4. How do drugs work?
Paul Ehrlich, Nobel Prize 1908, Salvarsan;
blood-brain barrier; “Lock and Key” hypothesis;
chemotherapy and “magic bullet”
The Lock - Active Site of Enzyme/Receptor
The Key - the Drug
5. The “Lock and Key”
analogy
Key
Lock
Binding
Here the KEY is the natural substrate
Binding of the KEY to the LOCK (an enzyme or a receptor)
then causes a response – a shape change in the
protein/receptor
6. The “Lock and Key”
analogy
Key
Lock
Binding Biological
Response
Here the KEY is the natural substrate
Binding of the KEY to the LOCK (an enzyme or a receptor) then
causes a response – a shape change in the protein/receptor
7. But when an effective drug is present
Biological response
is altered OR shut down
vs.
Binding of Drug
is preferred
Drug may bind preferentially to the “active site”
Antagonist – binds and BLOCKS
Agonist – binds and ACTIVATES
Partial agonist – induces a partial response
8. Major Therapeutic Targets
Infectious disease – anti-infectives
Anti-bacterial, anti-viral, anti-parasitic drugs
Metabolic disease
cancer, cardiovascular, diabetes,
inflammation, high blood pressure, neurological disease, pain
Other aspects of health care
Hormonal
treatments, contraception, vaccines, immunosuppresents, an
aesthetics, nutraceuticals, “
9. Getting a drug to market
Disease target - possible drug candidates
Pre-clinical testing; R&D (1-3 yrs)
Toxicology, “ADME”
Clinical R&D (2-10 yrs; Av. 5yrs)
Phase 1 – healthy volunteers
Phase 2 – small patient group
Phase 3 – larger patient group
Regulatory approval (2-10(!) yrs)
Market
Phase 4 – long term monitoring
10. Drug Making – Long, Risky &
Expensive
Source : PhRMA, Annual Membership survey 2009
11. Drug Approval Process – NDA &
ANDA
FDA Approval FDA Approval
NDA Submitted
ANDA Submitted
FDA review (2.5 Years)
FDA review ( 1 – 2 Years)
Extensive Human
Clinical Studies (3 Years)
Formulation
Clinical Studies - BA/BE Study (1 Year)
Effectiveness (2 Years)
Clinical Studies –
Safety (1 Year) Safety and Efficacy
Established by
IND Submitted
Discovery & Preclinical (3-4 Years) Clinical Trials of Innovator
Innovator / Branded Generic
13. CIMETIDINE (TAGAMET)
1979
US
H2 blocker; anti-ulcer/heartburn 1976
UK
1983 First drug to reach $1Bn
1974 Into volunteers
Cleared for OTC in 1995
1972 Cimetidine
1970
Burimamide
1968 First lead
1966
Programme starts
1964
14. Streptomyc
in
Is produced by the two Streptomyces species, namely :
a) S. griseus and
b) S.humidus.
Active against Gram –ve bacteria e.g., Mycobacterium tuberculosis
Discovery of Streptomycin :
Schatz, Bugie and Waksman (1944) first and foremost soil isolates
(bearning No : 18-16) derived from S. griseus (used largely as industrial
strains across the globe even today)
15. The various salts of
streptomycin are :
(i) Trihydrochloride
(ii) Trihydrochloride-cadium
(iii) Pantothenate
(iv) Sesquisulfate
16. Medium for Growth
Medium for the fermentative process of streptomycin production
essentially comprises of :
(a) Carbon Source : e.g., dextrin, glycerol, glucose, starch,
(b) Nitrogen Source : cotton seed meal, soyabean meal, casein-
hydrolysate, yeast and its extracts ; pure inorganic salts :
ammonium, ammonium nitrate.
(c) Vegetable/Animal Fat : e.g. soyabean oil, linseed oil.
17. Paramet
ers
Temperature : between 25-30°C(~ 28°C)
pH : Ranges between 7.6-8
Duration : 5-7 days
(yield > 1200 mcg . mL– 1)
Streptomycin hardly gets destroyed by the presence of contaminating
microorganisms.
19. Phase 1
Extends upto only 24 hours
Produces a large proportion of mycelium
Glucose up-take of the medium is very low
(which maybe the reason for low production )
20. Phase 2
Most crucial and critical stage
Streptomycin is eventually generated at a tremendously
rapid.
Extends from 1 day to almost 6/7 days of incubation
Three events take place precisely in this specific phase, namely :
(a) NH3 is fully consumed ;
(b) glucose also being used-up to the maximum extent ; and
(c) pH stands constant between 7.6 to 8.
21. Phase 3
complete depletion of „sugar‟ from the fermentation medium
stops the production.
Harvestment of the produced streptomycin before complete
production stops
22. Purification
Once the fermentation attains completion, the resulting mycelium is duly separated
from the ensuing fermented broth by filtration ; and thus, the streptomycin is
finally recovered.
The streptomycin produced is adequately adsorbed from the fermented broth onto
activated carbon particles, and subsequently subjected to elution from the carbon
particles by means of diluted mineral acid till streptomycin gets eluted almost
completely. The eluted product is precipitated by suitable solvents, filtered, and
dried under vacuum before further purification.
Note : The final product obtained must rigidly conform to the standards of purity and
assay as prescribed in the Official Compendia