Table of Contents
ELEMENT 5 – PHARMACOLOGY ......................................................................................... 1
5.1 – 5.4: Mechanisms of Drug Action I-IV .................................................................................. 1
5.5: Enzymes as Drug Targets ................................................................................................... 10
5.6: Introduction of the Autonomic Nervous System ................................................................ 14
5.7 & 5.8: Pharmacology of the Parasympathetic System I & II ................................................. 16
5.9 & 5.10: The Skeletal Neuromuscular Junction ..................................................................... 19
5.11: Pharmacology of the Sympathetic Nervous System ......................................................... 24
5.12: Pharmacology of the Sympathetic Nervous System (2) .................................................... 29
5.13: Pharmacology of the Sympathetic Nervous System (3) .................................................... 32
ELEMENT 5 – PHARMACOLOGY
5.1 – 5.4: Mechanisms of Drug Action I-IV
• What types of effect may a drug give? Beneficial (therapeutic effects) or harmful (side effects or
toxicity)
• What are prophylactic drugs used for? Prevention of a disease or symptom
• What is diazepam? A sedative, who’s brand name is valium
• What is sildenafil? Viagra
• What are the potential problems of drug therapy?
o Insufficiently selective
o The drug changes in structure and function in the body
o Patient variability, especially in age and sex with respect to hepatic system
o Drug interactions
o Idiosyncratic reactions – reactions you don’t know about
• Why is it inappropriate to take ibuprofen on warfarin? Warfarin is a blood thinner, 90% of which
invariably binds to albumin and so doesn’t confer any effect in the body. This is calculated so that
the right about of Warfarin is circulating and conferring a therapeutic effect. Ibuprofen travels in the
body in a similar way, and when you take ibuprofen, it displaces the warfarin on the albumin. This
means that [warfarin] in the blood greatly increases, so your blood won’t clot if you cut yourself and
you can bleed out.
• What is the therapeutic window? Drug concentration when therapeutic effects outweigh the side
effects
• Why do side effects arise from a taking a single drug, once?
o If the drug’s target is too widespread
o If the drug is not selective enough
• How does aspirin work? It inhibits the enzymes COX 1 (present in all cells) and COX 2 (expressed in
damaged cells), and therefore inflammation and pain is reduced. The cyclooxygenase enzymes are
responsible for the formation of prostaglandin, which mediates the inflammatory response (see
element 8)
• Give examples of each of the above?
o Target too widespread – Aspirin, because the COX enzymes also helps form a protective layer
in the stomach. So when you inhibit it you get ulcers.
o Drug not selective enough/other targets exist – Morphine, which causes constipation and is a
respiratory depressant.
,• How was heroine originally sold (fun fact)? Over the counter in Switzerland. It is methylated
morphine that therefore goes into the brain quicker à rush.
• What ways are there to administer a drug?
o Topical
o Inhalation
o Intravenously, intramuscular, subcutaneously
o Orally or sublingually
o Transdermal patch
o Rectally
• What is pharmacodynamics? The effects of the drug on the body
• What is pharmacokinetics? The way the body deals with the drugs
• How are non-polar drugs usually excreted? They’re excreted by the liver as bile, which then leaves
the body in the faeces. Lipophilic drugs are often stored in adipocytes and so can be ‘released’ over a
long period of time
• How are polar drugs usually excreted? By the kidneys, which then leaves the body in the urine
• What reasons could there be for a drug not being as effective as normal? Rapid metabolism,
enzyme induction (when a molecule induces the expression of an enzyme), poor compliance
• What reasons could there be for a drug being more effective than normal? Age, renal impairment,
poor metabolism, enzyme inhibition, drug interaction
• Where in the cell do drugs act?
o Ion channels
o Membrane receptors (main one)
o Intracellular enzymes
o Transporters
• How does tetrodotoxin work? It blocks sodium channels on the outside (compared to local
anesthetics which block on the inside) by binding to the COO- residue (on glu residue of channel)
with its positively charged guanidine group. This prevents action potentials from being produced.
Present in puffer fish and blue-ringed octopus
• How does cocaine work? It blocks the uptake 1 transporter, responsible for the recycling of
noradrenaline. This means that more noradrenaline remains in the synaptic cleft and more Aps are
created. Cocaine’s effects are concentrated in the areas of the brain associated with euphoria.
• How does fluoxetine/Prozac® work? It’s an antidepressant that blocks the reuptake of serotonin à
[serotonin] increases, as do feelings of happiness.
• What evidence is there for the presence of receptors? Langley’s experiment using nicotine (created
muscle twitch) and curare (stopped twitch even when nicotine is present)
• How does curare work? It competitively and reversibly binds to the nAChR receptor, replacing the
nicotine which the receptor needs to function. This prevents the conduction of an AP/muscle
contraction
• What types of receptors are there?
1. Ionotropic – an ion channel with a receptor binding site which opens/closes the channel
(fast)
2. Metabotropic – G-protein coupled receptors (medium speed)
3. Tyrosine kinase receptors – these phosphorylate tyrosine residues and lead to kinase
cascades. Growth factors use this (medium speed)
4. DNA-linked receptors – the slowest type of receptor
• What is the structure of ionotropic receptors?
o 5, sometimes 3, subunits (2x α, 2x β, δ, γ)
o Each subunit crosses the membrane 3 times and has one re-entrant loop
o Each subunit has a ligand binding site at the –NH2 end (extracellular)
o When activated, the subunits rotate, opening a channel
,• What happens to the structure as you develop from a baby? The γ subunit is replaced by a ε
subunit. This makes the channel able to open and close much more quickly, also allowing many
more ions through, conferring fast twitch, precise movements that adults have.
• What is the main neurotransmitter in the brain? Glutamate
• How do G-protein coupled receptors work?
o When the hormone is present at the receptor, the
G protein binds to the receptor
o This causes a conformational change in the G
protein
o The conformational change means that GDP now
has a lower affinity to the α subunit than GTP
does.
o GTP displaces GDP on the α subunit
o This causes a conformational change which
means that the α subunit dissociates from the
rest of the G protein.
• Which subunit(s) confer specificity? The α subunit, as its either αs, αi or αq
• Which subunit(s) takes part in the reaction? Either the α subunit (see element 4) or the β/γ dimer,
depending on the reaction
• What do the histamine receptors do?
o H1 receptors contract smooth muscle (e.g. in the bronchi)
o H2 receptors stimulate gastric secretions
• Receptors, as you know, can have different subtypes (e.g. α and β adrenergic receptors). How is
this useful for pharmacologists? It provides the opportunity to develop specific drugs that only
affect the one subtype needed. For example H1 antagonists can be used as an anti-allergy as it
dilates the bronchioles, reversing a common symptom of allergy, whereas H2 antagonists can be
used as an anti-ulcer treatment
• What’s the difference between an agonist and an antagonist? Agonists activate, antagonists
inactivate/block.
• What do the following terms mean?
Term Meaning
Affinity Ability of a drug to bind to a receptor
Efficacy Ability of a drug to activate a receptor (not applicable to antagonists)
Specificity Ability of a drug to only bind to the target receptor (no drug is 100% specific)
• For the reversible reaction D + R DR, what is the rate of association and the rate of
dissociation?
o Rate of association = k+1[D][R]
o Rate of dissociation = k-1[DR]
o k+1 and k-1 are rate constants
Note that at equilibrium, rate of association = rate of dissociation
• What is the KD? It’s the concentration of the drug when 50% of the receptors are occupied. It follows
that the lower the KD, the higher the affinity because less drug is required to bind 50% of the
receptors.
• What is RT? The total number of receptors. RT = sum of receptors in DR complexes + free receptors R
• What is P? P is the fractional receptor occupancy (i.e. [DR]/[RT]). P must never be expressed as a %.
This represents the fraction of receptors that are occupied by the drug
• What is the equation you need to remember for the exam…P=? P=[D]/[D]+KD
• Under what conditions is this equation valid?
1. Equilibrium
2. [drug] that you apply to the system = [drug] at the receptors (i.e. none is lost)
, 3. 1 drug molecule binds with one receptor molecule
4. a negligible amount of the drug that is added actually binds with a receptor
5. there is no cooperativity (when binding of one drug molecule affects the binding of others –
as in haemoglobin binding)
• Binding is said to be saturable. What
does this mean? It means that a drug
will only bind to receptors up to a
certain point, and that at that point even
if you add more drug you won’t get more
reaction, because there is a
maximum number of binding sites
available.
• What would the graph of P against
[drug] look like? It would be a
rectangular hyperbola (see right)
• Why does that graph not tell you
anything about the biological
response? Because biological response and % binding sites occupied are not related. One drug may
bind to only a few sites but exert a massive
response (high efficacy), whereas another drug
may occupy all of the sites but only exert a small
response.
• What percentage of protein in muscle are
receptors? 70%
• Why do we often semi-log the above graph?
Because it makes it easier to read off the
threshold KD and RT values more easily.
• What can be deduced from the following graph?
We can say that drug A has a higher affinity than drug B, which has a higher affinity than drug C. We
cannot say anything about their relative potencies because we do not know anything about their
efficacies (how good they are at exerting a response, once they are bound). For all we know drug C
might exert a massive response even though it is not very good at binding (high efficacy, low
