CENTRAL NERVOUS SYSTEM DRUGS-1

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.

10. Gabapentin and pregabalin 

MECHANISM OF ACTION

• The exact mechanism is unclear. 
• Gabapentin and pregabalin are analogues of GABA. Their clinical benefits are not mediated by the action on GABA receptors within the CNS but through binding to a subunit on T-type Ca2+ channels and selectively inhibiting the release of various neurotransmitters. Pregabalin is a higher potent analogue of gabapentin in chronic pain control.

INDICATIONS

• Partial seizures with or without secondary generalisation (as monotherapy or adjunct). 
• Neuropathic pain.

CAUTIONS AND CONTRA-INDICATIONS

• Hypersensitivity

SIDE-EFFECTS

• GI disturbance. 
• Weight gain. 
• Hypertension. 
• Dizziness and drowsiness. 
• Leucopenia. 
• Visual disturbances (e.g. diplopia).

MONITORING 

• No specific drug monitoring required.

DRUG INTERACTIONS

• Increased risk of CNS depression with opiates.
• Antacids containing aluminium and magnesium can reduce gabapentin bioavailability

IMPORTANT POINTS

• Abrupt withdrawal can cause anxiety, insomnia, pain and increases the risk of seizures in epileptics. Lower doses should be considered in the elderly and patients with renal impairment.
• Gabapentin should be started at a low dose and gradually increased inincrementsover2–3 days. Sedation, confusion and ataxia have been reported with rapid titration.