12.1 Anticonvulsants, Antidepressants, Psychotropics & Skeletal Muscle Relaxants
Key Takeaways
Gabapentin and pregabalin bind the alpha-2-delta subunit of voltage-gated calcium channels, need renal dose adjustment and add respiratory depression when combined with opioids.
Duloxetine (an SNRI), pregabalin, tricyclic antidepressants and sodium channel blockers are initial drug options for painful diabetic peripheral neuropathy; duloxetine, pregabalin, tapentadol ER and the capsaicin 8% patch carry FDA approval for it.
Phenytoin shows zero-order kinetics, induces CYP450 and causes gingival hyperplasia; carbamazepine causes hyponatremia and agranulocytosis and is first-line for trigeminal neuralgia; valproate causes neural tube defects.
Serotonin syndrome (clonus, hyperreflexia, hyperthermia) can follow SSRIs or SNRIs combined with tramadol, linezolid, methylene blue or MAO inhibitors; neuroleptic malignant syndrome causes lead-pipe rigidity and develops more slowly.
Tizanidine is contraindicated with ciprofloxacin or fluvoxamine (CYP1A2 inhibition causes severe hypotension), and abrupt baclofen withdrawal can cause seizures and hyperthermia.
12.1 Anticonvulsants, Antidepressants, Psychotropics & Skeletal Muscle Relaxants
The Part I outline lists central nervous system and autonomic agents: anticonvulsants, psychotropic agents, skeletal muscle relaxants, neuromuscular blocking agents and antidepressants. Autonomic drugs and neuromuscular blockers are covered in 10.2 and 10.3. These drugs matter in podiatry because several treat painful diabetic peripheral neuropathy, and many interact with the antibiotics, NSAIDs and opioids podiatric clinicians prescribe.
Anticonvulsants
| Drug | Mechanism | High-yield adverse effects and interactions |
|---|---|---|
| Phenytoin | Blocks voltage-gated Na+ channels (inactivated state) | Zero-order kinetics at therapeutic levels; gingival hyperplasia, hirsutism, nystagmus, ataxia; CYP450 inducer; fetal hydantoin syndrome; SJS/TEN (HLA-B*15:02); purple glove syndrome with IV extravasation |
| Carbamazepine | Na+ channel blocker | First-line for trigeminal neuralgia; agranulocytosis and aplastic anemia, hyponatremia (SIADH), autoinduction of its own metabolism, CYP inducer, HLA-B*15:02 SJS, neural tube defects |
| Valproate | Na+ channel block, increased GABA, T-type Ca2+ block | Hepatotoxicity, pancreatitis, tremor, weight gain, neural tube defects, CYP inhibitor (raises lamotrigine) |
| Lamotrigine | Na+ channel blocker | Life-threatening rash (SJS/TEN); requires slow titration |
| Levetiracetam | Binds synaptic vesicle protein SV2A | Irritability and mood changes; few drug interactions |
| Topiramate | Na+ block, GABA enhancement, carbonic anhydrase inhibition | Kidney stones, weight loss, cognitive slowing |
| Gabapentin and pregabalin | Bind the alpha-2-delta subunit of voltage-gated Ca2+ channels, reducing excitatory transmitter release | Sedation, dizziness, peripheral edema, weight gain; renally cleared, so dose reduction is needed in CKD; misuse potential; additive respiratory depression with opioids |
| Benzodiazepines | Increase the frequency of GABA-A chloride channel opening | Status epilepticus first-line (lorazepam); dependence; reversal with flumazenil |
Antidepressants
| Class | Examples | Key points |
|---|---|---|
| SSRIs | Sertraline, fluoxetine, citalopram, escitalopram | Sexual dysfunction, hyponatremia; bleeding risk with NSAIDs (platelet serotonin depletion); citalopram QT prolongation |
| SNRIs | Duloxetine, venlafaxine | Duloxetine is FDA-approved for painful diabetic peripheral neuropathy; avoid in heavy alcohol use or hepatic disease; venlafaxine can raise blood pressure |
| Tricyclic antidepressants | Amitriptyline, nortriptyline | Used at low doses for neuropathic pain; anticholinergic effects, orthostasis, sedation; overdose causes wide-QRS arrhythmias treated with sodium bicarbonate; avoid in older adults |
| MAO inhibitors | Phenelzine, tranylcypromine, selegiline | Tyramine hypertensive crisis; serotonin syndrome with meperidine, tramadol, linezolid and SSRIs |
| Atypical agents | Bupropion, mirtazapine, trazodone | Bupropion lowers the seizure threshold; mirtazapine causes sedation and weight gain; trazodone can cause priapism |
Serotonin Syndrome versus Neuroleptic Malignant Syndrome
| Feature | Serotonin syndrome | Neuroleptic malignant syndrome |
|---|---|---|
| Triggers | Serotonergic combinations (SSRI or SNRI plus tramadol, linezolid, methylene blue, MAO inhibitors, triptans) | Dopamine antagonists (antipsychotics, metoclopramide) |
| Onset | Hours (usually within 24 hours) | Days |
| Neuromuscular signs | Clonus, hyperreflexia, tremor | Lead-pipe rigidity, bradyreflexia |
| Treatment | Stop the drugs, supportive care, cyproheptadine | Stop the drug, cooling, dantrolene or bromocriptine |
Antipsychotics & Other Psychotropic Agents
- First-generation (typical) antipsychotics such as haloperidol block D2 receptors strongly. They cause extrapyramidal effects: acute dystonia, akathisia, parkinsonism and tardive dyskinesia.
- Second-generation (atypical) antipsychotics such as risperidone, olanzapine, quetiapine and aripiprazole cause metabolic syndrome (weight gain, hyperglycemia, dyslipidemia) and QT prolongation. Clozapine can cause agranulocytosis and requires blood count monitoring.
- Lithium has a narrow therapeutic index. NSAIDs, thiazides and ACE inhibitors raise lithium levels (10.5). It causes tremor, hypothyroidism, nephrogenic diabetes insipidus and Ebstein anomaly.
- Anxiolytics and sedatives: benzodiazepines and the "Z-drugs" (zolpidem) cause falls and confusion in older adults and are additive with opioids.
Pharmacologic Treatment of Painful Diabetic Peripheral Neuropathy
Diabetes care guidelines list gabapentinoids, SNRIs, tricyclic antidepressants and sodium channel blockers as initial pharmacologic options, chosen by comorbidities and adverse effect profile. FDA-approved agents for this indication include duloxetine, pregabalin, tapentadol extended-release and the capsaicin 8% topical patch. Opioids are not recommended as first-line therapy. Glycemic control, foot protection and treating contributing deficiencies (for example vitamin B12 deficiency from metformin, 9.1) remain essential.
Skeletal Muscle Relaxants & Spasticity Agents
| Drug | Mechanism | Key cautions |
|---|---|---|
| Baclofen | GABA-B agonist in the spinal cord | Sedation; abrupt withdrawal (especially intrathecal) causes seizures, hyperthermia and rebound spasticity |
| Tizanidine | Central alpha-2 agonist | Hypotension, hepatotoxicity; contraindicated with ciprofloxacin or fluvoxamine (CYP1A2 inhibition) |
| Cyclobenzaprine | Structurally related to tricyclics; brainstem action | Anticholinergic effects; serotonin syndrome risk with SSRIs and tramadol |
| Methocarbamol | Central depressant | Sedation |
| Carisoprodol | Metabolized to meprobamate | Misuse and dependence (controlled substance) |
| Dantrolene | Blocks RyR1 calcium release in skeletal muscle | Hepatotoxicity with chronic use; antidote for malignant hyperthermia |
| Botulinum toxin A | Cleaves SNAP-25, blocking acetylcholine release | Injected into the gastrocnemius-soleus for spastic equinus in cerebral palsy or after stroke |
Neuromuscular blocking agents (succinylcholine, rocuronium, vecuronium, cisatracurium) act at the motor endplate nicotinic receptor and are reviewed in 10.2.
Important
Combining gabapentinoids, benzodiazepines, muscle relaxants or sedating antihistamines with opioids compounds respiratory depression and fall risk, especially after foot surgery when patients use crutches or knee scooters.
A patient taking tizanidine for spasticity is prescribed oral ciprofloxacin for a Pseudomonas puncture wound. Which adverse outcome is most likely?
Hyperkalemia from combined blockade of epithelial sodium channels
Profound hypotension and sedation from markedly increased tizanidine levels
Loss of antibacterial activity because tizanidine chelates ciprofloxacin
Serotonin syndrome from combined serotonin reuptake inhibition
A patient taking sertraline is given tramadol after a bunionectomy. Within 12 hours she is agitated, febrile and diaphoretic, with inducible ankle clonus and hyperreflexia. Which management is most appropriate?
Dantrolene for presumed malignant hyperthermia
Stop serotonergic drugs, give supportive care, consider cyproheptadine
Additional tramadol for uncontrolled postoperative incisional pain
Bromocriptine for presumed neuroleptic malignant syndrome with rigidity
Which mechanism explains how pregabalin relieves painful diabetic peripheral neuropathy?
Blocking reuptake of serotonin and norepinephrine in descending pain pathways
Inhibiting cyclooxygenase-2 in the dorsal root ganglion
Agonism at the mu-opioid receptor in the substantia gelatinosa
Binding the alpha-2-delta subunit of voltage-gated calcium channels
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