Dugga 2 Flashcards
Why do many drugs contain an amine functional group?
They are partially ionised in the acidic environment of the stomach and the slightly alkaline environment of the blood but can cross cell membranes (such as intestinal cell membrane) in their non-ionised form. The ionised form gives a good water solubility and good binding interactions
Some highly polar drugs are able to cross cell membranes, how?
They can hijack transport proteins if the resemble the polar molecule that is usually transported. An example is levodopa which disguises as phenylalanine
Some small highly polar drugs are able to pass cell membranes, how?
They pass through small pores between the cells lining the gut
Polar drugs with high molecular weight can pass cell walls by a process called…
pinocytosis - the drug is engulfed by the cell membrane and carried in a membrane bound vesicle
What is pharmacodynamics?
How drugs interact with molecular target o produce a pharmocological effect
What is pharmacokinetics?
How a drug reaches its target in the body and how it is affected on the journey
What are the four main issues in pharmacokinetics?
ADME
Absorption Distribution Metabolism Excretion
Oral drugs must be sufficiently … to dissolve in the GIT and blood but sufficiently … to pass cell membranes
polar and fatty
Oral drugs have to be both … and … stable
chemically and metabolically
How many rotatable bonds do oral drugs usually have (max)
7
Does Lipinski’s rule apply to only oral drugs?
Yes
What may happen to some drugs that mean they won’t be active?
Absorbed in fatty tissue or bound to macromolecules
Do some drugs make use of metabolism to active?
Yes
Which reactions do phase I reactions involve?
Oxidation, reduction, hydrolysis
What structures are most prone to oxidations?
N-methyl groups, aromatic rings, terminal positions of alkyl chains, least hindered positions of alicyclic rings
What groups are prone to reduction?
nitro, azo (N=N) and carbonyl groups
What groups are prone to hydrolysis?
amides O=C-N) and esters (O=C-O)
What are phase II reactions?
Conjugations with polar groups on an already existing handle
When can oxidation of carbon occur?
If it is exposed or activated. Activated carbons next to sp2 or sp carbon centre most likely, carbons alpha to heteroatoms.
When do you have to think about first pass effect?
With oral drugs. They need to pass the cell lining of the intestine to move to the blood and also go through the liver
What is metabolism?
How our body makes compounds more water soluble for excretion. First oxidation, hydrolysis to create a handle, then conjugation with polar molecules
How do you avoid first pass effect?
Administer drugs in another way than orally
What is phase 1 metabolism?
The addition of or exposure of polar functional drugs. Cytochrome p450 enzymes break down.
How is the activity of CYP450 affected?
By food, chemicals and drugs
How does drug excretion take place?
Sweat, inhaled air, bile and mostly kidneys
What does the kidney do?
Filters the blood and drugs and their metabolites enter nephrons. Non-polar substances reabsorbed into blood but polar substances excreted in the urine.
How can safe dosing levels for a drug be determined?
Measurements of concentration of drug in the blood
What is therapeutic index
Area between efficacy level and toxic level
What is the half life of a drug?
Time taken for the concentration of drug in blood to fall to half
The time it takes to reach steady state concentration is … times the drugs half life
6
What is AUC?
Area under the plasma drug concentration curve represents total amount of drug available in the blood supply
How do you ensure the blood concentration of a drug remain within the therapeutic window?
Administer at correct dose and frequency
Can the half life of a drug be used to calculate how frequently a dose should be given?
Yes
What is a statin?
Cholesterol lowering drug acts as enzyme inhibitor
Where are type 1 statins derived from?
Fungal metabolites
Why do statins bind more strongly than natural substrate to the enzyme responsible for biosynthesis of cholesterol?
- An extra hydrophobic region forms additional hydrophobic interactions
- resistant to enzyme catalysed reactions
What is HTS and how can it be used?
High throughput screening involves the miniaturisation and automation of in vitro tests. A large number of tests can then be carried out in a short space of time
What is NMR and how is it used?
Nuclear magnetic resonance. Compounds affinity to a macromolecular target tested by NMR. The relaxation times of ligands bound to macromolecule shorter when they are unbound.
What is SPR, SPA and ITC and how can it be used?
Surface plasmon resonance, scintillation proximity assay, isothermal titration calorimetry are visual methods of detecting whether a ligand is bound to a macromolecular target
How can virtual screening be used?
To identify compounds that are most likely to be active in an experimental screening
What is a lead compound?
A compound that shows the desired pharmacological activity
Where can a lead compound be found in nature?
Plants (eg antimalaria drug), Microorganisms (penicillin), marine (antitumor agents), animals (antibiotic polypeptide from frog), venoms and toxins (antihypertensive agent)
What is an analgesic drug?
For pain relief
What are different ways to find lead compounds?
Nature,medical folklore, screening synthetic compounds, improving existing drugs, starting from natural ligand or modulator, computer aided design, serendipity
What is the agent responsible fir the biological activity of a natural extract called?
The active principle
What is a lead compound?
A structure that shows a useful pharmacological activity and acts as the starting point for drug design