Pharmacology of major neurological drugs

Antiparkinsonian

Class	Agents	Position
Levodopa + peripheral DDCI	Carbidopa, benserazide	Most effective for bradykinesia and rigidity; recommended first agent at any age. Motor fluctuations and dyskinesia with time
Dopamine agonists (non-ergot)	Pramipexole, ropinirole, rotigotine patch, apomorphine	Levodopa-sparing; impulse control disorders ~15-20%
Ergot agonists	Bromocriptine, pergolide, cabergoline	*Avoid - cardiac valvulopathy and retroperitoneal/pulmonary fibrosis*
MAO-B inhibitors	Rasagiline, selegiline, safinamide	Less effective than levodopa; useful early or as adjunct
COMT inhibitors	Entacapone (with each dose), opicapone (once daily), tolcapone	Prolong levodopa "on" time. Tolcapone: hepatotoxicity, restricted
Amantadine		The drug for dyskinesia
Anticholinergics	Benztropine, trihexyphenidyl	Tremor only, in the young. Avoid over 65

Anti-seizure medication - by mechanism

Mechanism	Agents
Na channel blockade	Phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide
SV2A binding	Levetiracetam, brivaracetam
GABA enhancement	Benzodiazepines, phenobarbital, vigabatrin (irreversible GABA-transaminase inhibitor)
T-type Ca channel	Ethosuximide (absence only)
AMPA antagonism	Perampanel
Multiple	Valproate, topiramate, zonisamide
Ca channel alpha-2-delta	Gabapentin, pregabalin

Other major classes

MS: interferon beta, glatiramer, teriflunomide | S1P modulators (fingolimod, siponimod) | dimethyl fumarate | anti-CD20 (ocrelizumab, ofatumumab), natalizumab, alemtuzumab, cladribine
Migraine: triptans (5-HT1B/1D) | gepants (ubrogepant, rimegepant, atogepant) | CGRP monoclonals (erenumab, fremanezumab, galcanezumab, eptinezumab) | ditans (lasmiditan)
Neuromuscular: pyridostigmine | corticosteroid + steroid-sparing | IVIg, plasma exchange | complement inhibitors (eculizumab, ravulizumab, zilucoplan) | FcRn antagonists (efgartigimod, rozanolixizumab)
Neuropathic pain: amitriptyline, duloxetine, pregabalin, gabapentin

Adverse effect frequencies worth carrying

Adverse effect frequencies worth carrying

Effect	Drug	Frequency
Impulse control disorder	Dopamine agonists	~15-20%
Irreversible visual field constriction	Vigabatrin	20-40% - mandates 6-monthly perimetry
Motor fluctuations	Levodopa	~50% at 5 years
Major congenital malformation	Valproate	~10% (background 2-3%)
Neurodevelopmental impairment / reduced IQ	Valproate in utero	~30-40%; autism risk ~4-5x
Hyponatraemia	Carbamazepine, oxcarbazepine	~5-20% (higher in the elderly)
Behavioural/psychiatric adverse effects	Levetiracetam	~10-15%
Serious rash / SJS	Lamotrigine (rapid titration, or with valproate)	~0.1-0.3%

Pharmacodynamics worth stating

Peripheral DDCI (carbidopa, benserazide) does not cross the blood-brain barrier -> blocks peripheral decarboxylation only -> more levodopa reaches the brain, far less nausea and hypotension
Entacapone inhibits peripheral COMT -> less levodopa methylated to 3-O-methyldopa -> more crosses into the CNS and the clinical response is prolonged
- Peripheral action only - so it must be given with each levodopa dose, and it does not work alone
Amantadine - increases dopamine release, blocks reuptake, antagonises NMDA receptors, and has anticholinergic activity
MAO-B inhibitors block central dopamine breakdown; selegiline is metabolised to amphetamine derivatives -> insomnia
Vigabatrin irreversibly inhibits GABA transaminase -> raises CNS GABA -> also the mechanism of retinal toxicity

Pharmacokinetics that change prescribing

Phenytoin follows zero-order (saturable) kinetics in the therapeutic range
- A small dose increase produces a disproportionate rise in level - increase by small increments and recheck
- Highly protein bound (~90%): in hypoalbuminaemia, renal failure or pregnancy, total level under-reads the active drug - measure free phenytoin or correct
Carbamazepine autoinduces its own metabolism over 2-4 weeks - levels fall after initial titration; recheck and re-titrate
Levodopa competes with dietary large neutral amino acids at the gut and blood-brain barrier -> take 30-60 min before protein
- Absorption depends on gastric emptying -> gastroparesis, constipation and H. pylori cause delayed-on and dose failure
Renally cleared, needing dose reduction in CKD: levetiracetam, gabapentin, pregabalin, topiramate, lacosamide, pramipexole, amantadine
Hepatically cleared: valproate, carbamazepine, phenytoin, lamotrigine

Enzyme induction and inhibition

Enzyme induction and inhibition - the highest-yield interaction principle

Enzyme INDUCERS: carbamazepine, phenytoin, phenobarbital, primidone; oxcarbazepine (weaker); topiramate at higher doses (>200 mg/day)
- Reduce efficacy of: hormonal contraception (including the implant), DOACs, warfarin, statins, calcineurin inhibitors, antiretrovirals, chemotherapy, corticosteroids
- Also increase vitamin D catabolism -> osteomalacia and osteoporosis with long-term use
Valproate is an enzyme INHIBITOR - raises lamotrigine levels; halve the lamotrigine dose and titrate slowly
Oestrogen-containing contraception induces lamotrigine glucuronidation - levels fall ~50%; levels drop in the pill-free week and rise again on stopping the pill
Non-inducing, interaction-light choices: levetiracetam, brivaracetam, lacosamide, gabapentin, pregabalin - preferred in oncology, transplant and complex polypharmacy

Recognising drug toxicity

Syndrome	Features	Culprits
Serotonin syndrome	Clonus (esp. inducible/ocular), hyperreflexia, agitation, hyperthermia, diarrhoea; rapid onset	MAO-B inhibitor (rasagiline > selegiline) + SSRI/SNRI, tramadol, pethidine, methadone, dextromethorphan, linezolid, triptans
Neuroleptic malignant syndrome	Lead-pipe rigidity, hyperthermia, autonomic instability, inc CK, slower onset, hyporeflexia	Dopamine antagonists; abrupt levodopa withdrawal (parkinsonism-hyperpyrexia)
Phenytoin toxicity	Nystagmus -> ataxia -> dysarthria -> encephalopathy as level rises	Zero-order kinetics, interactions, hypoalbuminaemia
Valproate hyperammonaemic encephalopathy	Confusion, lethargy, normal LFTs and normal valproate level	Valproate +/- topiramate. Check ammonia; carnitine may help
DRESS	Rash + fever + eosinophilia + hepatitis, 2-8 weeks in	Carbamazepine, phenytoin, lamotrigine, phenobarbital
SJS/TEN	Mucosal involvement, skin detachment	Carbamazepine, lamotrigine, phenytoin
Anticholinergic toxicity	Confusion, retention, dry, hot, dilated pupils	Benztropine, oxybutynin, TCA, amantadine

HLA pharmacogenomics - examinable

*HLA-B\15:02 -> carbamazepine/oxcarbazepine SJS-TEN**
- Test before starting in people of Han Chinese, Thai, Malay, Indonesian, Filipino or South Asian ancestry
*HLA-A\31:01 -> carbamazepine DRESS and other hypersensitivity** (European and Japanese ancestry)
Phenytoin and lamotrigine share cross-reactive hypersensitivity with carbamazepine - avoid substituting one aromatic ASM for another after a severe reaction

Therapeutic drug monitoring

Therapeutic drug monitoring - only where it earns its place

Phenytoin - narrow index, non-linear kinetics; free level if albumin low or in renal failure
Carbamazepine, valproate, phenobarbital - adherence, toxicity, pregnancy
Lamotrigine and levetiracetam in pregnancy - clearance rises substantially; levels fall and seizures break through
Most modern ASMs are titrated to clinical effect, not level. Treat the patient, not the number

Prescribing rules that apply across neurology

A. Prescribing rules that apply across neurology

Start low, go slow - especially lamotrigine, topiramate, dopamine agonists, pregabalin
Never stop an anti-seizure medication or levodopa abruptly - status epilepticus, parkinsonism-hyperpyrexia
Monotherapy at the maximum tolerated dose before adding a second agent
Match the mechanism to the syndrome; avoid combining two Na channel blockers if possible
Check every new drug against the induction/inhibition list above

Valproate - the highest-stakes prescribing decision in neurology

B. Valproate - the highest-stakes prescribing decision in neurology

*Contraindicated in women and girls of childbearing potential unless there is no effective alternative and the conditions of a pregnancy prevention programme are met*
- Documented specialist discussion and consent, negative pregnancy test before starting, effective contraception (preferably a long-acting reversible method), annual specialist review, boxed warning acknowledged
- Absolutely contraindicated in pregnancy for migraine and bipolar disorder; in epilepsy only if no alternative controls seizures
Also counsel male patients - a possible risk of neurodevelopmental disorders after paternal exposure has prompted precautionary contraception advice
Other toxicity: hepatotoxicity (fatal in POLG mutations - avoid in suspected mitochondrial disease), pancreatitis, hyperammonaemia, thrombocytopenia, weight gain, tremor, alopecia, PCOS
Where valproate is the only effective agent for genetic generalised epilepsy, say so explicitly and document the reasoning

Antiparkinsonian prescribing

C. Antiparkinsonian prescribing

Levodopa: 30-60 min before food; smallest effective dose, more frequent dosing rather than larger doses as fluctuations appear
- Check vitamin B6 with high-dose or infusion therapy - carbidopa/levodopa depletes B6 and seizures have been reported above 1000 mg/day of levodopa
Dopamine agonists: warn the patient AND a family member about impulse control disorders before the first script; ask at every review
- Also sedation and sudden-onset sleep - explicit driving advice; peripheral oedema, hallucinations
- Dopamine agonist withdrawal syndrome on tapering - anxiety, pain, dysautonomia, drug craving; taper slowly
MAO-B inhibitors: avoid fluoxetine, fluvoxamine, tramadol, pethidine, methadone, dextromethorphan and linezolid - serotonin syndrome
- Selegiline -> insomnia (dose in the morning)
Entacapone: give with every levodopa dose; harmless orange-brown urine discolouration, diarrhoea (may be delayed weeks)
Apomorphine: pre-treat with domperidone; *never combine with ondansetron - profound hypotension*
Antiemetics in Parkinson disease: domperidone or ondansetron only; *never metoclopramide or prochlorperazine*
Antipsychotics in Parkinson disease/DLB: quetiapine or clozapine only

Anti-seizure medication - agent-specific cautions

D. Anti-seizure medication - agent-specific cautions

Drug	Watch
Carbamazepine	Hyponatraemia/SIADH, drowsiness, ataxia, diplopia, leucopenia, aplastic anaemia and agranulocytosis (rare), drug-induced lupus, aseptic meningitis, angioedema; *HLA-B\15:02. Autoinduction - recheck the level at 4 weeks. Aggravates absence and myoclonic seizures**
Phenytoin	Gingival hyperplasia, hirsutism, coarse facies, cerebellar atrophy with chronic use, osteomalacia, folate deficiency, DRESS; cardiac arrest with rapid IV loading - max 50 mg/min, cardiac monitoring (use fosphenytoin)
Lamotrigine	Rash - slow titration is not optional; halve the dose with valproate; levels fall on oestrogen-containing contraception and in pregnancy
Levetiracetam	Irritability, aggression, depression, suicidality - ask directly; renal dose adjustment. Pyridoxine is sometimes used for behavioural effects
Topiramate	Cognitive slowing and word-finding difficulty, weight loss, renal stones, metabolic acidosis, acute angle-closure glaucoma, oligohidrosis; teratogenic (orofacial clefts); induces at >200 mg/day
Vigabatrin	Irreversible concentric visual field constriction in 20-40% - baseline and 6-monthly perimetry, informed consent. Reserved for infantile spasms and refractory focal epilepsy
Perampanel	Serious psychiatric and behavioural reactions - boxed warning
Lacosamide	PR prolongation - ECG if cardiac conduction disease
Sodium channel blockers generally	*Worsen myoclonic and absence seizures* - the classic prescribing error in juvenile myoclonic epilepsy

Contraception, pregnancy and bone health

E. Contraception, pregnancy and bone health

Enzyme-inducing ASMs reduce contraceptive efficacy - carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, topiramate >200 mg
- Use a copper or levonorgestrel IUD, or depot medroxyprogesterone - not the pill, patch, ring or implant
Pre-conception: folic acid 5 mg daily, aim for monotherapy at the lowest effective dose
Lamotrigine and levetiracetam are the preferred ASMs in pregnancy; monitor levels each trimester and reduce back down promptly postpartum
Long-term inducers -> vitamin D and calcium supplementation and bone density monitoring

Immunotherapy prescribing principles

F. Immunotherapy prescribing principles

Vaccinate before starting any immunosuppressive DMT; live vaccines contraindicated afterwards
Screen HBV, HCV, HIV, TB, VZV immunity before anti-CD20, S1P modulators, natalizumab, alemtuzumab, rituximab
PML risk: natalizumab (highest; JCV index), fingolimod, dimethyl fumarate (via lymphopenia)
Alemtuzumab: secondary autoimmunity - monthly FBE, UEC, urinalysis and thyroid function for 4 years after the last dose
IVIg: check IgA (anaphylaxis), thrombosis and renal risk, aseptic meningitis, haemolysis

Drug-disease interactions to know

Renal impairment -> reduce levetiracetam, gabapentin, pregabalin, topiramate, lacosamide, pramipexole, amantadine
Hepatic impairment -> avoid or reduce valproate, carbamazepine, phenytoin
Cardiac conduction disease -> caution with lacosamide, carbamazepine, phenytoin (IV), fingolimod (first-dose bradycardia)
Myasthenia gravis -> *avoid aminoglycosides, macrolides, fluoroquinolones, magnesium, penicillamine, beta blockers, neuromuscular blockers; statins may unmask it but are not contraindicated once the diagnosis is established*
Parkinson disease -> avoid dopamine antagonists (metoclopramide, prochlorperazine, typical antipsychotics)
DLB -> severe neuroleptic sensitivity, potentially fatal
Mitochondrial disease / POLG -> valproate causes fatal hepatic failure
Porphyria -> avoid carbamazepine, phenytoin, phenobarbital, valproate; safe: levetiracetam, gabapentin
Elderly -> anticholinergic burden (benztropine, oxybutynin, amitriptyline) causes delirium and falls

Drug-induced neurological syndromes

Parkinsonism - metoclopramide, prochlorperazine, antipsychotics, valproate, lithium, amiodarone, flunarizine
Tremor - valproate, lithium, beta agonists, ciclosporin, tacrolimus, amiodarone
Peripheral neuropathy - isoniazid, vincristine, platins, taxanes, metronidazole, nitrofurantoin, amiodarone, phenytoin, excess pyridoxine
Myopathy - statins, corticosteroids, colchicine, chloroquine, checkpoint inhibitors
Seizures - tramadol, bupropion, clozapine, theophylline, fluoroquinolones, imipenem
Idiopathic intracranial hypertension - tetracyclines, retinoids, excess vitamin A, corticosteroid withdrawal
Aseptic meningitis - NSAIDs, IVIg, trimethoprim, carbamazepine

Long-term effects

Levodopa: efficacy is maintained, but the therapeutic window narrows - the "honeymoon" of stable response lasts ~3-5 years, then fluctuations and dyskinesia
Dopamine agonists: impulse control disorders may persist and cause catastrophic financial or relationship harm; withdrawal syndrome on stopping
Enzyme-inducing ASMs over years: osteoporosis and osteomalacia, adverse lipids, folate deficiency, cerebellar atrophy (phenytoin), gingival hyperplasia
Valproate in utero: the harm is fixed and lifelong - this is why the prescribing conditions are so strict
Vigabatrin: visual field loss is irreversible and progressive with cumulative dose - stop at the first field change
Tolerance to benzodiazepines within weeks; withdrawal seizures on abrupt cessation
Long-term immunosuppression: infection, PML, malignancy risk, secondary autoimmunity, hypogammaglobulinaemia

Monitoring

Drug	What, how often
Vigabatrin	Perimetry at baseline then 6-monthly
Carbamazepine	FBE, LFT, Na at baseline, 4 weeks, then periodically
Valproate	LFT and FBE in the first 6 months; ammonia if encephalopathic; annual pregnancy prevention review
Phenytoin	Level (free level if albumin low); FBE, LFT
Alemtuzumab	FBE, UEC, urinalysis monthly + TFT 3-monthly, for 4 years
Natalizumab	JCV antibody index 6-monthly; MRI surveillance
Enzyme inducers long-term	Vitamin D, calcium, bone density
Levodopa (high dose/infusion)	Vitamin B6, weight, orthostatic BP

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