3.3 Central Nervous System & Antimicrobial Pharmacology

3.3 Central Nervous System & Antimicrobial Pharmacology

Quick Reference: Central nervous system (CNS) agents modify neurotransmitter kinetics to manage pain, psychiatric disorders, and seizures. Antimicrobial chemotherapy targets structural or metabolic differences between pathogens and host cells to eliminate bacterial, fungal, and viral infections without host toxicity.

Effective therapeutic management requires precise understanding of CNS receptor targets, metabolic toxicity pathways, antimicrobial mechanism classifications, and resistance mechanisms.

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Analgesics: Non-Opioid & Opioid Mechanisms

Pain management is organized hierarchically using the WHO analgesic ladder, starting with non-opioid analgesics and progressing to weak and strong opioids.

Paracetamol (Acetaminophen)

• Mechanism: Central inhibition of cyclooxygenase (COX-3 / COX-1 variant) and active cannabinoid system modulation ($AM404$ active metabolite). Lacks peripheral anti-inflammatory activity.
• Overdose & Hepatotoxicity:
  • Normal therapeutic doses undergo Phase II glucuronidation (60%) and sulfation (35%).
  • In overdose (>75–150 mg/kg), Phase II pathways saturate. Metabolism shifts to CYP2E1/CYP1A2, producing N-acetyl-p-benzoquinone imine (NAPQI).
  • When intracellular glutathione stores deplete below 30%, NAPQI binds covalently to hepatic parenchymal proteins, causing acute centrolobular hepatic necrosis.
  • Antidote: N-acetylcysteine (NAC) provides cysteine for glutathione regeneration and directly conjugates NAPQI. Most effective within 8 hours of ingestion.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Mechanism: Inhibit cyclooxygenase (COX-1 and COX-2) enzymes, preventing conversion of arachidonic acid to prostaglandins ($PGE_2, PGI_2$) and thromboxane.
• Non-Selective (Ibuprofen, Naproxen, Diclofenac): Inhibit COX-1 and COX-2.
• COX-2 Selective (Celecoxib, Etoricoxib): Preserve COX-1 homeostatic functions (gastric protection, platelet function) while reducing inflammation. Cardiovascular Risk: Imbalance between endothelial $PGI_2$ (inhibited) and platelet $TXA_2$ (uninhibited) increases atherothrombotic event risk.
• Adverse Effects: Gastric mucosal ulceration, acute kidney injury (due to loss of compensatory $PGE_2$-mediated afferent arteriolar vasodilation), sodium and water retention, exacerbation of asthma.

Opioid Analgesics

• Opioid Receptors: $\mu$ (Mu), $\kappa$ (Kappa), $\delta$ (Delta)—all $G_i$-protein coupled. Activation decreases intracellular cAMP, closes presynaptic voltage-gated $Ca^{2+}$ channels (inhibiting neurotransmitter release), and opens postsynaptic $K^+$ channels (hyperpolarization).
• Agents: Morphine, Oxycodone, Fentanyl, Buprenorphine (partial agonist), Methadone, Codeine, Tramadol (weak $\mu$-agonist + SERT/NET inhibitor).
• Opioid Toxidrome: Sedation, respiratory depression (decreased sensitivity of brainstem chemoreceptors to $\text{CO}_2$), pinpoint pupils (miosis), constipation, nausea, pruritus (histamine release).
• Reversal: Naloxone (competitive antagonist; short half-life requires repeated administration to prevent re-narcotisation).

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Psychotropic Agents & Neurotransmitter Modulation

Antidepressants

• SSRIs (Sertraline, Fluoxetine, Citalopram, Escitalopram): First-line. Block serotonin transporter (SERT). Adverse effects: GI upset, sexual dysfunction, hyponatremia (SIADH), QT prolongation (citalopram).
• SNRIs (Venlafaxine, Duloxetine): Block SERT and NET. Useful in comorbid neuropathic pain.
• Tricyclic Antidepressants (TCAs: Amitriptyline, Nortriptyline): Block SERT/NET plus $\alpha_1$, $M_1$, $H_1$ receptors. Overdose Lethality: Cardiac sodium channel blockade causes QRS prolongation, ventricular arrhythmias, hypotension, and seizures. Treated with IV sodium bicarbonate.
• Serotonin Syndrome: Co-administration of serotonergic agents (SSRIs, MAOIs, tramadol, linezolid, MDMA). Features: Hyperreflexia, clonus, autonomic instability, hyperthermia. Treatment: Supportive care, Cyproheptadine (5-HT antagonist).

Anxiolytics & Hypnotics

• Benzodiazepines (Diazepam, Lorazepam, Midazolam, Alprazolam): Positive allosteric modulators of $\text{GABA}_A$ receptors. Increase the frequency of $\text{Cl}^-$ channel opening $\rightarrow$ membrane hyperpolarization. Antidote: Flumazenil (risk of precipitating withdrawal seizures in dependent patients).
• Z-Drugs (Zopiclone, Zolpidem): Selective binding to $\alpha_1$-subunit of $\text{GABA}_A$ receptor for hypnotic action with less muscle relaxation.

Antipsychotics

• Typical / First-Generation (Haloperidol, Chlorpromazine): High $\text{D}_2$ receptor antagonism. Effective for positive symptoms; high risk of Extrapyramidal Symptoms (EPS) (dystonia, akathisia, parkinsonism, tardive dyskinesia) and hyperprolactinemia.
• Atypical / Second-Generation (Olanzapine, Risperidone, Quetiapine, Clozapine): Dual $5-\text{HT}_{2A}$ and $\text{D}_2$ antagonism. Lower EPS risk; high risk of metabolic syndrome (weight gain, dyslipidemia, diabetes).
• Clozapine: Gold standard for treatment-resistant schizophrenia. Unique adverse effect: Agranulocytosis (1-2%), requiring mandatory baseline and ongoing full blood count (FBC) monitoring.

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Antiepileptic Drugs (AEDs)

Antiepileptics suppress focal or generalized seizure activity by modulating voltage-gated ion channels or enhancing GABAergic inhibition.

• Carbamazepine: Blocks voltage-gated $\text{Na}^+$ channels. Powerful inducer of CYP3A4 (auto-induction). Screening for HLA-B*1502 allele required in Asian ancestry due to Stevens-Johnson Syndrome (SJS) risk.
• Lamotrigine: Blocks $\text{Na}^+$ and $\text{Ca}^{2+}$ channels. Requires slow dose titration to avoid life-threatening toxic epidermal necrolysis (TEN).
• Sodium Valproate: Broad-spectrum. Blocks $\text{Na}^+$ channels, T-type $\text{Ca}^{2+}$ channels, and increases GABA. Highly teratogenic (neural tube defects, cognitive impairment; prohibited in pregnancy unless no alternative exists).
• Levetiracetam: Binds synaptic vesicle protein SV2A, inhibiting neurotransmitter exocytosis. Minimal CYP interactions; excreted renally.

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Antibacterial Classes & Antimicrobial Resistance

Mechanisms of Bacterial Resistance

1. Enzymatic Inactivation: Production of $\beta$-lactamases (penicillinases, ESBLs, AmpC, carbapenemases) that hydrolyze the $\beta$-lactam ring.
2. Target Modification: Alteration of binding site (e.g., mecA gene in MRSA encoding PBP2a with low $\beta$-lactam affinity; vanA gene in VRE altering target to $D\text{-Ala-}D\text{-Lactate}$).
3. Efflux Pumps: Active transport of antibiotic out of bacterial cytoplasm (e.g., fluoroquinolone and tetracycline resistance in Gram-negative bacilli).
4. Decreased Permeability: Porin channel loss or down-regulation in outer membrane (Pseudomonas aeruginosa carbapenem resistance).

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Antifungals & Antivirals

Antifungal Agents

• Azoles (Fluconazole, Voriconazole, Itraconazole): Inhibit 14$\alpha$-demethylase (CYP51), blocking ergosterol synthesis. Inhibits human CYP450 enzymes.
• Polyenes (Amphotericin B, Nystatin): Bind directly to fungal ergosterol, forming transmembrane pores that leak intracellular $\text{K}^+$ and $\text{Mg}^{2+}$. Lipid formulations reduce nephrotoxicity.
• Echinocandins (Caspofungin, Micafungin): Inhibit $\beta$-(1,3)-$D$-glucan synthase, disrupting fungal cell wall integrity.

Antiviral Therapies

• Herpesviruses (Acyclovir, Valacyclovir): Phosphorylated by viral thymidine kinase to monophosphate, then by host enzymes to triphosphate, competitively inhibiting viral DNA polymerase.
• Influenza (Oseltamivir): Inhibits viral neuraminidase, preventing virion release from infected host cells.
• HIV Antiretrovirals: Combinations of NRTIs (tenofovir/emtricitabine), NNRTIs (efavirenz), Protease Inhibitors (darunavir), and INSTIs (dolutegravir/bictegravir).