Question 1

What advances are being made in quantitative systems pharmacology (QSP) models?

Accepted Answer

Quantitative systems pharmacology (QSP) integrates pharmacokinetic/pharmacodynamic (PK/PD) modelling with biological network models to describe drug action in the context of disease pathophysiology. QSP models are mechanistic — they incorporate receptor binding kinetics, signal transduction, gene regulatory networks, cell population dynamics, and physiological feedback loops — and are larger and more biologically detailed than traditional PK/PD models. Key QSP applications in 2027: (1) Virtual patient populations — QSP models simulate heterogeneous patient populations with variability in disease severity, target expression, and baseline physiology to predict clinical trial outcomes; used to optimise dose selection and trial design; (2) Disease progression models — QSP models of rheumatoid arthritis, Alzheimer disease, diabetes, and oncology describe disease natural history and how interventions modify disease trajectory over years; (3) Drug combination optimization — complex multi-drug interactions in oncology (combination immunotherapy, targeted therapy) are modelled to predict synergistic or antagonistic interactions; (4) Biomarker-dose-response relationships — QSP links PK to biomarker (PD) to clinical outcome, enabling model-informed precision dosing; (5) Regulatory applications — FDA's Quantitative Systems Pharmacology Initiative endorses QSP models for drug development decision-making and trial design, particularly in oncology and immunology.

Question 2

What are the key pharmacological mechanisms of currently approved CNS drugs?

Accepted Answer

CNS drug pharmacology involves modulation of synaptic neurotransmission through multiple receptor classes: (1) Antidepressants: SSRIs (fluoxetine, sertraline, escitalopram) inhibit the serotonin reuptake transporter SERT (SLC6A4), increasing synaptic serotonin; SNRIs (venlafaxine, duloxetine, desvenlafaxine) inhibit both SERT and NET (noradrenaline transporter); TCA (amitriptyline, clomipramine) — SERT/NET inhibition plus significant H1, muscarinic, alpha-1 blockade (side effects); mirtazapine — alpha-2 antagonist (increases NE/5-HT release) + H1 antagonist (sedation); ketamine/esketamine — NMDA receptor non-competitive antagonist, rapidly reverses TRD; MAOIs — irreversible (phenelzine, tranylcypromine) or reversible (moclobemide) MAO-A/B inhibition; (2) Antipsychotics: D2 receptor blockade is the common mechanism; atypicals add 5-HT2A antagonism (reduces EPS risk); aripiprazole is a D2 partial agonist; clozapine has unique efficacy in treatment-resistant schizophrenia via D4, H1, M1–M4, alpha-1/2 pharmacology; (3) Anxiolytics: benzodiazepines — positive allosteric modulators of GABA-A receptor (enhance Cl- conductance); buspirone — 5-HT1A partial agonist; pregabalin/gabapentin — alpha-2-delta (voltage-gated calcium channel subunit) ligands; (4) Anticonvulsants: sodium channel blockers (carbamazepine, phenytoin, lamotrigine), GABA potentiators (valproate, vigabatrin), calcium channel blockers (ethosuximide on T-type channels).

Question 3

How does biased agonism differ from conventional pharmacology and what clinical implications does it have?

Accepted Answer

Conventional pharmacology assumed that agonist binding to a receptor leads to proportional activation of all downstream signalling pathways — a concept called receptor "coupling". Biased agonism (or functional selectivity) challenges this: different ligands binding to the same receptor can preferentially activate specific downstream signalling pathways while having less effect on others. This occurs because GPCRs can couple to both G proteins (canonical signalling) and beta-arrestin (non-canonical signalling: receptor internalisation, desensitisation, and MAPK signalling). Ligands that preferentially activate G protein signalling over beta-arrestin recruitment (G-protein-biased agonists) produce different pharmacological profiles from balanced agonists: (1) Opioid receptors — G protein bias (analgesia, respiratory depression mediated by K+ channel opening) vs beta-arrestin recruitment (GI side effects, receptor desensitisation/tolerance). G-protein-biased mu-opioid agonists (oliceridine, TRV130) were developed to provide analgesia without beta-arrestin-mediated respiratory depression; oliceridine (Olinvyk) is FDA-approved; (2) Angiotensin AT1 receptor — TRV027 (biased AT1 agonist) was explored to produce vasodilation via beta-arrestin without G-protein-mediated vasoconstriction (did not succeed clinically but established the concept); (3) Glucagon-like peptide receptors — biased GLP-1R agonists are in development to separate insulinotropic effects from gastric emptying delay (nausea) effects.

Question 4

What are the pharmacological principles behind ion channel drug targets?

Accepted Answer

Ion channels are membrane proteins forming selective pores that control ionic flux across cell membranes, generating electrical signals. They are the targets of multiple important drug classes. Voltage-gated sodium channels (Nav1.1–1.9): blocked by local anaesthetics (lidocaine, bupivacaine — use-dependent block), antiarrhythmics (flecainide, mexiletine), and anticonvulsants (carbamazepine, phenytoin — use-dependent, state-dependent block preferentially in rapidly firing neurons). Voltage-gated calcium channels (VGCCs): L-type (Cav1.2) in cardiac and vascular smooth muscle — dihydropyridines (amlodipine, nifedipine — vascular selectivity) and non-dihydropyridines (verapamil — cardiac, diltiazem — intermediate); N-type and P/Q-type (Cav2.1/2.2) in neurons — ziconotide (spinal) blocks N-type; T-type (Cav3.1) — ethosuximide. HERG (hERG, Kv11.1) potassium channel: major contributor to cardiac action potential repolarisation (IKr current); block by drugs causes QT prolongation and risk of torsades de pointes; off-target HERG block is the most common cause of drug-induced QT prolongation (antihistamines, antibiotics, antipsychotics, antifungals). KATP channels: sulfonylureas (glibenclamide, glipizide) close pancreatic beta-cell KATP channels, depolarising the cell and triggering insulin release; K channel openers (minoxidil, diazoxide) used for hypoglycaemia treatment.

Question 5

What is the pharmacology of established and emerging cardiovascular drugs?

Accepted Answer

Cardiovascular pharmacology continues to evolve with new drug classes demonstrating mortality benefit beyond traditional targets: (1) SGLT2 inhibitors — repurposed from diabetes to heart failure and CKD; mechanisms of HF benefit: osmotic diuresis reducing preload, haemodynamic unloading, reduction in cardiac energy substrate shifting (ketone bodies), anti-fibrotic and anti-inflammatory effects, erythropoiesis stimulation increasing O2 delivery; empagliflozin and dapagliflozin now indicated for HFrEF and HFpEF regardless of diabetes status; (2) Sacubitril/valsartan (Entresto) — combination ARNI (angiotensin receptor-neprilysin inhibitor); sacubitril (LBQ657 active metabolite) inhibits neprilysin, preventing degradation of BNP/ANP (natriuretic peptides) which reduce preload and afterload; combined with valsartan ARB to avoid excessive bradykinin accumulation; PARADIGM-HF showed 20% reduction in CV death vs enalapril; (3) Mavacamten — cardiac myosin inhibitor reducing excessive cross-bridge formation in HCM; reduces LVOT gradient; (4) Finerenone — non-steroidal mineralocorticoid receptor antagonist; more selective than spironolactone/eplerenone; CV and renal benefit in diabetic kidney disease (FIDELIO-DKD/FIGARO-DKD); (5) Inclisiran — siRNA targeting PCSK9 hepatic mRNA; twice-yearly dosing; equivalent LDL-lowering to monthly PCSK9 inhibitor injections.

British Pharmacological Society Annual Conference 2027

Pharmacology Q&A

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