PHRM30003 MST 2 exemplar student answers

QUESTION A
Discuss the mechanism of action of the beta-lactam antibiotic piperacillin and the
rationale of why it is often used in combination with tazobactum.

Example 1
Beta-lactam antibiotics are a class of drugs that target transpeptidase (PBP), a key enzyme in
cell wall synthesis for bacteria. In bacterial cell walls, there are NAM and NAG chains that
are connected by a D-ala-D-ala connection that is synthesised by PBP in a transpeptidation
reaction. This ensures structural integrity for the cell wall, and as bacteria have high
intracellular pressures, the strength of the cell wall is vital for its survival. By introducing
beta-lactam antibiotics, the beta-lactam ring in piperacillin mimics the d-ala-d-ala substrate
and binds irreversibly to the active site of PBP. This binding ensures that PBP is unable to
facilitate transpeptidase reactions and thus compromises the structural integrity of the cell
wall.
Through overuse of these types of antibiotics following the discovery of penicillin, bacteria
have gained antibiotic resistance in the form of beta-lactamases that break down the beta-
lactam rings in these drugs. Tazobactum is a beta-lactamase inhibitor. This ensures that the
bacterial cells are unable to breakdown piperacillin. This effectively keeps piperacillin at a
sufficient concentration to have a therapeutic effect.

Example 2
Beta-lactam antibiotic piperacillin inhibits cell wall synthesis. It does this by mimicking the
D-ala-D-ala substrate and inactivates the transpeptidase enzyme PBP (which is responsible
for connecting NAG and NAM) by covalently bonding to the serine residues within the active
site. This is an irreversible inhibition that weakens the cell wall and causes the cell to burst
This is used in combination with tazobactum because tazobactum prevents the breakdown
of piperacillin by beta lactamase producing organisms by inhibiting the action of the b-
lactamases.

Example 3
• Beta-lactam piperacillin mimics the D-Ala-D-Ala substrate and inactivates the transpeptidase
• This disrupts peptidoglycan cross-linking during cell wall synthesis
• Weakens structural integrity of cell walls
• Tazobactam irreversibly inhibits beta-lactamase enzymes
• Beta-lactam can no longer be inactivated through binding to Beta-lactamase

What’s missing ? NAM NAG are the crosslinked cpeptidoglycans
QUESTION B
Briefly outline the cellular and molecular actions of opioid analgesics.

Example 1
Opioid analgesics share a common feature of binding to Mu opioid receptors to produce
cellular and molecular effects
Opioids work on neurons at the synapses - neurons are the primary way in which pain
signals are transmitted around the body. 
Presynaptically, opioids bind to mu-opioid
receptors on the cell surface to inhibit Ca2+ influx pumps. This has the molecular effect of
preventing vesicles filled with neurotransmitters from being released at the cell's synaptic
surface. This has the effect of reducing the concentration of neurotransmitters being
delivered across the synaptic gap.
Opioids also bind to mu-opioid receptors
postsynaptically. This binding causes K+ ion channels to increase K+ conductance. The efflux
of K+ causes postsynaptic hyperpolarisation, making it more difficult for Na+ channels to
make the cell reach threshold - and making it more difficult for an Action Potential (pain
signal, in this case) from being relayed in the secondary neuron, and stopping the pain signal
from reaching the periphery, dulling the unpleasant sensation.
The combined effect of less
NT and fewer APs greatly reduces the number of APs relayed. and therefore the intensity of
pain signals in the patient.

Example 2
Opioid analgesics activate μ opioid receptors on both the pre-and postsynaptic membranes.
At the presynaptic membrane:
Activation of μ opioid receptors stimulates inhibition of the Ca2+ influx into the axon
terminal. This results in decreased release of neurotransmitters (eg. glutamate) in vesicles
into the synaptic cleft.

At the postsynaptic membrane:
Activation of μ opioid receptors increases the export of K+ ions into the synaptic cleft. This
causes postsynaptic hyperpolarisation. This means that fewer of the V-gated sodium
channels reach the threshold potential. Thus, there is a decrease in action potential
generation.


QUESTION C1
Very similar bronchodilators are used in asthma and COPD but anti-cholinergic muscarinic
antagonist (ipratropium, aclidinium) are usually considered first line therapy for COPD.
What factors influence this preference?

Example 1
Anti-cholinergics e.g. long acting muscarinic anagonists (LAMAs) are used primarily in
treatment of COPD due to COPD's particular pathogenesis and its treatment goals.
LAMAs are used primarily because they are able to target the deeper, more terminal lung
structures of the lung innervated by parasympathetic nerves more so than earlier
generation ASM of bronchioles (that LABAs and SABAs can). The bio-distribution of
cholinergic nerves are higher in these deeper structures which are the sites of small airway
collapse seen in COPD that require widening, and this density means LAMAs are more
effective at reducing vagal cholinergic tone here which is the main reversible feature of
COPD.
In COPD there is also non-neuronal production of ACh by the tissue in deeper inflamed
structures which anticholinergics can respond to.
LAMAs are also preferred because they are more effective at reducing the mucus that
comes with chronic bronchitis of COPD than beta agonists and have less systemic effects as
inhaled anticholinergics are poorly absorbed from the GIT and lung compared to beta
agonists and their side effects on the heart and so on.
That is not to say beta agonists are not helpful: they will relax the airway smooth muscle
(ASM) and when combined with LAMAs increases dilation by 30-40%. Together, beta
agonists and LAMAs will help to relieve hyper inflation and symptoms of COPD.


QUESTION C2
Very similar bronchodilators are used in asthma and COPD but anti-cholinergic muscarinic
antagonist (ipratropium, aclidinium) are usually considered first line therapy for COPD.
Why do bronchodilators often work less well in COPD than asthma?

Example 1
bronchodilators in asthma Bind beta 2 receptors on smooth muscle cells, and via
upregulation of SERCA pump which brings calcium back into the sarcoplasmic reticulum, and
downregulation of action of IP3 receptor, inhibit smooth muscle contraction by inhibiting
MLCK from phosphorylating MLC, and allowing actin myosin cross bridge cycling to occur.
this directly stops airway narrowing as a result of smooth muscle shortening.
in COPD these drugs work in the same way as asthma, but due to compromised lung tissue,
there is less smooth muscle for the drug to work on and help to open the airways, it should
also be noted that In COPD the reason for breathlessness is lung collapse due to lack of
elastin activity, so bronchodilators do not necessarily work to open airways, as the
mechanism of airway obstruction is mechanical, and due to lack of elastin, not shortening of
smooth muscle cells.
Mucus secretion also increases the obstruction of airways in COPD, and bronchodilators do
not help to clear mucus, while they may help to open airway diameter and reduce the
amount that the mucus obstructs airflow, bronchodilators are not the most effective way to
combat mucus in the airways.