Week 01 Flashcards
1
Q
What are the steps From Target to Discovery of molecule or medicine?
A
Discovery and preclinical studies 3-6 years
Clinical studies 6-7 years
Regulatory review 0.5 - 2 years
Post marketing surveillance lifetime of drugs
2
Q
What is drug transport?
A
Understanding basic chemical characteristics of drug molecule and how those molecules travels throughout the body.
3
Q
What are the biologics?
A
They are proteins and larger molecules i.e. insulin, antibodies.
4
Q
What are the drug targets where do they work?
A
In enzyme: Ibuprofen is COX inhibitor. COX is enzyme. Ibuprofen stop or reduce the process when COX sends information to do something.
In receptor: Codeine It interacts in (GPCR) G protein couple receptors.
5
Q
What is ADME?
A
Absorption distribution metabolism and excretion
6
Q
So how ADME works for a medicine?
A
You experienced inflammation, so you took a tablet of ibuprofen, it distributed and absorbed in your body and give action by reduced inflammation then it goes to liver for metabolism by converting Sugar (Increase hydrophilicity) for Excretion by urine.
7
Q
What is a Drug?
A
Any substance absorbs in living organism modify its function.
8
Q
What is a Medicine?
A
A drug that has therapeutic or diagnostic usages.
9
Q
What is aspirin?
A
Acetylsalicylic acid. It is derived from Salicin and Salicin naturally extracted from Willow (leaves) and myrtle (leaves).
10
Q
When scientist succeeded isolating Salicin(active)powder from willow bark?
A
1820 and 1830s
11
Q
What is Salicin?
A
Salicin is a prodrug converted to salicyl alcohol and Glucose. And the salicyl alcohol metabolised or oxidised to salicylic acid in vivo and give good effect but poor as not all molecule gave good effect.
12
Q
Who discovered Aspirin?
A
German Scientist “Felix Hoffman” discovered modern form of aspirin through Bayer (company) in 1899 to market as Aspirin.
13
Q
What is the indication of Aspirin?
A
Analgesic
Antipyretic
Anti-inflammatory
14
Q
Does Aspirin is NSAIDs?
A
Yes
15
Q
Who discover the mechanism or how aspirin works at a molecular level provided by?
A
John Vane 1982 and achieved Nobel prize.
16
Q
What is antibiotic?
A
Compounds produced by bacteria and family which are capable of killing or inhibiting or competing microbial species.
17
Q
Who discovered penicillin?
A
In 1928, Alexander Fleming (bacteriologist) at Saint Mary Hospital in London.
18
Q
How Fleming discovered penicillin?
A
Colonized petri dish, Fleming noticed no Staphylococcus A colonies and some molds grown. So, he thought may be something secreted from Molds that’s why bacteria didn’t grow.
19
Q
When penicillin introduces as a medicine?
A
1941
20
Q
Which antibiotic is the first discovery in this world?
A
Beta lactam antibiotics
Bactericidal
21
Q
Who proposed Beta lactam antibiotics Structure?
A
Proposed in 1942 by Edward Abraham and confirmed in 1945 by Dorothy Hodgkin by X Ray crystallography.
22
Q
What is insulin?
A
Naturally occurring endogenous peptide hormone which is secreted from “pancreas” of our body.
23
Q
What insulin does?
A
Regulates the uptake (making use) of glucose. Diabetics patients unable to use stored energy (glucose) for function. Use as replacement of insulin.
24
Q
How many types of diabetes?
A
Two types
Type 1: Pancreas cannot produce insulin (chronic)
Type 2: Body is resistant to insulin.
25
Who discovered the structure of Insulin?
Dorothy Hodgkin
26
When Insulin Introduced as a medicine?
1920s
27
If we change amino acids of the structure of insulin what will happen?
Will alter its properties as a drug
28
When we eradicated smallpox and certified as Zero in the world?
Since 1979 but officially 8th in May, 1980, Certification endorsed by world health assembly Zero Smallpox.
29
Smallpox Caused by?
Variola major or Variola minor. (It is Infectious diseases)
30
What are the symptoms of smallpox?
```
Fever
Mouth sour
skin rash
Sore with filled with fluid
source become pustules
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31
Who first identified treatment for smallpox?
Edward Jenner
32
What is the first approved pill for contraception’s?
Enovid FDA in 1959
33
What are the benefits of Oral pills?
Changes sexual attitudes
Power of contraception in women’s hands
Influence lives of millions of individuals
Reduce Dysmenorrhoea and menorrhagia (heavy pain during periods)
Reduce risk of breast and ovarian cancer
34
What are the Oral contraceptives?
Synthetic Steroid Hormones
35
What is a Drug Lead?
A compound demonstrating biological activity likely to be therapeutically useful.
It is a starting point of chemical modification.
36
What is Potency?
When we give a dose of drug that required to produce a specific effect as compared to a standard reference.
37
Where do medicines comes from?
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Plants
Animals
Synthetic
Biologicals like proteins antibodies etc
Microorganisms
Venom's
Marine sources
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38
Taxol Paclitaxel (anticancer drugs) where are they from?
From the bark of the pacific yew tree.
39
How we can get/find a Drug Lead?
```
By Physical screening following:
Screening synthetic compound
Parallel synthesis
Purchased from libraries
Repurposing known drugs
molecules isolated from plants
By Directed screening following:
Structured based drug design
Virtual Screening (by the help of computer)
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40
(For direct screening) structure-based drug design can be experiment by determine 3D structure by?
Protein Crystallography
Electron Microscopy
NMR spectroscopy
41
What is salbutamol?
Beta 2 receptor agonist (it is a type of adrenergic receptors
42
What does addition of alkyl groups on Nitrogen and extra carbon do in salbutamol?
Addition of N gives appropriate Beta selectivity
| Addition of C gives or makes metabolically Stability
43
What is Ligand?
A molecule that binds to another (Larger) molecule
44
What is agonist and antagonist?
Agonist: Turn things up
Antagonist: Turns things down
45
What is a pharmacophore?
It is the 3D orientation of functional groups that responsible for a defined pharmacological activities.
46
Finding a drug lead through enhancing a side effect but how?
Existing drug side effects so enhancing side effect and eliminate original biological activity. Ex: Sildenafil (originally designed as vasodilator for angina but they have vasodilation other parts of the body. Has effect on erectile disfunction by lasting longer.
47
Chlorpromazine used for psychiatric medicine developed from?
Antihistamine Promethazine. It has sedative side effects.
| By enhancing its sedative side effects.
48
Does pharmacist can dispense sildenafil without prescription?
Yes
49
Luck and Serendipity mean?
The occurrence and development of events by chance in a happy or beneficial way.
50
Fexofenadine is 2nd generation antihistamine what is its earlier (1st) generation?
Terfenadine (had side effects cardiac arrythmia)
51
What is a Drug Analogues (analogs also known as “me too” drugs) for drug discovery?
A new lead must promise improvements over existing drug i.e. reduced side effects.
52
Where from Enalapril been developed?
Enalapril had developed from captopril (so no side effects like rash or loss of taste).
53
What is atomic structure?
Arrangement of electron to create bonds between atoms.
54
Nonbonding election is important for drugs for activity, hydrophilicity and other activity so what is Non-bonding electron mean?
They can Participate intermolecular interaction
They are reactive
Can make new bonds with other atoms or molecules
55
What is chemical bond?
```
Attractive force holds two atoms together
Different types:
Ionic,
Covalent i) Nonpolar
ii) Polar
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56
What is called valence electron or covalent bond?
Outer shell electrons stay by sharing their electrons with another atom’s electron.
57
What is Nonpolar covalent bond?
Electrons evenly shared.
| They are rare and only occur between similar atoms
58
What is Intermolecular force?
Not a formal chemical bond but a special type of attractive fore interaction. (Dipole-Dipole)
59
Ionic Bond what is it?
Electron transfer between atoms and thus become an anion (-) and cation (+). It happens because to be stable of its shell.
Held together by attraction of opposite charges and electrostatic interaction.
60
Many drugs exist as salts and what kind of bond they are?
Ionic bond(Positive and Negative attract)
61
What is Covalent bond?
It is ionic and they share their valence ions or electrons between atoms.
62
What is Nonpolar Covalent bond?
Sharing valance electron by two atoms.
63
What is polar covalent Bond?
Sharing of electrons are not equal.
Most drugs are Polar Covalent bond
They have different electronegativity pull electrons towards each other create dipole moment.
64
What different Bonding has in atoms?
C has 4 bonds (Fully saturated: holding as much water can be absorbed)
N has 3 bonds & 1 lone pair electrons (Not fully saturated)
O has 2 bonds and 2 lone pair electrons (Fully unsaturated)
65
Intramolecular vs Intermolecular interactions mean?
Intra: Same molecule Vs Inter: between different molecule.
66
Intermolecular interaction influence?
Boiling point, Melting point and solubility are greatly influenced by intermolecular forces.
This is a non-bonding interaction between two intermolecular forces like dipole and hydrogen bonds.
67
What is dipole?
Two poles. A bond or molecule whose ends have opposite charges between 2 molecule and it is a weaker bond than Ionic or covalent. Attach with electronegativity by partial charges.
68
What is Chirality?
Chiral molecules Cannot superimposed of their own mirror image.
69
What is achiral?
When a molecule has plane symmetry then it can be superimposed.
70
What atoms can be a Chiral centre?
Carbon, Sulfur, Phosphorus and Nitrogen
71
What is Enantiomers?
Enantio means opposite. So, we can say chiral molecule and its mirror image are enantiomers each other. Ex: left and right hand
They have very different biological activities. But they have similar physical properties i.e. solubility, melting point etc
Enantiomer measured by polarimeter. Each enantiomer interacts with a plane of polarised light in a different way.Based on their rotation on polarised light equal but opposite directions we name them + Dextro or – levoro
72
What is Racemate or racemic mixture?
a 1:1 enantiomer mixture called racemic mixture or racemate and when we analyse them in polarimeter it will be Zero because positive and negative light will cancel each other out so we get a reading of zero.
73
What is Diastereoisomer?
Not superimposable and not mirror image of each other
| They have different physical properties and different biological activities
74
Chloramphenicol is a broad-spectrum antibiotic which enantiomer are they?
RR isomer
75
What is Geometric isomers?
Different arrangement around a double bond.
| And they are not superimposable.
76
How we name a compound R or S?
Basis of atomic number, higher the number higher the priority. i.e a>b>c>d
If clockwise=> R (or remember right way)
Anticlockwise=>S
77
How we name a compound using E or Z system?
E opposite side
Z same side (Zame side remember)
So, for example one molecule and we take C as centre then we priotize between atoms of one side who wins and then we do same to other side as well.
78
What is Quality in context of medicine?
The fitness of the medicine for its intended use.
79
What is FITNESS of medicine?
Safe and efficacy
80
For discovery of new drug from lead compound to drug candidate?
Step 1
1st biological testing against known target=>Chemical synthesis or make more analogs and we can get some KI values which will tell us how effective drug is binds it target => after replacing different atoms in that molecule we choose best Structure with best result=>Then we get potential drug candidate=> Do animal test (to see solubility distribution in body if not good then go back and change analogs a bit to make better distribution properties)
81
What is involved in Non-Clinical trial involves in drug discovery pipeline?
Step 2
| Safety of animals through GLP
82
What is involves Clinical Trial during drug discovery pipeline?
Step 3
On human
Need to maintain GCP
To assess efficacy
83
How long it takes or costs for new drug discovery process takes?
```
30 out of Auckland
50 Diploma
30 age
Job Experience assistant 1
Manager 6
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84
How much estimated cost Pharmaceutical company spend to discover new drug to market?
Average 1.3 Billion for each marketed drug
| And failed drug doesn’t even account.
85
What is the difference between R&D vs commercial manufacturing of Medicine?
R&D:
Small scale reactions, not much focus on costs, Emphasis on improving efficacy and chemical properties.
Commercial manufacturing:
Optimizing drugs synthetic procedure, Emphasise on Cost and Time, Scaling up reactions
86
What safety consideration we need to keep while scale up our operation in commercial manufacturing?
Impurities
Reaction yields
Worker safety: Explosive
87
To reduce impurities or increasing yields for multiple steps reaction what we do to reduce toxicity?
We looked into the synthesis and try to find out how to make it easier.
In terms of Sildenafil: It has linear sequence reaction but later they have done convergent synthesis as a result the overall yield increased and by replacing reagents to improve safety.
88
Why Packaging is important?
Play major role on Stability
Shelf Life determine on packaging
Marketing or recognition of own drug
89
What is the function of Packaging?
Contamination, Protect from light moisture stress
Correct dosing based on labelling
Representation of product features
Protection from access to medicine by children or pregnant women.
Protection against counterfeits.
90
What is the difference between substandard vs counterfeits?
Substandard: Poor quality due to manufacturing process, storage, distribution.
Counterfeiting: Made illegally, fraudulently mislabelled, correct or wrong ingredients, fake packaging.
91
What I acid?
Acid is Proton doner, so it becomes conjugate base.
92
When we measure acid what factors determine the acidity of a molecule?
Z-H bond and its Proton with a large delta positive
| And its stabilised conjugate base.
93
What pKa measure for?
It is Ka, but when we do in Log scale then use p with Ka. i.e. pKa (so p= -log). pKa=-log Ka
pKa used to measure acid strength or equilibrium. It is a parameter to measure or identify where the equilibrium lies of a reaction. and how easily proton lost and become stable conjugate base.
94
Does same compound have same pKa?
Same compound does not have always same pKa, because it depends on other atoms or molecule within the compound. So, it is compound specific. But remember low pKa means strong acid.
95
Ionisation and unionisation of a compounds influence different physicochemical properties of a compound to work in our body?
Ability to diffuse through membrane.
Ability of Protein binding or intermolecular interaction, solubility etc.
(Different compartment of our body is different ph so where they will be ionized or unionized to significantly important to know as a pharmacist).
96
If someone ask how much or percentage is ionisation is this drug?
We can approximate unionised and ionised always in a given pH. So, the magnitude of the log scale through difference between pH and pKa we can estimate how much drug is ionised or unionised.
By positive or negative tells us which species is predominantly present acid or base. If we get – Con Acid. (PhpKa) and the result 0.5,1.0,2.0 tells us how much. see below
(On the other hand, remember if you get pH=pKa are same or so close each other like 1:1 in the mixture, it means 50 % of its concentration is acid & 50 % con Base).
97
Why carboxylic acids are acidic?
Because it has polar RZ-H bond.
| It can form stability in its conjugate base.
98
In drugs when a carboxylic acid becomes carboxylate ?
When proton present called carboxylic acid. When gives away that proton becomes carboxylate.
In drugs, carboxylate salt produce, with inorganic counterion. Like, sodium, potassium or mg
The counterion becomes part of the drug name.
99
How can the percentage of ionisation be approximated?
Drug example Aspirin?
Aspirin has pKa 3.5
(Plugging in) the delta pH=pH-pKa with this formula and get the result than interpret the number by following: - Acid +Base then Look for where is the conjugate acid is.if that is in LHS and unionised. And identify the proportion of drug ionised or unionised compound present based on the result.
100
Why we need to know percentage of ionisation of a drug?
For example, Aspirin,
In Stomach pH is 1-3 so mostly uncharged form. Can be absorbed through GIT barrier into the blood. Unionised species is good for passive diffusion.
In blood pH=7.4 mostly charged or ionised form. Better water solubility for distribution throughout the body. Ionised species is good for blood.
