CNS Pharmacology

CNS pharmacology presents unique challenges: drugs must cross the blood-brain barrier (BBB), achieve selective receptor targeting, and produce desired effects without intolerable side effects at non-target receptors.

BLOOD-BRAIN BARRIER

The BBB is formed by tight junctions between cerebral capillary endothelial cells, supported by astrocyte end-feet and pericytes. P-glycoprotein (P-gp) efflux pumps on the luminal membrane actively expel lipophilic drugs back into the bloodstream. Lipophilic, uncharged, small molecules cross most readily by passive diffusion. Active transport mechanisms carry glucose (GLUT1), amino acids, and some drugs across. Drugs that exploit lipophilicity include diazepam, heroin (diacetylmorphine), and thiopental. Quaternary amines (e.g., neostigmine) do not cross.

ANXIOLYTICS AND HYPNOTICS

Benzodiazepines (BZDs) are positive allosteric modulators (PAMs) of GABA-A receptors — they bind the benzodiazepine site (between α and γ subunits), enhancing the frequency of Cl− channel opening in response to GABA (not amplitude, which is the barbiturate effect). This increases inhibitory postsynaptic currents, producing anxiolysis, sedation, muscle relaxation, and anticonvulsant effects. BZD pharmacokinetics: triazolam and midazolam are short-acting (t½ hours — for insomnia and procedural sedation); diazepam and chlordiazepoxide are long-acting (t½ days — for alcohol withdrawal, generalised anxiety). Tolerance, dependence, and withdrawal (seizures, delirium tremens) are significant concerns with chronic use. Flumazenil (competitive BZD receptor antagonist) reverses BZD-induced sedation and respiratory depression. Z-drugs (zolpidem, zopiclone, zaleplon) are non-benzodiazepine hypnotics that bind preferentially to GABA-A receptors containing α1 subunits (sedation, amnesia) with less anxiolysis and muscle relaxation; still cause dependence. Buspirone is a 5-HT1A partial agonist: anxiolytic with no BZD cross-reactivity, no sedation, no dependence, but onset delayed 2 weeks (receptor downregulation required).

ANTIDEPRESSANTS

SSRIs (fluoxetine, sertraline, escitalopram) block the serotonin transporter (SERT), increasing synaptic 5-HT. Clinical onset is delayed 2-6 weeks despite immediate transporter blockade — this delay is partly explained by the receptor sensitivity hypothesis (autoreceptor downregulation required before net 5-HT output increases). Serotonin syndrome from interaction with MAOIs: hyperthermia, muscle rigidity, and clonus — potentially fatal. SNRIs (venlafaxine, duloxetine) block both SERT and NET (noradrenaline transporter); effective for depression and neuropathic pain (e.g., diabetic neuropathy, fibromyalgia). TCAs (imipramine, amitriptyline) block NET and SERT plus anticholinergic (M1 block — dry mouth, urinary retention, constipation), antihistamine (H1 block — sedation), and alpha-1 block (postural hypotension). TCA overdose: quinidine-like cardiac membrane stabilisation → QRS prolongation, ventricular arrhythmias, and seizures. MAOIs (phenelzine, tranylcypromine) irreversibly inhibit MAO-A (5-HT, NA, dopamine degradation) and MAO-B. Cheese reaction: dietary tyramine (normally metabolised by gut/liver MAO) enters systemic circulation → noradrenaline release → severe hypertensive crisis. Mirtazapine: alpha-2 antagonist — blocks presynaptic autoreceptors and heteroreceptors, increasing NA and 5-HT release; also 5-HT2 and 5-HT3 receptor antagonism, reducing nausea and improving sleep; weight gain via H1 block.

ANTIPSYCHOTICS

Typical antipsychotics (haloperidol, chlorpromazine) primarily block D2 dopamine receptors in the mesolimbic pathway (antipsychotic effect), but also in the nigrostriatal pathway (extrapyramidal side effects, EPS: acute dystonia, akathisia, drug-induced parkinsonism, tardive dyskinesia) and tuberoinfundibular pathway (hyperprolactinaemia → galactorrhoea, amenorrhoea, sexual dysfunction). Atypical antipsychotics: clozapine has high affinity for D4, 5-HT2A, and multiple other receptors — effective for treatment-resistant schizophrenia; risk of life-threatening agranulocytosis requires compulsory weekly full blood count monitoring. Olanzapine — metabolic syndrome (weight gain, dyslipidaemia, type 2 diabetes). Quetiapine — sedation, metabolic effects. Risperidone — D2/5-HT2A block, dose-dependent EPS. Neuroleptic malignant syndrome (NMS): rare but potentially fatal complication of any antipsychotic — hyperthermia, lead-pipe rigidity, autonomic instability, raised CK; requires immediate drug cessation, cooling, and often bromocriptine (D2 agonist) or dantrolene (muscle relaxant).

MOOD STABILISERS

Lithium: inhibits inositol monophosphatase (depleting IP3-mediated signalling) and glycogen synthase kinase-3 (GSK-3), affecting multiple signalling pathways. Narrow therapeutic index: target serum level 0.6-1.2 mmol/L (prophylaxis) or 0.8-1.2 mmol/L (acute mania). Requires monitoring of renal function and thyroid function (causes hypothyroidism). Toxicity signs: coarse tremor, confusion, ataxia, polyuria, arrhythmia, seizures. Valproate and carbamazepine are alternatives: valproate enhances GABAergic transmission and blocks voltage-gated Na+ channels; carbamazepine blocks voltage-gated Na+ channels (like phenytoin) and is also first-line for trigeminal neuralgia.