Compounds

Question 1

Riluzole

Answer 1

Approved in 1995, it is the only treatment approved in the UK for ALS.
It acts to reduce glutamate excitotoxicity by blocking presynaptic Na+ channels.
It has some effect on prolonging survival by ~3-6 months but a limited ability to improve symptoms.
Financial implications: costs the NHS up to £7.5 million/year, and stem cells therapeutics are much more expensive.

Question 2

Captopril and Enalapril

Answer 2

Angiotensin converting enzyme inhibitors (ACEIs) which prevent the formation of Angiotensin II, which normally acts to increase BP. Used for hypertension and heart failure.

ACEIs reduce arterial and venous vasoconstriction, therefore reducing afterload and preload, respectively.
They also reduce salt/water retention and hence reduce circulating volume by inhibiting aldosterone production.
Aldosterone causes fibrosis and stiffening of the heart. ACEIs therefore prevent cardiac remodelling.
ACEIs also potentiate the vasodilator bradykinin. However, bradykinin sensitises sensory nerves in the airways and therefore causes a cough.

Question 3

Bendroflumethiazide

Answer 3

Diuretic that inhibits the reabsorption of Na+ and Cl- in the distal convoluted tubule, reducing the circulating volume and therefore BP, as well as preload and afterload, therefore reducing workload of the heart.
Used in mild heart failure or in the elderly.

Question 4

Elexacaftor

Answer 4

CFTR corrector and potentiator used for cystic fibrosis.

Question 5

Statins

Answer 5

Statins like simvastatin and lovastatin inhibit HMG-CoA reductase and so cholesterol synthesis and increase LDL receptor expression, increasing LDL-c uptake.

Statins however also upregulated PCSK9, which breaks down LDL receptors, limiting their efficacy.

Statins also reduce the risk of CVD and mortality in people with normal cholesterol levels.
The cholesterol precursors geranyl pyrophosphate and farnesyl pyrophosphate are involved in post-translational modification of Ras an RhoA, involved in smooth muscle contraction. Statins inhibit this pathway independently of cholesterol levels.

There are some side effects associated with the use of statins, including hepatotoxicity and myopathy, with possible rhabdomyolysis which is more likely to occur with CYP3A4 inhibition or loss-of-function SNPs in the liver SLCO1B1 transporter.

Question 6

Zileuton

Answer 6

Lipoxygenase inhibitor in clinical use for asthma in the US. Prevents early phase bronchoconstriction.

Question 7

BI-836-880

Answer 7

Humanised bispecific nanobody acting as an inhibitor of tumour angiogenesis by targeting both VEGF and angiopoietin II messengers.
It is also linked to a proprietary domain to increase its half-life.

Question 8

AP-101

Answer 8

Future ALS treatment
Recombinant human IgG1 antibody that selectively binds the misfolded and aggregated SOD1 protein, promoting clearance.
It is currently in Phase II clinical trials.
Familial ALS participants must demonstrate SOD1 mutation to benefit from this drug.

AP-101 is administered intravenously. However, biologics cannot normally cross the BBB, so upper motor neurons cannot be targeted.
Possible approaches to overcome this issue include re-engineering biologics as BBB-penetrating IgG fusion proteins. This approach uses antibodies targeting receptors on the BBB to transport therapeutic biologics into the brain via receptor-mediated transport (RMT).

Question 9

Olamkicept

Answer 9

Fusion protein where the extracellular portion of gp-130 is fused to the Fc region of a human IgG antibody.
Binds IL-6 or the soluble ligand-receptor complex and prevents binding to gp-130 on the PM.
Used for autoimmune diseases.

Question 10

AZD4831

Answer 10

Myeloperoxidase (MPO) is produced by neutrophils in inflammation.
It catalyses the formation of HOCl but can also lead to oxidation of NO, which leads to impaired endothelium-dependent vasodilatation.
MPO is associated with vascular dysfunction such as microvascular inflammation and is increased in heart failure and atherosclerosis.
AZD4831 is a MPO inhibitor in phase II clinical trials. It reduces inflammation and fibrosis, improve microvascular function and facilitate vasodilation function in animal models of heart failure.

Question 11

ado-trastuzumab emtansine (T-DM1)

Answer 11

Antibody-drug conjugate for breast cancer.
Trastuzumab directs emtansine (DM1) to HER2 +ve cells.
T-DM1 is internalised by endocytosis and transported to lysosomes, where the linker is degraded to release DM1.
Emtansine is a cytotoxic drug that binds tubulin and prevents microtubule formation, causing mitotic arrest and apoptosis.

Question 12

Atezolizumab

Answer 12

Binds PD-L1 on cancer cells, preventing binding to PD-1 on T cells. T-cells can mount an immune response against the cancer cells.

Question 13

Lumacaftor and Tezacaftor

Answer 13

Cystic fibrosis treatments targeting CFTR folding.
Regular CFTR is glycosylated as part of post-translational modification.
Mutations in the transmembrane domain 1 (TMD1), like F508del, reduce glycosylation, which causes defective folding of the protein. The misfolded protein remains in the endoplasmic reticulum and is degraded.
Lumacaftor acts as a pharmacological chaperone during protein folding, so it increases the number of CFTR proteins that are trafficked to the cell surface.
It is thought to stabilise TMD1 during folding.
Tezacaftor is known as a CFTR corrector. It acts in a similar manner but binds a different region of TMD1.

Question 14

Tamoxifen

Answer 14

~70% of breast cancer tumours are oestrogen receptor (ER) positive.
Treated with selective oestrogen receptor modulators (SERMs) like tamoxifen.
Tamoxifen is metabolised by liver CYP2D6, as well as CYP3A4 and CYP2C9, into active metabolites such as 4-OH tamoxifen.
Around 7% of the population has a less active CYP2D6 isoform. This results in reduced active metabolite production and therefore a reduced therapeutic effect.
An increased tamoxifen dose is recommended for these individuals.

Question 15

Warfarin*

Answer 15

Oral anticoagulant.
The optimal plasma concentration of warfarin must be tightly controlled. A lack of efficacy and bleeding are both problems.
Clear case for improving risk management in individuals.
2,000,000 prescriptions per year (US)
8 bleeding events per 100 patients per year
There are two well-established genetic variants for warfarin efficacy and safety
Pharmacokinetic: CYP2C9 variants
Pharmacodynamic: Vitamin K epoxide reductase (VKOR) haplotype

Question 16

setipiprant and fevipiprant

Answer 16

Asthma treatments

Prostaglandin D2 effects are mediated through DP1 and DP2 receptors.
DP2 receptors are expressed on immune cells including Th2 cells, mast cells, basophils and eosinophils.
Selective DP2 receptor antagonists include setipiprant and fevipiprant. These inhibit activation of Th2 cells and eosinophils.

Setipiprant was in phase II clinical trials. It causes a reduction of hyperresponsiveness, but the observable benefit was no better than existing therapies, so it didn’t progress.
Fevipiprant causes a reduction in eosinophil numbers in asthma patients.

Question 17

Y27632

Answer 17

Y27632 is a rho kinase inhibitor that, when inhaled, produces rapid bronchodilation, which is maintained for 8 hours.

Rho kinase sustains smooth muscle contraction by inhibiting MLC phosphatase, an enzyme that dephosphorylates MLC to decrease smooth muscle contraction. This contributes to calcium sensitisation, airway narrowing and hyperresponsiveness.
Rho kinase also plays a role in airway remodelling as it stimulates the proliferation of fibroblasts and enhances their ability to produce ECM components like collagen, which contributes to increased airway stiffness and reduced lung function.
Rho kinase is also activated in eosinophils, causing recruitment.

Question 18

Leflunomide

Answer 18

DMARD
Leflunomide is metabolised to teriflunomide, which inhibits dihydroorotate dehydrogenase and therefore pyrimidine (T, C and U) synthesis.
Inhibits T-cell expansion.
Side effects: diarrhoea (20%), nausea, rash, alopecia (10%), abnormal liver function (5%), teratogenicity.

Question 19

Infliximab

Answer 19

Monoclonal antibody against TNFα, a major cytokine.
Used in autoimmune diseases.

Question 20

Adagrasib

Answer 20

Potent, orally available, small-molecule covalent inhibitor of KRAS.
It irreversibly and selectively binds KRAS G12C, locking it in its inactive GDP-bound state.
It also acts as PROTAC, marking the protein for proteasomal degradation.

Question 21

Spironolactone

Answer 21

Aldosterone receptor antagonist used in heart failure.
Prevents sodium reabsorption and fluid retention (diuretic).
Reverses LVH caused by aldosterone mediated fibrosis.

Question 22

Ribociclib and Palbociclib

Answer 22

Inhibitors of CDKs 4 and 6, used for the treatment of metastatic hormone receptor positive and HER2 negative tumours.
They sustain the active RB protein. Active RB suppresses E2F transcription factors and prevents transcription of genes required for cell cycle progression.
This leads to G1 cell cycle arrest and so reduces cancer cell proliferation.

Question 23

Anakinra

Answer 23

Endogenous peptide acting as IL-1 receptor antagonist.
Recombinant form used therapeutically for RA.

Question 24

Olokizumab

Answer 24

Binds IL-6 and prevents the receptor-ligand complex from interacting with gp-130.
Used in inflammatory diseases such as RA.

Question 25

bisoprolol, carvedilol, and nebivolol

Answer 25

Only β-adrenoceptor antagonists approved for heart failure. Stimulation of the receptors increases CO, so inhibition reduces it. Decreased CO is already occurring in CHF, so utilising these seems counterintuitive. However, there are some drugs which initially cause a worsening of HF but this is followed by a rebound, where cardiac function improves. This may be because antagonism actually leads to increased receptor expression or because this reduces workload on the heart. Alternatively, these particular antagonists may have another unidentified effect. These β-adrenoceptor antagonists reduce disease progression, symptoms and mortality due to antiarrhythmic activity.

Question 26

Panitumumab

Answer 26

Binds to HER1/EGFR and prevents its activation. It interestingly doesn’t lead to immune-mediated cytotoxicity due to the difference in the Ig antibody backbone used.

Question 27

Bevacizumab

Answer 27

Binds to VEGF and prevents it from activating its receptor on endothelial cell surfaces, thereby inhibiting downstream signalling and angiogenesis.

Question 28

Siltuximab

Answer 28

Binds IL-6 and prevents receptor interaction. Used in autoimmune diseases like RA.

Question 29

Bupalisib

Answer 29

Dual PI3K/mTOR inhibitor in clinical trials for various cancer types including breast and endometrial cancers.

Question 30

Olpasiran

Answer 30

siRNA that lowers the expression of apolipoprotein(a), a component of LDL, in the treatment of atherosclerosis.

Question 31

Catumaxomab

Answer 31

Trifunctional antibody used in epithelial cell adhesion molecule (EpCAM) positive cancers. As well as binding to EpCAM, it also binds to CD3 antigen on T-cells and to Fcγ receptors (FcγRs) on NK cells or macrophages, bringing two immune cells in close proximity to the tumour. Macrophages can phagocytose the tumour cell. No longer licensed for use as the drug company went bankrupt, but other companies are trying to resurrect trifunctional antibodies.

Question 32

Opioid receptor agonists for cough

Answer 32

Codeine and dextromethorphan act on µ opioid receptors in the cough centre. They produce effects that are marginally better than the placebo, but codeine is still considered the ‘gold-standard’ of cough treatment - Recent placebo-controlled studies have shown that codeine is no more effective than a placebo in suppressing cough caused by upper respiratory disorders or COPD. This contradicts older studies that did demonstrate codeine's efficacy. - Codeine’s efficacy in humans may be limited to specific situations due to the complex control mechanisms of cough. Codeine should be avoided in children under 18 years old. It is not readily available anymore as it can cause addiction and respiratory depression. Dextromethorphan should be avoided in children under 6. Diamorphine (Heroin) was synthesised in the 1890s at Bayer and was marketed for respiratory diseases as it was found to alleviate coughing, as well as slow and deepen respiration, helping clear the lungs of excess phlegm. Bayer claimed the compound to be free from abuse liability, but we now know this is untrue and the drug is no longer used.

Question 33

CDX-1140

Answer 33

Agonist antibody at CD40 on APCs. This activates T cells and can drive T cell dependent tumour regression.

Question 34

QX-314 and BW-031

Answer 34

QX-314 is a charged Na+ channel blocker that inhibits neuronal activity, similarly to local anaesthetics. It could be used for cough. Acts at the intracellular side, but it cannot cross the PM as it's charged. It can however cross through TRP channels, which are only expressed on sensory nerves. It is therefore co-applied with TRPV1 agonists to allow it to access the intracellular side of Na+ channels. These may initially worsen cough, having a similar effect to capsaicin, but sensory nerves then become desensitised. Alternatively, TRPM8 could also be activated with menthol and TRPA1 can be activated by cinnamaldehyde. BW-031 is a new compound that is 6x more potent than QX-314. It can inhibit cough reflex without co-application of TRP agonists. This is because TRP channels are already activated at low levels in inflammation, so the more potent drug can selectively target sensory nerves activated by inflammation.

Question 35

Tofersen

Answer 35

ALS treatment Antisense oligonucleotide that acts to downregulate SOD1 mRNA, therefore reducing synthesis of the protein. Approved by the FDA in 2023 but not yet approved by EMA and currently in Phase III clinical trials for patients with SOD1 mutations.

Question 36

Everolimus and Temsirolimus

Answer 36

mTORC1 inhibitors for renal cell carcinoma.

Question 37

Aminosalicylates

Answer 37

Mesalazine (5-aminosalicylate) is a DMARD. It increases PPAR𝛾 receptor activation, causing heterodimerisation with retinoid X receptors (RXR). The heterodimer translocates to the nucleus, binds DNA response elements and regulates gene expression to reduce synthesis of inflammatory mediators. Sulfasalazine is a prodrug metabolised to mesalazine. It is used in ulcerative colitis, as the metabolic conversion can be performed by the bacteria in the colon.

Question 38

Blinatumomab

Answer 38

Used clinically for the treatment of acute lymphoblastic leukemia (ALL). It binds to CD3 on T cells and CD19 on B cells, targeting T cells to malignant B cells.

Question 39

Tacrolimus

Answer 39

Calcineurin inhibitor, like cyclosporin, but it complexes with FKBP first instead. Used to prevent T-cell activation in organ transplants.

Question 40

Paxalisib

Answer 40

Dual PI3K/mTOR inhibitor. It is brain penetrant, so it can potentially treat brain metastases. Combination of Paxalisib with Trastuzumab reduces brain metastases in preclinical studies.

Question 41

AZD0780

Answer 41

Small molecular PCSK9 inhibitor for hypercholesterolemia. PCSK9 normally breaks down LDL receptors. It is upregulated by statins, which reduces their efficacy.

Question 42

Etanercept

Answer 42

Fusion protein of 2 soluble TNFα receptors attached to a Fc region. It mops up free TNFα. Used in autoimmune diseases.

Question 43

Enoximone

Answer 43

PDE3 selective inhibitor that induces airway smooth muscle relaxation and bronchodilation in asthmatic patients. However, inhibition of PDE3 in cardiac muscle increases the force of contraction, which limits its use.

Question 44

Trastuzumab (Herceptin)

Answer 44

The first HER2-targeted therapy approved by the FDA for treatment of HER2-positive breast cancer. It is a humanised monoclonal antibody against the extracellular cysteine-rich subdomain IV of HER2, preventing HER2 receptors from forming homodimers and activating signalling. It can also stimulate ADCC.

Question 45

Conatumumab

Answer 45

TRAIL receptor agonists (TRAs) activate death receptors (DRs) to stimulate apoptosis, which is impaired in cancer. Conatumumab is an antibody that binds to DR5 receptors, mimicking ligand activation by linking two receptors and therefore activating pro-apoptotic signalling.

Question 46

Engensis

Answer 46

Engensis is an ALS treatment that involves the delivery of a plasmid encoding hepatocyte growth factor (HGF), which plays a role in nerve cell growth, survival, and regeneration. This is injected directly into muscles Engensis has just finished Phase II trials The drug is also being tested in patients with painful diabetic neuropathy, Charcot-Marie-Tooth Disease Subtype 1A (CMT1A) and chronic non-healing foot ulcers. Used as direct delivery of GDNF has a limited effect due to short plasma half-life and poor BBB penetration.

Question 47

Omecamtiv mecarbil

Answer 47

Selective cardiac myosin activator used in HF. It reduces the rate of phosphate release, which keeps the myosin bound to the actin, strengthening the force of contraction of the cardiac muscle.

Question 48

Clopidogrel*

Answer 48

Alternative antiplatelet drug for post-MI secondary prevention and for atrial fibrillation. Its metabolite acts as an antagonist at P2Y12 receptors for ADP on platelets to prevent aggregation. Used as an alternative to aspirin for individuals sensitive to its GI side effects. (Aspirin inhibits COX, an enzyme crucial for the production of prostaglandins and thromboxane A2.) CYP2C19 haplotypes are associated with altered levels of the active metabolite. - CYP2C19*2 haplotype shows reduced activity (↓ active drug) - CYP2C19*17 haplotype is a gain of function (↑ active drug) Patients with one or two copies of *2 have a 2.5x higher risk of thrombosis after post-MI stent insertion. *17/*17 patients have increased bleeding risk and greater therapeutic effect. In the US, FDA has approved a Genetic Box Label for Clopidogrel, and some hospitals test for haplotype pre-treatment. There are alternative P2Y12 antagonists that can be given.

Question 49

Levodropropizine

Answer 49

Cough treatment, inhibits the release of sensory neuropeptides in vitro, producing comparable results to codeine and dextromethorphan.

Question 50

Roflumilast

Answer 50

PDE4 expression levels are raised in asthma and COPD. PDE4 is expressed on mast cells. PDE4 inhibitors, like Roflumilast, reduce the release of inflammatory mediators from mast cells. Has been shown to reduce eosinophil recruitment through the reduction in cytokine production in Th2 cells, which supports the role of PDE4 in inflammatory responses. PDE4 is also found in smooth muscle, but no clinical effect on bronchodilation has been shown with any inhibitors. Roflumilast is therefore not approved in asthma, but it is approved for the treatment of COPD.

Question 51

Benralizumab

Answer 51

Asthma treatment that acts by binding the the interleukin-5 receptor alpha (IL-5Rα) through its antigen binding site, preventing dimerization with the common beta (βc) chain, which prevents IL-5 from activating eosinophils and basophils. Benralizumab also binds to the FcγRIIIα receptor on NK cells via its Fc region, directing these to eosinophils and causing apoptosis. IL-5 is produced by Th2 lymphocytes in response to activation by APCs. IL-5 induces eosinophil differentiation and maturation, and contributes to the recruitment of these cells into the airways of asthmatic patients (chemotactic effects). IL-5 is also involved in damage to the epithelial layer through release of cytotoxic proteins. Benralizumab is used in uncontrolled asthma, particularly eosinophilic asthma.

Question 52

Gefapixant

Answer 52

P2X3 receptor antagonist in clinical application for cough. ATP is released from epithelial cells in response to inflammation and activates P2X3 ion channels on sensory nerves, stimulating cough.

Question 53

Sacubitril

Answer 53

Used in heart failure. Inhibits neprilysin, an enzyme that breaks down natriuretic peptides. Therefore allows natriuretic peptides to act at GC-A and GC-B receptors on smooth muscle to cause vasodilation and in the kidney to cause natriuresis. However, neprilysin also breaks down angiotensin II, so sacubitril is administered in combination with an AT1R inhibitor valsartan.

Question 54

Sirolimus (rapamycin)

Answer 54

Inhibits mammalian target of rapamycin (mTOR), which promotes tolerance to autoantibodies by promoting the expansion of T-regs. T-regs prevent autoimmunity by preventing T-cell responses. Used in organ transplants.

Question 55

Cyclosporin

Answer 55

Cyclosporin is a calcineurin inhibitor. Calcineurin is a Ca2+-dependent phosphatase that activates NFATc, a transcription factor which upregulates IL-2. IL-2 is an inflammatory cytokine required for T-cell activation. Cyclosporin binds to the cyclophilin protein, and the complex inhibits calcineurin, inhibiting T-cell activation. It is used in autoimmune diseases like ulcerative colitis, RA and psoriasis, and for preventing organ transplant rejection.

Question 56

Losartan

Answer 56

AT1 receptor antagonist, which are also called ATRAs, ARBs or sartans. Opposes the actions of angiotensin II at the AT1 receptor. Equally as effective as ACEIs, but they do not cause a cough.

Question 57

ivacaftor

Answer 57

Oral CFTR potentiator used for CF, keeping the channel open for longer and enabling Cl- transport. It was identified by phenotypic drug discovery using gain-of-function assays in cell cultures expressing the F508del mutant.

Question 58

Tocilizumab

Answer 58

Binds the soluble IL-6 receptor Used in RA but also severe COVID19 infections to prevent a cytokine storm and therefore reduce the likelyhood of medical ventilation and death.

Question 59

Abacavir*

Answer 59

HIV reverse transcriptase inhibitor introduced in 1998. 5% of patients develop immune hypersensitivity, which can be fatal. This is known as Stevens-Johnson syndrome and it affects the skin and other mucous membranes. Hypersensitivity reactions have a genetic basis. The MHC on antigen presenting cells is encoded by HLA genes. There are >1000 genetic variants/alleles. The T cell receptor (TCR) and CD4 bind the antigen/MHC complex. This activates T cells, triggering an immune response. Abacavir can initiate this immune reaction by binding the MHC encoded by the HLAB*5701 gene variant, leading to hypersensitivity.

Question 60

Capivasertib

Answer 60

Akt protein kinase inhibitor approved last year as a breast cancer treatment.

Question 61

Digoxin

Answer 61

Positive inotrope, strengthening heart contractions and allowing it to pump more blood, used for atrial fibrillation and HF. It inhibits the Na+/K+ ATPase pump, increasing contractility. However, it also impairs atrioventricular conduction at the AV node, which leads to heart block, bradycardia and reduced rate at which contraction passes from atria to ventricles. This may actually be beneficial in atrial fibrillation as it controls the ventricular rate. Dioxin has a narrow TI and can be toxic, so it is not commonly used.

Question 62

Ensifentrine

Answer 62

PDE3/4 dual inhibitor that shows airway smooth muscle relaxation and a reduction in eosinophil numbers. It is approved for COPD. It was found to improve lung function in clinical trials, so it may also gain approval for asthma. Delivery through inhalers would reduce cardiac side effects.

Question 63

Vericiguat

Answer 63

Soluble guanylyl cyclase stimulator, causing vasodilation. This results in increased renal blood flow and therefore prevention of RAAS compensatory mechanisms, increased coronary blood flow, and reduced work on the heart. Used in HF.

Question 64

inotuzumab ozogamicin

Answer 64

Antibody-drug conjugate used for acute lymphoblastic leukaemia (ALL). Inotuzumab is a monoclonal antibody that binds CD22 on the surface of (malignant) B cells. The antibody-drug complex gets internalised through receptor-mediated endocytosis and the drug is released as the linker connecting it to the antibody is cleaved and the antibody gets degraded. Ozogamicin is a potent DNA-damaging agent derived from calicheamicin. It binds to DNA in the nucleus, causing double-stranded breaks, inhibiting cell proliferation and ultimately leading to cell death.

Question 65

Pembrolizumab

Answer 65

Binds to PD-1 receptors on T-cells so PD-L1 on cancer cells can no longer bind, allowing T-cells to mount an immune response against the cancer cells. Used in triple-negative breast cancer tumours. These are harder to treat and often associated with poorer outcomes, resulting in an aggressive cancer phenotype.

Question 66

Tezepelumab

Answer 66

Asthma treatment, binds to TSLP (thymic stromal lymphopoietin), an epithelial-derived cytokine. TSLP is part of a class of cytokines known as alarmins produced by the airway epithelium in response to a perceived threat, such as inhaled allergens. Expression is increased in the airways of patients with asthma. TSLP is a major mediator of eosinophilic inflammation. It binds to the TSLP receptor, which forms heterodimer with the IL-7 receptor to stimulate inflammatory responses. This stimulates the differentiation of naïve T cells to Th2 cells. It also promotes airway remodelling, including smooth muscle proliferation. Tezepelumab prevents TSLP binding and dimer formation, inhibiting eosinophilic inflammation, Th2 differentiation and airway remodelling.

Question 67

Edaravone

Answer 67

ALS treatment Antioxidant drug that scavenges oxygen-containing free radicals released from degenerating motor neurons, protecting from ROS. It was originally developed for acute ischemic stroke. It is still not approved in Europe, despite gaining approval in the US in 2017, due to a lack of efficacy. It increases survival by ~6 months.

Question 68

Azathioprine and mercaptopurine

Answer 68

Azathioprine is a DMARD It is converted to mercaptopurine through glutathione conjugation, and then to the cytotoxic compound 6-TIMP by HPRT. 6-TIMP inhibits purine (A and G) and hence DNA synthesis by inhibiting amidophosphoribosyltransferase. Mercaptopurine is also metabolised to non-cytotoxic compounds by thiopurine methyltransferase (TPMT) - low activity causes toxicity.

Question 69

Dapagliflozin

Answer 69

SGLT2 inhibitor - increases sodium and glucose excretion in urine, which also pulls water in so blood volume is reduced. Developed for T2DM but also used in HF. SGLT2 inhibitors offer cardio-renal protection and reduce mortality in patients with heart failure. They decrease blood pressure without affecting the HR. This is probably due to prevention of renal damage which would normally increase sympathetic activity.

Question 70

NurOwn

Answer 70

Modified stem cells used as ALS treatment. These are mesenchymal stem cells transduced with neurotrophic factor (MSC-NTF), created using autologous bone marrow–derived MSCs and modifying them to secrete high levels of NTFs in addition to their well-documented intrinsic immunomodulatory properties.

Question 71

Methotrexate (MTX)

Answer 71

Methotrexate (MTX) is a DMARD acting as a dihydrofolate reductase (DHF reductase) inhibitor, inhibiting folic acid recycling and therefore thymine (pyrimidine) synthesis. There is not enough thymine to incorporate into DNA, so DNA and mRNA turnover are inhibited. Cell proliferation and protein synthesis are inhibited, inhibiting the proliferation of immune cells and antibodies. Tetrahydrofolate (THF) is converted to methylene THF. Thymidylate synthase uses methylene THF to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) and produce dihydrofolate (DHF) as a result. dTMP is required for thymine synthesis. DHF reductase converts DHF back into THF, recycling it and enabling the pathway to restart. Methotrexate inhibits DHF reductase, depleting folic acid stores. This inhibits thymine synthesis. Methotrexate can cause toxicity including: nausea, post dose “flu”, hepatotoxicity, lung alveolitis/fibrosis, teratogenicity, GIT effects, renal toxicity and blood disorders (bruising, unexplained bleeding) due to decreased turnover of cells involved in blood coagulation. Folic acid (folate/vitamin B6) administration reduces side effects. Therapeutic effect not affected, but we do not know why. It might be about balance, or the mechanism of action of MTX may be more complex. ** Methotrexate may increase adenosine levels by inhibiting its metabolism. Adenosine is a potent endogenous anti-inflammatory mediator, repressing T-cell activation and downregulating B-cell function. Adenosine-receptor antagonists, among which is caffeine, reverse or prevent the anti-inflammatory effects of methotrexate.

Question 72

Anti-metabolites

Answer 72

Mercaptopurine and methotrexate are also used to treat cancer as they inhibit cell proliferation. They are classed as “anti-metabolites”. Fluorouracil is also an anti-metabolite used in cancer. It is converted to FdUMP, which competes with dUMP for the thymidylate synthase enzyme, inhibiting thymine production.

Question 73

Furosemide

Answer 73

Loop diuretic, blocking the Na+/K+/2Cl- symporter. High ceiling, used in HF when pulmonary oedema is occurring.

Question 74

Dornase alfa

Answer 74

Used in cystic fibrosis, it is a synthetic version of the enzyme which cleaves extracellular DNA released from dying neutrophils in the airway, which contributes to increased mucus viscosity. Neutrophils are produced to combat the infections caused by pathogens trapped in the thick mucus, but these then die and release their DNA, thickening the mucus more.

Question 75

Obicetrapib

Answer 75

Obicetrapib is a cholesteryl ester transfer protein (CETP) inhibitor in clinical trials for hypercholesterolemia. CETP is a glycoprotein produced in the liver and adipose tissue, involved in the transfer of cholesterol esters from HDL to VLDL and LDL, reducing HDL-c levels. Previous inhibitors have failed. Torcetrapib increased mortality in clinical trials by increasing aldosterone levels and therefore BP and cardiac fibrosis. Other inhibitors have been abandoned due to a lack of clinical efficacy. However, obicetrapib +statins trials show a 33% decrease in LDL-c and 21% reduction in CV events over 1 year.

Question 76

Rituximab

Answer 76

In multiple sclerosis, B cells infiltrate the CNS and produce autoantibodies against myelin, causing degradation. Rituximab binds to CD20 on B cells and cross-link receptors, aggregating cells. B cells are now recognised by macrophages and NK cells, which leads to their removal. Rituximab is also used in RA.

Question 77

Pertuzumab

Answer 77

Directed against the extracellular dimerization domain (subdomain II) of HER2, preventing the receptor from forming heterodimers with HER3 or other receptors. It also causes ADCC.

Question 78

Idelalisib

Answer 78

PI3K inhibitor approved for the treatment of certain blood cancers including chronic lymphocytic leukaemia (CLL). It selectively inhibits the delta isoform of PI3K.

Question 79

Sotuletinib

Answer 79

Brain-penetrant kinase inhibitor, blocking the colony stimulating factor 1 receptor (CSF1R), a RTK. It targets microglia, reducing their proliferation. It therefore reduces neuroinflammation. It’s currently in Phase II clinical trials for ALS The drug also being tested in patients with advanced solid tumours

Question 80

Vemurafenib and debrafenib

Answer 80

The B-Raf V600E mutation stabilises the active conformation. This mutation is present in 50-70% of melanomas, as well as some other cancers. Vemurafenib interacts with the ATP binding site of the V600E Raf kinase, as it can form an ionic interaction with the glutamate side chain, but not with valine. This means that the treatment is selected for the mutated protein present in melanoma cells. Dabrafenib is a second in class drug approved. It is more selective and effective against brain metastases and it also targets the V600K mutation.

Question 81

Prednisolone

Answer 81

Oral steroid used to induce remission in rheumatoid arthritis. Upregulates annexin A1 (lipocortin), which acts through formyl peptide receptors (FPRs) to inhibit histamine release from mast cells, as well as the enzyme phospholipase A2 (PLA2) and therefore synthesis of inflammatory prostaglandins and leukotrienes. Also available as Predfoam enemas for IBS.

Question 82

Inclisiran

Answer 82

Small interfering RNA that inhibits PCSK9 synthesis, used for hypercholesterolemia. PCSK9 normally breaks down LDL receptors. It is upregulated by statins, which reduces their efficacy.

Question 83

Dupilumab

Answer 83

Anti-IL-4/13 antibody approved in 2017 for asthma and 2024 for COPD.

Question 84

CNS10-NPC-GDNF

Answer 84

Modified stem cells used as ALS treatment. Neural progenitor cells (NPCs) are transduced with glial cell-derived neurotrophic factor (GDNF) and differentiated into astrocytes. CNS10 indicates ‘clinical grade’. The cells are transplanted into the spinal cord, but 50% of patients developed pain. These are therefore currently in Phase I/2a trials for delivery directly into the motor cortex

Question 85

Abatacept

Answer 85

CTLA4-Ig fusion protein that binds CD80/86 on APCs and blocks binding to CD28 and CTLA4 receptors on T cells, inhibiting T cell activation. It is active in RA - reduced progression during a 12-month treatment period, with some evidence of sustained efficacy beyond it. Licensed in 2007 but not recommended by NICE due to its cost.

Question 86

Calcilytics: NPS2143

Answer 86

Calcium-sensing receptors (CaSRs) can couple to multiple G proteins: - Gq - stimulates intracellular calcium release - Gi - inhibits cAMP and therefore ASM relaxation. - G12,13 - RhoA kinase signalling pathway → contraction In asthma, there is an overexpression of CaSRs, which can lead to hyperresponsiveness. NAMs reduce calcium sensitivity and are called calcilytics. NPS2143 is a calcilytic that reduces calcium levels in ASM cells from asthmatics but not from control patients. This suggests a selective effect in asthmatics. In mice, it reduces airway hyperresponsiveness, inflammatory mediators, eosinophil recruitment and goblet cell hyperplasia and mucus hypersecretion.

Question 87

Lenzumestrocel (Neuronata-R®)

Answer 87

ALS treatment. These are bone marrow-derived mesenchymal stem cells (BM-MSC). This uses autologous cells, where pluripotent cells taken from a patient’s bone marrow are expanded, differentiated and transplanted via intrathecal injection. The cells are immunomodulatory with anti-inflammatory and neuroprotective effects The therapeutic is currently in Phase III trials and already approved in South Korea. There are some regulatory cautions with unethical clinics linked to ‘stem cell tourism’.

Question 88

Cetuximab (Erbitux)

Answer 88

EGFR antagonist, also capable of triggering antibody-dependent cellular cytotoxicity (ADCC), a process in which immune cells, such as NK cells and macrophages, recognise and kill target cells bound to the antibody. It is licensed for head, neck, colon and lung cancers.

Question 89

Vepsitamab

Answer 89

Bifunctional antibody that binds CD3 and MUC17 on tumour cells, directing T cells to the cancer cells. Mucins membrane proteins on epithelial cells making up the mucus in the GIT. Mucin17 (MUC17) is overexpressed in 50% of gastric cancers.

Question 90

Tofacitinib

Answer 90

Small molecular inhibitor of Janus kinase (JAK), which is involved in cytokine signalling downstream of the IL-6 receptor. The drug is no more effective than methotrexate, so NICE will only recommend the drug if the company agrees on a lower price.

Question 91

Alirocumab and Evolocumab

Answer 91

Monoclonal antibodies against PCSK9 for hypercholesterolemia. PCSK9 normally breaks down LDL receptors. It is upregulated by statins, which reduces their efficacy.