Pharmacology chapters
Sedative-hypnotics and antiepileptic drugs
How benzodiazepines, barbiturates and the Z-drugs act on the GABA-A receptor, their uses, dangers and antidote (flumazenil), and the antiepileptic drugs: mechanisms, drugs of choice for each seizure type, status epilepticus, key adverse effects and pregnancy issues.
- Benzodiazepines enhance GABA-A by increasing the frequency of chloride channel opening; barbiturates increase the duration of opening and at high doses open the channel directly, so they are far more dangerous in overdose; flumazenil reverses benzodiazepines (not barbiturates).
- Antiepileptic choices: valproate for generalised (tonic-clonic, absence, myoclonic) seizures except in women who could become pregnant (neural tube defects); ethosuximide for absence seizures; carbamazepine or lamotrigine for focal seizures; levetiracetam is widely used and safer in pregnancy.
- Status epilepticus: IV lorazepam or diazepam (or buccal/intranasal midazolam, rectal diazepam outside hospital), then a second-line drug such as IV phenytoin/fosphenytoin, valproate or levetiracetam; eclamptic seizures are treated with magnesium sulphate.
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The GABA-A receptor
GABA is the main inhibitory neurotransmitter in the brain. The GABA-A receptor is a ligand-gated chloride channel: chloride entry hyperpolarises neurons, making them harder to fire. Benzodiazepines, barbiturates, Z-drugs, alcohol, propofol and some general anaesthetics enhance it at different binding sites.
| Feature | Benzodiazepines | Barbiturates |
|---|---|---|
| Action | Increase the frequency of channel opening (need GABA) | Increase the duration of opening; at high doses open the channel directly (GABA-mimetic) |
| Safety in overdose | Relatively safe alone (wide margin) | Dangerous: respiratory depression, coma, death |
| Antidote | Flumazenil | None (supportive care; urine alkalinisation for phenobarbitone) |
| Enzyme induction | No | Yes (phenobarbitone is a strong CYP inducer) |
| Other | Dependence, withdrawal | Dependence; precipitate acute intermittent porphyria |
Benzodiazepines → frequency; barbiturates → duration ("barbiturates = duration", "frenzodiazepines").
Benzodiazepines
| Drug | Duration | Main uses |
|---|---|---|
| Midazolam | Short | Procedural sedation, induction, status epilepticus (buccal or IM) |
| Lorazepam | Intermediate | Status epilepticus (IV), anxiety; conjugated only, so suitable in liver disease |
| Alprazolam | Intermediate | Panic and anxiety disorders |
| Diazepam | Long (active metabolites) | Status epilepticus (IV or rectal), alcohol withdrawal, muscle spasm, anxiety |
| Chlordiazepoxide | Long | Alcohol withdrawal |
| Clonazepam | Long | Seizures, panic disorder |
Uses: anxiety, insomnia (short term), seizures and status epilepticus, alcohol withdrawal, premedication and sedation, muscle spasm.
Adverse effects: drowsiness, impaired driving, anterograde amnesia, paradoxical agitation (elderly, children), falls in the elderly, tolerance and dependence; withdrawal can cause anxiety, insomnia and seizures (so reduce gradually). Combined with alcohol or opioids they cause dangerous respiratory depression.
Flumazenil is a competitive antagonist at the benzodiazepine site. It can trigger seizures in people dependent on benzodiazepines or after tricyclic overdose, so it is used with care.
Z-drugs (zolpidem, zopiclone): act at the benzodiazepine site (BZ1); used for insomnia; reversed by flumazenil.
Barbiturates
- Thiopentone: ultra-short acting IV induction agent; short action due to redistribution from brain to muscle and fat.
- Phenobarbitone: long-acting; seizures (including neonatal seizures and status epilepticus), enzyme inducer (once used for neonatal jaundice).
- Contraindicated in acute intermittent porphyria.
Antiepileptic drugs
Mechanisms
| Mechanism | Drugs |
|---|---|
| Block sodium channels (prolong inactivation) | Phenytoin, carbamazepine, oxcarbazepine, lamotrigine, valproate (partly), topiramate |
| Block T-type calcium channels (thalamus) | Ethosuximide, valproate |
| Enhance GABA | Benzodiazepines, phenobarbitone, vigabatrin (inhibits GABA transaminase), tiagabine (blocks GABA reuptake), valproate |
| Act on synaptic vesicle protein SV2A | Levetiracetam |
| α2δ subunit of calcium channels | Gabapentin, pregabalin (also used for neuropathic pain) |
| Block glutamate (AMPA/NMDA) | Topiramate, perampanel |
Drug of choice by seizure type
| Seizure type | First choices | Avoid |
|---|---|---|
| Generalised tonic-clonic | Valproate (not in women of childbearing potential), lamotrigine, levetiracetam | (none specific) |
| Absence (petit mal) | Ethosuximide, valproate | Carbamazepine, phenytoin (can worsen absences) |
| Myoclonic | Valproate, levetiracetam | Carbamazepine, phenytoin |
| Focal (partial), with or without spread | Carbamazepine, lamotrigine, levetiracetam | (none specific) |
| Infantile spasms (West syndrome) | ACTH or steroids, vigabatrin (especially with tuberous sclerosis) | (none specific) |
| Status epilepticus | Benzodiazepine first (IV lorazepam or diazepam), then phenytoin/fosphenytoin, valproate or levetiracetam | (none specific) |
| Eclampsia | Magnesium sulphate | (none specific) |
| Febrile seizure (prolonged) | Buccal midazolam or rectal diazepam; treat the fever cause | (none specific) |
Choices follow commonly used guidance; check current local guidelines, especially for women who could become pregnant.
Key drugs and their adverse effects
| Drug | Important points |
|---|---|
| Phenytoin | Zero-order (saturation) kinetics at therapeutic levels; narrow therapeutic index (monitor levels); enzyme inducer. Adverse effects: gingival hyperplasia, hirsutism, coarse facies, nystagmus, ataxia, diplopia, megaloblastic anaemia (folate), osteomalacia (vitamin D), lymphadenopathy, SJS, fetal hydantoin syndrome. IV form can cause arrhythmias and hypotension (give slowly with ECG monitoring; fosphenytoin is safer); purple glove syndrome |
| Carbamazepine | Enzyme inducer (also induces its own metabolism: autoinduction). Drug of choice for trigeminal neuralgia; also bipolar disorder. Adverse effects: diplopia, ataxia, hyponatraemia (SIADH), agranulocytosis and aplastic anaemia, Stevens-Johnson syndrome (screen for HLA-B*1502 in people of South or East Asian ancestry where advised), liver toxicity, teratogenic (neural tube defects) |
| Sodium valproate | Broad spectrum; enzyme inhibitor. Adverse effects: hepatotoxicity (especially young children on several drugs), pancreatitis, weight gain, tremor, hair loss, thrombocytopenia, neural tube defects and developmental problems in exposed babies (avoid in girls and women who could become pregnant unless no alternative, with a pregnancy prevention programme) |
| Ethosuximide | Only for absence seizures; gut upset, drowsiness |
| Lamotrigine | Focal and generalised seizures; bipolar depression. Rash and SJS (titrate slowly; higher risk with valproate, which raises its levels) |
| Levetiracetam | Broad spectrum; few interactions; mood changes, irritability; relatively safe in pregnancy |
| Topiramate | Weight loss, kidney stones, word-finding difficulty, angle-closure glaucoma |
| Vigabatrin | Visual field defects |
| Gabapentin, pregabalin | Neuropathic pain more than epilepsy; sedation, dizziness |
Phenytoin = gums, hair, zero-order. Carbamazepine = trigeminal neuralgia, SIADH, agranulocytosis, SJS. Valproate = liver, pancreas, weight, neural tube defects. Ethosuximide = absence only.
Status epilepticus
A seizure lasting 5 minutes or more, or repeated seizures without recovery between them.
- Airway, breathing, oxygen, check glucose (give glucose if low; thiamine first in alcohol misuse).
- Benzodiazepine: IV lorazepam (or IV diazepam); if no IV access, buccal midazolam or rectal diazepam. Repeat once if needed.
- Second line if seizures continue: IV phenytoin or fosphenytoin, valproate or levetiracetam.
- Refractory: general anaesthesia (thiopentone, propofol or midazolam infusion) in intensive care.
Loading dose = 20 mg/kg IV
Maximum infusion rate = 50 mg/min in adults (1 mg/kg/min in children)
70 kg adult: 20 × 70 = 1400 mg
Fastest safe time = 1400 ÷ 50 = 28 minutes (monitor ECG and BP)
25 kg child: 20 × 25 = 500 mg
Rate limit 1 mg/kg/min = 25 mg/min → at least 500 ÷ 25 = 20 minutes
Doses follow common emergency teaching; always follow your hospital's current protocol.
Epilepsy and pregnancy
- All older antiepileptics carry some risk; valproate carries the highest (neural tube defects, developmental delay).
- Lamotrigine and levetiracetam have the most reassuring pregnancy data.
- Give folic acid (higher dose, 5 mg daily, before conception) to women on antiepileptics.
- Enzyme inducers (carbamazepine, phenytoin, phenobarbitone, topiramate) reduce the effect of oral contraceptives.
- Uncontrolled seizures also harm mother and baby, so drugs should not be stopped suddenly.
Expect: frequency vs duration of chloride channel opening, flumazenil, benzodiazepines in alcohol withdrawal and status epilepticus, thiopentone redistribution, barbiturates in porphyria, antiepileptic mechanisms, drug of choice for absence (ethosuximide) and drugs that worsen it, phenytoin kinetics and adverse effects, carbamazepine in trigeminal neuralgia and its adverse effects, valproate hepatotoxicity and teratogenicity, status epilepticus steps, magnesium sulphate in eclampsia.
Quick revision
- Benzodiazepines: frequency; barbiturates: duration. Flumazenil reverses benzodiazepines.
- Alcohol withdrawal: chlordiazepoxide or diazepam.
- Status epilepticus: lorazepam IV → phenytoin/fosphenytoin, valproate or levetiracetam.
- Absence: ethosuximide or valproate; avoid carbamazepine and phenytoin.
- Phenytoin: zero-order, gingival hyperplasia, hirsutism, nystagmus, ataxia.
- Carbamazepine: trigeminal neuralgia; SIADH, agranulocytosis, SJS; enzyme inducer.
- Valproate: hepatotoxic, pancreatitis, weight gain, neural tube defects.
- Eclampsia: magnesium sulphate.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
How do benzodiazepines and barbiturates differ in their action?
Both enhance the GABA-A chloride channel, but benzodiazepines increase how often it opens, while barbiturates increase how long it stays open and can open it directly at high doses.
What is the drug of choice for absence seizures?
Ethosuximide (or valproate if other seizure types are present as well).
What is the antidote for benzodiazepine overdose?
Flumazenil, used cautiously because it can trigger seizures.
Which antiepileptic drug causes gingival hyperplasia?
Phenytoin.