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Summary 4BBY1040- Fundamentals of Pharmacology
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4BBY1040- Fundamentals of PharmacologyL1: What is pharmacology?
• Pharmacology is the science of drugs. Therapeutics is the medicinal use of drugs whereas
pharmacy is how drugs are formulated. Toxicology deals with harmful effects of drugs.
• A drug is a chemical substance of known structure which produces a biological effect when
administered to a living organism.
• Drugs have a chemical name, common name (ibuprofen) and a proprietary name (nurofen). They
are usually categorised by therapeutic use or mechanism of action.
• They are exogenous molecules which micmic/block the actions of endogenous molecules. Most
bind to target proteins within the body.
• For a drug to be useful it must have high specificity, however no drug has complete specificity
which is why most drugs have side effects.
• Pharmacodynamics (PD) = what the drug does to the body whereas pharmacokinetics (PK) =
what the body does to the drug.
• The fundamentals of PK are absorption, distribution, metabolism and excretion (ADME).
• A depends on the size, lipid solubility, route of administration and chemical stability of the drug.
• D normally occurs by circulation of the blood plasma and diffusion into the ECF, which is
determined by water solubility. Other influencers include circulation of the patient, how well the
drug can bind to proteins in the plasma, and its ability to gain access to the organ.
• The volume of distribution (Vd) is the volume the drug would occupy if the total amount
administered was the same concentration as that found in blood plasma.
• Sometimes we want drugs to be localised to minimise side effects.
• M and E determine how long the drug will last. Drugs are usually metabolised in the liver and
excreted in the kidney.
• A drug’s half life is the time it takes for the plasma concentration (A) to fall by half.
• Clearance is the volume of blood plasma cleared of the drug in unit time.
L2: Sources of drugs and their nature Natural
Hypothesis
• Assay systems are methods used to measure the
products
Compound Potential Assay
Active chemicals
effect of a drug. libraries
Combinatorial
drugs systems
• High-throughput screening allows thousands of chemistry
Chemical optimisation
compounds to be screened per day. Animal
Toxicology testing Pharmacokinetics
• Combinational chemistry involves making a large and
“Safety pharmacology”
models
number of chemical compounds rapidly on a small drug
scale (3 substituents with 2 attachment points will candidate
yield 3 x 3 = 9 different compounds).
• Structure activity relationships (SARs) can be used to optimise the properties of a promising
drug as molecules with a similar structure tend to
have a similar effect. Pre-clinical Clinical Post-market
Discovery
Overall: £250-500 million
• Clinical Trials: Pre-clinical
Phase I
• Phase I is exploratory in humans and another Phase II
mammalian species and checks for potentially Phase III
dangerous side effects and unpleasant symptoms. Phase IV
Patent Patent
• Phase II determines how effective the drug is in granted expires
patients, and to confirm safety and tolerability. It is Generics
0 5 10 15
Page
20
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, split into 2 parts, exploratory and confirmatory.
• Phase III is confirmatory and evaluates how effective and safe the treatment is compared to the
current standard treatment or placebo.
• Phase IV is ongoing after the release of the drug and monitors the consequences of increasing
exposure in tens of thousands of patients.
L3: The concentration-response curve
• There are 3 types of pharmacological
100% 100%
experiments that measure drug effects:
• In vitro: studied on a piece of tissue kept
response
response
alive outside the body. rectangular symmetrical
hyperbola
• In vivo: studied in the living animal/human. sigmoid
• Ex vivo: an animal/human is given the
0% 0%
drug, then a tissue/organ is removed and 0
Drug concentration Log drug concentration
examined in vitro.
• For experiments in vitro, concentration are expressed as Moles per Litre (Molar M). Most drugs
produce a response at very low concentrations.
• When making a cumulative concentration-response curve the drug is not washed out between
different concentrations.
• For experiments in vivo we say the doses are expressed as weight of the drug per weight of the
animal (mgkg-1) as the volume of the blood is not known.
• Emax = the maximum response a drug can produce and the EC50 is the concentration of the drug
at Emax/2.
• Potency describes the concentration at which the drug is effective. The lower the EC50 the more
potent the drug.
• The potency of two drugs can be compared using the potency ratio (M):
M = EC50 (test) / EC50 (standard) or log M = log EC50 (test) - log EC50 (standard)
**If M<1.0 the test drug is more potent
• A bioassay is a technique which is used to measure how much of a drug is present by
measuring a biological response.
100%
• A 2+2 bioassay determines the relative potency of two drugs by
comparing 2 doses of drug A with 2 doses of drug B. drug A
“standard” log ‘M’
• The higher the therapeutic index, the less chance of a drug
response
producing toxic side effects in therapeutic use. drug B
“unknown”
log ‘M’
Therapeutic Index = TD50/ED50
where TD50 = toxic dose in 50% of the population and 0%
ED50 = effective dose in 50% of the population. Log drug concentration
L4: Drug action at receptors
• Receptors recognise/detect extracellular molecules and consequently bring about changes in
cell activity.
• They bind with certain drugs with a high degree of specificity and they are often named with
respect to what drugs they bind to.
Page 2 of 16
, • The affinity of a drug for its receptor is quantified as the molar
concentration of drug required to occupy 50% of the receptors at 100%
equilibrium (KD). Drugs with high affinity have low KD.
Receptors occupied (p)
• KD is the equilibrium dissociation constant. For the reaction:
50%
k1 [DR] k
D + R ⇌ DR KD = = −1
k-1 [D][R] k1
0%
• Agonists bind to a receptor and then activate it, meaning they have Log [D]
efficacy. This induces a conformational change in the receptor which
will lead to a response in the cell/tissue.
• All natural occurring neurotransmitters and hormones are agonists.
• Partial agonists have low efficacy and are therefore less effective at activating receptors.
• Many useful drugs are antagonists and inhibit the effects of drugs.
There are several forms:
response
• Competitive antagonists compete with the agonist for the same site
on the receptor but have 0 efficacy whereas non-competitive In presence of
antagonist
antagonists act on a different site on the receptor.
• Reversible competitive antagonists are often used in medicine and
can be overcome by increasing concentration of the agonist.
Log [agonist]
L5: Measurement of drug action at receptors
• Radioligand binding assays are used to measure the affinity of a new drug by labelling the drug
with a radioactive isotope. This can also tell us the number of
specific binding sites in the tissue. total
(moles per mg tissue)
• This will not produce a rectangular hyperbola graph as we are non-specific
Specific binding
detecting total binding (a mix of specific and non-specific
Bmax
binding).
• To isolate specific binding we introduce a cold, non-radioactive
version of the drug which binds to all receptor sites (non specific
specific sites). We can then subtract this from the total binding KD
value.
Labelled relaxin concentration
• The dose ratio is the ratio of the concentration of the agonist
producing the same sized response in the presence and absence of the antagonist. For
reversible competitive agonists this should increase linearly with concentration of the
antagonist.
• The pA2 is the -log ([molar conc of antagonist]) that produces a dose ratio of 2.
• To construct a Schild plot, produce a graph seen on the right and
response
read the logEC50 values produced. Use these to calculate the EC50
values. Calculate each dose ratio value by multiplying the EC50 of
only agonist with each antagonist EC50. 50%
• The Schild plot will have log [antagonist] as the x axis and log (dose
ratio - 1) as the y axis.
Log
[agonist]
The Schild equation: log (dose ratio - 1) = log ([antagonist]) - log (KB)
Read log EC50 values from here
• Log (KB) is the y intercept of the graph. -log (KB) = pA2.
• If the gradient of the line is not between 0.8-1.2, it is not a reversible competitive antagonist.
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