IDM Flashcards
How long could drug discovery and design and development take for one new drug ?
10-15 years
involves looking at 5000 - 10,000 compounds
costs 2B
What is the chronological order of developing a new drug and bringing it into the market ?
1) Pre- discovery
2) Drug discovery
3) Pre-clinical
4) Clinical trials
5) FDA review
6) scale-up MFG
7) Post- marketing surveillance
How long does each stage in the drug development process actually take ?
Drug discovery and preclinical is 3-6 years
Clinical trials is 6-7 years
FDA review and scale up to MFG is 0.5-2 years
Post marketing surveillance is indefinite.
How many phases are clinical trials made of ?
4 phases
if ya include PMS
how many volunteers in phase 1 clinical trials
20-100
how many volunteers in phase 2 clinical trials
100-500
how many volunteers in phase 3 clinical trials
1000-5000
how many compounds in drug discovery ?
5000-10000 compounds
how many of the compounds from “drug discovery” stage, go into “pre clinical” stage ?
250
How many compounds from the pre clinical stage, make it into clinical trials ?
5
How does disease tend to occur ?
When process in the body has stopped working
or when function is not normal
or when the body has become overactive
Hit molecule identification via
High throughput screening:
where many many compounds are held in these “compound banks” usually in pharmaceutical companies.
compounds are assayed against target to see if there might be a potential match.
Hit molecule identification via
“natural products” :
involves
organic compounds isolated from natural sources, that are produced by primary or secondary metabolism.
- no biological responsibilities in the host
- may lead to enhanced survival traits
What are the 5 “natural sources” :
Plant kingdom (plants)
microorganisms
Marine sources (aquatic life)
Animal sources
venoms and toxins
hit molecule identification via
“natural ligands”:
Molecules that already interact well with protein
can be chemically altered to generate “new hits” ( new matches)
For example, adrenaline and nor adrenaline helped with the development of salbutamol, dobutamine, xamoterol.
why might you have to modify exiting drugs even if they work well ?
For example,
If you would like for them to be consumed in a form that reduces toxic effects.
For example you may have a compound that is great at oral absorption, but intend for your drug to be an inhalation drugs, as this would be more effective at reducing toxicity.
One advantage of mustard gases ?
Mustard gases were further optimised to treat leukaemia
( condition where number of white blood cells increases rapidly)
What does “SAR’s” stand for ?
Structure activity relationships.
Whats the next stage after hit molecule identification ?
Lead molecule optimisation
Result of this is identity of 5 molecules with desired properties,
But not perfect.
Whats after lead molecule optimisation ?
Candidate selection stage
Brief description of “candidate selection” stage ?
This is where a molecule is selected for the “pre-clinical” stage
The main focus is to investigate toxicity
What does “candidate selection” stage involve ?
- in vitro tests on cells and in-vivo tests on animals
to investigate whether the compound has any effect on reproduction
and to identify potential carcinogens which would prevent any further development of the candidate.
- toxicity testing ( Acute toxicity and Long term toxicity testing)
Administering large doses to find out what the toxicity level is.
What is a “prodrug” ?
When a drug is “in-active” but after intake is METABOLISED into a pharmologically active drug.
( when metabolite formed is more active than the parent compound)
What’s another thing that is considered at the candidate selection stage ?
Formulation of the drug
combination of API
and
excipients
What is an “excipient” ?
An inactive substance that serves as the vehicle or medium for a drug or other active substance.
What are the 3 main regulatory bodies with regards to regulatory affairs ?
FDA USA ( Food and Drug Administration)
EMEA ( European Agency For the Evaluation of Medicinal Products).
MHRA (Medicines and Healthcare products Regulatory Agency)
Whats an “IND” ?
Investigational exemption to a New Drug application
Whats an NDA with relation to drug development process ?
NDA ( New Drug Application)
NDA will go to FDA
But an MAA ( Marketing authorisation application) will go to the EMEA.
( Large document with all the research)
What kinda drug tends to fly through drug development process ?
Orphan drugs
What is an orphan drug ?
New drugs that can treat diseases, that have never been able to be treated before.
What’s the final step for a medicine in the UK which has been successfully licensed and put on the market ?
Cost vs Benefit analysis
carried out by “ NICE”
national Institute for Health and Clinical Excellence.
- they decide whether the NHS should pay for novel drugs
- and decide if they are fine to be prescribed to patients or not.
What’s a novel drug ?
A drug that is molecularly distinct from prior drugs.
What is the general chronological order for “cheminformatics” ?
1) Candidate Drug library
2) Molecular modelling
3) Property profiles generated
4) Computational screening: to see if there or how much toxicity there is.
Advantages of cheminformatics ?
Fast
Low cost
Reduces animal testing
unsuitable cadidates ( too toxic) can be identified and rejected.
Can handle huge amounts of data
Disadvantages of cheminformatics ?
Predictions may sometimes be inaccurate
Need to develop/buy a arsenal of predictive models
complex software interface may put people off
Cheminformatics is not a “stand-alone” approach.
What is “repositioning” ?
Finding new uses for existing drug compounds
What is “orbital hybridisation” ?
When atoms hybridise ( Mix) in order to optimise geometry
And minimise the energy ( this is a good thing)
And produce orbitals with same energy level.
what are the 3 types of hybridisation states ?
sp, sp^2 , sp^3
Easy way to find out the hybridisation state of an atom ?
sp ^ (3-n)
Where “n” is the number of pi bonds associated with the atom.
what shape is 4sp^3 orbital ? (Hybridisation)
Tetrahedral shape 109.5 degrees
This shape allows the orbitals to be far apart from each other and therefore have the lowest possible energy.
What are sigma bonds ?
Single bonds
Are free to rotate
What are pi bonds
Double bonds
not free to rotate
What shape is 3sp^2 (Hybridisation)
Flat triangular shape
90 degrees
What shape is 2sp ( Hybridisation)
Linear
180 degrees
Briefly describe the structure of benzene ?
3 double bonds
3 single bonds
flat hexagonal shape
each bond in the same length
What is the hybridisation type of each carbon in benzene ?
sp^2
Is it good if the electrons are far apart from each other as possible ?
yeahhhhhhhhhhhhhhhhhhhhhhhhhhh
what is VSEPR theory ?
All it means is
Repulsion.
Resulting in electrons being far apart from each other as possible.
With regards to bond length, what does more “pi bond” mean ?
Decreased bond length.
more pi bond also tends to mean more “bond energy”.
What is “bond order” ?
The NUMBER of bonds between atoms.
What has greater bond angle, double bonds or single bonds ?
Double bonds.
due to greater repulsion
What are “structural isomers” ?
Different compounds with same molecular formula but different structural arrangement.
Stereoisomerism def ?
Same structural formula, different spatial arrangement.
What are the two types of stereo-isomers ?
1) Enantiomers
2) Diastereoisomers
Enantiomers def :
Non super imposable mirror images stereoisomers.
Is wedge line towards/away from you ?
WEDGE= TOWARDS
WEDGES COME TOWARDS US TO BE EATEN
Is dashed line towards/away from you ?
Away from you
What’s a “racemic mixture” ?
Contains 50% of each enantiomer
optically inactive
as they cant rotate plane polarised light.
What are a “pair of enantiomers” known as ?
Optical isomers
as they can rotate plane polarised light.
clock wise ppl rotation =
D enantiomer (+)
Anti-clockwise ppl rotation =
L enantiomer (-)
A sample that only contains ONE ENANTIOMER is known as what ?
homochiral / enantiomerically pure
what is a conformer ?
A compound that uses thermal energy to rotate it’s single bonds.
To visualise conformers we use New mans projection.
Difference between “conformation” and “configuration” ?
conformation is rotation of bonds
configuration is the breaking of covalent bonds.
What are the 2 different types of receptors that acetylcholine acts as ?
Nicotinic
and
Muscarinic receptors
how many conformers does cyclopropane have ?
ONE
chair vs boat (conformers) :
chair ( hydrogen more staggered/spread out)
boat ( hydrogens more eclipsed)
what are the 2 types of amino acids ?
L- amino ( Naturally occurring and are present in proteins, formed during translation in the ribosome)
D-amino ( rare and only found in some proteins by enzyme posttranslational modifications)
What are diasteroisomers ?
steroisomers that are not enantiomers
they idffer in physcial properties
How to find the maximum number of stereoisomers a compound can have ?
2n
where “n” is the number of chiral centres.
Solution def ?
A one phase system which consist of solute molecules dissolved in a solvent vehicle.
Solute def ?
A substance which is dissolved in solution.
Less solute than solvent present.
Solvent def ?
A substance that is used to dissolve a solute
Dissolution def ?
Mixing of solute and solvent to get solution.
What is an “amorphous solid” ?
Non - crystalline solid
- lacks order
If a substance is soluble in water, is it polar or non-polar ?
Polar
What is maximum solubility / equilibrium solubility ?
The maximum amount of solute that can be dissolved in a solvent under specific conditions.
Difference between molarity and molality ?
(solubility expressions)
Molarity: Number of moles of solute in one litre
Molality: Number of moles of solute in one kg
How does water get it’s polarity ?
The high electronegativity of oxygen compared to hydrogen, means that electrons are unequally shared, causing partial charges
giving water its polarity
How many “lone pairs” does water have ?
2
How many lone pairs on water are actually “available” ?
ONLY ONE
Non polar solvents:
Contain bonds between atoms with similar electronegativities
What are the 9 different factors that affect solubility :
1) Temperature
2) Kinetic energy
3) Pressure
4) Melting point
5) Molecular shape and symmetry
6) Molecular weight
7) Hydrogen bonding
8) Types of functional groups (Polar/non polar)
9) pH
How does an increase in temperature affect solubility ?
increases it
How does increase in kinetic energy affect solubility ?
increases it
By causing solute dispersion to increase and exposing solute to fresh solvent faster.
How does increasing pressure affect solubility ?
NO EFFECT, for solid and liquid systems
but there is for gases.
What does high melting point with relation to solubility ?
Normally compounds with a high melting point have LOW solubility.
Are symmetrical molecules more or less soluble than un-symmetrical molecules ?
less
- molecules pack closer together with stronger intermolecular forces
this results in higher melting points
which results in low solubility.
How does an increase in molecular weight affect solubility ?
Decreases solubility
Increasing molecular weight increases “non-polar” nature.
In pharmaceutical industry with regards to molecular weight and its affect on solubility, what is the rule of thumb ?
Less than 500 Da is low solubility.
More than 1200 Da should be avoided.
1 Da = 1 g/mol
How does hydrogen bonding affect solubility ?
Increased hydrogen bonding = increased solubility
How do polar functional groups affect solubility ?
Increase it
How do non-polar functional groups affect solubility ?
decrease it
they increase hydrophobic nature and disrupt hydrogen bonding with water.
What is “intrinsic solubility” ?
Solubility of unionised solute.
What are “colligative properties” ?
Affects solubility due to the AMOUNT of solute present, rather than the nature of the solid.
What are some examples of colligative properties ?
1) Lowering of vapour pressure
2) Increasing Boiling point and Decreasing Freezing point.
Osmosis def ?
Net movement of water from an area of high water concentration to an area of low water concentration across a partially permeable membrane, down a water potential gradient.
What is osmotic pressure ?
Pressure needed to stop movement of water.
What is “tonicity” ?
Overall
osmotic pressure gradient of both sides of the membrane
Hypotonic vs hypertonic vs Isotonic solution ?
Hypotonic- water will enter the cell and cell will swell and burst
Hypertonic - water will leave the cell and it will shrink and shrivel.
Isotonic- equal amounts of water entering and leaving cell.
Partitioning coefficient formula ?
P = (Non polar - polar) / polar
Log P
- Partioning coefficient only valid for solutes that are not charged.
Apparent partition coefficient :
Is for when the solute of interest is likely to be ionised instead of unionised.
Apparent partition coefficient equation ?
D = P x Fu
D (P app) = Apparent partition coefficient
P = Partition coefficient
Fu = Fraction of unionised drug
What is “Bioavailability” ?
Ability of a drug to be absorbed and used in the body.
What is one method of Log p determination ?
Shake flask method
What is the shake flask method ?
octanol and water are left to equilibrate
a substance is added
flask is shaken mechanically for less than an hour
and left to settle.
concentration of the substance in one solvent is found usually via UV spectroscopy.
Why is Octanol used in Log P determination ?
- used as the non polar solvent
- used because its structure represents the structure of a amphiphilic phospholipid ( phallic head and phobic tail)
- Log P can indicate whether or not a substance can pass through the phospholipid bi layer.
Amphiphilic meaning ?
Contains both hydrophobic and hydrophilic nature
E.g. phospholipids
What is the range of the dose administered in therapeutic dose ?
50 - 500 mg of API per dose
What actually is “pharmaceutical formulation” ?
Combination of API’s and Excipients
What are “excipients” ?
Inert ingredients, that are used to give the final dosage form ( tablet, capsule, cream etc).
Or to control characteristics of performance of the drug.
4 ways a drug can be eliminated from the body ?
1) Urine
2) faeces
3) sweating
4) exhaled air
Oral administration goes through what type of tract ?
GI tract
3 Advantages of oral administration ?
1) convenient
2) less expensive than other forms
3) Can be modified for extended release
Disadvantages of oral administration ?
1) Not good for unconscious patients
2) requires time for absorption and distribution
3) May be unable to swallow
4) Absorption time may be affected by the food eaten prior.
Common types of excipients used :
Write definitions for each
Filler ( Diluent)- bulk up the tablet
Binder- to hold tablet together and prevent breakage
Disintegrant- promote tablet break down
Glidant- to improve powder flowability
Anti- adherent- provide non-sticking properties
Lubricant- to help in manufacturing
Colourant- make visually appealing
Flavouring agent- improve taste
Filler:
Can increase size of tablets
- Lactose is the most common “filler”
- Filler may not be necessary is the dose of the drug is high
What’s a suitable replacement for the filler Lactose ?
Engineered xylitol
- Great excipient
Has been proven to produce tablets with improved physiochemical and biopharmaceutical properties.
Binder:
E.g. starch paste
Binders help to promote granulation.
Disintegrant :
Helps the tablet to break down into small fragments, when ingested.
- Helps the medicine to dissolve and be taken up by the body so that it can act more quickly.
Glidant :
Improves the flowability of the tablet granules or the powder, by reducing the friction between particles.
Preventing the formation of lumps.
One of the most common is “Aerosil” (0.2 % by weight).
Anti-adherent :
Stop powder from sticking to equipment as the tablet is made.
Lubricant :
Ensures that the tablet has a smooth surface
Reduce friction
Colourant :
Colours recognise your tablet
( Product identification)
More visual appeal
Flavouring agent :
Improve taste of the tablet
For chewable tablets or tablets that dissolve in mouth
- masks the unpleasant taste of API
Advantages of Capsules over liquid dosage forms ?
Lower cost
More stable
Longer half life
Advantages of Capsules over solid dosage forms ?
More elegant
Improved bioavailability
Versatile
Easily prepared and protected from light ( Due to the opaque shell).
3 Advantages of solutions ?
1) Fast absorption
2) Less GI tract irritation
3) Phase separation is not a concern
3 Disadvantages of solutions ?
1) Susceptible to microbial contamination
2) Possible hydrolysis of API
3) Unpleasant taste
What are Suspensions used for ?
Useful for administering insoluble or pooly soluble drugs.
Syrups :
Mask bad taste
Mainly administered to kids.
Used for coughs - Their viscosity allows increased “contact time” with affected areas.
Elixir :
Similar to syrups
Strong
Clear
Sugary - to mask the taste
LInctus:
Coats a soothing film over mucous membrane
Increases production of secretions
sipped slowly
What is Parenteral Administration ?
Any route of administration except GI tract
- Usually injection.
- systemic
whole body distribution.
Advantages of Parenteral administration ?
1) Drug doesn’t pass through intestinal tract
2) fast drug action
3) Eliminates many factors that may affect absorption rates
4) Suitable for unconscious patients.
Disadvantages of parenteral administration ?
1) Invasive
2) May introduce bacteria into the system
3) Painful or scary
What is Injection Fibrosis ?
Complication that may occur if the injections are delivered with
great frequency or improper technique.
Subcutaneous Injection:
Under the skin
Great method of administering insulin
Intradermal injection:
Top layers of skin
not as deep as subcutaneous injection
Intra-articular injection ?
Injecting into a “joint”.
E.g. knee joints
Intraperitoneal injection ?
Injection into the abdominal cavity
Intrapleural injection ?
Into alveoli or lungs.
- Prevents excessive amounts of fluid from building up.
Intravitreal injection ?
Injection into the “vitreous”
jelly like substance in the eye
Topical (local) application :
Contact with skin
Treat surface conditions
2 Advantages of topical application ?
1) Application can be direct to site of action
2) May have a systemic effect.
2 disadvantages of topical application ?
1) Skin acts as a natural barrier - affect the rate and amount of penetration
2) Concentration needed to provide therapeutic effect is difficult to determine.
ointments :
Greasy
used for their “softening effects”
Whats an epidermic ointment ?
Antiseptic ointment
Whats an endodermic ointment
Moisturising ointment
What’s an endodermic ointment
Moisturising ointment
What’s a diadermic ointment ?
Ointment used for “systemic”
Creams :
Less greasy than ointments
due to greater water content
Creams are either oil in water
or water in oil ( greasier than o/w)
Pastes vs ointments ?
Less penetrating
Less greasy
More thick
Pastes:
Good protective barrier when placed on skin
Just like an ointment, it will form,
an “unbroken water-impermeable film”
but the film will be opaque: which means it can be used as sun block cream.
What are gels :
A dispersion of small or large molecules ( gelling agents) in an aqueous liquid vehicle ( jelly)
- semi-solids which liquify on contact with the skin.
- common form of acne preparation
liniments :
fluid or semi solid preparations, that are applied to the skin.
- may contain alcohol
- should not be applied to broken skin.
What are lotions covered with to reduce “evaporation” ?
A waterproof dressing, reduces evaporation.
Poultice ?
A hot paste, thick in texture,
that reduces pain and inflammation.
2 Advantages of inhalation drugs ?
1) Very rapid absorption
2) Targeted directly at the lungs with low level of systemic absorption
2 Disadvantages of inhalation drugs ?
1) Bioavailability depends on inhaler technique
and size of drug particles generated by delivery technique
2) can cause mouth or tongue soreness, or hoarseness of voice
What is a “nebuliser” ?
Medication
- Liquid mist administered to airways
Pumps air through a liquid medicine to turn it into vapour that is inhaled by the patient
Nebulisers are only used for serious cases.
2 advantages of transdermal products ?
Don’t go through first pass metabolism
Fast abruption of drug transfer ( just wipe drug off skin)
Advantage of rectal administration ?
Fast absorption into haemorrhoidal veins, which drain directly into the inferior vena cava
- First pass metabolism is avoided
Disadvantage of rectal administration ?
May not be suitable after rectal surgery
What are the 2 different types of enema ?
1) Evacuant enema: Treat constipation, warmed to body temp b4 administration
2) Retention Enema : Volume does not exceed 100ml, no warming needed
where DOES “OTIC ADMINSTRATION” GO ?
EAR
Why should “oily nasal drops” be avoided ?
You have pilli hairs which trap bacteria and basically due to the interconnections between the earth and uranus the oil is gay
- SamrathSinghGill 2023
What are the 4 different classes of the “biopharmaceutics classification system” ?
Class I High Permeability High Solubility
Class II High Permeability Low Solubility
Class III Low Permeability High solubility
Class IV Low permeability Low solubility
Whats special about Class I drugs ?
Class I drugs are eligible for a “biowaiver” of in vivo bioavailability and bioequivalence
- Which means testing isn’t even necessary for FDA product approval
What actually is “primary manufacturing” ?
Making the API
What actually is “secondary manufacturing” ?
When the API is mixed with other agents,
to create the physical form that is required for drug delivery.
is H3O + the same as H+ ?
Yes
What is the pH range of natural water ?
Between 6.5-8
What is the formula for pH ?
pH = - log [H+]
[H+] =
10^-pH
What is a 10 fold change in hydrogen ion concentration ?
A “unit change” in pH
Whats a base ?
Proton acceptor
Bronsted lowry def:
Donates H+ to bases.
What is a conjugate base ?
Basic form of an acid
If it accepts a proton it will become the acid
What does amphoteric mean ?
Can act as both an acid and a base.
What is a base in terms of electrons (lewis def) :
Base is an electron pair donor
What is an acid in terms of elctrons ( lewis def):
Acid is an electron pair acceptor.
is water amphoteric ?
Yes.
What is the formula for carbonic acid ?
HCO3
Which bases are strong and which bases are weak ?
Hydroxides of Group1 and 2 metals are strong
What is the formula for Ka ?
Ka = [H+] [A-] / [HA]
What is the formula for pka ?
pka = -log10ka
What does a high pka indicate ?
Indicates a low ka and a weak acid
What does a low pka indicate ?
Indicates a high ka and a strong acid.
When [A-] = [AH] :
pH = pka
What is ka:
The dissociation constant for the ionisation of an acid.
What does pka tell us ?
how acidic a given hydrogen atom is
What happens if the pH is higher than the pka ?
Acid is more than 50% dissociated
What happens if the pH is lower than the pka ?
Acid is less than 50 % dissociated
what is the pka of the amino acid Histidine ?
6.0
What is a buffer ?
A solution with a known pH that resists change in pH.
What is the Henderson- Hassel Balch equation ?
pH = pka + log (A - / HA)
Henderson- Hassel Balch equation ?
( Alkaline buffers)
Ka = [H+] [B] / [BH+]
What’s the pH of the blood ?
7.4
Fraction of total ionised drug equation:
Fu = 1 / 1 + 10^(ph-pka)
What is the starting material used to make paracetamol ?
Phenol
as its low cost and readily available
What are the 5 main types of organic reactions:
1) Addition
2) Elimination
3) Substitution
4) Oxidation and reduction
5) Rearrangement
Whats a conjugation reaction ?
When 2 molecules react to form a larger molecule
How is an amide formed ?
Amine + Carboxylic acid -> Amide
Condensation reaction
is Ester hydrolysis a solw or fast reation ?
Slow
Why is Ester used ?
To “mask” and acid
which tends to have poor physiochemical properties.
What do you get when a “CH2 group” is adjacent to a C=O
An enolate
TO end the enless reacting of amines and halogens :
Reductive amination needs to occur
To end the endless reacting of amines and halogens :
Reductive amination needs to occur
What is reductive amination ?
Amine + C=O -> Imine
The imine is then undergoes reduction to form a primary amine
Imines contain a C=N
Whats an “agonist” ?
Something that activates a receptor to produce a biological response
What are the 4 main types of receptors ?
1) Ligand gated ion channels
2) G protein coupled receptors
3) Kinase receptors
4) Nuclear/intracellular response
If something is “endogenous” , what does this mean ?
Produced inside the organism
E.g. acetyl choline (ACh) is a receptor that is endogenous.
Process of ion channels ( Na+ and K+) ?
- ACh binds to receptor, causing ion channel to open, causing the plasma membrane to be more permeable to Na+ and K+ permeability.
2) Inward rush of Na + causes depolarisation to occur.
3) Inside of the plasma membrane is negatively charged compared to the extracellular surface, due to the uneven distribution of Na+ and K+ .
What’s the function of the NMJ ?
To transmit action potentials across motor neurones, across synaptic clefts
What enzyme catalyses the synthesis of ACh ?
Choline acetyltransferase (C.A.T).
Acetylcholinesterase does what ?
breaks down ACh
into acetic acid and choline.
What is one difference between ionotropic receptors and g protein coupled receptors ?
Ionotropic receptors are directly connected to their ion channels,
Whereas, GPCR’s are “indirectly” connected to their ion channels.
GPCR’s may contain…
Disulphide bonds.
What “sub- units” are G proteins made of ?
Alpha, beta and gamma
beta and gamma form a complex together ( Both hydrophobic in nature). Found in plasma membrane.
What are 2 properties of the alpha sub-unit in G-proteins ?
1) Can form a loose association with the Beta-gamma complex
2) Can help to catalyse the hydrolysis of GTP to GDP.
What are the 3 categories of G proteins ?
1) Gs - Stimulation
2) Gi - Inhibition
3) Gq - Activates phospholipase C
Parasympathetic nervous system ?
Rest and Digest system
What type of chemical/hormone bind to “adrenergic receptors” ?
Adrenalin and noradrenaline
What is the most popular thing that binds to a “kinase receptor” ?
Insulin
What bonds hold kinase-linked receptors together ?
Single alpha helix
and
Disulphide bridges
Whats “dimerization” ?
When 2 receptors pair up to form a “dimer”
When this happens autophosphorylation occurs, enhancing kinase activity.
What does SH2 bind to ?
Kinase linked receptors
Once bound they become activated.
What are cytokines ?
Small proteins that are released by cells that have an effect on cell-to-cell interactions.
- Important for co-ordinatiinf cellular communication and behaviour
What are cytokines ?
Small proteins that are released by cells that have an effect on cell-to-cell interactions.
- Important for co-ordinating cellular communication and behaviour
What is cGMP :
Cyclic guanosine monophosphate
- seondary messenger just like cAMP.
- catalysed by nitric oxide
What cells produce insulin ?
Beta cells of the islets of langerhans
Insulin recceptors:
2 alpha sub units
2 beta sub units
Sub-units that contain cysteine residues, enabling the formation of disulphide bridges.
Does insulin bind to alpha or beta sub-unit ?
Alpha
alpha vs beta subunits properties ?
Alpha sub units are Extracellular
Beta sub units are both extracellular and intracellular. The intracellular section has tyrosine kinase activity.
What do nuclear receptors do?
Regulate DNA transcription
What gland produces adrenaline ?
Adrenal glands
located in the medulla
What are “zinc fingers” in nuclear receptors ?
finger shaped poly peptide chains
Why is is called “zinc fingers”
This is because each finger
contains a zinc ion
held by 4 cysteine residues.
What part of protein is the “steroid binding site” ?
COOH end of the protein
What part of the protein acts as the regulatory domain, that can activate transcription of genes ?
NH2
What are the 3 domains of a steriod receptor ?
1) Ligand binding site domain
2) Zinc finger domain
3) Regulatory domain
Are steroids high or low in lipid solubility ?
High
What happens when a steroid binds to a receptor ?
A conformation change occurs (rotation of bonds)
and the receptor unfolds, exposing the zinc finger domain.
What do “mineralocorticoids do” ?
Stimulate the production of transport proteins that are involved with renal tubular function.
What are enzymes (as proteins)
Globular proteins that are biological catalysts
3 step process of enzymes ?
1) Substrate binds to the enzymes active site
2) Enzyme substrate complex is formed
3) Products of the reaction are then released.
What is acetytriethylcholine ?
A false transmitter that is stored in vesicles and then released at the post-synaptic membrane, in place of ACh
producing no depolarisation effect.
What does a “vesamicol” do ?
A drug that prevents ACh from being packed into vesicles.
What do Anticholinesterases do ?
INHIBITS acetylcholinesterase
allowing ACh to stay present in synaptic clefts for longer
What do acetylcholinesterases do ?
Break down acetyl choline
into
acetate and choline
What can be used in the diagnosis of myasthenia gravia (but has no real therapeutic use) ?
Edrophonium (quaternary ammonium compound).
Forms reversible ionic bonds
What is myasthenia gravia ?
Autoimmune disease that causes weak skeletal muscles
What are the 3 areas that are affected by anticholinesterases ?
1) Autonomic cholinergic synapses
2) Neuromuscular junctions (NMJ)
3) Central nervous system (CNS)
parasympathetic OR sympathetic nervous system for sweat gland release ?
sympathetic (stimulated by release of ACh).
What does the “blood brain barrier” do ?
Stops large polar molecules from entering the CNS
Draw backs of anticholinesterase drugs entering the CNS ?
Could cause convulsions, depressive effects
Which could lead to unconsciousness or respiratory faiulre.
What are the initial symptoms of myasthenia gravia ?
diplopia (drooping eye lids).
How does myasthenia gravia come about ?
By destruction of nicotinic receptors at the NMJ.
to treat this disease anticholinesterases are used.
What do monoamine oxidase enzymes do (MAO’s) ?
important for the break down of neurotransmitters
How do MAO inhibitors work ?
By stopping the enzymes from catalysing the oxidation of neurotransmitters in the cytoplasm.
Causing an increased amount of MAO neurotransmitters in neurone terminals,
causing leakage
so the neurotransmitter causes an effect.
Whats an example of an MAO inhibitor ?
Phenelzine
Why can Tyramine be bad ?
Bad
because end up travelling everywhere
replacing noradrenaline from its vesicles
causing NA to leak out of neurones and into synapses. This is lethal son
pharmacokinetics:
What the body does to the drug (ADME)
Pharmacodynamics:
What the drug does to the body
What is intrathecal administration ?
Spinal cord.
Why is parenteral administration good ?
Avoids GI tract (so essentially avoids first pass)
- rapid response
What actually is first pass metabolism ?
Idea that if the drugs in the body for too long,
it may already be metabolised to a different form,
which may be less effective.
Bioavailability formula (F):
F = Amount of drug absorbed by oral administration / amount of drug absorbed by IV administration
oral/IV
What is “half life” ?
Time it takes for plasma drug concentration to fall by half its original value.
Clearance equation:
Clearance = Rate of elimination / plasma drug conc
Zero order kinetics:
Rate of elimination is constant
and not dependent on drug concentration
Axis for half life graph ( T 0.5) ?
X axis = time
y axis = plasma concentration
First order kinetics:
Most drugs eliminated with first order
half life is constant
And rate of Elim is dependent on how much drug is present.
What is C 0 on a graph ?
Plasma conc when time is “zeero”
What is Css(av) ?
Average steady-state concentration
- where dose in is and elimination out is balanced.
What is the “therapeutic window” ?
The right amount of drug required to be effective.
What are the 4 factors that affect how easily drugs are distributed into tissues ?
1) Perfusion rate of tissue (blood flow through tissue)
2) Physiochemical ability of the drug to cross membranes
3) Nature of membranes
4) Extent to which the drug is bound
What is aim of distribution of drug ?
- Achieving steady state of plasma concentration ((suitable for regular dosing) (Distribution equilibrium)
or
- high plasma concentration, followed by removal of drug from the body ( suitable for single dose or after a course of medication)
Partition coefficient :
Is the uptake of drug
The larger the partition coefficient,,,
The longer it takes for distribution equilibrium to be achieved.
Partition coefficient (kp) equation :
Kp = Drug Conc in tissue / drug conc in blood
What crosses membrane easier, ionised or unionise drugs ?
unionised
To remove a drug via urine what characteristics are required
Water soluble (so drug can dissolve in water).
Alkaline drugs in a high pH are ? ( lipid solubility)
High lipid solubility- so are readily transported.
Acidic drugs in a low pH are ?
lipid soluble- readily transpoorted
Alkaline drugs in a low pH ?
less lipid soluble- not readily transported.
Acidic drugs in a high pH ?
Less lipid soluble.
one way to remember these 4 things are : IF IT MATCHES NATURE, THEN IT IS LIPID SOLUBLE.
Only unbound drug is…
free to distribute into tissues.
Does drug protein binding result in any pharmacological effect ?
no
In distribution what are the 2 types of R’s
R1 : delivery of drug to tissue depends on perfusion rate.
R2: Passage of drug across membrane, depends on physiochemical properties and nature of membrane.
Volume of distribution (Vd) equation :
Vd = amount of drug in body / amount of drug in blood
Vd tells how the drug is distributed across large compartments.
Where are lipid insoluble drugs normally ?
Normally confined to
plasma and interstitial fluid.
What is drug metabolism ?
Converting a lipid soluble drug into a more WATER soluble drug.
What are the 2 phases involved with drug metabolism ?
1) Phase I
2) Phase II
Phase I metabolism ?
Makes drug more water soluble
But main purpose is to prepare the drug for Phase II
Phase I metabolism (types of reactions) :
Oxidation and reduction
- hydrolysis
What is a prodrug:
Any compound that is metabolised in the body to yield a pharmacologically active compound.
Phase II metabolism :
Where a large water soluble molecule is joined onto a phase I metabolite.
Increasing water solubility even further.
What is the enzyme for “sulphate conjugation of paracetamol” ?
Cytochrome P450 located in the smooth endoplasmic reticulum of the liver.
What are acetylators and oxidators ? (metabolism) (pharmacokinetics)
fast and slow respectively
What are 3 main words that describe the properties of drugs ? (pharmacodynamics)
1) Affinity: How well a drug binds to a receptor.
2) Efficacy: how well it is making it do what it’s supposed to.
3) Specificity: how selective a ligand is. (specificity may be dependent on dosage used).
What type of forces attracts the drug to a receptor
elctrostatic forces.
Agonist vs Antagonist ?
Agonist: promotes the binding between a receptor and molecule
whereas,
Antagonist: Reduces the actions of agonists. (e.g. by blocking recceptors).
What is Emax ?
The estimated maximum response of a drug
What is EC 50 ?
The concentration required to produce 50% of max response.
Log dose response curves ?
As drug becomes LESS potent
curve shifts to the right
EC 50 value increases.
Competitive Antagonism:
Competitive antagonists bind selectively to receptors, but do not activate anything, instead they just BLOCK receptors.
Competitive antagonists have AFFINITY but NOT EFFICACY
- they binds reversibly with receptors
- in the presence of these, the amount of agonist molecules occupying receptors is reduced.
Why can competitive antagonism be seen as “surmountable” ?
Because it can be overcome by adding more agonists.
Agonist Dose response curve ?
Curve shifts to the right with increasing ANTAGONIST conc
Dose Ratio equation (EC 50) :
Dose Ratio = EC 50 [Antagonist] / EC 50 [no antagonist]
What is the aim of safety pharmacology ?
To characterise the Pk/PD relationship of a drugs adverse effects.
And predicts whether a drug is safe or not and how to manage the safety
PMS ?
Post marketing surveillance
- on a drug to confirm existence of adverse effects.
What is SRS ?
Spontaneous reporting system (to do with adverse effects)
Safety Pharmacology (what is prioritised first) ?
Regulatory authorities come first
Then scientific proof comes second
What’s an NCE ?
New chemical entity
What did Paracelsus say ?
“It’s the dosage that makes it either a poison or a remedy
What percentage of A and E emergency care is “toxicity” ?
10%
due to drug overdosing
To what 2 organs is toxicity commonly observed ?
Liver and kidney
Hepatotoxicity:
Toxicity in the liver:
Sometimes reactive metabolites can be formed that are even more toxic than the actual drug.
Hepatocytes get exposed to these toxic metabolites, making toxicity to the liver a commonly encountered ADR.
Whats one way to block certain toxic reactive metabolites ?
By replacing functional groups with atoms such as fluorine
- However, this may effect drug efficacy
Nephrotoxicity:
Toxicity of the kidney
drugs and their metabolites concentrate in the renal tubular fluid as water is reabsorbed,
which means the renal tubules are exposed to high concs of toxicity
What are the 2 main functions of the kidneys ?
1) to reabsorb water
2) To remove waste products from the blood
What are the 4 types of “Drug Exposure” categories ?
1) Acute- less than 24 hrs (single dose)
2) Subacute- 1 month (repeated dose)
3)Sub chronic- 1-3 months (repeated dose)
4) Chronic- more than 3 months (repeated dose)
What are the 2 types of categories ADR’s fall into ?
1) Related (Type A)
2) Unrelated (Type B)
Type A ADR’s :
- related to the drugs pharmacoligical action
- Releated to dose and susceptibility of the patient (how easily they contract disease).
- Type A ADR’s can be predicted
- Usually reversible in nature (by reducing dosage)
Type B ADR’s:
- unrelated to drugs main pharmacological actions
- can sometimes be predicted (when taken in overdose) or when susceptibility is increased
- Mostly unpredictable.
What are idiosyncratic drug reactions ?
IDR’s
- out of the ordinary reactions, that are NOT related to dose.
But are different for different individuals.
What is necrosis ?
Cell death
Are toxic metabolite reactions covalent or non-covalent ?
BOTH
What are the 4 types of non covalent processes that toxic reactive metabolites go through ?
1) Lipid peroxidation
2) Reactive oxygen species (ROS)
3) Depletion of Glutathione
4) Modification of sulfhydryl groups
Lipid peroxidation :
Peroxidation of unsaturated lipids by reactive metabolites or by “ROS”
Lipid peroxyradicals (ROO) can produce hydroperoxides (ROOH) which produce more ROO
CHAIN REACTION^ known as peroxidative cascade
ROS:
Reactive oxygen species
- involves the reduction of oxygen to form a “superoxide anion” (o2 -)
This is then converted to form:
Hydrogen peroxide
Hydroperoxy radicals (ROOH)
hydroxyl radicals (OH)
Oxygen
All are toxic
Glutathione: (GSH)
Gluthathione is an ANTItoxidant.
- Tripeptide containing cytesine, glycine and glutamate units.
What is the function of the GSh redox cycle ?
To PROTECT from “oxidative stress”
caused by For example: toxins or “GSH iso”
Glutathione depletion:
When GSh starts to fall to 20-30% of normal level,
This is bad cuz
cellular defence is greatly reduced and even cell death could occur, leading to severe toxicity.
What are 2 importanat sites for sulfyhydryl groups (SOH) ?
1) Actin
2) Ca 2+
Glutathione: (GSH)
Glutathione is an ANTItoxidant.
- Tripeptide containing cysteine, glycine and glutamate units.
In terms of drug safety what is NOAEL and LOAEL ?
NOAEL: No observable Adverse Effect Level (max dose leading to NO toxicity)
LOAEL: Lowest Observable Effect Level (min conc of a substance needed to elicit toxic effects).
TD 50:
Toxic dose that produces toxic effect in 50 % of test subjects
LD 50:
Lethal dose, that produces lethality in 50% of test subjects.
Therapeutic index equation:
TI = TD50 / EC 50
or could also be LD 50 for lethal dose instead of TD 50
Screening for toxicity:
In vitro tests - rapid screening for large numbers of compounds in a lab
- could generate numerous false positives and false negatives since they’re simplistic models.
most common test used is the “Ames test”
Purpose of a Ames test:
To turn a mutant thing into a non-mutant thing.
Uses salmonella stains of bacteria.
positive test: is seen by the increase in the rate of the revertant near the site where the test chemical is applied.
What is one way to increase the efficiency of Ames test ?
by adding fresh liver extracts.
In vivo tests:
much more reliable as they are whole- animal models complete with complex metabolic processes
However In vivo tests are time consuming and very expensive
And there are interspecies differences to consider
- in vivo tests usually require marketing approval from regulatory authorities.
Examples of common in vivo tests ?
1) COMET assay - identify substances that cause DNA damage
2) Reproductive/developmental toxicity screening test
3) Carcinogenicity studies
What does a combo of in vitro and in vivo tests usually include:
- Ames test
- in vitro test with cytogenetic evaluation of chromosomal damage
- In vivo test for chromosomal damage
- Reproductive/ developmental toxicity testing
- carcinogenicity testing
One way to reduce or replace “ in vivo animal tests” ?
Computational methods
to predict drug toxicity from knowledge of chemical structure alone.
What is a “pharmacophore” ?
The atoms/ functional groups and their relative positions, required for a specific activity to take place.
What is a toxicophore ?
A feature or functional group responsible for toxic properties.
During drug discovery, these must be replaced with other functional groups, in order for compound to pass through clinical trials.
What is thre group that replaces a toxicophere called ?
Isostere or bioisostere
When the pharmocophore and the toxicophore dont overlap, is it easier or harder to replace the toxiccophore ?
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