CENTRAL NERVOUS SYSTEM DRUGS-1
- 5-HT1 agonists (triptans)
- 5-HT3 antagonists
- Antihistamine anti-emetics
- Antipsychotics – atypical
- Antipsychotics – typical
- Benzodiazepines
- Carbamazepine
- Dopamine antagonist anti-emetics
- Drugs for dementia
- 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.
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