1. Medicinal chemistry Third stage Lecture 1
Drug Design
Dr. Narmin Hussen
B.Sc. In Pharmacy
M.Sc. In Ph.chemistry

2. Content Medicinal chemistry Drug design Drug distribution
Protein binding

3. Medicinal chemistry
Medicinal chemistry is the chemistry discipline concerned with the design, development and synthesis of pharmaceutical drugs.

4. Drug design
Drug
A drug is a chemical substant ,that can affect living processes , absorbed via a different route of administration causes a physiological change in the body.

5. Drug Design
The study of the shape of molecules in order to determine how they will bind receptors on cell or combine with other molecules.
One of the goals is to design drugs that will interact with receptors at specific sites.

7. There are several ways to do this:
Altering the molecule, which in turn , can change the biodistribution.
Biodistribution can be altered by
Changing the drugs solubility.
Enhancing its ability to resist being metabolized ( usually in liver).
Altering the formulation or physical characteristics of the drug.
Changing the rout of administration.

8. 2- Increasing specificity for the target receptor that will produce the desired pharmacological response while decreasing the affinity for undesired receptors that produce adverse response.

9. Stages of drug metabolism
Absorption- drug gets into bloodstream
Distribution - gets to site of action
Metabolism - is “changed” so that it can be excreted
Elimination - leaves the body

10. Drug distribution

11. Factors Affecting Drug Distribution
1. Tissue Permeability of the drug .
Physiochemical properties of drugs like ( molecular size , Pka , Partition coefficient ).
Physiological barriers to diffusion drug.
2. Organ/tissue Size and Perfusion Rate.
3. Binding of Drugs to Tissue Components.
4- Miscellaneous factors
age , pregnancy , diet , obesity ,disease and drug interaction).

14. Rate of absorption
I.V ( has no absorption)

15. Oral administration ?
Several factors affect the ability of the drug to be dissolved :
Chemical structure
Particle size and surface area
Crystal form
Type of tablet coating

16. Example Mesalamine Olsalazine Not effective orally
Metabolized to inactive form.
Used in the treatment of ulcerative colitis.
Olsalazine
This drug is adimer of pharmacologically active mesalamine.
In active form (prodrug)

17. Chloramphenicol Water solube (2.5mg/ mL) Bitterness
The palmitic acid moiety is added as an ester of chloramphenicol primary alcohol.
Reduce water solubility (1.05 mg / mL).

18. Enalaprilic acid Poor absorbed from the gastrointestinal tract.
Enalapril is the ethyl ester of enalapric acid , an active inhibitor of ACE .
The ester prodrug is much more rapidly absorbed orally than the pharmacologically active carboxylic acid.

19. Parenteral administration

20. Methylprednisolone
Both sodium succinate and acetate esters are hydrolyzed to the active methylprednisolone

21. Etertinate and Acitretin
Two drugs based on the retinoic acid .
Alter biodistribution and biological half life .
Used systemically to treat psoriasis.
Both drugs are potentially teratogenic.

22. Protein binding
There are many types of proteins in the blood plasma( ex. albumin).
These proteins bind to different types of drugs.
Drugs that are protein bound are not able to activate receptors unless they are free.
These proteins act like a sponge on many drugs ,not freeing the drug until the proteins are saturated.

23. After adding 6 units of drug A , all the drug is protein bound, there is no drug to activate receptors.
After adding 12 units of drug A, all the protein binding sites are saturated.

24. Now that protein binding sites are saturated, adding the drug results in the free drug to activate receptors.
Stopping or starting a drug that binds to plasma protein changes the free drug levels of other protein bound drugs.
Now that protein binding sites are saturated, adding the drug B results in higher levels of free drug A.

25. Example
A person was admitted to the hospital for surgery. A person took drug A( warfarin) as an anticoagulant (blood thinner) and drug B (phenytoin) as an anticonvulsant.
Both drugs are highly plasma protein binding drugs.
Three days before surgery the warfarin was stopped

26. Because warfarin is protein bound and stopped, this left binding sites available for phenytoin.
This increases the effective concentration of warfarin at receptor , leading to an increased prothrombin time and potential hemorrhage.
The extra binding sites bind to free drug B, making it unable to activate drug B (phenytoin) receptors.

28. Summary Factors Affecting Drug Distribution .
Several factors affect the ability of the drug to dissolve.
Prodrug
Protein binding

29. Home work
What is blood-brain barrier ? Why some drugs by passes it and some others are not?
Compare between the following:
passive and active diffusion through the mucosal cells.
Lipid bilayer and aqueous layer of cell membrane.
Why some drugs are prolong duration of action ? Give an example.
What is tissue depots? Explain your answer by giving some examples