Pharmacology · Short notes

CNS Pharmacology: Short Notes & Cheat Sheet

Sedative-hypnotics, antiepileptics, antidepressants, lithium, antipsychotics, antiparkinsonian drugs, opioids and anaesthetics.

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Short notes

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Levodopa and the Parkinson's drugs

Carbidopa and entacapone stop levodopa from being broken down in the periphery, so more reaches the brain. MAO-B inhibitors slow the breakdown of dopamine inside the brain.

Sedative-hypnotics

Benzodiazepines increase how often the GABA-A chloride channel opens. Barbiturates increase how long it stays open, and at high doses open it directly, which is why they are more dangerous in overdose.
Flumazenil reverses benzodiazepines. Z-drugs (zolpidem, zaleplon) act at the BZ1 site.
Lorazepam, oxazepam and temazepam are cleared only by glucuronidation, so they are safer in liver disease and in the elderly.
Diazepam and chlordiazepoxide are long-acting and used for alcohol withdrawal. IV lorazepam is first-line for status epilepticus.
Buspirone is a 5-HT1A partial agonist. It is not sedating and takes weeks to work, so it suits generalised anxiety.
Barbiturates induce CYP enzymes and are contraindicated in porphyria. Thiopental's short action comes from redistribution out of the brain, not from metabolism.

Antiepileptics

Phenytoin blocks Na+ channels and follows zero-order kinetics at therapeutic doses. Adverse effects: gum overgrowth, hirsutism, nystagmus, ataxia, and fetal hydantoin syndrome. It induces CYP enzymes.
Carbamazepine blocks Na+ channels and is the drug of choice for trigeminal neuralgia. Risks: SJS/TEN (HLA-B*1502, common in Asians), hyponatraemia, blood disorders, and autoinduction of its own metabolism.
Valproate is broad-spectrum. Risks: hepatotoxicity, pancreatitis, weight gain, and neural tube defects (the most teratogenic antiepileptic). It inhibits CYP enzymes.
Ethosuximide blocks T-type Ca2+ channels and is the drug of choice for absence seizures. Carbamazepine and phenytoin can make absence seizures worse.
Lamotrigine: serious rash, so the dose is increased slowly. Valproate raises its levels.
Others: gabapentin and pregabalin (α2δ subunit; also for neuropathic pain), levetiracetam (SV2A), topiramate (weight loss, kidney stones), vigabatrin (visual field loss; used for infantile spasms).

Antidepressants and lithium

SSRIs (fluoxetine, sertraline, citalopram) are first-line. They take 2–4 weeks to work and cause sexual dysfunction. Fluoxetine has the longest half-life.
SNRIs: venlafaxine (raises blood pressure) and duloxetine (also for neuropathic pain).
TCAs (amitriptyline, imipramine) cause anticholinergic effects, α-blockade and sedation. Overdose is dangerous: convulsions, coma and cardiotoxicity with a wide QRS, treated with sodium bicarbonate.
MAO inhibitors combined with tyramine cause a hypertensive crisis. Leave a 2-week washout before starting an MAOI, or 5 weeks after fluoxetine.
Bupropion helps smoking cessation, lowers the seizure threshold and causes no sexual dysfunction. Mirtazapine causes weight gain and sedation. Trazodone can cause priapism.
Serotonin syndrome (SSRI plus MAOI, linezolid, tramadol or triptan) causes clonus, fever and agitation. Treat with cyproheptadine.
Lithium is the drug of choice for bipolar disorder and has a narrow therapeutic range. Adverse effects: tremor, hypothyroidism, nephrogenic diabetes insipidus, and Ebstein anomaly in the fetus. Thiazides, NSAIDs and ACE inhibitors raise its level.

Antipsychotics and Parkinson's disease

Typical antipsychotics block D2 receptors. Haloperidol (high potency) causes more extrapyramidal side effects (EPS). Chlorpromazine (low potency) causes more sedation, anticholinergic effects and postural hypotension.
EPS appear in a typical order: acute dystonia (hours to days; treat with an anticholinergic), akathisia (propranolol), parkinsonism, then tardive dyskinesia (months to years; often irreversible).
Neuroleptic malignant syndrome (rigidity, fever, raised CK) is treated with dantrolene or bromocriptine.
Clozapine is for treatment-resistant schizophrenia. It can cause agranulocytosis, so white cell counts must be monitored. Olanzapine causes weight gain and metabolic effects. Risperidone raises prolactin. Aripiprazole is a partial D2 agonist.
Parkinson's disease: levodopa is given with carbidopa, which blocks peripheral dopa decarboxylase. Problems include wearing-off, on-off fluctuations and dyskinesia.
Other Parkinson's drugs: dopamine agonists pramipexole and ropinirole (can cause impulse-control disorders); MAO-B inhibitors selegiline and rasagiline; COMT inhibitors entacapone and tolcapone (hepatotoxic); amantadine; and trihexyphenidyl for tremor.
Metoclopramide and typical antipsychotics worsen Parkinson's. Domperidone does not cross the blood–brain barrier.

Opioids and anaesthetics

Morphine (μ agonist) causes pinpoint pupils, respiratory depression, constipation (no tolerance develops to this), urinary retention and histamine release. Its active metabolite, morphine-6-glucuronide, builds up in renal failure.
Codeine is a prodrug converted to morphine by CYP2D6. Tramadol is a weak μ agonist that also inhibits serotonin and noradrenaline reuptake, so it can cause seizures and serotonin syndrome.
Pethidine's metabolite norpethidine causes seizures. Methadone (long-acting, prolongs QT) and buprenorphine (partial agonist) are used for opioid maintenance therapy.
Naloxone reverses opioids but is shorter-acting than most of them, so doses may need repeating. Naltrexone is taken orally for alcohol and opioid dependence. Loperamide does not enter the CNS.
Inhaled anaesthetics: a low blood:gas partition coefficient means fast induction and recovery (nitrous oxide, desflurane, sevoflurane). A lower MAC means a more potent agent. Halothane can cause hepatitis.
Ketamine is a dissociative NMDA antagonist that raises blood pressure and can cause emergence hallucinations. Propofol is used for induction.
Local anaesthetics block Na+ channels. They are either esters (procaine, benzocaine, tetracaine; PABA-related allergy) or amides (lidocaine, bupivacaine). Bupivacaine is the most cardiotoxic.

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Drugs of choice

Condition	Drug
Status epilepticus	IV lorazepam → phenytoin / fosphenytoin
Absence seizures	Ethosuximide (or valproate)
Trigeminal neuralgia	Carbamazepine
Infantile spasms	Vigabatrin / ACTH
Bipolar disorder	Lithium
Resistant schizophrenia	Clozapine
Opioid overdose	Naloxone
Benzodiazepine overdose	Flumazenil
Serotonin syndrome	Cyproheptadine
Neuroleptic malignant syndrome	Dantrolene / bromocriptine
Acute dystonia	Benztropine / diphenhydramine
TCA overdose (wide QRS)	Sodium bicarbonate

Signature adverse effects

Drug	Remember
Phenytoin	Gum hyperplasia, nystagmus, zero-order kinetics
Carbamazepine	SJS (HLA-B*1502), SIADH, agranulocytosis
Valproate	Hepatotoxic, neural tube defects, pancreatitis
Vigabatrin	Visual field defects
Topiramate	Kidney stones, weight loss
Lithium	Tremor, hypothyroid, nephrogenic DI, Ebstein
Clozapine	Agranulocytosis, seizures, myocarditis
Bupropion	Seizures
Trazodone	Priapism
Halothane	Hepatitis
Bupivacaine	Cardiotoxicity

Memory aids

LOT: Lorazepam, Oxazepam, Temazepam: glucuronidation only, so they are safe in liver disease and the elderly.
FREquency vs DURation: BenzodiazePINES increase FREquency of Cl- channel opening; barbiDURates increase DURation.
Amides have two i's: Lidocaine, bupivacaine, prilocaine are amides; procaine and benzocaine (one i) are esters.

Exam traps

Tolerance develops to opioid-induced respiratory depression and nausea, but not to constipation or miosis.
Carbidopa does not cross the blood–brain barrier. That is the point: it only stops levodopa being converted in the periphery.
Selegiline is MAO-B selective at usual doses, so tyramine reactions are unlikely.
Phenytoin's half-life gets longer as the dose rises (zero-order kinetics), so small dose increases can cause toxicity.
Low-potency typical antipsychotics cause fewer EPS because of their own anticholinergic action.

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