Pharmacodynamics, Antimicrobials, and DMARDs

This lecture covers pharmacodynamics (PD) — what the drug does to the body — including receptor theory, then applies these principles to antimicrobial stewardship and disease-modifying therapy.

PHARMACODYNAMICS AND RECEPTOR THEORY

Drug targets fall into four categories: (1) Receptors (e.g., beta-adrenoceptors, opioid receptors, steroid nuclear receptors) — transmit intracellular signals when activated; (2) Enzymes (e.g., ACE inhibitors inhibit angiotensin-converting enzyme; NSAIDs inhibit COX; methotrexate inhibits dihydrofolate reductase); (3) Ion channels (e.g., ligand-gated: nicotinic ACh receptor; voltage-gated: local anaesthetics block Na+ channels); (4) Transporters (e.g., SSRIs block SERT; thiazides block NCC cotransporter).

Affinity (KD): the concentration of drug required to occupy 50% of receptor sites at equilibrium. A lower KD means higher affinity — the drug binds receptors at lower concentrations.

Potency (EC50): the concentration producing 50% of the maximal effect. More potent drugs achieve a given effect at lower concentrations. Potency determines dosing, but not clinical superiority.

Efficacy (Emax): the maximum effect achievable when all receptors are occupied. A drug with low Emax cannot achieve the same ceiling response as one with high Emax regardless of dose.

Agonists: bind and activate receptors (produce a response). Full agonists have Emax = 1 (relative to the tissue maximum). Partial agonists have Emax between 0 and 1. In the presence of a full agonist, a partial agonist at high concentration displaces the full agonist from receptors but achieves only its own submaximal Emax — acting as a functional antagonist. Example: buprenorphine (partial mu-agonist) reduces morphine effect in dependent patients.

Inverse agonists: bind to the receptor and produce an effect opposite to the natural agonist. Example: beta-carbolines at benzodiazepine-GABA-A receptors produce anxiety rather than sedation.

Competitive antagonists: bind reversibly to the active site; their effect is overcome by increasing agonist concentration (rightward shift of dose-response curve, Emax preserved). Example: atropine at muscarinic receptors.

Non-competitive (irreversible) antagonists: bind permanently or at an allosteric site; increasing agonist concentration does not overcome blockade (Emax reduced). Example: phenoxybenzamine (irreversible alpha-blocker) for phaeochromocytoma.

Therapeutic index (TI) = TD50/ED50. Narrow TI drugs (aminoglycosides, digoxin, lithium, warfarin, phenytoin, ciclosporin, vancomycin) require TDM.

ANTIMICROBIALS: MECHANISMS AND RESISTANCE

Beta-lactams (penicillins, cephalosporins, carbapenems, monobactams): inhibit transpeptidase (penicillin-binding proteins, PBPs) responsible for cross-linking peptidoglycan in the bacterial cell wall. Bactericidal. Resistance mechanisms: beta-lactamase production (hydrolysis of the beta-lactam ring; overcome by beta-lactamase inhibitors such as clavulanate, tazobactam); altered PBPs (MRSA — methicillin-resistant S. aureus — has acquired mecA gene encoding PBP2a with low affinity for beta-lactams).

Macrolides (azithromycin, erythromycin, clarithromycin): bind 50S ribosomal subunit, inhibiting translocation. Bacteriostatic. Resistance: efflux pumps (mef gene), ribosomal methylation (erm gene). CYP3A4 inhibitors — interact with warfarin, statins.

Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin): inhibit bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, preventing DNA supercoiling and replication. Bactericidal. Resistance: chromosomal mutations in gyrase/topoisomerase; efflux pumps.

Aminoglycosides (gentamicin, tobramycin, amikacin): bind 30S ribosomal subunit, causing misreading of mRNA and incorporation of wrong amino acids. Concentration-dependent killing; post-antibiotic effect (PAE) allows once-daily dosing. Nephrotoxic and ototoxic.

Vancomycin: glycopeptide; binds D-Ala-D-Ala terminus of peptidoglycan precursor, preventing cell wall synthesis. Activity against gram-positive organisms only. Vancomycin-resistant Enterococcus (VRE): modified terminal (D-Ala-D-Lac), reducing vancomycin affinity 1000-fold.

Antimicrobial stewardship: rational use of antimicrobials to minimise selection pressure for resistance. Principles: prescribe only when indicated (bacterial, not viral infection), culture before treating where possible, use narrow-spectrum agents when feasible, correct duration, de-escalate when sensitivities known.

DMARDs AND BIOLOGICS

Conventional synthetic DMARDs (csDMARDs): Methotrexate (MTX) — inhibits dihydrofolate reductase (DHFR), reducing tetrahydrofolate needed for purine/pyrimidine synthesis, and has anti-inflammatory effects via adenosine pathway. Given once weekly; folic acid supplementation reduces toxicity. Toxicity: hepatotoxicity (LFT monitoring), pneumonitis, myelosuppression, teratogenicity (absolute contraindication in pregnancy; men should also use contraception). Hydroxychloroquine — unclear mechanism (inhibits lysosomal acidification, TLR signalling); used in SLE and mild RA; retinal toxicity requires annual ophthalmology review.

Biologic DMARDs: target specific inflammatory mediators. TNF inhibitors (adalimumab, etanercept, infliximab) — monoclonal antibodies or fusion proteins blocking TNF-alpha. Risk: reactivation of latent TB (screen with Mantoux/IGRA before starting), serious infections, demyelination. IL-6 inhibitors (tocilizumab) — block IL-6 receptor; risk of masking fever and raising LFTs. IL-17 inhibitors (secukinumab) — used in psoriatic arthritis and ankylosing spondylitis. JAK inhibitors (tofacitinib, baricitinib) — targeted synthetic DMARDs blocking intracellular JAK-STAT pathway; oral agents. Risk: thromboembolic events (black box warning in some regions), infections, dyslipidaemia.

NSAIDs: inhibit COX-1 (constitutive, protects gastric mucosa via PGE2, maintains platelet TXA2) and COX-2 (inducible, mediates inflammation). Non-selective NSAIDs (ibuprofen, diclofenac, naproxen): GI toxicity (peptic ulceration, bleeding — prescribe PPI prophylactically in high-risk patients). COX-2 selective inhibitors (celecoxib, etoricoxib): reduced GI toxicity but increased cardiovascular risk (reduced prostacyclin PGI2, which normally inhibits platelet aggregation and causes vasodilatation).