Central Nervous System Drugs

The central nervous system (CNS) drug categories are among the most frequently prescribed and frequently misused classes in clinical practice. In South Africa, CNS disorders represent a significant disease burden — depression, anxiety, schizophrenia, epilepsy, Parkinson’s disease, and pain syndromes all require CNS-active pharmacotherapy. The pharmacist’s role encompasses appropriate drug selection, dispensing of controlled substances (schedule 5 and 6 drugs under the Medicines Act), management of drug interactions (especially with serotonergic drugs and MAOIs), monitoring for adverse effects, and ensuring adherence. For the SAPC examination, candidates must demonstrate thorough knowledge of drug mechanisms, indications, adverse effects, interactions, and the South African regulatory framework governing CNS-active medicines.

This topic builds on pharmacodynamics (pharma-006), pharmacokinetics (pharma-003 through pharma-007), drug interactions (pharma-008), and adverse drug reactions (pharma-009).

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Analgesics and Pain Management

The WHO Analgesic Ladder

The WHO three-step analgesic ladder, though originally developed for cancer pain, provides a framework for rational analgesic use in all pain:

Step	Drug Class	Examples	Indication
Step 1	Non-opioid ± adjuvant	Paracetamol, NSAIDs, antidepressants (for neuropathic pain), anticonvulsants	Mild pain (NRS 1–3)
Step 2	Weak opioid + non-opioid ± adjuvant	Codeine, tramadol, dihydrocodeine + paracetamol/NSAID	Moderate pain (NRS 4–6)
Step 3	Strong opioid + non-opioid ± adjuvant	Morphine, oxycodone, fentanyl, methadone ± antidepressants, anticonvulsants	Severe pain (NRS 7–10)

Key principles:

• Regular (around-the-clock) dosing rather than “as required” for continuous pain
• “By the clock” for persistent pain; “by the clock” + rescue dose for breakthrough pain
• Use adjuvant analgesics for neuropathic pain from the outset
• Treat breakthrough pain with immediate-release formulation of the same opioid
• Each step may include co-analgesics (adjuvants) for specific pain mechanisms

Paracetamol (Acetaminophen)

Mechanism: Central cyclooxygenase (COX) inhibition; also activates serotonergic descending pain pathways; no significant peripheral anti-inflammatory effect.

Dosing:

• Adults: 500 mg–1 g every 4–6 hours; maximum 4 g/day (4 × 1 g in SA)
• Weight-based in children: 10–15 mg/kg per dose
• Overdose: 150 mg/kg in children, >10 g in adults is potentially hepatotoxic

Pharmacokinetics:

• Oral bioavailability: 63–89% (wider range in children)
• Hepatic metabolism: glucuronidation (~50%), sulfation (~25%), CYP2E1 oxidation to toxic NAPQI (~5%)
• At therapeutic doses, NAPQI detoxified by glutathione
• At toxic doses: glutathione depleted → NAPQI accumulation → centrilobular necrosis

Antidote: N-acetylcysteine (NAC) — replenishes glutathione; also directly scavenges NAPQI. Most effective within 8 hours of ingestion.

SA context: Paracetamol is widely available OTC (schedule 1) in SA; paracetamol-containing combination products (e.g., pain mixtures with codeine) are schedule 5 or 6. Paracetamol overdose is a common presentation to emergency departments in SA.

NSAIDs

Mechanism: Non-selective inhibition of cyclooxygenase (COX-1 and COX-2) → decreased prostaglandin synthesis → anti-inflammatory, analgesic, antipyretic effects.

COX-1 effects (physiological)	COX-2 effects (pathological)
Gastric mucosal protection	Inflammation
Platelet aggregation (TXA₂)	Pain
Renal blood flow maintenance	Fever

NSAID types:

Drug	COX Selectivity	Key Features	SA Availability
Ibuprofen	Relatively COX-1 sparing	Short half-life; analgesic; anti-inflammatory	OTC schedule 1
Naproxen	More COX-1 inhibitory	Longer half-life; good for musculoskeletal	Schedule 2
Diclofenac	Some COX-2 inhibitory	Potent; availability concerns in some countries (CV risk)	Schedule 2
Mefenamic acid	Non-selective	Used for dysmenorrhoea	Schedule 2
Celecoxib	COX-2 selective	Less GI toxicity; CV risk	Schedule 3
Etoricoxib	COX-2 selective	Similar to celecoxib	Schedule 3

Adverse effects:

• GI: dyspepsia, erosions, ulcers, bleeding (COX-1 inhibition)
• Renal: acute interstitial nephritis, papillary necrosis (particularly with chronic use)
• Cardiovascular: ↑ risk of thrombotic events (stroke, MI) — all NSAIDs carry some CV risk; rofecoxib (withdrawn) had highest risk
• Bleeding: antiplatelet effect (aspirin is an NSAID but often listed separately for this property)
• Hypersensitivity: aspirin-exacerbated respiratory disease (AERD), urticaria
• Hepatic: transaminase elevations; cholestatic hepatitis (diclofenac)

COX-2 selective inhibitors and CV risk:

• Celecoxib, etoricoxib: increased risk of major adverse cardiovascular events
• Risk appears dose-dependent and duration-dependent
• Patients with established CVD, cerebrovascular disease, or significant risk factors for CVD should avoid or use with extreme caution

NSAIDs and specific concerns in South Africa:

• Indomethacin: not recommended in children (except for neonatal ductus arteriosus under specialist care)
• Ibuprofen in children: avoid if varicella infection (Reye’s syndrome concern; aspirin absolutely contraindicated)
• NSAID use in patients on warfarin: increase bleeding risk significantly

Opioid Analgesics

Mechanism: Bind to μ (mu), κ (kappa), and δ (delta) opioid receptors → Gi protein coupling → inhibition of adenylyl cyclase → ↓ cAMP → hyperpolarisation → decreased neuronal excitability and neurotransmitter release.

Opioid receptors and their effects:

Receptor	Effect
μ (mu)	Analgesia (supraspinal and spinal), euphoria, respiratory depression, miosis, decreased GI motility, physical dependence
κ (kappa)	Analgesia (spinal), sedation, dysphoria, psychotomimetic effects
δ (delta)	Analgesia, mood modulation

Weak Opioids

Codeine:

• Prodrug: ~10% converted to morphine by CYP2D6
• Available as: single agent, combination with paracetamol (schedules 5/6 depending on pack size), combination with ibuprofen
• Used for mild to moderate pain (typically combined with paracetamol or NSAID)
• SA scheduling: Schedule 5 (compound preparations with ≤12 mg codeine per tablet/unit dose); Schedule 6 (higher strengths or liquid preparations)
• CYP2D6 polymorphism critical: Poor metabolisers get minimal analgesia; ultrarapid metabolisers may get morphine toxicity from standard doses

Tramadol:

• Centrally acting analgesic; weak μ-opioid agonist + norepinephrine and serotonin reuptake inhibitor
• Metabolised by CYP2D6 to O-desmethyltramadol (active metabolite with higher μ-affinity)
• CYP2D6 poor metabolisers: reduced analgesia
• Serotonin syndrome risk when combined with other serotonergic drugs (SSRIs, SNRIs, MAOIs, St. John’s wort)
• Lower risk of respiratory depression than strong opioids; lower abuse potential than morphine

Strong Opioids

Morphine:

• Gold standard opioid analgesic; full μ-agonist
• Available: oral IR (immediate release), oral SR (sustained release), IV, IM, SC, epidural, intrathecal
• Dosing: IR 10–20 mg every 4 hours PRN; SR 10–20 mg every 12 hours regularly
• Active metabolites (M3G, M6G) accumulate in renal impairment → neurotoxicity (myoclonus, seizures)

Fentanyl:

• Synthetic μ-agonist; ~100× more potent than morphine
• Transdermal patches: for chronic severe pain in opioid-tolerant patients
• Available: IV, intranasal (for breakthrough cancer pain), buccal tablet, lozenge, patch
• Not suitable for acute pain or opioid-naïve patients

Oxycodone:

• Semi-synthetic; μ-agonist; oral bioavailability ~87%
• Available: IR and SR formulations
• Higher abuse potential than morphine; schedule 6 in SA

Methadone:

• Synthetic μ-agonist + NMDA receptor antagonist + serotonin reuptake inhibitor
• Very long and variable half-life (15–60+ hours) — accumulation risk
• Used for chronic pain (second-line), neuropathic pain, and opioid substitution therapy
• In SA, methadone for opioid substitution is strictly regulated; dispensed through approved addiction treatment centres

Opioid adverse effects:

• Respiratory depression (most dangerous; naloxone reversal)
• Constipation (no tolerance — prophylactic laxatives always needed)
• Nausea and vomiting (tolerance develops; antiemetics initially)
• Sedation, cognitive impairment
• Pruritus (histamine release with morphine; less with fentanyl/hydromorphone)
• Urinary retention
• Physical dependence and tolerance
• Hyperalgesia (paradoxical increased pain with long-term high-dose use)

Naloxone:

• Competitive μ-opioid antagonist
• IV/IM/SC: for reversal of respiratory depression in overdose
• IV infusion: for opioid-induced pruritus refractory to antihistamines
• Low-dose epidural: for post-Caesarean section pruritus without reversing analgesia
• Very short half-life (~30–60 min); may require repeat dosing or infusion

Adjuvant Analgesics for Neuropathic Pain

Neuropathic pain (burning, shooting, electric shock quality) responds poorly to conventional analgesics; adjuvant analgesics are first-line.

Tricyclic Antidepressants (TCAs):

• Amitriptyline, nortriptyline, imipramine
• Inhibit norepinephrine and serotonin reuptake; also block Na⁺ channels
• Dosing: start low (10–25 mg at night); titrate slowly; 4–6 weeks for full effect
• Adverse effects: anticholinergic (dry mouth, constipation, urinary retention, blurred vision), sedation, orthostatic hypotension, cardiac (prolonged QT, arrhythmias)
• Caution in elderly (anticholinergic effects, falls risk)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):

• Duloxetine, venlafaxine
• First-line for diabetic peripheral neuropathy, fibromyalgia, chronic musculoskeletal pain
• Duloxetine: 60–120 mg/day; venlafaxine 75–225 mg/day
• Fewer anticholinergic effects than TCAs; better tolerated
• Venlafaxine: withdrawal syndrome on abrupt cessation

Anticonvulsants:

• Gabapentin and pregabalin: α2δ subunit of voltage-gated Ca²⁺ channels → reduced neurotransmitter release

• First-line for postherpetic neuralgia, diabetic neuropathy, fibromyalgia, neuropathic cancer pain

• Pregabalin: more predictable pharmacokinetics than gabapentin; 150–600 mg/day in 2–3 divided doses

• Gabapentin: requires dose titration; 900–3600 mg/day in 3 divided doses

• Side effects: sedation, dizziness, peripheral oedema, weight gain

• Caution in renal impairment (both renally excreted)

• Carbamazepine: sodium channel blocker; first-line for trigeminal neuralgia

• Phenytoin: sodium channel blocker; less used now for neuropathic pain due to adverse effects

• Lamotrigine: sodium channel blocker; used for neuropathic pain in some protocols

Topical agents:

• Capsaicin: depletes substance P from sensory nerve endings; useful for small areas of neuropathic pain
• Lidocaine 5% patch: for postherpetic neuralgia; minimal systemic absorption
• Amitriptyline 10% cream: compounded; for localised neuropathic pain

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Antidepressants

Depression is one of the leading causes of disability worldwide. In South Africa, the burden of depression is amplified by HIV/AIDS, substance abuse, poverty, and violence. The South African Depression and Anxiety Group (SADAG) and the National Mental Health Framework guide management.

Major Depressive Disorder (MDD) — Diagnostic Criteria

At least 5 symptoms for ≥2 weeks, including depressed mood or anhedonia:

1. Depressed mood
2. Anhedonia (loss of interest/pleasure)
3. Weight/appetite changes
4. Sleep disturbance
5. Psychomotor changes
6. Fatigue
7. Feelings of worthlessness/guilt
8. Concentration difficulties
9. Suicidal ideation

Antidepressant Classes

Selective Serotonin Reuptake Inhibitors (SSRIs)

Mechanism: Selectively inhibit serotonin reuptake transporter (SERT) → increased synaptic serotonin.

Drug	Half-life	CYP metabolism	Key Features
Fluoxetine	Long (parent 4–6 days; norfluoxetine active metabolite 4–16 days)	CYP2D6 (strong inhibitor), CYP3A4	Long half-life; least likely to cause withdrawal; CYP2D6 inhibition persists
Sertraline	~26 hours	CYP2B6 (weak)	Preferred in patients with multiple drug interactions
Citalopram	~35 hours	CYP2C19, CYP2D6	QT prolongation (escitalopram lower risk)
Escitalopram	~27–32 hours	CYP2C19, CYP2D6	Active S-enantiomer of citalopram; less QT effect
Paroxetine	~21 hours	CYP2D6 (strong inhibitor)	Most anticholinergic; sedating; short half-life
Fluvoxamine	~15–22 hours	CYP1A2 (strong inhibitor), CYP2C19	Used for OCD; many drug interactions

Common adverse effects (all SSRIs):

• GI: nausea (usually transient), diarrhoea, constipation
• CNS: headache, insomnia or somnolence, anxiety (transient at initiation)
• Sexual dysfunction: decreased libido, anorgasmia, erectile dysfunction
• Weight changes: usually modest weight loss initially
• Serotonin syndrome (see below)
• Discontinuation syndrome (especially paroxetine, venlafaxine — short half-life drugs)
• Increased bleeding risk (impaired platelet serotonin uptake → reduced platelet aggregation) — important with NSAIDs, aspirin, anticoagulants

Serotonin syndrome — medical emergency: Caused by excess serotonergic activity in CNS. Features: altered mental status (agitation, confusion), autonomic instability (hyperthermia, tachycardia, hypertension, diaphoresis), neuromuscular abnormalities (hyperreflexia, clonus, rigidity), GI symptoms.

Drug combinations that cause serotonin syndrome (high-yield for SAPC):

• SSRI + MAOI (phenelzine, selegiline >5 mg/day): contraindicated — 2-week washout for most SSRIs before MAOI; 5 weeks for fluoxetine
• SSRI + tramadol (both serotonergic)
• SSRI + St. John’s wort (herbal — common in SA where it is sold for depression)
• SSRI + linezolid (weak MAOI)
• SSRI + meperidine (pethidine)
• SNRI + MAOI

Treatment: Stop serotonergic drugs; supportive care; cooling; benzodiazepines for agitation; cyproheptadine (serotonin antagonist) in severe cases.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Duloxetine:

• Also used for diabetic peripheral neuropathy, chronic musculoskeletal pain, fibromyalgia
• CYP1A2 and CYP2D6 substrate
• Adverse effects: nausea, dry mouth, constipation, decreased appetite, somnolence

Venlafaxine:

• Also used for generalised anxiety disorder (GAD) and social anxiety disorder
• CYP2D6 substrate; CYP3A4 inhibitor (weak)
• Discontinuation syndrome: taper rather than abrupt cessation

Tricyclic Antidepressants (TCAs)

Mechanism: Inhibit norepinephrine and serotonin reuptake; also block muscarinic (M1), histamine (H1), and α1-adrenergic receptors.

Examples: Amitriptyline, nortriptyline, imipramine, clomipramine (used for OCD)

Adverse effects: Anticholinergic (dry mouth, constipation, urinary retention, blurred vision, tachycardia), sedation, orthostatic hypotension, cardiac (prolonged QT), weight gain, sexual dysfunction, seizures (overdose).

In overdose: Cardiac arrhythmias (widened QRS), seizures, anticholinergic syndrome — all potentially fatal. Limited use in SA due to safety concerns; SSRIs preferred.

MAO Inhibitors (MAOIs)

Mechanism: Irreversibly inhibit monoamine oxidase A (MAO-A) and/or B (MAO-B) → prevents breakdown of norepinephrine, dopamine, serotonin.

Drug	MAO-A inhibition	MAO-B inhibition	Notes
Phenelzine	Irreversible, non-selective	Irreversible, non-selective	Hydrazine derivative; hepatotoxicity; requires tyramine-free diet
Tranylcypromine	Irreversible, non-selective	Irreversible, non-selective	Less hepatotoxicity than phenelzine
Selegiline	At low doses, selective for MAO-B	Selective MAO-B at low doses	Used for Parkinson’s disease (5–10 mg/day); at higher doses loses selectivity

Tyramine interaction (cheese reaction): MAO-A metabolises tyramine in the gut. MAOI + tyramine-rich foods (aged cheese, red wine, cured meats, fermented foods, soy products, some craft beers) → hypertensive crisis (severe hypertension, headache, intracranial haemorrhage, death).

SA context: Tyramine-rich foods are common in traditional South African cuisine (aged cheeses, dried game meats, fermented milk products like amasi). Patients on MAOIs must be counselled comprehensively on diet. MAOIs are rarely used first-line; when used, patient education is critical.

Antidepressant Treatment Algorithm

First-line (mild-moderate MDD): SSRI (sertraline, citalopram, escitalopram), SNRI (duloxetine, venlafaxine)

If inadequate response after 4–6 weeks at therapeutic dose:

• Ensure adherence
• Maximise dose if tolerated
• Consider switching to another first-line agent

If inadequate response after 2 first-line agents:

• Augmentation (add atypical antipsychotic, e.g., aripiprazole; or add TCA; or add buspirone)
• Combine two antidepressants (SSRI + bupropion)
• Refer to psychiatrist

If severe depression with psychotic features: Antidepressant + antipsychotic

Maintenance: Continue antidepressant for at least 6–12 months after remission; longer for recurrent episodes.

South African Context

SADAG and mental health: Depression screening in primary healthcare using the PHQ-9 (Patient Health Questionnaire-9) is recommended. Pharmacists can contribute to screening and referral.

Antidepressant availability in SA public sector: Fluoxetine, amitriptyline, and imipramine are on the EML for mental health disorders.

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Antipsychotics

Antipsychotic medicines are used for schizophrenia, bipolar disorder, and severe depression (as augmentation).

First-Generation (Typical) Antipsychotics

Mechanism: Predominantly D2 receptor blockade → reduces dopaminergic neurotransmission in the mesolimbic pathway (therapeutic effect) and nigrostriatal pathway (EPS side effects). Also varying affinity for other receptors (histamine, muscarinic, α-adrenergic).

Drug	Relative Potency	EPS Risk	Sedation	Anticholinergic
Chlorpromazine	Low	Moderate	High	High
Haloperidol	High	High	Low	Low
Fluphenazine	High	High	Low	Low
Trifluoperazine	High	High	Low	Low
Pericyazine	Moderate	Moderate	Moderate	Moderate

Adverse effects:

• Extrapyramidal symptoms (EPS): acute dystonia (first days), akathisia (days-weeks), parkinsonism (weeks-months), tardive dyskinesia (months-years)
• Hyperprolactinaemia (D2 blockade in tuberoinfundibular pathway): galactorrhoea, amenorrhoea, sexual dysfunction, gynaecomastia
• Sedation (H1 blockade)
• Anticholinergic effects (M1 blockade)
• Orthostatic hypotension (α1 blockade)
• QT prolongation (especially haloperidol, chlorpromazine)
• Neuroleptic malignant syndrome (NMS) — life-threatening emergency

Tardive dyskinesia (TD):

• Late-onset involuntary movements (orofacial dyskinesia most common; tongue protrusion, lip smacking, choreiform limb movements)
• Often irreversible; risk increases with duration of treatment and cumulative dose
• Treatment: switch to atypical antipsychotic; deutetrabenazine or valbenazine (VMAT2 inhibitors) — approved for TD in some settings
• Monitoring: AIMS (Abnormal Involuntary Movement Scale) assessment at baseline and periodically

Second-Generation (Atypical) Antipsychotics

Mechanism: D2 receptor blockade + 5-HT2A receptor blockade ( serotonin/dopamine interaction → reduced EPS compared to typicals).

Drug	Notable Features	Adverse Effects
Risperidone	High D2 potency; potent 5-HT2A	EPS (dose-dependent), hyperprolactinaemia (higher than others)
Paliperidone	Active metabolite of risperidone; LA injectable available	Similar to risperidone
Olanzapine	Good efficacy; weight gain, metabolic effects prominent	Weight gain, dyslipidaemia, hyperglycaemia (metabolic syndrome)
Quetiapine	Lower D2 affinity; more 5-HT2A; sedating	Sedation, orthostatic hypotension, metabolic effects (less than olanzapine)
Ziprasidone	Lower metabolic effects; causes QT prolongation	QT prolongation, injection-site reactions (IM)
Aripiprazole	Partial D2 agonist; 5-HT1A partial agonist	Less EPS, less hyperprolactinaemia, less metabolic effects
Clozapine	Only antipsychotic with proven superior efficacy for refractory schizophrenia; requires ANC monitoring	Agranulocytosis (mandatory monitoring), seizures, myocarditis, metabolic effects, sedation, sialorrhoea
Lurasidone	Minimal metabolic effects; causes QT prolongation	Akathisia, nausea

Clozapine — special monitoring:

• Reserved for treatment-resistant schizophrenia (failed response to 2 other antipsychotics)
• Requires weekly FBC (absolute neutrophil count) for first 18 weeks, then biweekly, then monthly if stable
• SAHPRA mandatory monitoring programme for clozapine in South Africa
• Agranulocytosis risk highest in first 3 months; risk lower after 6 months

Metabolic effects of atypical antipsychotics:

Drug	Weight Gain	Diabetes Risk	Dyslipidaemia
Clozapine	Highest	High	High
Olanzapine	High	High	High
Risperidone	Moderate	Moderate	Moderate
Quetiapine	Moderate	Moderate	Moderate
Aripiprazole	Low	Low	Low
Ziprasidone	Low	Low	Lowest

Monitoring protocol for antipsychotics:

• Baseline: weight/BMI, fasting glucose, lipids, blood pressure, ECG (if high risk)
• Ongoing: weight monthly initially, fasting glucose 3-monthly, lipids annually
• AIMS assessment at baseline and annually

Neuroleptic Malignant Syndrome (NMS)

Medical emergency; occurs with all antipsychotics (both typical and atypical).

Features: Hyperthermia (>38°C), muscle rigidity (“lead pipe”), altered mental status, autonomic instability (tachycardia, labile BP, diaphoresis), elevated CK, leukocytosis.

Management: Immediate antipsychotic cessation; supportive care (ICU); dantrolene (muscle relaxant) or bromocriptine (dopamine agonist); consider benzodiazepines for agitation.

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Anxiolytics and Sedative-Hypnotics

Benzodiazepines

Mechanism: Allosteric modulation of GABA-A receptors → increased frequency of chloride channel opening → enhanced GABAergic inhibition → anxiolytic, sedative, muscle relaxant, anticonvulsant effects.

Pharmacokinetics — important for SA exam:

Drug	Onset	Half-life (parent)	Active metabolites	Common uses
Diazepam	Fast	Long (20–100 hrs)	Yes (nordazepam, oxazepam)	Anxiety, muscle spasm, alcohol withdrawal, status epilepticus
Alprazolam	Fast	Short (12–15 hrs)	No	Panic disorder, anxiety
Lorazepam	Intermediate	Short (10–20 hrs)	No	Anxiety, sedation, status epilepticus (IV)
Midazolam	Very fast	Very short (1–4 hrs)	No (but active metabolite α-hydroxymidazolam)	Premedication, sedation, status epilepticus
Clonazepam	Fast	Long (18–50 hrs)	No	Myoclonus, seizures, anxiety

Adverse effects:

• CNS depression: sedation, impaired concentration, anterograde amnesia
• Respiratory depression (especially with other CNS depressants — opioids, alcohol)
• Paradoxical disinhibition (agitation, aggression) — more common in elderly, children, patients with brain injury
• Physical dependence and tolerance (develops over weeks to months)
• Withdrawal syndrome (anxiety, insomnia, tremor, seizures, delirium) — abrupt cessation after prolonged use
• Falls and fractures (especially in elderly)

Benzodiazepine dependence and withdrawal:

• Risk of dependence increases with dose and duration
• Withdrawal can be life-threatening (seizures) — requires gradual taper
• Long-acting benzodiazepines (diazepam) preferred for withdrawal management over short-acting (alprazolam)
• SA regulatory context: benzodiazepines are schedule 5 or 6 substances; prescriptions must be carefully managed

Flumazenil:

• Competitive GABA-A receptor antagonist
• Used to reverse benzodiazepine overdose (IV)
• Short half-life (~1 hour); may require repeat dosing or infusion
• Can precipitate seizures in patients dependent on benzodiazepines

Z-Drugs (Non-benzodiazepine hypnotics)

Mechanism: Selective BZ1 (ω1) subunit agonists on GABA-A receptors → sedative-hypnotic effect with less anxiolytic, muscle relaxant, and anticonvulsant activity than benzodiazepines.

Drug	Half-life	Features
Zopiclone	~5 hours	Metallic taste (common); some next-day impairment
Zolpidem	~2.5 hours	Shorter acting;幻觉, sleep-driving reported; less dependence than benzodiazepines
Eszopiclone	~6 hours	S-enantiomer of zopiclone; available in some markets

Adverse effects: CNS effects, complex sleep behaviours (sleep-driving, sleep-eating), hallucinations; dependence and withdrawal reported.

Buspirone

Mechanism: 5-HT1A partial agonist (anxiolytic without sedation, dependence, or rebound); also D2 partial agonist.

Key features:

• No sedation, no cognitive impairment, no interaction with alcohol
• Takes 2–4 weeks for full anxiolytic effect (not for acute anxiety)
• No withdrawal upon cessation
• Used for generalised anxiety disorder (GAD)

Pregabalin

Mechanism: Binds α2δ subunit of voltage-gated calcium channels → reduces calcium-dependent neurotransmitter release.

Used for: GAD, neuropathic pain, fibromyalgia, seizure control (adjunct).

Adverse effects: Dizziness, somnolence, weight gain, peripheral oedema, abuse potential (schedule 5 in SA).

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Anticonvulsants (Antiepileptics)

Overview of Seizure Types

Seizure Type	Features	Common Drugs
Focal (partial) seizures	One brain region;可以有或无意识改变	Carbamazepine, lamotrigine, levetiracetam, valproic acid
Generalised tonic-clonic	Whole brain; loss of consciousness; tonic then clonic phases	Valproic acid, lamotrigine, levetiracetam, phenytoin, carbamazepine
Absence seizures	Brief loss of awareness; no tonic-clonic activity	Ethosuximide, valproic acid
Myoclonic seizures	Sudden brief muscle jerks	Valproic acid, clonazepam, levetiracetam
Atonic seizures	Sudden loss of muscle tone	Valproic acid, felbamate

Major Anticonvulsants

Valproic acid (valproate):

• Broad-spectrum; effective for focal, generalised tonic-clonic, absence, myoclonic seizures
• Mechanism: multiple (GABA enhancement, Na⁺ channel blockade, T-type Ca²⁺ channel blockade)
• Adverse effects: hepatotoxicity (rare but severe — monitor LFTs), pancreatitis, weight gain, hair loss (reversible), tremor, thrombocytopenia, neural tube defects (teratogenic — spina bifida); polycystic ovary syndrome features
• Interactions: inhibits metabolism of many drugs; lamotrigine levels reduced
• In SA: widely used; available as oral and IV; EML includes valproic acid for epilepsy

Carbamazepine:

• First-line for focal seizures; not for absence or myoclonic seizures (may worsen)
• Mechanism: Na⁺ channel blockade
• Adverse effects: aplastic anaemia, agranulocytosis (monitor FBC), SIADH, hyponatraemia, Stevens-Johnson syndrome/TEN (HLA-B*1502 association — screen if Asian ancestry), hepatotoxicity, lupus-like syndrome
• Auto-inducer: induces own metabolism (auto-induction); also induces CYP3A4 → many drug interactions
• SA: available; used for trigeminal neuralgia as well as epilepsy

Phenytoin:

• Classic sodium channel blocker; first-line for focal seizures and status epilepticus
• Non-linear (Michaelis-Menten) pharmacokinetics — see pharma-007 for detailed discussion
• Adverse effects: gingival hyperplasia (good oral hygiene critical), hirsutism, coarse facial features, osteomalacia, peripheral neuropathy, haematological effects, teratogenicity (foetal hydantoin syndrome)
• Fosphenytoin: water-soluble prodrug; IV use for status epilepticus

Lamotrigine:

• Broad-spectrum (focal, generalised, absence); first-line in many protocols
• Mechanism: Na⁺ channel blockade, 5-HT blockade
• Adverse effects: rash (including SJS/TEN — risk highest in first 8 weeks; avoid rapid dose escalation); dizziness, headache
• Important: requires slow titration (start 25 mg daily; increase every 2 weeks); interaction with valproate (valproate doubles lamotrigine clearance → requires slower titration)
• SA: registered; EML includes lamotrigine

Levetiracetam:

• Broad-spectrum; effective for focal and generalised seizures
• Mechanism: SV2A protein binding (modulates synaptic vesicle exocytosis)
• Adverse effects: behavioural effects (irritability, aggression, depression); somnolence; rare haematological effects
• Minimal drug interactions; renal excretion (dose adjust in renal impairment)
• SA: registered; increasingly used first-line

Ethosuximide:

• First-line for absence seizures only
• Mechanism: T-type calcium channel blockade (thalamic neurones)
• Adverse effects: GI upset, headache, behavioural changes; rare agranulocytosis, SLE
• Not effective for other seizure types

** clonazepam:**

• Used for myoclonic seizures, absence seizures (adjunct), status epilepticus
• benzodiazepine — sedation, dependence with long-term use

Status Epilepticus Management

Stage	Time	Management
Early status	0–30 min	IV benzodiazepine (lorazepam 0.1 mg/kg or diazepam 0.15–0.2 mg/kg)
Established status	30–60 min	Fosphenytoin or phenytoin IV; or levetiracetam IV; or valproic acid IV
Refractory status	>60 min	IV anaesthetic (midazolam infusion, propofol, or pentobarbital)

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Parkinson’s Disease Pharmacotherapy

Parkinson’s disease (PD) results from degeneration of dopaminergic neurones in the substantia nigra → loss of striatal dopamine → basal ganglia dysfunction → motor symptoms.

Drug Classes for PD

Dopamine precursors:

• Levodopa + carbidopa (or benserazide): Carbidopa prevents peripheral conversion of levodopa to dopamine → more levodopa enters CNS; reduces peripheral dopamine side effects (nausea, vomiting, hypotension)
• Standard formulation: Sinemet (carbidopa-levodopa)
• Controlled-release: Sinemet CR (less fluctuations)
• Duodopa: intestinal gel infusion for advanced PD with motor complications

Dopamine agonists:

• Non-ergot: Pramipexole (D2/D3 agonist), Ropinirole (D2 agonist), Rotigotine (transdermal patch)
• Ergot: Bromocriptine, cabergoline (less used due to fibrotic complications)
• Adverse effects: nausea, somnolence, impulse control disorders (gambling, shopping, hypersexuality), hallucinations, oedema

MAO-B inhibitors:

• Selegiline (5 mg bd): inhibits MAO-B (dopamine metabolism in brain); early PD or adjunct; interacts with pethidine (meperidine) causing serotonin syndrome
• Rasagiline: similar; once daily
• safinamide: newer; MAO-B + glutamate release inhibition

COMT inhibitors:

• Entacapone, tolcapone: inhibit peripheral COMT → prolong levodopa half-life and reduce “off” periods
• Tolcapone: hepatotoxicity (monitor LFTs); only used when entacapone insufficient

Anticholinergics:

• Trihexyphenidyl (benzhexol), procyclidine: block muscarinic receptors in the striatum → reduce tremor and rigidity (not bradykinesia)
• Adverse effects: anticholinergic (dry mouth, constipation, urinary retention, blurred vision, confusion in elderly)
• Used mainly for tremor-predominant PD in younger patients

Amantadine:

• NMDA receptor antagonist; increases dopamine release; used for tremor and rigidity; also reduces dyskinesias

Huntington’s disease: Tetrabenazine — VMAT2 inhibitor; depletes dopamine; for chorea.

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SAPC Examination Focus Areas

High-yield topics for the SAPC exam:

1. Paracetamol overdose and NAC — mechanism of NAPQI, 8-hour treatment window
2. Opioid analgesic ladder — WHO three-step approach; appropriate escalation
3. Codeine + CYP2D6 polymorphism — poor vs ultrarapid metabolisers; tramadol serotonergic risk
4. Tramadol and serotonin syndrome — SSRI + tramadol, MAOI + tramadol interactions
5. SSRIs and serotonin syndrome — causative combinations; treatment (stop drug, supportive care, cyproheptadine)
6. Benzodiazepine dependence and withdrawal — flumazenil reversal; taper management
7. TCA overdose — cardiac arrhythmias (widened QRS), seizures, anticholinergic syndrome
8. Antipsychotic EPS and TD — dystonia, akathisia, parkinsonism, tardive dyskinesia; treatment; AIMS monitoring
9. Clozapine agranulocytosis — mandatory weekly FBC × 18 weeks; SAHPRA monitoring programme
10. Valproic acid — broad spectrum; hepatotoxicity; neural tube defects; pancreatitis
11. Lamotrigine — slow titration; SJS/TEN risk; valproate interaction (requires slower titration)
12. Phenytoin non-linear kinetics — saturation kinetics; protein binding;华南-维持 dose relationship
13. Levodopa + carbidopa — rationale for combination; peripheral vs central effects
14. Benzodiazepine scheduling — schedule 5/6; flumazenil availability
15. Neuroleptic malignant syndrome — hyperthermia, rigidity, CK elevation; management (stop drug, supportive care)

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Summary of Key Concepts

• Pain management follows the WHO analgesic ladder; neuropathic pain requires adjuvant analgesics (TCAs, SNRIs, gabapentinoids)
• Paracetamol overdose: NAPQI mechanism; NAC antidote; 8-hour window
• Opioid adverse effects: respiratory depression (naloxone reversal), constipation (prophylactic laxatives mandatory), dependence
• SSRIs are first-line for depression; monitor for serotonin syndrome and bleeding risk
• MAOIs: tyramine dietary restriction essential; hypertensive crisis with tyramine-rich foods
• Benzodiazepines: schedule 5/6; dependence risk; withdrawal requires gradual taper
• Antipsychotics: EPS (dystonia, akathisia, parkinsonism, TD) and metabolic effects; atypical generally preferred but clozapine for refractory cases
• Clozapine: mandatory ANC monitoring for agranulocytosis; SAHPRA programme
• Anticonvulsants: valproate (broad spectrum, hepatotoxic, teratogenic), lamotrigine (slow titration, rash), phenytoin (saturation kinetics), carbamazepine (auto-induction, SJS)
• Parkinson’s: levodopa-carbidopa (gold standard), dopamine agonists, MAO-B inhibitors, COMT inhibitors
• All CNS drugs with dependence potential are scheduled substances under the Medicines Act; pharmacists must manage prescriptions carefully