CNS Drugs 11 to 20
What is the mechanism of action of the SSRI drugs?
- Amine hypothesis – modulation of NET + SERT pathways by reuptake inhibition -> serotonin response
- Prolonged synaptic exposure to Serotonin leads to
- Probable time frame 3-6 weeks due to presynaptic/ post synaptic receptor / storage regulation
- SSRIs v HT specific v TCA 300-7000:1
Pass Criteria: Knowledge of amine hypothesis AND
- delayed response
- probable alteration in pre/post synaptic
What receptor/channel effects lead to the SSRI side effect profile?
- Very specific for HT (particularly 1) receptors –therefore serotonin syndrome/ restlessness.
- Minimal autonomic NE activation + mild muscarinic / Na channel, H1 block effects (safety/ tolerance).
- Possibly some alpha block (sexual dysfunction)
Pass Criteria: Specific HT PLUS one other
What is the mechanism of action of Carbimazepine?
- Tricyclic Compound
- Blocks sodium channels
- Inhibits high frequency repetitive firing neurons
- Decreases presynaptic transmission
- Inhibits uptake and release of noradrenaline in brain
What are the clinical indications for its use?
- Tonic clonic
- In combination with other seizure medications
- Trigeminal neuralgia
- Mood disorders
What are the potential adverse effects?
- GIT upset
- Blood dyscrasias
- Aplastic anaemia
- Skin Rash
- In toxicity
- Cardiac sodium channel blocking effect
- CNS depression
- Alters clearance of other drugs
What is the mechanism of action of the tricyclic antidepressants?
- Block amine (NAdr or Serotonin) reuptake pumps at presynaptic nerve endings
- prolongs duration of action of neurotransmitters at postsynaptic receptors.
- Most non selective
Pass Criteria: Amine block, Reuptake inhibitor
Describe the toxic effects in overdose and how are they mediated?
- Antimuscarinic. tachycardia, dry mouth, blurred vision, delirium, coma, Agitation; Urinary retention, reduced gastric motility,
- Sympathomimetic: tremor. Insomnia
- Sedation: additive effects
- Alpha1-antiadrenergic – postural hypotension, Hypotension, dizziness
- Fast sodium-channel blockade – reduced myocardial contractility, QT prolongation, cardiac arrhythmias;
- Respiratory depression;
- Neuromuscular irritability and seizures
- Some antimuscarinic
- Cardiac (mix)
- Na channel block effects
What are the clinical uses of chlorpromazine?
- Sedative for agitation
- D2 blockade in the mesolimbic and mesofrontal systems
What are the pharmocodynamic properties responsible for these effects?
- D2 blockade in the mesolimbic and mesofrontal systems
- Dopamine receptor blockade in the medullary chemoreceptor trigger zone & peripherally on the receptors on the stomach
- 5HT blockade
What are its adverse effects?
- Dry mouth
- Loss of accommodation
- Urinary retention
- Orthostatic hypotension
- Sexual dysfunction
- Neuroleptic Malignant syndrome
- Tardive dyskinesia
What is the mechanism of action of amphetamines?
- Indirectly cause increased release of catecholamines at synapses
- Competitively inhibits dopamine transport in pre-synaptic neurone (DAT), inhibits VMAT causing non-vesicular release of dopamine into synapse (& similarly for other catecholamines)
Describe the effects of amphetamines?
- Catecholamines; (increased arousal & decreased sleep) elevated HR (dysrhythmias) and BP (CVA)
- Dopamine release; euphoria, potentially abnormal movements & psychosis
- Serotonin; Appetite suppression, hallucinogenic & hyperthermia
Pass Criteria: CNS stimulation and cardiovascular effects to pass
How does ketamine affect the cardiovascular system?
- HR, BP and cardiac output increase
- Stimulate central SNS, and inhibits re-uptake of noradrenaline at sympathetic nerve terminals
Pass Criteria: Demonstrated understanding of CV effects of ketamine
What are the side effects of ketamine?
- Decreased RR
- Postoperative disorientation
- Sensory and perceptual illusions
- Emergence phenomenon
- Raised ICP– increases cerebral blood flow, oxygen consumption and ICP
Pass Criteria: 2 bold + 1 other
Describe the pharmacokinetics of propofol?
- Intravenous administration
- Distribution t1/2 2-8 min, redistribution t1/2 30-60 min
- Metabolism- rapidly in liver; total body clearance is greater than hepatic blood flow, suggesting extrahepatic mechanisms
- Excretion- urine as glucuronides and sulphates- <1% unchanged
Pass Criteria: Must get bolded point to pass
What are the side effects of propofol?
- Respiratory- dose-related depression of central ventilatory drive, apnoea,
- Cardiac- Marked decrease in blood pressure through decreased peripheral arterial resistance and venodilatation, and direct negative inotropic effect.
- Soy/egg allergy,
- Pain on injection
Pass Criteria: Knowledge of respiratory and cardiac effects of propofol
Describe how phenytoin is administered in status epilepticus?
- IV load 13-20mg/kg
- Given diluted in saline (precipitates in glucose)
- Max rate in adults of 50mg/min
- Continued 100mg Q6-8hrly
Pass Criteria: Dose mg/kg for iv route
Describe the adverse effects of phenytoin?
- Dose related: nystagmus, ataxia, diplopia
- Long term: gingival hypertrophy, hirsuitism, mild facial coarsening & peripheral neuropathy, abnormal Vit D levels (osteomalacia), low folate levels; megaloblastic anaemia; Foetal hydantoin syndrome.
- Idiosyncratic: skin rash; SJ syndrome; Lymphadenopathy; agranulocytosis.
- Rapid IV may cause hypotension/arrhythmia
- Drug interactions; reduced CL & binding in neonates
Pass Criteria: CNS + skin + CVS in iv admin
Describe the general pharmacokinetic characteristics of antipsychotic drugs?
- Most are readily but incompletely absorbed.
- Many undergo significant first pass metabolism
- Most are lipid soluble (lipophilic)
- Most have high PPB (92-99%)
- Most are completely metabolised by hepatic enzymes (oxidation; demethylation)
- These are catalysed by liver enzymes.
Pass Criteria: Lipid soluble. Hepatic metabolism. PLUS 1 other
Define the term “atypical” antipsychotic and provide an example?
- Newer antipsychotic agents with less propensity to cause extra-pyramidal side-effects. Better at treating negative features of schizophrenia.
- They share a greater ability to alter 5HT2A receptor activity than to interfere with D2-receptor action.
- Examples: olanzapine; clozapine; quetiapine; risperidone; loxapine
Pass Criteria: Less EPS. One example
Describe the adverse drug reactions to olanzapine?
- Weight gain
- Sedation (but less than typical antipsychotics)
- Minor orthostatic hypotension
- Minor anticholinergic effects (dry mouth, urine retention etc)
- (Extrapyramidal effects less prominent)
Pass Criteria: 2 Effects
What is the mechanism of action of flumazenil?
- Antagonist at the BZD binding site on the GABAA receptor (ligand-gated chloride channel).
- Decreases the binding of GABA.
- Blocks GABA-induced increase in Cl– permeability and influx of Cl– into the cell causing hyperpolarisation and decreased excitability of the neuron.
Pass Criteria: Specific BZD receptor antagonist at GABA receptor
What are the indications for flumazenil use?
- Avoid intubation or ICU admission in BZD overdose.
- Reverse BZD sedation after procedures
- Diagnostic role
Pass Criteria: Reverse the sedative effects of BZD
What potential problems should be anticipated when using flumazenil?
- Precipitate seizures in mixed overdoses with BZD and proconvulsants
- Precipitate seizures in pts taking BZD to control epilepsy
- Precipitate withdrawal symptoms and seizures in BDZ-dependent
- Duration of action is only 1-3hrs thus repeated administration may be necessary
- Reversal of BZD-induced respiratory depression has not been demonstrated, so respiratory and cardiovascular support may be required
- Adverse Effects: headache, visual disturbance, increased anxiety, nausea, light-headedness
Pass Criteria:Precipitate fits. Need for repeated doses