Neurotransmitters
1. What are the most important central nervous system (CNS) transmitters?
Glutamic acid, gamma-aminobutyric acid (GABA), acetylcholine, dopamine, norepinephrine, serotonin (5HT), and opioid peptides1
2. What is the mechanism of action of glutamic acid?
Excitatory by increasing the influx of cations by direct coupling and G-protein linked on the NMDA (N-methyl-d-aspartate) receptor. This receptor is a potential target for ketamine and phencyclidine (PCP).1
3. What is the mechanism of action of acetylcholine?
Excitatory and inhibitory on muscarinic receptors by decreasing and increasing potassium efflux by coupling diacylglycerol (DAG) and cyclic adenosine monophosphate (cAMP) receptors, respectively—excitatory on nicotinic receptor1
4. What is the mechanism of action of GABA?
Inhibitory by increasing the influx of potassium by direct coupling—potential target for anticonvulsants, sedatives, hypnotics, and some muscle relaxants1
5. Name the different GABA agonists receptors.
• Barbiturates—increase the duration of Cl– ion channel opening
• Benzodiazepines—increase frequency of Cl– ion channel opening
• Propofol acts on GABAA.
• Baclofen acts on GABAB.
• Valproic acid at high concentrations acts on GABA.2
6. What is the mechanism of action of flumazenil?
Flumazenil is a benzodiazepine receptor antagonist and decreases the frequency of Cl– ion channel opening.2
7. What is the nonbenzodiazepine drug that binds to a benzodiazepine receptor?
Zolpidem. Used in sleep disorders. It is not effective for chronic anxiety, seizure disorders, or muscle relaxation. It has less tolerance and dependence.2
8. Name a nonbenzodiazepine anxiolytic.
Buspirone: A partial 5HT1A receptor. It has no dependence effects and no symptoms of withdrawal.2
9. What are the important effects/side effects to remember when prescribing benzodiazepines?
They have sedative, amnestic, anxiolytic, antidepressant, and muscle relaxant properties. All are contraindicated in the first semester of pregnancy. If combined with opioids, this may result in hypotension and ventilatory depression. Those with long-duration action can result in cumulative sedation and impairment of intellectual and psychomotor function, and those with short half-life are less likely to sedate, but are more prone to cause withdrawal or rebound depression.2,3
10. What are the clinical findings of benzodiazepine withdrawal syndrome?
They include hypertension, tachycardia, muscle twitching, tremulousness, diaphoresis, confusion, dysphoria, and seizures.2,3
11. Summarize the effect of the main benzodiazepines, including onset of action, duration, and dosage.
Benzodiazepines are summarized in Table 4.1.4
12. What is the pharmacologic strategy in Parkinson treatment?
To restore normal neurotransmitter balance by
• Increasing dopamine activity
• Decreasing acetylcholine activity at muscarinic (M) receptors in the striatum
Drugs may improve symptoms, but do not alter the natural course of the disease.
Drug | Dose | Onset | Duration | Comments |
Midazolam | 1–2 mg IV | Rapid | Short (the shortest) | 4 times more potent than diazepam; excellent anticonvulsant; always monitor patient |
Clorazepate | 15–60 mg/d, divided | Rapid | Long | |
Diazepam | 2–10 mg BID-QID | Rapid | Long(the longest) | |
Flurazepam | 30 mg | Rapid/ intermediate | Long | |
Alprazolam | 0.25–0.5 mg TID | Intermediate | Intermediate | Antidepressant effects |
Chlordiazepoxide | 5–10 mg TID | Intermediate | Long | |
Lorazepam | 1 mg TID | Intermediate | Intermediate | Not metabolized in liver |
Halazepam | 20–40 mg TID | Intermediate | Long | |
Oxazepam | 10–15 mg TID | Intermediate/slow | Intermediate/ short | Not metabolized in liver |
Temazepam | 15–30 mg | Intermediate/slow | Intermediate | Not metabolized in liver |
Prazepam | 20–60 mg/d divided | Slow | Long | |
Abbreviations: IV, intravenously; BID, twice daily; QID, four times daily; TID, three times daily.
13. What are the drugs that increase dopamine function?
Levodopa is converted to dopamine by a dopa-decarboxylase. Carbidopa inhibits the peripheral decarboxylation and increases CNS availability of L-dopa. The former drug does not cross the blood–brain barrier (BBB).3
14. What are the actions of tolcapone and entacapone?
They inhibit peripheral catechol-O-methyltransferase (COMT), enhancing the CNS uptake of L-dopa and possibly reducing its on–off effects.3
15. What are the two dopamine receptor agonists?
Bromocriptine had been used as an adjuvant to levodopa. Because of its secondary effects such as hallucinations, confusion, and psychosis, it has been replaced by pramipexole and ropinirole. Selegiline is a selective monamine oxidase (MAO) type B inhibitor that increases dopamine in the CNS.3
16. What are the drugs that decrease acetylcholine function?
Benztropine and trihexyphenidyl. These drugs are M receptor blockers. They reduce tremor and rigidity, reduce extrapyramidal symptoms, exacerbate tardive dyskinesias, and cause atropine-like effects.3
17. Why do antipsychotic drugs cause atropine-like affects, postural hypotension, and sexual dysfunction?
They block dopamine D2 receptors, but they also block muscarinic and a receptors, causing atropine-like affects and postural hypotension and sexual dysfunction, respectively.3
18. What are the other side effects of a dopamine receptor antagonist?
Akathisia, acute dystonic reaction, extrapyramidal dysfunction, and endocrine dysfunction such as prolactinemia3
19. Extrapyramidal dysfunction can be reduced by using the new dopamine receptor antagonists. Provide examples of these drugs and their effects.
Clozapine blocks D2c and 5HT2 receptors, but it may cause severe agranulocytosis and a weekly blood test is required. Olanzapine blocks 5HT2 receptors and improves negative symptoms.3
20. What are the side effects after chronic dopaminergic receptor blockage?
After the use of older antipsychotic drugs, akathisia and tardive dyskinesia present months later (e.g., Haldol); both are reversible when the medication is stopped and when anticholinergic medications are initiated such as benztropine mesylate and trihexyphenidyl.3
21. What is neuroleptic malignant syndrome?
The neuroleptic malignant syndrome is an idiosyncratic life-threatening reaction to a neuroleptic medication. Patients present with hyperthermia, cardiovascular instability, muscle rigidity, and altered mental status due to enhanced sensitivity of dopamine receptors to blocking agents. This life-threatening condition can be treated with bromocriptine and dantrolene.3
22. What is/are the mechanism(s) of action of a tricyclic antidepressant?
They block the reuptake of norepinephrine and serotonin. They block muscarinic and a receptors, cause sedation, decrease seizure threshold, and have cardiotoxicity.3
23. What is the mechanism of action of the selective serotonin reuptake inhibitors (SSRIs) and their common side effects?
These include fluoxetine, paroxetine, and sertraline; they block the reuptake of serotonin (5HT). Their side effects are anxiety, agitation, bruxism, sexual dysfunction, seizures, and transitory weight loss.3
24. What is serotonin syndrome?
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur as a consequence of excess seratonergic activity in the central nervous system. It includes diaphoresis, rigidity, myoclonus, hyperthermia, instability of the autonomic nervous system, and seizures.
Epilepsy
25. Name the drugs of choice for generalized tonic-clonic seizures and their mechanism of action.
Valproic acid, phenytoin, and carbamazepine. They decrease axonal conduction by preventing Na+ influx through fast Na channels.4
26. What is the first-line drug for complex partial seizures?
Carbamazepine4
27. What is the mechanism of action of the first-line drug for absence seizures?
Ethosuximide. It decreases presynaptic Ca2+ influx through type-T channels in thalamic neurons.4
28. What are the most common side effects of phenytoin?
Sedation, ataxia, diplopia, acne, gingival overgrowth in children, hirsutism, osteomalacia, and hepatotoxicity4
29. What are the side effects of valproic acid?
Pancreatitis, hepatotoxicity, and thrombocytopenia.2
30. List some of the medications frequently used in neurosurgery that can lower seizure threshold.2,3
• Antidepressants: Baclofen, phenytoin at supratherapeutic levels
• Analgesics: Meperidine, fentanyl, and tramadol
• Anesthetics: Methohexital and enflurane
• Benzodiazepines
• Barbiturates and withdrawal of antiepileptic drugs
• Antibiotics: Cefazolin, imipenem, and metronidazole
• Radiographic contrast materials
31. What are the pharmacologic choices to treat seizures including status epilepticus?
• Lorazepam has several advantages: it can be given quickly with an antiseizure duration of 12 to 24 hours. It controls seizures in up to 90% of cases when compared with diazepam (76%). It has become the drug of choice. Dosage is as follows: 0.1 mg/kg (IV); usually 2 to 4 mg intravenously (IV) over 2 minutes and may administer again in 5 minutes.
• Diazepam or midazolam (10 mg) intranasally, buccally, or intramuscularly (IM) if no IV access available
• Fosphenytoin 20 mg/kg IV at 150 mg/min with continuous monitoring; may cause hypotension and cardiac depression.
• Continuous IV midazolam (load 0.2 mg/kg followed by 0.2 mg/kg to 2 mg/kg)
• Continuous IV propofol (load 1–2 mg/kg to 10 mg/kg followed by 1–15 mg/kg/h titrated to electroencephalographic (EEG) seizure control or burst suppression); be careful to guard against propofol infusion syndrome.
• IV valproate 30 to 40 mg/kg over 10 minutes followed by another 20 mg/kg if necessary. Levels may decrease if given concomitantly with meropenem or amikacin. Recent data have shown that it is a very good alternative; it does not cause sedation or hypotension. It may be associated with platelet dysfunction.
• Continuous IV pentobarbital (load 5 mg/kg at up to 50 mg/min, repeat 5 mg/kg boluses, followed by 0.5 to 10 mg/kg/h titrated to EEG seizure control or burst suppression)
• Thiamine 100 mg IV and 50 mL of D50 (50% dextrose in water) IV4
32. What is the mechanism of action of the levetiracetam?
It is not well understood, but involves binding to the synaptic vesicle protein SV2A. It has rapid titration, no drug interaction, and a good safety profile. Not metabolized by the liver, although dosage should be reduced in the presence of renal failure and extra doses should be given after dialysis. Doses are 500 to 1500 mg orally (PO) or IV. No need to check levels.4
Anesthetics, Analgesics, and Antiinflammatories
33. What is propofol infusion syndrome?
Propofol infusion syndrome is a rare and potentially fatal condition associated with high doses and long-term use of propofol. The syndrome produces metabolic acidosis, cardiac failure, rhabdomyolysis, hypotension, and death. Propofol should not be administered for more than 4 to 5 days. Extreme caution must be taken when using doses greater than 5 mg/kg/h or when usage of any dose exceeds 48 hours in critically ill adults.5
34. Who are most likely to suffer from propofol infusion syndrome?
Although propofol infusion syndrome was initially described in the pediatric population, occurrence in the adult population has been reported with increased frequency. The syndrome occurs in critically ill patients receiving high-dose propofol (> 5 mg/kg/h), steroids, and elevated catecholamine levels (endogenous or exogenous).5
35. What are the findings in an intrathecal baclofen pump overdose?
Hallucinations, seizures, confusion, psychotic behavior, respiratory depression, hypotension, and coma6,7
36. What is the time course for intrathecal baclofen withdrawal syndrome?
Intrathecal baclofen withdrawal syndrome usually manifests over 1 to 3 days, but can be fulminant in presentation. Treatment is restoration of baclofen, but IV benzodiazepine may be required.6,7
37. What are the toxic doses of acetaminophen?
Rare at doses of < 4000 mg/day, usually >10 g/d, but may occur at lower doses in patients with previous liver disease such as alcoholism, viral hepatitis, and autoimmune hepatitis, as well as in patients taking cytochrome P-450 enzyme-inducing drugs.3
38. What are the concepts that need to be kept in mind when prescribing nonsteroidal antiinflammatory drugs (NSAIDS)?
They do not create dependence. After a maximum dose they do not have further analgesia effects (ceiling effect).Taking them with meals/antacids and via IV route does not reduce gastrointestinal (GI) side effects; misoprostol (synthetic prostaglandin) may be effective in the reduction of such effects. All of them have a reversible inhibitory platelet function. Acetylsalicylic acid (aspirin) has an irreversible effect and inhibits platelet function for the 8- to 10-days life of the platelet. All of them cause water and sodium retention and potential nephrotoxicity.2,3
39. Discuss individual features of specific NSAIDS.
See Table 4.2.
Aspirin | Unique effectiveness in pain from bone metastasis (spine) |
Ibuprofen | Associated with Reye syndrome in children |
Ketorolac | Only parenteral NSAID. Very useful in neurosurgery patients who are very sensitive to narcotics. Usual safe doses in a healthy adult: 30 mg IV or IM every 6 hours, with a maximum of 120 mg/d |
Celecoxib |
Abbreviations: NSAIDS, nonsteroidal antiinflammatory drugs; IV, intravenously; IM, intramuscularly.
40. What are the most common antispasmodics used in spine surgery?
Although very commonly used after spine surgery, there is very little evidence of beneficial effect and their use in acute low back pain is dubious. Some of them are cyclobenzaprine, methocarbamol, and carisoprodol. Diazepam is a very efficient benzodiazepine (see above) to treat muscle spasms.2,3
41. What are the mechanisms of action of antiinflammatory steroids?
They include decreased leucocyte migration, increased lysosomal membrane stability decreasing phagocytosis, decreased capillary permeability, and decreased platelet activation, COX-2 expression, and interleukins.2,3
42. What is the half-life of cortisone?
90 minutes3
43. What is a normal physiologic replacement of steroids (under no stress)?
Prednisone 5 mg every morning and 2.5 mg every night PO or hydrocortisone 10 mg every morning and 5 mg every night.8
44. Which doses of steroids is unlikely to cause hypothalamic–pituitary–adrenal axis suppression?
Less than 40 mg of prednisone (or its equivalent) given in the morning for less than 1 week. Axis suppression will certainly occur after 40 to 60 mg daily of hydrocortisone (or its equivalent) after 2 weeks. After a month or more of steroids the axis may be depressed for almost one year.
45. What are the equivalent corticosteroid doses?
Dexamethasone 0.75 mg, methylprednisolone 4 mg, prednisone 5 mg, hydrocortisone 20 mg, and cortisone 25 mg2,3
46. What are other common side effects of steroids?
Hypertension, sodium and water retention, growth suppressant in children, GI bleeding, pancreatitis, impaired wound healing, hyperglycemia, glaucoma, osteoporosis, avascular necrosis of the hip or other bones, infections, hypercoagulopathy (inhibits tissue plasminogen activator), leukocytosis (even in the absence of infection), and hiccups (usually responds to chlorpromazine 25 to 50 mg three times daily PO)2,3
47. What are the neurologic side effects of steroids?
Mental agitation, “steroid psychosis,” spinal epidural lipomatosis, multifocal leukoencephalopathy, and pseudotumor cerebri2,3
48. What is the mechanism of action of opioid analgesics?
Opioid receptors are of multiple subtypes, all G-protein linked. Activation of presynaptic opioid receptors causes inhibition of Ca2+ influx through voltage-regulated ion channels, decreasing neurotransmitter release. Activation of postsynaptic opioid receptors results in increased K-efflux causing inhibition.1,2
49. Mention important characteristics of opioid analgesics.
Overdose is possible with potential seizure and respiratory depression. Physical and psychological tolerances may develop. They have no ceiling effects.2,3
50. List examples of weak opioids, their dosage, and delivery times.
Codeine 30 to 60 mg IM/PO every 3 hours as needed (PRN)
Propoxyphene 1 to 2 tablets PO every 4 to 6 hours PRN
Tramadol 50 to 100 mg PO every 4 to 6 hours PRN. This opioid binds to μ-opioid receptors inhibiting the reuptake of serotonin and norepinephrine.2,3
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