CNS Drugs 31 to 40
What are the major side effects of phenothiazine antipsychotics?
- dry mouth,
- dry eyes,
- urinary retention,
- Parkinson-like effects,
- tardive dyskinesia;
- Neuroleptic malignant syndrome
- Weight gain;
What mechanisms of drug action are responsible for these side effects?
- Alpha blockade;
- D2 antagonism;
- Serotonin receptor antagonism;
- Anti-histamine (H1)
How could the extra-pyramidal side effects be managed?
- Lower dose;
- Switch to an atypical drug (lower incidence of extra-pyramidal effects);
- Administer benztropine or diazepam;
- No effective treatment for tardive dyskinesia: prevention vital; monitor for early signs and reduce or cease anti-psychotic asap
What are the proposed mechanisms of action of valproate?
- Blocks Na channels
- thereby blocking sustained high frequency firing of neurones.
- Blockade of NMDA receptor mediated excitation.
- Increase GABA levels
Describe the toxic effects of valproate.
- Mostly within 4 months of initiation of treatment,
- Treat with intravenous L-carnitine.
- weight gain, appetite,
- Malformations in pregnancy
What interactions does valproate have with other anti-seizure drugs?
- inhibits metabolism and displaces from plasma proteins
- inhibits metabolism
- inhibits metabolism
- decreases clearance
What are the pharmacokinetics of tricyclic anti-depressants?
- Bioavaility = 40-50%,
- high first pass metabolism
- long half-time,
- large VOD,
- high tissue protein binding,
- high lipid solubility,
- metabolised in liver, active metabolites
What are the toxic effects of tricyclics in overdose?
- Na channel blocker,
- Psychiatric- psychosis, agitation, withdrawal
- Sympathomimetic tremor, insomnia,
- blurred vision, constipation, urinary, confusion, tachycardia cardiovascular-
- Weight gain
What drugs could be used in the treatment of tricyclic toxicity in overdose?
- Sodium bicarb 50-100 mEq IV
- Dopamine/NA for hypotension
Describe the pharmacokinetics of Lithium.
- rapid and near complete.
- peak levels in 30-120min
- total body water Vol.D 0.5 to 0.9L/kg
- Slow distribution into and out of CNS.
- T 1/2; @20 hours.
- Metabolism = none
- Elimination = renal excretion
What are some of the drug interactions with lithium?
- Thiazide diuretics- 25% reduction in lithium clearance
- Newer NSAID’s – similar reductions in clearance
- Neuroleptics (except clozapine) and antipsychotics-
- enhancement of extrapyramidal syndromes
What are some of the side effects of lithium?
- tremor, confusion, ataxia, dysarthria, new psychiatric symptoms
- Nephrogenic diabetes insipidis
– loss of responsiveness to ADH.
- Skin reactions; acneiform eruptions
Name some antiemetics used in the Emergency Department.
- Ondansetron (or Granisetron or Tropisetron)
- Diphenhydramine (or other antihistamines).
Compare the mechanisms of action of ondansetron and metoclopramide.
- Act at different receptors:
- Peripheral 5HT3 blockade (vagal and spinal afferents, Reduces sensory visceral output)
- Central 5HT3 blockade (vomiting centre and CTZ)
- D2 blockade (CTZ). Increases oesophageal motility. Increases LOS pressure. Increase gastric emptying
Describe the potential adverse effects of metoclopramide.
- agitation – common (20%), esp. elderly
- Extrapyramidal effects:
- acute dystonia,
- parkinsonian effects – more likely with higher doses
- Tardive dyskinesia with chronic dosing
Pass Criteria: Bold
List the drug classes which are used in management of acute agitation in the ED.
- Antipsychotics –
- Phenothiazines eg chlorpromazine
- Butyrophenones eg haloperiodol, droperidol
- olanzapine ,
- Barbiturates –
What is the predominant mechanism of action of the atypical antipsychotics.
- Serotonin (5HT2A) receptor antagonism
- Dopamine (D2) receptor antagonism (weaker effect)
Describe adverse effects of the atypical antipsychotics.
- Extrapyramidal reactions(less common than with older typical antipsychotics)
- Tardive dyskinesia
- Antimuscarinic effects – dry mouth, urinary retention etc Orthostatic hypotension
- Weight gain
- Agranulocytosis ( clozapine)
- Neuroleptic malignant syndrome
Outline the clinical uses of carbamazepine.
- Anticonvulsant; partial and generalised tonic-clonic seizures
- Treatment of bipolar mood disorder
- Trigeminal neuralgia
Describe the mechanism of its anticonvulsant activity.
- Blocks sodium channels Inhibits high-frequency repetitive firing of neurons
- Presynaptic blocker of synaptic transmission
Outline some of the side effects of carbamazepine.
- Ataxia and diplopia,
- GI upsets and hepatic dysfunction
- Erythematous skin rash
- Hyponatraemia and water intoxication
- Blood dyscrasias, including leukopenia common), and rarely aplastic anaemia and agranulocytosis.
Can you name some drug interactions involving carbamazepine?
- Enzyme induction (all anticonvulsants including itself).
- Valproic acid + phenytoin may inhibit carbamazepine elimination
Why is levodopa used in combination with carbidopa?
Carbidopa is a peripheral dopa decarboxylase inhibitor. Because it doesn’t penetrate the blood brain barrier, it reduces the peripheral metabolism of levodopa -> increased levodopa levels, increased half-life resulting in more dopa being available for entry into brain to exert its effects.
What are the adverse affects of levodopa?
Incidence decreased to < 20% if a peripheral decarboxylase inhibitor is added.
CVS: Arrhythmias-tachycardia, ventricular ectopics, AF. Due to increased catecholamine formation peripherally.
Dyskinesias: Up to 80% of those receiving levodopa for long periods.
Behavioural effects: Depression, anxiety, agitation, insomnia, nightmares, euphoria and mood changes. More common if taking a levodopa with a decarboxylase inhibitor. Due to higher levels presenting to the brain.
Fluctuations in clinical response occurs with increasing frequency as treatment continues.
Miscellaneous: Mydriasis, acute glaucoma, Coombs positive haemolytic anaemia, gout, abnormalities of taste and smell,
Brownish discolouration of saliva, urine or vaginal secretions, priapism, abn urea, LFTs.
Drug Interactions: Pyridoxine enhances metabolism of levodopa. Hence effect decreased.
3 systems to pass
What are the advantages of olanzapine over the older antipsychotics?
Prompt with: How does Olanzapine compare with haloperidol in terms of sedation, hypotensive effect and extrapyramidal toxicity? 2 out of 3, prompts allowed.
|Can be given as tablet, wafer or injection (widerLess unwanted dopamine effects, eg tardive dyskinesia, NMSDrug Usual Sedation Postural AntichoHne Extrapyrami Weightdaily hypotension rgic dal gainoraldose range(mg)|
|haloperidol 1-7.5 + + + +++ ++|
|Otanzapine 5-20 +++ + ++ + ÷++|
|Like clozapine, olanzapine has a wide range of receptor affinities. It is relatively well tolerated but drowsiness and dizziness can occur. Excessive weight gain may precipitate type 2 diabetes.|
|Transient elevation of liver enzymes has been associated with olanzapine, but this does not appear to be of clinical significance.|
What are the clinical conditions Olanzapine is prescribed for?
Wide Spectrum of use:
Autism spectrum disorders. Behavioural emergencies
Delirium: mood and behavioural disturbances; palliative care; AIDS
Dementia: General; Sleep disorder in patients with dementia (palliative care)
Acute treatment of mania: Olanzapine
2 of list
Describe the mechanism by which Serotonin Syndrome occurs.
Prompt: What receptors are involved in SS?
Excessive stimulation of serotonin receptors in the CNS due to overdose of single drug or concurrent use of several drugs. Predictable, not idiosyncratic.
Pass: Must get bold items
How do drugs cause excessive stimulation of serotonin receptors?
Prompt: Can you give an example
Inhibition of serotonin metabolism: meclobemide, amphetamines
Prevention of serotonin reuptake in nerve terminals: fluoxetine, paroxetine, sertraline, venlafaxine, tramadol, TCA
Serotonin release or increased intake of serotonin precursors: tryptophan, lithium,
Pass: Must identify at least 1 mechanisms with corresponding example