CENTRAL NERVOUS SYSTEM DRUGS-1
  1. 5-HT1 agonists (triptans)
  2. 5-HT3 antagonists
  3. Antihistamine anti-emetics
  4. Antipsychotics – atypical
  5. Antipsychotics – typical
  6. Benzodiazepines
  7. Carbamazepine
  8. Dopamine antagonist anti-emetics
  9. Drugs for dementia
  10. Gabapentin and pregabalin, 
1. 5-HT1 agonists (triptans) 
EXAMPLES 
Sumatriptan, zolmitriptan
MECHANISM OF ACTION 
  • Selective activation of 5-HT1 receptors that are predominantly located in cranial blood vessel walls. 5-HT1 receptors mediate vasoconstriction thereby relieving symptoms that are believed to result from the dilatation of intra- and extracranial vessels.
INDICATIONS
  • Treatment of acute migraine.
  • Cluster headache.
CAUTIONS AND CONTRA-INDICATIONS
  • Ischaemic heart disease or coronary vasospasm.
  • Peripheral vascular disease.
  • Previous stroke or TIA.
  • Severe hypertension.
SIDE-EFFECTS 
  • Dizziness.
  • Paraesthesia.
  • Tinnitus.
  • A transient rise in blood pressure.
  • Tachycardia and palpitations.
  • Very rarely, MI
MONITORING 
  • No specific drug monitoring required.
DRUG INTERACTIONS
  • Increased risk of CNS toxicity with SSRIs and MAOIs.
  • Plasma concentration of 5-HT1 agonists may be increased by macrolides and b blockers
IMPORTANT POINTS
  • 5-HT1 agonists are the preferred treatment for patients with migraines that do not respond to simple analgesia.
  • 5-HT1 agonists should be used in the established headache phase of an attack; they are not suitable for migraine prophylaxis.
  • Newer formulations include SC preparations, IN preparations and wafers for faster administration.
 
2. 5-HT3 antagonists 
EXAMPLES 
Ondansetron, granisetron
MECHANISM OF ACTION 
  • Selective5-HT3 receptor antagonists that act peripherally on vagal nerve endings of the GI tract and centrally in the CTZ.
  • 5-HT3 receptors in the CTZ in the area post rema of the medulla contribute to the perception of nausea and the control of vomiting.
INDICATIONS
  • PONV
  • Nausea and vomiting associated with cytotoxic drugs (chemotherapy) and radiotherapy
CAUTIONS AND CONTRA-INDICATIONS. 
  • Prolonged QT interval and cardiac conduction defects
  • Hypersensitivity
SIDE-EFFECTS
  • GI disturbance (especially constipation due to increased large bowel transit time)
  • Headache
  • Flushing
MONITORING 
  • No specific drug monitoring required
DRUG INTERACTIONS
  • Effects reduced by drugs that induce liver enzymes(phenytoin, carbamazepine, rifampicin).
  • Increased risk of torsades de pointes with other drugs that prolong the QT interval
IMPORTANT POINTS
  • Establish a cause for emesis prior to prescribing an anti-emetic.
  • Very effective anti-emetic agents, particularly for PONV.
  • Careful monitoring of symptoms if these drugs are used in patients with subacute bowel obstruction due to effects on large bowel motility.
 
3. Antihistamine anti-emetics 
EXAMPLES 
Cyclizine, promethazine
MECHANISM OF ACTION 
  • H1 receptor antagonists directly inhibit the CTZ in the medulla. They possess anticholinergic and anti-emetic properties.
  • Cyclizine also increases lower oesophageal sphincter tone and reduces the sensitivity of the labyrinthine apparatus.
INDICATIONS
  • Nausea and vomiting.
  • Hyperemesis in pregnancy (promethazine is first line).
  • Vomiting in labyrinthine disorders.
  • Nausea associated with motion sickness
CAUTIONS AND CONTRA-INDICATIONS
  • Severe prostatic hypertrophy.
  • Caution in patients at risk of closed-angle glaucoma
SIDE-EFFECTS
  • Drowsiness.
  • Headache.
  • Tachycardia (cyclizine).
  • Psychomotor impairment.
  • Antimuscarinic effects
MONITORING 
  • No specific drug monitoring required.
DRUG INTERACTIONS
  • Increased sedative effect with opiates
IMPORTANT POINTS
  • Establish a cause for emesis prior to prescribing an anti-emetic.
  • Sedative effects of antihistamines are likely to be potentiated in liver disease.
  • Cyclizine and promethazine are safe to prescribe in pregnancy
 
4. Antipsychotics – atypical 
EXAMPLES 
Clozapine, olanzapine, quetiapine, risperidone, amisulpride
MECHANISM OF ACTION 
  • Not a homogenous pharmacological class.
  • Atypical antipsychotics act predominantly via dopamine (D1 to D4) and 5-HT receptors.
INDICATIONS.
  • Schizophrenia and other psychoses.
  • Mania.
  • Sedation.
  • Anxiety and psychomotor agitation
CAUTIONS AND CONTRA-INDICATIONS
  • CNS depression and coma.
  • Severe cardiovascular disease.
  • Caution in patients with hepatic impairment.
  • Caution in epilepsy.
  • Caution in elderly patients and patients with risk factors for cerebrovascular disease (increased risk of stroke in older patients with dementia with olanzapine and risperidone)
SIDE-EFFECTS.
  • Sedation or agitation.
  • Postural hypotension.
  • Antimuscarinic effects.
  • Weight gain.
  • Neutropenia and agranulocytosis (clozapine only).
  • Myocarditis and cardiomyopathy (clozapine only).
  • Hyperglycaemia (particularly clozapine and olanzapine).
  • Rarely, neuroleptic malignant syndrome
MONITORING
  • Check FBC prior to starting clozapine and initially monitor counts weekly.
  • Cardiovascular assessment prior to starting clozapine.
DRUG INTERACTIONS 
  • Antagonism of sympathomimetics, anticholinergics and antiepileptic drugs may occur (the latter may lower seizure threshold).
  • Enhanced hypotensive effect with antihypertensive agents.
  • Increased risk of cardiac arrhythmias (including torsades de pointes) with other drugs that prolong the QT interval
IMPORTANT POINTS
  • Atypical antipsychotics are more effective in the treatment of negative symptoms of schizophrenia.
  • Withdrawal of antipsychotic after long-term therapy should be gradual to avoid the risk of acute withdrawal or rebound psychosis.
  • If a treatment is effective but compliance is poor, depot preparations may be considered
 
5. Antipsychotics – typical 
EXAMPLES 
Haloperidol, chlorpromazine, prochlorperazine, flupentixol
MECHANISM OF ACTION 
  • Not a homogenous pharmacological class.
  • Mixed antagonists at muscarinic, histaminergic, dopaminergic, serotonergic and adrenergic receptors.
  • Typical antipsychotics exert their predominant neuroleptic effect through blockade of dopamine D2 receptors.
INDICATIONS
  • Schizophrenia and other psychoses.
  • Mania.
  • Sedation.
  • Anxiety and psychomotor agitation.
  • Nausea and vomiting
CAUTIONS AND CONTRA-INDICATIONS
  • CNS depression and coma.
  • Severe cardiovascular disease.
  • Caution in patients with hepatic impairment.
  • Caution in epilepsy.
SIDE-EFFECTS
  • Sedation or agitation.
  • Extra-pyramidal symptoms.
  • Postural hypotension.
  • Cardiac arrhythmias (prolongation of QT interval).
  • Antimuscarinic effects.
  • Hyperprolactinaemia.
  • Rarely, neuroleptic malignant syndrome.
MONITORING 
  • ECG before initiating treatment and then annually with some typical antipsychotics.
DRUG INTERACTIONS
  • Phenothiazines (e.g. chlorpromazine, prochlorperazine) may enhance the CNS depressant effect of opioids, anxiolytics, sedatives, hypnotics and alcohol.
  • Antagonism of sympathomimetics, anticholinergics and antiepileptic drugs may occur (the latter may lower seizure threshold).
  • Enhanced hypotensive effect with antihypertensive agents.
  • Increased risk of cardiac arrhythmias (including torsades de pointes) with other drugs that prolong the QT interval
IMPORTANT POINTS
  • Withdrawal of antipsychotics after long-term therapy should be gradual to avoid the risk of acute withdrawal or rebound psychosis.
  • If a treatment is effective but compliance is poor, depot preparations may be considered
6. Benzodiazepines 
EXAMPLES 
Diazepam, lorazepam, chlordiazepoxide, midazolam, temazepam
MECHANISM OF ACTION 
  • Bind to benzodiazepine receptors that are coupled to GABA receptors. This increases theaffinity of GABA to its receptor and opens Cl- channels resulting in hyperpolarisation of the cell membrane, thereby preventing further excitation.
INDICATIONS
  • Short-term use in anxiety or insomnia.
  • Acute alcohol withdrawal.
  • Sedation.
  • Status epilepticus.
  • Muscle spasm
CAUTIONS AND CONTRA-INDICATIONS
  • Respiratory depression.
  • A neuromuscular disease affecting muscles of respiration.
  • Acute pulmonary insufficiency.
  • Should not be used as monotherapy to treat depression (with or without anxiety)
SIDE-EFFECTS
  • Drowsiness and lightheadedness.
  • Dependence.
  • Confusion.
  • Amnesia.
MONITORING 
  • Monitor respiratory effort and effect (respiratory rate and oxygen saturation).
DRUG INTERACTIONS
  • Should not be taken with alcohol due to increased sedative effect.
IMPORTANT POINTS 
  • Effect of excessive benzodiazepine use can be reversed by flumazenil. This is administered via IV route.
  • Chlordiazepoxide can be used to lessen the symptoms of alcohol withdrawal.
  • Chlordiazepoxide is given for limited time(3–10days) in reducing doses but should not be given if a patient is likely to continue drinking alcohol.
 
7. Carbamazepine 
MECHANISM OF ACTION 
  • Use-dependent blockade of voltage-gated Naþchannels responsible for the propagation of the action potential. Thus carbamazepine preferentially blocks the excitation of neurones that are firing repeatedly.
INDICATIONS
  • Epilepsy.
  • Prophylaxis of bipolar disorder.
  • Trigeminal neuralgia.
CAUTIONS AND CONTRA-INDICATIONS. 
  • AV conduction abnormalities (if not paced).
  • History of bone marrow suppression.
  • Acute porphyria.
SIDE-EFFECTS 
  • Nausea and vomiting.
  • Drowsiness.
  • Generalised erythematous rash.
  • Cardiac conduction disturbances.
  • Leucopenia.
MONITORING 
  • No specific drug monitoring required.
DRUG INTERACTIONS
  • Plasma levels can be enhanced by drugs inhibiting Cytochrome P450, including isoniazid, verapamil and diltiazem.
  • Plasma levels can be reduced by drugs that potentiate Cytochrome P450, including phenytoin, phenobarbitone and theophylline.
  • Reduces the anticoagulant effect of warfarin.
  • Anticonvulsant effect antagonised by antipsychotics.
IMPORTANT POINTS
  • Treatment should be started at a low dose with small incremental increases every 2 weeks.
  • Carbamazepine can be used in the prophylaxis of bipolar disorder if symptoms are not responding to lithium
 
8. Dopamine antagonist anti-emetics 
EXAMPLES 
Domperidone, metoclopramide
MECHANISM OF ACTION 
  • The anti-emetic effect is due to a combination of prokinetic activity, up-regulation of the parasympathetic nervous system and antagonism of dopamine D2 receptors in the CTZ.
INDICATIONS
  • Nausea and vomiting
CAUTIONS AND CONTRA-INDICATIONS
  • Phaeochromocytoma.
  • Prolactin-releasing pituitary tumour.
  • GI obstruction.
  • Perforation.
SIDE-EFFECTS
  • Extra-pyramidal symptoms.
  • Hyperprolactinaemia.
  • Neuroleptic malignant syndrome.
  • Rashes.
  • Tardive dyskinesia.
  • Confusion.
  • Drowsiness.
MONITORING 
  • No specific drug monitoring required.
DRUG INTERACTIONS
  • Metoclopramide increases plasma levels of ciclosporin and NSAIDs.
  • Ketoconazole increases the risk of arrhythmias when given with domperidone
IMPORTANT POINTS
  • Always establish a cause for vomiting prior to prescribing anti-emetics.
  • Dopamine antagonists can cause severe extrapyramidal side-effects when given to young adults and elderly patients.
  • Dopamine antagonists are particularly useful in vomiting secondary to chemotherapy and radiotherapy
 
9. Drugs for dementia 
MECHANISM OF ACTION 
  • Donepezil, galantamine and rivastigmine – inhibition of acetylcholinesterase thereby preventing the breakdown of ACh; the cholinergic hypothesis suggests that reduced ACh synthesis is a key aetiological factor in Alzheimer’s disease. Galantamine also acts as a partial agonist at nicotinic receptors.
  • Memantine – NMDA receptor antagonist that blocks the effects of pathologically elevated levels of glutamate that may contribute to neuronal dysfunction in Alzheimer’s disease.
INDICATIONS
  • Mild to moderate dementia in Alzheimer’s disease.
  • Mild to moderate dementia in Parkinson’s disease (rivastigmine only)
CAUTIONS AND CONTRA-INDICATIONS
  • Caution in cardiac disease.
  • Caution in asthma/COPD.
  • Caution in patients susceptible to peptic ulcers .
  • Caution in renal impairment.
SIDE-EFFECTS
  • GI disturbance.
  • Gastric or duodenal ulcers.
  • Drowsiness and confusion.
  • Rarely, arrhythmias and SA node/AV node block.
MONITORING 
  • Monitor MMSE(Mini-mental state examination) score every 6 months – treatment should only be continued while the score remains at or above 10 (out of 30).
DRUG INTERACTIONS
  • Increased risk of arrhythmias with agents that reduce heart rate (e.g. b blockers, digoxin, amiodarone).
  • Effects antagonised by antimuscarinics
IMPORTANT POINTS 
  • Exclude reversible causes of cognitive impairment prior to initiating treatment (e.g. hypothyroidism).
  • Drugs for dementia should only be started by specialists.
  • The clinical benefits of acetylcholinesterase inhibitors are modest with only about a 10% improvement in short-term memory, language and praxis abilities at best.