MO Flashcards
(516 cards)
1
Q
- Aspirin (Acetylsalicylic acid)
- Salicin
DRAW THESE 3 times - pg 8 L2
A
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2
Q
Salicin is found naturally in … & …
Ancient Sumerian clay tablets mention using willow leaves to treat … … - (inflammatory disease)
Egyptians knew of the …. properties of dried myrtle leaves
A
Salicin is found naturally in WILLOW & MYRTLE
Ancient Sumerian clay tablets mention using willow leaves to treat RHEUMATOID ARTHRITIS - (inflammatory disease)
Egyptians knew of the ANALGESIC properties of dried myrtle leaves
3
Q
Salicin isolation
1820s & 1830s, scientists succeeded in isolating the active ingredient, salicin, from … …
Salicin is a ….
A
Salicin isolation
1820s & 1830s, scientists succeeded in isolating the active ingredient, salicin, from WILLOW BARK
Salicin is a GLYCOSIDE
4
Q
Aspirin
Salicin activation
Draw the activation process L2, pg 11
A
Name of the class of chemical compounds comes from the white williow Salix alba - known as salicylic acid
- read over
5
Q
Aspirin
L2, pg 12
A
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6
Q
- Aspirin (acetylsalicylic acid) introduced by .. in 1899
- Salicylate (from …. acid) & … … … … .. (NSAID)
- Used for mild to moderate … (analgesia), to … …. (antipyretic), reduce pain and … (anti-inflammatory) in eg arthritis, also helps prevent … …
A
- Aspirin (acetylsalicylic acid) introduced by BAYER in 1899
- Salicylate (from SALICYLIC acid) & NONSTEROIDAL ANTIINFLAMMATORY DRUG (NSAID)
- Used for mild to moderate PAIN (analgesia), to REDUCE FEVER (antipyretic), reduce pain and SWELLING (anti-inflammatory) in eg arthritis, also helps prevent BLOOD CLOTS
7
Q
Penicillin
Draw the structure
- L2, pg 17
A
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8
Q
Penicillin
Prior to its discovery, no effective treatment for infections such as
- …
- ….
- ….
A
Penicillin
Prior to its discovery, no effective treatment for infections such as
- Pneumonia
- Gonorrhea
- Rheumatic fever
9
Q
Penicillin was the first true … discovered
A
Penicillin was the first true ANTIBIOTIC discovered
10
Q
What does antibiotics mean?
- Compounds produced by … and … which are capable of killing, or inhibiting, competing microbial species
A
What does antibiotics mean?
- Compounds produced by BACTERIA and FUNGI which are capable of killing, or inhibiting, competing microbial species
11
Q
Penicillin
- Penicillin initially identified from “… …” (fungus)
- Penicillin” from the Latin name …
Introduced as a medicine in …
- Beta lactam antibiotic was one of the first effective antibiotics used against …. infections
- Kills bacteria - ….
A
Penicillin
- Penicillin initially identified from “MOULD JUICE” (fungus)
- Penicillin” from the Latin name PENICILLIUM
Introduced as a medicine in 1941
- Beta lactam antibiotic was one of the first effective antibiotics used against …. infections
- Kills bacteria - ….
12
Q
Penicillin as a drug
Most productive strain came from … …. from a Peoria fruit market
A
Penicillin as a drug
Most productive strain came from MOULDY CANTALOUPE from a Peoria fruit market
13
Q
Insulin & Diabetes
Insulin is a naturally occurring (endogenous) peptide … secreted by the …
A
Insulin & Diabetes
Insulin is a naturally occurring (endogenous) peptide HORMONE secreted by the PANCREAS
14
Q
Insulin regulates the … .. …
- Increases .. … on cell surface
- Assist in the conversion of … to …
A
Insulin regulates the UPTAKE OF GLUCOSE
- Increases GLUCOSE TRANSPORT on cell surface
- Assist in the conversion of SUGAR to ENERGY
15
Q
Patients with …. can’t use the stored energy (glucose) in their bodies
A
Patients with DIABETES can’t use the stored energy (glucose) in their bodies
16
Q
Diabetes (Diabetes Mellitus)
- Type I: Pancreas cannot produce … (chronic condition)
- Type II: Body is resistant to …
A
Diabetes (Diabetes Mellitus)
- Type I: Pancreas cannot produce INSULIN (chronic condition)
- Type II: Body is resistant to INSULIN
17
Q
Insulin used as … therapy for diabetes
A
Insulin used as REPLACEMENT therapy for diabetes
18
Q
Before insulin was discovered, patients were on a .. … diet, only as much as they could metabolise, they soon …
A
Before insulin was discovered, patients were on a NEAR STARVATION diet, only as much as they could metabolise, they soon DIED
19
Q
Insulin first identified in … by Canadian researchers. The extract was tested on … showing that it worked
A
Insulin first identified in 1921 by Canadian researchers. The extract was tested on DOGS showing that it worked
20
Q
In 1922 the first patient recieved treatment with insulin from …. extract
A
In 1922 the first patient recieved treatment with insulin from OX-PANCREAS extract
21
Q
Insulin
First hormone to be …
A
Insulin
First hormone to be Isolated
22
Q
Smallpox
Smallpox was an infectious disease caused by either Variola major or Variola minor ….
A
Smallpox
Smallpox was an infectious disease caused by either Variola major or Variola minor VIRUSES
23
Q
.. in every 10 died from smallpox
- Survivors have permanent …. over large parts of their bodies, especially …
- Some left …
A
3 in every 10 died from smallpox
- Survivors have permanent SCARRING over large parts of their bodies, especially FACES
- Some left BLIND
24
Q
Smallpox symptoms
-
A
Smallpox symptoms
- Fever & vomiting
- Mouth sores
- Sores become pustules which then scab
25
Smallpox vaccine
- Edward Jenner found a dairymaid who had cowpox lesions and inoculated boy with the "matter"
- He then inoculated the boy again with fresh smallpox
- No disease developed
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26
Oral Contraceptives
- ... ... hormones
- R... & R....
- Introduced in ...
- Substantial /Significant health benefits as well as ...
Oral Contraceptives
- SYNTHETIC STEROID hormones
- RELIABLE & REVERSIBLE
- Introduced in 1960s
- Substantial /Significant health benefits as well as CONTRACEPTION
27
Molecular Drug Action
L3, page 10
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28
Finding a Drug Lead
Natural products
- Plants - Aspirin
* ..., ..., ...
- Analgesia
* ...
- Anticancer agent
* ....
- Heart failured
- First prescribed in 1785
- Still used
Finding a Drug Lead
Natural products
- Plants - Aspirin
* OPIODS, MORPHINE, CODEINE
- Analgesia
* TAXOL
- Anticancer agent
* DIGOXIN
- Heart failured
- First prescribed in 1785
- Still used
29
Finding a Lead
Natural Sources
* Micro-organisms - produce ... agents
- ....
- ...
* Marine sources - sponges, ... ...
* Venoms - extremely potent - specific
- ... & ...
* Animal - etc
Finding a Lead
Natural Sources
* Micro-organisms - produce ANTIMICROBIAL agents
- PENICILLINS
- LOVASTATIN
* Marine sources - sponges, CONE SNAILS
* Venoms - extremely potent - specific
- SNAILS & SNAKES
* Animal - etc
30
Finding a lead
Natural sources
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Finding a lead
Natural sources
- Plants
- Micro-organisms
- Marine sources
- Venoms
- Animals
31
Drug Leads
Venom - Ziconitide
- ...toxin
- ... for severe chronic pain
- Venom is a complex mixture of ...
- Isolated toxins (at the right level) are ...
Drug Leads
Venom - Ziconitide
- CONOtoxin
- ANALGESIC for severe chronic pain
- Venom is a complex mixture of NEUROTOXINS
- Isolated toxins (at the right level) are BENEFICIAL
32
Getting a lead - Physical Screening
* Screening ... ...
* Combinatorial chemistry or parallel synthesis;
- Rapid synthesis of a large number of ... but ... ... molecules
- Generates focused ...
* Purchased libraries of ...
More on L3, pg 15
Getting a lead - Physical Screening
* Screening SYNTHETIC COMPOUNDS
* Combinatorial chemistry or parallel synthesis;
- Rapid synthesis of a large number of DIFFERENT but STRUCTURALLY RELATED molecules
- Generates focused LIBRARIES
* Purchased libraries of COMPOUNDS
33
Getting a Lead - Directed Screening
* ... compounds
* ... based drug design
* ... screening
Getting a Lead - Directed Screening
* ENDOGENOUS compounds
* STRUCTURE based drug design
* VIRTUAL screening
34
Directed screening
| - L3, page 18
Endogenous compounds
- From Natural (endogenous) Ligands
- B2 adrenergic receptor agonist
35
Directed Screening - Endogenous Compounds
- From ... (endogenous) ligands
- Adrenaline hits all ... receptors (alpha & beta)
- Addittion of alkyl groups on ... gave appropriate beta selectivity
- Extra .... as meta position makes the molecule metabolically stable
- Draw diagram
L3, pg 19
Directed Screening - Endogenous Compounds
- From NATURAL (endogenous) ligands
- Adrenaline hits all ADRENERGIC receptors (alpha & beta)
- Addittion of alkyl groups on NITROGEN gave appropriate beta selectivity
- Extra CARBON as meta position makes the molecule metabolically stable
36
Selectivity is important
L3, pg 21
Agonist - turns things up
- B2 adrenergic receptor agonist
- Asthma
Antagonist - turns things down
- B adrenergic receptor antagonist "B-blocker"
- Cardiovascular disease (high blood pressure)
37
L3, pg 27 & 28
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38
Directed Screening - Known enzyme substrates
* ... enzyme substrates
- .. protease substrates (peptide) used as leads
- Enzyme hydrolyses (cuts) ... bonds
Directed Screening - Known enzyme substrates
* NATURAL enzyme substrates
- HIV protease substrates (peptide) used as leads
- Enzyme hydrolyses (cuts) PEPTIDE bonds
39
Directed Screening - Structure based drug design
*3D Structure determined experimentally
-
-
-
Directed Screening - Structure based drug design
* 3D Structure determined experimentally
- PROTEIN CRYSTALLOGRAPHY
- ELECTRON MICROSCOPY
- NMR SPECTROSCOPY
40
Structure based Drug Design Fragment based lead discovery
* Using fragments to find a lead
- L3, pg 27 & 28
- Screen a database of "small" fragments
Fragment based lead discovery
- Combine fragment A & fragment B (synthetically) to get structure C
- Activity (lower the better) of the combined drug is better than the sum of the two parts
41
Drug Screening - Fragment expansion
MAKING A DRUG
* Identify ... (in protein structure)
* Expand .... (protein structure) etc
Drug Screening - Fragment expansion
MAKING A DRUG
* Identify FRAGMENT (in protein structure)
* Expand FRAGMENT (protein structure) etc
42
Drug Screening - Finding a Lead
Computer Aided Drug design
* Molecular Modelling can be used to study .... sites of the drug target structure
* Design ... that will fit the binding site (known structure of binding site)
* Computerised searches of "in silico" database of small molecules against a protein site or "..."
Drug Screening - Finding a Lead
Computer Aided Drug design
* Molecular Modelling can be used to study BINDING sites of the drug target structure
* Design MOLECULES that will fit the binding site (known structure of binding site)
* Computerised searches of "in silico" database of small molecules against a protein site or "PHARMACOPHORE"
43
Drug Screening - Finding a lead
* Enhancing a side effect
- ... drug could act as a .. for another therapeutic use based on ... ...
- Enhance the .. ... and eliminate the initial biological activity
- .... - Originally designed as a vasodilator (angina)
Drug Screening - Finding a lead
* Enhancing a side effect
- EXISTING DRUG drug could act as a LEAD for another therapeutic use based on SIDE EFFECTS
- Enhance the SIDE EFFECT and eliminate the initial biological activity
- SILDENAFIL - Originally designed as a vasodilator (angina
44
Drug development
* Chlorpromazine (used in psychiatric medicine) was developed from the antihistamine ....
* Promethazine has ... side effects
* Structure was modified to ... the sedative effects
Drug development
* Chlorpromazine (used in psychiatric medicine) was developed from the antihistamine PROMETHAZINE
* Promethazine has SEDATIVE side effects
* Structure was modified to ENHANCE the sedative effects
45
Drug Discovery - Serendipity and the Prepared Mind
- Trying to study the effect of ... .. on .. ..
Drug Discovery - Serendipity and the Prepared Mind
- Trying to study the effect of ELECTRIC FIELDS on BACTERIAL GROWTH
46
Drug Discovery - Drug metabolism studies
* ... is a second generation antihistamine used to treat ...
* This superseded ... (1st)
* ... (1st) sometimes led to ... ...
* .... (1st) was ... (oxidised) in the body to ...(2nd) which had fewer side effects (no cardiac arythmia)
Drug Discovery - Drug metabolism studies
* FEXOFENADINE is a second generation antihistamine used to treat ALLERGY
* This superseded TERFENADINE (1st)
* TERFENADINE (1st) sometimes led to CARDIAC ARYRHMIA
* TERFENADINE (1st) was METABOLISED (oxidised) in the body to FEXOFENADINE (2nd) which had fewer side effects (no cardiac arythmia)
47
Atomic Structure
* Is the arrangement of .... that creates ... b/w atoms
* It is the ... or outer shell electrons that participate in ...
* ... valence electrons (also called lone pairs of electrons) in a molecule can participate in .... .... and can also be reactive and make new bonds with other atoms/molecules
Atomic Structure
* Is the arrangement of ELECTRONS that creates BONDS b/w atoms
* It is the VALENCE or outer shell electrons that participate in BONDING
* NONBONDING valence electrons (also called lone pairs of electrons) in a molecule can participate in INTERMOLECULAR INTERACTIONS and can also be reactive and make new bonds with other atoms/molecules
48
Draw the structures on L4, pg 8
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49
Name the different types of chemical bonds
Name the different types of chemical bonds
* Ionic
* Covalent
- Polar covalent
50
Ionic bonds
* transfer of ... b/w atoms, to give an ... & ...
* Electrons are NOT ....
* Ionic bonds are held together by attraction of .... charges
* What type of interaction are ionic bonds?
Ionic bonds
* transfer of ELECTRONS b/w atoms, to give an ANION & CATION
* Electrons are NOT SHARED
* Ionic bonds are held together by attraction of OPPOSITE charges
* What type of interaction are ionic bonds? - ELECTROSTATIC
51
Ionic bonds
Many drugs exist as salts, give an example:
Metoprolol succinate
52
Covalent bonds
* Sharing of ... electrons b/w atoms
* The shared electrons are called the ... electrons
* What type of bond it when electrons are evenly shared?
* When electrons are not evenly shared?
* Most drugs are ... covalent bonds
* Polar covalent is when atoms in the bond have different ...., Different electron pull
Covalent bonds
* Sharing of VALENCE electrons b/w atoms
* The shared electrons are called the BONDING electrons
* What type of bond it when electrons are evenly shared?
- NON-POLAR
* When electrons are not evenly shared?
- POLAR
* Most drugs are POLAR covalent bonds
* Polar covalent is when atoms in the bond have different ELECTRONEGATIVITY, Different electron pull
53
Covalent bonding L4, pg 14
- Look at the lecture slide
Covalent bonding in neutral, orgaanic (carbon containing) compounds:
- Carbon has four bonds
- Nitrogen has three bonds ( and one lone pair of electrons)
- Oxygen has two bonds (and two lone pairs of electrons)
- Hydrogen has one bond
54
Name 2 physical properties influenced by intermolecular forces
- boiling & melting points
| - Solubility
55
Name the 2 strongest intermolecular forces
- Dipole - Dipole interactions
| - Hydrogen bonds
56
Intermolecular interactions - Dipole - Dipole
* The ... charges of one molecule are attracted to an opposite .. charge in a nearby molecule
* Much ... forces than ionic or covalent bonds
Intermolecular interactions - Dipole - Dipole
* The PARTIAL charges of one molecule are attracted to an opposite PARTIAL charge in a nearby molecule
* Much WEAKER forces than ionic or covalent bonds
57
Intermolecular interactions - Hydrogen bonds
* A special type of .... interaction, generally much ..... than a non-hydrogen bond dipole-dipole interaction
* Each partner in the H-bond has ...., covalent bond
usually RO-H or RN-H or RF-H
Intermolecular interactions - Hydrogen bonds
* A special type of DIPOLE-DIPOLE interaction, generally much STRONGER than a non-hydrogen bond dipole-dipole interaction
* Each partner in the H-bond has POLAR, covalent bond
usually RO-H or RN-H or RF-H
58
Sterioisomer understanding
L4, pg 20
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59
Chirality
L4, pg 21 & 22
- Most compounds in living systems are CHIRAL
- It makes sense that drugs are interacting with living systems are also chiral
- A 'CHIRAL CENTRE' (or centres) is the atom(s) which is responsible for the non-superimposable property
- If a molecule has a plane of symmetry, then it CAN be superimposed on its own mirror image... This molecule is ACHIRAL
60
Chirality
- What atoms can be a chiral centre?
- Most commonly a tetrahedral carbon atom
- Sulfur
- Phosphorus
- Nitrogen
61
What are your hands?
Enantiomers
62
Enantiomers interact with a plane of polarised .. in a ... way
* This can be measured using a ...
* Because each enanitiomer interacts differently with polarised light - enantiomers are also called optical isomers or '... ...'
Enantiomers interact with a plane of polarised LIGHT in a DIFFERENT way
* This can be measured using a POLARIMETER
* Because each enanitiomer interacts differently with polarised light - enantiomers are also called optical isomers or 'OPTICALLY ACTIVE'
63
Enantiomers rotate plane-polarised light in ... but ... directions --> shown by ... or ...
+ is ...
- is ....
Enantiomers rotate plane-polarised light in EQUAL but OPPOSITE directions --> shown by (+) or (-)
+ is DEXTROROTATORY
- is LEVOROTATORY
64
A 1:1 mixture of enantiomers is called a ... or ... .., and analysing in a polarimeter gives a reading of zero
A 1:1 mixture of enantiomers is called a RACEMATE or RACEMIC MIXTURE, and analysing in a polarimeter gives a reading of zero
65
Diastereoisomers
* Are non superimposable and ... ... mirror images of each other
* Usually have ... physical properties
* Often have ... biological activities
Diastereoisomers
* Are non superimposable and ARE NOT mirror images of each other
* Usually have DIFFERENT physical properties
* Often have DIFFERENT biological activities
66
Geometric isomers
* usually have ... physical properties
* Can have ... biological properties
Diagram l4, pg 27
Geometric isomers
* usually have DIFFERENT physical properties
* Can have DIFFERENT biological properties
Diagram l4, pg 27
67
Measurable quality attributes of a drug/medicine
Drug molecule with?
- Few side effects (safe
| - Efficacy
68
Measurable quality attributes of a drug/medicine
* Dosage form:
- Right strength
- No/limited contamination
- Not degraded
69
Measurable quality attributes of a drug/medicine
* Packaging:
- In the right container
- Properly sealed container
- Protected against damage and contamination
- Correctly labelled
70
Drug pipeline
- Draw
L5, page 8
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71
Pre-clinical (non-clinical testing)
* Studies in ... models?
* GLP ... .... ...
* Applies to ... toxicology studies performed during research and development (preclinical testing) to asses ....
Pre-clinical (non-clinical testing)
* Studies in ANIMAL models?
* GLP GOOD LABORATORY PRACTICE
* Applies to ANIMAL toxicology studies performed during research and development (preclinical testing) to asses SAFETY
72
Clinical testing
* studies in ...
* GCP ... .... ...
* Applies to clinical testing of medicines in ... to asses ....
Clinical testing
* studies in HUMANS
* GCP GOOD CLINICAL PRACTICE
* Applies to clinical testing of medicines in HUMANS to asses EFFICACY
73
R&D (research & development)
* Emphasis on improving .... and .. properties
* Not much focus on ... of synthesis
* ... scale reactions
R&D (research & development)
* Emphasis on improving EFFICACY and CHEMICAL properties
* Not much focus on COST of synthesis
* SMALL scale reactions
74
Drug manufacture (process development)
* Optimising the drugs ... procedure
* Improve ... & ... to synthesis
* "..." reactions
Drug manufacture (process development)
* Optimising the drugs SYNTHETIC procedure
* Improve COSTS & TIME to synthesis
* "SCALING-UP" reactions
75
Some examples of R&D synthesis (dont need to learn)
L5, pg 16-19
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76
Reality for Packaging
- Plays major role on ... of the drug
- ... of drug determined in packaging
- Used in .... of drug - recognisable product
Reality for Packaging
- Plays major role on STABILITY of the drug
- SHELF-LIFE of drug determined in packaging
- Used in MARKETING of drug - recognisable product
77
List some functions of packaging
- Containment
- Correct dosing (eg inhalers)
Protection from access to medicine by children
- Identifier for the company used in marketing and protecting against counterfeits
78
... & .... play pivotal role in pharmaceutical companies identifying counterfeit drugs/medicines
PACKAGING & FORMULATION play pivotal role in pharmaceutical companies identifying counterfeit drugs/medicines
79
What is the Bronsted-Lowry definition of an acid?
- An acid is a proton (H+) donor
| - When it donates a proton it forms the conjugate base
80
Acid diagrams L6, pg 6
Acids have:
- A highly polarised Z-H bond -> proton with a large s+ve
- And/or a weak Z-H bond but a stabilised conjugate base
81
Ka (or pKa when represented on a log scale) describes acid strength- which is really a combined measure of?
1) How easily a proton is lost, and
| 2) How stable the conjugate base is
82
pKa =?
pKa = -log Ka
83
pKa diagram L6, pg 8
- The pKa is a measure of where the equilibrium lies
- Although a functional group often has a similar pKa in different compounds, pKa is COMPOUND SPECIFIC so has to be measured, like a melting or boiling point
- remember... pH is different - it is a measure of the acidity of a solution
84
Ionised versus unionised compounds have different physiochemical properties - Give some examples
- Ability to passively diffuse through a membrane
- Protein binding & other intermolecular interactions
- Solubility
85
Calculating percentage ionisation
What is the formula?
ΔpH = pH - pKa
86
If ΔpH -ve?
If ΔpH +ve?
If ΔpH -ve ----> ↑conjugate acid (pH ↑ conjugate base (pH > pKa)
87
ΔpH 0.5 =?
ΔpH 1.0 =?
ΔpH 2.0 =?
ΔpH 0.5 ----> 70%
ΔpH 1.0 ----> 90%
ΔpH 2.0 ----> 99%
88
What happens when pH = pKa?
There is a 1:1 mixture of conjugate acid & conjugate base
89
Draw carboxylic acid and its conjugate base
L6, pg 11
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90
Ionisation
* The negative value means the ... .... is the major form
* The conjugate acid is on the LHS and is ...
Ionisation
* The negative value means the CONJUGATE ACID is the major form
* The conjugate acid is on the LHS and is UNIONISED
91
Ionisation
* The positive value means the ... .... is the major form
* The conjugate base is on the RHS and is ....
Ionisation
* The positive value means the CONJUGATE BASE is the major form
* The conjugate base is on the RHS and is IONISED
92
Sulfonamides
L6, pg 19
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93
What is the Bronsted-Lowry definition of a base?
- A base is a proton (H+) acceptor
| - When it accepts a proton it forms the conjugate acid
94
Model on L7, pg 6
Bases have:
- A lone pair of electrons or a negative charge that can act as a NUCLEOPHILE
- Nucleophile: An atom or molecule that provides a pair of electrons to form a new covalent bond
95
pKa for 'bases'
L7, pg 7
pKa describes how strong an acid is
96
Amines
Draw a primary, secondary, teriary & quaternary amine
L7, pg 9
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97
What is an analine?
Draw an analine
- L7, pg 10
One ore more direct N-substituents attached to a phenyl ring
98
Draw a heterocyclic aliphatic amine
Draw a heterocyclic aromatic amine
L7, pg 11
dgfhv
99
Amines can hydrogen bond
1) More H-bonds in a pure solution of the amine =?
2) More H-bonds with a solvent =?
1) Higher melting/boiling point
| 2) More soluble
100
Most amines have a .... electron pair
These electrons are responsible for the ... properties
Most amines have a NON-BINDING electron pair
These electrons are responsible for the NUCLEOPHILIC properties
101
Name 2 reactions of amines relevant to pharmacy
- Salt formation
| - Alkylation
102
Salt formation
L7, pg 14
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103
Salt formation - drug example
L7, pg 15 & 16
Metoprolol
- B1-receptor antagonist (a "beta blocker")
- Treats hypertension
- Pharmaceutical is a salt: either tartrate or succinate
Atropine
- A tropine alkaloid
- Competitive antagonist of the muscarinic acetylcholine receptors (anticholinergic)
104
Metoprolol treats?
Hypertension
105
Atropine is isolated as a ... from the Atropa belladonna (deadly nightshade)
Atropine pKa 9.8, formulated as the .. ...
Atropine is isolated as a RACEMATE from the Atropa belladonna (deadly nightshade)
Atropine pKa 9.8, formulated as the SULFATE SALT
106
Carboxylic acids are predominantly ionised at pH 7.4 (and present as the conjugate ...)
Amines are also predominantly ionised at pH 7.4 (and present as the conjugate ....)
Carboxylic acids are predominantly ionised at pH 7.4 (and present as the conjugate BASE)
Amines are also predominantly ionised at pH 7.4 (and present as the conjugate .ACID)
107
Imine L7, pg 23
efrgthf
108
Imines are ... and can act as ...
Imines much weaker bases than an ... amine
Imines are NUCLEOPHILIC and can act as BASES
Imines much weaker bases than an ALIPHATIC amine
109
Imine L7, pg 24
wegrhtd
110
What is an alcohol
- Hydroxyl group bonded to saturated carbon
| - Oxygen has two pairs of non-bonded electrons
111
Draw the primary, secondary & tertiary alcohol groups
L7, pg 25
ewgrhtfy
112
Draw a
- Phenol
- Ether
- Inorganic salt
- Enol
L7, pg 26
fewgrt
113
Thiols L7 pg 29
gerehtrdy
114
The carbonyl group
Draw an
- Aldehyde
- Ketone
- Amide
- Carboxylic acid or Carboxyl group
- Ester
L8, pg 7
aszfdxgfch
115
The carbonyl group
- ... is more electronegative than ...
- Larger share of bonded electrons go towards ..., in addition to the lone electron pairs on oxygen
- The bond is not ...
- The bond is ...
The carbonyl group
- OXYGEN is more electronegative than CARBON
- Larger share of bonded electrons go towards OXYGEN, in addition to the lone electron pairs on oxygen
- The bond is not SYMMETRICAL
- The bond is POLAR
116
Name the properties of the carbonyl group
L8, pg 8
- Polar bond
| - Nucleophilic attack of the electrophilic carbonyl carbon can occur
117
Aldehydes & Ketones
What type of bond is there?
Hydrogen bonding
118
What does H bonding require?
requires a very polar Z-H bond partner to be present
119
Carbonyl O-atom may H-bond with what?
Protic solvents
| H2O, MeOH etc
120
What does Carbonyl O-atom H-bond with protic solvents increase?
- Aqueous solubility
121
No ... H-bonds with itself are possible because C-H bond is not polarised enough
No INTERMOLECULAR H-bonds with itself are possible because C-H bond is not polarised enough
122
Aldehydes & Ketones
- L8, pg 10
dxfcghvbj
123
Amides
Draw a primary, secondary & tertiary amide
L8, pg 10
wsaffdg
124
Draw a
- lactam
- Phosphonamide
- Sulfonamide
L8, pg 10
fvghjb
125
What type of bonds does amides have?
Hydrogen bonding
126
Amides - Hydrogen bonding
* Because amides are .., they can hydrogen bond w/ ... ....
Amides - Hydrogen bonding
* Because amides are POLAR, they can hydrogen bond w/ POLAR SOLVENTS
127
Amides are ..., contain .... bonds, however are chemically relatively ... therefore are chemically ...
Amides are POLAR, contain POLARISED bonds, however are chemically relatively UNREACTIVE therefore are chemically STABLE
128
Amides - reactivity & stability
- L8, pg 13
Amides are POLAR, contain POLARISED bonds, however are chemically relatively unreactive therefore are chemically stable
- The non-bonding electron pair of the nitrogen is delocalised into the adjacent carbnyl group
- Therefore... Amides are 1) not good bases, and 2) much less reactive towards nucleophiles at the carbonyl-carbon than ketones, aldehydes and esters are
129
Amides are the backbone of ... & ...
Peptides & Proteins
130
.... H-bonds are important for peptide and protein secondary structure
INTRAMOLECULAR H-bonds are important for peptide and protein secondary structure
131
Esters
Draw a
- 'normal' ester
- Thioester
- Lactone
- Carbamate
- Inorganic ester
L8, pg 20
sfdxgchvjhb
132
Esters - hydrogen bonding & polarity
* Esters are still ... as contain a carbonyl group but
* Can not form ... H-bonds with itself
* Can H-bond with ... ..., but not as well as RCO2H
Esters - hydrogen bonding & polarity
* Esters are still POLAR as contain a carbonyl group but
* Can not form INTERMOLECULAR H-bonds with itself
* Can H-bond with PROTIC SOLVENTS, but not as well as RCO2H
133
Esters - Reactivity & Stability
* Because esters have a polarised C=O bond and because C-O bond can be broken, esters are prone to ....
* Because esters have a polarised C=O bond and because C-O bond can be broken, esters are prone to HYDROLYSIS
134
Draw the ester hydrolysis on L8, pg 23
sxdcfghgvjhb
135
Esters
Prodrug - a drug in an inactive or significantly less active form, which is preferentially activated at the drug target
L8, pg 25
A prodrug may be designed to:
- Improve oral bioavailability of a drug
- Decrease off-target toxicity of a drug
- Increase lipophilicity of a drug
- Increase hydrophilicity of a drug
- More specific targeting of a drug
- Improve patient tolerance during administration of a drug (eg taste)
- Prolonged/slow release
136
Thioesters
Drugs with a carboxylic acids often metabolised via a ... .... ...
* Because esters have a polarised C=O bond and because C-O bond can be broken, esters are prone to a REACTIVE THIOESTER INTERMEDIATE
137
inorganic ester
L8, pg 27
- The combination of an alcohol with an inorganic acid -> an inorganic ester, NOT a salt:
- Glyceryl trinitrate (glycerol + nitric acid)
- "nitroglycerine"
- Pro-drug for nitric oxide -> results in vasodilation
- Used to treat angina pectoris
138
What is the huckel rule?
4n + 2
- An unsaturated, cyclic compound is aromatic when it has (4n + 2) shared electrons in the ring system ( where n is an number from 1-5)
139
What is a heterocycle?
- A cyclic compound with carbon and at least one other atom in the ring system
140
What i a hetero atom?
- Any atom that is not carbon or hydrogen
141
Benzene and derivatives
Name the benzene shape and properties
- Flat, planar, aromatic
- Quite unreactive, aromatic
- Unsaturated
142
Draw
- Benzene
- Phenyl
- Benzyl
- Phenol
L9, pg 9
dxcfhgv
143
Benzen naming
L9, pg 10
zsdxfcg
144
Is phenol a weak or strong acid?
- Weak acid
145
name 3 importan derivatives of benzene
- Phenol
- Analine
- Polycyclic compounds
146
Heterocyclic aromatic
Name some
- Pyrrole
- Imidazine
- Tetrazole
- Pyradine
- Quinoline
- Indole
147
Pyrrole
- Because nitrogen lone pair shared in aromatic ring, nitrogen can not act as a nucleophile, therefore not a ..., in fact is a very ... ...
Pyrrole
- Because nitrogen lone pair shared in aromatic ring, nitrogen can not act as a nucleophile, therefore NOT a BASE, in fact is a very WEAK ACID
148
Imidazole
One nitrogens lone pair is shared in the aromatic ring, but the other nitrogens lone pair is not shared in the aromatic ring so can act as a ...
Imidazole
One nitrogens lone pair is shared in the aromatic ring, but the other nitrogens lone pair is not shared in the aromatic ring so can act as a BASE
149
Pyridine
Because the nitrogen lone pair is not shared in aromatic ring, these electrons can act as a nucleophile, pyridine is a ... ...
Pyridine
Because the nitrogen lone pair is not shared in aromatic ring, these electrons can act as a nucleophile, pyridine is a WEAK BASE
150
Quinoline
Nitrogen behaves similar to pyridine nitrogen so therefore is a ... ...
Quinoline
Nitrogen behaves similar to pyridine nitrogen so therefore is a WEAK BASE
151
Quinoline was found to help?
Malaria
152
Indole
- The nitrogen lone pairs are taken up in aromatic resonance so do not act as a ...
- Similar to ... it is neutral (unionised) at physiological pHs
Indole
- The nitrogen lone pairs are taken up in aromatic resonance so do not act as a BASE
- Similar to PYRROLE
153
name some heterocyclic non-aromatic
- Piperidine
| - B-lactams
154
Piperidine
Similar to an acyclic aliphatic amine, piperidine is a ...
Piperidine
Similar to an acyclic aliphatic amine, piperidine is a BASE
155
B-lactams
- L9 pg 29 &30
Structure and properties
- 4 membered ring, strained, a cyclic amide
- Susceptible to enzymatic hydrolysis by B-lactamases
156
Proteins
Proteins are non branching polymers that form ...
Proteins are composed of a linear sequence of .... amino acids covalently linked via ... (peptide) bonds
A short chain of amino acids is a ...
Proteins
Proteins are non branching polymers that form MACROMOLECULES
Proteins are composed of a linear sequence of CHIRAL amino acids covalently linked via AMIDE (peptide) bonds
A short chain of amino acids is a PEPTIDE
157
Recombinant DNA
* Recombined (DNA) which does not occur ...
* Insertion of ... from a ... species (or altered DNA from the same species) into the ...
* (combine) DNA coding for ... protein (eg) insulin into ...
Draw the diagram on L10, pg 14
Recombinant DNA
* Recombined (DNA) which does not occur NATURALLY
* Insertion of DNA from a DIFFERENT species (or altered DNA from the same species) into the GENOME
* (combine) DNA coding for HUMAN protein (eg) insulin into BACTERIA
158
Recombinant protein insulin L10 pg 15 & 16
Insulin
- Produced in bacteria from bacterial "plasmid"
- Circular self-replicating DNA molecule
- Plasmid is "cut" with a restriction enzyme - cleaves the DNA
- Human DNA is inserted (cloned) into the bacterial plasmid
- Plasmid inserted into Bacteria (E.coli)
- An inducer signals protein synthesis
- Protein produced and purified)
159
Expression host - A comparison
1. Advantages
2. Disadvantages
L10, pg 18
```
Bacteria - E. coli
1.
- Inexpensive
- Easy to cultivate
- Rapid growth
- Ease of modification
- High yield
- Easy scale up
- Cost effective
- Virus free
2.
- Cannot form disulfide bonds
- Non-glycosylation
- Endotoxin
```
```
Yeast
1.
- Inexpensive
- Easy to cultivate
- Rapid growth
- Ease of modification
- Easy scale up
2.
- Hyperglycosylation
```
```
Mammalian cells
1.
- Humanised glycosylation
- Properly folded
2.
- Difficult to cultivate
- Low yeild
- Expensive
- Viral contamination
```
160
Recombinant Protein Advantages
- Translation of an ... human gene/protein leads to decreased chance of ... rejection
-
-
Recombinant Protein Advantages
- Translation of an EXACT human gene/protein leads to decreased chance of IMMUNE rejection
- MORE EFFICIENT
- LOWER COST
161
Protein Therapeutics - Pharming Mammalian hosts
- Transgenic Animals can be used to secrete protein in their ..
- .... (an anticoagulant) has been produced from the milk of goats that have been genetically modified to produce the human protein
Protein Therapeutics - Pharming Mammalian hosts
- Transgenic Animals can be used to secrete protein in their MILK
- ANTITHROMBIN (an anticoagulant) has been produced from the milk of goats that have been genetically modified to produce the human protein
162
Mammalian host advantages
- Large amounts produced
- Cheaper than mammalian cell culture
- Easily scaled up or down
- Proteins are folded and fully functional
- Proteins can be readily purified from the milk
163
Mammalian hosts disadvantages
- Long time to generate and validate transgenic cows
- Proteins cannot be harvested until lactation begins
- The transgene "may" affect the animal
164
Proteins in humans - Advantages of proteins over small-molecule drugs
* Proteins carry out highly specific functions that cannot be mimicked by a small ...
* Highly specific proteins have less ... for adverse side effects
* Therapeutic proteins also produced by the body - Well tolerated and .. .. to produce an immune response
* In diseases where genes are mutated or deleted, proteins are an effective ... ...
Proteins in humans - Advantages of proteins over small-molecule drugs
* Proteins carry out highly specific functions that cannot be mimicked by a small MOLECULE
* Highly specific proteins have less POTENTIAL for adverse side effects
* Therapeutic proteins also produced by the body - Well tolerated and LESS LIKELY to produce an immune response
* In diseases where genes are mutated or deleted, proteins are an effective REPLACEMENT TREATMENT
165
Protein Therapeutics
Name the 4 groups
Group 1 - With enzymatic or regulatory activity
* 1a: replacing a protein that is deficient or abnormal
* 1b: Augmenting an existing pathway
* 1c: Providing a novel function or activity
Group II - With special targeting activity
* IIa: interfering with a molecule or organism
* IIb: Delivering other compounds or proteins
Group III - Protein vaccines
* IIIa: Protecting against a deleterious foreign agent
* IIIb: Treating an autoimmune disease
* IIIc: Treating cancer
Group IV - Protein diagnostics
166
Group 1 - with enzymatic or regulatory activity
1a: Replacing a protein that is deficient or abnormal
1b: Augmenting an existing pathway
Ic: Providing a novel function or activity
- Insulin -diabetes
- Blood clotting factors (Factor VIII & IX) - Haemophilia
- Enzymes
- Fertility - assisted reproduction eg FSH
- Calcitonin - osteoporosis
- Exenitide - type II diabetes - from Gila monster
- Recombinantly expressed
- Botox - medical applications (dystonia), cosmetics
167
Group II - With special targeting activity
IIa: Interfering w/ a molecule or organism
IIb: Delivering other compounds or proteins
- mAB - Trastuzumab
- Enfurvitide - blocks a protein-protein interaction in HIV infection of host
- Trastuzumab emtansine
- Anti-body drug conjugate nAM + emtansine
168
Group III - Protein vaccines
IIIa: Protecting against a deleterious foreign agent
IIIb: treating an autoimmune disease
IIIc: Treating cancer
- eg HPV vaccine - Gardasil
- Clinical trails
- Clinical trials
169
Group IV - Protein diagnostics
Hormones:
Imaging agents:
- Growth Hormone Releasing Hormone
- Defective GH secretion
- Prostate Cancer Detection -(mAB) - imaging agent
- Imaging of acute venous thrombosis
- Hep C antigens - diagnosis of exposure
170
Draw the acid-catalysed ester hydrolyis summary
- L12, pg 6
dgcfhvg
171
What is an ester hydrolysed to give?
Gives:
| - Carboxylic acid & an alcohol
172
Acid-catalysed ester hydrolysis
* Under acidic conditions it is possible for a carboxylic acid and alcohol to form an...
- An excess of water drives the reaction to the ... of the product
Acid-catalysed ester hydrolysis
* Under acidic conditions it is possible for a carboxylic acid and alcohol to form an ESTER
- An excess of water drives the reaction to the RHS of the product
173
Acid-catalysed ester hydrolysis
Step one: Protonation
L12, pg 8
- The lone pair of electrons on the carbonyl oxygen attacks a proton
174
Acid-catalysed ester hydrolysis
Step two: Nucleophilic attack by water
L12, pg 9
- Lone pair of electrons on waters oxygen is the nucleophile
- If the carbonyl oxygen is not protonated, the water can act as a nucleophile because the carbonyl carbon is not electrophilic enough
175
Acid-catalysed ester hydrolysis
Further steps: proton transfer
L12,pg 10
- In equilibrium many species exist, including this one that leads to the cleaved products
- This species is now set up for a bond to break
176
Acid-catalysed ester hydrolysis
Final steps: What enables the C-O ester bond to break?
L12, pg 11
R-OH+ is a good leaving group, transfer of electrons to R-OH+ is favourable, produces a neutral alcohol
177
Base-catalysed ester hydrolysis
In Summary
* An ester is hydrolysed to give?
L12, pg 12
- Carboxylic acid and an alcohol
178
Base-catalysed ester hydrolysis
Step One: Hydroxide ion attack
L12, pg 13
- the hydroxide ion (base) attacks the carbonyl oxygen
179
Base-catalysed ester hydrolysis
Final steps
L12, pg 14
- C-O bond breaks and alkoxide (negatively charged alcohol) is produced
- Notice the reaction above is in equilibrium, but then this happens fast
- This reaction is not reversible under these conditions
- The product of the base catalysed reaction conditions is actually an alcohol and teh carboxylate, eg CO2NA if NaOH is the base
180
Effect of pH - acid catalysed
- L12, pg 15
efrgdt
181
Effect of pH - acid catalysed
What happens when its more acidic? -L12, pg 16
vub
- The rate of acid catalysed hydrolysis has been shown to be independent of pH in the approx. 4-7 pH range in some cases
- But generally in the stomach at pH 1.5-3 the rate of acid-catalysed ester hydrolysis is comparatively faster
182
Effects of pH - Base catalysed
What happens when its more basic?
There is no one answer to this
- Generally from pH 8 and above the basic the faster the rate of hydrolysis
183
Stability in vivo
In vivo an ester can be cleaved via ... ... or by ... ... ... ...
A drugs ester bond can be cleaved in
Stability in vivo
In vivo an ester can be cleaved via CHEMICAL HYDROLYSIS or by ENZYME CATALYSED ESTER HYDROLYSIS
A drugs ester bond can be cleaved in:
- Plasma
- Liver
- Gut
- Tissue
184
Ester hydrolysis can either be drug .... or ...
Ester hydrolysis converts a ... to the active drug
Ester hydrolyses inactivates an ... ....
Ester hydrolysis can either be drug ACTIVATING or DEACTIVATING
Ester hydrolysis converts a PRODRUG to the active drug
Ester hydrolyses inactivates an ACTIVE DRUG
185
Stability in vivo - pH
pH matters since different compartments in the body have different ...
rate of ester hydrolysis often changes at different ...
pH
186
Drug examples - Ester prodrugs
Heroin is a prodrug of ....
Heroin is ...
.... .... cleaved to reveal active drug morphine
Heroin more ... than morphine, diffuses through BBB faster
Drug examples - Ester prodrugs
Heroin is a prodrug of MORPHINE
Heroin is INACTIVE
ACETYL ESTERS cleaved to reveal active drug morphine
Heroin more LIPOPHILIC than morphine, diffuses through BBB faster
187
Drug examples - Lactone prodrugs
6-membered lactones - many of the statins (HMGCoA reductase inhibitors) are prodrugs containing a ...
Drug examples - Lactone prodrugs
6-membered lactones - many of the statins (HMGCoA reductase inhibitors) are prodrugs containing a LACTONE
188
Drug examples - Phosphate ester prodrugs
... .... is a prodrug of prednisolone
Hydrolysed by .... ....
Drug examples - Phosphate ester prodrugs
PREDNISOLONE PHOSPHATE is a prodrug of prednisolone
Hydrolysed by ALKALINE PHOSPHATASE
189
Physicochemical properties of drugs
* For a drug, what are we talking about? Aspects of...
- ionisation
- lipophilicity
- solubility
- hydrogen bonding
- Surface area
- Molecular size
190
Lipophilicty - logP
* The more lipophilic the molecule, the ... the logP
* LogP is always the ... species in water
Lipophilicty - logP
* The more lipophilic the molecule, the HIGHER the logP
* LogP is always the UNIONISED species in water
191
Lipophilicity - logD
logD is the measured distribution constant of a molecule between ... and a defined ... .... solution
Lipophilicity - logD
logD is the measured distribution constant of a molecule between OCTANOL and a defined pH AQUEOUSsolution
192
Definition of SAR
The relationship b/w chemical structure & pharmacological activity for a series of molecules
193
What is pharmacological activity?
It is any defined end point, there is no one answer, it must have context
194
Why determine and understand SAR?
- Increase drug potency
- Increase selectivity
- Increase or decrease duration of action
- Reduce toxicity
- Increase stability
195
Discovering SARs
L13, pg 17
Molecular structure and biological activity are correlated by observing the experimental results of systemic structural modification on defined endpoints
196
What is pharmacophore?
- The 3D spatial arrangement of functional groups that are responsible for a defined pharmacological activity
- The minimal skeletal required for the SAR
197
Isostere definition:
Bioosostere definition:
- Each functional group has similar molecular shape & volume and similar (bot not identical) physiochemical properties
- Above plus similar biological properties to the parent compound
- We only know this after biological testing and establishing SAR
198
Polyclonal antibodies
L11 pg 13
Natural immune response many cells make different antibodies
= polyclonal (many clones) response
= polyclonal antibodies
- Antigen = molecule capable of stimulating immune responses - proteins, sugars, lipids, small molecules
199
Polyclonal antibodies = natural antibodies
A single antibody is made by a ... ... (B cell)
Many plasma cells make different antibodies = ... ...
Polyclonal antibodies = natural antibodies
A single antibody is made by a PLASMA CELL (B cell)
Many plasma cells make different antibodies = POLYCLONAL RESPONSE
200
Antibodies used in therapy are predominantly ...
IgG
201
Commercial production of heterologous polyclonal antibodies
What are the 4 steps
Also a wee diagram on L11, pg 16
1) Inject antigen into rabbit
2) Antigen activates B cells
3) Plasma B cells produce polyclonal antibodies
4) Obtain antiserum from rabbit containing polyclonal antibodies
202
Heterologous Vs Homologous
Heterologous
- From animals
- Suitable for commercial production
- Need to be able to identify & purify a non-toxic antigen
- Can only be given a single dose from any given species or will develop life-threatening allergic reaction (anaphylaxis)
Homologous
- From people
- Used only in specific situations
- Natural antibodies as a result of infection
- No risk of anaphylaxis
203
Monoclonal antibody (mAb)
Synthetic antibody produced by ... technology
L11, pg 19
Monoclonal antibody (mAb)
Synthetic antibody produced by RECOMBINANT technology
204
Monoclonal antibodies
No control over?
First monoclonals antibodies (mAb) were murine (-o-) therefore issues with ...
Monoclonal antibodies
No control over?
- What antibodies are made - take what you can get
First monoclonals antibodies (mAb) were murine (-o-) therefore issues with ANAPHYLAXIS
205
Polyclonal vs monoclonal
L11, pg 27
Polyclonal
- From different B cells
- Mixed population
- Batch variability
- Bind to different areas of target
- Tolerant to small changes in target
- Cheaper to produce
- Quick to produce
- Can be heterologous (animals) or homologous (convalescent humans)
- Allergic reaction (anaphylaxis) possible
Monoclonal
- From a single B cell clone
- Single specificity
- No variability
- Bind to one area of target
- Not tolerant to small changes in target
- Expensive to produce but can produce forever
- Long development time
- Can be murine, chimeric, humanised or human
- Allergic reaction (anaphylaxis) possible to non-human antibodies
206
Overview of clinical uses of antibodies - therapeutics
- Neutralize
- Kill
- Modulate
207
Overview of clinical uses of antibodies - as carriers
- targeted delivery of agents to required site of action for reduced off-target activity and increased efficacy
- Killing agent
- Modulating agent
208
What happens if we do not have consistently high quality medicines?
- Therapeutic failure
- Wasted resources
- Death
209
Historical perspective: Thalidomide
Effective tranquilizer and pain killer, and used to cure ?
More than 10,000 children in 46 countries were born with deformities
- Morning sickness
210
What is quality assurance
- Quality in design
| - Quality in manufacture
211
Quality assurance encompasses all aspects of Drug Development Pipeline
L14, pg 12
zxdcfgvj
212
Pharmaceutical manufacturing and distribution
L14, pg 17
Raw materials manufacturing and supply --> Blending and other processing --> Dosage form --> Container closure system --> Storage --> Distribution --> Pharmacy
213
How can quality of the final product be ensured?
What are some problems with this approach?
Testing of finished products to ensure compliance to specification
- Reactive not preventive
- Does not address quality during storage and distribution
214
What can influence medicine quality during manufacture?
- Raw materials
- Packaging system
- Labelling
- Storage
215
Part 1 of Code - outline
Components:
- Personnel
- Premises & equipment
- Production
- Contract manufacturing and analysis
- Complaints and product recall
- Self inspection
- DOCUMENTATION
- QUALITY CONTROL
216
Components L14 pg 23-25
Personnel
- Training - most errors are due to insufficient training
- Personal hygiene - wash appropriately and do not touch product with hands
Premises and equipment
Production
217
What are the four types of GMP Documentation?
- Standard Operating Procedure (SOP)
- Manufacturing instructions
- Records
- Specifications
218
Documentation: Specifications
L14, pg 32 & 32
Standards and acceptable limits for quality of raw materials, formulations and finished products. They aim to ensure safety and efficacy of the final drug product
- Based on critical quality attributes
- Proposed and justified by the manufacturer and approved by regulatory authorities
- Defined in pharmacopoeias if the medicine has previously been marketed (off patent) or a medicine dossier (for new products)
219
Quality control (Part of GMP)
Testing and checking of .. ..., some intermediate products and the final product before release
Usually by a ... technique (IR or UV)
Quality control (Part of GMP)
Testing and checking of RAW MATERIALS, some intermediate products and the final product before release
Usually by a SPECTROSCOPIC technique (IR or UV)
220
What is spectroscopy?
Detection and analysis of electromagnetic radiation
221
How does spectroscopy enable quality control?
Obtain spectra (singular : spectrum)
222
L14, pg 37
What is happening to the drug/molecules?
- Absorbing energy
- Molecules can be defined in terms of their quantum states
- Electronic
- Vibrational
- Rotational
- Translational
- All molecules have energy levels within these quantum states that are discrete (quantised)
- The lowest energy form of the material is the ground state, when the electronic, vibrational, rotational and translational energies are at their lowest
223
Energy levels of molecules L14, pg 38
- Infrared (IR) and Ultraviolet (UV) energy useful in drug quality control
224
Pharmacopoeia
A set of official quality standards (monographs) for?
Drug products
225
Todays pharmacopoeias focus mainly on?
Assurance of quality of products using various tools of analytical sciences
226
What information is provided in a pharmacopoeia?
1. Verification of identity
2. Homogeneity (to ensure absence of specified impurities)
3) Purity (using assay methods)
227
1. Verification of identity
Test used:
- Proton or 13C-NMR
- Mass spectroscopy (MS)
- IR spectroscopy (IS)
- Melting point (m.p.)
228
Verification of identity tests
* Proton (1H) or carbon (13C) NMR
- Nuclear magnetic resonance
| - Gold standard to determine identity
229
Verification of identity tests
Mass spectrometry (MS)
L15, pg 11
Unbroken tablet compared to a broken tablet
230
Verification of identity tests
Infrared Spectroscopy (IS)
L15, pg 12
gjcdsv
231
2. Homogeneity (absence of specified impurities)
test for impurities
- Residual solvents (measured by gas chromatography)
- Inorganic compounds ( measured by "residue on ignition"
- Heavy metals
232
3. Purity (using assay methods)
Methods include:
- UV-Vis spectrophotometric assay
| - High performance liquid chromatography (HPLC)
233
Example of Quality Control tests paracetamol (raw material)
L15 pg 15
1. Identify the drug substance
- Is the material ...?
2. Determine the levels of impurities
- Water
- Inorganic impurities
- Heavy metals
- p-aminophenol
- p-chloroacetanilide
3. Assay the purity of the drug substance
- What percentage is ...?
234
Example of quality control tests conducted on paracetamol tablets (final product)
L15, pg 16
- HPLC Assay
- Dissolution rate
- TLC identification
235
Attenuated Total Reflectance - Type of IR spectrometer used in lab 2
L15, pg 20
rbhjfkev
236
Infrared Spectroscopy in drug identification
* Absorption of IR radiation by molecules (drugs) results in what?
* The simplest type of vibration is?
* The frequency of oscillation is governed by?
- Vibrations of the chemical bonds
- Stretching
- The mass of the two atoms
- The bond order (bond strength)
237
Vibration frequencies
L15 pg 22
- Spring model obeying Hookes law is used:
where
- v is the frequency of vibration
- k is the force constant or bond "stiffness"
- m1m2/m1+m2 is the "reduced mass" of the two atoms
From the above equation it is seen that:
1. Heavy atoms vibrate slower than light atoms (denominator = larger)
2. Unsaturated bonds vibrate faster than sing bonds: ir numerator = larger
eg
C≡C (2300) > C=C (1640) > C-C (1400 cm-1)
238
Types of vibrations measured in an IR spectrum
L15, pg 23
- Rocking
- Umbrella bend
- Scissor bend
- Symmetric stretch
- Asymmetric stretch
239
IR spectroscopy units
L15, pg 24
-By convention, the positions of bands (frequencies or absorptions) are expressed in wavenumbers (v):
ie 3000cm-1 = 3000 wavelengths (h) per centimetre
- Being a unit of frequency it is directly proportional to energy
240
Identification of drugs or unknown samples
1. Identification by comparison
L15, pg 26
The IR spectrum of paracetamol
- < 15000 cm-1 = fingerprint region - unique for every compound
- Spectra may be compared for a match (eg from a spectral database/pharmacopeia)
241
Identification of drugs or unknown samples
2. Functional group identification
L15, pg 27 & 28
- generally > 1500 cm-1
- certain frequency regions characteristic of certain bond types
- Some specific functional groups from the exact position of the band
- This is particularly useful for those functional groups possessing a double or triple bond
- Best example is a carbonyl bond (1600 - 1800 cm-1)
242
Identification of unknowns
3. Determination of functional group environment
L15, pg 29
- Conjugation effect (eg conjugation to a carbonyl group):
- Saturated ketone
- Conjugated ketone
- Doubly conjugated ketone
243
Effect of conjugation on stretching bands
L15, pg 30
- Resonance -> decrease π-character, increased o-character (of carbonyl group)
- The double bond is longer and weaker than expected
- Decreased K, therefore decreased wavenumber (v)
244
How can infrared radiation help in drug quality and identification?
L15, pg 31-33
Distinguishing between carbonyl groups
- Weak induction
- Strong induction
- Resonance
- Resonance
245
How do we measure UV-visible absorbance? - UV-Visible spectrophotometer
- Deuterium Lamp (190-350) nm (UV region)
- Tungsten Lamp (350-900 nm (Visible region)
- Xenon Flash Lamp
246
Measuring UV-Vis Spectra (Transmittance)
- Transmittance, T, is defined as: T = I/Io
- Transmittance is a ration with no units. it takes values between 0 and 1, but it is often expressed as a percentage
- Percentage transmittance = I/Io x 100
247
Energy Levels of molecules
| L18, pg 11
xcfytguh
248
Chromophores
* . Electronic transitions ( absorbance) are associated with a particular part of the ...
* For UV-Vis, the chromophore contains unsaturation
* the more conjugated the chromophore, the ... the wavelength of absorption
Chromophores
* . Electronic transitions ( absorbance) are associated with a particular part of the MOLECULE
* For UV-Vis, the chromophore contains unsaturation
- DOUBLE AND TRIPLE BONDS (πORBITALS)
- NON-BONDING (N) VALENCE ELECTRONS ASSOCIATED WITH π-BOND
* the more conjugated the chromophore, the LONGER the wavelength of absorption
249
Absorption of UV-Visible Light 1
L18, pg 14
- π --> π* most significant UV-Vis absorption
| - n --> π* other significant UV-Vis absorption
250
Concentration Effects for n --> π* Transition
L18, pg 15
- Only visible at high conc.
| - (π --> π much stronger absorption)
251
UV spectrum of paracetamol
L18, pg 16
sgfhg
252
Auxochromes
The absorption of ... are affected by auxochromes
L18 pg 18
Auxochromes
The absorption of CHROMOPHORES are affected by auxochromes
253
Auxochromic and Conjugation shifts
*Auxochromes can cause the following effects, often concurrently:
L18, pg 19
- Bathochromic shift - Displacement of maximum absorption to a longer wavelength (red shift)
- Hypsochromic shift - displacement of maximum absorption to a shorter wavelength (blue shift)
- Hyperchromic shift - Increase in absorption at a particular wavelength
- Hypochromic shift - decrease in absorption at a particular wavelength
254
Effects of Auxochromes on Benzene Absorption
L18, pg 20
redks n
255
Effect of conjugation on π-π* Transition
Increased conjugation has a .... & ... effect
Effect of conjugation on π-π* Transition
Increased conjugation has a BATHOCHROMIC & HYPERCHROMIC effect
256
PH-DEPENDENT SPECTRA 1
L18, pg 23
Drugs which have acidic or basic auxochromes have pH-dependent spectra (eg phenol and aniline)
- Hypsochromic and hypochomic shift
- Bathochromic and hyperchromic shift
257
pH- Dependent Spectra 2
L18, pg 24
xdfcgv
258
Identification by UV-Vis Spectroscopy
Problem:
L18, pg 27
dxfcyvu
259
Quantitative UV-Vis Spectroscopy Beer-Lambert Law
L18, pg 28
260
Molar absorptivity
L18, pg 30
dcfyvug
261
Chromatography
Physical method of separating two or more components based on their distribution b/w two phases:
how fast a compound moves is determined by its?
1. Stationary phase (solid)
2. Mobile Phase (liquid)
- Affinity for both the stationary and mobile phase
262
What does HPLC stand for?
L19 pg 7
high performance liquid chromatography
263
HPLC system
L19, pg 8
cedw
264
HPLC system
L19, pg 9
dvljsd
265
Manual injectors - information for lab
L19, pg 10
sdrsfg
266
Types of detectors
What are the cheapest ones?
L19, pg 12
- Variable wavelength UV detector
| - Diode array UV detector
267
Types of HPLC
- Normal phase HPLC - polar or hydrophilic
| - Reversed phase HPLC - nonpolar/hydrophobic
268
Normal phase column (TLC is usually normal phase)
L19, pg 14
- Silica as the stationary phase
- Forms hydrogen bonds with functional groups on drug molecules (eg OH, NH etc)
- High affinity for polar analytes
269
Normal phase HPLC Example
L19, pg 15
yhrdfg
270
Normal Phase Mobile Phase
* Increase ... solvent to improve separation (resolution) of analytes
* Due to increased retention of ... analytes
Normal Phase Mobile Phase
* Increase NON-POLAR solvent to improve separation (resolution) of analytes
* Due to increased retention of POLAR analytes
271
Reversed Phase column (C18)
Forms ... interactions w/ non-polar functional groups on drug molecules (Good indicator of lipophilicity at a experimentally defined pH)
L19, pg 17
Reversed Phase column (C18)
Forms HYDROPHOBIC interactions w/ non-polar functional groups on drug molecules (Good indicator of lipophilicity at a experimentally defined pH)
272
Reversed-phase HPLC example
- L19, pg 18
dsfdgcfhgvj
273
Reversed Phase Mobile Phase
* Resolution can be improved by changing the ... phase composition
* Increasing ... .... for RP-HPLC
L19, pg 19
Reversed Phase Mobile Phase
* Resolution can be improved by changing the MOBILE phase composition
* Increasing POLAR SOLVENT for RP-HPLC
274
Normal vs Reversed phase HPLC table
L19, pg 20
1. Stationary phase
2. Eluate composition
3. Elution order
4. Interactions
1. Normal phase - Polar (hydrophilic)
2. Mixture of non-polar and more polar organic solvent
3. Hydrophobic first then more hydrophilic
4. Hydrogen bonding
1. reversed Phase - Non-polar (hydrophobic/lipophilic)
2. Mixture of organics and aqueous solvents
3. Hydrophilic first then more hydrophobic
4. Hydrophobic interactions (indicates lipophilicity)
275
Isocratic Elution (reversed phase HPLC example)\
Composition of mobile phase remains ... over time
L19, pg 21
Constant
276
Mobile phase - Gradient elution
Composition of mobile phase .... over time
- Changes
277
Retention time (tR) can provide?
- Identity
| - Purity
278
Methods of Quantitation
- External standard method
- Internal standard method
- Standard addition method
279
Sample Preparation for HPLC
For biologiacal samples
- Protein precipitation and centrifugation
- Liquid-liquid extraction (LLE)
- Solid phase Extraction (SPE)
280
The External standard method
L19, pg 29
cvhgjbhckj
281
Single External Standard Method
L19, pg 30
sdjkcab
282
Calibration curve External Standard method
L19, pg 31
sderftgyh
283
Calibration Curve working Range
L19, pg 32
efksjajkn
284
The internal Standard Method
Compound that is ... to the analyte of interest
L19, pg 33
Different
285
The calibration curve & single standard method use what?
The ration of signals of analyte and IS ([X]/[IS])
286
Calibration Curve Internal Standard Method
L19, pg 34
adfesvjkbh
287
Choice of internal Standard (IS)
The IS must have properties .. to the analyte and behave similarly in all sample preparation steps:
1) IS must be easily resolved from ... and any ... matrix peaks
2) IS must have ... extraction properties to analyte
3) IS must give ... detector response to analyte
Choice of internal Standard (IS)
The IS must have properties SIMILAR to the analyte and behave similarly in all sample preparation steps:
1) IS must be easily resolved from ANALYTE and any ENDOGENOUS matrix peaks
2) IS must have SIMILAR extraction properties to analyte
3) IS must give SIMILAR detector response to analyte
288
Choice of internal Standards
L19, pg 36
- An internal standard is a different compound but with a similar structure to the drug being analysed
- pKa will give different extraction properties
289
Value of an internal standard (IS)
L19, pg 38
- Internal standards are also useful when unavoidable sample losses are expected
- eg during sample preparation prior to assay by HPLC
- If the internal standard is added to a sample prior to any losses during sample preparation, then the fraction of IS is the same as the fraction of analyte lost and the ration
290
1. Importance
(a) Drug stability in formulation and storage
L16, pg 6
dfvygu
291
1. Importance
(b) Drug stability in vivo
L16, pg 7
rtyu
292
2. Redox
(a) REDuction and OXidation
L16, pg 8
- A compound that is oxidised or reduced changes its oxidation state
- Redox reactions are electron transfer reactions
the symbol for oxidation is [O]
- the symbol for reductions is [H]
293
Redox
(b) The agent
L16, pg 9
gfdusyvc
294
Oxidation
What is oxidation?
L16, pg 10
Oxidation involves
- Loss of electrons
- Loss of hydrogen or Addition of oxygen
295
Oxidation mechanism
Very complex (we dont go through it)
L16, pg 11
db3iwe
296
How do oxygen radicals form?
- In drug formulations and during storage
| - In vivo
297
Oxidation Functional groups prone to oxidation
Alkenes can be oxidised to?
L16, pg 14
- Epoxides
| - Diols
298
Alkenes can be oxidised and eventually ....
cleaved
299
Alkenes oxidation in vivo
L16, pg 16
csgabh
300
Can unsaturated fatty acids be oxidised?
yessir
301
Oxidation
Thiols and thio ethers
L16, pg 17 & 18 & 19
asdfghj
302
Oxidation - Aromatic ring oxidation
* Catalysed by?
L16, pg 21
- Enzymes
- Oxidases
- Monoxygenases
- Cytochrome P450 enzymes
303
Oxidation
L16,pg22
sdfg
304
Aromatic ring oxidation example
- L16, pg23
dfxgchvjb
305
What is reduction?
L16, pg 24
- Gain of electrons
| - Addition off hydrogen or loss of oxygen
306
Mechanism and source of reductant
- Mecahnism is complex (we dont go over this)
sxdtfyguhi
307
What are the functional groups prone to reduction?
- Carboxylic acids
| - Ketones
308
Reduction example
L16, pg 27 & 28
dfghjhgf
309
Why is ester hydrolysis NOT a redo reaction?
Because the oxidation state of carbon is the same - it has the same number of bonds from carbon to oxygen
310
What is photolysis?
Exposure to electromagnetic radiation (light) may result in complex chemical reactions hence decompositions of drugs
311
Photolysis drug formulation and storage
- Folic acid photodegradation
312
Drug photolysis in vivo
* Sunlight can penetrate ...
- Skin .... Therefore can degrade drugs circulating in surface capillaries
313
What is an electrophilic aromatic substitution?
- One of the hydrogenn atoms on the aromatic ring is substituted with another functional group
314
Electrophilic aromatic substitution
Mechanism
Dont need to know this
L17, pg 7
dgfhvj
315
Why is understanding SEAr important?
- In drugs - aromatic hydroxylation often occurs during metabolism
316
E+ is the shorthand for an .....
Electrophile
317
What is dealkylation?
L17, pg 9
Replacement of an alkyl group (often a methyl group) with a hydrogen
318
Dealkylation mechanism
- Dont need to know this
- L17, pg 10
dfghjk
319
Dealkylation examples
L17, pg 12 & 13
fgfhj
320
Recap: Chemical reactions
L17, pg 16
dsfghyj
321
Whats a covalent drug?
Drugs that react with the biological target to form a covalent bond b/w the drug and the target
- Usually irreversible reaction
322
What is alkylation?
Transfer of an alkyl group
323
An alkyl bond can form b/w a drug and target
- The drug acts as the electrophile
| - The biological partner acts as the nucleophile
324
What are some example of the biological nucleophiles
- An alcohols
- An amine
- A thiol
325
What are some example of the electrophile?
Usually a carbon with a positive charge or an electron poor carbon
326
Alkylation examples
L17, pg 21 & 22
jhghjklkjh
327
What is acylation?
- Transfer of an acyl group molecule
328
Acyl bond can form b/w drug & target
- The drug acts as the electrophile
| - The biological partner acts as the nucleophile
329
Proteins are non branching polymers that form ...
Composed of linear sequence of (chiral) ... ... covalently linked via amide (peptide) bonds (blue)
Proteins are very large and .... (compared to small molecules)
Proteins are non branching polymers that form MACROMOLECULES
Composed of linear sequence of (chiral) AMINO ACIDS covalently linked via amide (peptide) bonds (blue)
Proteins are very large and UNSTABLE (compared to small molecules)
330
Biologics as Large Molecules
What are some products?
- Functional proteins & polypeptides
- Vaccines
- Combination products
331
Large Molecules can be digested
... Are readily digested in our GI tract
Large Molecules can be digested
PROTEINS Are readily digested in our GI tract
332
Protein therapeutics
* Proteins are very large and ...
* Structure held together by ... (mostly noncovalent) forces
- H-bonding, electrostatic interactions
* Easily destroyed by relatively mild ... conditions
* Easily destroyed by the body - ... - ....
Protein therapeutics
* Proteins are very large and UNSTABLE
* Structure held together by WEAK (mostly noncovalent) forces
- H-bonding, electrostatic interactions
* Easily destroyed by relatively mild STORAGE conditions
* Easily destroyed by the body - HYDROLYSIS - PROTEASES
333
Protein therapeutics
* Biologics are more ... (easily broken down) than small molecules
* Require ... storage
* ... & ... consuming to manufacture
* Often produced in .... batches
Protein therapeutics
* Biologics are more LABILE (easily broken down) than small molecules
* Require LOW-TEMP storage
* COSTLY & TIME consuming to manufacture
* Often produced in SMALL batches
334
Protein Stability
Common issues
- Light, heat, air, trace-metal sensitivity
335
Protein Stability
Degradation Issues
Name some Noncovalent & Chemical (covalent)
L20, pg 14
Noncovalent
- Denaturation
- Aggregation
- Precipitation
- Adsorption
Chemical (covalent)
- Deamidation
- Oxidation
- Disulfide exchange
- Proteolysis
- Glycosylation
- Base catalyzed racemization (of chiral amino acids)
- Beta elimination
336
Protein Stability - Denaturation
L20, pg 16
fcyvguh
337
Protein Stability - Aggregation
L20, pg 17
- Formation of macromolecular complexes
- Covalent/hydrophobic association
- Affect binding/activity
- Irreversible
- Immunogenic
- Delivery
338
Protein Stability - Factors affecting Aggregation :
* Exposure to different interfaces in production
- Liquid - air, liquid-solid, liquid-liquid
* Mechanical stresses
- Stirring/pumping
* Interaction w/ metal surfaces
- Presence of other molecules
339
Protein Stability
L20, pg 19
- Adsorption
| - Precipitation
340
Protein Stability - Oxidation
* Protein is altered ...
* Occurs on individual amino acid side chain due to?
Protein Stability - Oxidation
*Protein is altered CHEMICALLY
* Occurs on individual amino acid side chain due to?
- AIR (OXYGEN)
- PEROXIDE
- LIGHT
341
Protein Stability - Oxidation
L20, pg 23
Most susceptible amino acids
- Methionine - oxidation of the sulfur
- Cysteine - oxidation of the sulfur
342
Protein Stability - Oxidation
L20, pg 24
Tyrosine - results in covalent aggregation; addition of hydroxyl groups
Tryptophan - becomes reactive
Histidine - generate additional hydroxyl species
- Can lead to the cleavage of the aromatic ring
- These are all aromatic ammino acids
343
Protein Stability
Photo-Oxidation can lead to changes in what structures of proteins?
- Primary
- Secondary
- Tertiary
344
Protein Stability - Deamidation
Occurs with?
Results in?
Occurs with?
- Asparagine (Asn)
- Glutamine (Gln)
Results in?
- Aspartic acid (Asp)
- Glutamic acid (Glu)
345
Degradation issues - Proteolysis
Proteolytic ... will occur
Result in .... of protein
Degradation issues - Proteolysis
Proteolytic HYDROLYSIS will occur
Result in FRAGMENTATION of protein
346
Proteins in vivo
L20, pg 28
- Proteolysis (enzymatic)
- Small proteins (<30kDa) filtered by the kidneys
- Allergenic (reactions)
- Loss due to insolubitlity / adsorption (syringe)
- not the advertised conc.
347
SWOT analysis
- read over
L20, pg 29
- Strengths
- Weaknesses
- Opportunities
- threats
348
Gene therapy definition:
Gene tharapy involves the introduction of genetic material into an individual, or the modification of the individuals genetic material, in order to achieve a therapeutic objective
349
Gene therapy aims to cure disease caused by genetic defects by changing gene expression
- Model
L21, pg6
dfghbj
350
Read the introduction to gene therapy on L21, pg 7
- gene therapy uses sections of the nucleic acid deoxyribonucleic acid (DNA) to treat or prevent disease
- The DNA is carefully selected to correct the effect of a mutated gene that is causing disease
- Gene therapy is a promising treatment option for some genetic disease, including muscular dystrophy and cystic fibrosis, sickle cell anemia, hemophilia, and severe combined immunodeficiency
- high hopes however limited success
351
Gene therapy techniques - Gene replacement therapy
Used to:
Aim:
Model on L21, pg 14
- Used to treat diseased caused by a mutation that stops gene from producing a functioning product, a protein
- Aim: add DNA containing a functional version of the lost gene back into the cell
352
Gene therapy techniques - Gene inhibition therapy
Suitable for:
Aim:
model on L21, pg 15
- Suitable for the treatment of infectious diseases, cancer and inherited disease caused by inappropriate gene activity
- Aim to introduce a gene whose product either: inhibits the expression of another gene
353
Gene therapy techniques - Gene cell killing therapy
Suitable for:
Aim:
Model on L21, pg 16
- Suitable for disease such as cancer that can be treated by destroying certain groups of cells
- Aim is to insert DNA into a diseased cell that causes that cell to dies
354
What are the main clinical indications addressed by gene therapy?
- Cancer diseases
- Monogenic diseases
- Infectious diseases
- Cardiovascular diseases
355
How does gene therapy work?
- A vector delivers the therapeutic gene into a patients target cell
- The target cell become infected with the viral vector
- The vectors genetic material is inserted into the target cell
- Functional proteins are created from the therapeutic gene causing the cell to return to a normal state
356
Viral vector
Advantages:
Disadvantages:
Viral vector
Advantages:
- High uptake into cells
- Can be modified to target specific cells
- They are modified so dont replicate and kill the target cell
Disadvantages:
- Gene size is limited
- Patients immune response to the virus results in poor response
- Potential to integrate into genome causing disease (cancer)
357
Non-Viral vector
Advantages:
Disadvantages:
Non-Viral vector
Advantages:
- No immune response
- Easily formulated and assembles
- Cheaper
- Gene size not limited
- Cell/tissue targeting
Disadvantages:
- Low levels of gene expression
358
Somatic gene therapy definition:
Germline gene therapy definition:
L21, pg 35
cdvfdgfhg
359
Challenges to gene therapy:
- Delivering the gene to the right place and switching it on
- Avoiding the immune response
- Making sure the new gene doesnt disrupt the function of other genes
- The cost of gene therapy
360
Recognize different macromolecules as drug targets:
L22, pg 9
- Micro organism
- Proteins
- DNA
361
Drug .... are found inside cells, cell membranes, or on the cell surface
Drugs ... with macromolecules (eg protein, DNA) --> "binding"
Action occurs at ... ... (eg active site of an enzyme)
L22, pg 10
Drug TARGETS are found inside cells, cell membranes, or on the cell surface
Drugs INTERACT with macromolecules (eg protein, DNA) --> "binding"
Action occurs at BINDING SITE (eg active site of an enzyme)
362
Drug - Protein Interactions - Covalent bond
* Drug can interact with an "... ..." of ... eg nucleophile R-OH (serine)
- Forming a ... ....
- Bond resulting from the sharing of electrons b/w atoms
.... Chemical bond formation, often ....
Bond energies strength
L22, pg 11
Drug - Protein Interactions - Covalent bond
* Drug can interact with an "ACTIVE SITE" of ENZYME eg nucleophile R-OH (serine)
- Forming a COVALENT BOND
- Bond resulting from the sharing of electrons b/w atoms
NEW Chemical bond formation, often IRREVERSIBLE
Bond energies strength: 200 - 400 kj mol-1
363
L22, pg 12
crvgtbh
364
Drug - Protein interactions - Intermolecular Bonds
Name the Non-covalent interactions:
L22, pg 13
- Electrostatic/ionic
- H-bond
- van der waals (hydrophobic interactions)
- - Dipole-sipole & ion-dipole
365
Intermolecular bonding - Electrostatic or Ionic Bonds
... Intermolecular bond (20 - 40 kj mol-1)
Attraction of ... charges (think ionised)
L22, pg 14 & 15 & 16
Intermolecular bonding - Electrostatic or Ionic Bonds
STRONGEST Intermolecular bond (20 - 40 kj mol-1)
Attraction of OPPOSITE charges (think ionised
366
Intermolecular Bonding - Hydrogen Bonding
- Attractive force b/w ... & ....
- HBD - hydrogen linked (covalently) to an .... atom
- HBA - atoms w/ ... .... (electron rich, electronegative)
L22, pg 17 & 18 & 19 & 20
Intermolecular Bonding - Hydrogen Bonding
- Attractive force b/w H-BOND DONOR & H-BOND ACCEPTOR
- HBD - hydrogen linked (covalently) to an ELECTRONEGATIVE atom
- HBA - atoms w/ NBP ELECTRONS (electron rich, electronegative)
367
Intermolecular Bonding
Drug - DNA Minor Goove bindong
Minor Groove binding
- Drug makes ... bonding interactions
Intermolecular Bonding
Drug - DNA Minor Goove bindong
Minor Groove binding
- Drug makes HYDROGEN bonding interactions
368
Intermolecular Bonding - Van der waals interactions
* Very ... (2 - 4 kj ol-1) interactions (London Dispersion forces / Hydrophobic interactions)
* Interactions b/w .... regions of different molecules
- eg aliphatic substituents
* "electronic distribution" is never even, transient areas of low & high electron densities
- ... ....
* These temporary dipoles induce the same on other .... (think magnets)
L22, pg 22 & 23 & 24 & 25
Intermolecular Bonding - Van der waals interactions
* Very WEAK (2 - 4 kj ol-1) interactions (London Dispersion forces / Hydrophobic interactions)
* Interactions b/w HYDROPHOBIC regions of different molecules
- eg aliphatic substituents
* "electronic distribution" is never even, transient areas of low & high electron densities
- TEMPORARY DIPOLES
* These temporary dipoles induce the same on other MOLECULES (think magnets)
369
Intermolecular Bonding - π - π stacking
* π Stacking - ... interactions - also alkenes
* Classic example ....; purine/pyrimidine bases
L22, pg 26
Intermolecular Bonding - π - π stacking
* π Stacking - AROMATIC interactions - also alkenes
* Classic example DNA; purine/pyrimidine bases
370
π - π stacking
Benzene
- Greater ... ... on the face (π orbitals)
- Reduced .. ... on the edge
L22, pg 27
π - π stacking
Benzene
- Greater ELECTRON DENSITY on the face (π orbitals)
- Reduced ELECTRON DENSITY on the edge
371
Intermolecular Bonding - π - cation interactions
L22, pg 28 & 29 & 30
xrdtcfygui
372
Intermolecular Bonding - Dipole-dipole & ion-dipole interaction
* Molecules w/ ... dipoles eg ketone
* Local dipole present in .. ...
* Charged / ionic group interacts w/ a ... in a second molecule
L22, pg 31 & 32
Intermolecular Bonding - Dipole-dipole & ion-dipole interaction
* Molecules w/ PERMANENT dipoles eg ketone
* Local dipole present in BINDING SITE
* Charged / ionic group interacts w/ a DIPOLE in a second molecule
373
Intermolecular Bonding Terminology
L22, pg 33
cfegtry
374
Intermolecular Bonding - Repulsive interactions
* Stops molecules ... w/ each other
* Orbitals overlap when molecules come together: ...
* Two like charges are ...
L22, pg 34 & 35
Intermolecular Bonding - Repulsive interactions
* Stops molecules MERGING w/ each other
* Orbitals overlap when molecules come together: REPULSION
* Two like charges are REPELLED
375
Intermolecular Bonding - Water & Hydrophobic interaction
L22, pg 36
efregthyt
376
Drug - Protein/DNA interactions
L22, pg 37
rgehty
377
Metal Coordination
L22, og 38
cdfgty
378
Drug - DNA interactions
L22, og 39 & 40
fchgvjbk
379
4 types of receptors:
L23, pg 5
1) Ligand gated ion channels (ionotropic receptors)
2) G-protein-coupled receptors (metabotropic)
3) Kinase-linked receptors
4) Nuclear receptors
380
Receptors as drug targets - briefly look
L23, pg 7 & 8 & 11
edrt
381
receptors as Drug targets - Briefly look
Receptor activation
L23, pg 12
rghtyu
382
Ligand-gated ion channels
Examples:
L23, pg 14 & 15
- Nicotinic acetylcholine (Ach) receptor (nAChR), gamma-aminobutyric acid type A (GABAA)
383
Ligand-gated ion channels Ionitropic receptors
L23, pg 16 & 17
sefgrt
384
G-protein coupled receptors
L23, pg 20 & 21 & 22
dxfgfchgvj
385
What is the structure of GPCRs?
- 7 membrane spanning helices
| - Conserved structure
386
GPCRSs
L23, pg 24
efrgt
387
Examples of GPCR receptors:
- Dopamine
- Histamine
- Muscarinic (acetylcholine)
- Opioid (peptides)
- Adrenaline
- Peptide hormones
388
GPCRs summary
L23, pg 26
dfesrdgtfy
389
Types of receptors - Kinase-linked receptors
L23, pg 28 & 29
wdqefr
390
Kinase-linked receptors Summary
- L23, pg 30
sdfxgfchgvjh
391
Nuclear receptors
- L23, pg 32 & 33 & 34
ewfag
392
Nuclear receptors
L23, pg 36
xdfgchv
393
Nuclear receptors
L23, pg 37 & 38
edwfrgt
394
Receptor Summary L23, pg 39
edfw
395
Other Drug Targets - DNA / RNA
L23, pg 40
frgerfw
396
Other Drug Targets
- "other proteins"
L23, pg 41 & 42 & 43
e3rgbvfcd
397
Drug-receptor interaction
What is drug affinity?
What contributes to how well a drug binds to a receptor?
- The physical interaction b/w the drug and receptor
- Drug AFFINITY measure how strongly a drug interacts w/ the receptor
- Both the on and off rates
398
Law of mass Action
* Same principle as a ... ... in equilibrium (eg proton dissociation equilibrium for pKa)
* Assuming .. and ... interact in a reversible manner
* Kon is proportional to the concentration of ... and ...
* Koff is proportional to the concentration of ...
L24, pg 9
Law of mass Action
* Same principle as a CHEMICAL REACTION in equilibrium (eg proton dissociation equilibrium for pKa)
* Assuming DRUG and RECEPTOR interact in a reversible manner
* Kon is proportional to the concentration of D and R
* Koff is proportional to the concentration of DR
399
Dissociation binding constant (Kd)
Kd also referred to as the "... ... .."
Kd is measure ...
Kd has the unit ... (molar)
L24, pg 10
Dissociation binding constant (Kd)
Kd also referred to as the "EQUILIBRIUM DISSOCIATION CONSTANT"
Kd is measure EXPERIMENTALLY
Kd has the unit M (molar)
400
Dissociation binding constant (Kd)
L24, pg 11 & 12
efwrfred
401
Drug-receptor interaction - Graphing drug-receptor interactions
If [D] equals Kd then?
What does this mean?
L24, pg 13
Drug-receptor interaction - Graphing drug-receptor interactions
If [D] equals Kd then?
- [R] and [DR] must be equal
What does this mean?
- This means that half of the receptors are free and half are bound to D
402
Drug--receptor interaction - site of interaction
The orthosteric binding site:
The allosteric binding site:
L24, pg 14
The orthosteric binding site:
- The site that the receptors endogenous ligand binds to
- If a drug binds to the orthosteric site of the receptor we can describe the drug as orthosteric
The allosteric binding site:
- Any receptor site that other than the endogenous ligand binding site
- If a drug binds to any receptor location/site other thanthe orthosteric site we can describe the drug as allosteric
403
Dose-response relationships
L24, pg 15
regt
404
Dose-response relationships
What is a dose-response relationship?
L24, pg 16
- Often depicted as a dose-response curve (log scale, x axis)
- Shows the relation b/w drug dos and magnitude of drug effect
- Drugs vary in effectiveness, we can plot many different effects even for one drug
405
* Agonist definition:
Agonist can have different efficacy
* 'Full' agonist:
* partial agonists:
- A ligand that interacts with and activates a receptor, producing a signal
- Agonist have both affinity and some efficacy
* 'Full' agonist:
- Activate the receptor to the highest response/signal level (full efficacy)
* partial agonists:
- Can only activate the receptor to a lower or lesser extent (lower efficacy) relative to a full agonist
406
Agonists - Dose-response relationship
* A dose-response curve for an agonist reveals the ... & ....
L24, pg 19
Agonists - Dose-response relationship
* A dose-response curve for an agonist reveals the EFFICACY & POTENCY
407
Agonist - dose-response relationship (eg agonist with the same efficacy but different potency)
L24, pg 20
edfrty
408
Dose-response relationship (eg agonist w/ a variety of potency and efficacy)
- L24, pg 21
sxdfcghv
409
What are endogenous agonists?
L24, pg22
Your bodys own agonist, made 'in house
| - Eg dopamine is an endogenous agonist of the dopamine receptor
410
Agonists - What about drugs that are agonists?
* in vivo, most ... ... compete with an ... .... for binding to the receptor. Once bound, a ...'...' occurs
* A non-competitive .. ... (allosteric agonist) binds to a site distinct from the ... .... binding site. It can induce a signal itself or it can attenuate the endogenous agonist signal
* in vivo, most AGONIST compete with an ENDOGENOUS AGONIST for binding to the receptor. Once bound, a RECEPTOR 'SIGNAL' occurs
* A non-competitive AGONIST DRUG (allosteric agonist) binds to a site distinct from the ENDOGENOUS AGONIST binding site. It can induce a signal itself or it can attenuate the endogenous agonist signal
411
Antagonist definition
L24, pg 24 & 25
ewfrt
412
Inverse Agonist
L24, pg 26 & 27
gthyujiuytg
413
Summary
L24, pg 28 & 29
zdxfdgch
414
Ligand binding can change GPCR shape
a) ... binding induces/stabilises an 'active' receptor shape
Agonist binding at the membrane surface side of the receptor changes the ... ... at he inner membrane side
This change of shape is what allows proteins such a G protein to ..., and hence a receptor signal occurs
Ligand binding can change GPCR shape
a) AGONIST binding induces/stabilises an 'active' receptor shape
Agonist binding at the membrane surface side of the receptor changes the RECEPTOR SHAPE at he inner membrane side
This change of shape is what allows proteins such a G protein toBIND, and hence a receptor signal occurs
415
Ligand binding can change GPCR shape
a) Agonist binding induces/stabilises an 'active' receptor shape
Part of the reason for differences in ... and .... b/w different agonists is the stabilisation of a slightly different GPCR confirmation
L25, pg 11
Ligand binding can change GPCR shape
a) Agonist binding induces/stabilises an 'active' receptor shape
Part of the reason for differences in EFFICACY and POTENCY b/w different agonists is the stabilisation of a slightly different GPCR confirmation
416
Ligand binding can change GPCR shape
b) Inverse binding stabilises 'inactive' confirmations
L25, pg 12
frgtbr
417
Ligand binding can change GPCR shape
c) Ligands can bind to different locations of a GPCR
L25, pg 13
cvhgfgh
418
Appreciate change in GPCR shape can result in a signal
* A ligand/drug can have '... ...'
L25, PG 14
Appreciate change in GPCR shape can result in a signal
* A ligand/drug can have 'FUNCTIONAL SELECTIVITY"
419
Appreciate change in GPCR shape can result in a signal
a) G protein mediated signalling
L25, pg 16 & 17
srdtf
420
Appreciate change in GPCR shape can result in a signal
b) B- arrestin mediated signalling
- L25,pg 18
sretdyfugi
421
Appreciate change in GPCR shape can result in a signal
c) Signalling summary and secondary messengers
L25, pg 19 & 20
fghjjhgf
422
Appreciate change in GPCR shape can result in a signal
d) functional selectivity
L25, pg 21 & 22 & 23 & 24
xcghjkl
423
Enzymes as Drug targets - Cycloxygenase (COX)
* .... the converison of Arachidonic acid to Prostaglandin H2
* ... "inhibits" this process
L26, pg 6
Enzymes as Drug targets - Cycloxygenase (COX)
* CATALYSES the converison of Arachidonic acid to Prostaglandin H2
* IBUPROFEN "inhibits" this process
424
Enzymes as Drug targets - Beta lactam antibiotic
L26, pg 8
edrtfyg
425
Enzymes as Drug targets - DD-transpeptidase
* DD-transpeptidase
is an ... involved in cell wall biosynthesis
* Beta-lactam antibiotics "..." this proces
* Beta-lactam antibiotics ... ... ...
Enzymes as Drug targets - DD-transpeptidase
* DD-transpeptidase
is an ENZYME involved in cell wall biosynthesis
* Beta-lactam antibiotics "INHIBIT" this proces
* Beta-lactam antibiotics MIMIC THE SUBSTRATE
426
Enzymes as drug targets - Tamiflu
L26, pg 10
jbhgfd
427
Enzymes catalyse chemical reactions
L26, pg 11 & 13
kjhgfdfgh
428
Enzymes as drug targets - Enzyme inhibitors - L26, pg 15
efsgrt
429
Enzymes as drug targets - Enzymes catalyse chemical reactions
L26, pg 16
kjhgf
430
Enzymes as Drug targets - Definitions
L26, pg 17
easfrgt
431
Enzymes as Drug targets - Enzyme inhibitors
Derived from?
- Substrate (natural/endogenous ligand)
- Product
- Allosteric regulators
432
Enzyme as drug targets - Enzyme inhibitors
L26, pg 20
lkjhgfc
433
Enzyme inhibitors - Competitive inhibition:
If concentration of substrate increases?
L26, pg 21 & 22 & 23
- Inhibitor competes w/ the natural substrate for the active site
- Reversible
If concentration of substrate increases?
- It competes more effectively with the drug for the active site
434
Irreversible inhibitors:
eg inhibitor forms an:
Neither:
Increase substrate concentration will not:
L26, pg 24 & 25 & 26
- inhibitors that bind to the active site and block it permanently
eg inhibitor forms an:
- Irreversible covalent bond w/ the enzyme
Neither:
- Competitive nor non-competitive
Increase substrate concentration will not:
- Reverse inhibition
435
Allosteric (non-competitive) inhibitors
L26, pg 27 & 28 & 29 & 30
- Inhibitors bind reversibly (or irrreversibly) to the allosteric site
- Enzyme can be naturally regulated by allosteric binding
- Can cause induced fit or conformational (shape) change in the active site
- Substrate cannot recognise. the active site
436
Competitive - Transition-state inhibitors
L26,pg 31 & 33 & 34
lkjhgf
437
Enzy,e as Drug targets - Enzymes catalyse chemical reactions
- L26, pg 32
kjhgf
438
Enzymes as Drug targets - suicide inhibitors:
L26, pg 35 & 36
Kill the enzyme
| - Inhibits the bacterial enzyme B-lactamase
439
enzymes as Drug targets - Isozyme selectivity
Defintion:
COX targets for ...
COX-1 is:
COX-2 is:
L26, pg 37
- Enzymes that catalyse the same reaction but have different primary sequence
COX targets for IBUPROFEN
COX-1 is: ACTIVE UNDER NORMAL HEALTHY CONDITIONS
COX-2 is: ACTIVATED IN DISEASES SUCH AS RHEUMATOID ARTHRITIS
440
Enzyme inhibitors summary
L26, pg 38
kjhgf
441
Ligand binding
L26, pg 39 & 40 &41
lkjhgf
442
Enzymes & inhibitors L26, pg 42
kjhg
443
Factors affecting drug bioavailability:
- Amount of intact drug which reaches systemic circulation
- Intravenous provides immediate bioavailability
- Oral bioavailability
444
Factors affecting Oral Drug Bioavailability
L27, pg 7
- Absorption
- Transport
- Biological barriers
- Metabolism
- cytochrome P450
- Excretion
- kidneys
- GIT
445
Factors Affecting Drug Absorption
- Route of Administration
- Properties of the drug
- Patient factors
446
Have a wee look at the cell membrane
L27, pg 9
zxcvghj
447
Mechanisms of Drug Absorption
* Absorption requires transport across membranes
* Transport processes include:
L27, pg 12
a) Passive diffusion acrosse cells (transcellular)
b) Passive diffusion between cells (paracellular)
c) Carrier-mediated transport across cells
d) Endocytosis (or pinocytosis)
448
Diffusion
* Diffusion is the process of ... .. of individual molecules of a substance brought about by ... .... .... in response to a ... .....
* The random molecular movement is called ... ... and it allows a particle to move from one part of a container to another
Diffusion
* Diffusion is the process of MASS TRANSFER of individual molecules of a substance brought about by RANDOM MOLECULAR MOTION in response to a CONCENTRATION GRADIENT
* The random molecular movement is called BROWNIAN MOTION and it allows a particle to move from one part of a container to another
449
Diffusion processes - across barrier
Random motion of the molecules:
* from an area of .... concentration (activity) to an area of ... concentration
* a '...." process
* Rate of movement/transfer proportional to ... .... of molecule
L27, pg 14
Diffusion processes - across barrier
Random motion of the molecules:
* from an area of HIGH concentration (activity) to an area of LOW concentration
* a "PASSIVE" process
* Rate of movement/transfer proportional to CONCENTRATION GRADIENT of molecule
450
Ficks laws of diffusion
Ficks first law of diffusion:
Ficks second law of diffusion:
Ficks laws of diffusion
Ficks first law of diffusion:
- Most drugs follow first law
- describes the flow of a material through a unit crosssection of.a barrier in unit time
Ficks second law of diffusion:
- Describes the change in concentration at a particular point in the system w/ time
451
Laws of diffusion
| L27, pg 17
lkjhg
452
Ficks first law of diffusion
L27, pg 18 - Not assessed on the equation - but maybe learn it. IDK.
iuyt
453
Factors influencing diffusion:
L27, pg 19
- Diffusant/drug related factors
| - Medium related factors
454
Passive diffusion in GI tract
* The grater the area A of the barrier, the ... drug absorbed
* Thus absoption from small intestine ..... absorption from stomach:
* The greater the lipophilicity of the drug, the ... it is absorbed
Passive diffusion in GI tract
* The grater the area A of the barrier, the MORE drug absorbed
* Thus absoption from small intestine >> absorption from stomach:
* The greater the lipophilicity of the drug, the FASTER it is absorbed
455
The pH-Partition Theory
* The relationship b/w ...,... at the .... site and the absorption characteristics of drugs in the body
* Drugs are absorbed by passive diffusion of the .... drug only
The pH-Partition Theory
* The relationship b/w pKa, pH at the ABSORPTION site and the absorption characteristics of drugs in the body
* Drugs are absorbed by passive diffusion of the UNIONISED drug only
456
The pH in the various compartments from which drugs can be absorbed or re-absorbed are as follows:
L27, pg 23
- Plasma - 7.4
- Stomach - 1-3
- Small intestine - 5-7
- Colon - 7-7
- Urine - 4.5-8
457
Effect of ionisation
L27, pg 24 & 25 & 26 & 27 & 28 & 29
jhghj
458
Homework - Absorption of acids and bases L27, pg 30 & 32
;kljhg
459
Michaelis-Menton Enzyme Kinetics
L28, pg 6
lkjhgfdsf
460
Concentration Dependence 1 & 2 & 3
Graph
L28, pg 9 & 10 & 11
kjhgfd
461
Facilitated Transport
Same as passive diffusion: High to low concentration, BUT :
- Uses a transport protein
| - eg glucose uses a carrier protein
462
Active transport
L28, pg 13
- Carrier-mediated (active) transport utilises transmembrane proteins (transporters)
- Primary active transport (uses ATP for energy) to pump against the conc. gradient
- eg P-gp export pump important for drug distribution
- Secondary active transport (no ATP used)
463
Membrane Transporters
1) Influx transporters:
2) Efflux transporters:
L28, pg 14
Membrane Transporters
1) Influx transporters:
- Facilitated transport of drung into cell
- High substrate selectivity
2) Efflux transporters:
- ATP energy-dependent transport
- Low substrate selectivity
464
Relevant Subfamilies of Transporters
1) influx transporters
2) Efflux Transporters
- Only really need to know this one
Relevant Subfamilies of Transporters
1) influx transporters
- organic anion & cation transporters (OATs & OCTs)
- Organic anion transporting poplypeptides (OATPs)
- Organic cation transporter novel type (OCTNs)
- Peptide transporter (PepT1)
2) Efflux Transporters
- P-glycoprotein multidrug resistance proteins (P-gp or MDR1)
465
Transporters at the Gut wall
L28, pg 16
dwefgrthyu
466
Transporters at the BBB
L28, pg 17 & 18
kjhjhgv
467
How P-glycoprotein (P-gp) functions and its interactions w/ substrates and inhibitors
L28, pg 20 & 21 & 22 & 24 & 25
cghjhgfg
468
Pharmocokinetics (ADME)
- Drug Absorption (MO27)
How drug reaches blood supply
- Drug distribution (MO28)
- Where does the drug go
- Drug Metabolism (MO29-MO32)
- Enzyme degredation/modification
- Phase I & II metabolism
- Prodrug activation
- Drug Ecretion (MO27)
469
First Pass Metabolism
- This applies to ... ingested by any route other than intravenous injection
- .... metabolism in which tissue(s) metabolise the drug before it reaches the ... .... (blood)
L29, pg 6
First Pass Metabolism
- This applies to XENOBIOTIC ingested by any route other than intravenous injection
- PRESYSTEMIC metabolism in which tissue(s) metabolise the drug before it reaches the SYSTEMIC CIRCULATION (blood)
470
Factors affecting bioavailability:
L29, pg 7
- Non absorption
| - Liver
471
DMEss in the hepatocyte (liver cell)
Metabolism occurs mainly in two sub-cellular organells:
* Phase 1 enzymes & UGT are almost exclusively on the ...
* Phase 2 enzymes (except UGT) are almost exclusively in the ...
DMEss in the hepatocyte (liver cell)
Metabolism occurs mainly in two sub-cellular organells:
- ENDOPLASMIC RETICULUM (ER)
- CYTOSOL (SOLUBLE FRACTION)
* Phase 1 enzymes & UGT are almost exclusively on the ER
* Phase 2 enzymes (except UGT) are almost exclusively in the CYTOSOL
472
Xenobiotic (Foreign Compound) Metabolism
* Xenobiotics are:
* ... .... are metabolised to ... ... compounds to .... their excretion
* Metabolism generally results in .... (detoxification)
* Some compounds are .... by metabolism
Xenobiotic (Foreign Compound) Metabolism
* Xenobiotics are: Foreign compounds consumed into the body
* LIPOPHILIC COMPOUNDS are metabolised to MORE POLAR compounds to FACILITATE their excretion
* Metabolism generally results inDEACTIVATION (detoxification)
* Some compounds are BIOACTIVATED by metabolism
473
The Two Phases of Metabolism
Phase 1:
Phase 2:
L29, pg 18
The Two Phases of Metabolism
Phase 1:
- A new functional group is added to a drug or an existing one is modified
- Reactions include oxidation, reduction & hydrolysis
Phase 2:
- A conjugation reaction in which a polar molecule is transferred from a reactive cofactor to a functional group:
- already present in the drug
- Introduced by a phase ! reaction
474
Types of phase 1 & 2 reactions
L29, pg 19
kjhgfghjk
475
Direct phase 2 metabolism
* What drugs can undergo direct conjugation?
- Carboxylic acid
- Phenol
- Amine groups
476
Phase I: Location of CYPs & UDPGT
L29, pg 21
iuy
477
Microsomal Oxidation
L29, pg 22
kjhgf
478
CYP active site 1
L29, pg 23
lkjh
479
CYP free-redical oxidative mechanism
- L29 pg 25
jhgfghj
480
CYP Nomenclature 2 & Drug metabolising CYP isoforms
The ... & ... families are the most involved in drug metabolism
L29, pg 25 & 26
The CYP3A & CYP2C families are the most involved in drug metabolism
481
CYP450 selectivity
CYP3A4 substrates:
- L29, pg 27
lkjh
482
CYP inhibitors & inducers
L29, pg 29
kjhg
483
The complete ADME picture
- L29 pg 32
fcdaefr
484
Aliphatic (C-H) Oxidation L30, pg 7 & 8 & 9 & 10 & 11
bhjk
485
Benzylic Oxidation & Allylic oxidation- Still aliphatic
L30, pg 12 & pg 13
jhgfghj
486
Alkene & Aromatic oxidation
L30, pg 14 & 15 & 16 & 17
fghjkjhgf
487
Dealkylation
L30, pg 19 & 20 & 21 & 22 & 23 & 24
fergthy
488
oxidation
L30, pg 25 & 26
kjhgf
489
Deamination L30, Pg 27 & 28
dfghj
490
Phase II Conjugation Reactions
Phase II reactions involve:
L31, pg 4
Phase II Conjugation Reactions
Phase II reactions involve: conjugation of a polar group to a drug, toxic xenobiotic or endogenous molecule
491
Enzymes & functional groups
Dont need to memorise this
- L31, pg 5
kjhgfghj
492
Glucuronidation:
L31, pg 6 & 7 & 8
hgfdfghj
493
Types of glucurinides:
L31, pg 9
Types of glucurinides:
- O-Glucuronidation (eg Aspirin)
- N-Glucuronidation (eg Felbamate)
494
Sulfation:
* Important in the transport and metabolism of:
L31, pg 12
- Endogenous compounds
- Phenolic drugs
- High affinity, low capacity enzymes
495
Examples of Sulfation L31, pg 13
iuythj
496
Methylation
* Occurs at the ------ to form metabolites that are equally or more active than the parent compound
* Mainly occurs with .... compounds rather than ...
* Uses the cofactor (...)
* does not always increase ...
L31, pg 14
Methylation
* Occurs at the O, N & S to form metabolites that are equally or more active than the parent compound
* Mainly occurs with ENDOGENOUS compounds rather than DRUGS
* Uses the cofactor (SAM)
* does not always increase POLARITY
497
N- and S- Methylation
L31, pg 15
jhgfdfgh
498
Catechol O-Methyltransferase (COMT)
- COMT transfers a methyl group to the ... & .... phenolic group of catecholamines
- L31, pg 16
Catechol O-Methyltransferase (COMT)
- COMT transfers a methyl group to the META & PARA phenolic group of catecholamines
499
Acetylation:
L31, pg 17
jhghjk
500
Amino Acid Conjugation
Reacts w/ the amino group of an amino acid:
L31, pg 18
- usually glycine
- catalysed by transacetylase
Xenobiotic carboxylic acids are either glucuronidated or conjugated with glycine
- Glycine conjugation is preferred at low doses
- Glucuronidation at high doses
501
Glutathione Conjugation
- (I didn't see it in the assessable tasks)
- L31, pg 19
lkjhgfds
502
Enzyme Polymorphism in DMEs
Individuals can be ... metabolisers (PMs) or ... metabolisers (FMs)
* PMs can experience ...
* FMs can experience ... ...
Enzyme Polymorphism in DMEs
Individuals can be POOR metabolisers (PMs) or FAST metabolisers (FMs)
* PMs can experience TOXICITY
* FMs can experience DRUG FAILURE
503
Poly morphism random shit
(don't really need to learn) Just need the idea kind of
L31, pg 22 & 23 & 24
- Polymorphic enzymes
- Acetylation polymorphism
- Consequences of CYP2D6 PM phenotype
504
Phase 1 Metabolically Activated Prodrugs
L32, pg 4
fgh
505
Benefits of a prodrug
A prodrug may be designed for:
- Improving membrane permeability
- Prolonging activity
- Masking toxicity & side effects
- Varying water solubility
- Drug targeting
- Improving chemical stability
506
Prodrugs can be metabolically activated by:
- Oxidation
- Hydrolysis
- Reduction
507
Oxidation in Prodrug Activation
* ... ... can catalyse activation of prodrugs
* ... group used to mask polar groups
* Improves ... ....
Oxidation in Prodrug Activation
* CYP450 ENZYMES can catalyse activation of prodrugs
* METHYL group used to mask polar groups
* Improves MEMBRANE PERMEABILITY
508
Oxidation in prodrug activation
* Methylation can be used to prolong ... activity
L32, PG 8
Oxidation in prodrug activation
* Methylation can be used to prolong DRUG activity
509
CYP450 Oxidative Prodrug Activation
L32, pg 9
kjhgf
510
Oxidation in prodrug Activation
Aromatic Oxidation:
L32, pg 10
jhgfd
511
Oxidative Decarboxylation
* ... used to improve membrane permeability
* Converted to dopamine by a .... enzyme
L32, pg 11
Oxidative Decarboxylation
* L-dopa used to improve membrane permeability
* Converted to dopamine by a DECARBOXYLASE enzyme
512
Other Types of Metabolically Activated drugs
* Prodrug - group essential for activity is deactivated
* Actvie drug functional group
L32, pg 13
kjhgfd
513
Metabolically Activated prodrugs
* Enalapril
* Lysine ester prodrug of estrone
L32, pg 14
dfghj
514
Metabolically Activated Cancer Prodrugs
* Protease prodrug activation ( metalloproteinases (MMP)
L32, pg 15)
bnm
515
Metabolically Activated Prodrugs - Reduction activated prodrugs
L32, pg 16
ddfghy
516
Self-immolative/Eliminating Linker (SIL)
* Linker built-in b/w the ... and ...
What are the two types of SILs?
L32, pg 18
Self-immolative/Eliminating Linker (SIL)
* Linker built-in b/w the TRIGGER and DRUG
What are the two types of SILs?
- Electronic cascade-mediates
- Cyclisation-mediated
