Antiepileptics and sedatives
Sedatives, Antiepileptics and Antiparkinson Drugs: FCPS Part 1 Pharmacology
Benzodiazepines, barbiturates, antiepileptics, antiparkinson, dementia and addiction drugs for FCPS Part 1. Explains GABA-A mechanisms, enzyme induction and inhibition, valproate and phenytoin toxicity, status epilepticus, levodopa wearing-off and carbidopa.
GABA-A receptor: how sedatives and many antiepileptics work
GABA is the main inhibitory transmitter. The GABA-A receptor is a ligand-gated chloride channel; chloride entry hyperpolarises the neuron. Benzodiazepines, barbiturates, propofol, alcohol and several antiepileptics act here.
| Feature | Benzodiazepines | Barbiturates |
|---|---|---|
| Action on the channel | Increase the frequency of opening | Increase the duration of opening; open it directly at high dose |
| Need GABA present | Yes (ceiling effect) | No at high dose (no ceiling) |
| Overdose | Rarely fatal alone; dangerous with alcohol or opioids | Fatal respiratory depression |
| Antidote | Flumazenil (may precipitate seizures) | None |
| Enzyme induction | No | Strong inducer |
| Contraindication | Respiratory failure, myasthenia | Acute intermittent porphyria (induce ALA synthase) |
- Benzodiazepine effects: anxiolysis, sedation, anticonvulsant, muscle relaxation, anterograde amnesia. Diazepam and chlorpromazine share sedation and potentiation of other CNS depressants.
- A barbiturate added to an MAO inhibitor produces exaggerated, prolonged sedation, because MAO inhibitors also inhibit hepatic metabolism of barbiturates.
Benzodiazepines in practice
| Drug | Half-life and features | Use |
|---|---|---|
| Midazolam | Shortest-acting; water-soluble | Procedural sedation, premedication, buccal for seizures |
| Triazolam | Ultra-short oral hypnotic | Insomnia (rarely used) |
| Lorazepam | Intermediate; glucuronidation only | IV for status epilepticus; liver disease |
| Oxazepam, temazepam | Glucuronidation only, no active metabolites | Safest in cirrhosis |
| Diazepam | Long; active metabolite (desmethyldiazepam) | Status (IV, rectal), muscle spasm, alcohol withdrawal |
| Chlordiazepoxide | Long-acting | Alcohol withdrawal |
| Clonazepam | Long | Myoclonic seizures, panic |
- In liver disease, oxidised benzodiazepines (diazepam, chlordiazepoxide) accumulate. Oxazepam or lorazepam, cleared by glucuronidation that is preserved in cirrhosis, are safer; over-sedation can mimic or trigger hepatic encephalopathy.
- Paradoxical disinhibition: an elderly patient given midazolam becomes restless and aggressive instead of drowsy. More benzodiazepine usually worsens it.
- Problems: tolerance, dependence, withdrawal seizures (taper), falls in the elderly. Z-drugs (zolpidem, zopiclone) act at the benzodiazepine site. Buspirone (5-HT1A partial agonist) is a non-sedating anxiolytic with slow onset.
Alcohol and drug dependence
- Delirium tremens (48–72 hours after the last drink): agitation, tremor, sweating, fever, tachycardia and visual hallucinations (insects). Treat with a benzodiazepine (chlordiazepoxide or diazepam; lorazepam or oxazepam in liver failure) and IV thiamine before glucose.
- Relapse prevention: acamprosate (modulates glutamate NMDA transmission, reduces craving, renally excreted, so suitable with liver disease); naltrexone (opioid antagonist, hepatotoxic at high dose); disulfiram (inhibits aldehyde dehydrogenase, acetaldehyde reaction). Metronidazole causes a similar reaction.
- Opioid dependence: methadone (long-acting full agonist) or buprenorphine (partial agonist) maintenance has the strongest evidence for reducing deaths and relapse. Tolerance is lost after detox or prison release, so overdose risk is high.
- ADHD: methylphenidate blocks dopamine and noradrenaline reuptake; monitor height, weight, BP and pulse.
Antiepileptic drugs
| Drug | Mechanism | Uses | Key adverse effects |
|---|---|---|---|
| Sodium valproate | Na+ channel, raises GABA, T-type Ca2+ | Broad spectrum: generalised and focal | Teratogenic (neural tube defects, developmental delay); fulminant hepatotoxicity (highest in children under 2 on polytherapy); pancreatitis, weight gain, tremor, hair loss, thrombocytopenia, hyperammonaemia; enzyme inhibitor |
| Carbamazepine | Na+ channel | Focal seizures, trigeminal neuralgia, bipolar | Enzyme inducer (and autoinduction), hyponatraemia, agranulocytosis, diplopia, ataxia, SJS with HLA-B*15:02; worsens absence and myoclonic seizures |
| Phenytoin | Na+ channel | Focal, tonic-clonic, status | Zero-order kinetics at therapeutic levels; gum hypertrophy, hirsutism, coarse facies, nystagmus, ataxia, folate deficiency, osteomalacia, fetal hydantoin syndrome; IV: hypotension, arrhythmia |
| Lamotrigine | Na+ channel | Focal and generalised; preferred in pregnancy; bipolar depression | Rash, SJS (slow titration) |
| Levetiracetam | SV2A vesicle protein | Focal, generalised, status, pregnancy | Irritability, depression |
| Ethosuximide | T-type Ca2+ (thalamus) | Absence only | GI upset |
| Gabapentin, pregabalin | α2δ Ca2+ subunit | Neuropathic pain, focal seizures | Sedation, misuse |
| Topiramate | Multiple | Seizures, migraine | Weight loss, renal stones, angle closure |
| Phenobarbital | GABA-A (duration) | Neonatal seizures | Sedation, inducer |
| Vigabatrin | Inhibits GABA transaminase | Infantile spasms (tuberous sclerosis) | Visual field loss |
Interactions: inducers and inhibitors
- Inducers (carbamazepine, phenytoin, phenobarbital) speed metabolism of the combined pill, warfarin, steroids and other antiepileptics. A woman on the combined pill who starts carbamazepine risks contraceptive failure: use a copper IUD, levonorgestrel IUS or depot medroxyprogesterone (not the implant or progestogen-only pill, which inducers also defeat). Conversely, oestrogen lowers lamotrigine levels.
- Valproate inhibits glucuronidation of lamotrigine, roughly doubling its level: adding valproate to lamotrigine causes rash and toxicity, so halve the lamotrigine dose.
- Drugs that lower the seizure threshold and can break control: tramadol, bupropion (especially with bulimia), tricyclics, some antipsychotics (clozapine), quinolones, pethidine.
- Phenytoin in pregnancy is continued with folic acid 5 mg. Enzyme-inducing drugs cross the placenta and induce fetal metabolism of vitamin K, so the newborn has deficient vitamin K-dependent carboxylation of factors II, VII, IX and X: bleeding with prolonged PT and normal platelets. Give the baby vitamin K at birth.
- Before surgery, antiepileptics are continued (give the morning dose; use IV forms if nil by mouth).
Seizure type and status epilepticus
- Generalised tonic-clonic: valproate (men), lamotrigine or levetiracetam (women who could become pregnant). Focal: lamotrigine or levetiracetam. Absence: ethosuximide or valproate. Myoclonic: valproate or levetiracetam. Infantile spasms: steroids or vigabatrin.
- Status epilepticus: airway, glucose; benzodiazepine at 5 minutes (IV lorazepam, buccal midazolam or rectal diazepam), repeat once; then IV levetiracetam, phenytoin or valproate; then anaesthesia (thiopental or propofol) by 30–60 minutes.
Exam trap Ethosuximide is for absence seizures only; carbamazepine and phenytoin can worsen absence and myoclonic seizures.
Antiparkinson drugs
Parkinson disease is loss of dopaminergic neurons in the substantia nigra pars compacta, leaving relative cholinergic excess in the striatum.
| Drug | Mechanism | Notes |
|---|---|---|
| Levodopa with carbidopa or benserazide | Dopamine precursor plus peripheral dopa decarboxylase (aromatic L-amino acid decarboxylase) inhibitor | Most effective; carbidopa reduces nausea and hypotension and lets more levodopa reach the brain; dark urine |
| Dopamine agonists (ropinirole, pramipexole, rotigotine) | D2 agonists | Younger patients; impulse control disorders, sleep attacks; ergot agonists cause fibrosis |
| MAO-B inhibitors (selegiline, rasagiline) | Slow dopamine breakdown | Early or adjunct |
| COMT inhibitors (entacapone) | Slow peripheral levodopa breakdown | Reduce wearing-off; orange urine |
| Amantadine | Dopamine release, NMDA antagonist | Reduces dyskinesia; livedo reticularis |
| Antimuscarinics (benzhexol) | Muscarinic block | Tremor; confusion in elderly |
| Apomorphine | Potent SC agonist | Rescue for "off" periods |
- Wearing-off and peak-dose dyskinesia after years of levodopa: surviving nigral terminals can no longer store dopamine and release it steadily, so brain levels follow each dose up and down. Protein-rich meals reduce effect because large neutral amino acids compete for gut and BBB transport.
- Avoid haloperidol, metoclopramide and prochlorperazine; use domperidone (does not cross the BBB) for nausea, for example after cholecystectomy, and quetiapine or clozapine for psychosis.
- Abrupt levodopa withdrawal can cause a neuroleptic malignant-like syndrome.
Remember Carbidopa works outside the brain so that levodopa can work inside it.
Dementia, motor neuron disease and other movement drugs
- Donepezil, rivastigmine, galantamine (acetylcholinesterase inhibitors) for mild to moderate Alzheimer disease. They raise vagal acetylcholine at the heart, causing bradycardia, heart block and syncope.
- Memantine (NMDA antagonist) for moderate to severe disease or when cholinesterase inhibitors are not tolerated. Neither changes disease progression.
- Riluzole reduces glutamate release and modestly prolongs survival in ALS; it does not improve strength.
- Chorea: tetrabenazine (VMAT2). Spasticity: baclofen (GABA-B), tizanidine, dantrolene, botulinum toxin. Essential tremor: propranolol, primidone.
Related psychiatric drug facts tested with this chapter
| Problem | Key fact |
|---|---|
| Acute dystonia or parkinsonism on haloperidol | Procyclidine (antimuscarinic) |
| Tardive dyskinesia | Supersensitive, upregulated striatal D2 receptors; procyclidine worsens it |
| Agitation in dementia | Antipsychotics raise stroke and death risk; severe sensitivity suggests Lewy body dementia |
| Post-operative delirium | Find and treat the cause first (pain, retention, hypoxia, infection, drugs) |
| Lithium plus thiazide | More proximal lithium reabsorption, toxicity |
| MAO inhibitor plus cheese | Tyramine releases noradrenaline |
| Sertraline with tramadol | Serotonin syndrome (clonus, hyperthermia) |
| Clozapine constipation | Antimuscarinic gut slowing; can cause ileus |
Antidepressants and antipsychotics are covered fully in the next chapter.
How FCPS asks about this
- Benzodiazepine versus barbiturate mechanism: frequency versus duration of chloride channel opening.
- Benzodiazepine for withdrawal in cirrhosis: oxazepam or lorazepam (glucuronidation only).
- Most serious valproate toxicity: fulminant hepatotoxicity; also neural tube defects.
- Rash after valproate added to lamotrigine: valproate inhibits lamotrigine metabolism.
- Newborn bleeding after maternal phenytoin: vitamin K-dependent factor deficiency.
- Carbidopa action: inhibits peripheral dopa decarboxylase.
- Antiemetic in Parkinson disease: domperidone.
Test yourself on this topic
5 of the 89 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
Three days after admission for a fracture, a heavy drinker becomes agitated, tremulous, sweaty and feverish, and sees insects on the walls. What is the diagnosis and first-line drug?
Answer: Delirium tremens; benzodiazepine
Alcohol withdrawal timeline: tremor, sweating, anxiety and craving from 6–12 hours; withdrawal seizures at 12–48 hours; delirium tremens at 48–72 hours (confusion, visual or tactile hallucinations, fever, tachycardia, autonomic instability—can be fatal). Treatment: benzodiazepines in a reducing regimen (chlordiazepoxide; lorazepam if liver failure), fluids, electrolytes, and parenteral thiamine (Pabrinex) before glucose to prevent Wernicke encephalopathy. Antipsychotics lower the seizure threshold and are not first-line.
Alcohol withdrawal
- 6–12 h: tremor, sweating
- 12–48 h: seizures
- 48–72 h: delirium tremens
- Treat: benzodiazepine + IV thiamine before glucose
Remember Shakes at 6, fits at 24, DTs at 48.
Why the other options are wrong
- Wernicke's; haloperidol Wernicke: confusion, ophthalmoplegia, ataxia; treat with thiamine.
- Alcoholic hallucinosis; nothing Hallucinosis occurs with clear consciousness; this patient is delirious.
- Hepatic encephalopathy; lactulose No liver failure picture.
- Schizophrenia; olanzapine Acute withdrawal, not psychosis.
A 7-year-old girl has many brief daily episodes of staring with eyelid flickering, provoked by hyperventilation; EEG shows 3 Hz spike-and-wave discharges. Which drug should be avoided because it can worsen this seizure type?
Answer: Carbamazepine
Childhood absence epilepsy: brief absences with 3 Hz generalised spike-and-wave on EEG, triggered by hyperventilation. Thalamocortical T-type calcium channels drive the rhythm; ethosuximide blocks them and is first-line for pure absences; valproate is used when generalised tonic-clonic seizures coexist (avoided in girls where possible because of teratogenicity); lamotrigine is an alternative. Carbamazepine, oxcarbazepine, phenytoin, gabapentin and vigabatrin can aggravate absence and myoclonic seizures.
Absence seizures
- EEG: 3 Hz spike-and-wave
- Mechanism: T-type Ca²⁺ channels (thalamus)
- Drugs: ethosuximide, valproate, lamotrigine
- Avoid: carbamazepine, phenytoin
Remember Carbamazepine makes absences worse.
Why the other options are wrong
- Ethosuximide First-line for absence seizures.
- Sodium valproate Effective; caution in females.
- Lamotrigine Alternative.
- Levetiracetam Broad-spectrum; generally safe.
A woman on the combined oral contraceptive pill starts carbamazepine for epilepsy. What advice is needed?
Answer: Carbamazepine may make the pill fail
Carbamazepine, phenytoin, phenobarbital, topiramate and rifampicin induce hepatic enzymes, speeding metabolism of oestrogen and progestogen and causing contraceptive failure. A copper or levonorgestrel IUD, or medroxyprogesterone injection, is recommended instead. Valproate does not induce enzymes but is highly teratogenic.
Enzyme inducers and the pill
- Inducers: carbamazepine, phenytoin, rifampicin
- Faster breakdown of hormones
- Risk: contraceptive failure
- Use IUD or depot injection
Remember Inducers wash the pill out.
Exam trap Lamotrigine levels fall with the combined pill; the interaction runs both ways.
Why the other options are wrong
- No interaction exists Enzyme induction is well known.
- The pill will raise carbamazepine to toxic levels Not the main interaction.
- Carbamazepine increases the pill's clotting risk Not the main issue.
- She should take the pill twice daily Not an appropriate solution.
A man with alcohol dependence wants medication to stay abstinent after detoxification. He has chronic liver disease with raised transaminases and does not want a drug that makes him ill if he drinks. Which drug reduces craving by acting on glutamate (NMDA) transmission and is excreted by the kidney?
Answer: Acamprosate
Three drugs help maintain abstinence after alcohol withdrawal. Acamprosate is thought to restore the balance between glutamate and GABA transmission disturbed by chronic drinking, reducing craving. It is renally excreted and not metabolised by the liver, so it suits patients with liver disease (but not severe renal impairment). Naltrexone, an opioid receptor antagonist, reduces the rewarding effect of alcohol and craving, but can cause hepatotoxicity and must not be given with opioids. Disulfiram inhibits aldehyde dehydrogenase, so drinking causes acetaldehyde accumulation: flushing, nausea, palpitations and hypotension. It relies on aversion and is contraindicated in heart disease. Chlordiazepoxide treats withdrawal, not relapse; thiamine prevents Wernicke's encephalopathy.
Alcohol dependence drugs
- Withdrawal: chlordiazepoxide + thiamine
- Acamprosate: glutamate/NMDA, renal excretion
- Naltrexone: opioid antagonist; avoid with opioids
- Disulfiram: blocks aldehyde dehydrogenase; aversion
Remember Acamprosate for the liver patient; disulfiram only for the motivated and fit.
Exam trap Metronidazole and some cephalosporins also cause a disulfiram-like reaction with alcohol.
Why the other options are wrong
- Disulfiram Disulfiram works by making the patient ill if he drinks, which he does not want.
- Naltrexone Naltrexone reduces craving via opioid receptors and has hepatotoxic potential.
- Chlordiazepoxide Chlordiazepoxide covers withdrawal, not long-term abstinence.
- Thiamine Thiamine prevents Wernicke–Korsakoff; it does not reduce craving.
An 80-year-old after hip surgery becomes confused and agitated at night, pulling at lines. What is the first step in management?
Answer: Find and treat the cause
Delirium is an acute, fluctuating disturbance of attention and awareness caused by an underlying problem. Common causes after surgery include infection, pain, urinary retention, constipation, dehydration, low sodium, hypoxia, drugs (opioids, anticholinergics, sedatives) and alcohol withdrawal. Management is to find and treat the cause, with non-drug measures: orientation, glasses and hearing aids, sleep, family presence. Drugs are a last resort for severe distress or danger.
Delirium
- Acute, fluctuating inattention
- Find the cause
- Infection, pain, retention, drugs
- Non-drug measures first
Remember Delirium is a symptom: find the illness.
Exam trap Hypoactive delirium (quiet, withdrawn) is often missed.
Why the other options are wrong
- Give IV haloperidol Only if severe distress or danger, short-term.
- Restrain physically Worsens agitation and injury.
- Start a benzodiazepine Worsens delirium unless alcohol withdrawal.
- Transfer to psychiatry Delirium is a medical problem.
Where this sits in the CPSP syllabus
- Paper 1: Autonomic and CNS drugs, Sedatives, antiepileptics, antiparkinson drugs
- Medicine & Allied, Paper 2: Systemic drugs, Neurological and psychiatric drugs
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