases therefore

• Unionized molecules cross cell membranes more

• Ionizable groups can be masked, e.g. converting

• However, other factors also affect the amount

• Acid sensitivity can be a major problem for some

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Incorporating a side-chain R group that is electron-withdrawing, e.g. phenoxymethyl

Electron density on carbonyl reduced

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Solubility Add ionizable centre

BBB Increase lipophilicity

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

Hinweis: Dieses Dokument ist urheberrechtlich geschützt. Die Vervielfältigung,

Mohammed sofyan Alqadsi, fas.cn11@gmail.com

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