CNS Pharmacology
1. What this chapter covers, and how NEET PG actually tests it
Central nervous system pharmacology is often learned as disconnected lists of drug classes and their side effects.
Almost every drug here works by raising or lowering one of five neurotransmitters, and its side effects are that same change occurring somewhere you did not intend.
Dopamine, serotonin, noradrenaline, GABA and acetylcholine account for the great majority of the subject.
The extrapyramidal effects of antipsychotics are not a separate phenomenon from their antipsychotic action; both are dopamine blockade, in different pathways.
| Transmitter | Raised by | Lowered by |
|---|---|---|
| Dopamine | Levodopa, agonists, amphetamine | Antipsychotics, metoclopramide |
| Serotonin | SSRIs, SNRIs, MAOIs, triptans | Some antiemetics |
| GABA | Benzodiazepines, barbiturates, valproate | Flumazenil |
| Acetylcholine | Anticholinesterases | Antimuscarinics, tricyclics |
| Glutamate | Ketamine, memantine, lamotrigine |
2. The dopamine pathways and antipsychotics
2.1 Four pathways, four consequences
Antipsychotics block dopamine D2 receptors everywhere, and each of the four dopamine pathways produces a different consequence.
| Pathway | Effect of blockade |
|---|---|
| Mesolimbic | Antipsychotic benefit for positive symptoms |
| Mesocortical | Worsening of negative symptoms |
| Nigrostriatal | Extrapyramidal side effects |
| Tuberoinfundibular | Hyperprolactinaemia |
That table explains almost every antipsychotic question, because the therapeutic effect and the three main adverse effects are all the same pharmacological action in different places.
Hyperprolactinaemia occurs because dopamine is the natural inhibitor of prolactin release, so blocking it removes the brake, producing galactorrhoea, amenorrhoea and gynaecomastia.
2.2 The extrapyramidal syndromes by timing
| Syndrome | Onset | Features |
|---|---|---|
| Acute dystonia | Hours to days | Oculogyric crisis, torticollis |
| Akathisia | Days to weeks | Inner restlessness, inability to sit still |
| Parkinsonism | Weeks to months | Bradykinesia, rigidity, tremor |
| Tardive dyskinesia | Months to years | Orofacial choreoathetosis |
Tardive dyskinesia is the one that may be irreversible and the one that worsens on stopping the drug, because chronic blockade has upregulated the receptors.
Acute dystonia is treated with an anticholinergic such as benztropine, which restores the dopamine-acetylcholine balance in the striatum.
Akathisia is frequently misread as worsening agitation, and increasing the antipsychotic dose makes it worse.
2.3 Atypical antipsychotics
Atypical agents combine D2 blockade with 5-HT2A antagonism, and the serotonergic action is thought to reduce extrapyramidal liability.
Their trade-off is metabolic: weight gain, dyslipidaemia and diabetes, which is why metabolic monitoring is standard.
Clozapine is reserved for treatment-resistant schizophrenia and is the most effective agent, but requires monitoring for agranulocytosis, and also causes myocarditis, seizures and hypersalivation.
Risperidone raises prolactin most among the atypicals; olanzapine causes the most weight gain; aripiprazole is a partial agonist and is comparatively weight-neutral.
Neuroleptic malignant syndrome presents with hyperthermia, lead-pipe rigidity, autonomic instability and a raised creatine kinase, and is treated by stopping the drug and giving dantrolene or bromocriptine.
3. Antidepressants and mood stabilisers
3.1 The classes and what distinguishes them
Selective serotonin reuptake inhibitors are first-line because their toxicity in overdose is far lower than that of older agents, not because they are more effective.
They cause gastrointestinal upset, sexual dysfunction, hyponatraemia particularly in the elderly, and an initial increase in anxiety.
All antidepressants take two to four weeks to work, because the benefit depends on receptor downregulation and neuroplastic change rather than on the immediate rise in synaptic transmitter.
That delay is why the immediate transmitter increase cannot be the therapeutic mechanism, and why suicide risk may briefly rise as energy returns before mood does.
Tricyclics block reuptake but also block muscarinic, histaminic and alpha-1 receptors, which produces their anticholinergic, sedative and postural hypotensive effects.
In overdose tricyclics cause the three Cs: coma, convulsions and cardiotoxicity, with QRS widening from sodium channel blockade treated with sodium bicarbonate.
Monoamine oxidase inhibitors cause hypertensive crisis with tyramine-containing foods, because tyramine normally degraded in the gut instead reaches the circulation and displaces noradrenaline.
Serotonin syndrome combines altered mental state, autonomic instability and neuromuscular hyperactivity with clonus and hyperreflexia, and its onset is within hours.
3.2 Distinguishing serotonin syndrome from neuroleptic malignant syndrome
| Feature | Serotonin syndrome | Neuroleptic malignant syndrome |
|---|---|---|
| Onset | Hours | Days |
| Neuromuscular | Clonus, hyperreflexia | Lead-pipe rigidity |
| Bowel sounds | Increased | Normal or reduced |
| Pupils | Dilated | Normal |
| Treatment | Cyproheptadine | Dantrolene, bromocriptine |
Clonus and hyperreflexia versus lead-pipe rigidity is the cleanest single discriminator, and the speed of onset supports it.
3.3 Choosing between antidepressants
Since the classes are broadly equal in efficacy, selection is driven by side effect profile and by comorbidity, which is exactly how the exam frames it.
Mirtazapine causes sedation and weight gain, which makes it useful in a depressed patient with insomnia and poor appetite rather than a drawback.
Bupropion is weight-neutral and does not cause sexual dysfunction, but lowers the seizure threshold and is therefore avoided in eating disorders and epilepsy; it also aids smoking cessation.
Venlafaxine and duloxetine inhibit both serotonin and noradrenaline reuptake, and duloxetine additionally helps neuropathic pain.
Fluoxetine has by far the longest half-life, which reduces discontinuation symptoms but lengthens the washout needed before starting a monoamine oxidase inhibitor.
Paroxetine has the shortest half-life and the most marked discontinuation syndrome, with dizziness and electric-shock sensations.
Sertraline is generally preferred after myocardial infarction because of its cardiac safety data.
3.4 Lithium and the mood stabilisers
Lithium has a narrow therapeutic index and is renally excreted, so anything reducing renal clearance raises the level.
Thiazides, non-steroidal anti-inflammatory drugs, ACE inhibitors and dehydration all raise lithium levels, and each does so by reducing renal excretion.
Long-term effects are hypothyroidism, nephrogenic diabetes insipidus and tremor; toxicity causes coarse tremor, ataxia, confusion and seizures.
It is teratogenic, causing Ebstein anomaly.
Valproate, carbamazepine and lamotrigine are alternatives; lamotrigine is favoured for bipolar depression and carries the risk of Stevens-Johnson syndrome if titrated too quickly.
4. Antiepileptics, anaesthetics and analgesics
4.1 Antiepileptic drugs
| Drug | Mechanism | Distinctive adverse effect |
|---|---|---|
| Phenytoin | Sodium channel block | Gingival hyperplasia, hirsutism, zero-order kinetics |
| Carbamazepine | Sodium channel block | Hyponatraemia, agranulocytosis, autoinduction |
| Valproate | Multiple | Weight gain, tremor, hepatotoxicity, teratogenicity |
| Lamotrigine | Sodium channel block | Stevens-Johnson syndrome |
| Levetiracetam | SV2A binding | Behavioural change, irritability |
| Ethosuximide | T-type calcium block | Absence seizures only |
Ethosuximide works only in absence seizures because T-type calcium channels in the thalamus generate the three-per-second spike-wave discharge, and those channels are not involved in other seizure types.
Carbamazepine and phenytoin worsen absence and myoclonic seizures, so they must not be used when the seizure type is uncertain in a child.
Valproate is the most teratogenic common antiepileptic and is avoided in women of childbearing potential wherever an alternative exists.
Status epilepticus is treated with a benzodiazepine first, then a loading dose of an agent such as levetiracetam, valproate or phenytoin.
Carbamazepine induces its own metabolism, which is why levels fall after a few weeks on an unchanged dose and the term autoinduction is used.
Phenytoin must never be given rapidly intravenously, because the propylene glycol diluent causes hypotension and arrhythmia; fosphenytoin avoids this and can be infused faster.
Enzyme-inducing antiepileptics also accelerate vitamin D metabolism, which is why long-term users develop osteomalacia and are monitored for it.
4.2 Sedatives and general anaesthetics
Benzodiazepines increase the frequency of chloride channel opening; barbiturates increase its duration.
That mechanistic difference is why barbiturates can open the channel without GABA at high dose and are therefore far more dangerous in overdose, while benzodiazepines require GABA to be present and have a ceiling.
Flumazenil reverses benzodiazepines but may precipitate seizures in dependent patients.
Propofol gives rapid smooth induction with antiemetic effect but causes hypotension and pain on injection.
Ketamine is a dissociative anaesthetic acting at NMDA receptors that preserves airway reflexes and raises blood pressure, but causes emergence delirium.
Thiopentone is ultra-short acting because of redistribution rather than metabolism, which is why repeated doses accumulate.
Halothane causes hepatitis; all volatile agents and suxamethonium can trigger malignant hyperthermia.
4.3 Opioids and other analgesics
Opioids act at mu receptors, producing analgesia, respiratory depression, miosis, constipation and euphoria.
Tolerance develops to almost every opioid effect except constipation and miosis, which is why a laxative is co-prescribed for the duration of treatment.
Morphine has active metabolites accumulating in renal failure; fentanyl is safer there.
Pethidine's metabolite norpethidine is proconvulsant, and pethidine with a monoamine oxidase inhibitor causes serotonin syndrome.
Tramadol adds serotonin and noradrenaline reuptake inhibition, which lowers the seizure threshold and adds serotonin syndrome risk.
Naloxone has a shorter half-life than most opioids, so repeated doses or an infusion may be needed after the initial reversal.
4.4 Local anaesthetics
Local anaesthetics block voltage-gated sodium channels from the inside of the axon, so the drug must first cross the membrane in its unionised form and then ionise to act.
That two-step requirement is why local anaesthetics fail in infected tissue: the acidic environment keeps more of the drug ionised outside the cell, so too little crosses to reach the channel.
Small unmyelinated fibres are blocked first, which is why pain and temperature go before touch, and motor function last.
Amides contain two letter i sounds in their names — lidocaine, bupivacaine, prilocaine — and are hepatically metabolised; esters such as procaine and tetracaine are hydrolysed by plasma esterases and are more allergenic because they yield para-aminobenzoic acid.
Adrenaline is added to prolong the block and reduce systemic absorption, and is traditionally avoided in end-arterial territories.
Systemic toxicity progresses from perioral tingling and tinnitus through seizures to cardiovascular collapse.
Bupivacaine is the most cardiotoxic, because it dissociates slowly from cardiac sodium channels, and intravenous lipid emulsion is the specific treatment for severe toxicity.
Prilocaine causes methaemoglobinaemia, treated with methylene blue.
5. Parkinson disease and dementia
5.1 Antiparkinsonian drugs
Levodopa is given with carbidopa, a peripheral decarboxylase inhibitor that does not cross the blood-brain barrier.
That combination increases the fraction of levodopa reaching the brain and reduces peripheral dopamine effects such as nausea, which is why the peripheral blocker matters as much as the levodopa.
Long-term levodopa produces motor fluctuations, wearing off and dyskinesias, which is why treatment is sometimes delayed in younger patients.
Dopamine agonists such as pramipexole and ropinirole cause impulse control disorders including gambling and hypersexuality, which must be asked about directly.
Selegiline and rasagiline inhibit monoamine oxidase B; entacapone inhibits catechol-O-methyltransferase and extends levodopa's effect.
Amantadine helps dyskinesia, and anticholinergics help tremor in younger patients but worsen cognition in the elderly.
Levodopa absorption competes with dietary protein at the same amino acid transporter, which is why patients with motor fluctuations are advised to separate doses from protein-rich meals.
Antipsychotics and metoclopramide can produce a drug-induced parkinsonism indistinguishable from the disease itself, and it is symmetrical rather than asymmetrical, which is the useful clue.
Domperidone is preferred to metoclopramide for nausea in Parkinson disease because it does not cross the blood-brain barrier and so does not worsen the motor symptoms.
5.2 Dementia and other agents
Donepezil, rivastigmine and galantamine are central anticholinesterases used in mild to moderate Alzheimer disease.
Memantine is an NMDA antagonist used in moderate to severe disease, limiting excitotoxicity.
Triptans are 5-HT1B and 5-HT1D agonists that cause cranial vasoconstriction, and are contraindicated in ischaemic heart disease for that reason.
Migraine prophylaxis is a separate decision from acute treatment, and propranolol, topiramate and amitriptyline are the established options.
Topiramate causes weight loss, paraesthesia, renal stones and cognitive slowing, while amitriptyline suits a patient with coexisting insomnia.
Medication overuse headache is the trap in chronic headache stems, since frequent analgesic use perpetuates the very headache being treated and the answer is withdrawal rather than escalation.
5.3 Dependence and withdrawal
Withdrawal syndromes are examined by asking which are dangerous, and the answer follows from what the substance was suppressing.
Alcohol and benzodiazepine withdrawal can be fatal, because both suppress a GABA system that becomes chronically downregulated, leaving unopposed excitation when the drug is removed.
Opioid withdrawal is intensely unpleasant but not usually life-threatening, because opioids do not suppress a system whose loss causes seizures.
Alcohol withdrawal runs a predictable timeline: tremor and anxiety at six to twelve hours, seizures at twelve to forty-eight hours, and delirium tremens at forty-eight to seventy-two hours.
Chlordiazepoxide or diazepam is used for alcohol withdrawal, with thiamine given before glucose to avoid precipitating Wernicke encephalopathy.
Acamprosate, naltrexone and disulfiram support abstinence, disulfiram by blocking aldehyde dehydrogenase so that acetaldehyde accumulates.
Opioid dependence is managed with methadone, a full agonist, or buprenorphine, a partial agonist that must not be started until withdrawal has begun.
Nicotine dependence is treated with replacement therapy, bupropion or varenicline, a partial agonist at the nicotinic receptor.
6. Worked examples
Example 1
A young man on haloperidol develops an oculogyric crisis six hours after his first dose.
The timing places this precisely within the extrapyramidal sequence, since dystonia is the earliest of the four syndromes.
Dopamine blockade in the nigrostriatal pathway leaves acetylcholine relatively unopposed in the striatum.
Restoring the balance with an anticholinergic such as benztropine reverses the dystonia rapidly.
Had the presentation been at two years rather than six hours, the answer would be tardive dyskinesia, which anticholinergics worsen rather than help.
Example 2
A patient on fluoxetine is given tramadol for back pain and within hours develops agitation, sweating, hyperreflexia and sustained clonus.
Two serotonergic drugs have been combined, since tramadol inhibits serotonin reuptake as well as acting at opioid receptors.
Clonus and hyperreflexia with onset in hours identify serotonin syndrome rather than neuroleptic malignant syndrome, which develops over days and produces lead-pipe rigidity instead.
Increased bowel sounds and dilated pupils support the same conclusion.
Treatment is withdrawal of the serotonergic agents, supportive care and cyproheptadine.
Example 3
A patient stable on lithium is started on a thiazide for hypertension and develops coarse tremor, ataxia and confusion.
Lithium is handled like sodium by the proximal tubule, and anything causing sodium avidity increases lithium reabsorption.
A thiazide induces volume depletion, so the proximal tubule reabsorbs more sodium and, with it, more lithium.
The lithium dose has not changed, but its clearance has fallen and the level has risen into the toxic range.
The same mechanism applies to non-steroidal anti-inflammatory drugs, ACE inhibitors and simple dehydration.
7. Traps the exam sets repeatedly
Treating tardive dyskinesia with an anticholinergic. Anticholinergics help acute dystonia and parkinsonism but worsen tardive dyskinesia.
Increasing the antipsychotic dose for akathisia. The restlessness is caused by the drug, so raising the dose worsens it.
Confusing serotonin syndrome with neuroleptic malignant syndrome. Clonus and hyperreflexia within hours means serotonin; lead-pipe rigidity over days means neuroleptic malignant syndrome.
Using carbamazepine or phenytoin in a child with absence seizures. Both worsen absence and myoclonic seizures.
Forgetting that tolerance never develops to opioid constipation. A laxative is needed throughout treatment, not just initially.
Expecting a local anaesthetic to work in an abscess. The acidic environment keeps the drug ionised outside the cell, so too little crosses the membrane to reach the sodium channel.
Treating opioid withdrawal as the dangerous one. Alcohol and benzodiazepine withdrawal can kill; opioid withdrawal is severe but rarely fatal.
Giving glucose before thiamine in alcohol withdrawal. Glucose consumes the remaining thiamine and can precipitate Wernicke encephalopathy.
Summary
Almost every central nervous system drug raises or lowers one of five transmitters, and the side effects are that same change in an unintended location.
Antipsychotic benefit and the three main adverse effects are all D2 blockade in four different dopamine pathways.
The extrapyramidal syndromes are separated by timing, and tardive dyskinesia is the late one that worsens on withdrawal.
Atypical antipsychotics trade extrapyramidal effects for metabolic ones, and clozapine is most effective but requires monitoring for agranulocytosis.
Antidepressants take two to four weeks because the benefit is neuroplastic rather than a direct consequence of raised transmitter.
Clonus and hyperreflexia within hours identify serotonin syndrome; lead-pipe rigidity over days identifies neuroleptic malignant syndrome.
Anything reducing renal clearance raises lithium levels, including thiazides, non-steroidals, ACE inhibitors and dehydration.
Ethosuximide works only in absence seizures because thalamic T-type calcium channels generate that specific discharge.
Barbiturates open the chloride channel without GABA at high dose, which is why they lack the ceiling that makes benzodiazepines safer.
Tolerance develops to nearly every opioid effect except constipation and miosis.
Local anaesthetics must cross the membrane unionised and then ionise to block the sodium channel, which is why they fail in infected tissue.
Bupivacaine is the most cardiotoxic local anaesthetic, and intravenous lipid emulsion is the specific treatment.
Alcohol and benzodiazepine withdrawal are the dangerous ones, because both leave a downregulated GABA system unopposed.
Antidepressant choice is driven by side effect profile rather than efficacy, which is why mirtazapine suits insomnia and bupropion suits weight concern.
